BIBLIOGRAFIA SELECTIVA

Algunos aspectos de los TB requieren una consideracin especial en la mujer: a) El impacto de gnero sobrer el curso de la enfermedad: las caractersticas clnicas son similiares entre hombres y mujeres, pero las mujeres experimentan mas episodios depresivos que los hombres b) Las mujeres experimentan mas experiencias de ciclaciones rapidas, manias mixtas y manias inducidas por antidepresivos que los hombres, quizs por el excesivo tratamiento con antidepresivos e inadecuado uso de estabilizadores del animo c) Cuando aparece una mujer con un TB que presenta episodios depresivos o ciclaciones rapidas es importante optimizar estabilizadores de animo, chequear funcin tiroidea y evaluar el uso de los antidepresivos. d) La relacin entre TB y ciclo mentrual es relativamente desconocido e) Algunos estudios indican que existen en las mujeres bipolares mas alterasciones anmicas pre-menstruales que engrupos controles f) Otros estudios sugieren que los TB de las mujeres empeoran en la fase menopausica con mas disturbios emocionales y conversiones a ciclaciones rapidas, pero todava no existe una explicacin clara de como las transiciones hormonales impactan el curso de la enfermedad bipolar en las mujeres. g) Existe una pre-concepcion de que el embarazo protege a la mujer de los TB. Esto no es cierto para los TB, donde los factores de recaida durante este periodo incluyen bruscas suspensiones de estabilizadores de animo, una historia de 4 o mas episodios afectivos previos y un periodo de alteracin anmica intraparto. h) El periodo post-parto es particularmente de alto riesgo para la mujer. Las recaidas alcanzan niveles entre 20 a 50%, de entre las cuales un 40 a un 67% experimentan una mania o depresin en el post-parto i) Las mujeres con TB tiene 100 veces mas posibilidades de hacer una psicosis post-parto que las mujeres sin esta patologa j) En relacin a la medicacin: existe evidencia de que los efectos de la medicacin puede impactar en la salud reproductiva de la mujer. Un ejemplo de ello es la aparicin de Ovarios poliquistico como un trastorno endocrino grave relacionado con infertilidad anovulatoria. Este sndrome se caracteriza por disfuncin ovulatoria (poli, oligomenorrea), evidencia de hiperandrogenismo o hiperandrogenemia y exclusin de otras endocrinopatas como disfuncin tiroidea, hiperprolactinemia o sndrome de Cushing. k) La terapia con Litio en mujeres se asocia con hipotiroidismo y tiroiditis mas frecuentemente que en hombres l) Los efectos sobre la contracepcin oral son importantes de considerar, ya que esta se puede deteriorar ya que la medicamentacion por los TB puede inducir enzimas hepticas que al aumentar el metabolismo de los

m) n) o)

p)

anticonceptivos puede disminuir su eficacia. A la inversa, los anticonceptivos pueden inducir un metabolismo acelerado de medicamentso para los Tb como la Lamotrigina, la cual requerira ser aumentada No existe interaccion medicamentosa entre anticonceptivos y Litio, Valproato y antipsicticos atpicos Durante el ambarazo: anlisis de riesgos-beneficios La lamotrigina es el medicamento que parace mas seguro de usar en el embarazo, cuando las mujeres persisten en sus embarazos y requieren medicamentacion El post-parto es asociado con recaida: la profilaxis con medicamentacion en el tercer trimestre del embarazo y en el post-parto inmediato puede evitar la recaida.

II.- TRASTORNOS DEL NIMO: Concepto y evolucin:

Los trastornos del nimo son un fenmeno frecuente en la consulta clinica, con una prevalencia que oscila segn los distintos estudios entre el 9 al 17%. La mitad de ellos corresponde a episodios depresivos severos, 3.5% a distimias y 1,5% a trastornos bipolares. La clasificacion de este tipo de trastornos ha sufrido una evolucion considerable estas ltimas 4 decadas. En efecto, las principales clasificaciones anteriores se sustentaban en teorias etiopatognicas variadas; por ejemplo en el caso de las depresiones se distinguan las exgenas, vinculadas a causalidades psicgenas o exgenas por oposicin a las endgenas de naturaleza predominantemente biolgicas, distinciones que han sido olvidadas con posterioridad en funcin de su escasa validacin cientfica a favor de clasificaciones puramente descriptivas con objetivos nosogrficos y de investigacin clnica. En el DSM IV-TR contina en esta materia la tradicin inaugurada en el DSM III, ubica estos trastornos bajo la rbrica del Trastornos del nimo, ya que todos ellos se caracterizan por los cambios significativos del humor o cambios tmicos. As, para el caso de las depresiones aporta varias precisiones a la clasificacin de las depresiones al individualizar categoras especificantes o criterios de definicin suplementarias, no excluyentes, y que permiten definir en el seno de las diversas categoras diagnsticas, sub-grupos de pacientes que comparten rasgos comunes desde el punto de vista sintomtico, antecedentes evolutivos y antecedentes personales, lo que favorece a su vez, mejores estrategias preventivas y teraputicas. Los criterios de especificacin (sintomticos y evolutivos) los trataremos a continuacin del estudios de los cuadros nucleares.

El DSM IV-TR incorpora tambin una distincin con respecto a los TB. Los separa en TB tipo I (constituido por 1 o mas episodios maniacos acompaado de episodios depresivos mayores) y, TB tipo II (constitudos por uno o mas episodios depresivos mayores acompaados al menos de uno de naturaleza hipomanica). A estas formas puras descritas en el Manual, hay que agregar la consideracin clnica, sustentada por variadas investigaciones, que los estados depresivos y maniacales, relativamente independientes, se suelen presentar como rasgos disfricos constituyendo episodios mixtos (Angst y Sellaro, 2000), es decir, los sujetos pueden experimentar exaltacin estando a la vez ansiosos o deprimidos, y estos estados pueden alcanzar severidad, traducindose en conductas con alto descontrol o peligrosidad para si mismo o para otros. Los trastornos depresivos Los trastornos depresivos se registran a todo lo largo de la historia de la medicina desde los escritos hipocrticos que introdujeron el trmino de melancola hasta Kreapelin, quien acu el concepto de maniaco-depresivo para separar esta entidad nosolgica de la demencia precoz, a fines del siglo XIX. Posteriormente, ya en la era de los aos 80 del siglo XX, con la aparicin del DSM, el diagnstico de los trastornos depresivos ha ganado operacionalidad y fiabilidad. Con el DSM IV se hacen comparables los criterios con el sistema diagnstico de la OMS (ICD 10). El DSM IV-TR describe depresiones unipolares y bipolares, siguiendo una distincin, basada fundamentalmente de Leonard (1957) que desprendi de la Psicosis ManiacoDepresiva original de Kraepelin aquellos trastornos depresivos que cursaban sin episodios maniacos o hipomaniacos, y los diferenci de los trastornos con alternancias episdicas entre manas y depresiones (bipolares), inaugurando una distincin que se ha revelado muy interesante desde el punto de vista de la clnica, de los antecedentes familiares y de la investigacin cientfica. Sin embargo, la claridad expositiva se ve dificultada en la medida que existen pacientes fronterizos entre stas dos distinciones, lo que ha llevado a algunos autores a introducir el concepto de espectro bipolar para integrar a un grupo de pacientes, sobre todo parientes cercanos de pacientes bipolares, siguiendo el principio de que ste grupo de pacientes con expresin clinica de tipo unipolar tendran una expresion genotpica bipolar. El estudio pionero de Akiskal de 1983 se ha visto reforzado en este sentido por estudios ulteriores (Allilaire y Hantouche, 2001). Sin duda, esta discusin que permanece abierta debera ser continuada con el desarrollo de aproximaciones diagnsticas ms elaboradas (DSM V?) y de tcnicas de diagnstico que permitan conocer con ms precisin factores de vulnerabilidad, riesgo de recurrencias o ndices de evolucin de mayor severidad. Las depresiones unipolares aparecen en el Informe sobre el Estado de la Salud en el Mundo de la OMS (2003), como la 4ta causa de carga de enfermedad entre hombres y mujeres mayores de 15 aos en todo el planeta, detrs del VIH-SIDA, las cardiopatas isqumicas y los accidentes vasculares cerebrales, lo que significa, mas all del sufrimiento personal de quienes las padecen, un impacto econmico y social considerable dado tanto por la prdida de productividad que implica como por los

gastos sanitarios que conlleva, muchas derivadas de la falta de diagnstico y tratamiento oportunos y adecuados o la de presencia de una patologa enmascarada por sntomas somticos, muy comunes en los Centros de Atencin Primaria de Salud y generalmente subdiagnosticadas en nuestra realidad.

Criterios de diagnstico de los trastornos depresivos unipolares (DSM IV-TR): TDM y Distimia El trastorno depresivo mayor simple es el ms comn y severo de los trastornos depresivos unipolares, que se caracteriza por la aparicin de uno (y regularmente mas de uno) episodio depresivo de una duracin de 2 semanas, representando un cambio con respecto al nivel anterior de funcionamiento del sujeto. El criterio A. del DSM IVTR exige al menos 5 de 9 categoras sintomticas, entre las cuales debe estar presente al menos 1 de 2 sntomas que llamaremos cardinales del cuadro: a) humor depresivo presente prcticamente todos los das y durante la mayor parte de ste y, b) la prdida de inters o de capacidad para experimentar placer, ambos sealados por el sujeto u observado por los otros. Examinaremos psicopatolgicamente los sntomas del criterio A desde un punto de vista descriptivo con cierta detencin: a) El humor depresivo se traduce psicopatologicamente en un tono afectivo permanentemente triste, cuya intensidad es variable segn el cuadro, que inunda el mundo subjetivo del sujeto quien siente que pierde el sentido de la vida o del mundo como algo accesible. Los psicopatologos de orientacin fenomenologica describen el estado de animo deprimido como aquel mundo para el sujeto que no solo es apagado, gris y sin objetivos vitales estimulantes, (sino que) el mundo se hace opaco, ( Peregrina C. H. Fundamentos Antropologicos de la Psicopastologia, Ed. Polifemo, Madrid, 2006, p. 391). Es decir, se trata de un paciente que vive en un estado de dolor moral que a veces es intolerable, hecho de remordimientos, aburrimiento y disgusto por la vida o aoranzas por un pasado irrecuperable. El futuro esta cerrado, sus sentimientos estan empobrecidos. En esta situacin extrema, el desinteres es global y manisfiesto. Este segundo sntoma cardinal, que impide experimentar placer se conoce como b) anhedonia

Los otros sntomas que deben encontrarse en nmero de tres (3) para hacer el diagnstico son: c) agitacin o enlentecimiento motor, percibido por los otros, casi todos los dias y no meramente sealado por el paciente. Psicopatolgicamente el sujeto se observa con inquietud motora que se expresa como intranquilidad y dificultad para relajarse, hablar premioso, movilidad de miembros, piernas o manos. Sin embargo, lo que predomina en la depresion es el elemento de enlentecimiento motor caracterizado por la disminucion de la movilidad espontanea, con un sujeto de mirada triste o caida, con hablar pausado, monosilabito, hipomimico, que da la impresin de sentirse agobiado o exigido frente a cualquier esfuerzo menor o cotidiano. Cuando predomina

el componente de agitacin, el cuadro clinico toma el nombre de depresion agitada, que plantea dudas diagnosticas diferenciales con los cuadros bipolares mixtos. d) Disminucin de capacidades cognitivas tales como dificultad para pensar o concentrarse, acompaadas de indecisin en torno a actividades cotidianas como por ejemplo, con que vestirse o como jerarquizar las tareas diarias, que en los casos graves pueden ser vividos penosamente e) sentimientros de desvalorizacin o culpabilidad persistente durante todos los dias y casi todo el dia, en la forma de rumiaciones persistentes que en caso de episodios depresivos mayores pueden ser de naturaleza psicticos. En esta situacion los delirios de culpabilidad (DIEGO). Un tipo particular de depresion mayor de tipo psicotica es el Sndrome de Cotard que se expresa como(Diego)

Sin embargo, el episodio depresivo mayor simple o nico no es la regla clinica: la recurrencia se produce en el 60% al 85% de los casos. Esta recurrencia se define por la presencia de 2 o ms episodios depresivos mayores con un perodo intercrtico de eutimia de al menos 2 meses. El estudio de Keller de la NIMH (Keller, MB y col., Time to recovery, chronicity, and levels of pschicopathology in major depresin. A 5-years prospective follow-up of 413 subjects. Arch Gen Psychiatry, 1992; 49: 809-16), mostr que entre el 25% al 40% de los pacientes presentaban una depresion posterior o recidiva dentro de los 2 aos, con el agravante que a mayor nmero de recidivas disminuye el espacio temporal intercritico y aumentan las posibilidades de recurrencia, alcanzando el 95% despus de tres episodios en la vida del sujeto. La hiptesis de que despus de los 65 aos, la recurrencia disminua su aparicin se ha revelado no ser cierta, y por el contrario, las remisiones son menores ela evolucin de la enfermedad con persistencia de sntomas residuales, la comorbilidad es mas acentada, la cronicidad se hace mas evidente y la mortalidad alcanza una tasa de 40%. Se les llama sntomas residuales a aquellos que persisten ms all del episodio depresivo que alcanzan una remisin eutmica completa, tales como la fatiga, los trastornos sexuales, del sueo o la anhedonia en un tono menor. En el curso de su evolucin, su agravacin sera un ndice de la aparicin de una nueva recurrencia o un factor de riesgo de recidiva de 3 a 6 veces mayor en relacin a pacientes con remisin intercrtica completa, como tambin un factor de riesgo de una tasa mayor de suicidabilidad y cronicidad. La cronicidad alude a la persistencia temporal de los sntomas depresivos de un episodio depresivo mayor durante o sobre los 2 aos. Doble depresin La condicin clnica de una doble depresin es otra forma clnica de presentacin de la depresin que tiene importancia porque se trata de la superposicin de dos entidades clnicas distintas de la esfera depresiva: la distimia, que se caracteriza por ser un trastorno crnico con una duracin mnima de 2 aos, con un compromiso afectivo caracterizado por una falta crnica de ganas, sentimientos de prdida de esperanzas, trastornos del sueo y del apetito, en intensidad insuficiente para ser diagnosticado como depresivo mayor, sin intervalos libres mayores a un par de meses,

pudiendo ser de aparicin precoz o tarda dependiendo si aparece antes o despus de los 21 aos; y un episodio de depresin mayor, descrito anteriormente. La identificacin de este esquema de presentacin clnica tiene igualmente importancia debido a la evolucin de la enfermedad con mas recadas o al menos recurrencias, y de mayor gravedad psicopatolgica, sobre todo, si el cuadro distmico es de aparicin precoz. Cuales son los sntomas centrales de la depresion? Como se aprecia, el DSM IV TR construye el diagnostico de DM sobre dos requisitos esenciales: nimo depresivo y prdida de interes o placer en casi todas las actividades del individuo. Sin embargo, los sntomas restantes son tambien, desde el punto de vista terapeutico y psicopatologico esenciales de considerar en la perspectiva de establecer subtipos depresivos, que constituyen especificaciones sintomaticas y evolutivas muy importantes a la hora de plantear un tratamiento para el paciente. A la vez, una revision critica de los criterios diagnosticos a la luz de los avances neurocientificos es pertinente para comprender que la depresion, al igual que la esquizofrenia en una entidad compleja y heterogenea, que es mas que los meros criterios diagnosticos del DSM IV y requiere, por lo tanto, mas investigacin clinica y neurobiologica para un manejo completo. Curiosamente, por ejemplo, los dos sntomas centrales requeridos para hacer el diagnostico de DM, animo depresivo y perdida de interes o placer, alcanzan una sensibilidad y especificidad entre 83 y 92% para el diagnostico, con lo que para confirmar el diagnostico se requieren ademas la presencia de los otros sntomas de la DM en multiples combinaciones, lo que explica la heterogeneidad sintomatica intradiagnostica del cuadro clinico, dando cuenta de la dificultad clinica para hacer el diagnostico por un lado, y por el otro, la aparicion de los subtipos depresivos que vamos a estudiar posteriormente. Revisemos por lo tanto, los sntomas de la depresion a la luz del interes, ahora para el diagnostico y el tratamiento de la depresion, de otros elementos clinicos y neurobiologicos recientemente considerados. Con respecto a los sntomas considerados cardinales de la depresion: a) Animo depresivo. En el recorrido historico de la depresion se han ido suplantando conceptos, que desde un punto de vista clinico se revelan esenciales en su pertinencia de uso como objetivo terapeutico, su relacion con otras manifestaciones clinicas o en la consideracin de las manifestaciones psicopatologicas como potenciales marcadores diagnosticos del cuadro depresivo. Me refiero a la tristeza vital como caracteristica psicopatologica central de la depresion. Este concepto, central en la fenomenologia de la depresion, no forma parte de los criterios exigidos para el diagnostico en el DSM IV. La tristeza vital, historicamente, como concepto asociado a la melancolia, viene desde los tiempos hipocraticos. En el siglo XIX, Kreapelin la asocia al retardo motor y psiquico. Por lo tanto es anterior al concepto de depresion, y su olvido en el DSM IV, hasta ahora no permitia una revision critica como elemento central de la depresion, en su importancia para la descripcin de sus aspectos clinicos, sus vinculos con los sntomas neurovegetativos y su uso como un objetivo en el tratamiento.

Si consideramos la asociacin historica del concepto de tristeza vital con los elementos de melancolia y retardo psiquico y motor y lo comparamos con los requisitos de los sistemaS DE CLASIFICACION ACTUALES del diagnostico de depresion: 5 de varios sntomas tales como variacin de peso, insomio, agitacin o retardo psicomotor, sentimientos de impotencia, concentracin disminuida, sentimientos de culpa, recurrentes pensamientos de muerte, que deben incluir animo depresivo o perdida de interes, nos damos cuenta que de que la tristeza vital esta incluida aunque no se la requiera explcitamente para el diagnostico. Esto se ve mas claramente cuando se utilizan herramientas tales como las Escalas diagnosticas en la depresion, cuyo ejemplo es la Escala de Hamilton. Estas escalas describen una frecuencia sintomatica que decrece de la siguiente manera: animo depresivo, cansancio y dolor, ansiedad psicologica, sentimientos de culpa y retardo psicomotor. Este patron confirma la importancia clinica de la tristeza vital en el diagnostico de la depresion, pues engloba fenomenologicamente las caracteristicas descritas. Que importancia tiene considerar la tristeza vital como electo central de la depresion? Primero, es un marcador de la profundidad de la depresion EN DIRECTA RELACION con un subgrupo de pacientes depresivos con caracteristicas melanclicas, en su forma de tratamiento, y en sus complicaciones. Segundo, en su relacion con los sntomas neurovegetativos de la depresion: estos sntomas son importantes componentes del estado depresivo e incluyen trastornos del sueo, modificaciones del apetito, ansiedad autonomica que engloba sntomas cardiovasculares, respiratorios y genito urinarios diferentes de los sntomas somaticos generales que incluyen cansancio, tension muscular y dolores fisicos. Algunos estudios demuestran que las benzodiazepinas y b-bloqueadores tienen una accion esecifica sobre los sntomas neurovegetativos pero producen tristeza, con lo que se concluye que los sntomas neurovegetativos enmascaran la depresion. Pero ademas, existen otros argumentos de sta estrecha relacion entre sntomas vegetativos y depresion: uno de los sntomas importantes de la depresion es el insomnio. La persistencia del insomnio en una persona es un indicador de que se va a producir una depresion dentro de un ao con una frecuencia de 3 veces ms que en un individuo sin este sntoma. En pacientes con episodios de DM diagnosticada, la presencia de 2 semanas de insomnio puede ser indice de un nuevo episodio depresivo. Otro sntoma vegetativo, el apetito, se vincula a la anorexia y a la perdida de peso en la depresion, configurando una comorbilidad frecuente entre depresion y anorexia hasta el extremo que se ha postulado que la anorexia y la bulimia pueden ser una variante de un trastorno del animo o debida a una vulnerabilidad genetica compartida por ambos fenmenos patologicos. La hiperfagia, otro sntoma vegetativo, descrito en la depresion, tiene vinculaciones con la hipesomnia y la disregulacion emocional en un subtipo de depresion, llamada atipica, que estudiaremos posteriormente. Concluyendo, la tristeza vital es una manifestacin psicopatologica central en el sndrome depresivo aunque su presencia no sea un requisito para el diagnostico de acuerdo al DSM IV TR. Sin embargo, es una caracteristica clinica frecuente en los en los pacientes, con gravitacin importante en la calidad de vida diaria, y un marcador de eficacia de medicamentos antidepresivos. El alivio de la tristza vital

es tambien un signo de buen pronostico en relacion a la remision del trastorno o un indicador, si persiste, de mal pronostico o alta recurrencia. Por lo tanto, si bien la depresion no se reduce a la tristeza vital, si es justificable considerarla como un sntoma central del sndrome depresivo. Otras manifestaciones sintomaticas, las veremos mas adelante cuando revisemos los subtipos depresivos como criterios de especificacin clinica de los TB.

Los trastornos bipolares: La caracterstica central de los TB es la alternancia de episodios depresivos y episodios de exaltacin anmica (hipomana o mana). Conocida en el siglo XIX como locura circular o locura con doble forma en los trminos de J-P Falret y J. Baillarger, fue reconceptualizada por E. Kraepelin como psicosis manico-depresiva hasta la dcada de los 80 del siglo XX, en que por convencin, en el DSM se le llama Trastorno Bipolar. En las clasificaciones internacionales de las enfermedades mentales, y particularmente en el DSM IV-TR, que usamos como gua para la descripcin clnica de la patologa, se le encuentra en el captulo de los Trastornos del Humor o afectivos, en razn de la recurrencia de los trastornos tmicos que la constituyen. Su reconocimiento clnico se define por sintomatologa de una intensidad y duracin mnimas que se acompaa de un grado de sufrimiento e incapacidad importantes, generalmente de evolucin crnica, cuyos accesos o episodios son recurrentes de duracin variables de semanas o meses dependiendo de la correccin de su tratamiento, con perodos intercrticos de normalidad psicolgica y funcional. Se estima que el Trastorno Bipolar Tipo I, que resulta de la alternancia de un episodio depresivo mayor y un episodio manico tpico tiene una prevalencia de 1%, en tanto que el TB tipo II, caracterizado por trastornos depresivos recurentes con alternancia de perodos de exaltacin anmica atenuada o hipomana, tendra una prevalencia menor (0,5%). Sin embargo, tales cifras parecieran ser ms altas. En la actualidad se discute si otros comportamientos anormales y dainos para las personas, en una comprensin amplia de un espectro bipolar, no debieran integrarse a la frmula clnica de trastornos afectivos para posibilitarles un tratamiento semejante. En el DSM IV-TR los trastornos bipolares como se ha sealado, estn clasificados dentro del captulo de los trastornos afectivos o del humor. Como sabemos, las formas tpicas del trastorno se configuran con alteraciones anmicas recurrentes: mana, hipomana y depresin, o con episodios mixtos en que los sntomas depresivos se acompaan de excitacin, adquiriendo manifestaciones muy diversas, variables con cada paciente, lo que a menudo dificulta el diagnstico por su polimorfismo clnico y sus periodos intercrticos de normalidad. Caracterizaremos psicopatolgicamente a continuacin, los episodios manicos e hipomaniacos, que juntos al episodio depresivo mayor ya descrito, constituyen la arquitectura bsica de los TB.

La mania La mania se caracteriza por un periodo delimitado de exaltacion del estado animico del sujeto que se transforma en euforico y expansivo, llegando a veces a ser agresivo e hiperreactivo. La mania, clsicamente se manifiesta de manera aguda comenzando a veces de manera esteorotipada a la forma der un sntoma que anuncia el episodio, como por ejemplo insomnio y ansiedad por ordenar papeles o libros, para despus dar paso a la manifestacin aguda. Cuando est instalada en paciente, podemos observar una variada gama de formas clnicas, donde en pacientes graves no es infrecuente encontrarnos con intervalos cortos de manifestaciones euforicas reemplazadas por manifestaciones de tristeza o sentimientos de desesperacin. El paciente duerme poco, bebe mucho, y presenta conductas en el plano sexual que pueden llegar la exhibicionismo o la obscenidad, mas alla de un control moral o de un sentido social de comportamientos adecuado frente a otros. Esta desinhibicion es a la base de proyectos imposibles o gastos extravagantes e incluso de comision de delitos, como robar dineros o no respetar reglas del transito, herir o lesionar a terceros. Un elemento importante de recordar es que las manifestaciones clnicas del paciente son congruentes con su estado animico. El estado maniacal se instala en horas y dias. (ver momentos de la mania) Para establecer el diagnostico es necesario reunir un cierto numero de sntomas durante un periodo determinado. (Continuar).

Para hacer el diagnostico de Hipomania de acuerdo al DSM IV TR se requiere: La experiencia por un tiempo limitado de un estado de humor elevado, expansivo o irritable Duracion al menos de 4 dias La presencia de 3 o (4 en el caso de irritabilidad), de los sntomas de la mania Episodio asociado a cambio de funcionamiento, observado por otros Sntomas de severidad que no implique deterioro funcional, hospitalizacion o psicosis

Pero con este estricto criterio, uno de los problemas mas importantes que se presentan y que marcan la sensibilidad limitada de los sistemas de clasificacion actuales de los TM est dado por los muchos casos de diagnostico errneos del TDM en su relacion a los TB. Como establecer el limite. En efecto, estudios epidemiologicos demuestran que slo un 10 a un 20% de todos los pacientes con DM, cumplian con los criterios actuales de un TB, en circunstancias que el porcentaje de pacientes que se encuentran actualmente en control por DM, en un 60% pueden ser identificados, usando un instrumento de Checkist para Hipomania, como pacientes bipolares II. Que ocurre clnicamente? Segn diversos investigadores los tres primeros criterios de la hipomania son problematicos y necesitan una revision o son muy restrictivos. Asi es como recientes desarrollos en el diagnostico de los episodios hipomaniacos recomiendan agregar una categora sintomatica de actividad incrementada al arbol sintomatico del cuadro, con lo que se explica el paso del 10 al 20% al 60% de hipomanias. En efecto, cuando se hace una clinica cuidadosa y se investiga emprendimiento, actividad aumentada, baja fatigabilidad, menor necesidad de sueo, hablar mas, viajar mas u ocuparse de muchas otras cosas, o se usa un listado

especifico para hipomania, se logra hacer el diagnostico correcto. Por otro lado, cuando se encuentran sntomas hipomaniacos que no alcanzan los 4 dias, tampoco se hace el diagNostico en circunstancias que los estudios clinicos demuestran que el episodio tiene una duracion de entre 1 y 3 dias, y esto es especialmente importante en nios y adolescentes. Asi, este concepto de hipomania subumbral identifica mas del 25% de pacientes con un diagnostico errneo de DM. Este criterio amplio de hipomania induce un significativo cambio diagnostico desde DM a Hipomania y por lo tanto a TB II. La significacin de este cambio implica ocuparse adecuadamente de un trastorno, el Bipolar, que es mas severo que la DM, con recidivas mas fuertes, comorbilidad mas compleja y tasas de mortalidad mayores.

Especificaciones de intensidad: leve-moderada-severa

Especificaciones sintomticas: psicticapost Parto

Atpicamelanclicacrnicacatatnica

a) depresion atipica: el concepto de depresion atipica se ha consolidado en diferentes estudios que han validado la presencia de algunos sntomas que la caracterizan, tales como un desgano o astenia severa, expresada por el enfermo como pesadez en los miembros superiores y piernas, hiperfagia con accesos bulimicos, aumento de peso e hipersomnia. Sin embargo, la dificultad para experimentar placer (anhedonia) no es tan marcada, conservando la capacidad de reaccionar con alegria o placer a cosas cotidianas y positivas. Por la ansiedad severa, esta forma de la enfermedad depresiva, esta asociada a intentos suicidas y tiende a presentarse precozmente en mujeres, en comorbilidad con otras patologas. (Matza, Revicki, Davidson, 2003). Varios aspectos, en base a datos recientes, pueden ser comentados: a) primero, la anhedonia, considerada un sntoma cardinal del episodio depresivo. En las depresiones atpicas, la anhedonia no es importante en la mayora de los casos. Neurobiologicamente, el grado de anhedonia se asocia a un dficits de actividad del estriado ventral (incluyendo al nucleo accumbens) y un exceso de actividad de la regin ventral de la corteza ventral (incluyendo la corteza prefrontal ventromedial y la corteza orbitofrontal), con un rol central, aunque

no exclusivo de la dopamina, con importancia central en el sistema de recompensa, modulada por la serotonina y los receptores opiodes entre otros. Por lo tanto, tendramos que concluir que en esta especificacin depresiva, las etapas nuerobiologicas para reconocer el estimulo, y determinar si es es un estimulo que es hednicamente relevante, y posteriormente expresar la emocin, estn relativamente indemnes; b) segundo, la ansiedad como aspecto relevante. Curiosamente, la ansiedad no es considerada como un sntoma central de acuerdo a los criterios del DSM IV TR, pero estudios clnicos demuestran que el 90% de los pacientes presentan una co-concurrencia de sntomas ansiosos y depresivos y un 50% de ellos cumplen con los criterios para considerar un trastorno ansioso como comorbilidad de la depresin, por lo tanto, en DM, la comorbilidad es la regla y no la excepcin. Por ello es que, considerando el DSM V, Watson ha propuesto 3 subclases de trastornos emocionales: TB, Trastornos por Distress (DM, Distimia, TAG y Stresss posttraumtico), y trastornos por miedo (TP, agarofobia, fobia social y fobia especifica), conisedarndo un continuum entre la ansiedad y los trastornos depresivos, en contraste con la sepracion entre los trastonos anmicos y los ansiosos iniciados hace tres dcadas atrs. Desde el punto de vista clnico, esto tiene mucha importancia porque los pacientes con ansiedad importante tienen una respuesta menor al tratamiento, y alta tasa de recaidas, lo que explica la alta incidencia de intentos suicidas en este tipo de pacientes; c) tercero, la relacin de esta variedad depresiva con aparicin precoz en mujeres y en comorbilidad con otras patologas. Ademas de los conocidos trabajos de Brown y Harris, La depresin en la mujer, otros estudios mas actualizados muestran que las mujeres tienen un riesgo hereditario de hacer depresin mayor que los hombres, reafirmando que los factores medioambientales dados a conocer por Brown y Harris en sus investigaciones, son mayores en los hombres, quienes aparentemente hacen mas adicciones que depresiones, en respuesta a ellos. Otros aspectos actuales de la relacin genero (mujeres) y trastornos afectivos, los revisaremos a propsito de la relacin de estos trastornos con la regulacin hormonal en los trastornos del humor.

b) Depresion melancolica. Es una especificacin sintomatica del episodio depresivo mayor que alude a las caracteristicas de gravedad o intensidad del cuadro, con presencia relevante de sintomatologa vegetativa, como por ejemplo insomnio precoz o matutino, con variaciones circadianas en que el paciente se siente bastante mal en las maanas para experimentar alivio a la hora vespertina o al acostarse, perdida de apetito y por lo general de peso corporal, acompaado de desgano o astenia para casi todo tipo de actividades e incapacidad para experimentar placer (anhedonia). De acuerdo a Tellenbach, los pacientes melancolicos suelen ser exigentes y exagerados por el orden, escrupulosos, evitadores de conflicto, inflexibles e inseguros, muy buenos en su

trabajo, concienzudos y pesimistas, lo que obviamente ayudaria experimentar sus sensaciones y emociones con mayor intensidad

c) Depresion cronica: esta especificacion se aplica cuando la totalidad de slos sntomas requeridos para hacer el diagnostico de episodio depresivo mayor se encuentran presentes a lo menos por aos, o tambien a las recidivas con persistencia de sintomatologa residual durante el mismo periodo de tiempo o a la asociacin de un trastorno depresivo mayor a un trastorno distimico que conceptualmente es mayor a 2 aos (depresion doble). Entre los factores de riesgo de cronicidad se encuentra la precocidad del primer episodio, los trastornos premorbidos de personalidad, antecedentes familiares de trastornos del humor y la intensidad o gravedad de los episodios recurrentes

d) Depresion catatnica. De presentacion rara en la clinica psiquiatrita, se encuentra asociada a la rigidez extrema en segmentos o totalidad del cuerpo y a negativismo u oposicionismo del enfermo sin fundamentacion plausible a cualquier solicitud o pedido del clinico para realizar una evaluacion medica. A veces, la catatonia o la catalepsia del paciente se trastoca en hiper excitacin o gestualidad esterotipada, bizarra o compleja, que obliga a hacer diagnostico diferencial con otras patologas psiquiatricas (eqz) o medicas.

e) Depresion psicotica. En el contexto maniaco y depresivo, es decir, en los dos polos del trastorno del humor podemos encontrar sintomatologia psicotica en los cuadros de mayor intensidad y gravedad. En la literatura psiquiatrita clasica se encuentran como sinonimos depresion endogena y depresion psicotica y en la literatura mas reciente, segn (Vallejo, J y Gast Ferrer, C. Trastornos Afectivos: ansiedad y depresin. Masson, Barcelona, 2000), de depresiones delirantes en que se estudia la posibilidad de incorporarlos como entidades distintas en el DSM, y no meramente como una condicion mas grave de los Trastornos depresivos severos. Si bien las manifestaciones delirantes en la depresion alcanzan un porcentaje relativamente bajo en el curso de episodios depresivos mayores severos (18,5% en el estudio de Ohayon y Schatzberg de 2002), lo mas importante de retener es la congruencia que debe existir entre los contenidos delirantes con la conducta y expresin mimica del sujeto enfermo. Los temas del delirio depresivo pueden ser variados: (Diego). Los sntomas alucinatorios vivenciados por los pacientes depresivos psicoticos son caractersticamente voces de indignidad, pecado o condena, congruentes con su expresion ideo-afectiva La misma congruencia entre expresin, conducta y contenido delirante debe esperarse en un paciente maniaco, hecho de megalomania y proyectos grandiosos donde el paciente es un genio, un profeta, un redentor social, un gran inventor, omnipotente, invencible, pero sin juicio de realidad. Esta forma de presentacion de la psicopatalogia maniacal, extravagante y expansiva, seria

incongruente en un paciente en un estado maniaco que creyera ser perseguido, influenciado corporalmente o sometido a vigilancia desde la distancia, donde deberiamos hacer un diagnostico diferencial con un proceso esquizofrenico. f) Cuadros clinicos de aparicion en el post-parto. Este cuadro presente en las primeras 4 semanas despus del parto en el 10 al 15% de las mujeres, fue incorporado al DSM IV para describir no tan solo cambios depresivos psicoticos y no psicoticos, sino tambien Trastornos bipolares o cuadros maniacales. El episodio depresivo mayor que puede surgir en esa etapa es indiferenciable del cuadro clinico apararecido en cualquier otra etapa de la vida y que ha sido ya descrito. Importante es de considerar que no cualquier modificacion del estado animico en el sentido depresivo es una depresion post-parto, ya que la mayoria de las mujeres desarrollan un cuadro de disforia menor entre el primer y quinto dia del alumbramiento, caracterizado clnicamente por paso rapido de la alegria al llanto, con oscilaciones del estado animico temporal. Estos cambios animicos, reactivos al stress del nacimiento y a la nueva rutina de cuidados del recin nacido, es vivido a veces con desconcierto por el hecho de que ante la presencia de una nueva vida, deberia solo esperarse felicidad. Cuando la sintomatologa se hace mas evidente o intensa, alcanzando grados moderados y en extensin mayor a los 5 dias, es necesario hacer el diagnostico diferencial con una autentica depresion post-parto por el riesgo de alcanzar mayor severidad o requerir hospitalizacion. Entre los factores de riesgo se encuentran el ser primipara y los accidentes obstetricos o abortos previos, antecedentes anamnesticos de depresiones en el curso del embarazo, factor cierto y consensual, que a su vez se vinculan con comportamientos riesgosos de la futura madre como el tabaquismo, el uso de alcohol y drogas, control insuficiente del embarazo. Los sentimientos negativos o ambivalentes con respecto al embarazo y las complicaciones obstetricas tambien son relevantes de considerar en la historia clnica. Los factores socio-economicos juegan un rol semejante a cualquier otra depresion vivida en el curso de la vida, traducidos en un sostn social dbil, bajo nivel de educacin, empleo precario o sin empleo, carencias afectivas, historia de violencia y abuso sexual en la infancia con la consecuencia comun de perdida de autoestima y baja confianza en su rol materno. Los factores de riesgo de tipo endocrinologicos, con excepcion del hipotiroidismo, no han podido ser claramente establecidos como factores unicos (Kuijpens y al. 2001). La evolucion a una depresion mayor o a un trastorno bipolar de mayor gravedad que implica sintomatologa de tipo psicotica require hospitalizacion y cuidados especializados, se manifiestan entre la primera y tercera semana del post-parto y la clinica y puede, en algunos casos delirantes de negacion del hijo, implicar conductas o fines felicidas. El tratamiento de ambas formas, no psicoticas y psicoticas de la depresion y manias no difieren del manejo habitual en estos cuadros

Algunos aspectos de los TB requieren una consideracin especial en la mujer: q) El impacto de gnero sobrer el curso de la enfermedad: las caractersticas clnicas son similiares entre hombres y mujeres, pero las mujeres experimentan mas episodios depresivos que los hombres r) Las mujeres experimentan mas experiencias de ciclaciones rapidas, manias mixtas y manias inducidas por antidepresivos que los hombres, quizs por el excesivo tratamiento con antidepresivos e inadecuado uso de estabilizadores del animo s) Cuando aparece una mujer con un TB que presenta episodios depresivos o ciclaciones rapidas es importante optimizar estabilizadores de animo, chequear funcin tiroidea y evaluar el uso de los antidepresivos. t) La relacin entre TB y ciclo mentrual es relativamente desconocido u) Algunos estudios indican que existen en las mujeres bipolares mas alterasciones anmicas pre-menstruales que engrupos controles v) Otros estudios sugieren que los TB de las mujeres empeoran en la fase menopausica con mas disturbios emocionales y conversiones a ciclaciones rapidas, pero todava no existe una explicacin clara de como las transiciones hormonales impactan el curso de la enfermedad bipolar en las mujeres. w) Existe una pre-concepcion de que el embarazo protege a la mujer de los TB. Esto no es cierto para los TB, donde los factores de recaida durante este periodo incluyen bruscas suspensiones de estabilizadores de animo, una historia de 4 o mas episodios afectivos previos y un periodo de alteracin anmica intraparto. x) El periodo post-parto es particularmente de alto riesgo para la mujer. Las recaidas alcanzan niveles entre 20 a 50%, de entre las cuales un 40 a un 67% experimentan una mania o depresin en el post-parto y) Las mujeres con TB tiene 100 veces mas posibilidades de hacer una psicosis post-parto que las mujeres sin esta patologa z) En relacin a la medicacin: existe evidencia de que los efectos de la medicacin puede impactar en la salud reproductiva de la mujer. Un ejemplo de ello es la aparicin de Ovarios poliquistico como un trastorno endocrino grave relacionado con infertilidad anovulatoria. Este sndrome se caracteriza por disfuncin ovulatoria (poli, oligomenorrea), evidencia de hiperandrogenismo o hiperandrogenemia y exclusin de otras endocrinopatas como disfuncin tiroidea, hiperprolactinemia o sndrome de Cushing. aa) La terapia con Litio en mujeres se asocia con hipotiroidismo y tiroiditis mas frecuentemente que en hombres bb) Los efectos sobre la contracepcin oral son importantes de considerar, ya que esta se puede deteriorar ya que la medicamentacion por los TB puede inducir enzimas hepticas que al aumentar el metabolismo de los anticonceptivos puede disminuir su eficacia. A la inversa, los anticonceptivos pueden inducir un metabolismo acelerado de medicamentso para los Tb como la Lamotrigina, la cual requerira ser aumentada

cc) No existe interaccion medicamentosa entre anticonceptivos y Litio, Valproato y antipsicticos atpicos dd) Durante el ambarazo: anlisis de riesgos-beneficios ee) La lamotrigina es el medicamento que parace mas seguro de usar en el embarazo, cuando las mujeres persisten en sus embarazos y requieren medicamentacion ff) El post-parto es asociado con recaida: la profilaxis con medicamentacion en el tercer trimestre del embarazo y en el post-parto inmediato puede evitar la recaida.

Especificaciones de la evolucion de los trastornos del nimo: longitudinal, con ciclacin rpida y estacional

a) Evolucion longitudinal de los trastornos del animo El conocimiento detallado de la anamnesis psiquitrica del paciente que indica cuadros recidivantes o recurrentes de depresion mayor y mania, si el grado de recuperacion intercritica fue incompleto, o antecedentes de distimia o ciclotimia, son importantisimos para el pronostico del cuadro actual, ya que tales condiciones previas tienden a la agravacin o cronicidad de la depresion o trastorno del animo tipo I y II. (Ghaemi y al. 2001 y 2002) Han elaborado una lista que deben hacer sospechar en la historia clinica del paciente deprimido, la existencia (genotipica) de un trastorno bipolar en formas atipicas de presentacion o del espectro bipolar: precocidad de aparicion del episodio depresivo mayor, depresiones mayores recurrentes, historia familiar de trastorno bipolar en parientes de primer grado, temperamento hipertimico, episodios depresivos mayores con caracteristicas psicoticas, depresiones del post-parto, antecedentes de mania o hipomania inducidas por antidepresivos, ausencia de resspuesta a tres tratmientos antidepresivos bien conducidos. Obviamente, todos estas formas de presentacion y antecedentes a lo largo de la evolucion longitudinal del trastorno timico de que se trate est asociado a tratamientos mas largos e intensivos a fin de lograr la recuperacion animica de los pacientes b) Evolucion de los trastornos del animo (Tipos I y II) con ciclos rapidos. Consensualmente definidos como aquellos episodios de trastornos del humor en numero de 4 o mas por ao, ya sean episodios de mania, hipomania, depresion mayor o mixtos, separados por al menos 2 meses. Se correlaciona a una respuesta mas mala al Litio, con una preferencia marcada de presentacion en el sexo femenino (70 a 90% de prevalencia), con factores de riesgo asociado antecedentes de tratmientos frecuentes con antidepresivos, antecedentes familiares o una comorbilidad endocrina como hipotiroisdismo y ciertos problemas neurologicos tales como traumatismos o secuelas traumaticas de un

TEC. A diferencia de los pacientes que presentan un trastorno bipolar clasico, los cicladores rapidos empiezan generalmente por una depresion mayor, lo que tiene importancia en la medida que la mayoria de esos pacientes se trata con antidepresivos. Por lo tanto, frente a pacientes con depresiones mayores recurrentes, se debera poner atencin en aspectos evolutivos anteriores, ya que algunos investigadores que tienden a ampliar el espectro bipolar, incluyen especialmente cuadrado de hipomanias leves con una duracion menor a 3 dias, que pueden pasar desapercibidas, y que revelarian una predisposicin o vulnerabilidad especial por episodios maniacos-depresivos, ya que el tratamiento exclusivo con antidepresivos puede ser inductor de virajes timicos. La misma preacuacion debera tomarse frente a pacientes frente a numerosos trastornos de personalidad, especialmente la limtrofe, con un episodio depresivo mayor, que a juicio de estos autores (Akiskal, Angst) serian manifestaciones subsindromaticas de tipo bipolar. Una particular condicion clinica descrita, por su extrema severidad y dificultades en el tratmiento, es el pasaje sin transicin entre un estado y otro, condicion que ha recibido el nombre de alternancia timica rapida. Junto con constituir una mayor gravedad del cuadro clinico, la ciclacion rapida tambien se ha asociado a una mayor hetero-peligrosidad del paciente, con un riesgo suicida importante a la salida de un episodio maniaco. En suma, su importancia como especificacion evolutiva radica en el peor pronostico del cuadro, la necesidad de reforzar tratamiento con mas de un estabilizador del animo, el potencial riesgo suicida u hetero-agresivo y la mayor cronicidad. c) Evolucion longitudinal con caracteres estacionales. Segn el DSM IV-TR se aplica tanto a las modalidades evolutivas de episodios depresivos mayores sin trastornos bipolares como a los Trastornos Bipolares I y II. Como su nombre lo indica, los episodios timicos tiene una recurrencia y una remision en periodos caracteristicos del ao. Generalmente comienzan en otoo o invierno y mejoran en primavera. La intensidad del cuadro depresivo es ligero o moderado, acompaado de astenia y sntomas parecidos o iguales a la depresion con caracteres atipicos, es decir, hipersomnia, hiperfagia y una apetencia por los dulces, la que implica aumento de peso. Aunque la mayoria piensa que esta modalidad depresiva no es particularmente distinta a las otras formas, se ha sugerido que en ella juega un rol las variaciones de la secrecion circadiana de la melatonina y de una vulnerabilidad genetica, aunque no se haya hasta ahora demostrado una asociacin entre el fenotipo clinico y los genes reguladores de los ritmos circadianos, aunque se sabe que estos ritmos son controlados por relojes celulares endogenos que se encuentran en los ncleos supra-quiasmaticos del hipotalamo anterior sobre cada cara del III ventrculo y que cuando son destruidos experimentalmente implica la desparicion de varios ritmos como el de sueo-vigilia, temperatura corporal, liberacin hormonal. Pero el reloj biologico tambien es dependiente de factores externos como los medioambientales que son capaces a su vez de modificar los ritmos como ocurre en los viajes transhemefericos. La luz que aparece en un momento inhabitual es capaz, en los mamiferos, de inducir la transcripcion genetica en los genes del reloj biologico por la via retinohipotalamica a los

ncleos supra-quiasmaticos para sincronizar el reloj personal con el ritmo alternante de luz y oscuridad. La melatonina participaria en la transferencia de la informacin por la mediacin de cambios moleculares y modulacion de sntesis proteica. La relacion entre los ritmos biologicos internos y los cambios timicos esta bien establecida, como se aprecia clnicamente en cualquier episodio depresivo mayor (alteracin sueo-vigilia, secrecioes hormonales, etc), que es expresiva de la periociodad circadiana de la reactividad emocional, donde tambien juega un rol la melatonina. Para el caso de la evolucion longitudinal estacional de los episodios timicos, los autores actuales han puesto de evidencia con pruebas cientificas, observaciones clasicas sobre el ritmo estacional de algunos cuadros psiquiatricos y conductas suicidas, por ejemplo, en Kreapelin que precisaba que en las psicosis maniaco-depresivas un 5% de los pacientes hacian depresiones en invierno y mania en primavera o, el sociologo E. Durkheim que hacia la observacin que los piques suicidas se concentraban en meses de primavera y verano. Dichos ritmos estacionales de episodios timicos estarian en relacion con la luminosidad o extensin de los dias y la secrecion de la melatonina por la glandula pineal. La luz intensa suprime la liberacin nocturna de esta hormona en los seres humanos. Este hecho de que la liberacion de melatonina no se produzca durante sino solo en las noches y de que la luminosidad la suprima sugiere que las depresiones estacionales producidas en invierno tiene como origen un desequilibrio cronobiologico en su sntesis vinculada a la extensin del periodo de oscuridad propios de esa estacion del ao. En consecuencia, tal perturbacin puede ser corregida exponiendo al paciente a la luz (fototerapia), en las maanas durante un par de horas. Otras hiptesis sealan que las modificaciones clinicas estacionales pueden deberse a efectos de desfasajes temporales. En esta situacin, los relojes internos situados en la epifisis y el hipotalamo (nodulos supra-quiasmaticos) que se activan con la luminosidad del amanecer, se desincronizan por un atraso funcional en invierno, lo que explica la desincronizacion de otros ritmos biologicos como el ciclo sueo-vigilia en esta modalidad evolutiva del trastorno timico. Rohan, 2003 ha demostrado tambien que factores cognitivos y comportamentales se asocian a la estacionalidad de la depresion y observ que la rumiacion y preocupacin o ideacin negativa durante el otoo era un indicador de la intensidad y severidad mayor de la depresion invernal. El rol de la serotonina tampoco ha sido descuidado, en la medida que es el precursor directo de la melatonina, lo que nos conduce a pensar que los mecanismos responsables de las variaciones estacionales de los trastornos del humor son complejos y depende de factores individuales y la naturaleza de los factores ambientales.

III.- Incidencia y Prevalencia IV.- Factores de riesgo e hiptesis teoricas de la etiologia de los atrastornos del humor

De acuerdo a la ultimas investigaciones disponibles en relacion a la etiologia de los Trastornos del humor (Kendler, Garner y Prescott, 2002), stos son mejor comprendidos en terminos de interacciones complejas de factores biologicos, geneticos y psicosociales, en que cada uno de los factores individualmente identificados puede jugar un rol variable dependiendo del peso especificos que tenga. Las investigaciones sobre la etiologia de los trastornos del humor tienen tres grandes limitaciones: diagnostico univoco, relativa dificultad de acceso al cerebro y su funcionamiento y la complejidad de los mecanismos causales y la interaccion de factores biologicos, geneticos y medioambientales. Las herramientas de investigacin son la genetica, la bioqumica, la farmacologa, la electroencefalogragia, la imaginologia cerebral y la neuropsicologa 1.- Neurobiologa de la depresion y de los TB Gentica Holmans y Levinson y sus repectivos equipos (2007), investigadores de la genetica de los trastornos mentales, han sealado claramente el significativo rol que juegan los genes en la determinacin de la vulnerabilidad a la depresion y TB. Al igual que en el caso de la esquizofrenia, mientras mas cercano es el vinculo genetico, mas probabilidades existen de que sus miembros compartan un cuadro depresivo mayor o un TB. Para eliminar el probable sesgo medioambiental, los investigadores se han concentrado en el estudio de los gemelos uni y di-cigotos. En el caso de los gemelos verdaderos que comparten el 100% del material genetico, la tasa de concordancia es mucho mas alta que para los dicigotos que comparten solo el 50% de su dotacion genetica, indicando una clara contribucin genetica. Pero la concordancia de acuerdo a la dotacion genetica de cada uno de estos grupos no es lineal, sino que solo explica una tasa de concordancia de 2 veces mas elevada en el grupo de los monocigotos que en los di-cigotos, dejando un espacio importante a otros factores explicativos como los medioambientales, donde los factores estresantes por ejemplo, son llamados a jugar un rol tan importante o mas, segn Kendler y Prescott, 1999, que los propiamente geneticos. Jokela y cols, ha desarrollado otro modelo que explora las articulaciones de la genetica con el medioambiente en la genesis de los trastornos del humor, que pueden ofrecernos respuestas mas completas en torno a este interesante dominio de la causalidad de los trastornos del humor. Depresion ansiedad

Es stress juega un rol muy significativo en las depresiones mayores y tambien en la determinacin de la vulnerabilidad en los TB.

Neurotrasmisores y anomalias cerebrales

Desde hace mas de medio siglo los investigadores se han ocupado de la investigacin sobre los fundamentos biologicos de los trastornos del humor en relacion a la accion medicamentosa de los antidepresivos que aumentaban los niveles de norepinefrina y serotonina en el cerebro, MEJORANDO EL ESTADO ANIMICO DE LAS PERSONAS. La investigacin actual descarta el efecto unico de los neurotrasmisores como productores de la depresion, dado el desfase que se produce entre el comienzo del tratamiento y la respuesta terapeutica, centrandose en otras posibles respuestas basadas en las irregularidadwes del numero de receptores neuronales que reciben a los neurotrasmisores, ya sea en su sensibilidad a ciertos receptores o a las irregularidades del proceso por las cuales estas subtancias quimicas se comunican con los receptores (Oquendo y cols, 2007). Por ello se acepta ahora que los medicamentos actuan en estos dos niveles para producir mejoria en los pacientes, reconociendose ademas, que la complejidad es mayor, puesto que existen diferentes tipos y subtipos de receptores para cada neurotrasmisor, lo que le confiere especificidad a unos antidepresivos mas que a otros, con el factor adicional de que es posible que la accion terapeutica del antidepresivo sea ademas, por acciones sobre distintos sistemas de neurotrasmisores. Entre los neurotrasmisores implicados en los cuadros depresivos se encuentran la norepinefrina, la serotonina y la dopamina, pero tambien alteraciones en segundos mensajeros y factores de transcripcion genetica. En la presente decada, Zalsman y cols, 2006 han puesto de manifiesto la accion de la acetil colina, el GABA, y el glutamato entre otros. (mas en Vallejo Ruiloba) En estudios mas actualizados se ha puesto de relieve la interaccion complementaria de varios neurotrasmisores o neuromoduladores. Es el caso de la serotonina, cuyos bajos niveles en el espacio intersinaptico esta asociado a la etiologia de la depresion, solo en interaccion con dos otros neuromoduladores, la noradrenalina y la dopamina. La hiptesis sostiene que el rol de la serotonina es de regulacin de la saciedad, el sueo y de las emociones (Spoont, 1992), de donde se desprende que la falla en el proceso de regulacin de los otros sistemas de neurotrasmin dopaminergica y norepinefrenica, explicaria las variaciones del estado del humor en los pacientes (teoria permisiva), al permitir la accion de los otros neurotrasmisores con todos sus sub-tipos. Las deficiencias en la trasmisin serotoninergica en los pacientes depresivos ha sido comprobada por medio de estudios de imagineria cerebral (Tomografia por emision de positrones) La investigacin sobre los fundamentos biologicos de la depresion se ha visto enriquecida en la ultima decada por los estudios de imgenes cerebrales (SPECT) que dan cuenta de anomalias en ciertas areas del cerebro. En sujetos depresivos, por ejemplo, se encuentra una actividad metabolica disminuida en las regiones pre-frontales al compararlas con sujetos sanos (Davidson, 2002). En otras investigaciones con pacientes depresivos mayores y TB se han encontrado anomalias en regiones cerebrales implicadas en el control de las emociones (Steele y cols, 2007). Ya sabemos que las estructuras limbicas, de las cuales forman parte el hipocampo, la amigdala y la corteza pre-frontal son centrales en la regulacin

de las emociones, de lo cual se deriva que sus lesiones o anomalias funcionales tienen efectos que se expresan en sntomas y deficits propios de los depresivos, los que tendrian sus bases neurobiologicas precisamente en estas diferentes areas del cerebro lesionadas. Asi, la reduccion de volumen asociado a su hiperactividad, de la zona ventral del sistema limbico, constituida por la amigdala, la insula, el striatum ventral y la parte ventral del gyrus cingular anterior y el cortex prefrontal, (con roles de percepcin, respuesta y regulacin de las emociones), se correlaciona con una restriccin de la respuesta emocional y una percepcin de las emociones con valencia negativa. La hipofuncin del sistema dorsal que incluye el hipocampo, se expresa en una disminucin de la funcion reguladora del sistema ventral a traves de trastornos cognitivos, humor depresivo y anhedonia Estos hallazgos no son sorprendentes si recordamos que en todas las areas implicadas, tanto la noradrenalina como la serotonina juegan roles relevantes en el control de los impulsos nerviosos. Obviamente, el desarrollo de posteriores investigaciones pueden permitir una distincin mayor en los procesos biologicos y neurofuncionales comprometidos en los trastornos del humor y, al mismo tiempo profundizar en un proceso de recalibracion de la sicopatologa o sntomas de la enfermedad en relacion a las areas especificas afectadas.

Endocrinologia y depresion

La hiptesis que vincula a la depresion con el sistema hormonal dice relacion con el stress y la reactividad del eje Hipotalamo-Hipofisis-Glandulas Suprarrenales. (describir eje en Primera Parte) El antecedente de hipersecrecion de cortisol en pacientes depresivos es antigua, correspondiente con la observacin de que los pacientes con sndrome o enfermedad de Cushing presentan a menudo formas clinicas severas de depresion y ansiedad y niveles aumentados de produccin y secrecion de glucocorticoides. En individuos sometidos a estrs, En los pacientes deprimidos, el eje se encuentra exigido, encontrandose niveles de cortisol y CRF elevados en 20 a 40% de los pacientes ambulatorios con depresion aguda y en el 60% de los pacientes con TDM. Las investigaciones recientes han demostrado que la concentracin permanentemente elevada de cortisol puede contribuir a la atrofia de celulas del hipocampo, observable con tecnicas de imagineria cerebral en depresiones cronicas y recurrentes. En relacion a esta estructura cerebral, existen elementos que permiten sostener que los pacientes con mas altos indices de hipercorticolemia, tiene mayor atrofia hipocampica, compromiso de la memoria declarativa dependiente de sta zona del cerebro y, en los estudios post-mortem de cerbros de pacientes depresivos o tratados con glucocorticoides, un grado de apoptosis mayor a grupos controles (McEwen, 2005). Otros estudios han reportado una disminucin del numero de receptores a los glucocorticoides en el hipocampo y la corteza prefontal en suicidas. Si bien es difcil saber si estos cambios estructurales son de origen geneticos o el resultado de una activacion

crnica del eje HHS, si son coherentes con la hiptesis de la hiperactividad sealada y las consecuencias clinicas de depresion con consecuencias suicidas. Desde el punto de vista de la evaluacion clinica para documentar esta relacion, se ha recurrido a la prueba de la supresin de la dexametasona que consiste en la administracin por via oral de 1 a 2 mgs de dexametasona a las 23 horas, para medir los niveles de cortisol plamatico al dia siguiente. Lo esperable normalmente es la reduccion o supresin de la liberacin de cortisol por el feedback negativo de la liberacin de la ACTH, lo que solo se produce en el 50% de los pacientes depresivos y con TB. Esto significa que el otro 50% que no presenta supresin han desarrolado una hipersensibilidad del eje y un deterioro de los mecanismos de feed back, lo que se asocia a una peor evolucion del trastorno, mayor intensidad sintomatica y un mayor riesgo de recaidas tras el tratamiento, a pesar de la mejoria clinica (Nelson y Davis, 1997). La prueba descrita no discrimina otros trastornos psiquiatricos tales como los trastornos alimentarios y el TOC, por lo que ha sido descartada como til para el diagnostico, lo que no significa inutilidad como marcador biologico de mejoria en los pacientes depresivos (Gillespie y Nemeroff, 2005). Pero, las relaciones endocrino-psiquiatricas no se reducen a lo sealado. El otro sistema biologico implicado junto a los trastornos del eje HHS es la neutrofina, que se conoce como el factor neurotrofico del cerebro (brain derived neurotrophic factor), implicado en trastornos del proceso de mala adaptacin del hipocampo en relacion con procesos depresivos y en estrecha relacion con los mecanismos reguladores del stress. La cascada de reacciones moleculares derivadas que lleva al dficit del factor neurotrofico del cerebro, que a su vez interviene en la fisiopatologa de la depresion, es compleja, pero ya existen evidencia de que el tratamiento cronico con antidepresivos induce experimentalmente en animales de laboratorio aumento de los niveles de ARNm para incrementar el BDNF (factor neurotrofico), con lo que se inaugura una nueva via de comprensin tanto de los mecanismos patogenicos como terapeuticos en el estudio de la depresion. Aunque en general los pacientes depresivos son eutiroideos, la mayor parte de los pacientes presentan alteraCIONES en la funcion tiroidea (Braumgartner, 2000) que se traducen en elevaciones ligeras en las concentraciones sericas de T4 y disminucin de T3, desaparicin del incremento nocturno en la concentracin de TSH y predisposicin a la tiroiditis autoinmune (Foltyn, 2002). Hendrick y cols, 1998) tambien ha encontrado que en el 25% de los pacientes con depresion existe una reduccion de la respuesta de la TSH frente a la TRF, lo contrario evidenciado en los hipotiroidismos primarios. El estudio de las relaciones de otras hormonas y la depresion debe ser objeto de un analisia ms detallado que excede las pretensiones de ste texto. Sueo y ritmos circadianos

La relacion entre sueo y trastornos del humor es estrecha. En una poblacin general,la queja de insomnio se asocia a depresion mayor en un 3,3% de los casos, cifra que aumenta en los pacientes derivados a un centro del sueo por insomnio donde se encuentra un 32% de depresiones mayores. Asimismo el insomnio cronico es un factor de riesgo de depresion, existiendo por lo tanto, una relacion reciproca entre estos dos trastornos. Recordemos que el ciclo del sueo se compone de dos fases principales: la fase de sueo REM y la fase de sueo No-REM. Desde que el sujeto se duerme, pasa por varias sub-etapas de sueo cada vez mas profundo, que satisface casi todas las necesidades de reposo, para alcanzar al cabo de 90 minutos la fase de sueo REM o fase de movimientos oculares rapidos, fase donde el cerebro se activa y se comienza a soar. A medida en que avanza la noche, el individuo acumula mas sueo REM. Esta arquitectura del sueo se ve alterada en sujetos depresivos en quienes se encuentra reduccion de la fase del sueo con ondas lentas, es decir, la fase mas favorecedora del reposo (Jindal, 2002). Esta disminucin de la actividad lenta del sueo ha sido corroborada por analisis secuenciales del EEG que demuestran ademas la reduccion de amplitud de las ondas lentas y un aumento de las frecuencias rapidas precoces en pacientes deprimidos en relacion a grupos controles. Este comienzo precoz del sueo paradojal se acompaa de una extensin anormalmente larga, anomalia que junto a las otras descritas, varian en relaciona distintos factores tales como la edad, sexo, severidad, forma clinica y evolucion de la depresion, siendo en general, mas acentuadas y mas frecuentes en los pacientes de edad que en los jvenes, en que se considera que una latencia menor del sueo paradojal inferior a los 90 minutos es patologica. Las perturbaciones del sueo aparecen a veces, antes de que se desencadene el trastorno afectivo y son persitentes despus de la mejoria clinica del paciente, siendo por lo tanto, signos importantes dee recidivas o vulnerabilidad mayor a la recurreencia. Tambien se ha considerado que la normalizacion del sueo paradojal con tratamiento antidepresivo es un signo que predice buena respuesta terapeutica. El caso de la depresion estacional caracterizado por una cronologa y sintomatologa especial, es tratado en eltexto como una especificacin longitudinal de la evolucion del trastorno (ver )

Actividad ondulatoria cerebral

2.- psicologa Acontecimientos vitales

Muchos factores participan en la la descompensacion de los cuadrso afectivos y provienen de los mas diferentes dominios, des los estacionales hasta factores sociologicos: uno de los mas conocidos en la literatura psicologica es el de los

acontecimientos vitales, los que sin embargo, por si solos, pareciera no pueden explicar la aparicion o la genesis de un trastorno del humor. Si bien la solidex de la la relacion entre acontecimientos de vida ha sido establecido con claridad en los cuadrso depresivos, no ocurre lo mismo repecto de los trastornos bipolares. Judd, L. The long-term natural history of the weekly sintomatic status of bipolar disorder. Arch Gen Psychiatry 2002; 59: 530-7) desde la epidemiologia ha puesto de manifiesto la dificultad para este tipo de estudios en la medida que los sntomas residuales intercriticos contaminan la fuente de los acontecimientos vitales estresantes para el sujeto como potenciales factores etiopatogenicos de la enfermedad. Varios investigadores, desde Krepelin en adelante, se inclinan mas bien por considerar estos acontecimientos vitales como consecutivos a la enfermedad mas que factores gatillantes de ella. Variso estudios controlados y prospectivos que han utilizado instrumentos especificos, no han aportado datos convincentes sobre el rol precipitante de los episodios timicos, pero si de que los pacientes tenian un numero mayor de acontecimientos estresantes registrados, mas numerosos, mas inesperados y mas severos que las poblaciones de control. La heterogeneidad de los resultados obtenidos hace pensar que ellos son el resultado de la complejidad del concepto de acontecimiento vital y de su evaluacin. En efecto, el concepto de acontecimiento vital considerado de manera aislada, pura y simple, se ha revelado un poco esteril. El acontecimiento vital es mas bien un sntoma, fruto del azar pero tambien del medioambiente en que el sujeto se desarrolla, por lo que la tendencia actual es reremplazarlo por un concepto mas integrador, la ruptura de los ritmos sociales del individuo que puede dar cuenta tanto del acontecimiento en si como del contexto y significacin subjetiva que tal ruptura tiene para el paciente. Una investigacion interesante es la de Malkoff-Schwartz y al. Que ha analizado las recaidas de los TB considerando los acontecimientos vitales, pero desde una perspectiva que diferencia el nivel de estrs inducido, pr una parte, y el impacto sobre el sueo que ese acontecimiento pidiera tener, en un segundo termino, vinculANDO de este modo el concepto de acontecimiento al de perturbacion de un ritmo vital, el sueo, con lo que el cambio en el ritmo social de un individuo que padece de un TB que por ejemplo, al cambiar de trabajo debe trabajar de noche, puede deencadena una recaida, precisamente por el impacto que tiene sobre ese individuo un cambio en su ritmo de vida, el que se revela entonces como un predictor mas fiable que el mero acontecimiento vital.

Incapacidad adquirida

M. Seligmann (1973, 1975), acu el concepto de impotencia adquirida para sealar que los sujetos pueden deprimirse por el hecho que ellos aprenden a considerarse impotentes para cambiar sus vidas. En el laboratorio demostr que la exposicin a fuerzas incontrolables enseaba a los animales de experimentacin que eran impotentes para cambiar su situacin, situacin que era extensible a las personas que mostraban comportamientos similares, instaurando un verdadero

circulo vicioso, donde los fracasos producen sentimientos de impotencia, preludio de posteriores fracasos. Para responder a la objecin del porque algunas personas logran salir de la depresion, Seligmann y cols, sealan que la percepcin de falta de control sobre el reforzamiento conductual por si mismo no explica el fenmeno, sino que ademas se necesita considerar los factores cognitivos y mas aun, la manera como el sujeto se explican sus fracasos o desencuentros, refundando la teoria de la impotencia adquirida por aquella de los estilos atributivos, que es un estilo personal de atribucin, llegando a la conclusin que quienes explican las causas de sus fracasos por factores internos o creencias que stos dependen de sus inadecuaciones personales, o por factores globales o defectos generalizados de su personalidad o, por factores estables de su personalidad, tienen una vulnerabilidad mayor a episodios depresivos. Asi, cada dimension atributiva contribuye especficamente al sentimiento de impotencia, donde las atribuciones internas para los acontecimientos negativos se vinculan a la autoestima baja, las atribuciones estables a la cronicidad o persistencia de las cogniciones negativas y las atribuciones globales a la generalizacin de los sentimientos de impotencia ante los acontecimientos negativos. La confirmacion de este modelo en las personas ayudaa a predecir tasas mas elevadas de depresion en el curso de la vida (Alloy y cols, 2000) Cognicion negativa 3.- aspectos sociales y culturales Matrimonio Mujeres Sostn social 4.- Vulnerabilidad potencial: los endofenotipos (leboyer) En los familiares cercanos, de primer grado, se ha desarrollado una estrategia complementaria consistente en buscar y utilizar ciertas medidas bioqumicas, de imagineria, cognitivas, etc para detectar vulnerabilidad a desarrollar la enfermedad. Para cumplir con los criterios de marcadores eficaces de vulnerabilidad, los endofenotipos deben cumplir con los rerquisitos de estar presentes antes del comienzo de la enfermedad y ser estables en el tiempo (hereditarios).

En los trastornos bipolares se han podido identificar anomalias biologicas y electrofisiologicas. Por ejemplo la disminucin del transporte de la serotonina y disminucin de la tasa de serotonina plaquetaria; tambien deficits de todas las etapas de tratamiento de la informacin perceptivo-motora registrada por amplitud de la P300 y el alargamiento de de los potenciales evocados y de los tiempos de reaccion. Desde el punto de vista cognitivo existen tres maracadores de vulnerabiulidad compartida con la EQZ: un deficits de capacidades de inhibicin (test de Stroop), un deficits de capacidades de abstraccin en los sub-test de similitudes del WAISR y un deficits de control mental de la WMS-R.

Estos estudiso son todava preliminares y deben ser replicados en poblaciones amplias V.- Trastornos del nimo y suicidio VI.- Tratamiento

ESQUIZOFRENIA 1.- Historia y Concepto: La historia conceptual de la esquizofrenia est estrechamente vinculada a los desarrollos nosogrficos de la psiquiatra del siglo XIX. Desde Pinel a Kraepelin y de ste autor a nuestros das han pasado ms 200 aos, tiempo que ha conocido varias elaboraciones nosogrficas para aislar y clasificar las enfermedades mentales. Pero es E Kraepelin, que conceptualiza en 1899 la demencia precoz quien echa las bases modernas de la enfemedad. Este psiquiatra alemn fue el primero en establecer una entidad patolgica nica a partir de tres estados hasta ese tiempo considerados como distintos: la catatonia, la hebefrenia y la paranoia, sobre la base de su comienzo precoz y su pronstico reservado. Para Kreapelin, la demencia precoz consiste en una serie de estados, cuya caracterstica comn es una destruccin peculiar de las conexiones internas de la personalidad psquica. Los efectos de este dao predominan en las esferas emocional y volitiva de l a vida mental. (Kraepelin, E. La Demencia Precoz, Ed. Polemos, B. Aires, 2010, p. 27). Los criterios evolutivos, de tipo degenerativos o en vas de una demenciacin, otorgan al cuadro clnico una entidad diferenciada, una forma bien caracterizada de enfermedad, como expresin de un proceso mrbido nico, aunque a menudo, como cuadro clnico, divergentes unos de otros, adoptando ya sea la forma catatnica, hebefrnica, o paranodea. En su concepcin ontolgica-naturalista de la enfermedad, como algo ajeno al individuo, concibe como para todo fenmeno natural, un origen o etiopatogenia, buscando, a travs de la investigacin clnica en conexin con otras disciplinas (histopatologa, estadstica) un factor causal que explicara la emergencia de la enfermedad: existencia de lesiones cerebrales de origen txico, factores hereditarios, son considerados entre otros en sus investigaciones precursoras en psiquiatra clnica. Eugene Bleuler, a comienzos del siglo XX (1911), introduce un cambio conceptual importante al sistema kraepeliniano, expandiendo la nocin de demencia precoz al considerar que no es la demencia el criterio central en la patologa sino la escisin de las diversas funciones psquicas del individuo afectado. As distingue sntomas fundamentales y accesorios, primarios y secundarios en una doble perspectiva que enriquece la clinica de la esquizofrenia, a la vez que la divide en cuatro sub-formas: paranoidea, catatnica, hebefrnica y simple. El capitulo I de su libro La Demencia Precoz o el grupo de las esquizofrenias analiza los sntomas fundamentales de la enfermedad. La manera de concebir la esquizofrenia en la perspectiva sealada tiene el mrito de relevar los factores intrapsiquicos en la comprensin de la enfermedad. Durante las dcadas siguientes, varios clnicos europeos (fundamentalmente) propusieron otras tantas subclasificaciones y subnosologas al interior del amplio arco fenotpico de las esquizofrenias, que incluyen los trastornos esquizoafectivos y esquizofreniformes. Desde el punto de vista diagnstico, Kurt Schneider, psiquiatra alemn y Profesor de Psiquiatra de Heidelberg, orden los sntomas en los de primer rango, patognomnicos de la esquizofrenia, distinguindolos de aquellos de segundo rango. Tal valoracin se refiere solamente al diagnstico, no se afirma nada con respecto a la teora de la esquizofrenia,

como sucede con los sntomas bsicos y los sntomas accesorios de Bleuler o los sntomas primarios y secundarios del mismo autor. Con respecto a los sntomas de primer orden dice, Entre los numerosos modos anormales de vivencia que surgen en la esquizofrenia existen algunos a los que denominamos sntomas de primer orden, no porque creamos que se trata en ellos de alteraciones bsicas, sino porque poseen un muy especial valor, tanto para el diagnstico frente a lo psquicamente anormal y no psictico, como frente a la ciclotmiaDichos sntomas, citados en el mismo orden, son los siguientes: sonorizacin del pensamiento, or voces que dialogan entre s, or voces que acompaan con comentarios los propios actos, vivencia de influencia corporal, robo del pensamiento y otras influencias del pensamiento, percepcin delirante, as como todo lo vivido como hecho e influenciado por otros en sector del sentir, de las tendencias y de la voluntad. All donde tales modos de vivencia se hallen francamente presentes y no se encuentren enfermedades somticas bsicas, hablamos clnicamente y con reservas de esquizofrenia. Pues ha de ser tenido precisamente en cuenta que todos ellos pueden surgir en ocasiones en aquellos estados psicticos que brotan sobre el terreno de una enfermedad bsica captable: en las psicosis alcohlicas, en el estado crepuscular epilptico, en las psicosis anmicas y otras psicosis somticas, en los ms diversos procesos cerebrales. Podra quiz reconocerse, adems, otros sntomas esquizofrnicos de primer orden. Pero nos limitamos a aquellos que resultan susceptibles de ser captados sin excesiva dificultad, tanto conceptualmente como en la explosin clnica. Entre los de segundo rango, se encuentran las reacciones del paciente a las vivencias propias del proceso esquizofrnico: ocurrencias delirantes, perplejidad, vivencia de empobrecimiento afectivo, distimias y alucinaciones. Esta tentativa de orden de los sntomas de la esquizofrenia en funcin de su contribucin al diagnstico, por su pragmatismo y simplicidad, ha sido considerada por varios autores, entre ellos, Van Praag (1976) como una de las ms convincentes, con una influencia considerable sobre el desarrollo de las actuales clasificaciones, bsicamente el DSM. Los desarrollos postkraepelinianos y bleulerianos enfatizan la concepcin dualista de la enfermedad: orgnica-psicolgica, sta ltima tendencia vinculada al psicoanlisis freudiano al cual adhiere Bleuler. Henry Ey, notable psiquiatra francs, discuti las tesis bleulerianas en varios escritos, el primero de 1926, en que se acercaba a Kraepelin, para despus, rechazar las teoras mecanicistas y constitucionalistas en la medida que vinculan estrechamente los sntomas y el cuadro clnico a sus condiciones lesionales o biolgicas. Por lo tanto, al no pronunciarse sobre la etiologa endgena o exgena del proceso esquizofrnico, seala que lo esencial del problema de la Demencia Precoz o de los estados esquizofrnicos no consiste en saber si se trata de un proceso o de una constitucin, sino mas bien la importancia de la reaccin psquica en el mecanismo esquizofrnico, es decir, de un proceso esquizofrnico que tiene a la base una organicidad y una psicognesis en el determinismo de sus sntomas, acercndose a la postura de Bleuler, sosteniendo que una enfermedad est a la base del proceso mrbido, que engendra directamente los signos primarios de dficits, siendo la mayora de los sntomas observados signos secundarios no dependientes del proceso primario sino de la actividad psquica intacta, emancipada, no controlada, subyacente en el individuo. A comienzos del siglo XXI, la investigacin clnica se encuentra centrada alrededor de la necesidad de definir con mayor claridad el concepto de esquizofrenia y si su validez en el plano descriptivo como lo acoge el DSM IV- TR es suficiente para agrupar los distintos

genotipos de la enfermedad. Hasta ahora, la investigacin etiolgicoa y fisiopatolgica se ha orientado por un conjunto de rasgos de la enfermedad que se han demostrado consistentes desde el punto de vista epidemiolgico para mantenerla como unidad: prevalencia uniforme en todos los pases del mundo, presencia histrica, comienzo precoz, mayor incidencia en hombres, persistencia del cuadro a pesar de la escaza descendencia. Otra preocupacion actual de los investigadores es el de conocer mejor los sntomas negativos y positivos del cuadro clnico y el desarrollo de nuevos mtodos de tratamientos. Los nfasis clnicos en los sntomas negativos han significado un impulso al estudio de los aspectos neurocognitivos del la EQZ, en un esfuerzo por comprender los mecanismos bsicos que los expliquen. El modelo cognitivo permite el desarrollo de una teora general de la enfermedad consistente con la heterogeneidad sintomtica y el uso variado de tcnicas desde las imgenes cerebrales hasta los estudios neuropsicolgicos, lo que facilitara el estudio a nivel molecular de la enfermedad tanto como los conductuales, los que complementados con los estudios genticos ofrecen un potencial de conocimientos para forzar cada vez mas la mirada mdica en torno a las manifestaciones clnicas de la enfermedad en relacin con sus variadas y complejas manifestaciones causales. Siendo la esquizofrenia un problema frecuente, paradjicamente los progresos son pequeos en la comprensin y formulacin de nuevas estrategias de tratamiento. Los avances conocidos en esta dcada, sin embargo, permiten tener una esperanza mayor para el desarrollo de nuevos medicamentos para objetivos especficos dentro de la heterognea diversidad de sntomas y gravedad de la poblacin afectada. Las lneas de investigacin en este sentido se orientan a conocer mejor el primer episodio, la respuesta teraputica y consecuencias para el pronstico de la enfermedad. El abordaje de esta primera fase de la enfermedad, desde el punto de vista de su planificacin e implementacin farmacolgica y educativa, se revela como objetivo estratgico importantsimo para el desarrollo consecuente de la enfermedad y su pronstico. Una importancia similar tiene la comprensin, deteccin y manejo de los disturbios metablicos del tratamiento antipsictico. La preocupacin por los aspectos del deterioro cognitivo, central en la fisiopatologa de la enfermedad, es un nuevo tpico en un escenario donde la medicamentacin es mas efectiva en reducir los sntomas positivos que los negativos de la enfermedad, sieno stos ltimos determinantes para lograr reinsertar a los pacientes no solamente en la comunidad sino tambin para permitirle reanudar sus estudios, trabajo y relaciones sociales y afectivas.

En suma, el modelo de trabajo seguido hasta aqu se puede describir en varios planos: a) Etiolgico. En la bsqueda de la gnesis de la esquizofrenia convergen varios factores en investigacin: DNA, expresin gentica, virus, toxinas, nutricin, complicaciones obsttricas y del parto con dao cerebral, experiencias psicolgicas b) Fisiopatologia. Desarrollo cerebral desde el nacimiento a comienzos de la edad adulta (Formacin neuronal, migracin de las neuronas, gnesis sinptica, apoptosis neuronal, cambios dependientes de la actividad neuronal) c) En un plano mas profundo, los procesos de disrupcin anatmica y funcional de la conectividad y comunicacin neuronal, que lleve a comprender el deterioro de los

procesos cognitivos fundamentales en un primer paso para posteriormente conocer el deterioro de los procesos cognitivos de segundo orden (atencin, memoria, lenguaje, emocin) d) Correlacin con la clnica y la sintomatologa de la esquizofrenia (alucinaciones, delirios, sntomas negativos, hablar desorganizado) con los hallazgos neurofisiopatolgicos de la enfermedad Todos estos aspectos sern sintetizados al analizar los factores de riesgo y las teoras actuales de la esquizofrenia.

2.- Psicopatologa clnica Esta enfermedad se caracteriza por presentar una gama muy extensa de comportamientos y sntomas, mezclados de diversas formas en el curso de su evolucin junto a una heterogeneidad de factores de riesgo y fisiopatologa diversa, lo que no permite distinguir un sntoma patognomnico. Para el clnico en sus comienzos, establecer el diagnstico suele ser difcil. Por ello suele ser adecuado establecer un marco referencial bsico de cmo podemos reconocer en una primera entrevista a individuos potencialmente esquizofrnicos. En una primera aproximacin clinica podremos distinguir distintos sndromes psicopatolgicos que pueden orientar al diagnstico criteriolgico, propio del DSM IV-TR: El sndrome disociativo

Caracterizado por la disociacin entre la expresin, conducta y contenido mental de las producciones del individuo, el que se presenta a la evaluacin clnica con un comportamiento bizarro y discordante ideo-afectivamente, con un tinte extrao que compromete el sistema de pensamiento y las emociones, las que son incoherentes o disarmonicas, en un marco de desorganizacion global de la personalidad, donde se pueden apreciar: 1) desorganizacin intelectual; con un compromiso precoz en el rendimiento escolar o laboral, a menudo acompaado de trastornos del curso del pensamiento (trastornos formales, del flujo o del curso del pensamiento), con suspensiones breves o bloqueos en el discurso de tipo inmotivado o enlentecimiento de ste, con laxitud en su estructura lgica donde los objetivos o propsitos no aparecen organizados con coherencia o con una idea directriz, haciendo del discurso del paciente, un conjunto de ideas poco comprensibles o incomprensible del todo. Los trastornos del contenido del pensamiento, se traduce en empobrecimiento y alteracin del sistema logico de ste, donde el paciente se expresa de manera incomprensible, a menudo con un estilo de pensamiento sumamente abstracto, siendo incapaz de explicar sus propositos o

en otras oportunidades con explicaciones pseudos-logicas o con un marcado racionalismo (mrbido). El lenguaje suele ser meramente comunicativo, es decir sin intencionalidad de convencer y dejar claramente establecida su intencin en el interlocutor, a veces estereotipado intercalando en sus frases palabras o frases sin relacion a un estimulo concreto, o haciendo uso de palabras inventadas (neologismos) o usando palabras fuera de contexto (paralogismo). 2) desorganizacin afectiva; donde es caracterstica la ambivalencia afectiva con presencia simultanea de sentimientos contradictorios traducidos en actitudes y propositos incongruentes o bizarros (paratimias), afectos inapropiados o fuera de contexto, reacciones afectivas paradojicas e inexplicables. Frecuentemente se encuentra tambien aplanamiento afectivo enmarcado en un comportamiento autistico, con prdida de la propositividad vital, es decir, desinteres o falta de motivacin por su futuro personal o profesional. 3) desorganizacin motora; cuya caracteristica es el comportamiento discordante, con mltiples manifestaciones motoras tales como estereotipias gestuales, sonrisas inmotivadas, negativismo u oposicionismo, paraquinesias (descargas motoras imprevisibles), ecomimias, catalepsias, hasta llegar a veces a la catatonia traducida en una inmovilidad global acompaada de mutismo, que dan a su comportamiento general un aspecto extrao o bizarro El sndrome paranodeo o delirante De hallazgo frecuente en la clinica, pero a veces difcil de detectar por la reticencia o cautela del paciente a expresar el contenido de sus delirios. La observacin del paciente demuestra conciencia lcida y aptitudes cognitivas y afectivas relativamente indemnes, con un discurso formal poco desorganizado y sin aplanamiento afectivo. El delirio y las alucinaciones del paciente giran alrededor de temas de persecucin o grandeza. En el paciente esquizofrnico se nutren de fenmenos pseudoperceptivos tales como las alucinaciones auditivas llamadas veras por su caracteristica de darse en el contexto de conciencia lcida y sin mediacin de un estmulo que las justifique, ya sea en forma de ecos del pensamiento, o intra-psiquicos como sensaciones de pensamientos extraos introducidos en su propio cuerpo. Otros mecanismos frecuentes en el delirio del paciente esquizofrnico consisten en robo o adivinacin del pensamiento, comentarios de actos o pensamientos, pensamientos o actos impuestos, que pueden estar en el origen de conductas agresivas (auto o heteroagresivas). Otros mecanismos delirantes que a menudo se encuentran presentes son las intuiciones u ocurrencias o interpretaciones delirantes, o en el comienzo del cuadro, una sensacin de extraeza ambiental, frecuentemente con un sentimiento de hostilidad hacia su persona. Mas raramente en la actualidad, se presentan alucinaciones corporales o cenestsicas, con la sensacin de ser intervenido, disuelto, manipulado en sus organos. 1) Temas del delirio: en general, pueden abarcar diferentes tpicos de la vida del paciente, destacando estadsticamente los relacionados con persecucin, religiosos, erotomanicos, de auto- referencia. En la fase adolescente, se

observan con frecuencia los vinculados a temas corporales (dismorfobias, identitarios), vividos con intensa angustia o perplejidad. 2) Organizacin del delirio: la psicopatologa del delirio esquizofrnico que forma parte de las alteraciones de la estructura o contenido del pensamiento se presenta en un sujeto lcido de conciencia en la forma de convicciones disparatadas, no estructurados o no sistematizadas, con fallas lgicas, que desplazan a los juicios normales y con capacidad de influir sobre la conducta del individuo en forma concordante o discordante. Se diferencia del delirio deliroide propio de los desarrollos paranoicos comprensibles en el sentido de Jaspers, porque ste crece sobre un estado anmico previo en el sujeto (por ejemplo sobrevalorado o desconfiado) y tiene forma y estructura sistematizada, lgica y coherente.

El sndrome catatnico

Caracterizado por un sindrome psicomotor de pasividad y perdida de iniciativa, negativismo, y eventualmente con accesos paroxisticos en una evolucion alternante. El negativismo es un trastorno del comportamiento maracdo por actitudes oposicionistas activas y paradojicas que puede incluir desde el rechazo a alimentarse o a obedecer cualqiuier solicitud, incluso las banales. La catalepsia es una perdida de la iniciativa motriz con rigidez muscular particular que permite la induccion de conductas impuestas como dejar al paciente con uno o los dos barzos levantados por largo tiempo, etc, fenomeno conocido como flexibilidad cerea. Tambien puede ocurrir lo contrario en la forma de resitencia a la mobilizacion pasiva con una hipertonia muy marcda que evoca una franca oposicion.

El sndrome autistico El autismo esquizofrnico es un particular estado del sujeto en el que ste se encuentra lejano de s como de los otros, revelando la ruptura de su vida psiquica. La discordancia ideo-afectiva que acompaa al retraimiento social pasivo del individuo, hacindolo ver lejano, distante, desinteresado por su mundo mas inmediato, como sumido en sus propias cavilaciones, indiferente a los otros, es lo propio de una austismo pobre por contraste con el autismo rico, propio de los enfermos delirantes o alucinados, que parecen vivir en un mundo mgico y propio, secreto e ilgico, poco comunicable y sin principio de realidad.

El concepto fue acuado por Bleuler quien entiende autismo como la predominancia de la esfera emocional y el aislamiento del paciente, como uno de los 3 pilares de la esquizofrenia, junto a la disociacin y la ambivalencia afectiva.

Formas clinicas de comienzo y hallazgos neurobiologicos en la primera fase de la ezquizofrenia Formes dbut brutal La bouffe dlirante aigu ( elle ne signe pas chaque fois une entre dans la schizophrnie)est la forme typique d'entre dans la maladie. D'autres lments font craindre une entre dans la schizophrnie comme l'tat dpressif atypique associ avec une anorexie, une asthnie, une insomnie et des troubles thymiques (ides noires, ides de mort, tristesse, dgot). Cet tat dpressif ne relve pas d'une structure nvrotique et n'entre pas non plus dans le cadre d'une psychose maniacodpressive. A la faveur de ce mode d'entre dans la schizophrnie on note :

1. des traits de caractre schizode :

o o o o o o o o o

Attitude de repli, avec un dsintrt relatif pour le monde extrieur (introversion). Fuite des contacts sociaux (peu ou pas d'amis). Gens timides et effacs. Incapacit exprimer leurs- Contact froid et distant. Incapacit prouver du plaisir. Intrt rduit pour la sexualit. Vie imaginaire souvent intense mais bizarre, avec un grand intrt pour les choses abstraites. Indiffrence aux normes et aux conventions sociales. L'adaptation sociale est possible mais restreinte. de l'humeur ;

2.une oscillation 3.un grand vide affectif. Formes dbut progressif

Les troubles peuvent s'installer progressivement sur des semaines, des mois, un an ou deux. Elle peut dbuter avec :
o o o

une baisse de rendement intellectuel ; un chec inhabituel un examen ; l'abandon d'un emploi ;

o o o o o o o o

la modification du caractre : tendance l'isolement, hostilit envers le milieu familial ; le renoncement aux activits de loisir sans justificatif ; l'engagement pour des choses marginales : sotrisme, occultisme ; l'apparition de troubles d'allure nvrotique : anxit, angoisse floue ; une symptomatologie obsessionnelle : sujet assig de doutes ; une symptomatologie hystrique ; des plaintes ; une dysmorphophobie.

Puede la esquizofrenia ser diagnsticada en una fase prodrmica? Esta pregunta surge a comienzos del siglo XXI marcada por la esperanza de actuar proactivamente en trminos de atenuar la sintomatologa o prevenir la aparicin clnica de la enfermedad, o limitar la futura severidad de los sintomas, cronicidad o daos cognitivos y sociales en el paciente. El concepto de prdromo en sicopatologa no ha sido definido para la esquizofrenia, pero podra referirse al cambio experimentado por un sujeto desde una personalidad prmorbida a la aparicin de sintomas clinicos francos. Algunos autores describen un conjunto de sntomas inespecficos o negativos que son continuados por leves o medianos sntomas positivos, acompaados de malestar y desgano (Hafner y al., 1998). Los rasgos de una personalidad esquizotpica y un signo aislado de un EQZ sin malestar o desgano no parecen ser prdromos sin que se rena un conjunto mas coherente de manifestaciones que se pueda correlacionar con un alto riesgo de convertirse en un cuadro clnico establecido. Yung y Mc Gorry (1996) desarrollaron criterios de alto riesgo clnico para identificar un trastorno psictico en un futuro cercano. Dentro de estos criterios aparece relevante un declive funcional y un rasgo gentico que pueda corresponder a un trastorno esquizotpico de personalidad, ser pariente en primer grado de un paciente esquizofrnico o presentar sintomatologa psictica sin que se cumplan los criterios necesarios para considerarlos perteneciente al criterio A de la definicin de psicosis esquizofrnica como lo exige el DSM IV-TR, dada su insuficiente duracin o severidad. Otra forma de documentar un prdromo es la de identificar sntomas bsicos, entendiendo por ello, a semejanza de los sntomas residuales de la enfermedad, sntomas subclnicos pero perturbadores que implican distorsiones del pensamiento, habla, percepcin, afecto, etc., susceptibles de ser reconocidos mediante la aplicacin de una Escala de Anlisis como la escala de Bonn, desarrollada por Klosterkotter y col., 1997, 2001, que puede predecir en presencia de sntomas bsicos la aparicin de una esquizofrenia con posterioridad en 70% de los casos. Entre los factores predictores que se han revelado mas exactos, se encuentran los que semejan a los sntomas positivos, tales como contenidos inusuales de pensamientos, suspicacia o ideas paranoides o bizarras, historia de consumo de drogas (marihuana, alcohol). En los estudios cognitivos aparecen como relvantes dficits en memoria de trabajo, espacial, fluencia verbal, declarativa verbal. El funcionamiento social empobrecido bajo 50 en el GAF se ha asociado a la aparicion

de psicosis en los 12 meses siguientes, hasta el extremo que ste hallazgo es indiferente a que se encuentra en pacientes jvenes con una psicosis en curso. Paralelamente al uso de instrumentos neuropsicolgicos como la escala mencionada, se han usado otros instrumentos propios de la imaginologa cerebral. Los estudios de imgenes cerebrales han demostrado consistentemente las anomalas cerebrales en pacientes esquizofrnicos, implicando disminucin del volumen de la substancia gris y aumento de volumen del tercer ventrculo y de los ventrculos laterales, asociado a la aparicin infantil del cuadro y a su desarrollo crnico. El estudio sugiere que esta anomala es progresiva, ya que aparece en el primer ao de tratamiento en alrededor de un 3 % de pacientes, es decir, desde comienzos de la enfermedad, en relacion al uso de antipsicticos y como expresin de un proceso degenerativo (Cahn, W y col., Arch Gen Psych. 2002; 59, 10021010). La investigacin neurobiolgica ha avanzado en la comprensin de la sintomatologa de comienzo del tratorno esquizofrnico. Howes, O and col. (Arch Gen Psychiatry, 2009; 66 (1): 13-20, encontr que la captacin de F-dopa era elevada en pacientes con prdromos sintomticos de EQZ en niveles intermedios con respecto a aquellos que ya haban desarrollado la enfermedad. Estos datos sugieren que los niveles aumentados de actividad dopaminrgica subcortical a nivel de estriatal estn siempre presente en los pacientes antes de que aparezca clnicamente el cuadro clnico, hallazgo consistente con el rol etiolgico de la dopamina en la esquizofrenia y con la posibilidad de atenuar los sntomas prodrmicos y la aparicion de la enfermedad con el tratamiento neurolptico precoz.

vi)

El cuadro clnico: criterios diagnsticos de la esquizofrenia segn el DSM IV TR

De acuerdo al sistema clasificatorio de las enfermedades de la APA, DSM-IV TR, se deben cumplir rigurosamente varios criterios (A, B, C, D, E, F) para establecer el diagnostico de sta enfermedad.

A.- Sntomas caracteristicos De las 5 formas clinicas mencionadas en el criterio A se requiere la presencia de 2 mas elementos clinicos que se analizaran, durante un tiempo significativo de al menos un mes o menos, cuando ellos han respondido favorablemente a un tratamiento medico para establecer la presuncin de enfermedad. Sin embargo, la duracion de la evolucion necesaria para el diagnostico es objeto de controversias, ya que existen trastornos psicoticos breves cuya dificultad para diferenciarlos de una forma de comienzo de la esquizofrenia es imposible si no se atiende a un periodo prudencial de 1 mes. Por lo tanto, la naturaleza diferente de ambos trastornos deben llevarnos a la consideracin de un episodio psicotico breve sobre todo cuando nos enfrentamos a un paciente delirante agudo en que no existen otros fenmenos clinicos que evoquen una desorganizacin psiquica propia de un cuadro esquizofrenico o cuando existan factores desencadenantes, alteraciones del animo o antecedentes familiares de trastornos del animo. Los 4 primeros criterios clinicos sealados en la letra A.- son sntomas positivos, calificados asi porque su ausencia como fenomeno clinico en el sujeto normal es la regla, mientras que el quinto criterio clinico caracteristico requerido es o son los sntomas negativos, que representa una funcion normal atenuada o ausente en el sujeto enfermo. A.1.- Ideas delirantes La definicin clasica del DSM IV de delirio es la creencia errnea que implica interpretaciones falsas de percepciones o de experiencias del sujeto, con elementos tematicos variados, de los cuales el mas frecuente estadsticamente es el tema persecutorio, seguido del de autorreferencia. La diferenciacin entre una idea delirante de una obsesiva o una reiterativamente angustiosa en torno a un hecho preocupante para un sujeto puede ser difcil y se debe atender al grado de conviccin y a la forma comunicativa de la persona examinada. K. Jaspers le otorga las caracteristicas de ser apodicticas, es decir, de certeza subjetiva absoluta y afirmadas con conviccin extraordinaria, no influenciables por conclusiones cientificas o por la experiencia, y de contenidos imposibles, caracteristicas que se resumen en el concepto de incomprensibilidad. Roa agrega otras caracteristicas que acentuan un grado de contradiccin flagrante entre la expresin, conducta y el contenido de dichas ideas: tendencia a guardarlas en la intimidad, argumentacin escasamente coordinada, pasividad de la conducta frente a la gravedad de lo revelado, no verificacin en base a coincidencias. Caractersticamente tambien, las ideas delirantes pueden tener como objeto de su contenido el si mismo o el entorno del sujeto. En el primer caso, el contenido de la idea delirante puede estar referida a una relacion particular del enfermo con una divinidad o con seres sobrenaturales, lo que traduce un trastorno de la vivencia de la realidad propia como en el caso de los delirios misticos o religiosos o en los delirios de transformacin o metamorfosis delirante, donde el contenido de la idea esta referida a la transformacin de la vivencia de identidad del propio yo, y en el segundo caso, el contenido de la idea esta referida a la exterioridad del yo, como en el caso de la desrealizacion delirante donde el paciente experimenta la sensacin de extraeza que proviene de un

entorno cargado de significaciones perturbadoras, lo cual es vivido con un estado afectivo de perplejidad o temor indescifrable por el paciente. El DSM IV-TR agrega que cuando las ideas delirantes son bizarras, es decir, cuando expresan una idea abiertamente absurda e incomprensible que desafia toda lgica, incluyendose dentro de esta denominacin las ideas delirantes de influencia que revela un trastorno de la significacin de vivencias propias en relacion a los lmites del yo, sta sola manifestacin psicopatologica es suficiente para cumplir con las condiciones del criterio A. En el sndrome de influencia, el paciente tiene la sensacion de ser manejado desde fuera por una fuerza extraa que se instala dentro de l, obligandolo o inhibiendolo en sus actos, gestos o pensamientos, fuerza extraa que opera de diversas maneras, brujera, rayos laser, fluidos magneticos, aparatos captadores del pensamiento a la forma de radares o incluso de extraos que los manipulan por fuerza telepaticas o hipnticas. Dependiendo de un estado afectivo exaltado o deprimido o de un compromiso o perturbacin de conciencia, las ideas delirantes adquieren el nombre de deliroides o deliriosas, pero ellas conducen a configuraciones diagnosticas distintas a la esquizofrenia. A.2.- Alucinaciones. Son fenmenos psicopatolgicos que corresponden a trastornos de la percepcin y pueden comprender todos los organos sensoriales. En la patologa esquizofrnica se encuentra con frecuencia mayor las del rgano auditivo, y en este caso, cuando el paciente refiere voces en nmero de dos o mas que comentan sus acciones o gestos, tienen el mismo alcance diagnostico de las ideas bizarras. Desde el punto de vista de la psicopatologa clasica, las alucinaciones son percepciones sin objeto real y cumplen los requisitos descritos por Jaspers para las percepciopnes: corporeidad, objetividad, nitidez y frescura sensorial. Se agregan las caracteristicas de constancia, retencion facil, independencia de la voluntad y admisin pasiva. Mazzarelli discute la caracteristica de frescura sensorial, ya que sta no siempre se da, pudiendo ser las alucinaciones, en ocasiones fenmenos nebulosos y vagos, o solo ser percibidas como cuchicheos inintelligibles. De acuerdo a la claridad de conciencia o no en que se den, reciben el nombre de alucinacin vera o alucinosis, en que el paciente, aun comprometido de conciencia, no otorga al fenmeno ninguna interpretacin delirante y reconoce una causalidad morbida en su origen, generalmente de origen txico (alcoholismo por ej). Un ordenamiento importante por su relevancia psicopatologica, es aquel que las estudia segn el organo sensorial comprometido y pueden ser simples fenmenos elementales (acfenos) o ms complejas (quemaduras). Se reconocen: a) b) c) d) e) f) g) alucinaciones auditivas: alucinaciones visuales alucinaciones olfativas alucinaciones gustativas alucinaciones tctiles alucinaciones cenestsicas alucinaciones cinticas

A.3.- Discurso desorganizado El paciente presenta distorsiones en el lenguaje hablado y en la comunicacin con los otros, por lo que una conversacin para entender lo que le ocurre es difcil o imposible. A la base de ste fenmeno se encuentra un pensamiento desorganizado, trastornos del curso formal y la laxitud en las asociaciones, fenmenos de los cuales los sujetos no tiene autocrtica. En el DSM IV-TR se insiste fundamentalmente en las distorsiones del lenguaje mas que en las del pensamiento, como expresin de un fenmeno psicopatologico positivo perceptible clnicamente por los dichos del paciente, que traduce las variadas formas que puede adquirir la desorganizacin del lenguaje que la sicopatologa clasica recoge en el capitulo de trastornos del pensamiento (Capponi, R. Sicopatologa y Semiologia Psiquitrica, Ed. Universitaria, Santiago, 7 Ed. 2002, pp. 92-100). Los fenmenos mas comunes observables en los pacientes esquizofrnicos son el lenguaje laxo o con prdida de los nexos asociativos, que traduce un pensamiento disgregado, que Bleuler atribuye a un estilo de pensamiento que no esta al servicio de una idea rectora, sino que a causalidades insolitas, o a conjunto de ideas sobredeterminadas afectivamente que influyen en el contenido del pensamiento, o las meras casualidades, o a la semejanzas de sonidos. Roa destaca que lo que el paciente dice disgregadamente no dice relacion con contenidos de verdad o falsedad, sino a la manera de ordenar sus pensamientos y su secuencia logica en relacion a la continuidad temporal de su expresin, a la vivencia de su espontaneidad e impronta personal, a la facilidad o dificultad en su gestacion, condiciones en las que influyen variados fenmenos tales como los neologismos o invenciones de palabras con significaciones especiales para el paciente, las esterotipias verbales, las pararespuestas, la tendencia a la perseveracion, el gusto por el lenguaje metaforico, simbolico o enigmtico, el pensamiento ambivalente, entre otros. En la medida que se encuentra clnicamente desorganizaciones moderadas del discurso, los fenmenos psicopatologicos de base pueden pasar desapercibidos, ya que no interfieren gravemente el lenguaje y la comunicacin intersubjetiva. Lo mismo puede ocurrir en las fases de comienzo y residuales de la enfermedad, donde en general, la desaorganizacion del lenguaje es menor que en los periodos de estado, revelando solo pequeos defectos. Importante es diferenciar clnicamente un pensamiento disgregado que se traduce en un discurso desorganizado, dado por la irrupcin de ideas secundarias que obstaculizan la direccion del pensamiento hacia una meta logica determinada que en un grado extremo puede expresarse como una ensalada de palabras, del pensamiento incoherente en que el paciente se expresa desorganizadamente saltando de un tema a otro, dando la impresin que el discurso pierde el sentido de conjunto A.4.- Comportamiento desorganizado. Muchos pacientes tiene esta forma de presentacin caracterzada por sntomas de desorganizacin conductual y cognitiva que se traducen en pensamientos guiados por coincidencias asociativas que contribuyen a la disgregacin del pensamiento. El sntoma clsico del trastorno formal del pensamiento es la laxitud de ste que puede llegar hasta una forma extrema de pensamiento ininteligible que se conoce con el nombre de ensalada de palabras en la psicopatologa clsica caracterizado por un patrn incoherente de palabras sin relacin lgica entre ellas. A estas manifestaciones clsica se agrega los neologismos, o palabras creadas por el propio paciente, el descarrilamiento del

lenguaje, etc que contribuye a darle fisonomia a esta forma de presentacin del cuadro clinico A.5- Sntomas negativos: aplanamiento afectivo, alogia o perdida de la voluntad

3.- Epidemiologa y Causas de la EQZ (factores de riesgo y teoras etiopatolgicas de la enfermedad) Los conceptos bsicos en epidemiologa son prevalencia e incidencia. Por prevalencia se entiende el nmero de casos de una patologa que se observan en un perodo definido de la vida en una poblacin dada. La incidencia en cambio, es un concepto que se refiere al nmero de casos nuevos que aparecen en una poblacin en un tiempo definido (generalmente un ao). Pese a las dificultades que presenta la enfermedad esquizofrnica para la investigacin epidemiologica (sndrome multicausal y heterogneo, gran variabilidad en su conceptualizacin desde la demencia precoz de Morel, reconsiderada por Kraepelin hasta nuestros das, influencia de diferentes sistemas clasificatorios o de diagnstico empleados para designar el caso), existe consenso entre los investigadores que la enfermedad tiene una prevalencia en la poblacin mundial de alrededor de 1%, con una distribucin entre 0,2% y 1,5% (Ho, Black y Andreasen, 2003). La incidencia, que se calcula habitualmente a partir de las admisiones en rgimen hospitalizado, y en un anlisis de una serie de estudios entre los aos 1965 y 2001 en mas de 30 pases, permiti concluir que era de 0,15 por mil, con diferencias entre pases desarollados y en vas de desarrollo, explicables por diferente nivel de acceso a los cuidados mdicos y aproximaciones sociales a la enfermedad (McGrath y cols, 2004). Diferencias de incidencia de esquizofrenia se observa tambin entre los sexos: la probabilidad de aparicin de la enfermedad (alrededor de la adolescencia) disminuye en el hombre con el paso de los aos, lo que no impide que aparezca en forma tarda, mientras que la edad media de aparicin en las mujeres es de 36 aos, con una mayor probabilidad de aparecer a edades tardas, en un esquema opuesto al gnero masculino, siendo, en el estudio de Ho, Black y Andreasen, 2003, el pronstico en las mujeres mas favorable que en los hombres. Los mismos autores sealan que el promedio de vida de stos pacientes es inferior a la poblacin general, en parte explicada por el ndice de suicidios mayor en sujetos afectados por una enfermedad crnica y con dificultades evidentes para adaptarse a la vida social, a menudo sin sostn social ni afectivo. Otros factores de fluctuacin puede ser el resultado de la influencia de factores culturales en el diagnstico de la enfermedad, a partir de las conocidas diferencias diagnsticas de la psiquiatra europea en relacin a la americana. En la actualidad, los sistemas de clasificacin criteriolgicos, DSM IV-TR y el CIE de la OMS, en conjunto con las entrevistas estandarizadas y las Escalas y Cuestionarios (Inventarios Generales y Escalas especficas) son instrumentos que han tendido a homogeneizar los estudios a nivel internacional y a hacer mas vlidas y fiables sus conclusiones. Por otro lado, el desarrollo de la Epidemiologa Analtica que estudia los factores de riesgo, ha contribuido a formular hiptesis causales susceptibles de aclarar la

etiopatogenia de los trastornos mentales, aunque debemos decir que la interpretacin de correlaciones estadsticas entre la frecuencia de un trastorno y las diversas variables estudiadas, sean estas socio-econmicas, psicolgicas, incluidas las biolgicas, no es suficiente para establecer un verdadero vnculo causal, dada la naturaleza mulifactorial de la patologa psiquiatrica, lo que es muy cierto en el caso de la esquizofrenia. Asimismo, la epidemiologa psiquitrica cuenta con metodos de evaluacin de tcnicas de tratamiento y de prevencin que ofrecen la posibilidad de mejorar la eficacia de la eleccin teraputica y hacer mas eficientes los servicios de salud mental, aunque debamos reconocer que no todos estos mtodos sean generalmente aceptados en Psiquiatra, dado el hecho de que el individuo enfermo no es exactamente la media estadstica como lo piensan los economistas de la salud. Factores de riesgo y teoras de la EQZ Se han formulado varias hiptesis causales basadas en la epidemiologa y la discriminacin de factores de riesgos que permite estructurar su estudio etiopatognico: La etiologa es mltiple. La esquizofrenia es una enfermedad que se ha desarrollado ms o menos uniformemente desde hace siglos. Esto ha hecho pensar a los investigadores que no est en relacin con un tiempo histrico o un lugar determinado, sugiriendo que la influencia de muchos factores pueda conducir a una via comn que sera la expresin clnica de la enfermedad La patofisiologa de la enfermedad se debe a un anormal desarrollo de la regulacin y expresin neuronal. La diferencia con las enfermedades degenerativas reside en que en la esquizofrenia no se observan marcadores de muerte cerebral o gliosis, lo que induce a pensar que el trastorno reside ms bien en la maduracin y desarrollo de los procesos cerebrales. La enfermedad es producto de la conectividad neuronal defectuosa. La moderna imaginera cerebral ha permitiendo identificar distintas reas cerebrales tales como la corteza frontal, corteza temporal, tlamo, complejo del hipocampo, ganglios basales, cerebelo, etc., comprometidas, lo que sugiere que la patologa no se produce por una disfuncin en un rea especfica, sino mas bien por disfunciones de circuitos cerebrales o sistemas de neurotrasmisores a lo largo y ancho del cerebro humano. El fenotipo o cuadro clnico de la enfermedad es definido por un metaproceso ms que por los sntomas clnicos. La va final o punto de convergencia de varios factores etiolgicos sera la que define el cuadro clnico, como sucedera con el cncer. La disregulacin celular es al cncer como la disregulacin de los procesos de informacin cerebral es a la esquizofrenia La enfermedad tiene un curso que comienza generalemente en la adolescencia o temprano en la vida adulta, se prolonga toda la vida y tiene slo ocasionalmente una recuperacin. La sintomatologa es ms marcada en los primeros aos y se acompaa de dficits importantes en la vida social, laboral y afectiva del sujeto. La importancia de un diagnstico y tratamiento precoz se considera bsicos para el futuro del paciente

Factores de riesgo Gentica En la actualidad, est fuera de toda duda que los genes son responsables de la vulnerabilidad de algunos individuos a desarrollar una esquizofrenia. Esta influencia no es de un solo gen sino de conjunto de muchos, en interaccin compleja y no del todo conocida hasta hoy. En efecto, investigaciones recientes en este campo, confirman las primeras apreciaciones de Kallmann, quien examin familias de esquizofrnicos en la dcada de los aos 30 del siglo pasado y constat que a mayor severidad del cuadro clnico en un padre, mayores posibilidades de desarrollo de esta enfermedad exista en su descendencia, encontrando, adems un desarrollo de todas las formas de la enfermedad en una misma familia. Gottessman y Schields (1982), sostienen que del riesgo general de la poblacin a padecer esquizofrenia, ste se multiplica por 10 en los parientes de primer grado del paciente, siendo mas elevada para hermanos y hermanas (13%) que para sus hijos (10%) o padres (6%), explicando las diferencias entre colaterales y ascendientes de primer grado por la menor paternidad de los pacientes esquizofrnicos. Las cifras varan dependiendo del nmero de individuos de una misma familia y en funcin de la severidad del cuadro clnico, como ocurre con la recurrencia del 21% en hijos de padres hebefrnicos por relacin a solo 10% en hijos de padres paranoides, subtipo del cuadro clnico mas benigno. El riesgo gentico de padecer la enfermedad se acrecienta si los 2 padres son esquizofrnicos, caso en que los hijos tienen el 46% de posibilidades de tambin serlo. En contraste con stos hallazgos para los parientes de primer grado, los parientes de segundo grado (nietos, o tos por ejemplo) solo tiene un 3% de riesgo de padecer una esquizofrenia, con lo Gottessmann (1991) concluye que el riesgo de desarrollar esquizofrenia es proporcional con el nmero de genes compartidos que un individuo tiene con el paciente de referencia. Estudios posteriores a los indicados muestran cifras inferiores a las sealadas (Maier y col, 2002), seguramente infludas por los criterios mas restrictivos del DSM IV para el diagnstico en relacin a los mas subjetivos de pocas pasadas (5% para los parientes de primer grado, 3,1% para los de segundo grado). Pero, en todos los trabajos se insiste sobre el riesgo de recurrencia de la enfermedad como una variable directa de la carga gentica familiar, que se traduce en ms sujetos enfermos en una familia, mayor proximidad en el grado familiar y mayor gravedad del cuadro clnico en los sujetos afectados. Los estudios que vinculan esquizofrenia y gentica son abundantes en la ltima dcada y si bien no dejan lugar a dudas de su relacin, no son suficientes para demostrar la implicacin de los factores genticos en la etiologa de la enfermedad. Por ello, los estudios realizados en gemelos e hijos de stos, son fundamentales para poner en evidencia su real alcance y la influencia de otros factores etiopatognicos en el trastorno. Estos trabajos de investigacin se basan en la comparacin de las tasas de concordancia para la enfermedad entre gemelos monocigotos (que comparten el 100% de su dotacin gentica y medioambiente) y gemelos dicigotos que comparten el 100% de su medioambiente pero slo el 50% de sus genes, de lo que surgen las hiptesis bsicas: 1) si los genes son los nicos responsables del trastorno: si se comparte el 100% de los genes, el otro gemelo autntico tambin ser esquizofrnico, si se comparte el 50% de los genes, el otro gemelo tendr 50% de ser esquizofrnico; 2) si el medio ambiente fuera el nico factor responsable de la enfermedad, no deberan existir diferencias entre los gemelos mono y di-cigotos. El estudio de David Rosenthal que estudi

a 4 gemelas idnticas que crecieron en el mismo ambiente familiar disfuncional siendo las 4 enfermas esquizofrnicas, demostr que las relaciones de la gentica y el ambiente en la gnesis de la esquizofrenia no son simples ni evidentes: compartiendo dotacin gentica y ambiente, cada una de las hermanas tuvo una evolucin, edad de aparicin, sntomas y consecuencias distintas, lo que habla de otros factores intervinientes tales como las vivencias fsicas o psicolgicas individuales en el desarrollo de la enfermedad. En efecto, una revision reciente de la literatura demuestra que las tasas de concordancia intrapares para los monocigotos alcanza cifras entre 41 y 65% en relacin a cifras entre 0 y 28% para di-cigotos, lo que significa que la verdad de la influencia gentica en la esquizofrenia es mediana, pero mas importante para los que comparten el mismo material gentico que para los que no, confirmndose la importancia de los factores medioambientales, los cuales tambin son importantes en la vida intrauterina para los gemelares que se ven perturbados en su crecimiento o en su mayor mortalidad perinatal. Craddock, N (Phenotypic and genetic complexity of psychosis, 2008) y al., comenta que a medida que la potencialidad de las tcnicas de gentica molecular permiten conocer las variaciones del ADN que inluencian la susceptibilidad gentica de las enfermedades, las psicosis y especialmente la esquizofrenia se revela como una enfermedad gentica y clnicamente compleja, es decir, una enfermedad que no sigue patrones mendelianos de trasmisin, que amerita ser investigada con tcnicas adecuadas para poder identificar las variantes de riesgos que pueden influir en la gnesis de la enfermedad. En este proceso de conocimiento, la heterogeneidad sintomtica, las clasificaciones diagnsticas y la identificacin clnica de fenotipos que reflejen la entidad biolgica gentica subyacente, se han revelado como las mayores limitaciones. De acuerdo a McClellan y al., la esquizofrenia es el tpico caso de una enfermedad familiar que responde a un modelo gentico de trasmisin de tipo multifactorial que implica la accin de mltiples genes en interrelacin con el medio ambiente. Un mecanismo consiste en mutaciones raras con efectos pequeos a largo plazo, aunque no se descartan anormalidades cromosmicas en la enfermedad. Los estudios en gentica molecular de los ltimos aos son consistentes con el riesgo aportado por mltiples alelos de efectos modestos, como los identificados DTNBP (Straub y al., 2002; Williams y al., 2005), neuregulina 1 (NRG1), (Stefansson y al., 2002; Tosato y al., 2005; Munafo y al., 2006) and D-amino acid oxidase activator (DAOA, G72/G30; Chumakov et al, 2002; Detera-Wadleigh & McMahon, 2006). Los patrones de efecto de la carga gentica basados en pequeos cambios son consistentes con los encontrados en estudios de enfermedades complejas no psiquitricas (Todd, 2006). En contraste, los raros alelos largos de efectos prolongados identificados inequvocamente incrementan el riesgo dramticamente por la va de produccin de aberraciones cromosmicas (Craddock et al, 2005). Como se aprecia, la esquizofrenia es una enfermedad genticamente compleja donde coexisten modelos genticos de variantes raras con efectos prolongados y variantes comunes con efectos pequeos que contribuyen a influenciar la suceptibilidad de la enfermedad o a su expresin genotpica. La fisiopatologa de este proceso es todava incompletamente comprendido, pero los investigadores reconocen definiciones fenotpicas como ocurre con

la glicemia como medicin de la diabetes que se usan en psiquiatra como marcadores para el reconocimiento tanto de la esquizofrenia como los TB, como es por ejemplo el gene activante de la D-amino acido oxidasa (DAOA) (Chumakov et al, 2002; Hattori et al, 2003. (Jablensky, 2006; Braff et al, 2007). Otros investigadores piensan que existen beneficios tericos importantes en el uso de endofenotipos como intermediarios del fenotipo como las neuroimgenes o los test cognitivos para la definicin de grupos homogneos de pacientes o para tener un acceso mas directo a a las anormalidades que median los efectos de los genes en psicopatologa, aunque estas aproximaciones al problema no estn excentas de dificultades (Owen et al, 2005). Por ello una clnica o una psicopatologia efectiva es todava necesaria para caracterizar a los individuos, debindose avanzar en ambos campos metodolgicos como lo sugiere Berrios: el clnico descriptivo y el de los estudios genticos. En este ultimo campo, el avance ha sido sostenido. Una revisin sumaria tanto del uso del los endofenotipos como de los estudios en cognicin servirn para tener una visin panormica de los logros de la primera dcada del siglo XXI. Los endofenotipos en la esquizofrenia Los endofenotipos son ciertas medidas neuroqumicas, fisiolgicas o metablicas que son productos de la accin de muchos genes en interaccin con el ambiente que se expresan subyacentemente en la fisiopatologa del cuadro, como marcadores de vulnerabilidad. Para cumplir con esta funcin deben tener ciertos requisitos de estabilidad, heredibilidad, especificidad y replicabilidad; asi por ejemplo, si existe una especfica evidencia de que una determinada dimensin neurocognitiva o neurofisiolgica est en relacin con una especfica anormalidad molecular de la esquizofrenia, y se presenta estable y permanentemente en los sujetos no afectados por la enfermedad, estamos enfrente de un endofenotipo que sera expresin de una vulnerabilidad o riesgo probabilstico de hacer una enfermedad clnica. Los endofenotipos tienen una cercania mayor a la gentica que a la clinica de la esquizofrenia, por lo tanto, estn estrechamente vinculados a la herencia de factores de riesgo y a la comprensin de las bases genticas de la enfermedad, contexto en el cual, el poliformismo de un solo nucletido induce anormalidades en dominios endofenotipicos distintos como la neurocognicin, desarrollo neuronal, metabolismo y neurofisiologa. Para una enfermedad mendeliana como la de Huntington los cambios en el cdigo gentico de las secuencias de los aminocidos producen cambios en la fisiologa alterando la integridad neurofuncional del individuo, cambios no obvios en la esquizofrenia, donde interactan factores ambientales con los genticos y epigenticos. Para encontrar los endofenotipos genticos en la esquizofrenia, los investigadores han utilizado un mtodo que usa simultneamente herramientas neurobiolgicas y de la gentica molecular para identificar las funciones cerebrales especficas que pueden ser causadas por el polimorfismo gentico anormal. La racionalidad del investigador asume que all donde existe una discreta anormalidad gentica asociada con esquizofrenia, cada una de ellas puede producir un cambio especfico en una protena que se refleja en una discreta anormalidad funcional, de tal modo que si hay varios genes anormales, la funcin anormal de cada uno de ellos podra ser identificable. En este camino, un primer paso comienza con los estudios que vinculan la esquizofrenia con dficits especficos, para

despus identificar la evidencia de la segregacin y la heredibilidad en los cercanos no afectados clnicamente, ya que el anlisis gentico depende de la correlacion genotipoendofentotipo dentro del pedigre individual de los miembros de una familia. Pero, esta bsqueda es compleja, porque no existe ningn criterio a priori para decidir si un elemento particular de la esquizofrernia refleja el efecto de un solo gene. Marcadores y endofenotipos genticos en la Esquizofrenia Ante la conclusin inequvoca de que la esquizofrenia es una enfermedad que tiene una gran determinacin de tipo gentico o biolgico, la pregunta que subsiste es cual es su modo de trasmisin, ya que la alteracin de un solo gen se revela imposible para explicar su heterogeneidad? Varios autores coinciden en que el efecto mltiple o asociativo de genes se revela como importante para estos efectos (Marikangas, Risch, 2003). La metodologa de investigacin es simple y consiste en evaluar simultneamente otras caracteristicas hereditarias en sujetos cuya familia presenta la ocurrencia de una patologa psiquiatrica. De sta manera se conocen marcadores genticos que tiene una localizacin conocida en un gene, que si aparecen vinculados a la aparicin de una patologa, sugiere la proximidad entre el gene responsable de la enfermedad y el marcador situados en un mismo cromosoma. Esta es la base de un modelo de investigacin que tendr gran desarrollo en los aos venideros en funcin de nuevas orientaciones teraputicas basada en la genmica. Con stas tecnicas, en la revisin de Waterwort y cols., (2002) se ha encontrado que las regiones 1q21-22, 5p14-13, 5q21-33, 8p21-22, 10p11-15 y 13q32 deben contener los genes que estan implicados en la aparicin de la esquizofrenia. Un estudio de Escamilla, M. (The Am J. of Psy, 2009, 166:442-449) encontr un locus del gen de la esquizofrenia en el cromosoma 17 q21 en un nuevo conjunto de familias de ascendencia mexicana y de Amrica Central, sugiriendo que la ubicacin de los locus en diversos cromosomas corresponde a las diferencias tnicas. Entre los marcadores para la esquizofrenia estudiados en los ltimos aos, el del movimiento ocular focalizado sobre un objeto en movimiento regular es el que mas se conoce. Se encuentra en la mitad de los parientes de primer grado de pacientes esquizofrnicos y tambin, en ausencia de vnculo familiar con esquizofrnicos, en individuos que presentan un trastorno o rasgos de personalidad esquizotpico. Consiste en la deficiente capacidad que tienen estos pacientes o un nmero importante de ellos para seguir el movimiento pendular montono de un objeto en relacin a individuos normales, en forma independiente a la medicacin o institucionalizacin (Campion, Thibaut y cols., 1992). Hasta ahora, adems de los marcadores, se han podido identificar algunos endofenotipos genticos. Ejemplo se stos son: XXXXXXXXXXXXXXXXXXXXX Las ventajas que ofrece esta nueva forma de aproximarse al fenmeno psictico esquizofrnico es que con el tiempo cada uno de los grupos clnicamente diferenciados de pacientes puede ser eventualemnte caracterizados endofenotpicamente, con lo cual llegar a conocerse especficamente la arquitectura gentica y neurofisiolgica subyacente con obvias repercusiones en sus pobilidades de tratamiento diferenciado para cada uno de esos grupos clnicamente diferenciados (psiquiatra personalizada).

En resumen, las ventajas potenciales de este mtodo son: a) la comprensin de las variables fisiolgicas y neurales de los endofenotipos puede permitir un conocimiento directo de la actividad sinptica y otros mecanismos neurobiolgicos para llegar al conocimiento de las bases genticas de la enfermedad, 2) la estrategia endofenotpica es importante para cuantificar los anlisis de ligamiento gentico, con mas rendimiento que la clnica, 3) la comprensin biolgica sistemtica del endofenotipo facilita el conocimiento e identificacin de mas genes candidato de la enfermedad. Como se comprender, esto implica reducir la heterogeneidad y complejidad del estudio de trastornos, intrnsicamente complejos y mulifactoriales y adems, propendr a facilitar diagnsticos precisos en etapas tempranas de la enfermedad, e incluso facilitar la identificacin de individuos con alto riesgo y subgrupos patolgicos, posibilitando tratamientos precoces e intervenciones preventivas.

Eventos pre y paranatales como factores de riesgo Eventos prenatales y de alrededor del nacimiento han sido profusamente investigados en el ltimo tiempo en su relacin con la esquizofrenia, sobre todo los ocurridos en el segundo trimestre del embarazo, constituyndose en factores de riesgo que si bien no tienen el poder predicitivo de lo gentico, si explican algunas variaciones significativas. Entre estos eventos destaca la exposicin a las hambrunas, materiales radiactivos y enfermedades virales maternas, toxemia e hipoxia, nacimientos en pocas invernales, condiciones todas que deben mezclarse con otros factores de riesgo y factores precipitantes para posibilitar la emergencia de la enfermedad. Las hiptesis consideradas sobre la etiologa infecciosa o viral de la esquizofrenia parte de la constatacin de variaciones estacionales del nacimiento en pacientes cuya enfermedad se manifest con posterioridad. En general, tales estudios llaman la atencin sobre el hecho de que el riesgo de desarrollar la enfermedad aumenta en sujetos expuestos a infecciones virales en el segundo trimestre del embarazo durante periodos de pandemia como la ocurrida en 1957, o en periodos de mayor concentracin de enfermedades virales, lo que ocurre habitualmente en invierno. Los estudios finlandeses de Machon y al. 2002 y de Mednick en 1994, ha precisado esos vnculos a nivel de poblaciones y de individuos, reforzado por Brown y al. 2004, que analizando los sueros con anticuerpos anti influenza conservados desde 1960 en adelante, demostr que la exposicin fetal en la primera mitad del embarazo aumentaba el riesgo de una esquizofrenia en la edad adulta posterior en 7 veces. El mecanismo de accin viral se explicara por las reacciones cruzadas entre anticuerpos virales y antgenos fetales o por consecuencias inespecficas a la infeccin donde la secrecin de citoquinas no puede excluirse. Nakamura y cols., ha encontrado virus Borna en varias regiones cerebrales en autopsias de individuos esquizofrnicos, relacionndolo con los trastornos en el desarrollo producido por un virus conocido por afectar la materia cerebral a travs de una reaccin inmune. Entre los factores especficos de infecciones prenatales implicadas en la etiologa de la esquizofrenia se encuentra la rubeola, que incrementa el riesgo en 10 a 20 veces en relacin a la poblacin normal. Un parsito como el Toxoplasma gondii, se asocia con un incremento relativo de 2,5 veces de la esquizofrenia, mientras que para el virus del herpes simple tipo 2 se han encontrado anticuerpos IgG maternales elevados para HS tipo 2 en sujetos que mas tarde desarrollaron

trastornos psicticos includa la esquizofrenia (Buka y al.), aunque despus no se pudieran replicar estos hallazgos. Los mecanismos mediante los cuales estas infecciones puedan llevar a una posterior esquizofrenia no han sido absolutamente definidos, pero recientes modelos animales sugieren fuertemente que la influenza por ejemplo, y la activacin inmunolgica tiene efectos sobre el cerebro fetal que aparecen concordantes con los hallazgos observados en la esquizofrenia. La asociacin entre esquizofrenia y segundo trimestre del embarazo son todava poco claras, ya que entre los muchos roles que juegan las citoquinas y especialmente la quemoquina en la fisiopatologa de la enfermedad, se encuentra la adherencia de neutrfilos a las clulas endoteliales y su asociacin con corioamionitis en nios nacidos de trmino, a su vez con una significativa correlacin de un elevado nivel de interleukinas en el suero materno y neonatal en el segundo trimestre del embarazo.

Factores de riesgo durante la niez y la adolescencia Varios factores de riesgo ambientales han sido mencionados como importantes en esta poca de la vida de los sujetos. Entre los ms prominentes destacaremos la relacin con el uso de la marihuana, (dada su uso extensivo y sus dudas sobre sus efectos patgenos), y el estrs y las emociones como factores precipitadores de la enfermedad. Caracteristicas psicolgicas y electrofisiolgicas de la esquizofrenia Disfunciones cognitivas La pobreza en el rendimiento en los test neuropsicolgicos en pacientes esquizofrnicos en relacin a los sujetos normales se explica tradicionalemnte por la va de consecuencias de la clnica esquizofrnica, hospitalizacin prolongada o comienzo precoz de la enfermedad. Actualmente se agrega a lo anterior, una segunda va explicativa que asocia especficamente un conjunto de dficits cognitivos de los pacientes a la fisiopatologa de la esquizofrenia. Las evidencias basadas en estudios de la ltima dcada del siglo XX y la primera del siglo XXI, que se examinan a continuacin, demuestran con claridad que la desviacin cognitiva entre los pacientes esquizofrnicos en relacin a la poblacin normal alcanza al 75 al 85%, presentando puntuaciones menores hasta en 19 puntos en promedio en los test de inteligencia, y anormalidades especficas en una serie de funciones neuropsicolgicas tales como la memoria de trabajo, atencin y funciones ejecutivas. Estas deficiencias se encuentran desde el primer episodio psictico y en pacientes que no han recibido medicamentacin neurolptica, en quienes Sakyn y al., document alteraciones en la atencin, abstraccin, memoria y aprendizaje. La atencin, como habilidad cognitiva especfica no es un contructo unitario pues incluye funciones de alerta, orientacin y control ejecutivo, bsica para mantenerse en estado de alerta, y se encuentra moderada o severamente comprometida en los individuos enfermos. Las funciones de abstraccin y ejecutivas han sido comnmente asimiliadas a las funciones del lbulo frontal, originado caractersticas clnica-fenomenologicas similares entre la esquizofrenia y los trastornos neurolgicos que comprometen esta rea cerebral tales como la abolicin de la voluntad, la

prdida del juicio social, la reduccin de la espontaneidad. Concepciones recientes incluyen sub-procesos entre las funciones ejecutivas relacionadas con redes de trabajo corticales que comprometen otras reas cerebrales que sustentan actividades complejas como la bsqueda de conocimientos alamacenados por largo tiempo, la planificacin y abstraccin, la automonitorizacin, la inhibicin de las respuestas inmediatas en post de la persecucin de objetivos de largo plazo. La memoria, a diferencia de lo crea Bleuler, tambin se encuentra detreriorada en la esquizofrenia. La memoria a largo plazo ha sido dividida en memoria declarativa y memoria no declarativa en base a sus caractersticas claves. La primera ha sido estudiada en la enfermedad y consistemente se ha encontrado un dficit en la memoria de eventos como memoria para hechos (memoria episdica y semntica respectivamente) (Cirello y al.) La segunda, memoria no declarativa vinculada al simple condicionamiento clsico, o parendizaje asociativo, aunque no ha sido el foco de los estudios, se presume relativamente preservada. La memoria de trabajo, dentro de la cual se distinguen dos tipos: verbal y visoespacial, es un sistema para almacenar temporalmente y manipular la informacin en la ejecucin de tareas cognitivas complejas como el aprendizaje, razonamiento y comprensin, y la rapidez con la cual las diferentes operaciones cognitivas se realizan estn deterioradas en los pacientes esquizofrnicos. Una explicacin para estos dficits cognitivos en la enfermedad es ser la consecuencia de la severidad de los sntomas asociada a factores como edad, educacin o duracin de la enfermedad, con una consistente evidencia que asocia los dficits cognitivos a los sntomas negativos de la enfermedad y, por el contrario, una dbil evidencia que los asocia a los sntomas postivos. Pero, estas hiptesis encuentran su limite cuando encontramos pacientes con un grado minimo de severidad sintomtica y un profundo deterioro de las funciones cognitivas. Por el contrario, es claro que la esquizofrenia cursa con severo deterioro cognitivo, el cual es persistente e independiente de la sintomatologa positiva o negativa del paciente y de los tratamientos con neurolpticos y puede observarse tambin en familiares de los pacientes psicticos. Las evidencias de esta observacin se encuentran en la temprana revisin de Alyward y col. (Intelligence in schizophrenia: meta-analysis of the research. Schizophr. Bull. 1984; 10:430-439) y replicado en varios estudios actuales (Cf. Heinrichs RW., The primacy of cognition in schizophrenia. Am. Psychol. 2005; 60:229242), que reafirma la amplia aceptacin de los dficits cognitivos como una caracterstica central de la esquizofrenia y no como un mero epifenmeno (Heaton RK., and al., Stability and course of neuropsycological dficits in schizophrenia. Arch. Gen. Psychiatry. 2001; 58:24-32) de ella, constituyendo un foco de atencin preferencial a partir del proyecto MATRICS. Functional Co-Primary Measures for Clinical Trials in Schizophrenia: Results From the MATRICS Psychometric and Standardization Study Michael F. Green, Ph.D., Keith H. Nuechterlein, Ph.D., Robert S. Kern, Ph.D., Lyle E. Baade, Ph.D., Wayne S. Fenton, M.D., James M. Gold, Ph.D., Richard S.E. Keefe, Ph.D., Raquelle Mesholam-Gately, Ph.D., Larry J. Seidman, Ph.D., Ellen Stover, Ph.D., and Stephen R. Marder, M.D.

Abstract
OBJECTIVE: During the consensus meetings of the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMHMATRICS) Initiative, the U.S. Food and Drug Administration took the position that a drug for this purpose should show changes on 1) an accepted consensus cognitive performance measure and 2) an additional measure (i.e., a co-primary) that is considered functionally meaningful. The goal of the current study was to describe steps to evaluate four potential co-primary measures for psychometric properties and validity. METHOD: As part of the five-site MATRICS Psychometric and Standardization Study (PASS), two measures of functional capacity and two interview-based measures of cognition were evaluated in 176 patients with schizophrenia (167 of these patients were retested 4 weeks later). RESULTS: Data are presented for each co-primary measure for test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to functioning, tolerability/practicality, and number of missing data. CONCLUSIONS: Psychometric properties of all of the measures were considered acceptable, and the measures were generally comparable across the various criteria, except that the functional capacity measures had stronger relationships to cognitive performance and fewer missing data. The development and evaluation of potential co-primary measures is still at an early stage, and it was decided not to endorse a single measure for clinical trials at this point. The current findings offer the initial steps to identify functionally meaningful co-primary measures in this area and will help to guide further evaluation of such measures.

The National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) Initiative was created to stimulate the development of cognition-enhancing drugs for schizophrenia (13). As described in two other articles (4, 5), a key deliverable for the MATRICS Initiative was the selection, through a broad-based multidisciplinary consensus process, of a standard cognitive battery: the MATRICS Consensus Cognitive Battery (6). The U.S. Food and Drug Administration (FDA) indicated at the MATRICS meetings that significant improvement on a consensus cognitive performance endpoint would be necessary, but not sufficient, for drug approval. In addition to changes in cognitive performance, the FDA will require improvements on a functionally meaningful co-primary measure that would have more face validity for consumers and clinicians than cognitive performance measures (3). This requirement presents a notable challenge because of the absence of accepted or validated co-primary measures for this purpose.

One possible co-primary measure might be an assessment of community functioning. However, change in community status (e.g., return to work, increased social relationships, or higher degree of independent living) involves many intervening variables (both personal and social factors) that act between underlying cognitive processes and these functional outcomes. These intermediate steps would make it difficult to see the functional benefits of cognition-enhancing effects (710). Similarly, improvements in cognition would be expected to take considerable time to translate into functional improvements (11). Finally, changes in daily functioning would depend on nonbiological factors that are typically uncontrolled in clinical trial studies (e.g., the availability of psychosocial rehabilitation, social support networks, local employment rates, and training opportunities). Hence, alternative co-primary measures were considered that might change more directly and on a comparable time course with cognitive improvement. Such measures include standardized tests of functional capacity or interview-based assessments of cognition. Functional capacity refers to an individuals capacity for performing key tasks of daily living. To assess functional capacity, participants simulate in the clinic such real-world activities as holding a social conversation, preparing a meal, or taking public transportation (12, 13). Good performance on such measures does not mean that a person will perform the tasks in the community, but it does mean that the person could perform the task if he or she had the opportunity and was willing. Because performance on measures of functional capacity do not depend on social and community opportunities, they are more likely to be temporally linked with treatment-related changes in underlying cognition. Another approach for co-primary measures was to consider interview-based assessments of cognitive abilities. Different interview-based approaches to cognition have been used, including asking people to estimate their own cognitive abilities or asking subjects to estimate the extent to which their daily lives are affected by cognitive impairment. Interview-based approaches present a challenge because it is often difficult for individuals (healthy subjects as well as patients) to estimate their own performance abilities (14, 15). Recently, some cognitive assessment interviews have been developed in which the ratings of psychotic patients are supplemented with ratings from informants (e.g., caregivers), an approach that might have advantages over previous assessments that used only self-reports (16, 17). The goal of the current study was to evaluate the reliability, validity, and appropriateness for use in clinical trials of four potential co-primary measures: two measures of functional capacity and two interview-based measures of cognition. With this goal in mind, these four measures were added to the MATRICS Psychometric and Standardization Study (PASS) and assessed for their test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to outcome, practicality/tolerability, and number of missing data.

The complete methods for this study are presented online (the data supplement is available at http://ajp.psychiatryonline.org). A brief summary is presented here.

The data in this article are part of the five-site MATRICS PASS. Phase 1 was conducted with 176 schizophrenia patients tested twice at a 4-week interval (4), and phase 2 included 300 community subjects to collect co-norming data for the tests in the final battery (5). To evaluate the co-primary measures, we used a similar approach to that used to evaluate the cognitive performance measures and considered 1) test-retest reliability, 2) utility as a repeated measure, 3) relationship to functional status, 4) tolerability/practicality, and 5) number of missing data. In addition, we evaluated the degree to which co-primary measures correlated with cognitive performance (3). Based on discussions at consensus meetings and recommendations of the MATRICS Outcomes Committee (1) (A. Bellack, chair), two approaches to co-primary measures were considered: measures of functional capacity and self-report measures of cognition. Two measures were selected from each approach. Unlike the large consensus and data collection process that was used to select cognitive performance tests for the MATRICS Consensus Cognitive Battery, the selection of potential co-primary measures was based on expert recommendations from the committee. The functional capacity measures were the Maryland Assessment of Social Competence (13) and the University of California at San Diego (UCSD) Performance-Based Skills Assessment (18). The interview-based measures of cognition were the Schizophrenia Cognition Rating Scale (16) and the Clinical Global Impression of Cognition in Schizophrenia (17). Cognitive performance was assessed with the MATRICS Consensus Cognitive Battery (4, 5). As described more fully in the first article (4), community functioning was assessed with variables from the Birchwood Social Functioning Scale (19), supplemented with work and school items from the Social Adjustment Scale (20).

Study

Group

The study group for these analyses is the same as described in the first article (4): across the five performance sites, 176 patients were assessed at baseline and 167 were assessed at the 4-week follow-up.

Test-Retest

Reliability

The results for test-retest reliability are shown in Table 1. The table shows the intraclass correlation coefficient (ICC), which takes into account changes in mean level. Both the ICC and Pearsons r are shown in the online data supplement; differences for the two statistics were minor. The test-retest reliability was good across measures; a correlation of 0.70 or greater is generally considered to be acceptable test-retest reliability for clinical trials, and most of the tests were in that range or higher. The one exception was the medication management component of the UCSD Performance-Based Skills Assessment that had relatively low reliability. As mentioned above, this was a secondary measure of the UCSD Performance-Based Skills Assessment. For the self-report measures, the reliability was slightly higher for the interviewers and informants than for the patients.

Utility

as

Repeated

Measure

Tests are considered useful for clinical trials if they show a relatively small practice effect or, if they have a practice effect, the effect is not so large that subjects scores approach the ceiling. To examine a tests utility as a repeated measure, we assessed scores at baseline and 4 weeks later, change scores, the variability of change, and the number of administrations at which the subjects performed at the ceiling or floor, defined as the best or worst score possible on the test (shown in Table 2). Note that in some of the tables, the direction of scoring differs among test indices. Scores for which lower is better are noted. The practice effects were generally small, and the highest was for the UCSD Performance-Based Skills Assessment total score (Cohens d=0.23). Other effect sizes for practice effects with the coprimary measures were small, but some were statistically significant with the large group size. Finally, a few tests showed ceiling effects, including the medication management component of the UCSD Performance-Based Skills Assessment, the patient report on the Schizophrenia Cognition Rating Scale, the nonverbal score from the Maryland Assessment of Social Competence, and the total score from the UCSD Performance-Based Skills Assessment.

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TABLE 2

Relationship

to

Cognitive

Performance

Because the co-primary measures are intended to serve as face valid indicators of the consequences of underlying changes in cognition, it is important that they correlate with cognitive performance. We examined the correlations of the co-primary measures with each of the components of the MATRICS Consensus Cognitive Battery (in the data supplement), as well as a composite score from the 10 tests (shown in Table 3). For this purpose, the composite score was calculated by standardizing each of the cognitive tests (mean of 0 and SD of 1) and then summing the standardized scores. The MATRICS Consensus Cognitive

Battery scoring program now has a more systematic way to derive a composite score that involves two renorming steps, first for each of the domain scores that have multiple measures and second for the final composite score. We present the simplified composite score in this article because the PASS data were collected and analyzed before the MATRICS Consensus Cognitive Battery scoring program existed, so the data in Table 4 are those that were reviewed by the MATRICS Neurocognition Committee and submitted to NIMH and the FDA. To compare the strength of correlations among measures, we included only subjects with complete data on all four measures (i.e., listwise deletion, N=156). The correlation between the UCSD Performance-Based Skills Assessment total score and cognitive performance was significantly higher than for both interview-based summary measures (Schizophrenia Cognition Rating Scaleinterviewer and Clinical Global Impression of Cognition in Schizophrenianeurocognitive state composite) (t=4.13, df=153, p=0.001). The UCSD Performance-Based Skills Assessment correlation with cognitive performance was also higher than the one for the Maryland Assessment of Social Competence Effectiveness score (t=2.50, df=153, p<0.03).

Relationship

to

Self-Reported

Functional

Outcome

The sites differed substantially in the functional status of the patients (e.g., one site had only a single subject working, and another site consisted largely of patients in a long-term residential program). Because of these cross-site differences in functional status, the correlations between co-primary measures and functional outcome varied from site to site. Given this variability, we present correlations two ways: a correlation for all subjects across sites and also the median correlation across the five sites. Both of these methods tend to underestimate the correlations that would be observed if patients at all sites included a wide range of functional levels. However, the results (Table 4) allow for direct comparisons among the measures. Most of the correlations were modest, and there were no notable differences in the strength of the correlations across co-primary measures.

Tolerability/Practicality
Tolerability refers to the participants perspective of a measure (i.e., how interesting, pleasant, or burdensome it is to take). Similar to what was done with the cognitive measures (4), the subjects were asked immediately after each co-primary measure to point to a number on a 7-point Likert scale (1=extremely unpleasant, 7=extremely pleasant) to indicate the degree to which they found the measure pleasant. Practicality refers to the administrators view of the measure (i.e., how difficult it is to set up, train staff, administer, and score). Practicality was assessed with a 7-point Likert scale for setup, administration, and scoring, as well as a global score. The ratings were made by the administrators of the co-primary measures after completion of data collection for the entire group. Table 5 presents the data on tolerability and practicality, as well as the mean length of time for administration. For the two functional capacity measures, both tests were considered to be practical and tolerable, with the UCSD Performance-Based Skills Assessment generally rated higher than the Maryland Assessment of Social Competence. We did not record scoring as part of the practicality rating for the Maryland Assessment of Social Competence because that test was scored centrally, not at the local sites. However, a practical consideration is that this test required the additional step of centralized scoring, a process

that typically required 2030 minutes per assessment. For the two interview-based measures, both tests had acceptable ratings, with the Schizophrenia Cognition Rating Scale generally rated higher than the Clinical Global Impression of Cognition in Schizophrenia because it was easier to score and could be administered in roughly half the time. Of course, investigators desiring cognitive domain coverage might nevertheless prefer the Clinical Global Impression of Cognition in Schizophrenia.

Missing

Data

Table 6 shows the number of data missing across both assessments, not counting the nine missing assessments for the subjects who did not return for the retest. The number of missing data is quite small for both functional capacity measures, with the UCSD Performance-Based Skills Assessment showing fewer missing data than the Maryland Assessment of Social Competence. For the interview-based measures, the data collection was nearly complete for the patient interviews, but about 14% of the informant interviews (across both assessment periods) were missing. This pattern reflects the expected challenge in identifying and locating suitable informants for the patient participants in clinical trials.

Site

Differences

We also evaluated site differences among representative measures from each of the four coprimary measures (effectiveness from the Maryland Assessment of Social Competence, total score from the UCSD Performance-Based Skills Assessment, and the interviewers ratings from each self-report measure) with a series of one-way analyses of variance (ANOVAs). The UCSD Performance-Based Skills Assessment did not show significant differences across sites, but the other three measures did (Maryland Assessment of Social Competence effectiveness: F=3.39, df=4, 161, p<0.03; Schizophrenia Cognition Rating Scaleinterviewer: F=6.67, df=4, 165, p<0.001; Clinical Global Impression of Cognition in Schizophrenia composite: F=20.73, df=4, 165, p<0.001). The differences across sites on these co-primary measures may be partially a result of the fact that the sites differed in terms of the average functional level of the patients. Hence, we view the differences as a reflection of actual group differences as opposed to a failure of cross-site reliability of administration.

This article evaluated four potential co-primary measures that may be used in clinical trials of cognition-enhancing drugs for schizophrenia. Early discussions with the FDA indicated that approval of a cognition-enhancing drug for schizophrenia would require changes on a

consensus measure of cognitive performance, as well as on a functionally meaningful coprimary measure. We considered four different potential co-primary measures, two measures each from two distinctive approaches: measures of functional capacity and interview-based measures of cognition. Several summary points can be drawn from these data. First, all four measures had acceptable test-retest reliability. An added component of the UCSD Performance-Based Skills Assessment (medication management) had lower reliability, perhaps because scores on this component tended to be at or near the ceiling. Second, most tests had adequate range. A practice effect was noted for the UCSD Performance-Based Skills Assessment total score. The measures with the most prominent ceiling effects included the medication management component of the UCSD Performance-Based Skills Assessment (which is separate from the main test) and the Schizophrenia Cognition Rating Scalepatient rating (which is not the primary rating for this interview). Third, the relationships to cognitive performance were notably higher for functional capacity measures (in particular the UCSD Performance-Based Skills Assessment) than for the interview-based measures of cognition. This pattern is consistent with findings that interview-based assessments of cognition generally do not correlate well with objective cognitive performance (15). Also, the UCSD Performance-Based Skills Assessment, the Maryland Assessment of Social Competence, and the MATRICS Consensus Cognitive Battery can all be considered performance measures, and therefore they share some method variance. Fourth, all measures had modest relationships to community functional status that were somewhat lower than expected. Fifth, missing data were more frequently observed for the interview-based measures because of the difficulty in contacting individuals who could serve as informants. The blind across measures was not absolute. The raters who administered the functional capacity measures also administered the cognitive performance tests (although the scoring for the Maryland Assessment of Social Competence was done centrally). The testers did not have access to any information on functional status or the interview-based measures of cognition. The staff members who conducted the interview-based measures of cognition did not have access to the functional status interviews, but they were not fully blind to functional status because these measures include questions about the degree to which cognitive impairment interferes with activities of daily living. Another limitation of these data are that they were collected in the absence of cognitive change. One would ideally want to know the sensitivity of these measures to changes in cognition as opposed to measuring when the cognition was presumably stable. Questions about the sensitivity of coprimary measures to change in cognitive performance will await identification of a potent cognition-enhancing drug or perhaps could be examined in the context of cognitive remediation programs. The relationships between the co-primary measures and functional status were somewhat lower than expected and lower than reported in other studies (10, 16). The ratings of community functioning were based entirely on subject self-reports (not observation and not informants), which may have limited the validity of the ratings. In addition, the correlations may have been limited by substantial differences in functional status across the five sites and considerable variability in the size of the correlations across sites that may be attributable to instances of within-site community functioning homogeneity. At some sites,

the range of community functioning was restricted by treatment setting constraints (e.g., residential treatment) that were not simply due to cognitive or functional capacity levels. A restricted range of within-site variance on the community functional status measure would be expected to reduce the magnitude of the correlations with co-primary measures. In this situation, it was difficult to obtain a representative indication of the associations; however, the values do provide a reasonable basis for comparison of the four measures, all of which performed comparably. The MATRICS Neurocognition Committee reviewed the data presented in this article and concluded that because all of the potential co-primary measures performed reasonably well, it was difficult to make a narrow recommendation to NIMH and the FDA. A clearly stated objective for the MATRICS Initiative was to select a single consensus cognitive performance battery (the MATRICS Consensus Cognitive Battery) for use in clinical trials of cognition-enhancing drugs for schizophrenia. In contrast, the Neurocognition Committee was not asked to recommend any particular co-primary measure, and the committee did not do so. The Neurocognition Committee noted that if one needed to choose a co-primary measure for a clinical trial at this time, the UCSD Performance-Based Skills Assessment (with modifications to address the ceiling effect) had the advantage of a strong association with cognitive performance. A revised version of the UCSD Performance-Based Skills Assessment with adjusted difficulty level is currently available. The two interview-based measures were similar in structure, and their summary scores were highly correlated (r=0.68; in comparison, the correlation for the two functional capacity measures was 0.30). If it was desirable to include an additional co-primary measure that reflects the interviewbased approach, the Schizophrenia Cognition Rating Scale has the advantage of better tolerability and practicality, although it lacks domain ratings. The evaluation and selection of co-primary measures raises questions about validity. The key concern of the FDA is demonstrating that a new cognition-enhancing drug affects cognitive performance and meaningful functional abilities. At present, evidence of content validity of co-primary measures may be more available than evidence of construct or external validity. That is, the content of these measures can be evaluated for its functional meaningfulness from the perspectives of patients, clinicians, and families. Further establishment of construct or external validity, including relationships to cognitive performance and community functioning, will take time. A related validity issue is whether co-primary measures need to be sufficiently distinct (i.e., involve different constructs) from cognitive performance measures. For example, some functional capacity measures resemble neurocognitive tests in mode of administration. However, at this point, distinctiveness of cognitive performance and co-primary measures does not appear to be a concern of the FDA. A co-primary measure could in theory be a modified version of a cognitive performance test (if it has content of clear functional relevance) or a modified version of a community functioning scale (if sufficiently sensitive to change within a clinical trial). At this stage of development, associations between co-primary measures and cognitive performance may be more critical than those with everyday functional outcome, given that improvements in functional capacity may still require additional rehabilitation in specific daily living or work skills to be translated into community functioning.

Representatives of the FDA indicated to the MATRICS Neurocognition Committee that any of the four co-primary measures would be acceptable at this point for use in clinical trials. However, given the early stage of method development in this area, the Neurocognition Committee expects that stronger measures using these approaches, or using entirely different approaches to assessment, might be developed. This is a fertile area and one in which developments are occurring at a rapid pace. The importance of functional assessment for serious mental disorders and its role in drug evaluation has been reflected in several recent developments. For example, a new program at NIMH, Functional Assessment in Mental Disorders, has recently been created. Also, a new academic/industry consortium (MATRICS-Co-Primary and Translation) has been formed to facilitate the evaluation of potential co-primary measures for use in clinical trials. Finally, NIMH recently sponsored a consensus meeting on functional assessment for psychiatric disorders (21). Hence, the results presented in the current article should be viewed as a good starting point for evaluation, comparison, and discussion of potential functionally meaningful co-primary measures, with expectations that future developments will lead to improved tools in this domain.

Disfunciones neurofisiolgicas

La medicion de la respuesta cerebral a traves de los estimulos externos ha sido una estrategia en la investigacion de la fisiopatologia de la esquizofrenia que ha permitido conocer la anormalidad cognitiva y sensorial de la enfermedad y sus asociaciones genticas. Una de las mediciones mas conocidas es la del movimiento ocular en respuesta al estmulo de perseguir un objeto que se mueve lentamentamente ante los ojos del individuo y la onda electroencefalografica caracteristica en respuesta al estimulo. Las personas normales responden siguiendo el objeto uniformemente, mientras que algunos de los pacientes con esquizofrenia no lo pueden hacer y responden con movimientos sacadicos, lo que no se explica por la psicosis ni por la medicacin sino que existira hipotticamente un defecto cerebral que vinculara el procesamiento de la informacion y el movimiento de los ojos, implicando la corteza parietal posterior y la corteza frontal medial, constituyendose en un marcador neurobiolgico de la enfermedad. Otras mediciones neurofisiologicas como los potenciales evocados representan un metodo de referencia en la exploracion de los procesos cognitivos en la esquizofrenia. En efecto, el deficit y bloqueo sensorial que se encuentra en la esquizofrenia se analiza usando un par de estimulos auditivos (P 50), expresando la diferencia entre el primer estimulo y el segundo como un porcentaje. Los sujetos normales suprimen la segunda respuesta con porcentajes tipicos que no alcanzan a 40% a diferencia de los individuos esquizofrenicos y la mitad de los parientes de primer grado que no suprimen la respuesta alcanzando generalmente porcentajes mayores a 50%. Esto significa que los pacientes con esquizofrenia tienen un deficit en la filtracion o supresion sensorial, por lo que son inundados de estimulos externos que no pueden ordenar. Este deficit que bolquea parcialmente la respuesta sensorial expresado por la onda P 50 aparece como un rasgo genetico de la enfermedad en tanto esta presente en los pacientes y en sus parientes de primer grado, y se correlaciona con la

disminucion de la atencion o dificultades cognitivas del individuo, en relacin a su vez con zonas cerebrales (regiones prefrontales y temporoparietal, hipocampo y sistema limdico) donde la accion de los antipsicoticos atipicos como la Clozapina son mas efectivos (Lawrence, E and al., Varied effects of atypical neuroleptics on P 50 auditory gating in schizophrenia patients. A. J. Psychiatry 161:1822-1828, October 2004) permitiendo por lo tanto, un estudio mas preciso de las bases neurofisiologicas que distinguen este neuroleptico atipico de la accion de otros neurolepticos como de los neuro trasmisores o vias implicadas en el fenomeno. Otro endofenotipo de sta naturaleza es la onda P 300, no ya vinculado a deficits atencionales sino que con procesos que vinculan laxitud de asociaciones en el sentido de Bleuler con anomalias de las representaciones conceptuales en su relacion con la memoria semantica de largo plazo. La onda P est referida a una onda positiva que aparece despues de 300 ms de provcado un estimulo que indica grosso modo el tiempo de procesamiento cognitivo del estmulo y la amplitud de la onda, implica el al aspecto energtico, es decir, el volumen de neuronas implicadas en la genesis del proceso cognitivo, con lo que se constituye un marcador de la actividad neuronal en relacion con el procesamiento cognitivo del individuo. En los estudios con pacientes esquizofrnicos, la onda P se encuentra alterada tanto en su amplitud como en su tiempo de latencia representando las anomalias cognitivas de ese individuo, correlacionadas con disminucion de volumen de areas corticales tales como el lbulo temporal, especificamente en el giro temporal medial y en zonas frontales (Jeon YW., and al., Meta-analisys of P 300 and schizophrenia patiens, paradigms, and practical implications. Psychophysiology, 2003; 40 (5) 684-701

Trastornos del espectro esquizofrnico Basados en los estudios de adopcin y de familia donde se demuestra una frecuencia importante de trastornos psiquiatricos entre los familiares de un paciente ndice (esquizofrnico), se ha acuado el concepto de espectro de la esquizofrenia para agrupar aquellas entidades que comparten ciertos rasgos clnico-fenomenologicos y genticos, caractersticas cognitivas y eventualmente aspectos fisipopatologicos (Siever, L., Davis, K., The pathophysiology of schizophrenia disorders: perspectives from spectrum. Am. J. Psychiatry 161:398-413, March. 2004) Este espectro comprende en la actualidad los trastornos de personalidad del cluster A del DSM IV-TR (TP esquizotipicos, paranoides y esquizoides), el trastorno esquizofrniforme y el Trastorno esquizo-afectivo. Desde el punto de vista epidemiolgico, un 20 % de los familiares de un pciente esquizofrnico tiene manifestaciones clnicas o endofenotipicas de este espectro, por lo tanto, tienen sntomas o inhabilidades que le impiden un desarrollo funcional en lo laboral o social que podra beneficiarse de un tratamiento. Estas personas, familiares en

primer grado del paciente presentan en general trastornos cognitivos como los sealados anteriormente, que comprometen deterioros en la atencin, comprensin del lenguaje, fluencia verbal, memoria espacial y de trabajo. Estructura y funcin cerebral El desplazameinto de la mirada mdica en psiquiatra para observar fenmenos intracraneanos ha tenido un desarrollo espectacular solo en los ltimos aos. Los avances han sido tanto en la claridad o resolucin de las imgenes como de las tcnicas empleadas desde la Tomografia axial computarizada a la Tomografia por emisin de positrones, del SPECT (Tomografia de emisin de un solo foton) a la Resonancia Nuclear Magnetica incluyendo la RNM funcional, de la Espectroscopia por Resonancia Magnetica, ultrasonido y Magnetoencefalografia, tcnicas todas que posibilitan una visin extraordinaria de la estructura y funcin cerebral en el individuo vivo, aportando nuevos hallazgos acerca del rol de las anormalidades cerebrales en diversos trastornos psiquitricos en una perspectiva dinmica que va desde las lesiones locales hasta el sistema integral del cerebro, desde la materia gris a la sustancia blanca y las redes neurales implicadas en la patofisiologa de los distintos trastornos psiquitricos en un intento de explicar la produccin de la clnica psicopatolgica que los caracteriza.

Teorias de la esquizofrenia: En el estudio de la esquizofrenia, las teorias de la enfermedad juegan un rol especfico.

Hasta el momento actual, hemos dado cuenta de una acumulacin de conocimientos y evidencias empricas que necesitan ser ordenadas en funcin de iluminar el desarrollo posterior del conocimiento y explicar ciertos aspectos de como se producen ciertos aspectos de la enfermedad. Obviamente tenemos que comprender el desarrollo teorico acerca de la esquizofrenia al interior de un paradigma cientfico propio de las ciencias naturales que en esta fase del conocimiento del fenomeno, limitado e incompleto como lo hemos constatado, pueda sin embargo servir para explicar lo observado y predecir futuras observaciones, contrastar diferentes puntos de vista, determinar aspectos crticos y abducir inferencias lgicas para mejorar el desrrollo explicativo, e incrementar el conocimiento en el sentido Popperiano. Sin embargo, este desarrollo plantea dilemas ticos, ya que no es posible conducir investigaciones en seres humanos vulnerables por via enteramente experimentales, lo que no implica que las teoras desarrolladas a partir de poner en relaciones fenmenos naturales propios de la enfermedad no sirvan para el logro de algunos objetivos cientficos, como el comprensin de la interaccion temporo-espacial de factores causales proximales y lejanos o de variaciones en grado frecuencia de ciertas relaciones causales en vista de la consecuencia final, considerada como la causa proximal suficiente en la teora de la etipatogenesis de la enfermedad, ya sea esta dopaminergica, de trastornos de la conectividad o trastorno del neurodesarrollo. Hechas estas consideraciones, se est en condiciones de entender la manera de como los multiples factores encontrados en la

investigacin previa de la esquizofrenia se pueden integrar en los diferentes niveles de anlisis, para explicar con coherencia los mecanismos que lleven al resultado final de la produccin de sntomas o a la enfermedad, ya sean estos de sumacion, interaccion, transduccin o cascada de acontecimientos. Por ejemplo, el mecanismo de sumacin puede explicar la sintomatologa positiva o negativa de la esquizofrenia, mientras que el de transduccin puede hacerlo en relacin a una causa distal (influencia gentica) que contribuye a un rasgo conductual proximal a travs de un proceso de transduccin regulando una protena especifica que actua por una via especifica en el cerebro del paciente. El mecanismo de interaccin se explica por la concurrencia de factores de riesgo, como en el caso de distintos genotipos respondiendo a diversas condiciones ambientales para dar cuenta de la mayor o menor vulnerabilidad individual. En cambio, el mecanismo en cascada se refiere influencias particulares que son transducidas o integradas en terceras causales que inluencian a su vez a otras, como por ejemplo ocurre en un proceso de despolarizacin, que envuelve una cadena de reacciones que termina por expresarse en conducta. Las perspectivas tericas consideradas segn lo anterior, convergen en que todas dan cuenta de un rango de observaciones de hechos mas o menos establecidos acerca de la enfermedad para construir sus hiptesis explicativas, las cuales pueden no ser exclusivas porque difieren en nfasis, ya que por ejemplo el sistema dopaminergico interactua con el sistema glutaminergico o porque ambos sistemas pueden ser interferidos por disrupciones de la conectividad de los circuitos neurales. Por lo tanto, al ser perspectivas abiertas, no se descarta otra nueva que pueda aparecer en el futuro para dar cuenta con mayor exactitud de los avances en los hechos de la enfermedad que la investigacin produce. Angus W. MacDonald13 and S. Charles Schulz3 (What We Know: Findings That Every Theory of Schizophrenia Should Explain) han resumido 22 hechos considerados por los investigadores en el campo de la esquizofrenia para construir una explicacin teorica de la enfermedad: 6 de ellos son hechos bsicos, 3 factores etiolgicos, 6 pertenecientes al mbito farmacolgico, y 5 del dominio de la patologa: Los hechos, resumidos, considerados son: 1.-La esquizofrenia es una enfermedad heterogenea desde el punto de vista sintomatico como alucinaciones, delirious, pensamiento desorganizado y disfunciones cognitivas con predominancia variable entre los individuos. Algunos autores sugieren que la psicosis es la categora superior que integra a la esquizofrenia y otros subtipos. Estas observaciones abren la posibilidad de exmen de nuevas preguntas en torno a dimensiones y sindromes asociados a la enfermedad 2 El Segundo hecho es epidemiologico: la enfermedad, usando crierios objetivos de diagnostico tiene una prevalencia de 0,7 a 1,2% de la poblacin.2,50 con algunas zonas donde se concentra mayormenet el riesgo, como en el norte de Suecia2, y con remisiones y recaidas en relacin a la cultura, como por ejemplo en Africa con menor tasa de recaidas que en Europa o los pases industrializados50 3. y 4- El tercer y cuarto factor se relaciona con la diferencia de gnero: los hombres y mujeres se enferman en cantidad similar hasta la pubertad. Despues aparecen diferencias en

relacin al inicio del cuadro, que en mujeres es de alrededor de los 36 aos con piques despus de la menopausia 4,51,52. Ademas, las mujeres tiene un curso ms benigno y responden mejor a la medicamentacion, cuya consecuencia se atribuye a un rol protector estrognico sobre el cerebro en desarrollo 5.- El quinto hecho es epidemiolgico: los gemelos monocigotos tienen una tasa de discordancia de hasta 50% en condiciones mabientales distintas, lo que sugiere que mucha gente con un riesgo aumentado para esquizofrenia, nunca manifiesta la enfermedad7 y que un factor no mensurable puede jugar un rol importnate 6.- El sexto hecho es farmacolgico y dice relacin con que especficos y potentes agentes bloqueadores de los receptores D2 no son los mas efectivos para el tratamiento de la esquizofrenia. Esto deja abierta la pregunta sobre el rol que juegan otros neurotrasmisores en la psicosis, como el sistema serotoninergico o el glutaminergico 7.- En relacin a los hallazgos de la genetica molecular, el septimo hecho etiologico dice relacin con slo 2 regiones, (8p y 22q) con fuerte ligamiento en esquizofrenia. 8.- El octavo factor se vincula con resultados provenientes de la gentica cuantitativa que aportan antecedentes sobre los parientes de primer grado de los pacientes esquizofrnicos entre quienes se encuentran pequeos cambios en las funciones cognitivas65, diferencias en la funcin y estructura cerebral 66 -67 referidos a la vulnerabilidad gentica y a la presencia de endofenotipos que pueden permitir el estudio de los mecanismos subyacentes a la presencia activa de la enfermedad 9.- El ltimo factor etiolgico subsume los factores medioambientales asociados a la expresin de la enfermedad: la epidemiologa reconoce factores ligados a la migracin, factores estacionales, entre otroa que junto a los factores de riesgo genticos conducen a la manifestacin de la esquizofrenia clnica. 10.- Factor derivado de la farmacologia y tratamiento de la enfermedad, recoge la observacion de que mientras la ocupacin de los receptores D2 cerebrales es rpida, los sntomas se resuelven tardamente en trminos incluso de semanas, lo que lleva al planteamiento de la existencia de otros mecanismos para el xito del tratamiento de una psicosis, tales como el efecto de un segundo mensajero, efectos sobre los aspectos genticos de la funcin celular, etc., que son actualmente explorados. 11.- El onceavo hecho est relacionado con la accin psicomimtica de la anfetamina. Dosis prolongadas de anfetamina produce sntomas del tipo paranoide que sustenta la teora dopaminergica de la esquizofrenia. Estudios recientes con PET demuestra que los pacientes esquizofrnicos presentan una especie de derrame de dopamina como consecuencia del uso de anfetaminas en relacin al grupo control 72,73. Aunque este hecho no es exclusivo de la esquizofrenia, ya que opera en otras patologias74 y otras drogas pueden exzacerbar sntomas de la enfermedad, el hecho es interesante para explicar el rol de la dopamina en la etiopatogenia de la enfermedad.

12.- Este hecho dice relacin con otras drogas con efectos psicomimeticos como los antagonistas del receptor del N-metil-D-acido asprtico (NMDA). Como se sabe, la Fenilciclidina y Ketamina produce sntomas semejantes a la esquizofrenia, no reversibles con neuroplpticos tradiconales, lo que sugiere una hiptesis de trabajo distinta a la dopaminergica y abre posibilidades a vas distintas de tratamiento de la enfermedad a travs de la accin del glutamato sobre compuestos tales como la N-acetilcisteina 77 en la reduccin de los sintomas refractarios de la esquizofrenia. 13.- Este hecho dice relacion con las intervenciones psicosociales en el tratamiento de la enfermedad. Se sabe que estos efectos son pequeos o moderados 24, pero importantes para la psicoeducacion y reduccion de las recaidas en los pacientes, al centrarse en la reduccin de los conflictos familiares y en la reitegracion socila de los pacientes. Ultimamente, el uso de tcnicas como la de remediacin cognitiva, representa una oportunidad para una mejora en reas cognitivas deficitarias en la esuizofrenia 81 y apoyo consistente para la eficacia del tratamiento psicosocial de los pacientes 14.- Este hecho relaciona el tiempo de enfermedad y el comienzo del tratamiento y su efecto sobre las consecuencias futuras para el individuo, en que existe una relacin inversa entre mayor extensin temporal de la enfermedad y recuperacin posible25, lo que aparece confirmado en estudios posteriores 84. El estudio de Melle y al., 85 en Noruega evidencia con claridad el impacto del diagnostic y tratamiento precoz en la reduccion de los efectos posteriors de la enfermedad en los pacientes en trminos de tasa de suicidalidad85 y la severidad de la psicosis. 15 y 16.- Hechos recientes referidos a la patologa de la enfermedad: la fisiopatologa de la esquizofrenia se ha enriquecido con las evidencias encontradas en el cerebro post-morten. La reduccin de la densidad de la espinas dendriticas que pertenecen a las neuronas ubicadas en la region aferente de la columna cortical de la corteza prefrontal dorsolateral ofrecen elementos de juicio para comprender como la esquizofrenia es posible como enfermedad cerebral29 Las relaciones de stas zonas con el hipocampo, una estructura muy vulnerable a los daos precoces como la hypoxia91esta siendo intensamente investigada en la actualidad. 17.- Hecho relacionado con estudios post-morten y con recientes hallazgos de la accion del sistema GABAergico, han proveido conocimientos sobre la actividad de las neuronas piramidales que coordinan el funcionamiento cognitivo, regularmente afectado en la enfermedad92. 18.- Desde los hallazgos de Weinberger y al94 describiendo las alteraciones estructurales del cerebro de pacientes esquizofrenicos, hasta estudios posteriors que no correlacionan estos hallazgos con el tiempo de evolucion de la enfermedad, han aparecido varios estudios que describen los cambios dinamicos de la morfologia cerebral desde el primer episodio de la enfermedad101,102 que aportan evidencias acerca de lo precoz que son estos cambios 19.- Este hecho esta vinculado con los mismos hallazgos anterior, entrega conocimiento complementario con tecniocas de RNM que refleja la disminucion de distintas areas corticales en relacion con grupos controles, sin relacion con la ampliacion ventricular, que

demuestra que las reducciones de volumen de regiones especificas de la corteza no son similares106. Cual es la relacin entre estos hallazgos y cmo contribuyen estas diferencias estructurles en el funcionamiento cerebral y cual es su expresion clinica, es algo actualmente en estudio. 20.- The 20th fact attempts to encompass the breath of findings from the past 2 decades that have found a number of brain processes to be abnormal (either unusually high or more commonly unusually low) in patients with schizophrenia. While brain function has long been hypothesized to be awry in schizophrenia,107 the seminal work of Ingvar and Franzen108 was the first to implicate more specific brain regions using biological measures, in this case prefrontal cortex. Recent reviews of functional abnormalities continue to implicate prefrontal cortex and more specifically dorsolateral prefrontal cortex as a region that shows reduced activity with adjoining regions showing at times increased activity.109 Reviewers have been thus far reluctant to summarize this abnormality into a simple pattern of findings due to differences across studies both because of the tasks used and the predictable differences in performance on tasks that tap working memory and executive functions that utilize this region37 (see fact #21). Scalp recordings have also been used to measure functional abnormalities. One of the most successful paradigms to date has come from the mismatch negativity waveform which occurs, eg, following an aberrant tone within a string of monotones. This signal, thought to have a source within the superior temporal lobe's primary and secondary auditory cortices, shows a large effect size across more than 32 studies.35 The P300 signal is similarly reduced in patients across 46 studies that used oddball paradigms, in which an unexpected stimulus occurs within a series of similar stimuli.36 The P300, which is a positive deflection that occurs approximately 300 ms following the oddball stimulus, is diffusely generated and is generally found to be largest at medial central and parietal sites. Other electrophysiological abnormalities that have received considerable attention in the schizophrenia literature include the P50 (an early response to observing a stimulus), prepulse inhibition or PPI (a change in responsivity to the second stimulus in a pair), and reductions in gamma rhythm synchrony (3080 Hz electrical activity). Thus, functions subserved by a number of brain regions and a number of neurotransmitter systems are affected by the illness. Although some exceptions have been reported, the pattern of functional neuroanatomical impairments is wide spread and nonspecific. Furthermore, it remains largely unknown which regions are most closely linked to variation in symptom expression (fact #1).

Behavioral Facts
The process yielded 2 facts about the behavioral impairments associated with schizophrenia. First, since the time of Bleuler,110 impairments in cognitive functions such as attention have been noted in schizophrenia. Loren and Jean Chapman observed that patients were impaired across a broad swathe of cognitive domains and coined the term generalized deficit to succinctly capture this observation.111 More recently, the independent work of Heinrichs and Dickinson and their colleagues28,39,40 have quantified the behavioral deficits in schizophrenia patients. The 21st fact on our list highlights this observation. These meta-analyses suggest that patients perform about 1 SD worse than controls on clinical neuropsychological tasks. Some tasks show an even greater deficit (up

to d = 1.57 for coding tasks, which require a combination of speed, working memory, and executive functions40). Unfortunately, the generality of this impairment might limit its usefulness for understanding schizophrenia. That is, if all cognitive functions are impaired, no brain system or neurotransmitter system in particular is implicated by these data. Research in this domain may yet find an implicit task demand shared by all such tests that accounts for this common deficit. For example, an important perceptual (eg, gestalt perception), executive control (eg, rule maintenance), or motor function (eg, response threshold) might lead to deficits across many seemingly unrelated tasks. It remains likely, however, that the strong effects associated with cognitive impairments in schizophrenia represent a convergence of many, more subtle, brain deficits.90 Irrespective of their specificity or source, cognitive impairments appear to have important implications for patients everyday lives. This is the 22nd and last fact on our list. Green et al41 reviewed 18 studies that used neuropsychological test indices to predict a range of variables, ranging from the total number of hours worked to quality of life, 6 months to 2 years later. These studies are generally consistent in demonstrating medium (d > 0.50) to large (d > 0.80) effect sizes for these associations. These data are insufficient to confirm a causal relationship. Another explanation of the strength of this relationship is that both cognitive performance and functional outcomes reflect an underlying continuum of severity. However, there is a small but growing body of evidence that targeting patients cognitive impairments leads to improvements in functional outcomes, such as the number of hours worked,112 which is more consistent with a causal relationship. Of course this observation also has a number of important treatment implications. The challenge remains, however, as to how best to match patients to appropriate psychosocial interventions to maximize their potential gains. This is particularly difficult work and requires sample sizes substantially larger than those generally used in such treatment outcome studies. Previous SectionNext Section

Conclusion and Preface

The consensus facts reviewed above are by the time of this publication a part of a larger series of efforts to systematize and sort through what we know about schizophrenia. As noted in the introduction, our particular approach to these facts was informed by a desire to see them drawn together into a coherent theory of schizophrenia. In this regard, the Minnesota Consensus Group did not believe that it was either necessary or desirable for the theoreticians to account for every finding in schizophrenia. Among the basic facts, fact #3 (sex differences), fact #4 (age of onset), fact #5 (heritability), and fact #6 (antipsychotic action) were felt to be the most likely to sharpen the differences between theoretical accounts. Among the etiological facts, only fact #9 (environmental risk factors) was incorporated for the sake of this exercise. Three of the pharmacological and treatment facts were highlighted, including fact #10 (medication response lag), fact #11 (psychomimetic effects of dopamine agonists), and fact #12 (psychomimetic effects of glutamate agonists). And among the pathological facts, fact #16 (reduced dendritic spine density) and #17 (reduced G67 levels) required an account. Interestingly, it was not felt that either of the 2 behavioral facts was likely to distinguish between theories.

To what extent would a different group or a different process have distilled a different set of facts from the schizophrenia literature? A serendipitous point of reference in this regard is the recent work of Tandon et al.113 Rather than group consensus informed by expert consultation, these reviewers performed a systematic review of 6000 abstracts and over 2000 articles. In many respects, their final list bears a striking similarity to ours. This is likely in large part because both adopted a similar structure (in their case clinical features, epidemiology, neurobiology, and treatment) and both took advantage of the recent proliferation meta-analyses. There are still a number of noteworthy differences that the authors of that work and this project are reconciling.114 For example, that work highlights as a fact a 2-fold increase in age-standardized mortality beyond the increased risk for suicide. This is a well-supported finding that had so far not come to our attention. The current set of facts is the product of a number of additional constraints. We have endeavored to make statements that are consistent with the current state of our knowledge, integrate a very large literature into a manageable number of facts, preserve accessibility to a broad audience by avoiding jargon where possible, and be sensitive to the different perspectives of caregivers, patients, and patients family members. As the list continues to be refined in the future, it will be useful to keep in mind the importance of falsifiability by tightening the statements and strengthening the parameter estimates. In this special section, there are 3 accounts by leading theoreticians about how these key facts should be understood from each of their perspectives. First, Drs Stephan, Friston, and Frith (in press) describe how an NMDA-induced failure of synaptic connectivity can give rise to these various phenomena. Next, Drs Howes and Kapur (in press) outline a revised dopamine hypothesis, incorporating recent work on dopamine's role in ascribing motivational importance, or salience. Finally, Drs Fatemi and Folsom (in press) draw attention to neurodevelopmental models of schizophrenia. Such models are informed by changes in the nervous system through embryogenesis and childhood and are conscientious of the kinds of insults that can derail normative developmental trajectories. These 3 papers go far beyond accounting for our 10 test facts, however. For interested readers, they open up the depth of the literature that supports their perspective. The authors also had challenges to address a sticky question: what evidence would cause them to abandon their hypothesis. The last paper of this special section is contributed by Tyrone Cannon of the University of California at Los Angeles. Dr Cannon's crucial contribution to this project is to reflect on our state of theorizing and to highlight the challenges of theorizing in a field bedeviled by quasi-experimental data (Cannon, in press). In reflecting upon the theories that can be built around the current set of facts, he notes they are not incompatible. As a result, an important next step is to further draw out the implications of each position to more fully delineate the domains in which they make conflicting predictions. This endpaper is particularly suitable for the current project, which began with the goal of comparing theories on a level playing field of facts. Cannon's conclusions move the challenge back to theories, by asking that they specify more rigorously the ways in which they differ in their implications and predictions. Of course this is not merely the role of their proponents, but it is a challenge for all of us in the field to strengthen and systematize our thinking about these issues.

Previous SectionNext Section

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Dopamina
La hiptesis dopaminrgica de la esquizofrenia:

La hiptesis dopaminrgica de la esquizofrenia surgi despus de comprobarse el efecto de los neurolpticos sobre ste neurotrasmisor, transformndose en una de las teoras etiopatolgicas ms populares para la enfermedad, en funcin de las siguientes evidencias: Los medicamentos antipsicticos (neurolpticos) eficaces para reducir los sntomas de la esquizofrenia son antagonistas de la dopamina Estos medicamentos producen o pueden producir efectos laterales semejantes a la Enfermedad de Parkinson, la que se caracteriza por una deficiencia de dopamina Las anfetaminas, compuestos qumicos activantes del sistema de la dopamina, produce sintomatologa parecida o exacerba la sintomatologa esquizofrnica El L-dopa, agonista de la dopamina y anti-parkinson, produce sntomas semejantes a la esquizofrenia en ciertos pacientes

o o

Las primeras hiptesis de Carlsonn y Lindqvist en 1963 sostenian que los sntomas positivos de la esquizofrnia se deban a una hiperactividad de la trasmisin dopaminergica. Los investigadores de ese tiempo basaron sus conclusiones en la evidencia de que los antipsicticos eran antagonistas de los receptores D2, especialmente a nivel del stratium, a cuya hiperactividad del sistema dopaminergico se le atribuyo la emergencia de la psicosis. Esta hiptesis no explica sin embargo la presencia de sntomas negativos ni los sntomas cognitivos de la esquizofrenia, lo que obligoa una reformulacin de la teora clsica, que implica la funcin de la corteza prefrontal , avalada por una cantidad importante de estudios (Cf. Golman-Rakic, 2000) que sostienen que un dficits en la trasmisin de la dopamina y de los receptores DA D1 de esta regin cerebral esta implicada en los trastornos cognitivos presentes en los pacientes, dando origen a una hiptesis de desequilibrio entre la hiperactivacion subcortical y el dficit prefrontal de la dopamina como responsables de la enfermedad. Una de las evidencias de este cambio hipottico se basa en que los neurolpticos clsicos, potentes antagonistas de los receptores dopaminergicos, no bastan para hacer desaparecer los sntomas negativos de la esquizofrenia, y no hay accin inmediata de mejoria sintomatica a pesar de un bloqueo casi inmediato de los receptores, adems de las evidencias aportadas por la imaginera funcional de la presencia de un metabolismo disminuido en la regin dorso lateral de la corteza pre-frontal y de su activacin frente a tareas especificas. A partir de este hallazgo, se ha podido distinguir dos zonas cerebrales con actividad dopaminergica: una cortical con la hipoactividad sealada y que inerva la region prefrontal y una zona sub-cortical, con hiperactividad y mas sensibilidad a los neurolpticos, con lo que destaca una segunda hiptesis etiopatognica de la esquizofrenia basada en la modificacin del equilibrio funcional ya mencionado entre las estructuras corticales y sub-corticales.

Estudios posteriores al ao 2000, sugieren que la relacin dopaminaesquizofrenia es mas compleja, (ya que este neurotrasmisor presente en varias regiones cerebrales parece actuar como un interruptor que facilita o inhibe la accin de otros neurotrasmisores), y compromete al menos tres alteraciones neuroqumicas especficas. La primera, referida a la hiperestimulacin de lo receptores D2 de la dopamina en la regin estratial, zona cerebral profunda en relacin con los movimientos motrices, antagonizada por neurolpticos de segunda generacin; la segunda, referida a la deficiencia en la estimulacin de los receptores dopaminrgicos prefrontales DA D1 que intervienen en el pensamiento, con responsabilidad en sntomas de ese orden en la esquizofrenia, y la tercera, que implica un disfuncionamiento del metabolismo del glutamato, a su vez, posiblemente responsable de ciertas anomalas citoarquitecturales descritas en sta patologa, ya que lo receptores glutaminergicos intervienen en el control de la migracin neuronal y de su crecimiento (Golf, Coyle, 2001). The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophreniaversion III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

En efecto, la mayoria de los estudios de pacientes con esquizofeenia usando tecnicas de imagenes revelan incremento de capacidad de sintesis dopaminergica a nivel de la funcion presinaptica de la dopamina estratial, constituyendose popr lo tanto en una evidencia replicable de las anormalidades cerebrales de la enfermedad. Incluso, los individuos que reunen los criterios de alto riesgo para desarrollar la enfermedad y aquellos con manifestaciones prodromicas en el estudio de Howes (2009), tenian niveles elevados comparados con sujetos normales y medianos con respecto a individuos ya enfermos activamente, confirmando la hipotesis de la sobreactividad dopaminergica a este nivel en el comienzo de la enfermedad.
o o

El glutamato es un neurotrasmisor excitatorio que tiene relaciones reciprocas con las proyecciones dopaminergicas corticales. Los investigadores han dado cuenta de que substancias antagonista no competitivas de los receptores del ac. N-metil D-aspartico inducen desordenes cognitivos y comportamentales que son parecidos a los sntomas negativos de los esquizofrnicos, y la inyeccin de fenciclidina disminuye la trasmisin dopaminergica a nivel de la corteza frontal pero aumenta la actividad dopaminergica en la regin mesolimdica, lo que favorece la sensibilizacin del sistema dopaminergico al estrs, con lo que se concluye que la hipoactividad dopaminergica cortical fsvorece la hiperreactividad dopaminergica mesolimdica al medioambiente mediada por una disminucin del tono glutaminergico, lo que ha hecho concluir que la disfuncion dopaminergica y el glutamato se potencian recprocamente en la ewsquizofrenia, constituyendo un verdadero circulo vicioso. Por ello, algunas substancias que son capaces de estimular inidrectamente la sctividad de los receptores NMDA, podran tener una cierta eficacia en el tratamiento de los sntomas negativos de la esquizofrenia. Tambien se ha sostenido que el disfuncionamiento del sistema glutaminergico puede estar implicado en las anomalas citoarquitecturales de las clulas, por su relacin en el control de la migracin neuronal, del crecimiento neuronal y de la gnesis de las sinapsis neuronales e incluso por estar involucrada en fenomenos de excito-toxicidad favorecidas por la hipoxia natal u otros desordenes bioqumicos que puedne llevar a la muerte neuronal. En efecto, se ha dsostenido que la patofisiologia del glutamato es inseparable del funcionamiento de sistema GABA ergico, ya que las anormalidades funcionales de la sinapsis glurtamoergicas contribuye a la neuropatologa GABAergica asociada a la esquizofrenia, en concreto, por ejemplo, los dficits de la actividad oscilatoria dependeinte del disfuncionamiento glutaminergico, puede ser el resultado de deficts funcionales del sistema GABAergico, lo que tambin interviene en la desinhibicin de las redes corticales, produciendo hiperactividad o eficiencia rducida. Obviamente, la comprensin incompleta hasta la fecha de este funcionamiento aparentemente opuesto de ambos sistemas puede ayudar a

entender mejor la variabilidad sntomatica y los dficits asociados a esta compleja patologa. Desde 1963 en adelante hasta el ao 2010 la estrategia de los investigadores ha sido la de identificar los mecanismos funcionales de este neurotrasmisor y su recepcion con el objetivo terapeutico correspondiente. En general, el hecho de que todos los medicamentos antipsicoticos con la inclusin de los agonistas parciales como el Aripripazol bloque los receptores D2 de la dopamina, y la imaginologia demuestre niveles altos de receptores D2 en individuos gemelares de sujetos con EQZ, lo que sugiere que estos receptores aumentados son necesarios para la eclosion de la psicosis, que estos receptores sean marcadores para el pronostico de la enfermedad, unidos a la evidsencia de que sintomticamente el cuadro clinico mejora cuando el 70% de los receptores es ocupado por antipsicoticos y empeora con psicoestimulantes, etc., son elementos que avalan la hiptesis original, aunque todava quede mucho por investigar en las diversas areas de las bases moleculares de la hipersensibilidad de la dopamina en una amplia variedad de alteraciones cerebrales, incluida la EQZ, sus relaciones con la genetica y sus mecanismois de control, para desarrollar antagonistas especificos efectivos en el tratamiento optimo de la enfermedad y de otras condiciones clinicas tales como la Enf. De Parkinson, el TDA, tambien asociadas a el rol cerebral de la dopamina.
o o

Las relaciones del sistema serotoninergico con el sistema dopaminergico se han puesto de relieve a partir de la evidencia de que ciertos agonistas de la serotonina (LSD), pueden indicir fenmenos psicticos como las alucinaciones. En el ultimo tiempo aparece la sugerencia de un aumneto del tono serotoninrgico central en pacientes esquizofrnicos, que parece ser mayor en los pacientes resistentes a los antipsicticos, que responden a la clozapina, un medicamento antagonista del receptor 5HT2a, de lo que se desprende de que este neurotrasmisor tiene un rol en la etiologa de la EQZ por la activacin de la corteza prefrontal mediada por un receptor 5HT2a alterado o por la interaccion dopamina-serotonina. Antagonistas de este receptor se han revelado beneficiosos para los sntomas negativos y positivos de la EQZ (Abi-Darghman, 2007), y antagonistas del receptor 5HT2aR que activan las proyecciones dopaminergicas del sistema limdico a la corteza se han revelado efectivos para combatir los sntomas negtivos del cuadro clinico

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence,

findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

Key words

Introduction
The hypothesis that dopamine and dopaminergic mechanisms are central to schizophrenia, and particularly psychosis, has been one of the most enduring ideas about the illness. Despite a relatively inauspicious startdopamine was initially thought to be a precursor molecule of little functional significancethe idea has evolved and accommodated new evidence to provide an increasingly sophisticated account of the involvement of dopamine in schizophrenia. This review summarizes the evolution of the dopamine hypothesis, which we characterize as having 2 main prior incarnations (version I, the original incarnation, and version II, which was articulated in 1991 and has been the guiding framework since). The main effort in this article is to synthesize the evidence since version II and articulate what we call The Dopamine Hypothesis of Schizophrenia: Version III, which represents the most parsimonious account of the current state of knowledge. We call it version III because we expect it to be revised. However, we highlight features of version III that we believe are sufficiently well established that they are likely to be constant in future revisions, as well as aspects that are still in evolution. Finally, we review the explanatory power of the hypothesisindicating the known aspects of schizophrenia that it can and cannot explain. Previous SectionNext Section

The Dopamine Hypothesis: Version I

The first version of the dopamine hypothesis could be entitled the dopamine receptor hypothesis. It emerged from the discovery of antipsychotic drugs1 and the seminal work of Carlsson and Lindqvit who identified that these drugs increased the metabolism of dopamine when administered to animals.2 Further evidence came from observations that reserpine, which is effective for treating psychosis, was found to block the reuptake of dopamine and other monoamines, leading to their dissipation.3 Studies showing that

amphetamine, which increases synaptic monoamine levels, can induce psychotic symptoms (reviewed in Lieberman et al4) provided additional evidence. It was not until the 1970s, however, that the dopamine hypothesis was finally crystallized with the finding that the clinical effectiveness of antipsychotic drugs was directly related to their affinity for dopamine receptors.57 The focus at the time was on excess transmission at dopamine receptors and blockade of these receptors to treat the psychosis (eg, Matthysse8 and Snyder9). While version I accounted for the data available then, it was seen as a hypothesis of schizophrenia as a whole without a clear articulation of its relationship to any particular dimension (eg, positive vs negative symptoms) and no link was made to genetics and neurodevelopmental deficits (understandably as little was then known about them), and there was little clear indication of where the abnormality was in the living brainthis would require the later application of in vivo imaging techniques. Additionally, dopamine was thought of in isolation, with little consideration of how it might relate to known risk factors for schizophrenia, and finally there was no framework for linking the dopaminergic abnormality to the expression of symptoms. Previous SectionNext Section

The Dopamine Hypothesis: Version II

In 1991, Davis et al10 published a landmark article describing what they called a modified dopamine hypothesis of schizophrenia that reconceptualized the dopamine hypothesis in the light of the findings available at the time. The main advance was the addition of regional specificity into the hypothesis to account for the available postmortem and metabolite findings, imaging data, and new insights from animal studies into corticalsubcortical interactions. It was clear by this stage that dopamine metabolites were not universally elevated in the cerebrospinal fluid (CSF) or serum of patients with schizophrenia. Also the focus on D2 receptors was brought into question by findings showing that clozapine had superior efficacy for patients who were refractory to other antipsychotic drugs despite having rather low affinity for and occupancy at D2 receptors. Furthermore, the postmortem studies of D2 receptors in schizophrenia could not exclude the confounds of previous antipsychotic treatment, and the early positron emission tomography (PET) studies of D2/3 receptors in drug-naive patients showed conflicting results. Taken together, these findings were incompatible with the simple excess dopaminergic neurotransmission proposal of version I. Furthermore, there was the paradox that dopamine metabolite measures were reduced in some patients with schizophrenia while still correlating with symptom severity and response to antipsychotic drugs. Davis et al10 drew on these inconsistencies and the emerging evidence that dopamine receptors show different brain distributionscharacterized as D1 predominantly cortical and D2 predominantly subcorticalto provide a basis for suggesting that the effects of abnormalities in dopamine function could vary by brain region. However, it was PET studies showing reduced cerebral blood flow in frontal cortex that provided the best evidence of regional brain dysfunction in schizophrenia. Hypofrontality in these studies was directly correlated with low CSF dopamine metabolite levels. Because CSF dopamine metabolite levels reflect cortical

dopamine metabolism, they argued that the relationship between hypofrontality and low CSF dopamine metabolite levels indicates low frontal dopamine levels. Thus, the major innovation in version II was the move from a one-sided dopamine hypothesis explaining all facets of schizophrenia to a regionally specific prefrontal hypodopaminergia and a subcortical hyperdopaminergia. While the evidence for this in humans was indirect, animal studies provided direct evidence of a link between hypo- and hyperdopaminergia. Lesions of dopamine neurons in the prefrontal cortex result in increased levels of dopamine and its metabolites and D2 receptor density in the striatum,11 while the application of dopamine agonists to prefrontal areas reduced dopamine metabolite levels in the striatum.12 This provided a mechanism to propose that schizophrenia is characterized by frontal hypodopaminergia resulting in striatal hyperdopaminergia. Furthermore, Davis et al10 hypothesized that negative symptoms of schizophrenia resulted from frontal hypodopaminergia, based on the similarities between the behavior exhibited by animals and humans with frontal lobe lesions and the negative symptoms of schizophrenia. Positive symptoms were hypothesized to result from striatal hyperdopaminergia, based on the findings that higher dopamine metabolite levels are related to greater positive symptoms and response to antipsychotic drug treatment. Although a substantial advance, there are a number of weaknesses in version II of the dopamine hypothesis, many of which the authors acknowledged at the time. Much of the evidence for the hypothesis relied on inferences from animal studies or other clinical conditions. There was no direct evidence for low dopamine levels in the frontal cortex and limited direct evidence for elevated striatal dopaminergic function. It was unclear how the dopaminergic abnormalities were linked to the clinical phenomenathere was no framework describing how striatal hyperdopaminergia translates into delusions or how frontal hypodopaminergia results into blunted affect, for example. Furthermore, it has subsequently become clear that the cortical abnormalities are more complicated that just the hypofrontality proposed at that time (eg, see reviews by Davidson and Heinrichs13 and McGuire et al14) and little clear evidence of frontal hypodopaminergia in schizophrenia has emerged (see below). But, more importantly, version II predated the studies into the neurodevelopment and prodromal aspects of schizophrenia, did not describe the etiological origins of the dopaminergic abnormality, and, beyond specifying hyperdopaminergia or hypodopaminergia, did not pinpoint which element of dopaminergic transmission was abnormal. Previous SectionNext Section

New Evidence and the Rationale for Version III

Much has changed since version II. There have been more than 6700 articles and 181000 citations to the topic of dopamine and schizophrenia since 1991. It is not possible to provide a comprehensive review of all the new findings since then, much less try to weave them into a coherent hypothesis. So, the focus of our effort is to identify the 5 most critical streams of new evidence, briefly summarize what we see as the key findings from these, and use them to develop the most parsimonious understanding of the role of dopamine in schizophreniaversion III.

Previous SectionNext Section

Advances in Neurochemical Imaging of Schizophrenia

Presynaptic Dopamine Function and Synaptic Dopamine
Although it is not possible to measure dopamine levels directly in humans, techniques have been developed that provide indirect indices of dopamine synthesis and release and putative synaptic dopamine levels. Presynaptic striatal dopaminergic function can be measured using radiolabelled L-dopa, which is converted to dopamine and trapped in striatal dopamine nerve terminals ready for release. This provides an index of the synthesis and storage of dopamine in the presynaptic terminals of striatal dopaminergic neurons (see review by Moore et al15). Seven out of 9 studies in patients with schizophrenia using this technique have reported elevated presynaptic striatal dopamine synthesis capacity in schizophrenia,1622 with effect sizes in these studies ranging from 0.63 to 1.89.23 The other 2 studies, both in chronic patients, reported either a small but not significant elevation24 or a small reduction in levels.25 All the studies that investigated patients who were acutely psychotic at the time of PET scanning found elevated presynaptic striatal dopamine availability,1821 with effect sizes from 0.63 to 1.25.23 This, then, is the single most widely replicated brain dopaminergic abnormality in schizophrenia, and the evidence indicates the effect size is moderate to large. The next step in dopamine transmission is the release of dopamine. Striatal synaptic dopamine release can be assessed following a challenge that releases dopamine from the neuron using PET and single photon emission computerized tomography (SPECT). The released dopamine competes with the radioligand and leads to a reduction in radiotracer binding and is considered to be an indirect index of released dopamine.26,27 All the studies using this approach have found evidence of roughly doubled radiotracer displacement in patients with schizophrenia compared with controlsan elevation that is again equivalent to a moderate to large effect size.2832 Finally, if dopamine synthesis is increased and is more sensitive to release in the face of challenges, one would expect heightened levels of endogenous synaptic dopamine when patients are psychotic. Evidence in line with this comes from a SPECT study using a dopamine depletion technique that found that baseline occupancy of D2 receptors by dopamine is also increased in schizophrenia.33

Dopamine Receptors
PET and SPECT studies have used various radiotracers to image dopamine D2/3 receptors in schizophrenia. As Davis et al10 noted, the findings of the initial studies were inconsistent, with some reporting increased D2/3 receptor binding in schizophrenia3436 and others no difference from controls.37,38 There have now been at least 19 studies investigating striatal D2/3 receptors in patients with schizophrenia and 3 metaanalyses.30,39,40 These meta-analyses conclude that there is at most a modest (10%20%) elevation in striatal D2/3 receptor density in schizophrenia independent of the effects of antipsychotic drugs. This appears to be specific to D2/3 receptorsstriatal D1 receptor densities are unaltered,30,39,41,42 and this elevation may be regionally specific because

these increases are not seen in the extrastriatal regions. If anything, there is a decrease in D2/D3 receptors in extrastriatal areas such as the thalamus and anterior cingulate.4346 The D2 receptor exists in 2 states, and it remains to be determined if the balance between these 2 states is altered in schizophrenia.47 Also, because the current tracers bind to a mix of D2 and D3 receptors, it is difficult to be precise whether changes are in the D3 or the D2 subtype of the receptorsthough preliminary data with a recently developed tracer, [11C](+)-4-propyl-9-hydroxynaphthoxazine, show that there is no abnormality in high states or in D3 receptors in schizophrenia.48 Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors, and D1 dysfunction has been linked to cognitive impairment and negative symptom in schizophrenia (see reviews by Goldman-Rakic et al49 and Tamminga50 among others). Three studies have investigated D1 receptor levels in drug-free patients with schizophrenia and found associations with cognitive impairment and negative symptoms. One reported reduced D1 receptor density41 another no difference from controls,42 and a further study using a different radiotracer reported increased D1 levels.51 This variation may be explained by different properties of the radiotracers: the effect of dopamine depletion on binding by the tracer used in the first 2 studies may obscure D1 receptor density elevation that is detectable by the tracer used in the last study.52 The increased binding shown by the tracer used by Abi-Dargham and colleagues, which was directly correlated with cognitive impairment, is thus consistent with chronic low levels of dopamine in the prefrontal cortex underlying cognitive dysfunction in schizophrenia, assuming that there has been a compensatory D1 receptor density upregulation.51 Further studies in patients are required to clarify this, particularly because both tracers may also bind to serotonin receptors.53

Treatment and Dopamine Receptors

Over 120 neurochemical imaging studies have investigated the in vivo effects of antipsychotic treatments on dopamine receptors in schizophrenia (see, eg, review by Frankle and Laruelle54). These show that at clinical doses all currently licensed antipsychotic drugs block striatal D2 receptors. Furthermore, a threshold striatal D2 blockade is required for antipsychotic efficacy, but this is not sufficientsome patients show little improvement despite high D2 occupancy.5557 A major stumbling block for the dopamine hypothesis used to be the notion that antipsychotic response was delayed for 23 weeks after the start of treatment (see review by Grace et al58). However, there is now convincing evidence that there is no delayed response: the onset of antipsychotic action is early,59,60 this response is related to striatal D2 receptor occupancy,61 and D2 occupancy at as early as 48 hours predicts the nature of response that follows over the next 2 weeks.62 Thus, the original tenet of version I still standsdopamine D2 receptors continue to dominate and remain necessary for antipsychotic treatment and the imaging data has further strengthened the quantitative and temporal aspects of this relationship. In summary, the molecular imaging studies show that presynaptic striatal dopaminergic function is elevated in patients with schizophrenia and correlates most closely with the symptom dimension of psychosis and blockade of this heightened transmission, either by

decreasing dopamine levels or blocking dopamine transmission, leads to a resolution of symptoms for most patients. Previous SectionNext Section

Advances in Understanding the Genetic Etiology of Schizophrenia

The dopamine hypothesis version II was published before the Human Genome Project and the huge advances in genetic research in schizophrenia. After over 1200 studies, it seems clear that no one gene encodes for schizophrenia.63 Rather, in common with many other complex diseases, there are a number of genes each of small effect size associated with schizophrenia.63 The gene database on the Schizophrenia Research Forum (http://www.schizophreniaforum.org) provides a systematic and regularly updated metaanalysis of genetic association studies. As of autumn 2008, 4 of the top 10 gene variants most strongly associated with schizophrenia are directly involved in dopaminergic pathways. The strongest association is with a gene variant affecting the vesicular monoamine transporter protein (rs2270641, odds ratio 1.63). This protein acts to accumulate dopamine and other monoamines into vesicles, which fits with the PET studies that show elevated radiolabeled dopamine accumulation into striatal vesicles in schizophrenia. Additionally, other gene variants in the list of the strongest associations, such as in the genes for methylenetetrahydrofolate reductase and V-akt murine thymoma viral oncogene homolog 1, indirectly affect the dopaminergic system among other effects.64 Many of the other gene variants in the top list are involved in brain development, such as the gene for dysbindin, or influence more ubiquitous brain transmitters such as glutamate or -aminobutyric acid (GABA).63,64 While recent findings have breathed great interest in the copy number variations in schizophreniathe early evidence there also suggests that they are rare, tend to be unique to families, and are unlikely to account for more than a few percent of schizophrenia.63,6567 It would be premature to try and synthesize these genes into a pathway leading to dopamine abnormality because the precise number, nature, function, and association of these genes to schizophrenia is evolving. The most parsimonious statement that can be made today is that while a number of genetic associations have been identified, none of them accounts for the majority of schizophrenia and most of them are likely to be susceptibilities. Of the ones that have been identified, some have already been tied to altered dopamine transmission.68 However, the functional relevance of most of them to dopamine function is not known.68 This view of schizophrenia genetics then reemphasizes a critical role for other interacting factors particularly the environmental risk factors for schizophrenia. Previous SectionNext Section

Environmental Risk Factors for Schizophrenia

A large number of disparate environmental factors clearly contribute to the risk for schizophrenia, yet many hypotheses of schizophrenia, including previous versions of the

dopamine hypothesis, make no allowance for them. Markers of social adversity such as migration, unemployment, urban upbringing, lack of close friends, and childhood abuse are all associated with a well-established increased risk for schizophrenia that cannot readily be explained by genetic factors alone.69 These factors either directly index social isolation/subordination or are linked to these experiences.70 Studies in animals of social isolations7173 and subordination73,74 find that these factors lead to dopaminergic overactivity. Other environmental factors, such as pregnancy/obstetric complications, act in early life to increase the subsequent risk of schizophrenia (reviewed by Cannon et al,75 Geddes and Lawrie,76 and Kunugi et al77). There is now substantial evidence from animal models that pre- and perinatal factors can lead to long-term overactivity in mesostriatal dopaminergic function (reviewed by Boksa and El-Khodor78 and Boksa79). For example, neonatal lesions affecting the hippocampus80,81 or frontal cortex82 increase dopamine-mediated behavioral responses in rats, as does prenatal stress, whether induced by corticosterone administration83 or maternal handling.84 Neonatal exposure to toxins also leads to increased dopamine-mediated behavioral responses85 and elevated striatal dopamine release.86 Prenatal and neonatal stress, such as maternal separation, also increases striatal dopamine metabolism83 and release.87,88 The latter findings parallel the increased presynaptic dopaminergic function found in schizophrenia. A number of psychoactive substances also increase the risk of schizophrenia. The relationship between stimulants, psychosis, and their effects on dopaminergic function has already been considered (eg, Lieberman et al,4 Angrist and Gershon,89 and Yui et al90). However, recent PET imaging work has shown that even a few doses of a stimulant may sensitize the striatal dopamine system and can lead to enduring increases in dopamine release to amphetamine even after many months of abstinence.91 Since earlier versions of the dopamine hypothesis, cannabis use has emerged as a risk factor for schizophrenia.92,93 The main psychoactive component of cannabis primarily acts at cannabinoid receptors,94 and this as well as other cannabinoid agonists have been shown in animals to increase striatal dopamine release.95,96 Initial findings indicate this is the case in man as well,97 a result supported by observations that dopamine metabolite levels are increased in patients admitted during a first episode of psychosis associated with cannabis use.98 Psychoactive drugs acting on other systems may also indirectly act on the dopaminergic system by potentiating dopamine release caused by other effects. This has been shown for the Nmethyl-D-aspartic acid (NMDA) blocker ketamine, which has been found to increase amphetamine-induced dopamine release in healthy humans to the levels seen in schizophrenia.99 These new data therefore indicate that even psychoactive drugs that do not directly act on the dopamine system can impact on dopamine release through indirect effects. Previous SectionNext Section

Multiple Routes to Dopamine Dysfunction: Interacting Environmental and Genetic Factors

Genes and environmental factors do not exist in isolation. Many add to each other, and some show synergistic effects on the risk of schizophrenia or brain abnormalities associated with schizophrenia (see, eg, Cannon et al100 and Nicodemus et al101 and reviews by Mittal et al102 and van Os et al103). Furthermore, animal studies indicate that at least some of these factors interact in their effects on the dopamine system: social isolation rearing potentiates the later effects of stimulants104,105 or of stress106 on the dopamine system.105 Similar effects have also been found in humans, where striatal dopamine release in response to stress was increased in people who reported low maternal care during their early childhood.107 Additionally, there are interactions with other neurotransmitter systems: dopamine release is not seen under the influence of ketamine alone108 but enhances the action of amphetamine, suggesting the effects of NMDA blockade, or by extension other putative causes of glutamatergic dysfunction, such as neonatal insults, are modulatory. GABA interneurons are also involved in the regulation of subcortical dopamine function and have been implicated in schizophrenia.109 Interactions between gene variants, including those influencing dopaminergic function, and environmental risk factors are another possible route to dopaminergic dysfunction. This is illustrated by findings that variants of the catechol-O-methyltransferase gene (involved in dopamine catabolism) interact with early cannabis exposure to increase the subsequent risk of psychosis110 and, in other studies, to increase stress reactivity and paranoid reactions to stress (see review by van et al70). Family history of psychosis also interacts with environmental factors such as urbanicity to increase the risk of schizophrenia.111,112 Additionally, genetic risk for schizophrenia appears to interact with obstetric complications: some schizophrenia genetic factors make the individual more susceptible to the effects of obstetric complications, such as frontal and temporal structural abnormalities (see review by Mittal et al102). As reviewed above, animal studies indicate that frontal and temporal dysfunction can lead to increased striatal dopamine release and suggest that this is another route to dopamine dysregulation. While further work is clearly needed to investigate the nature and extent of all these possible interactions, the evidence indicates that many disparate, direct and indirect environmental and genetic, factors may lead to dopamine dysfunction and that some occur independently while others interact. The striking empirical fact is this: the relative risks for developing schizophrenia that are accorded to migration (about 2.9113), obstetric complications (about 2.0, see meta-analyses75,76), and frequent cannabis or amphetamine use (2.09 for cannabis93 and about 10 for amphetamine use114) are considerably higher than those for any single gene variant. Thus, as the dopamine hypothesis evolves, the scientific challenge will be not just to find predisposing genes but to articulate how genes and environment interact to lead to dopamine dysfunction. Previous SectionNext Section

Findings From the Prodrome and Extended Phenotype of Schizophrenia

Another area of significant neurobiological research over recent years has focused on the early signs, or prodrome, of the illness and the subtler manifestations of symptoms within family members and the population at large. These groups are at increased risk of schizophrenia but have not yet developed the illness. Evidence from studying these groups therefore has the potential to provide information about the causal chain of events leading to the development of schizophrenia. Individuals meeting clinical criteria for a high risk of psychosis, eg, have an approximate 400-fold increased risk of developing of psychotic illnesses, predominantly schizophrenia, within the following few years.115,116 They show elevated striatal [18F]-dopa accumulation, which is positively associated with greater symptom severity and approaches the levels seen in patients with schizophrenia.20 Elevated presynaptic striatal dopaminergic function is also seen in other groups with an increased risk of developing psychosis, such as schizotypy,117,118 and the relatives of people with schizophrenia.119 The latter also show a greater change in dopamine metabolite levels in response to a given stressor than healthy controls120 and an association between greater change in dopamine metabolite levels with higher levels of psychotic-like symptoms following stress.121 These dopaminergic abnormalities appear intermediate to those seen in patients with schizophrenia,20,117,120 although this needs to be tested in adequately powered studies. Overall, these findings indicate that dopaminergic abnormalities are not just seen in people who are frankly psychotic but are also seen in people with risk factors for psychosis, who often have symptoms, albeit at a less severe level. Furthermore, stress in these individuals has been linked to both an increase in these symptoms and an increase in dopaminergic indices (see review by van et al70). This suggests that the dopaminergic abnormalities might underlie psychosis proneness and shows how the environment might further impact on this to lead to frank psychosis. A further development since version II of the dopamine hypothesis is the evidence regarding structural differences prior to the onset of schizophrenia. Individuals with prodromal signs also show brain structural deficits, quite like those in patients, although to a lesser degree (see review by Wood et al122), as do the relatives of people with schizophrenia and people with schizotypal features123 (see review by Dickey et al124). These brain abnormalities are in frontotemporal regionsthe same areas where lesions in animals result in striatal dopaminergic abnormalities.80,82,125 There is also evidence of longitudinal brain structural changes in schizophrenia (eg, DeLisi126 and van Haren et al127) and people at risk of schizophrenia.122,128 However, the contribution of factors such as medication129,130 and cannabis use131 to the longitudinal brain changes has yet to be fully resolvedas such these changes are not addressed in the proposed dopamine hypothesis: version III. It is not just brain structure that is altered in these individuals at risk of schizophreniathere are functional differences as well that are generally in similar brain regions to those seen in schizophrenia (see reviews by Fusar-Poli et al132 and Lawrie et al133) and a similar pattern of neurocognitive impairments to those seen in schizophrenia, although again to a lesser degree (see review and subsequent studies by Brewer et al,134 Eastvold et al,135 and Simon et al136). Parsimoniously, one can conclude that striatal dopaminergic elevation is present in a compromised brain in schizophrenia and that the same appears true in the extended phenotype. Furthermore, there is some evidence that the 2 are connected in the prodrome as well as in schizophrenia: greater striatal dopaminergic elevation in prodromal

individuals is directly associated with poorer neurocognitive function and altered activation in frontal cortical areas during the task.20 There are also indications that there may be a gradation in the degree of dopaminergic elevation, although direct comparisons are required to substantiate this. Finally, recent studies in schizophrenia and its prodrome have begun to further localize the presynaptic dopamine elevation in the striatum to the parts functionally linked to associative cortical areas.20,137 Previous SectionNext Section

Schizophrenia or Psychosis
The diagnosis of schizophrenia encapsulates patients with markedly different clinical features and courses (see reviews by Dutta et al138 and Peralta and Cuesta139). Classification systems have attempted to deal with this categorically by proposing subtypes and intermediate syndromes.138,139 On the other hand, factor analyses have identified a number of symptom dimensions: positive, negative, disorganized, affective, and cognitive, eg, Dutta et al138 and Peralta and Cuesta.139 The dominance and mix of the dimensions may fluctuate during the natural history of the illness.138,139 Additionally, many patients meet Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria for other psychiatric disorders as well.140 Despite this variability, it remains the fact that the vast majority of patients with schizophrenia come to clinical attention due to their psychosis. However, psychosis itself is not unique to schizophrenia. About 8% of the general population also report psychotic experiences, and in some 4% or so this is associated with impairment and distress (see review by van Os et al141). Thus, the distinction between clinical and subclinical psychosis may reflect interacting personal and sociocultural factors as much as it does biology.141 The paragraph above underlines that it would be highly implausible that any one biological factor could deterministically explain a diagnosis of schizophrenia. A much more likely scenario is that a biological dysfunction may contribute to one of the major dimensions of the illness. The evidence certainly suggests that striatal dopamine function appears most elevated in people who are acutely psychotic whether in the context of schizophrenia or psychosis seen in another condition. The dopamine dysfunction is present even in subjects reflecting the extended phenotypefamily members, people with schizotypy, and symptomatic individuals at high risk of psychosis.20,117,119 Thus, the current evidence is consistent with dopamine hyperfunction being most closely linked to the dimension of psychosis. Insofar because psychosis is a hallmark of schizophrenia, dopamine abnormality is routinely seen in schizophrenia. However, we would predict that if nonpsychotic forms of schizophrenia were studied (and such a category is allowable under the DSM-IV), they would not show similar dopamine abnormalitiesthus dissociating psychosis from schizophrenia. Previous SectionNext Section

Specificity of Presynaptic Striatal Dopamine Elevation to Schizophrenia or Psychosis

Striatal dopamine elevation is not seen in mania, depression, or other psychiatric disorders without psychosis142147 and not related to measures of anxiety or depression in people with psychotic symptoms.20,148 Thus, it is not a nonspecific indicator of psychiatric morbidity. However, striatal dopamine elevation is seen in psychosis associated with psychosis in at least one disorder other than schizophrenia.22 Furthermore, dopamine blockade with antipsychotic drugs does not respect diagnostic boundaries eitherit is effective for psychosis related to mania, depression, or Parkinson disease149,150 as well as for psychosis in schizophrenia. While further studies and direct comparisons are required, dopamine elevation appears specifically related more generally to psychosis proneness and not just to psychosis in schizophrenia. Previous SectionNext Section

Linking Dopamine Abnormalities to Clinical Expression of Schizophrenia

If a neurochemical hypothesis (based on dopamine or any other neurotransmitter) is to explain a psychiatric illness defined by its clinical expression, it has to link the 2. A major shortcoming of the first 2 versions of the dopamine hypothesis was the total silence on the issues of how dopaminergic abnormalities led to the clinical expression of the disease. Since version II of the dopamine hypothesis, developments in neuroscience have provided increasing evidence of dopamine's role in motivational incentive salience. The experiments and syntheses of data by Berridge and Robinson,151 Robbins and Everitt,152,153 and Schultz and others154158 have implicated a distinct role for subcortical dopamine systems in incentive or motivational salience and reward prediction, respectively. These conceptualizations provided a framework to link neurochemical dysfunction to clinical expression using concepts of salience and reward. According to one such extension of the dopamine hypothesis,159,160 the abnormal firing of dopamine neurons and the abnormal release of dopamine leads to an aberrant assignment of salience to innocuous stimuli. It is argued that psychotic symptoms, especially delusions and hallucinations, emerge over time as the individual's own explanation of the experience of aberrant salience. Psychosis is, therefore, aberrant salience driven by dopamine and filtered through the individual's existing cognitive and sociocultural schemasthus allowing the same chemical (dopamine) to have different clinical manifestations in different cultures and different individuals.159,160 Incentive salience models also provide a plausible explanation for negative symptoms: dopamine dysregulation may increase the noise in the system, drowning out dopaminergic signals linked to stimuli indicating reward, eg, Roiser et al161 and Seamans and Yang.162 The net result would be reduced motivational drive that would lead over time to negative symptoms, such as social withdrawal, and neglect of interests. As an explanation, this has face validity, and there is some evidence that schizophrenia is associated with reduced ventral striatal activation to reward, and greater reduction is related to higher levels of negative symptoms.163 However, this proposal and

the hypothesis linking low frontal dopamine levels to the cognitive impairments in schizophrenia both need to be tested by further in vivo studies of neurochemical function in patients. Previous SectionNext Section

The Dopamine Hypothesis of Schizophrenia: Version III

We propose a revised third version of the dopamine hypothesis to account for the new evidence, drawing on the work of many previous reviews (eg, Laruelle and AbiDargham,32 van et al,70 Cannon et al,164 and Howes et al165). The hypothesis has 4 distinctive components. Firstly, we hypothesize that multiple hits interact to result in dopamine dysregulation the final common pathway to psychosis in schizophrenia. This is illustrated schematically in figure 1. Second, the locus of dopamine dysregulation moves from being primarily at the D2 receptor level to being at the presynaptic dopaminergic control level. Third, dopamine dysregulation is linked to psychosis rather than schizophrenia, and perhaps in the fullness of time it will be about psychosis proneness. The exact diagnosis, however, reflects the nature of the hits coupled with sociocultural factors and not the dopamine dysfunction per se. And finally, the dopamine dysregulation is hypothesized to alter the appraisal of stimuli, perhaps through a process of aberrant salience.

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Fig. 1. Multiple hits interact to result in striatal dopamine dysregulation to alter the appraisal of stimuli and resulting in psychosis, whilst current antipsychotic drugs act downstream of the primary dopaminergic dysregulation. Previous SectionNext Section

Implications of the Dopamine Schizophrenia: Version III

Hypothesis

of

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis. There is some evidence from healthy volunteers that acute antipsychotic treatment does increase presynaptic dopamine synthesis capacity,166 and while successful subacute treatment can reduce this,167 it is nevertheless elevated in patients who have received antipsychotic treatment for many years.17 This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects. Previous SectionNext Section

What About the Other Dimensions of Schizophrenia in Version III?

An attractive feature of version II was that it proposed a dysfunction in the dopamine system as a complete explanation for schizophrenia: a prefrontal hypodopaminergia leading to a subcortical hyperdopaminergia. We depart from this parsimony in version III mainly because in the last 2 decades there has been little convincing evidence for this sequence of dopamine dysfunction. On the other hand, the last 2 decades have provided substantially more evidence about the multiple routes (genetic, neurodevelopmental, environmental, social) that lead to the striatal hyperdopaminergia, as discussed earlier. Furthermore, the appreciation of the dimensional nature of symptoms of schizophrenia also speaks for partial independence of the different features (cognitive, negative) from psychosis.139 There is of course correlational evidence that striatal dopamine abnormalities are associated with poor performance on cognitive tasks17,20,168 and suggestion that higher striatal dopamine synthesis capacity is linked to functional abnormalities in the cortical regions engaged by these tasks.168,169 However, it should be noted that recent data suggest that these frontal/cognitive changes need not necessarily be primary but instead may arise as a consequence of striatal dysfunction.170 Thus, in contrast to version II, which proposed a single pathway, we propose that changes in multiple transmitter/neural systems underlie the cognitive dysfunction and negative symptoms of schizophrenia, and in many cases these dysfunctions precede the onset of psychosis. It is when these pathways, in convergence with other biological or environmental influences, lead to striatal dopamine hyperfunction that psychosis becomes evident and the label of schizophrenia is assigned. Thus, rather than being a hypothesis of schizophreniaversion III is more accurately a dopamine hypothesis of psychosis-in-schizophrenia. It remains to be tested whether this is specific to psychosis of schizophrenia or is seen with psychosis in other disorders too.

Previous SectionNext Section

What Would Lead to a Rejection of the Hypothesis?

Because so much is unknown, it is given that the hypothesis will be revised as more data become available. The more intriguing question is whether one can envisage evidence that would lead to a wholesale rejection of the hypothesis. The 2 central claims of version III are the primacy of the presynaptic abnormality and the claim that dopamine is the final common pathway. Two different kinds of evidence could lead to a complete rejection of the hypothesis. PET studies directly implicating presynaptic dopamine dysfunction are a major foundation of this new version of the hypothesis. PET data require to be modeled to provide estimates of L-dopa uptake or synaptic dopamine levelsand the results are inferred rather than direct measurements. Thus, if it turns out that the body of evidence based on PET imaging is a confound or an artifact of modeling and technical approaches, this would be a serious blow for version III, though the data behind versions I and II would still stand strong. While possible, we think this to be highly unlikely. What is perhaps more likely is that a new drug is found that treats psychosis without a direct effect on the dopamine system. In other words, the dopamine abnormalities continue unimpeded, and psychosis improves despite them. A good example of such a new drug might be LY2140023, an mGlu 2/3 agonist.171 If this were to be an effective antipsychotic and it could be shown that the new pathways do not show any interaction with the dopamine system, then the fundamental claim of version III, that it is the final common pathway, would be demolished. A similar situation would arise if a pathophysiological mechanism that does not impact on the dopamine system is found to be universal to schizophrenia. Much more likely is the possibility that the hypothesis will be revised but with a stronger version IV. The next decade will provide more information on the role of dopamine, particularly how genetic and environmental factors combine to influence the common pathway, and better drugs will be developed that directly influence presynaptic dopaminergic functionboth logical successors to the idea of a final common pathway. Previous SectionNext Section

Conclusions
A considerable body of new evidence has amassed in the last 2 decades that is not compatible with reconceptualization of Davis and colleagues of the dopamine hypothesis of schizophrenia. To account for these developments, we have elaborated the dopamine hypothesis of schizophrenia: version IIIthe final common pathway. This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. Furthermore, it provides a framework linking the abnormal neurochemistry to symptoms and explains both why many disparate risk factors and functional and structural abnormalities are associated with schizophrenia but are not specific to schizophrenia. It provides an explanation for overlapping findings in people with risk factors for schizophrenia and explains eventual diagnosis not in neurochemical terms but as the result of individual factors interacting with the sociocultural milieu. In addition to

funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. It follows from this that future drug development should focus on the systems acting on the funnel points leading to the final common pathway. Previous SectionNext Section

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Otros neurotrasmisores Sistemas neurales Factores del desarrollo neuronal

La teora del neurodesarrollo, intenta explicar la etiopatogenia de la enfermedad en base a los daos producidos por diversos agentes en el primer y segundo trimestre del embarazo sobre los circuitos neurales en la adolescencia o al comienzo de la vida adulta dando lugar a las manifestaciones clnicas de la esquizofrenia. Para ello rene toda la evidencia acumulada de la patologa cerebral desde las anomalas morfolgicas hasta los cambios en la expresin normal de las protenas involucradas en la migracin neuronal temprana, desde los factores ambientales como complicaciones obsttricas e infecciones virales hasta las complejas relaciones genes-medioambiente, para sustentar las bases del modelo del desarrollo-neuronal de la esquizofrenia. De acuerdo a este punto de vista etiopatogenico de la enfermedad, sta seria el producto de un proceso patolgico que tiene un origen gentico-ambiental en el embarazo o en periodo peri-natal, que se expresa cuando el cerebro alcanza un estado de cierta maduracin anatmica y funcional 1 activando los circuitos neurales patolgicos durante la adolescencia o la adultez temprana 2,3,4. Una de las primeras evidencias de sta forma de entender la etiopatogenia vincul el parecido de la epilepsia del lbulo temporal a la esquizofrenia6. Keshavan, mas adelante, refiere que la injuria tisular temprana lleva en periodos criticos del desarrollo del sistema

nervioso a combinar su accin sobre redes neurales especificas, responsables de los prodromos sintomaticos en individuos que mas tarde desarrollan la enfermedad, sobrer todo en la adolescencia cuando la perdida de plasticidad y la eliminacin de sinapsis lo permite 8,9 Por otro lado, la injuria cerebral derivada de las anomalias congenitas en los pacientes esquizofrenicos se encuentran suficientemente fundadas10,11 e incluyen

desde estenosis del conducto de Silvio y agenesia del cuerpo calloso, hasta estigmas faciales que se vinculan con anomalas propias del primer trimestre del embarazo, y otras relacionadas con el segundo trimestre, como los dermatoglifos en pacientes y parientes de esquizofrenicos. Mas adelante, en la niez, se encuentran signos neurolgicos blandos en individuos que posteriormente desarrollan la enfermedad 1416, como tambien signos de deterioro social y animico, ansiedad y dificultades en la atencion en hijos de padres con esquizofrenia, como signo de alto riesgo para el desarrollo posterior del trastorno, enfatizando el hecho de que la enfermedad es un sndrome derivado de un desarrollo cerebral anormal.
Las complicaciones obsttricas y peri-natales en pacientes esquizofrnicos tambin han sido objeto de variadas investigaciones que demuestran lesiones cerebrales hemorrgicas, por hipoxia o isquemia. Las infecciones virales y las fechas de nacimiento en invierno como fuente de potenciales infecciones y daos en el SNC en pacientes psicticos esquizofrnicos han sido documentados en el estudio finlandes30 en relacin a la epidemia de gripe de 1957, con un incremento del riesgo para esquizofrenia del 50%, estudio replicado con posterioridad sealando la misma asociacin2 . Otras evidencias de agentes infecciosos en el embarazo relacionados con incremento de riesgo de esquizofrenia posterior incluyen el toxoplasma gondii, la rubeola y los retrovirus. Los mecanismos por los cuales actan los virus en el cerebro del feto son la infeccin directa via transplacentaria y la via por induccin de produccin de citoquina por el sistema inmune de la madre 4448, conocida por la regulacin del normal desarrollo cerebral e implicada en gnesis cortical anormal5052, por lo tanto, con un rol preponderante en el neurodesarrollo. Otros factores ambientales asociados al mismo efecto posterior son la hambruna durante el embarazo 63,64 y el factor Rh 65. Ademas, es necesario decir que la expresin gentica cerebral cambia en respuesta a la infeccin viral pre-natal7173 lo que constituye una de las variadas vias por las cuales la infeccion puede desarrollar una esquizofrenia posterior. Otra via es la activacin de la respuesta inmune materna que altera los niveles de citoquina 48.

Desde el punto de vista genetico, los investigadores han comprobado anormalidades cromosmicas y genes especficos, cuyo modo de trasmisin en la esquizofrenia no correponde al modelo mendeliano, implicados en el crecimiento y migracin celular

91 mielizacion

myelination,89,99 regulation of presynaptic membrane function,92,93 and -aminobutyric acidmediated (GABAergic) function.89,94 By far, the most well-studied and replicated data deal with genes involved in oligodendrocyte- and myelin-related functions. Hakak et al89 using mostly elderly schizophrenic and matched control dorsolateral prefrontal cortex (DLPFC) homogenates showed downregulation of 5 genes whose expression is enriched in myelin-forming oligodendrocytes, which have been implicated in the formation and maintenance of myelin sheaths. Later, Tkachev et al99 using area 9 homogenates from Stanley Brain Collection showed significant downregulation in several myelin- and oligodendrocyte-related genes such as proteolipid protein 1,96 myelinassociated glycoprotein, oligodendrocyte-specific protein CLDN11, myelin oligodendrocyte glycoprotein, myelin basic protein, neuroregulin receptor v-erb-a erythroblastic leukemia viral oncogene homolog 3 (ERBB3), transferrin, olig 1, olig 2, and SRY Box 10. 99 Mirnics et al92 showed downregulation of genes involved in presynaptic function in the PFC such as methylmaleimide-sensitive factor, synapsin II, synaptojanin 1, and synaptotagmin 5. Vawter et al93 showed downregulation of histidine triad nucleotidebinding protein and ubiquitin-conjugating enzyme E2N. Another important family of genes involved in schizophrenia are genes involved in glutamate and GABAergic function220,221. Hakak et al89 showed an upregulation of several genes involved in GABA transmission, such as GAD65- and 67-kDa protein genes. However, several reports have shown decreases in these proteins in schizophrenia.97,98,100 Hashimoto et al94 showed a downregulation of parvalbumin gene, and Vawter et al93 showed downregulation of glutamate receptor -amino-3-hydroxyl-5-methyl-4-isoxazoleproprionate (AMPA). Another gene family of import in schizophrenia deals with signal transduction. Hakak et al89 showed upregulation of several postsynaptic signal transduction pathways known to be regulated by dopamine, consistent with the dopamine hypothesis of schizophrenia95,101 such as cAMP-dependent protein kinase subunit RII- and nel-related protein 2. In a similar vein, Mirnics and Lewisl90 also showed downregulation of RGS4 gene in PFC of schizophrenia. Recently in a study of temporal gyrus, Bowden et al,102 found that a number of genes related to neurotransmission (GRIN2B, GRIP2, SYT7), neurodevelopment (DAB1,

SEMA5A), and intracellular signaling (PIK3R1, CACNG2) were significantly altered.102 Chung et al91 showed upregulation of heat shock 70 gene in schizophrenic brain.91 A number of schizophrenia candidate genes have been found to change in PFC over the course of the life span in brain samples from control subjects via microarray: (1) RGS4 and glutamate receptor metabotropic 3 (GRM3) expression decreased across the age range, (2) PRODH and DARPP32 expression increased with age, and (3) NRG1, ERBB3, and nerve growth factor receptor showed altered expression during the years of greatest risk for the development of schizophrenia.103 Interaction Between Genes and Environment
Genetic risk factors may also interact with obstetric complications to increase risk of schizophrenia,104106 and it has been suggested known susceptibility genes for schizophrenia were more likely than randomly selected genes to be regulated by hypoxia/ischemia.107 Nicodemus et al108 recently tested whether a set of 13 schizophrenia susceptibility genes thought to be regulated in part by hypoxia statistically interact with obstetric complications. Four genes: v-AKT murine thymoma viral oncogene homolog 1, brain-derived neurotrophic factor, DTNBP1, and GRM3 showed significant interactions,76 and all 4 have been shown to have neuroprotective roles.107 In a study of schizophrenia candidate genes, Schmidt-Kastner et al107 found that at least 50% were regulated by hypoxia and/or were expressed in the vasculature.107 These genes included CHRNA7, COMT, GAD1, NRG1, RELN, and RGS4.107 The authors proposed that the interaction of genes and internal environmental factors, in this case hypoxia, resul t in developmental perturbations leading to a predisposition to schizophrenia.107 However, additional external factors would have to come into play postnatally for the full development of schizophrenia.107 Another approach to studying the genetic contribution is to examine rare structural variants including microduplications and microdeletions. These have previously been shown to underlie illnesses including neurological and neurodevelopmental syndromes.109 Two recent reports by Walsh et al110 and the International Schizophrenia Consortium111 have used this approach in subjects with schizophrenia. Walsh et al110 found that novel deletions and duplications of genes were present in 5% of controls compared with 15% of subjects with schizophrenia (P < .0008) and 25% of subjects with early-onset schizophrenia (P < .0001). The majority of genes identified were disproportionately associated with pathways important for brain development, including synaptic long-term transmission, NRG signaling, axonal guidance, and integrin signaling.110 A large-scale genome-wide survey of copy number variants (CNVs) performed by the International Schizophrenia Consortium111 revealed that subjects with schizophrenia were 1.15 times more likely to have a higher rate of CNVs than controls.111 Associations with schizophrenia were found for large deletions of regions on chromosomes 1, 15, and 22 impacting a number of genes.111

Interestingly, 19 of the genes impacted in both articles have also been significantly upregulated or downregulated following prenatal viral infection at embryonic days 9, 16, and 18 with our animal model (table 4) providing further convergence between our model and human genetic data. Two genes, v-erb-a erythroblastic leukemia viral oncogene homolog 4 (Erbb4) and solute carrier family 1 (glial high-affinity glutamate transporter), member 3 (Slc1a3), have been previously associated with schizophrenia.112,113 Erbb4 gene codes for a transmembrane tyrosine kinase receptor for NRG1. This gene is involved in neuron and glial proliferation, differentiation, and migration processes. Binding of Erbb4 and NRG1 leads to NMDA receptor current propagation, a process that is apparently defective in schizophrenia.112 A recent report shows that polymorphisms in NRG1 are associated with gray and white matter alterations in childhood-onset schizophrenia,114 a striking similarity seen in our viral model of schizophrenia, where brain atrophy also occurs in puberty in the exposed mice.71 The significant increase in Erbb4 mRNA we have observed may be due to decreases in levels of NRG1 in the exposed mice.71 Erbb4 also interacts with 2 other genes common to both lists: discs, large homolog 2115 and membrane-associated guanylate kinase, inverted 2 at neuronal synapses.116 View this table:

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Table 4. Novel Structural Variants in Genomic DNA That Delete or Duplicate Genes in Subjects With Schizophrenia and Controls Similar to Genes Significantly Altered Following Prenatal Viral Infection Slc1a3 codes for a glutamate transporter found on glial cells that functions to regulate neurotransmitter concentrations at excitatory glutamatergic synapses.117,118 Slc1a3 has been shown to be elevated in thalamus of subjects with schizophrenia.113 We have also observed elevated levels of Slc1a3 mRNA following prenatal viral infection at E16 in cerebellum at P56, in hippocampus at P0, and in PFC at P14 (S.H.F., unpublished observations, 2008). The 506-kb deletion that disrupts Slc1a3 also disrupts S-phase kinaseassociated protein 2 (Skp2), which suppresses apoptosis mediated by DNA damage,118 and leads to the formation of a chimeric transcript.110 Interestingly, Skp2 mRNA is similarly elevated in cerebellum at P56 following prenatal viral infection at E16 (S.H. Fatemi, unpublished observations, 2008). Further analysis of some of the virally regulated brain genes in the exposed progeny that were also similarly disrupted in subjects with schizophrenia by microdeletions or microduplications included (1) HpaII tiny fragments locus 9c, which is involved in nucleic acid metabolism, has recently been shown to be associated with a deficit in sustained attention within schizophrenia in a Taiwanese cohort119; (2) protein tyrosine kinase 2, also known as focal adhesion kinase, which is involved in axonal outgrowth120; and (3) SWI/SNFrelated, matrix-associated, actin-dependent regulator of chromatin, subfamily a,

member 2, which is involved in cell differentiation and may be involved in the conversion of oligodendrocyte precursor cells to neural stem cells.121 A recent study by Carter122 has demonstrated the importance of the interaction of genes related to the life cycles of pathogens and schizophrenia. Carter examined 245 schizophrenia candidate genes and found that 21% interact with influenza virus, 22% interact with herpes simplex virus 1, 18% interact with cytomegalovirus, 12.6% interact with rubella, and 16% interact with Toxoplasma gondii.122 These percentages suggest a general overrepresentation of pathogen-related genes in the set of schizophrenia candidate genes. These genes code for ligand-activated receptors (fibroblast growth factor receptor 1 [FGFR1]), adhesion molecules (neuronal cell adhesion molecule 1 [NCAM1]), molecules involved with intracellular traffic (DISC1), among others.122 Carter122 suggests that the variability observed in gene association studies may be partly explained by presence/absence of the pathogen that would affect the strength of association.

Brain Pathology
A consistent observation in schizophrenia is the enlargement of the cerebroventricular system. The abnormalities are present at onset of disease, progress slowly,1 and are unrelated to the duration of illness or treatment regimen.10 Additionally, cerebroventicular enlargement distinguishes affected from unaffected discordant monozygotic (MZ) twins. A large number of computed tomography and magnetic resonance imaging (MRI) studies indicate lateral and third ventricular enlargement and widening of cortical fissures and sulci.123 Furthermore, gross brain abnormalities have been identified in DLPFC, hippocampus, cingulate cortex, and superior temporal gyrus.10,124 Some reports also indicate presence of brain structural abnormalities in individuals at high risk for development of schizophrenia and in unaffected first-degree relatives of subjects with schizophrenia.125 More recently, studies of white matter tracts show evidence of disorganization and lack of alignment in white fiber bundles in frontal and temporoparietal brain regions in schizophrenia.126 Numerous reports have documented the presence of various neuropathologic findings in postmortem brains of patients with schizophrenia.127 These findings consist of cortical atrophy, ventricular enlargement, reduced volume of amygdala and parahippocampal gyrus, and cell loss and volume reduction in thalamus.127,128 Several cytoarchitectural studies give credence to the idea of early abnormal laminar organization and orientation of neurons in subjects with schizophrenia including (1) decreased entorhinal cellularity in superficial layers I and II, incomplete clustering of neurons in layer II, and the presence of clusters in deeper layers where they are normally not found129; (2) findings similar to those in the entorhinal cortices in PFC and cingulate cortex127,130,131; and (3) reduced nicotinamide alanine dinucleotide phosphate (NADPH)-diaphorase (NOS)positive cells (remnants of the embryonic subplate zone) in cortical layers I and II and increased density in deep layers (subcortical white layer or the putative vestigial subplate zone) in DLPFC and hippocampal and lateral temporal cortices.132 Specific regions of the frontal cortex are associated with schizophrenia, most notably the DLPFC (for a review see Bunney and Bunney130) as well as the orbitofrontal cortex, medial PFC, and ventromedial PFC.133135 Changes in the

frontal cortex include abnormal translocation of NADPH-diaphorasepositive cells132 and reduced gray matter volume.136 Hippocampal abnormalities include disturbed cytoarchitecture, abnormal translocation of NADPH-diaphorasepositive cells, and an overall reduction in volume.132,137 A greater prevalence of hippocampal shape anomaly, characterized by a rounded shape, medial location, and a deep collateral sulcus, has been found in familial schizophrenia patients.138 There is also evidence of irregular arrangement of neurons in the entorhinal cortex and disoriented pyramidal cells in CA1CA3 subfields in subjects with schizophrenia when compared with controls.139,140 Moreover, there is evidence of biochemical changes, including glutamatergic and GABAergic dysfunction in the hippocampus of subjects with schizophrenia.141,220,221 In cerebellum, reduced cell size in Purkinje cells have been observed.127 Structural MRI studies have shown cerebellar atrophy associated with schizophrenia.142144 More recently, however, a study has shown an increase in cerebellar volume in subjects with schizophrenia.145 Additionally, functional MRI investigations using cognitive tests have demonstrated decreased activation in cerebellum of schizophrenic patients.146148 Several recent reports using MRI and diffusion tensor imaging have shown reduced white and gray matter diffusion anisotropy in patients with schizophrenia.149151 In brain white matter, water diffusion is highly anisotropic, with greater diffusion in the direction parallel to axonal tracts. Thus, reduced anisotropy of water diffusion has been proposed to reflect compromised white matter integrity.150 Reductions in white matter anisotropy reflect disrupted white matter connections, which is consistent with the disconnection model of schizophrenia.152 Reduced white matter diffusion anisotropy has been observed in prefrontal, parietooccipital, splenium of corpus callosum, arcuate and uncinate fasiculus corpus callosum, parahippocampal gyri, and deep frontal perigenual regions of schizophrenic patients.150,153157 It is conceivable that downregulation of genes affecting production of myelin-related proteins, as well as other components of axons, may lay the foundation for white matter abnormalities that develop later in life in subjects who become schizophrenic.98,99 Recently, the dysregulation of white matter metabolites have been observed in elderly patients with schizophrenia.158 Compared with healthy subjects, patients with schizophrenia displayed lower N-acetyl compounds, lower myoinosotol, and higher glutamate and glutamine in white matter regions.158 The authors suggest lower Nacetyl compounds may indicate reduced neuronal content, lower myoinosotol may suggest decreased glial content or dysfunction, while the elevated glutamate and glutamine could be due to excess neuronal release of glutamate or glial dysfunction in glutamate reuptake.149 A more recent study by the same group found that elderly patients with schizophrenia with elevated levels of glutamate and glutamine in white matter had lower negative positive and negative syndrome scale (PANSS) scores but greater deficits in executive function.159 Table 5 summarizes the findings of selected research articles on brain abnormalities observed in subjects with schizophrenia. View this table:

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Table 5.

Summary of Selected Brain Abnormalities Observed in Subjects With Schizophrenia Previous SectionNext Section

Explanatory Capacity of the Neurodevelopmental Model of Schizophrenia

Epidemiology of Schizophrenia
Schizophrenia affects 1% of the adult population in the world.160 The point prevalence of schizophrenia is about 5/1000 population,161 and the incidence is about 0.2/1000 per year.161 This incidence rate was reported to be comparable in most societies162; however, recent studies suggest greater variability.161 Schizophrenia has an earlier onset in males with mean ages of onset of 20 and 25 years in males and females, respectively.10,161 Reports have indicated, however, that there are no sex differences in the lifetime risk of developing schizophrenia.163 However, a meta-analysis by Aleman et al164 of studies of the incidence of schizophrenia found that overall there was evidence for a sex difference in the risk of developing schizophrenia. Interestingly, in countries with a medium development index, the sex difference was not apparent.164 The authors suggest that factors related to industrialization may play a role.164 While age of first psychotic episode is generally during adolescence, 23.5% of patients with schizophrenia experience their first episode after age 40 years.165167 The prevalence of early adult onset, following extensive remodeling of the brain circuitry during adolescence, rather than onset evenly distributed by age, lends credence to the neurodevelopmental model.

Heritability of Schizophrenia
Emerging evidence points to schizophrenia as a familial disorder with a complex mode of inheritance and variable expression.10,80,168 While single-gene disorders like Huntington disease have homogenous etiologies, complex-trait disorders like schizophrenia have heterogeneous etiologies emanating from interactions between multiple genes and various environmental insults.80 Twin studies of schizophrenia suggest concordance rates of 45% for MZ twins and 14% for dizygotic twins.10,169 Consistent with this, a recent metaanalytic study showed a heritability of 81% for schizophrenia.169 Despite this high genetic predisposition, an 11% point estimate was suggested for the effects of environmental factors on liability to schizophrenia.80,169 The interaction of genes and the environment (as discussed in The Neurodevelopmental Theory of Schizophrenia and Supportive Evidence), particularly in utero is likely to be very important. Additionally, adoption studies show a lifetime prevalence of 9.4% in the adopted-away offspring of schizophrenic parents vs 1.2% in control adoptees.170 The adoption studies also clearly show that postnatal environmental factors do not play a major role in etiology of schizophrenia.80 However, this issue remains controversial and needs to be interpreted carefully in view of the ample support for effects of environment on schizophrenia development.

Drug Abuse and the Development of Schizophrenia

Drug abuse has also been linked to the development of schizophrenia. It has been demonstrated that administration of D-amphetamine (which acts on the dopaminergic tracts) to healthy volunteers leads to production of psychotic symptoms and worsens psychosis in schizophrenic subjects.10 Moreover, heavy cannabis use in adolescence may lead to the development of later schizophrenia and that this is mediated by dopamine.171 However, hallucinogens like lysergic acid diethylamide (LSD) or psilocybin (acting on serotonin system) or dissociative anesthetics like ketamine or phencyclidine (acting on glutamate system) also cause psychotic symptoms10,172 suggesting that alterations of the dopaminergic system alone are not solely responsible for the development of schizophrenia.

Pyramidal Cell Abnormalities and Schizophrenia

As mentioned in The Neurodevelopmental Theory of Schizophrenia and Supportive Evidence, there are numerous neuroanatomical deficits in the brains of schizophrenic subjects. Glantz and Lewis173 observed that pyramidal cells located in layer III of the DLPFC of subjects with schizophrenia exhibited a 23% reduction in spine density when compared with normal controls suggesting a decrease in excitatory inputs to these cells.173 These same cells also exhibit a 9.2% reduction in somal volume.174 Taken together, the authors conclude that these findings indicate disruption of the thalamocortical and corticocortical circuits.174 As with other alterations including reduced fractional anisotropy of the white matter or altered hippocampal volume or shape, these changes in pyramidal cells suggest neurodevelopmental dysfunction.222

The Role of the Reelin and GABAergic Signaling Systems in Schizophrenia

Several studies now implicate the pathological involvement of RELN gene or its protein product in schizophrenia. Reelin helps in normal lamination of the brain during embryogenesis and affects synaptic plasticity in adulthood.5,175,176 Impagnatiello et al177 used northern and western blotting and immunocytochemistry to show reductions in reelin mRNA and protein in cerebellar, hippocampal, and frontal cortices of patients with schizophrenia and psychotic bipolar disorder. Reduction in reelin was associated with significant decreases in GAD67-kDa protein in the same postmortem brains.178 A later immunocytochemical report179 showed significant reductions in reelin immunoreactivity in schizophrenic and bipolar patients. However, these authors detected similar decreases in hippocampal reelin protein levels in nonpsychotic bipolar and depressed subjects, suggesting that reelin deficiency may not be limited to subjects with psychosis alone.179,223 Fatemi et al98 subsequently demonstrated significant reductions in Reelin, as well as GAD65-kDa and GAD 67-kDa proteins, in cerebella of subjects with schizophrenia, bipolar disorder, and major depression98,180 as well as in mice following prenatal viral infection (figure 3). Further confirmatory data relating to Reelin abnormalities in brains of schizophrenic patients were demonstrated by Eastwood et al,181 who showed a trend for reduction in Reelin mRNA in cerebella of schizophrenic subjects; these reductions in Reelin mRNA correlated negatively with semaphorin 3A. The authors suggested that these findings were consistent with an early neurodevelopmental origin for

schizophrenia and that the reciprocal changes in Reelin and semaphorin 3A may be indicative of a mechanism that affects the balance between inhibitory and trophic factors regulating synaptogenesis.181

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Fig. 3. Reelin is Reduced in Hippocampus of Individuals With Schizophrenia and in Cerebral Cortex Following Prenatal Viral Infection. A. The values expressed on the y-axis are reelinpositive adjusted cell densities per square millimeter localized to hippocampal CA4 areas in control and schizophrenic subjects. The number of brains used is 15 (control) and 15 (schizophrenic). Each point is the mean for 24 sections analyzed per brain. A crossbar localized over each scatter plot represents mean Reelin-positive adjusted cell density value per group. Mean values for schizophrenic subjects are significantly reduced when compared with control values (analysis of variance, P < .05). B. The top panel shows a graph depicting the hemispheric Reelin-positive Cajal-Retzius (CR) cell counts in layer I of the cortex of prenatally infected (I) and sham-infected control (C) animals. The number of Reelin-positive CR cells was significantly reduced in infected brains compared with control brains (P < .0001). The lower panel shows light micrographs of layer III in coronal sections of prenatally infected and sham-infected cortex. Originally published in Fatemi et al.67,179

Effects of Various Antipsychotics Neurodevelopment of Schizophrenia

on

Brain

Genes

Involved

in

Pharmacotherapy is the primary mode of treatment for the psychotic symptoms of schizophrenia. All drugs currently used to treat schizophrenia mediate their actions through the dopamine D2 receptor.182 With the exception of aripiprazole, which acts as a partial agonist, both typical and atypical antipsychotics are antagonists of the D2 receptor.183185 Dopamine hyperactivity may contribute to psychotic symptoms and that dopamine antagonists like chlorpromazine treat the psychotic symptoms.10 Clozapine is a dibenzodiazepine and the prototype for most of atypical antipsychotics (agents that may treat positive, negative, or cognitive symptoms of schizophrenia have decreased liability for extrapyramidal symptoms (EPS) and tardive dyskinesia [TD], may

be effective for a proportion of treatment-nonresponsive patients and exhibit greater 5HT2 over D2 receptor antagonism and do not cause hyperprolactinema).186,187 Clozapine has been shown to be effective in treatment-resistant schizophrenia.188 Thus, clozapine remains the only antipsychotic agent to date that is Food and Drug Administration approved for treatment-resistant schizophrenia.189 Additionally, other studies have shown superiority of clozapine vs typical agents in treatment of total psychopathology, EPS, and TD and categorical response to treatment.124 Clozapine reduces positive, negative, and cognitive symptoms of schizophrenia without causation of EPS, TD, or hyperprolactinemia.10 Additionally, clozapine has been shown to reduce depression and suicidality.10,124 The time course over which antipsychotic agents take effect is variable. In an analysis of studies measuring antipsychotic response during the first 4 weeks of treatment, Agid et al190 found that there was a reduction in total scores of the Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale (PANSS) of 13.8% during week 1, 8.1% during week 2, 4.2% during week 3, and 4.7% during week 4. The authors hold that these results reject the delayed onset model of antipsychotic action; rather, antipsychotic response begins within the first week and accumulates over time.190 However, Emsley et al,191 using a benchmark of a 20% improvement in total score on the PANSS for clinical response, found that 22.5% of subjects with first-episode schizophrenia did not achieve clinical response until 4 weeks of treatment or later. Taken together, these studies demonstrate the variability of time to antipsychotic response. It has been hypothesized that antipsychotic agents affect various brain genes, leading to changes in synaptic structure and function that may underlie clinical response.192 Olanzapine is a second-generation antipsychotic agent that, like clozapine, exhibits greater 5HT2A than D2 antagonism193 but does not share clozapine's propensity for agranulocytosis. One of the important genes upregulated by chronic olanzapine treatment is Reln88 (figure 4). Recent reports show that Reelin receptor, apolipoprotein E receptor 2 (ApoER2), interacts with and alters, the conformation of NMDA receptors, NR2A and NR2B.175 Additionally, Reelin induces tyrosine phosphorylation of NR2A and NR2B receptors in hippocampal tissue,175 thus modulating NMDA receptor activity and synaptic plasticity in the hippocampus. Supporting evidence for the potential role of olanzapine in enhancing neuroplasticity was recently shown by Lieberman et al,194 who demonstrated a cessation of brain gray matter loss in brains of patients with schizophrenia that were treated with olanzapine for 12 weeks and not in those treated for the same time period with haloperidol. Additionally, Wang and Deutch195 have also shown that olanzapine prevented decreases in spine density of basilar dendrites on layers II, III, and IV of PFC pyramidal neurons in rats lesioned with 6-hydroxydopamine. Finally, olanzapine, but not haloperidol, increased expression of the polysialilated form of neural cell adhesion molecule in rat PFC, suggesting a possible role for this molecule in the efficacy of olanzapine.196 NCAM appears early in development and is important during brain morphogenesis.

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Fig. 4. (A) Reelin Bands of 410, 330, and 180 kDa From the Prefrontal Cortex Homogenates (70 g protein per lane) of Representative Olanzapine-Treated and Control Rats Are Shown. Mean Reelin 410 (B), 330 (C), and 180 (D) kDa/-actin ratios for olanzapine-treated (filled histogram bars) and control rats (unfilled histogram bars) are shown. Levels of Reelin 410 kDa/-actin (B) and Reelin 180 kDa/-actin (D) were significantly increased vs controls (P = .0033 and .0001, respectively). Reelin 330 kDa/-actin (C) was nonsignificantly increased vs controls. Origianlly published in Fatemi et al.88 In recent years, COMT has drawn much interest as a modulator of PFC function, cognitive abilities, and the genetic disposition toward schizophrenia. COMT metabolizes catecholamines197 and is known to modulate dopamine levels in the PFC.198,199 Recently, our laboratory200 conducted experiments testing a number of atypical antipsychotics, mood stabilizers, and antidepressants (clozapine, fluoxetine, haloperidol, lithium, olanzapine, and valproic acid [VPA]) to investigate which genes and proteins were affected by chronic treatment of the above agents. Rats were randomly assigned to 1 of the 6 drug groups or sterile saline and administered drug or diluent for 21 days. Microarray results showed a significant (P<.05), 2-fold decrease in COMT in PFC in all drugtreatment groups (except for olanzapine) when compared with controls. Protein levels for the 28-kDa membrane-bound isoform of COMT were significantly downregulated in VPAtreated PFC (P = .0073)200 (figure 5). Protein levels for the 240kDa cytosolic isoform of COMT were significantly downregulated in PFC by clozapine (P = .014), lithium (P = .0006), olanzapine (P = .046), and VPA (P = .0073) and were significantly upregulated by fluoxetine (P = .0063) 200 (figure 5). In summary, as is evident (vide supra), various antipsychotics exert their clinical actions not only through classical neurotransmitters but also via numerous brain genes that may explain the variable course of clinical response. Some of these genes may also be involved in etiology of schizophrenia (e.g. Reelin).

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Fig. 5. Effects of Psychotropic Agents on Catechol-O-Methyltransferase (COMT) Expression in Rat Frontal Cortex. A, C, E, G, I, and K correspond to protein levels from frontal cortices of clozapine-, fluoxetine-, haloperidol-, lithium-, olanzapine-, and sodium valproatetreated rat brains, respectively. B, D, F, H, J, and L correspond to protein levels from frontal cortices of saline-treated rat brains, respectively. Originally published in Fatemi and Folsom200. Previous SectionNext Section

Evidence in Support of Other Models of Schizophrenia

In addition to the neurodevelopmental model, there are alternative models that have been used to explain the etiology of schizophrenia. It is likely that due to the heterogeneous nature of schizophrenia that multiple factors interact to produce the disease state such as disruptions in the dopaminergic, serotonergic, and glutamatergic systems as well as neurodegenerative changes. With regard to epidemiology, a number of social factors have been shown to increase the risk of schizophrenia including urban birth and upbringing,201 quality of maternal-child relationship,202,203 and migration204, a risk that increases when the immigrant group is a small minority indicating that isolation and lack of support may be important factors. An alternative explanation, however, may be that urban birth and migration may well be consistent with the neurodevelopmental hypothesis in that these represent, respectively, an environment in which one is exposed to more pathogens and an environment in which one may have not developed native antibodies or other resistances to pathogens. Abuse of drugs that affect the dopaminergic (amphetamine, cannabis), glutamatergic (PCP), or serotonergic (LSD) systems also may lead to psychotic symptoms and the development of schizophrenia. While many brain imaging and postmortem studies have yielded structural differences between subjects with schizophrenia and healthy controls, there are other reports showing no differences between schizophrenic patients and controls.205 Moreover, there is debate as to whether the observed changes represent developmental or neurodegenerative changes or the result of antipsychotic medications.206 Critics of the neurodevelopmental model claim that it does not fully account for a number of features of schizophrenia, including the long gap between neurodevelopmental insult and the development of symptoms, the progressive clinical deterioration observed in some patients, and evidence of progressive changes in certain ventricular and cortical brain

structures.1,207209 Longitudinal studies have demonstrated evidence of an increase in ventricular volume over a period of 24 years among first-episode patients.143,210 Moreover, a decline in frontal lobe volume and posterior superior temporal gray matter volume over a period of 4 years has been reported in patients with chronic schizophrenia.211 A mechanism to explain the progressive elements of schizophrenia is apoptosis, or programmed cell death (reviewed by Jarskog et al212), especially synaptic apoptosis in which apoptosis is localized to distal neurites without inducing immediate neuronal death.213 In a series of studies of postmortem temporal cortex, Jarskog et al214 found reduced expression of Bcl-2, a molecule that protects against apoptosis, in schizophrenic brains. A further study showed that the ratio of proapoptotic molecule Bax to Bcl-2 was increased in the same region, suggesting that these neurons were receptive to apoptotic stimuli.215 Interestingly, caspase 3, the caspase molecule most associated with apoptosis in the CNS215 is not upregulated in temporal cortex of subjects with schizophrenia,216 suggesting that chronic apoptosis is not taking place, in contrast to classic neurodegenerative disorders.216 The vulnerability of neurons to proapoptotic insults such as oxidative stress and glutamate excitotoxicity could lead to selective dendritic and synaptic losses observed with schizophrenia.212,222 However, the neurodegenerative model has been critiqued by Weinberger and McClure.206 The authors point out that there is a lack of expression of genes involved with DNA fragmentation and response to injury from postmortem studies.206 Moreover, longitudinal studies of cognitive function, which would serve as a measure of cortical neuronal system integrity, do not support a progression of loss of function that would be expected by the neurodegenerative hypothesis.218 A means to test for alternate theories to the neurodevelopmental model is through our animal model of prenatal viral infection. Longitudinal studies, in which animals are infected at specific gestational periods and then followed through late adulthood, with brains collected at specific postnatal time points, could help establish whether alternate models are valid. If important genes that have been linked to schizophrenia are not affected at early time points such as birth, childhood, adolescence, or early adulthood but are only turned on or off in mid-late adulthood, it would provide evidence against the neurodevelopmental model. Brain imaging experiments on animals from the same studies could help establish whether there is analagous progressive changes in ventricular or cortical structures observed in subjects with schizophrenia, providing evidence for the neurodegenerative model. Previous SectionNext Section

Conclusions
The vast majority of evidence supports a neurodevelopmental model of schizophrenia genesis. Evidence from genetic studies suggest a high degree of heritability of schizophrenia and point to a number of potential candidate genes that may be perturbed early in development leading ultimately to the development of psychotic symptoms. Genes involved with cell migration, cell proliferation, axonal outgrowth, myelination, synaptogenesis, and apoptosis are affected in subjects with schizophrenia, pointing to

neurodevelopmental insults. Imaging studies have shown differences between the brains of subjects with schizophrenia and normal controls in a number of brain regions including the PFC, cerebellum, hippocampus, and amygdala. There is strong evidence from epidemiological studies and animal models that viral infection during pregnancy increases the risk for schizophrenia in the offspring. The presence of neurological soft signs in children who later develop schizophrenia also points to a neurodevelopmental etiology of schizophrenia. Si bien mltiples teoras se han propuesto sobre el origen de la esquizofrenia, con mucho, la gran mayora de la evidencia apunta al modelo del desarrollo neurolgico en el que los insultos del desarrollo tan pronto como el plomo a finales del primer trimestre o principios del segundo a la activacin de circuitos neuronales patolgicas durante la adolescencia o juventud la edad adulta que conduce a la aparicin de los sntomas positivos o negativos. En este informe se examina la evidencia de patologa cerebral (la ampliacin del sistema de cerebroventricular, cambios en la organizacin laminar gris y materia blanca, y anormal), la gentica (cambios en la expresin normal de protenas que participan en la migracin temprana de las neuronas y la gla , la proliferacin celular, crecimiento axonal sinaptognesis, y apoptosis), factores ambientales (aumento de la frecuencia de complicaciones obsttricas y el aumento de las tasas de nacimientos con esquizofrenia debido a la atencin prenatal infecciones virales o bacterianas), y las interacciones gen-medio ambiente (un nmero desproporcionado de los genes candidatos de la esquizofrenia son regulados por la hipoxia, microdeleciones y microduplications, la sobrerrepresentacin de los genes relacionados patgenos entre los genes candidatos de la esquizofrenia) en apoyo al modelo de desarrollo neurolgico. Nos relacionamos el modelo de desarrollo neurolgico a una serie de conclusiones acerca de la esquizofrenia. Por ltimo, tambin examinar explicaciones alternativas sobre el origen de la esquizofrenia, incluyendo el modelo neurodegenerativas. Palabras clave El cerebro los genes modelo animal patologa epidemiologa modelo de antivirales esquizofrenia Seccin SectionNext anterior La teora del desarrollo neurolgico de la esquizofrenia y la evidencia de apoyo La esquizofrenia es un trastorno neurolgico que afecta a los jvenes en la pubertad y se manifiesta por una alteracin en la cognicin y la emocin junto con negativo (es decir, abulia, alogia, apata, funcionamiento social pobre o inexistente) y positivo (presencia de alucinaciones, delirios) los sntomas. Segn la hiptesis del neurodesarrollo, la etiologa de la esquizofrenia puede implicar procesos patolgicos, causados por factores genticos y ambientales, que empiezan antes que el cerebro se acerca a su estado adulto anatmicas en adolescencia.1 Estas anomalas del desarrollo neurolgico, el desarrollo en el tero ya desde finales de primera o principios del segundo trimester2 para algunos y para otros a partir de entonces, se ha sugerido que conducen a la activacin patolgica de los circuitos neuronales durante la adolescencia o la adultez temprana (a veces debido al estrs grave), lo que conduce a la aparicin de los sntomas positivos o negativos o both.2, 3,4 A principios de trabajo neuropatolgicos indican que algunos casos de resultado de la

esquizofrenia desde embriolgico maldevelopment.5 E. Slater tambin se refiri a las similitudes maldevelopmental entre la epilepsia del lbulo temporal y la esquizofrenia y destac su neuropatolgicos posible basis.6 La aparicin de pruebas de trastornos del desarrollo cortical en la esquizofrenia y el desarrollo de varios modelos animales plausible de la esquizofrenia, el 7, que se basan en varios paradigmas que producen alteraciones del comportamiento o alteracin de la sensibilidad a los frmacos dopaminrgicos slo en los animales adolescentes o adultos, han fortalecido la relacin entre trastornos del desarrollo y la esquizofrenia. El concepto de la esquizofrenia como un trastorno del desarrollo neurolgico es tambin compatible con otros epidemiolgicos y clnicos de las lneas de evidencia, discute en las secciones siguientes. A "2-hit" modelo propuesto por Keshavan8, 9 obras en el marco de la teora del desarrollo neurolgico en el que trastornos del desarrollo durante dos momentos crticos (desarrollo temprano del cerebro y la adolescencia) se combinan para producir los sntomas asociados con la esquizofrenia. Segn este modelo, los primeros insultos de desarrollo puede conducir a la disfuncin de las redes neuronales especficos que representan los signos premrbida y sntomas observados en las personas que ms tarde desarrollar schizophrenia.8 En la adolescencia, la eliminacin excesiva de las sinapsis y la prdida de la plasticidad puede explicar la aparicin de symptoms.8, 9 Anomalas Congnitas Mltiples marcadores indicativos de anomalas congnitas del desarrollo neurolgico de los insultos se han encontrado en schizophrenia.10, 11 anomalas incluyen agenesia del cuerpo calloso, estenosis del acueducto de Silvio, hamartomas cerebrales, y del cavum septum pellucidum. Presencia de las orejas de implantacin baja, epicanto ojo, y amplios espacios entre los dedos primero y segundo se sugiere primer trimestre anomalies.10, 11 Existe, sin embargo, el apoyo a dermatoglifos anormales en pacientes con esquizofrenia que indica un segundo trimestre event.12 , 13 informes de mltiples indican la presencia de signos neurolgicos blandos premrbida en los nios que posteriormente desarrollan schizophrenia.14-16 posturas de las manos leves y transitorios movimientos coreoatetoides se han observado durante los 2 primeros aos de vida en nios que han desarrollado posteriormente schizophrenia.15, 17 Adems, los malos resultados en las pruebas de atencin y desempeo neuromotor, el humor y el deterioro social, y la ansiedad excesiva se ha informado que se producen con mayor frecuencia en nios de alto riesgo con un esquizofrnico parent.18, 19 Todos estos hallazgos son consistentes con la esquizofrenia como un sndrome del desarrollo anormal del cerebro. Factores Ambientales Hay una gran cantidad de investigacin epidemiolgica que demuestra un aumento en la frecuencia de complicaciones obsttricas y perinatales en esquizofrnicos patients.20 Las complicaciones observadas incluyen hemorragias periventicular, la hipoxia y isqumica injuries.10, 21 Existe tambin una slida coleccin de informes que indican que los factores ambientales , especialmente infeccin viral, puede aumentar el riesgo para el desarrollo de schizophrenia.22, 23 de Hare et al24 y Machon et al25 informaron sobre el exceso de pacientes esquizofrnicos que nace a finales del invierno y la primavera como indicadores de posibles infecciones de influenza responsable de estos casos. De hecho, la mayora de los cerca de 50 estudios realizados en los aos indican que el 5% y un 15% el exceso de nacimientos de esquizofrenia en el hemisferio norte se producen durante los meses de enero y March.26 28 El nacimiento de invierno exceso no se ha demostrado que es debido a los patrones inusuales de la concepcin en las madres oa un metodolgicos artifact.26, 29

Machon et al 25 y Mednick et al30 demostraron que el riesgo de la esquizofrenia se increment en un 50% en los individuos finlandeses cuyas madres haban estado expuestas a la gripe A2 1957 durante el segundo trimestre del embarazo. Ms tarde, 9 de los 15 estudios realizados Mednick replicado los hallazgos de una asociacin positiva entre la exposicin prenatal y la gripe schizophrenia.2 Estos estudios de asociacin mostr que la exposicin durante los meses 4 al 7 de gestacin ofrece una ventana de oportunidad para el virus de la gripe a causa de sus efectos teratgenos en el embrin brain.4 Adems, 3 de cada 5 cohortes y estudios de casos y controles de apoyo a una asociacin positiva entre la esquizofrenia y la exposicin materna a la gripe prenatally.31-33 Estudios posteriores han demostrado que otros virus, como rubella34 tambin puede aumentar el riesgo para el desarrollo de la esquizofrenia en la descendencia afectada expuesta mothers.26, 34 Un estudio de Brown35 resumen que (1) hubo un 10 - con el riesgo 20 veces mayor de desarrollar esquizofrenia despus de la exposicin prenatal a la rubola, (2) la exposicin prenatal a la gripe en el primer trimestre aument 7 veces, y la infeccin a principios o mitad de la gestacin un aumento del riesgo de 3 veces, y (3) la presencia de anticuerpos maternos contra el plomo Toxoplasma gondii a 2.5 veces mayor risk.35 Por el momento, las pruebas ms emocionantes de la vinculacin viral la exposicin al desarrollo de la esquizofrenia fue publicado por Karlsson et al 23, quienes proporcionaron datos que sugieren un posible papel de los retrovirus en la patognesis de schizophrenia.22 Karlsson et al23 identificaron las secuencias de nucletidos homlogos a los genes de la polimerasa retrovirales en el lquido cefalorraqudeo de 28.6% de los sujetos con esquizofrenia de origen reciente y en el 5% de los pacientes con esquizofrenia crnica. Por el contrario, tales secuencias retrovirales no se encontraron en ninguna de las personas con enfermedades neurolgicas no inflamatorias o normal subjects.22, 23 Ms recientemente, Perron et al.220 mediante un inmunoensayo para cuantificar los niveles sricos de retrovirus endgenos humanos GAG de tipo familiar W y un sobre ( ENV) las protenas en los pacientes con esquizofrenia y controles emparejados. antigenemia positiva para la ENV se encontr en 23 de 49 (47%) y de GAG en 24 de 49 (49%) de los pacientes con esquizofrenia. En cambio, para los sujetos de control slo 1 de 30 (3%) para ENV y 2 de 49 (4%) para GAG fueron positivos en los donantes de sangre (p <0,01 para ENV, p <.001 para GAG), que proporciona una prueba ms de una asociacin entre retrovirus y schizophrenia.220 El resultado de estos estudios y los anteriores informes epidemiolgicos es que la esquizofrenia puede representar el fenotipo comn de un grupo de trastornos cuya etiopatogenia supone la interaccin entre las influencias genticas y los riesgos ambientales, tales como los virus de operacin en el cerebro de maduracin processes.22 Por otra parte, la identificacin de posibles factores de riesgo ambientales, como el virus de la influenza o retrovirus endgenos, tales como retrovirales-9 de la familia y la especie humana endgena retrovirus-W observado por Karlsson et al 23, contribuirn a orientar las intervenciones tempranas en la represin de la expresin de estas transcripciones. Un enfoque alternativo sera vacunar contra la influenza por lo tanto influir en el curso y resultado de la esquizofrenia en el susceptibles individuals.22 Hay al menos dos mecanismos que pueden ser responsables de la transmisin de los efectos virales de la madre al feto. (1) A travs de la infeccin viral directo: Hay clnicas, as como experimental directa, reports36-39 muestran que la influenza humana A la infeccin viral de la madre embarazada puede causar el paso transplacentario de carga viral para el feto. En una serie de informes, Aronsson y sus colegas utilizaron el virus de la gripe humana (A/WSN/33, una cepa neurotrpica del virus de influenza A) el da 14 del embarazo, para

infectar a embarazadas C57BL / 6 ratones por va intranasal. El ARN viral y la nucleoprotena se detectaron en el cerebro fetal, y el ARN viral persiste en el cerebro de los descendientes expuestos durante al menos 90 das de vida postnatal lo que demuestra la evidencia para el paso transplacentario del virus de la influenza en los ratones y la persistencia de los componentes virales en el cerebro de la progenie en los jvenes adulthood.38 Adems, Aronsson et al.38 han demostrado que 10 a 17 meses despus de la inyeccin de la gripe humana del virus en bulbos olfatorios de TAP1 ratones mutantes, que codifica ARN viral de la protena no estructural NS1 fue detectado en el cerebro medio de los ratones expuestos. El producto del gen NS1 se sabe que juega un papel regulador en la clula husped metabolisms.40 Varios estudios in vitro han demostrado tambin la capacidad de la influenza humana del virus para infectar las clulas de Schwann, astrocitos 41, clulas de la microglia y neuronas, 36 y GABArgicas del hipocampo clulas, 42,43 selectivamente causantes de la infeccin persistente de las clulas diana en el cerebro. (2) A travs de la induccin de la produccin de citoquinas: Varios informes clnicos y experimentales demuestran la capacidad de infeccin de la influenza humana para inducir la produccin de citoquinas sistmicas por el sistema inmunitario materno, la placenta, el feto o incluso itself.44-48 nuevos informes muestran la presencia de evidencia serolgica de la exposicin materna a la gripe como causa de aumento del riesgo de esquizofrenia en offspring.4 hijos de madres con inmunoglobulina G y elevados niveles de inmunoglobulina M, as como anticuerpos frente a virus herpes simple tipo 2, durante el embarazo tienen un mayor riesgo de schizophrenia.49 Las citoquinas como la interleuquina (IL)-1, IL-6 y factor de necrosis tumoral (TNF-) son elevados en las madres embarazadas despus materna infection44, 45,48 y despus de la infeccin en animales models.47, 48 Todas estas citoquinas Se sabe que regulan el desarrollo normal del cerebro y han sido implicados en anormales corticogenesis.50-52 Adems, la expresin de ARN mensajero (ARNm) de las citocinas en el sistema nervioso central (SNC) es regulada durante el desarrollo tanto en el hombre y en el ratn ,53-57 haciendo hincapi en el importante papel que juegan las citoquinas en el desarrollo neurolgico. IL-1, IL-6 y TNF- atravesar la placenta y son sintetizadas por la madre, de 58 aos por la placenta, de 59 aos y por la materna fetus.59 niveles de TNF- e IL-8 han demostrado ser elevados en embarazos humanos en los que la descendencia va a desarrollar schizophrenia.4, de 59 aos una serie mayor relevancia de los estudios en modelos animales diferentes para mostrar el resultado de la esquizofrenia que la infeccin materna con la gripe humana imitar poli I: C, un ARN sinttico de doble cadena que estimula una citoquina respuesta en los ratones, pueden causar alteraciones en la inhibicin prepulso (PPI) de 60, despus de la exposicin materna a E. coli endotoxina lipopolisacrido de clulas de la pared, la interrupcin causa de sensoriomotor que bloquea en el offspring.61 Por ltimo, la exposicin materna a poly I: C tambin causa perturbado la inhibicin latente en rat.62 Todos estos modelos sugieren que la estimulacin directa de la produccin de citoquinas por infecciones o agentes inmunognicos causar interrupciones en el cerebro de varios ndices estructurales o de comportamiento que guardan relacin con la esquizofrenia. Otros factores asociados con el aumento de nacimientos con esquizofrenia incluyen la hambruna durante el embarazo, incompatibilidad de Rh factor de 63,64, 65 y autoinmunidad debido a enfermedades infecciosas agents.66 Una serie de modelos animales estn actualmente en uso para estudiar la esquizofrenia y determinar posibles nuevas terapias (revisado por Carpenter y Koenig7). Nuestro laboratorio ha estudiado los efectos de la infeccin prenatal virus de la influenza humana en el da 9 de embarazo en BALB / c y ratones C57BL / 6 y su descendencia. Estos estudios

demostraron los efectos nocivos de la influenza en el cerebro cada vez mayor de la descendencia expuesta. En pocas palabras, el da 9 de embriones (E9) BALB embarazadas / c. Los animales fueron expuestos a la influenza A/NWS/33 (H1N1) o el vehculo, tras la determinacin de la dosis viral, que causa pulmonar subletal y la infeccin respiratoria superior. ratones embarazadas se les permiti entregar los cachorros. El da de la entrega fue considerado el da 0. cerebros de ratn infectados antes del nacimiento desde el primer da despus del parto 0 mostraron reducciones significativas en los recuentos de clulas positivas reelina en la capa I de la neocorteza y otras capas corticales (P <0,0001) en comparacin con controls.67 Considerando que la capa que las clulas de Cajal-Retzius producido reelina significativamente menor en animales infectados, las mismas clulas mostraron que la produccin normal de calretinina y la xido ntrico sintasa neuronal (nNOS) en comparacin con el control de brains.67 Este trabajo ha sido confirmado recientemente por Meyer et al68 que tambin se observa una disminucin de clulas positivas reelina en la corteza prefrontal medial (PFC) despus de poli I: C en la exposicin E9 y E17. Adems, la infeccin viral prenatal en E9 dado lugar a diversas comportamiento abnormalities.60 Estos incluyen la conducta exploratoria anormal, debido a dificultades para manejar el estrs, similar a lo que se observa en la esquizofrenia. Las cras de ratones expuestos mostraron significativamente menos tiempo explorando su entorno de control frente a mice.60 Por otra parte, las cras de ratones expuestos en contacto entre s con menos frecuencia que los ratones control, lo que sugiere alteracin social behavior.60 Por ltimo, las cras de ratones expuestos muestran un resultado anormal respuesta de sobresalto acstico, similar al dficit de PPI en esquizofrnicos tratados subjects.69 Administracin de la clorpromazina agentes antipsicticos (un agente tpico) y clozapina (un agente atpico) 60, los agentes que tratan los sntomas esquizofrnicos y corregir los dficit de PPI en los pacientes, provoc un aumento significativo de IPP en los expuestos frente a los ratones controles, para corregir el PPI deficits.60 La respuesta de cras de ratones expuestos a dos antipsicticos demuestra que nuestro modelo animal tiene validez predictiva de los sntomas positivos de schizophrenia.60 Nuestro laboratorio ha demostrado previamente que la infeccin de ratones Balb / c en el Grupo E-9 tiene efectos nocivos en el cerebro morphology67, de 70 aos (figura 1). Prenatalmente cerebros infectados de P0 disminuye aparecen en neocortical e hipocampal thickness.67 densidad Adems, los cerebros en P0 mostraron un incremento de clulas piramidales y redujo significativamente clulas piramidales nucleares size.70 En la edad adulta (P98), segua habiendo un aumento de la densidad de las clulas piramidales y nonpyramidal densidad celular y una reduccin significativa en la celda piramidal nucleares size.70 En conjunto, estos datos sugieren que la infeccin viral prenatal en E9 (finales de primer trimestre) causas persistentes cambios perjudiciales en la morfologa del cerebro. El anlisis morfomtrico de cerebro tambin revelaron numerosos defectos despus de la infeccin de ratones C57BL / 6 en el E18 (segundo trimestre de retraso). Anlisis del cerebro y las zonas laterales de volumen ventricular en el cerebro postnatal mostraron una atrofia significativa del volumen del cerebro en aproximadamente equivalente al 4% (P <0.05) en la descendencia de P35 expuestos mice.71 Hubo reducciones significativas en el volumen para el cerebelo (P < 0,001) y el hipocampo (p <0,00005) en P35.71 anisotropa fraccional del cuerpo calloso revel atrofia de sustancia blanca en la descendencia P35 (P <0,0082) de exposicin mice.71

Ver una versin ms grande: En esta pgina En una nueva ventana Descargar como diapositivas de PowerPoint Fig. 1. Imgenes por resonancia magntica revela significativas (P <0.05) Atrofia cerebral en mltiples reas cerebrales de las cras de ratn de 35 das de edad infectadas por virus (panel derecho) en comparacin con los ratones infectados-Sham (panel izquierdo). Publicado originalmente en Fatemi y otros72 cambios en la expresin de genes del cerebro tambin en respuesta a la atencin prenatal virales infection.71-73 los datos de expresin gnica mostraron una disminucin significativa (P <0.05) por lo menos 1,5 veces arriba o regulacin a la baja de los genes en el frontal (upregulated 43 y 29 downregulated en P0, 16 upregulated y upregulated downregulated en P14 17, y 86 y 24 downregulated en P56), del hipocampo (upregulated 129 y 46 downregulated en P0, upregulated 9 y upregulated downregulated en P14 12, y 45 y 17 downregulated en P56), y cerebelosa (120 upregulated y la regulacin a la baja en P0 37, 11 y upregulated downregulated 5 en P14, y el 74 upregulated y downregulated 22 en P56) reas de ratn offspring.71 varios genes, que han sido implicados en etiopatogenia de la esquizofrenia, se demostr que se afect significativamente (P <0,05) en la misma direccin y la magnitud del cambio fue validado por la reaccin de la polimerasa cuantitativa en tiempo real de la cadena (QRT-PCR) 71 (tabla 1). Tambin hubo varios genes que se sabe estn involucrados en el procesamiento del ARN de la gripe-mediada y que se upregulated en las 3 reas del cerebro y segua estando presente en P0, por ejemplo, la protena NS1 la gripe vinculante y el receptor de aril hidrocarburos translocador nucleares genes.71 Ver esta tabla: En esta ventana En una nueva ventana Tabla 1. Microarrays y Resultados QRT-PCR para una seleccin de genes afectados en los ratones infectados E18 infeccin viral prenatal puede conducir al desarrollo de la esquizofrenia en mltiples formas (figura 2). Una forma es a travs de un mecanismo epigentico en el que la hipermetilacin de promotores de molculas como ADN metiltransferasa 1 (DNMT1) da lugar a alteraciones en la expresin de los genes candidatos de la esquizofrenia. ARNm DNMT1 ha demostrado ser mayor en los cerebros de los sujetos con schizophrenia.74 activacin de DNMT1, a su vez, hypermethylates promotores de reelina y decarboxilasa del cido glutmico (GAD) de 67 kDa genes de la protena resultante en los niveles de disminucin de estos molecules.75 Estos cambios contribuir al desarrollo anormal del cerebro y el cido alterado-aminobutrico (GABA), la sealizacin y la gnesis de la esquizofrenia posterior. La infeccin materna tambin puede conducir a la activacin de la respuesta inmune materna que lleva a alteraciones de los niveles de citoquinas incluyendo IL-1, IL-6 y TNF- que regulan el desarrollo normal del cerebro y se alteran los siguientes materna infection.44, 45,48 Los cambios pueden conducir a la cortical anormal development50-52 y, en ltima instancia, la esquizofrenia. expresin viral prenatal tambin puede conducir a alteraciones en la expresin de genes que estn involucrados en la comunicacin entre clulas y cambios en la estructura de la clula debido a la

despolimerizacin de actina crnica (SH Fatemi y pueblos M., observaciones inditas, 2007). Acuaporina 4 se localiza en los astrocitos y clulas ependimarias en el cerebro y est involucrado con agua transport.76, 77 Aquaporin cuatro expresin de la protena se redujo significativamente en el da postnatal 35 en neocrtex en ratones Balb / c despus de la infeccin en la E978, posiblemente resultando en la morfologa celular alterada. Del mismo modo, despolimerizacin de actina crnica puede alterar la expresin gentica en la esquizofrenia (SH Fatemi y pueblos M., observaciones inditas, 2007). nNOS, que se asocia con F-actina, muestra la expresin alterada despus de la infeccin viral prenatal a E9 y puede mostrar alteraciones en la expresin siguiente interrupcin de actina. despolimerizacin de actina (con citocalasina D) hace que la internalizacin de la subunidad NR1 de N-metil-D-aspartato (NMDA) y por lo tanto disminucin de las corrientes de NMDA que conduce a alteraciones en la sealizacin, pero se desconoce si esto ocurre en la esquizofrenia. Nuestro laboratorio ha observado aumento significativo de la nNOS en P35 y una disminucin significativa en P56 que pueden conducir a la sinaptognesis alterado y excitotoxicidad en neonatales brains.79 Ver una versin ms grande: En esta pgina En una nueva ventana Descargar como diapositivas de PowerPoint Fig. 2. Una hiptesis de cmo la infeccin viral prenatal podra contribuir al desarrollo de la esquizofrenia. infeccin viral prenatal puede dar lugar a (1) la activacin de un ADN metiltransferasa (DNMT1) que a su vez cambios en la metilacin de los promotores de una variedad de genes que conducen a alteraciones de los niveles de molculas como la protena decarboxilasa del cido glutmico 67-kDa (GAD67) y dndome vueltas ( SH Fatemi, observaciones no publicadas) .74,75 Estos cambios pueden dar lugar a un desarrollo anormal y cido alterado -aminobutrico (GABA), la sealizacin y posterior gnesis de la esquizofrenia, (2) la activacin de la respuesta inmune materna que lleva a alteraciones de los niveles de citoquinas incluyendo IL (IL)-1, IL-6 y factor de necrosis tumoral (TNF) 44,45,48 normal del cerebro que regulan development.50-52 Los cambios pueden conducir a un desarrollo cortical anormal y, en ltima instancia, la esquizofrenia, y (3 ) alteraciones en la expresin de genes que estn involucrados en la comunicacin entre clulas y cambios en la estructura de la clula debido a la despolimerizacin de actina crnica (SH Fatemi y pueblos M., observaciones inditas, 2007) puede llevar a la desregulacin de mltiples sistemas de sealizacin que se han observado en la esquizofrenia . * Rutas que necesitan un apoyo ms sustancial. Gentica El modo de transmisin en la esquizofrenia es desconocida y muy probablemente complejas y no Mendelian.10 el 80 anomalas cromosmicas muestran evidencia de la participacin de una translocacin equilibrada recproca entre los cromosomas 1q42 y 11q14.3, con una interrupcin de interrumpida en la esquizofrenia 1 y 2 (DISC1 y DISC2) genes en 1q42, que es asociado a schizophrenia.80, 81 Adems, una asociacin entre una delecin en 22q11, la esquizofrenia y el sndrome velocardiofacial ha sido reported.82 ratones con sensoriomotor similares presentan deleciones que bloquea abnormalities.83 Vinculacin y asociacin studies80, 84,85 muestran 12 regiones cromosmicas que contienen 2.181 conocida genes84 y 9 especficas genes80 como implicada en la etiologa

de schizophrenia.80 Variaciones / polimorfismos en los genes incluyendo nueve neuregulina 1 (NRG1), protena de unin a distrobrevina 1 (DTNBP1) , G72 y G30, el regulador del G-protena sealizadora 4 (RGS4), catecol-O-methytransferase (COMT), prolina deshidrogenasa (PRODH), y DISC1 DISC2, el receptor de serotonina 2A, y D3 receptor de la dopamina (DRD3) se han asociado con esquizofrenia (tabla 2). Sin embargo, de los genes candidatos diferentes, no hay un nico gen cuya asociacin gentica a la esquizofrenia se ha replicado en todos los study.86 Ver esta tabla: En esta ventana En una nueva ventana Tabla 2. Los genes de riesgo para la esquizofrenia Otra forma de estudiar las bases genticas de la esquizofrenia utiliza la tcnica de ADN microarray.87, 88 Estos estudios se basan en el descubrimiento de genes o controles sanos reprimidos o estimulado significativamente en bien caracterizados tejidos post-mortem de cerebros de los sujetos con esquizofrenia y acertaron y los linfocitos perifricos obtenidos de los controles sanos emparejados y esquizofrnicos y tratados con antipsicticos cerebros de los roedores (tabla 3). Genes implicados en la respuesta a los frmacos o en la etiopatogenia de la esquizofrenia pueden ser comparados y estudiados para comprender mejor los mecanismos responsables de este illness.87 Ver esta tabla: En esta ventana En una nueva ventana Cuadro 3. Los genes candidatos: Los estudios post mortem y Modelos Animales Los marcadores biolgicos compatibles con la presencia prenatal de insultos del neurodesarrollo en la esquizofrenia incluyen cambios en la expresin normal de protenas que participan en la migracin temprana de las neuronas y clulas gliales, proliferacin celular, crecimiento axonal, sinaptognesis y la apoptosis. Algunos de estos marcadores se han investigado en los estudios de varios insultos prenatal en modelos animales el potencial para la esquizofrenia por lo tanto til para descifrar los mecanismos moleculares de la gnesis de schizophrenia.7 Varios informes recientes implican a varias familias de genes que estn involucrados en la patologa de la esquizofrenia utilizando la tecnologa de microarrays de ADN, es decir, los genes implicados en la transduccin de seal ,89-98 el crecimiento celular y la migracin, el 91 mielinizacin, 89,99 regulacin de la funcin de la membrana presinptica, 92,93 y aminobutrico mediada por el cido (GABA) function.89, 94 Por el momento, el ms estudiado y replicado tratar los datos con los genes implicados en funciones de oligodendrocitos y afines de la mielina. Hakak et al89 utilizando en su mayora ancianos con esquizofrenia y control de la misma corteza prefrontal dorsolateral (crtex prefrontal dorsolateral) homogeneizados mostr regulacin a la baja, de 5 de genes cuya expresin se enriquece en los oligodendrocitos que forman la mielina, que han sido implicados en la formacin y mantenimiento de las vainas de mielina. Ms tarde, Tkachev et al99 con rea de 9 homogeneizados de cerebro Coleccin Stanley mostr regulacin a la baja significativa en varios genes de la mielina y los oligodendrocitos-relacionados, tales como protena de 1,96 proteolipdica glicoprotena asociada a la mielina, la protena especfica de oligodendrocitos CLDN11, glicoprotena de mielina de oligodendrocitos, protena bsica de

mielina , el receptor neurorregulina v-erb-un oncogn eritroblsticos leucemia viral homlogo 3 (ERBB3), transferrina, Olig 1, Olig 2 y SRY el recuadro 10. 99 Mirnics et al92 demostraron regulacin a la baja de los genes implicados en la funcin presinptica de la CPF, como el factor methylmaleimide sensible, sinapsina II, sinaptotagmina 1, y sinaptotagmina 5. Vawter et al93 demostraron regulacin a la baja de la histidina en las protenas de unin a la trada de nucletidos y E2N enzima ubiquitina-conjugacin. Otra familia importante de genes implicados en la esquizofrenia son los genes involucrados en glutamato y GABA function220, 221. Hakak et al89 mostraron una regulacin al alza de varios genes implicados en la transmisin de GABA, como GAD65 y genes de la protena 67-kDa. Sin embargo, varios informes han puesto de manifiesto la disminucin de estas protenas en schizophrenia.97, 98.100 Hashimoto et al94 mostraron una regulacin a la baja del gen parvalbmina y Vawter et al93 demostraron regulacin a la baja de los receptores de glutamato -amino-3-hidroxi-5-metil-4-isoxazoleproprionate (AMPA). Otra familia de genes de la importacin en ofertas de la esquizofrenia con la transduccin de seales. Hakak et al89 demostraron regulacin al alza de la transduccin de seal postsinptica varias vas conocidas para ser regulada por la dopamina, en consonancia con la hiptesis de la dopamina de schizophrenia95, 101 como AMPc-protena quinasa dependiente subunidad RII- y la protena relacionada con nel 2. En una vena similar, Mirnics y Lewisl90 tambin mostr regulacin a la baja del gen RGS4 en PFC de la esquizofrenia. Recientemente en un estudio de la circunvolucin temporal, Bowden et al, 102 se encuentran que un nmero de genes relacionados con la neurotransmisin (GRIN2B, GRIP2, SYT7), desarrollo neurolgico (DAB1, SEMA5A), y de sealizacin intracelular (PIK3R1, CACNG2) fueron significativamente altered.102 Chung et al91 demostraron regulacin al alza de choque trmico 70 genes en esquizofrnicos brain.91 una serie de genes candidatos de la esquizofrenia se ha encontrado que el cambio en el PFC en el transcurso de la vida en muestras de cerebros de los sujetos de control a travs de microarrays: (1) RGS4 y el glutamato receptores metabotrpicos 3 (GRM3) disminucin de la expresin en todo el rango de edad, (2) la expresin PRODH y DARPP32 aumenta con la edad, y (3) NRG1, ERBB3, y el crecimiento del nervio receptor del factor mostr alterado expresin durante los aos de mayor riesgo para el desarrollo de schizophrenia.103 La interaccin entre los genes y el medio ambiente Los factores genticos de riesgo tambin puede interactuar con complicaciones obsttricas que incrementan el riesgo de la esquizofrenia ,104-106 y se ha sugerido conocidos genes de susceptibilidad para la esquizofrenia era ms probable que los genes seleccionados al azar para ser regulada por hypoxia/ischemia.107 Nicodemo et al108 recientemente probaron si un conjunto de 13 genes de susceptibilidad a la esquizofrenia cree que es regulada en parte por la hipoxia estadsticamente interactuar con complicaciones obsttricas. Cuatro genes: homlogo murino timoma v-AKT oncogn viral 1, el factor neurotrfico derivado del cerebro, DTNBP1 y GRM3 mostraron interacciones significativas, 76 y las 4 se ha demostrado que han neuroprotector roles.107 En un estudio de genes candidatos de la esquizofrenia, Schmidt-Kastner et al107 encontr que al menos el 50% estaban regulados por la hipoxia y / o se expresaron en el vasculature.107 Estos genes incluyen CHRNA7, COMT, GAD1, NRG1, RELN y RGS4.107 Los autores proponen que la interaccin de los genes y los "internos" los factores ambientales, en este caso la hipoxia, dar lugar a perturbaciones del desarrollo que conduce a una predisposicin a schizophrenia.107 Sin embargo, otros factores externos que tienen que entrar en juego despus del nacimiento para el pleno desarrollo de la

esquizofrenia .107 Otro enfoque para el estudio de la contribucin gentica es examinar raras variantes estructurales incluyendo microduplications y microdeleciones. Estos han sido demostrado que la base de las enfermedades neurolgicas y del desarrollo neurolgico incluyendo syndromes.109 Dos informes recientes de Walsh et AL110 y la esquizofrenia Internacional Consortium111 han utilizado este enfoque en los sujetos con esquizofrenia. Walsh et AL110 encontr que la novela supresiones y duplicaciones de genes estaban presentes en el 5% de los controles en comparacin con 15% de los sujetos con esquizofrenia (P <0,0008) y el 25% de los sujetos con esquizofrenia de inicio temprano (P <0,0001). La mayora de los genes identificados se asociaron de manera desproporcionada con las vas importantes para el desarrollo del cerebro, incluyendo la transmisin sinptica a largo plazo, NRG sealizacin, gua axonal, y la integrina signaling.110 Una encuesta a gran escala en todo el genoma de las variantes de nmero de copia (CNV) realizado por la esquizofrenia Internacional Consortium111 revel que los sujetos con esquizofrenia tenan 1,15 veces ms propensos a tener una tasa ms alta de la CNV que controls.111 Asociaciones con esquizofrenia se han encontrado grandes deleciones de las regiones en los cromosomas 1, 15, y 22 que afectan una serie de genes.111 Curiosamente, 19 de los genes afectados en ambos artculos tambin han sido significativamente sobreexpresados o regulados a la baja despus de la infeccin viral prenatal en da embrionarias 9, 16 y 18 con nuestro modelo animal (tabla 4) proporcionar una mayor convergencia entre nuestro modelo y los datos genticos humanos. Dos genes, v-erb-un oncogn eritroblsticos leucemia viral homlogo 4 (ErbB4) y soluto compaa de la familia 1 (transportador glial de glutamato de alta afinidad), miembro 3 (Slc1a3), se han asociado previamente con schizophrenia.112, 113 ErbB4 gen codifica para una transmembrana tirosina quinasa del receptor de NRG1. Este gen est involucrado en la proliferacin neuronal y glial, diferenciacin y los procesos migratorios.

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Funding
National Institute of Child Health and Human Development (5R01-HD046589-04 to S.H.F.); Stanley Medical Research Institute (02R-232 to S.H.F.).

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Corteza limdica

Tratamiento: psicolgico-biologico-social

Para hacer distinciones tiles entre los roles ambientales y genticos en la etiologa de la enfermedad, Tiniari y cols (1991, 2000 y 2003) ha hecho estudios en nios adoptados de madres esquizofrnicas, que han demostrado la importante determinacin gentica de la esquizofrenia, que multiplica por 10 el riesgo del nio adoptado en la infancia de llegar a ser esquizofrnico en relacin a la dbil probabilidad que tiene otro que no es descendiente en primer grado de un padre esquizofrnico, con lo que se puede concluir que incluso un ambiente de adopcin no modifica demasiado el riesgo de un nio que pertenece a una familia con carga gentica esquizofrnica de desarrollar la enfermedad (Plomin, 1990).

Otros tipos de marcadores, por su importancia, los revisaremos a proposito de los aspectos neuropsicolgicos y neurobiolgicos.

2.-Neurobiologa 2.1.-

Estructura cerebral y daos neurolgicos blandos

Los estudios posteriores al ao 2000, reafirman la existencia de daos o disfuncionamientos cerebrales en pacientes esquizofrnicos. Estos resultados hablan con claridad de las alteraciones anatomicas en los cerebros de pacientes con esta enfermedad, especialmente de una disminucin de la materia gris cortical en aquellas areas relacionadas con las tareas cognitivas y la emocionalidad de los individuos. Una de las primeras modificaciones anatmicas sealadas es la hipertrofia ventricular en muchos pacientes, generalmente del Tercero y los ventrculos laterales, lo que ha sido interpretado como signo de deficiente crecimiento o atrofia cerebral. La hipertrofia indicada se presenta mas en hombres que en mujeres (Goldstein y Lewine, 2000), y parecen estar en relacion con la edad y cronicidad del cuadro clinico. En efecto, Highley y cols, en 1999 seala que la densidad menor de neuronas en el neocortex tanto a nivel prefrontal como temporal, se relaciona con el gyrus temporal superior, especialmnente a izquierda, es decir, en una estructura vinculada estrechamente al lenguaje. Paralelamente, a los estudios citoscopicos que revelan disminucin de neuronas corticales, se constata una reduccion del cuerpo celular de dichas neuronas, importante porque incide en diversas anomalias que afectan otras estructuras cerebrales, en relacin por ejemplo, con las zonas hipocampicas, vinculadas a los trastornos de memoria en los sujetos esquizofrenicos o en las estructuras del ncleo ventral postero-lateral del talamo, implicada en muchas redes y funciones neuronales. Los estudios post-morten tambin se refieren a la desdorganizacion de la arquitectura de las neuronas corticales, sobre todo a las celulas piramidales del hipocampo y del gyrus para-hipcampico, lo que revela anomalias precoces en relacion con la migracin de neuroblastos corticales ern el curso del segundo trimestre de la vida intrauterina (Cannon, Mednick, 1991), hiptesis que ha sido estudiada posteriormente y que dice relacion con la estructura neuronal transitoria llamada sub-placa cortical que tiene como funcin ayudar, como guia de la migracin de las neuronas, el curso del desarrollo cerebral. Los estudios indican que estas neuronas intersticiales tienen una distribucion ectopica profunda en la materia blanca de los sujetos esquizofrenicos adultos, confirmando el defecto migratorio neuronal (Akbarian, 1996). Otas anomalias de la citoestructura neuronal ha sido observada a nivel de las dendritas, que ha dado base morfologica a anomalias sinapticas moleculares, vinculandolas a factores geneticos pero tambien a la influencia de factores psicosociales como moduladores de la densidad de las espinas

dendrticas (Silva-Gomez y cols, 2003). Tambien, a nivel del tejido de sostn glial se han encontrado evidencia de cambios citoestructurales: la glia, conformada por astrositos, oligodendrocitos y la microgla, es un elemento importante del sistema nervioso, que interviene en la migracin neuronal, y en la funcion trofica y energetica del metabolismo neuronal a lo largo de la vida, y se encuentra reducida en los cerebros de esquizofrenicos (Falkai y cobs, 1999). Especficamente, se han observado disminucin de astrocitos a nivel cortical, correlacionado con la deficiencia migratoria neuronal (Niizato, 2001), de oligodendrocitos, correlacionado con atrofia neuronal dada su funcion trofica y energetica, y fundamentalmente por su rol en la mielinizacion de las fibreas del tejido nervioso, basica para la optimizacion del influjo nervioso, con lo que una mala calidad de mielinizacion afecta profundamente la conectividad neuronal, lo que puede ser responsable en los pacientes de su desorganizacin funcional. Como se puede apreciar, la esquizofrenia es una patologa compleja, asociada a sntomas postivos y negativos, donde se encuentran variados trastornos en al organizacin estructural macro y microscopica del cerebro, como tambien en su metabolismo funcional, asociado a anomalias de las vias de neurotrasmision dopaminergica, serotoninergico y del sistema GABA, lo que explica la sorprendente variabilidad del cuadro clinico y las dificultades de su abordaje terapeutico. Es importante recalcar que estos hallazgos pueden desarrollarse progresivamente y ser previos a la aparicion de la enfermedad (Weinterberger, 1995) Desde el punto de vista funcional, muchas investigaciones han puersto de relieve la disminucin del metabolismo frontal en pacientes crnicos, o en estados residuales, la que estara en relacin con la disminucin de los rendimientos cognitivos que evaluan funciones ejecutivas, traducidas en deficits en los procesos atencionales, dificultades en la planificacin de tareas o trastornos de memoria, a su vez relacionadas con los sntomas negativos de la esquizofrenia.

5.- Tratamiento 6.- Otros Trastornos psicticos 7.- Trastornos cognitivos de la Esquizofrenia 1. De la semiologa como factor explicativo de los trastornos del pensamiento: De Kraepelin- Bleuler-Schneider-Crow y Andreassen a la clnica de finales del siglo XX 2. Los trastornos cognitivos de la esquizofrenia como fenmenos primarios

La anormalidad de la funcion de la corteza pre-frontal y la neurotrasmision dopaminergica, son fenmenos relacionados en la EQZ. (Meyer-Linderberg, A. and col, Nature Neuroscience 5, 267-261, 2002) La identificacin de las anormalidades moleculares que subyacen a la fisiopatologa de la EQz, es un paso necesario en el desarrollo de nuevas intervenciones terapeuticas. Desde el punto de vista cognitivo, se ha relacionado la disfuncion de la corteza prefrontal dorsolateral con la memoria del trabajo. La cascada de efectos moleculares de las disfunciones del glutamato, dopamina y GABA en esa area lleva al deterioro de la memoria del trabajo, en los pacientes esquizofrenicos La hiptesis clasica de la funcion de la DOPAMINA EN LA GENESIS DE LA EQZ postula la hiperactividad de trasmisin dopaminergica en los recptores D2, lo que se cdorrelaciones con la buena respuesta de los sintomas positivos a los neurolepticos. Otra de las mayores evidencias para este piunto de vista es l a potencialidad psicomimetica de agentes como la anfetamina que estimulala concentracin sinaptica de la dopamina. Despus del nfasis inicial de este rol, los autores reconceptualizaron la hiptesis a una hiperdopaminergia subcortical con hipodopaminergia prerfrontal para llegar a una etapa donde se reconoce la etiologia multifactorial de la enfermedad y la relevancia de distintos fenmenos: embarazo y riesgos obstetricos, estrs, genetica, uso de drogas, etc que conducen a una via final comun, aumentar la actividad dopaminergica presinaptica estratial. (Howes, O., Kapur, S. Schizophr. Bull. 2009; 35:549-562) Los problemas para coordinar pensamientos y acciones en relacion a objetivos internos son caracteristicos en los pacientes esquizofrenicos, y responsable de las persistentes y maladaptativas conductas. El sustrato neural de tales dificultades se ha estudiado implicando diversas areas de la corteza prefronatl lateral relacionadas con el procesamiento de la informacin contextual cuyo deterioro se traduce en altas y bajas en el control de la atencin, memoria de trabajo y los procesos episdicos de la memoria. Koechlin y colaboradores ha demostrado que en esta area del cerebro se lleva a cabo un proceso ejecutivo en cascada que controla la conducta en funcin de un objetivo (Barbalat, G y col, Arch Gen Psych, 2009; 66 (4) 377-386) Jablensky, A. Subtyping schizophrenia: implications for genetic research. Mol. Psychiatry, 2006 , 11, 815-836, sugiere en base a sus estudios de linkaje genetico y categoras diagnosticas de los sub-tipos clinicos de la esquizofrenia que esta no es una entidad homogenea, dada la pobre coherencia de la clinica con los datos recogidos por la genetica y la biologa, sugiriendose reemplazar el concepto de esquizofrenia por el concepto pre-kraepiliano de psicosis unitaria. En otras palabras, la identidad del cuadro esquizofrenico reposa en una construccion conceptual que empiricamente se ha demostrado valida para sostener su presencia ante la insuficiencia de un sistema diagnostico fundado en la etiopatogenia de la enfermedad.

-------VOL 63 No 10, Oct 2009 -----

Vulnerabilidad en la etiopatogenia de los trastornos psiquitricos (Guelfi-Rouillon) En la actualidad no se discute el origen multifactorial de los problemas psiquitricos. Como lo sostiene Barlow, el cuadro clnico depende de una cadena causal de elementos o factores de vulnerabilidad genticos, medioambientales y psicosociales que interactan complejamente a la manera como ocurre en los sitemas matematicoa altamente complejos (explicar), donde uno de los factores que intervienen solo aumenta la probabilidad de que se desarrolle una enfermedad. En esta visin probabilstica, la idea de factor de vulnerabilidad constituye la piedra angular de una concepcin etiologoca que se aleja totalmente de la idea de una etiologa causal natural de una enfermedad mental, para entenderla en interaccion con otros factores de riesgo igualmente capaces por su peso especifico de gatillar el desarrollo de una patologa, en un proceso largo y complejo. En este contexto, la investigacin reciente en psiquiatra ha podido estudiar un numero relativo de factores de vulnerabilidad que inciden en la etiopatogenia de las enfermedades mentales. Ejemplos de esta anturaleza es la relacin entre eventos o complicaciones obsttricas y la aparicin posterior de una esquizofrenia o la relacin de determinados virus contrados por la madre durante el embarazo, y convenientemente documentados con estudios sricos, en relacin con un aumento del riesgo de una esquizofrenia (1-2) en estudios poblacionales. Factores de vulnerabilidad de tipo genticos Desde los primeros trabajos de Kraepelin se puso atencin a el carcter familiar de las enfermedades psiquitricas mas comunes, intuicin que se ha visto confirmada por los estudios sitematicos de distintos autores a propsito de la esquizofrenia, los trastornos bipolares, como tambin al TOC y ciertas adicciones, para hacerse extensiva en los ltimos tiempos a ciertas categoras transnosgraficas como el suicidio o dimensiones de la personalidad. Para todas ellas han sido los estudios en gemelos y en nios adoptados los que han dado las claves para comprender el rol etiolgico de los factores de vulnerabilidad genticos en la subsecuente aparicin de la enfermedad, como tambin del modo no mendeliano de trasmisin de stas en la medida que la accin se encuentra mediatizada por otros factores de vulnerabilidad como lo son los medioambientales o los del desarrollo. Los primeros estudios de esta naturaleza se realizaron en los aos 70-80 del siglo pasado, impulso que continua con el desarrollo de los marcadores genomicos y los extraordinarios progresos de la biologa molecular, para dar como resultado mas de 10 localizaciones cromosmicas para cada una de las enfermedades estudiadas, aunque subsiste el problema mayor de un mejor telescopaje en concepto de Berrios entre la psicopatologa, imprecisa y heterogenea respecto de los factores de vulenrabilidad subyacentes a esas condiciones clnicas, que requiere, segn este autor, un esfuerzo de mayor precisin conceptual para identificar sub-grupos de pacientes homogneos para conducir investigaciones de este tipo, tratando de vincular con mayor vlidez, sntomas especficos e investigacin endofenotipica. Para el logro de

stos objetivos de correlacin de componentes genticos de una enfermedad multifactorial con sntomas y formas clnicas determinadas y precisas, los investigadores han orientado su trabajo en dos direcciones: a) eligiendo un sntomaobjetivo que corresponda a una caracterstica definida de tipo clnica, bioqumica o anatmica de un sujeto afectado por una enferemedad que pueda asociarse a un gentotipo suceptible de producirla para el logro de la homogeneidad requerida, o b) buscando entre los parientes de primer grado individuos no afectados que tengan un marcador endofenotipico de la enferemdad que pueda correlacionarse con dicha enfermedad. Entre los sntomas-objetivo, que se han elegido y que permiten por sus caractersticas individualizar sub-grupo de pacientes mas homogneos desde el punto de vista etiolgico respondiendo a un modo de trasmisin gentico simple, esta la edad de comienzo de la enfermedad, la respuesta al tratamiento, la severidad, ciertas dimensiones clnicas. Asi, la edad de comienzo precoz de la enfermedad esta asociada a un riesgo familiar alto tanto para la esquizofrenia como para los trastornos bipolares, o el perfil clnico o sntomas especficos de la esquizofrenia en sus formas deficitarias primarias, con catatonia peridicas o con coexistencia o no de trastornos del animo, constituyen ejemplos junto a otros de como se redefinen fenotipos para el anlisis de componentes genticos de las enfermedades mentales. (Ejemplos -Ojos y eqz- de asociaciones para la eqz y los tb, sucidio y TOC) Factores de vulnerabilidad medioambiental Factores sociodemogrficos: Celibato Aislamiento social Aislamiento afectivo Precaria insercin laboral o profesional Bajo nivel socioeconmico Vida urbana Falta de soporte social Ser migrante Pero estos factores tambin pueden ser consecuencias deletreas del trastorno propiamente tal Acontecimientos vitales y estrs Acontecimientos de vida con fuertes compnentes emocionales El impacto de lsos acontecimientos vitaels es modulado por las capacidades de adaptacin al estrs del sujeto, Para el caso de los <TB, el rol atribuido aa los acontecimientos vitales es aquel de modelo neurobiolgico que reposa sobre una memoria, que explica la evolucin recurrente de los trastornos, la aceleracin de los ciclos y el desencadenamiento de ellos a travs de un estrs cada vez menos importante. El rol de las relaciones perturbadas precoces entre padres e hijos (separaciones, pobreza de intercambios afectivos, fiscos, maltrato, etc tambin

ah sido evocado en realacion a al desarrollo ulterior de eqz y de trastornos del humor Factores biolgicos Tardos: Toxicos (marihuana, cocana y anfetaminas pueden desencadenar el comienzo de una enfermedad o intervenor en su evolucin La marihuana ha sido vinculada al desarrollo de una psicosis esquizofrnica Agentes infecciosos Despues de la gripe de 1918 se conoce la incriminacin de del virus en la gnesis de cuadros esquizofreniformes por Menninger, pero tambin ha sido estudiada como un factor de riesgo precoz asi como el estreptococo hemoltico b en la etiologa del TOC en el nio Factores de aparicin precoz El punto de partida ha sido el desequilibrio estacional en el nacimiento de futuros pacientes en estudios realizados en el hemisferio norte donde la tasa de esquizofrnicos nacidos en invierno o a comienzos de la primavera sobrepasa el 5% en relacin a la poblacin genral, cifra que sin embargo no es especifica de la Eqz porque se da tambin enotras patologas TB y abusos de substancias o alcohol. Las hiptesis de neurodesarrollo fundada en argumentos clnicos, experimentales o de imgenes cerebrales implica el rol de complicaciones obsttricas e infecciosas en el desarrollo precoz de anomalas del desarrollo neuronal tales como perturbaciones en la migracin neuronal o de la diferenciacin laminar de la corteza, especialmente en el 2do trimestre del embarazo, pero tambin entodo el curso del embarazo implicando desde los procesos de diferenciacin neuronal hasta los mas tardos de crecimiento dendrtico y axonal, hasta los de mielinizacion que persiste hasta el comienzo de la edad adulta, especialmente a nivel de la corteza prefrontal

A PET study of teh pathofisiology of negative syntoms of schizophrenia. Spotkin. S., y col. Am. J. of Psychitry, 159: 227-237, 2002 Los sintomas negativos de la esquizofrenia incluyen abulia, anhedonia, disminucion de la atencion y disminucion de la expression emocional, asociados a pobre function premorbida, al sexo masculine y a un Ci bajo. Los tratamientos con antipsicoticos no demuestran un resultado positivo en el tratamiento de estos sntomas, los que tieneden a la cronicidad, y a favorecer el mal pronostico de la enfermedad. Han sido asociados al dao estructural de regiones de la corteza prefrontal, relacionados con una hipodopaminergia del sustrato central

Fisiopatologia del espectro esquizofrnico (Siever, 2004)

Hallazgos neurobiologicos en la primara fase de la EQZ

Entre los variados hallazgos de procesos neuropatologicos encontrados con RNM en la primera fase de la esquizofrenia se encuenta deficits de materia gris, volumen ventricular normal o aumentado, disminucin del volumen del ncleo caudado, ausencia de la normal asimetra entre regiones pre-fronattales, pre-motoras y occisito-temporale, cisura pequea en el cuerp calloso, anormalidades en el cuerpo pelicidum, cambios en el volumen del hipocampo, todo lo que habla de un fenmeno difuso y variado que reflaja alteraciones de la conectividad funcional y estructural del cerebro, sobre todo en la region temporal media y la corteza prefrontal. Hallazgos en relacion al volumen del hipocampo Investigacin de influencias tempranas en e desarrollo neuronal Complicaciones obstetricas y malformaciones congenitas en la EQZ (VER SCHIZOPHRENIA: pathophysiological mechanisms TERENIUS, L.) Sedvall, G., and

Factores de riesgo precoces y tardios en la EQZ: exposicin obstetrica; signos neurologicos, anomalias en la conducta y en la cognicion infantil; desde la niez a la apricion de la psicosis; factores de riesgo propios del medio urbano, la migracin, etc.; factores de riesgo proximos a la enfermedad, acontecimientos vitales y uso de substancias----un modelo integrado Hallazgos neurobiologicos en las primeras fases de la esquizofrenia

Altered Effect of Dopamine Transporter 3'UTR VNTR Genotype on Prefrontal and Striatal Function in Schizophrenia
Diana P. Prata, PhD; Andrea Mechelli, PhD; Marco M. Picchioni, MD; Cynthia H. Y. Fu, MD, PhD; Timothea Toulopoulou, PhD; Elvira Bramon, MD, PhD; Muriel Walshe, PhD; Robin M. Murray, MD, PhD; David A. Collier, PhD; Philip McGuire, MD, PhD Arch Gen Psychiatry. 2009;66(11):1162-1172. ABSTRACT

Context The dopamine transporter plays a key role in the regulation of central dopaminergic transmission, which modulates cognitive processing. Disrupted dopamine function and impaired executive processing are robust features of schizophrenia. Objective To examine the effect of a polymorphism in the dopamine transporter

gene (the variable number of tandem repeats in the 3' untranslated region) on brain function during executive processing in healthy volunteers and patients with schizophrenia. We hypothesized that this variation would have a different effect on prefrontal and striatal activation in schizophrenia, reflecting altered dopamine function. Design Case-control study. Setting Psychiatric research center. Participants Eighty-five subjects, comprising 44 healthy volunteers (18 who were 9repeat carriers and 26 who were 10-repeat homozygotes) and 41 patients with DSMIV schizophrenia (18 who were 9-repeat carriers and 23 who were 10-repeat homozygotes). Main Outcome Measures Regional brain activation during word generation relative to repetition in an overt verbal fluency task measured by functional magnetic resonance imaging. Main effects of genotype and diagnosis on activation and their interaction were estimated with analysis of variance in SPM5. Results Irrespective of diagnosis, the 10-repeat allele was associated with greater activation than the 9-repeat allele in the left anterior insula and right caudate nucleus. Trends for the same effect in the right insula and for greater deactivation in the rostral anterior cingulate cortex were also detected. There were diagnosis x genotype interactions in the left middle frontal gyrus and left nucleus accumbens, where the 9repeat allele was associated with greater activation than the 10-repeat allele in patients but not controls. Conclusions Insular, cingulate, and striatal function during an executive task is normally modulated by variation in the dopamine transporter gene. Its effect on activation in the dorsolateral prefrontal cortex and ventral striatum is altered in patients with schizophrenia. This may reflect altered dopamine function in these regions in schizophrenia.

INTRODUCTION

Jump to Section The dopamine transporter (DAT; SLC6A3 [GenBank Top DQ307031]) plays a key role in the regulation of central Introduction Methods dopaminergic transmission by mediating dopamine reuptake 1 Results from the synaptic cleft into the presynaptic terminal. In the Comment mammalian brain, DAT messenger RNA is localized in cell Author information 2-3 bodies of dopaminergic neurons. Its expression is highest in References synapses in the striatum, substantia nigra, and ventral tegmentum,4-6 although it is also abundant in the thalamus and in the insular, motor, posterior parietal, and posterior cingulate cortices.6-7 It is expressed in lower levels in the prefrontal, anterior cingulate, primary sensory, and occipital cortices,6-8 especially within intrasynaptic as opposed to extrasynaptic extracellular space, and the rate of dopamine uptake in these areas is relatively slow.9 In these brain regions with low

levels of DAT, intracellular degradation by catechol O-methyltransferase (COMT) and uptake by nonspecific transporters such as the norepinephrine transporter may play a relatively greater role in the regulation of local dopamine availability. In these regions, DAT is mainly extrasynaptic and may primarily regulate dopamine volume transmission, the spillover of dopamine into the extrasynaptic space. 10-12 The human DAT gene has a polymorphic 40base pair (bp) variable number of tandem repeats (VNTR) in the 3' untranslated region (DAT 3'UTR VNTR). This yields several alleles ranging from 3 to 11 copies of the 40-bp repeats, with 9 and 10 being the most common.13 Although this polymorphism does not affect protein structure,14 it may influence transcription. Four independent studies15-18 have found the 10-repeat allele to be associated with higher levels of DAT expression, although there is 1 report of lower expression19 and 1 of no association.20 This DAT 3'UTR VNTR has been previously associated with Parkinson disease,21 alcoholism,22 attention23-24 25-26 deficit/hyperactivity disorder, and Tourette syndrome. Previous functional neuroimaging studies of memory paradigms in healthy subjects have reported an effect of DAT 3'UTR VNTR on prefrontal activation, and an additive interaction between this effect and that of a functional polymorphism for COMT (Val158Met) in prefrontal cortex.11, 27-29 Nonlinear interactions between the effects of the DAT and COMT polymorphisms on hippocampal 28 and striatal29 activation have also been reported in the context of reward and memory tasks, respectively. Schizophrenia is associated with alterations in the dopaminergic input to the cerebral cortex30-34 and the striatum.35-38 The same variation in DAT activity may thus have different effects on brain function in patients with schizophrenia and healthy volunteers. The aims of the present study were to examine the influence of DAT genotype on regional brain function during a verbal fluency task and to assess the extent to which this is altered in schizophrenia. We used functional magnetic resonance imaging to study samples of healthy volunteers and patients large enough to yield subgroups of sufficient size to detect effects of the DAT 3'UTR VNTR genotype on activation. Subjects underwent imaging while they performed a phonologic verbal fluency task, which normally engages the prefrontal, insular, and cingulate cortex; the striatum; and the thalamus39-47 and is associated with impaired performance48-49 and altered prefrontal activation44, 47, 50-53 in patients with schizophrenia.54-55 Because they express high levels of DAT4-7 and are also engaged during verbal fluency tasks,44, 46 we predicted that variation in DAT 3'UTR VNTR would modulate activation in the striatum, thalamus, and insula. Our second hypothesis was that variation in the DAT 3'UTR VNTR genotype would have a different effect in patients compared with controls in 2 areas where there is good evidence that dopamine function is perturbed in schizophrenia: the striatum35-38 and the dorsolateral prefrontal cortex.30-34 Although the prefrontal cortex does not express high levels of DAT, it is connected to the striatum via the corticothalamostriatal loop,11, 27 and variation in the DAT 3'UTR VNTR genotype influences activation in the prefrontal cortex as well as the striatum.27, 29 In addition, the prefrontal cortex is a robust site of altered activation in schizophrenia during verbal fluency and other cognitive tasks.30-34

METHODS

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SUBJECTS

A total of 85 subjects participated. All were native English speakers and gave written informed consent in accordance with protocols approved by the local research ethics committee. Patients who had a diagnosis of schizophrenia from their clinical team and met DSM-IV criteria for schizophrenia (n = 41) were recruited from the South London and Maudsley National Health Service Trust. The DSM-IV diagnosis was made by an experienced psychiatrist (including M.M.P.) using a structured diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry56 and Schedule for Affective Disorders and Schizophrenia57). When interview data were missing or incomplete, the diagnosis was determined by means of the Operational Criteria Checklist.58 The Schedules for the Assessment of Positive and Negative Symptoms were used to measure psychopathologic symptoms at the time of imaging. All patients were in a stable clinical state and had previously been treated with antipsychotic medication; however, 5 were not taking antipsychotic medication at the time of imaging. The mean duration of antipsychotic treatment was 12 years. Healthy volunteers (n = 44) had no history of mental illness and no first-degree relatives with a psychotic disorder, as assessed by the Family Interview for Genetic Studies. Subjects who met DSM-IV criteria for a substance misuse disorder were excluded. All subjects were genotyped for DAT at 3'UTR VNTR. This yielded 18 subjects who were 9-repeat carriers (2 of whom were homozygotes) and 26 subjects who were 10repeat homozygotes in the healthy volunteer group, and 18 who were 9-repeat carriers (2 homozygotes) and 23 who were 10-repeat homozygotes in the patient group. Fisher exact tests or 2 tests (for categorical variables) and analysis of variance tests (for numeric variables) were calculated with SPSS version 15.0 (SPSS Inc, Chicago, Illinois) to detect demographic differences in relation to genotype, diagnosis, and their interaction. There were no significant differences (P > .05) between the patient and control groups in age, ethnicity, or handedness, but patients had a lower mean IQ, fewer years of education, and a higher proportion of males (Table 1). Within the total sample and within each diagnostic group, there were no significant differences (P > .05) between genotype subgroups in any of the demographic variables. No demographic variables showed a significant genotype x diagnosis interaction, except for sex. Within the patient group, the genotype subgroups did not differ significantly (P > .05) in total scores on the Schedule for the Assessment of Positive Symptoms (mean [SD], 6.6 [6.6]) or Schedule for the Assessment of Negative Symptoms (mean [SD], 7.8 [5.1]) scores, nor in the duration (mean [SD], 12.2 [9.5] years), dose (chlorpromazine equivalents; mean [SD], 598.8 [452.3]), or type (first or second generation) of antipsychotic medication.

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Table 1. Demographic Features and VF Error Means in Relation to Diagnosis, DAT 3'UTR VNTR Genotype, and Their Interaction

GENOTYPING DNA was extracted from blood or cheek swabs by standard methods. 64 Amplification of the 3'UTR VNTR region was performed by a polymerase chain reaction using the forward primer 5'TGGCACGCACCTGAGAG3' (melting temperature, 60.8C) and the reverse primer 5'GGCATTGGAGGATGGGG3' (melting temperature, 62.3C). Its products were then separated under UV light after electrophoresis on a 3.5% agarose gel containing ethidium bromide. Genotyping was successful in 88 subjects (98%). Genotype frequencies were similar to frequencies described in the literature. The patient group was in Hardy-Weinberg equilibrium (P > .99; calculated with GENEPOP65), but the control group showed a minor deviation (P = .03), which was apparently due to the presence by chance of a rare homozygous genotype, a 6/6 repeat, in a single individual. Three subjects carrying genotypes with alleles other than the 9-repeat or the 10-repeat allele (as well as 2 subjects for whom genotype calling was unreliable) were not included in the 85-subject sample further analyzed, to reduce allelic heterogeneity. VERBAL FLUENCY TASK During a "generation" condition, subjects were visually presented with a series of letters and were required to overtly articulate a word beginning with each letter. This was contrasted with a "repetition" condition in which subjects were presented with the word rest and were required to say "rest" out loud. A blocked design was used, with letter and rest cues presented in blocks of 7 events. The demands of the task were manipulated by presenting 2 different sets of letter cues, termed easy and hard.46 These had previously been shown to be associated with a significant difference in behavioral performance in healthy volunteers.46 The easy condition involved the presentation of letters that are normally associated with relatively large numbers of correct responses and relatively few errors (eg, T, B, S), whereas the hard condition involved letters associated with the generation of fewer correct words and relatively more errors (eg, N, E, G). Five blocks of rest trials alternated with 5 blocks of easy letters or hard letters, resulting in a total of 70 generation and 70 repetition trials. Verbal responses were recorded, permitting the identification of "incorrect" trials in which the subject did not generate any response or generated repetitions, derivatives, or grammatical variations of a previous word. Further details are provided in the eMethods section.44, 46, 66-67 IMAGE ACQUISITION T2*-weighted gradient-echo single-shot echo-planar images were acquired on a 1.5-T, neuro-optimized imaging system (IGE LX System; General Electric, Milwaukee, Wisconsin) at the Maudsley Hospital, London, England. Twelve noncontiguous axial planes (7-mm thickness, 1-mm section skip, 3.75 x 3.75-mm voxel size in plane, and 64 x 64-mm matrix size in plane) parallel to the anterior commissureposterior commissure line were collected during 1100 milliseconds in a "clustered" acquisition (echo time, 40 milliseconds; flip angle, 70), which permitted articulatory responses to be made when images were not being acquired, minimizing the effects of head movement on the blood oxygen level dependent signal.46 Immediately after each acquisition, a letter was presented (remaining visible for 750 milliseconds; height, 7

cm; subtending a 0.4 field of view), and a single overt verbal response was made during the silent portion (duration, 2900 milliseconds) of each repetition (repetition time, 4000 milliseconds), with an image acquired during 1100 milliseconds. Head movement was minimized by a forehead strap. To ensure that subjects heard their responses clearly, their speech was amplified by a computer sound card and then relayed back through an acoustic magnetic resonance imaging sound system and noise-insulated headphones. Further details are provided in the eMethods section. BEHAVIORAL ANALYSIS The effect of task load, genotype, diagnosis, and their interaction on the level of accuracy of verbal responses (measured by the number of incorrect responses during imaging) was assessed by means of a multivariate 2 x 2 x 2 analysis of variance, with diagnosis and genotype as between-subject factors and task load as a within-subject factor. IMAGE ANALYSIS Analysis was performed with SPM5 software (http://www.fil.ion.ucl.ac.uk/spm),68 running under MATLAB 6.5 (MathWorks Inc, Sherbon, Mass). To minimize movementrelated artifacts, all volumes from each subject were realigned and unwarped (by means of the first as reference resliced with sinc interpolation), normalized to a standard MNI-305 template, and spatially smoothed with an 8-mm full-width at halfmaximum isotropic gaussian kernel. First, the statistical analysis of regional responses was performed in a subject-specific fashion by convolving each onset time with a synthetic hemodynamic response function. To minimize performance confounds, we modeled correct and incorrect trials separately by using an event-related model, yielding 4 experimental conditions: (1) easy generation, (2) hard generation, (3) repetition, and (4) incorrect responses. The last was excluded from the group analysis to control for effects of group differences in task performance. Correct responses among the generation events (35 events in the hard version and 35 in the easy version) were contrasted with 70 repetition events. To remove low-frequency drifts, data were high-pass filtered by using a set of discrete cosine basis functions with a cutoff period of 128 seconds. Parameter estimates were calculated for all brain voxels by means of the general linear model, and contrast images for "easy generation > repetition" and "hard generation > repetition" were computed in a subject-specific fashion. Second, the subject-specific contrast images were entered into a full-factorial 2 x 2 x 2 analysis of variance, with task load as a repeated measurement, to permit inferences at the population level.69 This allowed us to characterize the impact of the experimental task on brain activation in easy and hard conditions separately within each of the 4 experimental groups (9-repeat carrier controls, 10/10-repeat controls, 9-repeat carrier patients, and 10/10-repeat patients) and test for the main effects of diagnostic group and genotype and their interaction. We modeled task load to minimize error variance but report results for the hard and easy conditions combined. Individuals with the 9/9 allele were grouped with heterozygotes to form a group of sufficient size to be included in an analysis of variance. The t-images for each contrast at the second level were transformed into statistical parametric maps of the Z statistic. In regions where there was an a priori hypothesis, we report results that survived family-wise error (FWE) at P < .05 after small-volume correction (SVC). Regions of interest for the main effect of DAT (right and left insula, right and left thalamus, and right and left caudate nucleus) were defined by means of the automated anatomical labeling atlas70 provided in PickAtlas71-72 for SPM5. Regions of

interest for the diagnosis x genotype interaction were also defined with PickAtlas, using a 10-mm-radius sphere centered on foci reported in previous studies showing effects of the DAT 3'UTR VNTR genotype (in interaction with the COMT Val158Met genotype) on activation in the left striatum (15, 9, 9)29 and middle frontal gyrus ( 38, 38, 30).27 In the rest of the brain (where we did not have a priori hypotheses), we used FWE correction across the brain at P < .05. Because no effects were detected with this threshold, we report trends evident at P < .001, uncorrected, with a cluster extent of 10 voxels, for completeness. To assess how much of the interindividual (+ error) variance in blood oxygen leveldependent activation was explained by variation in genotype, we used the p2 (partial eta squared) measure of effect size in SPSS, after extracting the subjects' beta-measure at the voxel of peak activation. In regions where there was a significant effect of genotype, we assessed the potentially confounding effects of antipsychotic medication with a linear regression analysis, using duration, type (first or second generation), and dose (in chlorpromazine hydrochloride equivalents) of antipsychotic treatment as covariates. Sex was included as a covariate of no interest in the image analysis because this varied with genotype in the sample. To confirm that other demographic variables did not influence the findings, we repeated the analysis using each as a covariate of no interest.

RESULTS

PERFORMANCE

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Expectedly, there was a significant (P < .05) main effect of task demand on the number of incorrect responses (F = 50.36; P < .001), as there was for diagnosis, with patients making more errors than controls (F = 8.72; P = .004). The main effect of genotype was not significant (F = 1.10; P = .30). There was no significant interaction between task demand, diagnosis, and genotype (F = 1.18; P = .28). However, there was a trend for a diagnosis x genotype interaction (F = 3.56; P = .06), irrespective of task load, reflecting poorer performance in 10/10-repeat than 9-repeat carrier patients but the converse in healthy volunteers, especially during the hard version (Table 1). NEUROIMAGING DATA Main Effect of Task In both diagnostic groups, word generation (irrespective of task difficulty or genotype) was associated with activation in a distributed network that included, bilaterally, the inferior frontal, insular, and dorsal anterior cingulate cortex; the caudate and the thalamus; and the left middle frontal, superior temporal, and inferior parietal cortex (FWE P < .05) (Figure 1). Conversely, repetition was associated with greater engagement of the rostral anterior cingulate gyrus, precuneus, and occipital cortex.

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Figure 1. Activation common to both groups during verbal fluency (at family-wise error P < .05). In both controls and patients with schizophrenia, there was activation (ie, word generation minus repetition) in the lateral prefrontal cortex, insula, and thalamus and deactivation (ie, word repetition minus generation) in the precuneus and rostral anterior cingulate gyrus.

Main Effect of Diagnostic Group Activation in the left inferior frontal gyrus (44, 18, 30; Z = 3.4), anterior insula (34, 14, 8; Z = 3.3), and frontal operculum (36, 14, 12; Z = 3.6) was greater in patients than in healthy volunteers (P < .001, uncorrected). There were no areas more activated in healthy volunteers than in patients, and there were no between-group differences in deactivation. Main Effect of DAT 3'UTR VNTR Genotype Within the regions of interest, the 10/10-repeat group showed greater activation than the 9-repeat carrier group in the left insula ( p2 = 5.6%) and in the right caudate nucleus ( p2 = 5.4%) (right anterior insula FWE P = .02; left caudate nucleus FWE P = .03, SVC) (Figure 2 and Table 2), irrespective of diagnosis. Inspection of the parameter estimates (plotted in Figure 2A for the left insula) showed that these main effects were driven by relatively strong effects of genotype in the patient group. Also, the focus of maximal significance in the left insula (30, 6, 16) was close to the focus of the cluster where patients showed greater activation than controls (34, 14, 8, as noted earlier). None of the regions of interest showed greater activation in 9-repeat carriers than in 10-repeat homozygotes.

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Figure 2. Main effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3' untranslated region) on activation during word generation relative to repetition. A, Subjects with the 10/10-repeat genotype showed greater activation in the left insula (plotted), in the right caudate nucleus (family-wise error P < .05 after small-volume correction), and in the right insula (P < .001,

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uncorrected) during word generation than did carriers of the 9-repeat allele. B, In the anterior cingulate gyrus bilaterally, subjects with the 10/10-repeat genotype showed greater deactivation during word generation than did carriers of the 9-repeat allele (P < .001, uncorrected).

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Table 2. Main Effect of DAT 3'UTR VNTR Genotype on Activation and Diagnosis x DAT 3'UTR VNTR Genotype Interaction After SVC at FWE P < .05 in Regions of Interesta

Whole-brain analysis indicated that, irrespective of diagnosis, subjects in the 10/10repeat group showed greater activation than those in the 9-repeat carrier group (P < .001, uncorrected) in the left anterior insula ( 30, 6, 16; Z = 3.5; p2 = 5.6%) and in a right-sided cluster focused at 26, 4, 18 (Z = 3.6; p2 = 6.6%) that included the right caudate (reported for the foregoing region of interest analysis) and the adjacent part of the right insula. The plot of the parameter estimates was similar to that of the left anterior insula (described in the previous paragraph; Figure 2A). There was also a trend (P < .001, uncorrected) for a main effect in the rostral part of the anterior cingulate gyrus bilaterally (2, 40, 2; Z = 3.4; and 2, 40, 2; Z = 3.3; 2 p = 6.7). Exploration of the parameter estimates (Figure 2B) showed that this reflected deactivation during word generation (ie, more activation during repetition than generation), which was more pronounced in the 10/10-repeat group than in the 9-repeat carrier group. Group x Genotype Interaction There was an interaction between the effects of diagnosis and genotype in the left middle frontal gyrus ( p2 = 6.4%) and in the left nucleus accumbens ( p2 = 4.8%) (left middle frontal gyrus FWE P = .05; left nucleus accumbens FEW P = .02, SVC) (Figure 3 and Table 2). In the former region, there was no statistically significant difference in activation between the DAT 3'UTR VNTR genotypes in healthy volunteers, but in patients the 9-repeat allele was associated with significantly greater activation (left middle frontal gyrus FWE P = .004, SVC; p2 = 21.5%). In the left nucleus accumbens, healthy volunteers with the 10/10-repeat genotype showed more activation than 9repeat carriers, whereas the opposite applied in the patients. No other brain regions showed a diagnosis x genotype interaction (at P < .001, uncorrected).

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Figure 3. Interaction between effect of diagnostic group and of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3' untranslated region) on activation during word generation relative to repetition in the left middle frontal gyrus (A) and the left ventral striatum (nucleus accumbens) (B). The effect of genotype in controls was significantly different from that in patients with schizophrenia (family-wise error P < .05 after small-volume correction).

Effects of Potentially Confounding Factors on Activation Linear regression analysis indicated that activation in the areas where there were significant effects of DAT (either irrespective of or dependent on diagnosis) was not related to the dose, type, or duration of antipsychotic treatment, even at a very liberal statistical threshold (P = .5, uncorrected). Analyses included sex as a covariate of no interest. Repeating these analyses after covarying independently for IQ, years of education, or ethnicity did not alter the location or the Z score of the reported results.

COMMENT

Jump to Section Our hypothesis that the DAT 3'UTR VNTR genotype would Top influence task-related activation was confirmed in the left Introduction Methods insula and caudate nucleus. In both of these regions, the 10 Results repeat allele was associated with greater activation than the 9 Comment repeat allele in both healthy and schizophrenic subjects. A Author information whole-brain analysis also demonstrated a trend for the same References effect of genotype in the part of the right insula homologous to that identified in the region-of-interest analysis. The insula, especially in the left hemisphere, plays a major role in verbal fluency and other language-related tasks44, 46-47,51 and expresses high levels of the DAT relative to other cortical areas.7 Greater insular activation in carriers of the 10-repeat allele can be interpreted in terms of the putative effects of dopamine on the "efficiency" of cortical function. According to this model, 10-repeat carriers, who have more DAT than 9-repeat carriers, remove dopamine from synapses more rapidly, reducing dopamine to a level that is suboptimal for the local signal to noise ratio, reducing the efficiency of cortical function, and leading to increased activation.31-33 This is, to our knowledge, the first evidence of an effect of the DAT 3'UTR VNTR genotype on function in the insula in humans, previous effects having been reported in the hippocampus (in interaction with COMT genotype) and in the prefrontal cortex. 11, 27-29 The caudate nucleus is, with the putamen, the brain area with the highest expression of DAT7 and is also implicated in verbal fluency and articulation.73-76 It is a major termination site of central dopaminergic projections from the brainstem.77 The extent to which the foregoing

model of dopaminergic tuning of cortical efficiency is also applicable in the striatum is unclear. There was a trend for the 10-repeat allele to be associated with greater deactivation during word generation than the 9-repeat allele in the rostral anterior cingulate cortex. The relatively greater engagement of this region during verbal repetition (compared with generation) may be related to its involvement in the "default" network that mediates internally generated processes during low-level baseline conditions.78-80 The more marked response in individuals with the 10/10-repeat genotype might reflect an effect of lower dopamine activity on the efficiency of cingulate cortical function during the baseline condition, although the concept of the dopaminergic modulation of efficiency is derived from studies of prefrontal cortex during working memory tasks.78-80 The direction of the DAT 3'UTR VNTR's effect on cingulate activation is the same as that of a previous report,11 although this was in a more dorsal part of the gyrus during a working memory task. Consistent with our hypotheses about genotype x diagnosis interactions, there was an interaction in the left middle frontal gyrus. In this region, there was significantly greater activation in patients carrying the 9-repeat than the 10/10-repeat genotype but a similar response in the 2 genotype subgroups in healthy volunteers. The 9repeat allele is associated with lower gene expression15-18 and hence weaker DAT activity and higher dopamine levels. The fact that this effect of genotype was evident in patients with schizophrenia, accounting for more than one-fifth of the interindividual variance (21.5%), but not controls, raises the possibility that the effect of the 9repeat allele interacts with other factors contributing to the perturbation of dopamine function in the disorder. In schizophrenia, it is thought that dopamine activity is increased in the striatum but decreased in the cortex.81-84 Dopamine transporter is present at relatively low levels in the prefrontal cortex, whereas it is abundant in the striatum,4, 6, 85 and therefore the effects we observed in the prefrontal cortex may be secondary to effects of the DAT 3'UTR VNTR genotype in the striatum. The striatum receives dopaminergic input from the substantia nigra and the ventral tegmental area. Dopamine transporter removes dopamine from the intrasynaptic space of these terminals, reducing stimulation of dopamine receptors, which, in the striatum, are predominantly D2.86-88 Stimulation of these receptors leads to inhibitory effects on the thalamus, which then projects to the prefrontal cortex. A decrease in DAT activity associated with the 9-repeat allele may therefore increase synaptic dopamine levels and, thus, D2 stimulation in the striatum, inhibiting the thalamus and decreasing its excitatory input to the prefrontal cortex, which is thought to be necessary for an optimal signal to noise ratio in the prefrontal cortex. In schizophrenia, increased striatal dopamine activity may be amplified in patients with the 9-repeat allele, further increasing local dopamine levels and inhibition of the thalamus, leading to a marked reduction in the signal to noise ratio in prefrontal pyramidal neurons. 89 This could account for the increased prefrontal activation we detected in patients with the 9repeat allele. A similar interaction was evident in the left nucleus accumbens. In healthy volunteers, this region was more active during verbal repetition than generation in 9-repeat carriers, but there was no difference between the conditions in subjects with the 10/10-repeat genotype. The converse applied in the patient subgroups (Table 2). As discussed in relation to the interaction in the prefrontal cortex, in schizophrenia, increased dopamine activity in the striatum may alter the impact of variation in DAT genotype on local dopamine levels, producing the opposite effect on activation in patients compared with controls.

Because antipsychotics have an antagonistic effect on central dopamine receptors and because all of our patients were receiving antipsychotic drugs, the potentially confounding effects of medication on our findings in patients with schizophrenia must be considered. Antipsychotics can modulate presynaptic dopamine up take capacity9092 and cortical activation93 and may also affect performance of verbal fluency94-95 and other cognitive tasks,92, 96-97 although these findings have not always been replicated.98 Moreover, antipsychotic medication may reduce DAT activity via blockade of D2 receptors.99 Therefore, it is possible that differences in the effect of genotype between patients and controls may have been related to effects of medication rather than an effect of schizophrenia. In view of these concerns, we examined the potential effect of dose, type, and duration of antipsychotic treatment on activation in regions where we found significant effects of genotype. There was no evidence that the effects of genotype we observed were related to effects of medication on activation in these regions. Nevertheless, the possibility that the differences in the effects of genotype in patients compared with controls were related to medication as opposed to schizophrenia cannot be excluded without repetition of the present study in medication-naive patients. However, recruiting and performing imaging in a large sample of this type would be logistically difficult. The network of areas engaged by the verbal fluency task in the present study is consistent with that reported in several previous studies.44, 46-47,51 Patients showed greater activation than healthy volunteers in the left middle frontal gyrus, frontal operculum, and anterior insula. Many previous comparisons of patients with schizophrenia and volunteers have found differences in left frontal activation during verbal fluency, although some have reported decreases and others, increases. 44, 47, 5053,100-103 This inconsistency may partly reflect differences in sample sizes and the degree to which the effects of impaired task performance in schizophrenia have been controlled for. The present sample was comparatively large, and the effects of differential task performance were minimized by using a paced paradigm, online monitoring of behavioral performance, and restriction of the analysis to images associated with correct responses. Greater prefrontal activation in schizophrenia during cognitive tasks after controlling for differential performance may reflect impaired prefrontal cortical efficiency.104 The effect of the DAT 3'UTR VNTR genotype on verbal fluency performance has not been investigated before, to our knowledge. Although there was no significant main effect of genotype, there was a trend for a diagnosis x genotype interaction, which reflected poorer performance of the hard condition in 10/10-repeat than in 9-repeat carrier patients but the converse in healthy volunteers. Previous studies in healthy subjects suggest that the DAT 3'UTR VNTR genotype does not influence performance on working memory tasks,11, 27 but that the 10-repeat allele is associated with a higher number of commission errors during the Continuous Performance Test and with impaired selective attention and response inhibition.105 The trend for poorer verbal fluency performance in the 10/10-repeat group with schizophrenia might thus reflect an influence of the DAT 3'UTR VNTR genotype (and hence dopamine) on attention and response inhibition, both of which are involved in executing verbal fluency tasks. Because the sample size in the present study was powered to detect differences at the neurophysiologic rather than the neuropsychological level and because the task was paced (reducing task demands), it is possible that more marked effects of DAT genotype on performance would have been evident in a larger sample, using an unpaced version of the paradigm. We cannot exclude the possibility that the effects of the DAT 3'UTR VNTR genotype

were due to other polymorphisms in strong linkage disequilibrium with the 3'UTR VNTR. The latter was selected because it has been shown to have the greatest functional effect on DAT expression.15-18 We compared individuals with one or two 9repeat alleles against those with none (10/10-repeat group) because it was difficult to recruit a sufficient number of individuals homozygous for the 9-repeat allele. This precluded examination of whether the effect of the risk allele is better described by a dominant/recessive or additive model. Although, in most subjects, IQ was assessed by means of the Wechsler Adult Intelligence Scale, different versions of this instrument were used and, in a minority of subjects, IQ was assessed by means of the Quick Test. However, previous studies have shown that the IQ estimates obtained from these scales are highly correlated.59-64 Moreover, even if using different instruments had influenced the IQ estimates, it is unlikely to have affected the results because the proportion of subjects assessed with each version was matched across genotype groups. We used an event-related approach in the image analysis, although this is not ideal for data acquired via a block design with fixed interstimulus intervals. Although we modeled correct and incorrect trials separately to minimize the potentially confounding effects of differences in performance accuracy, reaction times were not measured, so the findings could have been influenced by differences in response speed.

AUTHOR INFORMATION

Correspondence: Diana P. Prata, PhD, Institute of Psychiatry, Kings College London, PO67, De Crespigny Park, London SE5 8AF, England (d.prata@iop.kcl.ac.uk). Submitted for Publication: November 15, 2008; final revision received March 16, 2009; accepted April 17, 2009.

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Author Contributions: Dr Prata had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Financial Disclosure: None reported. Funding/Support: Dr Prata was funded by the Fundacao para a Ciencia e Tecnologia, Lisbon, Portugal. Dr Fu was supported by a Wellcome Travelling Fellowship and Dr Picchioni by a Wellcome Trust Training Fellowship. Role of the Sponsors: The sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, or approval of the manuscript. Additional Contributions: We thank the reviewers for their useful suggestions. Mitul Mehta, MA, PhD (Institute of Psychiatry, King's College London), provided invaluable comments. Author Affiliations: Division of Psychological Medicine and Psychiatry (all authors), Social, Genetic, and Developmental Psychiatry Centre (Drs Prata and Collier), Department of Psychology (Dr Mechelli), and St Andrew's Academic Centre (Dr

Picchioni), Institute of Psychiatry, King's College London, London, England.

REFERENCES

1. Masson J, Riad M, Chaudhry F, Darmon M, Adouni Z, Conrath M, Giros B, Hamon M, Storm-Mathisen J, Descarries L, El Mestikawy S. Unexpected localization of the Na+/Cldependent-like orphan transporter, Rxt1, on synaptic vesicles in the rat central nervous system. Eur J Neurosci. 1999;11(4):1349-1361. FULL TEXT | PUBMED

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Prenatal Infection as a Risk Factor for Schizophrenia

1. Alan S Brown1,2 + Author Affiliations 1.
2

College of Physicians and Surgeons, Columbia University; New York State Psychiatric Institute, Columbia University, New York, NY; and Mailman School of Public Health, Columbia University, New York, NY
1

1.

To whom correspondence should be addressed; e-mail: asb11@columbia.edu.

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Abstract
Accumulating evidence suggests that prenatal exposure to infection contributes to the etiology of schizophrenia. This line of investigation has been advanced by birth cohort studies that utilize prospectively acquired data from serologic assays for infectious and immune biomarkers. These investigations have provided further support for this hypothesis and permitted the investigation of new infectious pathogens in relation to schizophrenia

risk. Prenatal infections that have been associated with schizophrenia include rubella, influenza, and toxoplasmosis. Maternal cytokines, including interleukin-8, are also significantly increased in pregnancies giving rise to schizophrenia cases. Although replication of these findings is required, this body of work may ultimately have important implications for the prevention of schizophrenia, the elaboration of pathogenic mechanisms in this disorder, and investigations of gene-environment interactions.

Key words

infection virus schizophrenia prenatal epidemiology

Evidence supporting the hypothesis that prenatal infection plays a role in the etiology of schizophrenia is increasing. This article focuses on recent work from our group and others which has demonstrated that gestational exposure to influenza, other infections, and elevations of specific pro-inflammatory cytokines are associated with an increased risk of schizophrenia. In these investigations several methodological advantages have been brought to bear on informative birth cohorts and have helped to support and extend this hypothesis. These design advantages include prospective data using biomarkers on infection in maternal serum samples and direct assessment of cases. Previous SectionNext Section

Specific Prenatal Infections and Biomarkers Implicated in Schizophrenia

Rubella

Inflammatory

Prenatal rubella is a well-known central nervous system teratogen and possibly is a cause of some childhood psychiatric disorders.1 We therefore hypothesized that this infection might also increase risk for adult schizophrenia. To test this hypothesis, we examined the risk of schizophrenia in members of a cohort in New York City who were born to mothers with clinical rubella, which was serologically confirmed. We found that 20% of prenatally rubella-exposed subjects were diagnosed with adult schizophrenia, suggesting a 10 to 20fold increase in risk.2 A decline in IQ between childhood and adolescence in this cohort was highly predictive of schizophrenia in the offspring.

Influenza
Among the in utero infections that are plausible risk factors for schizophrenia, influenza has been the most commonly examined. In a seminal study, Mednick et al.3 demonstrated an increase in risk of schizophrenia among Finnish individuals who were in the second

trimester of fetal development during the 1957 A2 influenza pandemic; however, over 25 subsequent studies reported inconsistent findings,4 leading investigators to question the viability of the hypothesis. Although these studies were groundbreaking, a significant limitation was the reliance on ecologic data to define influenza exposure, such that individuals were considered to have been influenza-exposed based only on having been in utero during one or more influenza epidemics. Since most were not influenza-exposed, this led to nondifferential misclassification of exposure, which may bias the effect toward the null. To address this limitation, we obtained serologic measures of antibody status in individual pregnancies to document influenza, then related the exposure to risk of schizophrenia in offspring using direct, research-based interviews.5 The sample was derived from the Prenatal Determinants of Schizophrenia Study based on a large and well-characterized birth cohort in northern California that was followed up for schizophrenia.6 We found that serologically documented influenza exposure during early to mid-gestation was associated with a 3-fold increased risk of schizophrenia; first trimester exposure to influenza conferred a 7-fold increased risk.5

Toxoplasmosis
Like rubella, Toxoplasma gondii, a ubiquitous intracellular parasite, is a well-known central nervous system teratogen.7 We investigated whether elevated maternal antibody to this infection was related to onset of schizophrenia in adult life. Using bioassays on maternal archived serum from the same northern California birth cohort as in the influenza study described above, we demonstrated that elevated maternal toxoplasma IgG antibody was associated with a 2 1/2-fold increase in risk of schizophrenia.7

Herpes Simplex Virus Type 2 (HSV-2)

In another birth cohort, Buka et al.8 found elevated maternal IgG antibody to HSV-2 in offspring who later developed psychotic disorders, including schizophrenia. In a larger sample consisting exclusively of schizophrenia and schizophrenia spectrum disorder cases, however, we were not able to replicate this finding.9

Cytokines
Cytokines and chemokines are known to mediate the host response to infection and thus might explain associations between different prenatal infections and schizophrenia. In our birth cohort study in northern California, we demonstrated that second-trimester maternal levels of the chemokine interleukin-8 (IL-8) were nearly twice as high for offspring who later developed schizophrenia, compared with controls. In a smaller sample an association was demonstrated between maternal TNF- and psychotic disorders among offspring.10 Previous SectionNext Section

Interpretation and Limitations of the Findings

These findings have provided the strongest evidence to date that prenatal infection contributes to risk for schizophrenia. They must, however, must be viewed with caution. First, there have yet to be attempts to replicate most of these results in the published literature. Second, the mechanisms by which these infections might lead to schizophrenia have not been well delineated. Potential mechanisms include teratogenic effects of maternal antibodies on neurodevelopment and a surge in circulating cytokines. Recent animal models suggest that influenza and immune activation have effects on the fetal brain that appear to be concordant with findings observed in schizophrenia.11 With regard to toxoplasmosis, an increase in IgM antibody, an indicator of recent infection, was not found; thus, the observed increase in IgG antibody may have resulted from an infection occurring months or years prior to the measurement. Nonetheless, since toxoplasma remains in a latent, sequestered state for many years following infection, it is conceivable that suppressed reactivation of this parasite by a chronic maternal immune response, rather than the organism itself, may be responsible for the association. The reasons for the association between second-trimester IL-8 and schizophrenia are also unclear, in part because the many roles of this chemokine are still under investigation. Among its known functions, IL-8 is involved in the adherence of neutrophils to endothelial cells and in free radical formation.12 Nonetheless, the plausibility of IL-8 as a risk factor for schizophrenia is supported by the fact that this chemokine has been associated with chorioamnionitis in infants born at term, and a significant correlation has been observed between maternal and neonatal serum IL-8 levels. A third limitation is that we have yet to investigate whether these infections and immune disturbances act in concert with one another to increase schizophrenia risk. This work is underway. Previous SectionNext Section

Future Directions
We wish to highlight 3 potential implications of this work for future research and interventions. First, it is important to test the plausibility of this hypothesis and to identify pathogenic mechanisms by which these infections increase schizophrenia risk. This can be addressed by translational approaches, such as that noted above for influenza, and by clinical studies, which we have been conducting, that aim to relate prenatal infection to brain anomalies that have been observed in adult patients with schizophrenia. Second, we believe that it is essential for future work to investigate interactions between prenatal infection and susceptibility genes. Given that the effect sizes observed have been moderate, it is likely that prenatal infection increases risk of schizophrenia only among subgroups of vulnerable individuals, including those who are genetically predisposed or who have been exposed to other environmental factors. This work could help to provide a more complete picture of disease causation and potentially aid in the identification of vulnerability genes.

Finally, studies of prenatal infection and schizophrenia may hold considerable promise for preventive efforts. Our data on influenza indicated that as many as 14% of schizophrenia cases would not have occurred if influenza infection during early to mid-gestation had been prevented.5 This may have important public health implications, given that there are many available preventive strategies for influenza and other infections, including vaccination, antibiotics, and simple hygienic measures. In summary, our data thus far suggest that several prenatal infections and inflammatory biomarkers may contribute to the etiology of schizophrenia. It must be emphasized, however, that these findings require replication in independent samples before any specific public health measures are recommended. Nonetheless, the study of prenatal infection in schizophrenia promises to play an important role in revealing at least some of the biological underpinnings of this devastating disorder. Previous SectionNext Section

Acknowledgments
This manuscript was supported by the following grants: NIMH 1R01MH 6326401A1 (A.S.B.), NIMH 1R01MH06249 (A.S.B.), NIMH 1K02MH6542201 (A.S.B.), a NARSAD Independent Investigator Award (A.S.B.), NICHD N01-HD-13334 (B.A. Cohn), and NICHD NO1-HD-63258 (B.A. Cohn). We wish to acknowledge the following individuals for their contributions to this work: Ezra S. Susser, M.D., Dr.P.H., Catherine A. Schaefer, Ph.D., Barbara van den Berg, M.D., Barbara Cohn, Ph.D., Michaeline A. Bresnahan, Ph.D., Charles P. Quesenberry Jr, Ph.D., Liyan Liu, M.D., M.Sc., the late Jacob Yerushalmy, M.D., Gilman Grave, M.D., Roberta Christianson, M.A., and Justin Penner, M.A. We also wish to thank the National Institute for Child Health and Development and the Public Health Institute, Berkeley, Calif.

The Author 2006. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

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References
1. 1. 1. Chess S, 2. Korn S, 3. Fernandez P . Psychiatric Disorders of Children with Congenital Rubella. New York, NY: Brunner/Mazel; 1971.

2. 2. 1. 2. 3. 4. Brown AS, Cohen P, Harkavy-Friedman J, et al

. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry 2001;49:473-486. CrossRefMedlineWeb of Science 3. 3. 1. 2. 3. 4. Mednick SA, Machon RA, Huttunen MO, Bonett D

. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988;45:189-192. Abstract/FREE Full Text 4. 4. 1. Bagalkote H . Maternal influenza and schizophrenia in the offspring. Int J Ment Health 2001;29:3-21. 5. 5. 1. 2. 3. 4. Brown AS, Begg MD, Gravenstein S, et al

. Serologic evidence for prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004;61:774-780. Abstract/FREE Full Text 6. 6. 1. 2. 3. 4. 5. Susser ES, Schaefer CA, Brown AS, Begg MD, Wyatt RJ

. The design of the Prenatal Determinants of Schizophrenia Study. Schizophr Bull 2000;26:257-273. Abstract/FREE Full Text 7. 7. 1. 2. 3. 4. 5. 6. Brown AS, Schaefer CA, Quesenberry CP Jr, Liu L, Babulas VP, Susser ES

. Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J Psychiatry 2005;162:767-773. Abstract/FREE Full Text 8. 8. 1. 2. 3. 4. 5. 6. Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH

. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001;58:1032-1037. Abstract/FREE Full Text 9. 9. 1. 2. 3. 4. 5. Brown AS, Schaefer CA, Quesenberry CP Jr., Shen L, Susser ES

. No evidence of relation between maternal exposure to herpes simplex virus type 2 and risk of schizophrenia. American Journal of Psychiatry. In press. 10. 10. 1. 2. 3. 4.

Buka SL, Tsuang MT, Torrey EF, Klebanoff MA,

5. Wagner RL, 6. Yolken RH . Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav Immun 2001;15:411-420. CrossRefMedlineWeb of Science 11. 11. 1. 2. 3. 4.

Shi L, Fatemi SH, Sidwell RW, Patterson PH

. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003;23:297-302. Abstract/FREE Full Text 12. 12. 1. 2. 3. 4.

Brown AS, Hooton J, Schaefer CA, et al

. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry 2004;161:889-895. Abstract/FREE Full Text

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Neurophysiological Schizophrenia: The Candidate Measures

1. Bruce I. Turetsky1,2, 2. Monica E. Calkins2,

Endophenotypes of Viability of Selected

3. 4. 5. 6.

Gregory A. Light3, Ann Olincy4, Allen D. Radant5 and Neal R. Swerdlow3

+ Author Affiliations 1. Department of Psychiatry, 10th floor, Gates Building, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 2. 3Department of Psychiatry, University of California San Diego, La Jolla, CA 3. 4Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO 4. 5Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 1. 1To whom correspondence should be addressed; tel: 215-615-3607, fax: 215-6627903, e-mail: turetsky@bbl.med.upenn.edu.
2

Next Section

Abstract
In an effort to reveal susceptibility genes, schizophrenia research has turned to the endophenotype strategy. Endophenotypes are characteristics that reflect the actions of genes predisposing an individual to a disorder, even in the absence of diagnosable pathology. Individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia and would, therefore, reduce the complexity of genetic analyses. Unfortunately, despite there being rational criteria to define a viable endophenotype, the term is sometimes applied indiscriminately to characteristics that are deviant in affected individuals. Schizophrenia patients exhibit deficits in several neurophysiological measures of information processing that have been proposed as candidate endophenotypes. Successful processing of sensory inputs requires the ability to inhibit intrinsic responses to redundant stimuli and, reciprocally, to facilitate responses to less frequent salient stimuli. There is evidence to suggest that both these processes are impaired in schizophrenia. Measures of inhibitory failure include prepulse inhibition of the startle reflex, P50 auditory evoked potential suppression, and antisaccade eye movements. Measures of impaired deviance detection include mismatch negativity and the P300 event-related potential. The purpose of this review is to systematically evaluate the endophenotype candidacy of these key neurophysiological abilities. For each candidate, we describe typical experimental procedures, the current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported gene associations. We conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.

Key words

prepulse inhibition P50 antisaccade mismatch negativity P300 ERP

Previous SectionNext Section

Introduction
In an effort to finally reveal susceptibility genes ensconced in the human genome, schizophrenia research has turned, at a remarkable pace, to the endophenotype strategy. Endophenotypes are characteristics, usually assessed in a laboratory, that reflect the actions of genes predisposing an individual to a specific disorder, even in the absence of any diagnosable pathology. As relatively simple, well-defined and quantifiable biobehavioral characteristics, individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia. Ideally, therefore, endophenotypes could serve as dissected components of the complex schizophrenia phenotype, reflecting fewer genes and thereby reducing the complexity of the genetic analyses required to identify contributing genes. Investigations of endophenotypes of psychopathology have accelerated because of a growing recognition of the promise of the approach, as described by Gottesman and Gould1 in their influential and oft-cited discussion of the strategy. At the time of their report, a MEDLINE search for endophenotype identified 62 entries between the years 2000 and 2002, compared with 16 articles prior to 2000. For 2003 through June 2006, an additional 109 publications with keyword endophenotype have been added to MEDLINE, reflecting a substantial increase over all prior years. The psychopathology research field is now abuzz with the endophenotype term. Unfortunately, the term is sometimes applied indiscriminately to any characteristic observed to be deviant in affected individuals. There is a risk, with the science striving to advance so quickly, that the rigorous critical evaluation of candidate endophenotypes will fall to the wayside. There are several criteria, rationally stemming from their proposed use as tools for revealing the genetic and neurobiological underpinnings of psychopathology, that candidate measures should meet, if they are to be considered viable endophenotypes.14 While there is some variability in specific criteria, it is generally agreed that the ideal candidate endophenotype would exhibit the following features: 1. It is associated with a disorder and represents a robust impairment that is stable and reproducible in an individual subject, with high test-retest reliability and state independence. 2. It is highly heritable, so that intra- and interfamilial variance could be attributed to shared genetic, rather than environmental, factors.

3. It cosegregates with illness within families but is also evident in unaffected members. 4. In growing recognition of the necessity of large samples for well-powered analyses, the candidate's measurement should be rapid and easy, so that it can be readily acquired in large numbers of patients with minimal subject cooperation or effort. 5. It reflects a discrete and well-understood neurobiological mechanism that is both informative for the pathophysiology of a disorder and indicative of the action of a limited number of genes. Individual endophenotypes fulfilling these criteria may constitute independent risk factors that identify different unrelated types of genetic risk. Conversely, if multiple deficits tend to coaggregate in the families of patients with a specific disorder, it would suggest that the combined set of deficits reflect a single, common variant of genetic risk for the disorder. An alternative to the use of a single endophenotype is to combine endophenotypes or create a composite, multivariate endophenotype, in order to better identify genetic risk.57 Although there is a growing interest in the investigation of multivariate endophenotypes,7 10 most research to date has centered on the evaluation of individual candidate endophenotypes. If individual candidates are to form a multivariate endophenotype, it is arguably important that each candidate stand alone as a viable endophenotype. Schizophrenia patients exhibit well-documented deficits in several laboratory-assessed neurophysiological abilities that have been proposed as candidate endophenotypes. Observed deficits extend from the earliest preattentive stages of information processing to relatively late higher cortical processes. However, it has been suggested that a breakdown in the processes that regulate the inflow of information from the environment is fundamental.11 Successful processing of sensory inputs requires the ability to screen out or inhibit intrinsic responses to redundant or irrelevant inputs and, reciprocally, to enhance or facilitate responses to deviant, novel, or salient stimuli. There is evidence to suggest that both these discrete but related processes are impaired in schizophrenia. Among measures of inhibitory failure, those most commonly studied in schizophrenia are prepulse inhibition (PPI) of the startle reflex, P50 auditory evoked potential suppression, and AS eye movements. Among measures of impaired deviance detection, mismatch negativity (MMN) and the P300 event-related potential (ERP) have been most commonly studied. While there have been reviews of particular aspects of the literature related to the endophenotype candidacy of each of these neurophsyiological measures,12,13 to our knowledge, there have been no reviews describing how well each individual candidate fulfills all the above criteria. The primary purpose of the current review is, therefore, to offer a systematic evaluation of the endophenotype candidacy of the key neurophysiological abilities implicated in schizophrenia. For each candidate, we describe typical experimental procedures, current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported specific gene associations. As a reflection of the current state of the field, we first review the extensive literature on each individual candidate endophenotype. We then conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.

Previous SectionNext Section

Measures of Inhibitory Failure

Prepulse Inhibition of Startle
PPI is the normal reduction in startle that occurs when a startling stimulus is preceded 30 300 ms by a weak prestimulus.14 PPI is deficient in schizophrenia patients and unaffected relatives,1519 suggesting that it may be a trait marker for individuals at risk for developing the disorder (rather than a marker of schizophrenia per se). Experimental Procedures The assessment of PPI requires appropriate stimulus delivery time-locked to the acquisition of a valid measure of startle response magnitude. Though startle can also be elicited via a robust, abrupt visual, or tactile (air puff or electrical) stimulus, acoustic stimuli allow a high degree of experimental control and precision, and avoid logistical complexities of delivering electrical shocks to acutely psychotic individuals. The motor response most often used to assess startle and PPI in humans is the contraction of orbicularis oculi (OO) via electromyographic (EMG) measures during the first 250-ms epoch after startle stimulus onset. There are many variants of startle/PPI acquisition procedures. For one common test procedure, subjects sit in a comfortable chair in a sound-attenuated room with a constant, neutral visual field (because any weak noise or visual stimulus can serve as a prepulse). Because of potential lateralized differences in the neural regulation of PPI, and its deficits in clinical populations,16 bilateral eyeblink measures are optimal. EMG electrodes are positioned below and lateral to each eye over OO, with a ground electrode behind one ear. Common blink acquisition and scoring parameters are described elsewhere.20 Startle stimuli are most commonly presented binaurally through headphones. Importantly, most studies reporting PPI deficits in schizophrenia populations use an uninstructed test session, in which test subjects are informed that they will hear noises, but are not instructed to perform any task related to those noises, that might engage volitional or attentional mechanisms.19 Stimulus parameters and test session design are selected based on the specific experimental questions of highest priority. Typically, in our studies, a test session includes a total of 74 active and 18 blank no-stim trials, and lasts 23.5 minutes, beginning with a 5-minute acclimation period with 70-dB (A) sound pressure level (SPL) white noise that continues throughout the session. Startle stimuli are 40-ms 115-dB (A) SPL noise bursts. Prepulses are discrete 20-ms noise bursts 15 dB above background, with onset 30, 60, or 120 ms prior to pulse onset. Figure 1 illustrates the effect of a prepulse on the magnitude of the startle response. Neurobiology of PPI

Preclinical studies have demonstrated that PPI in rodents is regulated by cortical structures (mesial temporal cortex and medial prefrontal cortex [PFC]) and subcortical structures (striatum, pallidum, and pontine tegmentum).21 This limbic cortico-striato-pallido-pontine circuitry converges with the primary startle circuit at the level of the nucleus reticularis pontis caudalis (NRPC). Studies of the neurobiology of PPI in humans reveal both similarities and differences from findings in animal models. For example, evidence of profound PPI deficits in patients with Huntington disease (HD)22,23 support the role of the striatum in the regulation of PPI in humans and parallel findings of PPI deficits after excitotoxic lesions of the striatum in rats and in mice transgenic for the HD gene.24,25 Neuroimaging studies in schizophrenia patients and normal comparison subjects confirm both the role of limbic cortico-striatopallido-thalamic (CSPT) circuitry in the normal regulation of PPI21,,26 and the association between CSPT abnormalities and PPI deficits in patients. Also consistent with a number of preclinical findings is the fact that PPI deficits are observed in other clinical populations, ranging from Tourette syndrome to seizure disorders, with known or presumed pathology in limbic CSPT circuitry.19 On the other hand, pharmacological studies of PPI in normal humans raise questions as to whether the PPI neural circuit blueprint in rodents can be easily translated across species.21,27 Thus, while the indirect dopamine (DA) agonist, D-amphetamine, reduces PPI in both normal humans and some rodent strains, the N-methyl-D-aspartate (NMDA) antagonist ketamine, and the serotonin releaser methylene-dioxy-methamphetamine have opposite effects on PPI across speciesdisrupting PPI in rodents but increasing PPI in clinically normal humans. A similar pattern is observed with the mixed DA agonist/NMDA antagonist amantadine. Direct DA agonists potently disrupt PPI in rats, but their effects in humans are not as convincing. Both atypical antipsychotics and nicotine have been reported to increase PPI across species but perhaps only under certain experimental conditions. Abnormality in schizophrenia Schizophrenia patients exhibit abnormal PPI despite having relatively normal responses to startling stimuli, as indicated by measures of startle amplitude, latency, and latency facilitation. Empirically, these PPI deficits indicate that in the immediate aftermath of a stimulus, the central nervous system in schizophrenia is overly responsive to a second stimulus. Conceptually, this deficit of time-locked, automatic inhibition puts the information contained in the initial stimulus at greater risk of being degraded, thereby disrupting its appropriate cognitive or behavioral impact. Importantly, there is no direct evidence that the sensory processing of the prepulse is degraded in patients nor is there direct evidence that this presumed degradation of prepulse processing causes impairments in the cognitive functions that depend on the intact sensory processing of the prepulse. However, PPI deficits in schizophrenia patients are not modality specific,20 and they correlate with distractibility28 and thought disorder29,30 measures and more global scales of functioning.31 Reliability

Some forms of PPI exhibit robust test-test reliability in normal comparison subjects, over intervals of several months.32,33 Thus, intraclass correlations exceeding 0.90 have been observed for PPI elicited over 3 consecutive months, using relatively intense prepulses34 and 30- to 120-ms prepulse intervals. With shorter prepulse intervals, and/or weaker prepulse intensities, PPI is less reliable over time.34,35 Stability Relatively few studies have assessed the longitudinal stability of PPI deficits in schizophrenia patients. While PPI deficits have been reported by several groups in relatively stable, medicated schizophrenia cohorts,16,19,3640 others report that PPI deficits occur only in patients who are in an acute symptomatic phase of a psychotic episode and resolve in these same patients as symptoms subside.41 One complexity in interpreting such state-related changes in PPI relates to the role of antipsychotic medications in both symptomatic improvement and potentiation of PPI (see below). Heritability Very convincing evidence for the genetic control of PPI comes from studies in rodents. For example, Francis et al42 reported that mice generated via embryonic transplants into a different maternal strain exhibited PPI phenotypes of the embryo and not of the maternal uterine or rearing environments. Thus, PPI appears to be linked closely to genotype in mice. PPI levels differ substantially across mouse strains,43 and strain-specific PPI phenotypes are stable over multiple generations. One published study has directly assessed heritability of PPI in humans. Anokhin et al44 assessed PPI in 40 monozygotic (MZ) and 31 dizygotic (DZ) female twin pairs and used structural equation modeling to demonstrate heritability that accounted for over 50% of PPI variance. Menstrual cycle phase was not matched in these twin pairs, suggesting that heritability may have actually been higher, given the likely added variance in this sample based on the differential hormonal state influences on PPI (see below).45,46 Cadenhead et al16 reported PPI deficits in first-degree relatives of schizophrenia probands. Preliminary analyses17 using an impaired criterion of PPI (>1 SD below control means) revealed an impaired PPI status in 8/12 unaffected siblings of schizophrenia probands vs 5/25 controls (P < .005); analyses using impaired schizophrenia probands and their unaffected siblings revealed a relative risk of impaired PPI of 3.13. Pearson correlation between sib-pairs was .66. This finding of impaired PPI in unaffected siblings of schizophrenia patients was recently replicated by Kumari et al18 in larger samples. Preliminary analysis of the Consortium on the Genetics of Schizophrenia (COGS) data sample, for 284 individuals, found PPI heritability to be significant at 0.24 (P < .05) (T. A. Greenwood, D. L. Braff, K. S. Cadenhead, M. E. Calkins, D. J. Dobie, R. Freedman, M. F. Green, R. E. Gur, R. C. Gur, G. A. Light, J. Mintz, K. H. Nuechterlein, A. Olincy, A. D. Radant, L. J. Seidman, L. J. Siever, J. M. Silverman, W. S. Stone, N. R. Swerdlow, D. W. Tsuang, M. T. Tsuang, B. I. Turetsky, N. J. Schork unpublished data). Other Factors Influencing Endophenotype Utility

Antipsychotics.

The initial report of PPI deficits in schizophrenia patients15 predated the use of atypical antipsychotics. Subsequent clinical reports have suggested that atypical antipsychotics are associated with greater and potentially normalized PPI levels in schizophrenia patients.19,31,40,41,47 Because an overwhelming number of schizophrenia patients are currently treated with atypical antipsychotics, it is possible that PPI deficits in this population are a vanishing biomarker. Alternative strategies for understanding the biology and clinical implications of deficient sensorimotor gating have become increasingly important, including the use of optimized stimulus features (eg, 60-ms prepulse intervals),48 broadband stimuli and prominent background noise,49 unmedicated schizophrenia41,50 and schizophrenia spectrum patients,16,51 unaffected family members, and populations of low-gating controls.48
Nicotine.

Progating effects of nicotine have been reported in measures of both PPI and P50 ERP suppression.19,5254 If nicotine use per se is associated with increased PPI, then the higher rates of smoking among schizophrenia patients would be expected to diminish patient vs control group differences in PPI measures and to diminish measures of heritability.
Sex Differences.

Sex differences and menstrual cyclicity in PPI have been reported by several different groups45,46,5558 and may have important implications for the interpretation of PPI differences in schizophrenia vs control populations. Typically, open subject recruitment in studies favors ascertainment of male patients and female controls. Because men exhibit more PPI than women, this ascertainment bias artificially diminishes control vs schizophrenia group differences. Menstrual cyclicity of PPI adds uncontrolled variance that may differentially affect control vs patient samples, and without carefully timed measurements, this state-sensitive cyclicity of PPI must diminish apparent heritability. Nevertheless, PPI deficits have been reported in both male and female schizophrenia patients.37,45,49 Specific Genes Associated With PPI Three lines of evidence implicate specific genes or gene regions in the regulation of PPI. First, PPI deficits in both HD23,58 and 22q11 deletion syndrome59 suggest that the genes affected in both these disorders modify brain circuitry that regulates PPI. In both cases, animal models with homologous genetic defects also exhibit PPI deficits.25,60 Second, quantitative trait loci (QTLs) have been identified either through interval mapping in inbred rat strains (QTLs on chromosomes 2 and 18)61 or recombinant congenic mouse strains (5 QTLs across chromosomes 3, 5, 7, and 16)62 or through the use of chromosome substitution strains in mice (2 QTLs on chromosome 16).63 Third, reverse genetic approaches have identified a long list of genes which, when inactivated via constitutive or conditional knock out techniques, are associated with a reduction in PPI.64

Most genes associated with lower vs higher levels of PPI may be unrelated to reduced PPI in schizophrenia or other disease states. The most potent physiological influence on acoustic PPI is hearing threshold because an organism that cannot detect a prepulse will not exhibit PPI. Thus, many or most candidate PPI genes identified via gene inactivation or mapping strategies in inbred and recombinant rodents will likely be associated with hearing threshold. Beyond the level of sensory registration, the most potent physiological influence on PPI is exerted at the level of the pedunculopontine nucleus (PPTg), which mediates PPI via its impact on the NRPC.65 For the same reasons noted for hearing threshold, genetic studies of PPI will likely be influenced strongly by genes coding for the normal function of the PPTga structure that does not play a central role in models of the pathophysiology of schizophrenia. In contrast, the PFCwhich is suspected to be a critical substrate for some symptoms of schizophreniais likely to be 3 or 4 synapses removed from the primary startle circuit and, in a normal human or rodent, genes controlling the PFC will likely contribute only weakly to any gene mapping signal based on levels of PPI. Conversely, we know that the HD gene exerts a powerful control on the viability of striatal circuitry that regulates PPI and that this gene is strongly associated with low or absent levels of PPI in humans and animal models. Yet, despite this, it is almost certain that no gene mapping efforts based on the PPI phenotype in normal rodent strains, or reverse genetic models based on constitutive or conditional knockout strategies (absent the insertion of the HD gene), will ever link the HD gene to low levels of PPI. Importantly, PPI is a measure that reflects the normal function of specific brain circuits, and genes associated with PPI deficits in neuropsychiatric disorders are likely to be ones that contribute uniquely to dysfunction in those brain circuits. Such genes will be most effectively identified through the use of affected and at-risk individuals, in whom deficient PPI is used as an endophenotypea surrogate marker for neural circuit dysfunction that contributes to the vulnerability for the expression of the full clinical phenotype.

P50 Auditory Evoked Potential Suppression

The P50 wave is a midlatency auditory evoked potential that exhibits reduced amplitude, or suppression, when a second click sound is presented 500 ms after an initial click. This paired-click experimental procedure is referred to as the conditioning-testing paradigm.66 Although the functional significance for this response suppression has not been clearly established, it is thought to reflect the brain's inhibitory control of its response to stimuli.11 In this model of response suppression, the first click stimulus initiates or conditions the inhibition and the second tests its strength. Thus, the conditioning response is generally maximal because no inhibitory circuits have yet been activated, and the test response is smaller because of the action of these inhibitory mechanisms. Alternative explanations of P50 suppression have been proposed, such as a protracted refractory or recovery period following the first click response. This explanation is contradicted, however, by the finding that the P50 test response actually increases when the interstimulus interval becomes very short (eg, 100 ms).67 The generally accepted measure of the inhibitory gating effect is the ratio of the test amplitude to the conditioning amplitude. Experimental Procedures

Subjects typically are supine, with their neck supported to minimize myogenic artifacts. The auditory stimuli are clicks, delivered 50 dB over the subject's auditory threshold.68 The stimuli are presented in trains of pairs, with an intrapair interval of 0.5 seconds and an interpair interval of 10 seconds. Subjects are instructed simply to remain awake, with their eyes open and fixed at a distant target; a behavioral response is not required. Electroencephalographic (EEG) activity is monitored, recorded and processed according to previously published methods.6870 Trials containing EEG or electro-oculographic (EOG) activity greater than 30 V within the first 80 ms following the auditory stimulus are rejected. The operationalization of this criterion replaces an earlier procedure that relied on the technician's judgment to accept or reject individual trials. The conditioning P50 wave is identified as the most positive peak of the average auditory evoked potential, occurring 4080 ms after the conditioning stimulus, measured relative to the preceding negative trough. To be accepted, a P50 wave must be >0.5 V, and any corresponding EOG activity must be lower in amplitude than the P50 wave itself. The test wave is identified as the most positive peak occurring after the test stimulus, within 10 ms of the latency of the conditioning response. The ratio of the P50 test and conditioning amplitudes defines the strength of the inhibitory response, with a larger value indicating less robust inhibition or suppression. Figure 2 illustrates the test and conditioning responses in both schizophrenia patients and healthy control subjects. The P50 is a relatively small ERP component, and questions have been raised concerning the effect of noise on the detection and measurement of the P50 signal. To address this question, a detailed trial-by-trial statistical analysis of P50 measurement has been performed.71 This analysis demonstrated that normal subjects had average evoked P50 conditioning responses that were significantly larger than the prestimulus EEG activity. Their test responses, in contrast, were not significantly different from the prestimulus EEG. Schizophrenia subjects had conditioning waves that were both similar in amplitude to those of controls and significantly different from the prestimulus activity. However, the patients' test responses were also significantly larger than the prestimulus EEG. In the single-trial analysis, selection of the largest wave in the 4080 ms poststimulus interval resulted in identical amplitudes for prestimulus, conditioning and test periods in both normal and schizophrenia subjects. This demonstrates that, although the signal-to-noise ratio is too low to reliably identify the P50 wave in individual trials, averaging increases the signal-to-noise ratio to a level that is adequate to reliably distinguish the P50 response from background activity. Neurobiology of P50 suppression P50 suppression is regulated by wide-ranging neural circuitry, prominently involving hippocampal structures72 as evidenced from depth recordings in humans using an electrode that penetrated the hippocampus73 and single-neuron recordings.74 The penetrating recordings showed that the hippocampus generates a response 50 ms poststimulus, and the neuronal recordings showed that the response to repeated stimulation quickly diminishes. These findings in humans have been modeled in rats to determine the underlying synaptic mechanisms. Ablation of the CA3-CA4 area of the hippocampus, in rats, eliminates the P20-N40 complex, considered the analog of the human P50.75 One major input pathway to

CA3-CA4 is from the medial septal nucleus through the fimbria-fornix. Lesion of this cholinergic pathway causes CA3 and CA4 neurons to lose their gating response to sensory stimuli. Cholinergic inputs to CA3-CA4 are further implicated by the fact that antagonists of the lower affinity nicotinic receptors, such as -bungarotoxin, block the gating response76; antagonists of high-affinity nicotinic receptors, such as mecamylamine, or muscarinic receptor antagonists have no effect on gating. CA3-CA4 interneurons might be the final mechanism for suppression, as they are activated by this cholinergic input. These interneurons release -aminobutyric acid (GABA) onto the pyramidal neuron, which depresses its membrane potential so that it cannot discharge. GABA activates GABAA- and GABAB-type receptors on the pyramidal neuron, which together inhibit neuronal firing for up to 300 ms. A still longer inhibition may involve presynaptic GABAB receptors located on the perforant pathways' synaptic terminals on the apical dendrites of the CA3 neurons. Although GABA is released primarily at the cell body of the CA3 neurons, if enough GABA is released by burst of interneuron activity, it may diffuse to the apical dendrites and contact GABAB receptors on the presynaptic terminals of the perforant pathway fibers, inhibiting their release of the excitatory neurotransmitter glutamate. Then the perforant path can no longer send sensory information to the CA3 pyramidal neuron, so the response to the test stimulus is diminished. Activation of the interneurons' nicotinic receptors by cholinergic medial septal inputs could provide the additional burst activity for sufficient GABA release. It is important to note that sensory gating has also been observed in other brain regions. Using a combination of hippocampal depth electrodes, subdural strip, and grid electrodes in epilepsy patients, evidence of sensory gating was found in the hippocampus, the temporoparietal region (Brodmann's area 22 and 2) and the PFC (Brodmann's areas 6 and 24), with the neocortical habituating responses peaking around 50 ms and hippocampal responses peaking around 250 ms poststimulus.77 This suggests that sensory gating may be a multistep process with an early temporoparietal and prefrontal phase and a later hippocampal phase. The extent to which the gating deficits observed in schizophrenia are mediated by hippocampal vs other cortical or subcortical inputs remains a matter of some debate. That brain cholinergic systems regulate at least some of these gating deficits is supported by findings that P50 suppression abnormalities in both schizophrenia patients52 and their relatives78 resolve temporarily after administration of the cholinergic nicotinic receptor stimulant, nicotine. Further evidence for nicotinic involvement in schizophrenia is the decreased expression of the -7 nicotinic receptor as evidenced by 124I--bungarotoxin binding or immunoreactivity.7983 Noradrenergic neurotransmission may also be involved in the P50 auditory evoked response. Administration of yohimbine affects the release of norepinephrine by the blockade of alpha-2 presynaptic noradrenergic receptors that normally inhibit norepinephrine release. Yohimbine causes loss of auditory evoked potential gating in humans and rats.84,85 Although norepinephrine is probably not a major determinant of the abnormality in inhibition in schizophrenia, there is some correlation with plasma 3-Methoxy-4-Hydroxyphenylglycol levels.86 Abnormality in Schizophrenia

Initial studies by Adler et al,87 Freedman et al,88,89 and Siegel et al90 showed that there was a failure of P50 suppression in schizophrenia patients, consistent with theories of failed inhibitory function.91 The deficit has been associated with diminished performance on neuropsychological measures of attention.92 Some groups have failed to replicate this finding, while others have replicated it but found it to be unrelated to self-reports of sensory disturbance.9395 A common misconception, in this regard, is that normal inhibition means that healthy subjects do not hear the second sound. The role of inhibition is not to block all sound or other stimuli from reaching the hippocampus. Rather, it blocks weaker stimuli so that the responses to strong stimuli are emphasized. In the absence of inhibition, the hippocampus becomes hyperactive and then it can no longer respond to stimuli, a phenomenon called occlusion. Evidence for occluded responses to novel stimuli in the hippocampus, in schizophrenia, comes from several types of neuroimaging studies.96 The inhibition of weaker stimuli is also easily overcome by making the stimuli more relevant.97 P50 suppression deficits in schizophrenia patients are persistent98 and found in both acutely ill and more stable schizophrenic outpatients.87,88,99 The P50 deficit is present in both predominantly positive symptom and negative symptom patients,100 though some studies have reported that the phenomenon is significant mainly in the disorganized/undifferentiated patients compared with the paranoid subtypes.101 P50 suppression deficits are also present in schizotypal patients.102 Unmedicated schizophrenia patients have unusually small P50 waves, and the amplitude of the waves is normalized by neuroleptic treatment.103 However, although the P50 increases in amplitude during treatment, it increases for both the conditioning and the test responses, so that the P50 ratio remains abnormally high. Individuals treated with clozapine, though, exhibit normalization of their P50 ratios coincident with improvement in their clinical symptoms.104,105 Clozapine, which releases acetylcholine in the hippocampus, may thereby indirectly act on the nicotinic receptor to normalize the P50 ratio, as people with schizophrenia also decrease the number of cigarettes they smoke while taking this medication.106 Clozapine also has the property of 5-Hydroxytryptamine 3 (5HT3) antagonism, which activates the nicotinic receptor. Acute administration of odansetron, a highly selective 5HT3 antagonist, induces a similar effect of improvement in P50 auditory gating in schizophrenia.107 Direct -7 nicotinic receptor agonism with 3-(2,4dimethoxybenxylidene) anabaseine also normalizes the P50 ratio in a double-blind, placebo-controlled study of 12 people with schizophrenia.108 Other atypical neuroleptics which may not have direct nicotinic agonism or 5HT3 antagonism have more variable effects on the P50 ratio. In 2 separate investigations,109,110 risperidone had only a marginal effect on P50 suppression, while olanzapine normalized it in one study110 and partially improved it in the other.109 A third study111 of 14 schizophrenia patients assigned to double-blind treatment with haloperidol or olanzapine found no group differences in P50 ratio. Thus, while risperidone does not appear to highly influence gating, the data on olanzapine remain inconsistent. Reliability Problems in test-retest reliability have been noted by several investigators.112 Although conditioning and test amplitudes were reliably measured, the test-to-conditioning ratio was

not. All cerebral evoked potential measurements include both a signal and a noise component. A ratio measurement that includes noise in both the numerator and the denominator will approach an asymptote of 1 as the noise increases.113 This problem is exacerbated by the relatively low signal-to-noise ratio of the P50 compared with other auditory evoked potential components. Though a reliable test-to-conditioning ratio is difficult to obtain due to its inherent mathematical properties, ie, test and conditioning are not independent, so that the shared variance between test and conditioning cannot be completely eliminated,112,113 the test-to-conditioning ratio nevertheless has the greatest power to distinguish normal subjects from schizophrenic subjects.113 Furthermore, the schizophrenia P50 suppression deficit has been reliably reproduced in large numbers of subjects across multiple sites.99,114119 Stability Waldo et al120 measured P50 suppression in 13 normal subjects, 10 days apart. P50 suppression was 66.5% on day 1 and 69.5% on day 10. There was no significant change in the gating of auditory test responses over this period. The change between days for individual subjects was generally within the 8% mean variability observed with repeated recordings in other groups of normal subjects. Griffith et al68 recorded 10 schizophrenia patients and 10 healthy subjects on 3 occasions. The intraclass correlation was 0.73. Additionally, Hall et al121 measured P50 suppression in 19 MZ twin pairs on 2 separate occasions and found a P50 ratio intraclass correlation of 0.66. Heritability Young et al122 examined P50 suppression in 15 normal MZ twin pairs and 12 normal DZ twin pairs. The upper limit of the heritability estimate (calculated as twice the difference between the MZ and DZ intraclass correlations) was 1.0. The 95% confidence limit for the lower limit of heritability was 0.44. Hall et al121 examined P50 suppression in 40 healthy MZ twin pairs and 30 DZ twin pairs and reported a heritability estimate for the P50 test-toconditioning ratio of 68%. Interestingly, preliminary heritability analysis of the COGS data sample (n = 201) revealed a nonsignificant heritability estimate of 0.07 for the test-toconditioning ratio. However, the difference in amplitude between the P50 responses to the first and second clicks, which is an alternate way of measuring suppression, had quite high heritability (h2 = 0.53, P = .005) (T. A. Greenwood, D. L. Braff, K. S. Cadenhead, M. E. Calkins, D. J. Dobie, R. Freedman, M. F. Green, R. E. Gur, G. A. Light, J. Mintz, K. H. Nuechterlein, A. Olincy, A. D. Radant, L. J. Seidman, L. J. Siever, J. M. Silverman, W. S. Stone, N. R. Swerdlow, D. W. Tsuang, M. T. Tsuang, B. I. Turetsky, N. J. Schork unpublished data). Specific Genes Associated with P50 Suppression The P50 auditory evoked potential endophenotype has been linked with a genetic marker at the locus of the CHRNA7, the gene coding for the -7 subunit of the nicotinic receptor.123 Furthermore, the presence of a single nucleotide polymorphism in the 15q14 gene CHRNA7 5 core promoter is significantly associated with P50 suppression deficits (P = .008).110 Association of CHRNA7 polymorphisms with P50 gating has been replicated, but the

specific allelic associations differ, which suggests that responsible mutations have not yet been unambiguously identified.124126

AS Eye Movement Dysfunction

The AS task, first described in 1978127 utilizes the intrinsically precise and quantifiable nature of oculomotor performance to assess a specific aspect of oculomotor/cognitive function. Experimental Procedures To perform the AS task, subjects are seated in a dark room with their heads stabilized, and their eye position is ascertained with high precision, typically using infrared oculography or EOG, while they watch a specialized sequence of dot movements. A single AS trial commences with fixation on a central point, followed by an unpredictably located stimulus to the left or right. Rather than looking at this stimulus, the subject is asked to look at the mirror image location on the opposite side of the screen. Thus, the participant must inhibit an unwanted, reflexive saccade to the stimulus. A cue then appears signaling the location of a correct response and then the target returns to central fixation for the next trial. Duration of each task component, the number of potential different AS target locations, and maximal and minimum distances from center, vary across studies. There may be a gap, simultaneous offset and onset, or overlap between central fixation and the AS cue stimulus, and this factor appears to affect the magnitude of schizophrenia-control differences.128 Direction of the first major saccade determines whether the subject has made an incorrect AS (sometimes referred to as a prosaccade or reflexive error) vs a correct AS. Figure 3 illustrates the infrared tracings associated with correct and incorrect AS performance. The summary variable is typically the proportion of incorrect (error) saccades, or sometimes proportion of correct AS, over all trials. Neurobiology of AS Correct performance of the AS task requires accurate perception, ability to transform location information to a mirror image representation, and suppression of a reflexive visually guided saccade to the AS stimulus as well as nonspecific task demands such as motivation, ability to comprehend the task, and willingness to hold one's head still. While the oculomotor system is composed of many cortical and subcortical areas, certain areas appear crucial for accomplishing the unique demands of the AS task. Sensory transformation of location information appears to occur in the lateral interparietal area,129,130 although PFC may also be involved.131 Damage to dorsolateral PFC causes decreased frequency of correct AS132 and specific neurons in PFC activate specifically during AS.133136 Amemori et al137 have argued that this phenomena reflects working memory. Finally, single-unit recordings in monkeys demonstrate that supplementary eye field neurons are active during tasks that require generation of saccades based on internal

representations of location including the AS task.138 Thus, parietal, prefrontal, and supplementary oculomotor areas appear uniquely relevant to AS performance. Neuroimaging and performance data indicate that basic sensorimotor processes involved in visually guided saccade generation appear essentially normal in schizophrenia.139 Because schizophrenia patients generally make at least 50% of correct AS responses, and often will generate corrective saccades despite an initially incorrect response, they clearly understand the task itself and appear to have sufficient motivation. Raemaekers et al,140 using functional magnetic resonance imaging (fMRI) found that while schizophrenia patients activated frontal and parietal areas normally during an AS task, they failed to activate the striatum as much as controls and concluded that dysfunction of a frontal striatal saccade suppression network explains the poor performance of schizophrenia patients. Patients with lesions of dorsolateral PFC and/or abnormalities of the caudate exhibit increased AS error rates, while patients with cortical lesions of the frontal eye fields, supplementary eye fields, posterior parietal cortex, and temporal cortex do not.141 This suggests that the increased error rate observed in schizophrenia patients, described below, is consistent with dorsolateral prefrontal cortical dysfunction.142,143 Imaging144,145 and ERP146 studies in schizophrenia patients and healthy individuals have tended to support this conclusion, though not ubiquitously.147 Abnormality in Schizophrenia In the late 1980s, Fukushima et al148 reported that schizophrenia patients evince a greater number of inappropriate reflexive saccades to the target in an AS task than nonpsychiatric controls. Since then, more than 50 studies have consistently reported this effect.149159 Notably, there have been no investigations, to our knowledge, failing to find that schizophrenia patients generate more errors than controls. Moreover, particular AS task manipulations have been reported to enhance the magnitude of effect.128,160163 Inconsistencies in the literature have been noted regarding the diagnostic specificity of this AS dysfunction to schizophrenia patients,143,164 with some reports of increased AS error rates in members of other psychiatric disorders, such as major depression165 and bipolar disorder.166 Conversely, evidence has been cited suggesting that increased AS error rates do not characterize performance of mood or anxiety disordered patients.167 Although the question is unresolved, increased error rates in mood disorder patients would not be deleterious to the endophenotype status of AS performance; eye movement dysfunction in some mood disorder patients may reflect shared genetic susceptibility influencing mechanisms that contribute to both clinical state and poor AS performance.168 While error rate has been most extensively investigated in schizophrenia, other parameters, including latency, gain, and accuracy, have also been examined. Anomalies in response latency may provide evidence of visual processing inefficiencies. Schizophrenia patients have been reported to exhibit longer latencies on correct AS responses than control subjects,128,160,169 potentially reflecting compensatory slowing due to difficulties inhibiting unwanted reflexive saccades.160 Although less commonly measured, latencies to error responses suggest that they do not differentiate schizophrenia patients from nonpsychiatric controls.160,161 Latency to correct responses thus appears to tap an aspect

of performance that is distinct from latency to incorrect responses, highlighting the importance of differentiating the 2, a distinction that is not routinely made in current investigations. Several studies have reported reduced spatial accuracy of AS in schizophrenia patients.128,150,158,169,170 This abnormality may implicate parietal and prefrontal cortical control of sensorimotor coordinate transformations150 or impairment in generating saccades from internal representations in the supplementary motor area. Reliability A number of studies have shown good test-retest reliability of AS error rate over periods ranging from several months to many years among patients with schizotypy,171 schizophrenia patients,172,173 first-degree relatives,173 and controls.174 Our recent analysis of data from the COGS sample of schizophrenia patients (n = 103) and community comparison subjects (n = 138) suggests high within-session reliability of the AS paradigm at 7 sites (range = 0.770.96).175 Moreover, there were no significant cross-site differences in performance, suggesting that high-quality AS data can be obtained across multiple sites using standardized measures, equipment, and training procedures.175 Stability Recent studies of the test-retest stability of AS error rates have suggested high temporal stability in schizophrenia patients (r = .87, test-retest interval = 2.78 years),172 and in a mixed group of schizophrenia patients and their relatives (r = .73, test-retest interval = 1.82 years).173 The results are consistent with 2 other reports examining performance in groups of psychiatric patients (r = .75, test-retest interval = 1 year,176 r = .90, test-retest interval = 1 week177). It has been reported that first-episode,158,178180 remitted,142 and unmedicated181 schizophrenia patients all manifest AS deficits, further suggesting that the deficits are not merely a reflection of clinical state or chronicity of illness. The majority of studies examining the relationship between medication and AS error rates have described the results as nonsignificant.140,148,161,180,182187 However, there is some evidence that AS performance in schizophrenia may actually improve with nicotine administration155,188 and with some medications, including risperidone189 and cyproheptadine treatment.190 Nonetheless, in general, the AS deficit observed in schizophrenia is temporally stable and does not appear to be attributable to clinical variables such as medication exposure, current symptomatology, and chronic illness. Thus, the available evidence is consistent with the trait stability of the AS deficit in schizophrenia patients. Heritability Malone and Iacono,191 using a large sample of identical and fraternal healthy twin girls, found a high heritability of 0.57 for AS performance; no other published studies have examined heritability. However, preliminary analysis of the COGS data (n = 340) found a very similar heritability estimate of 0.49 (P < .0001) (T. A. Greenwood, D. L. Braff, K. S. Cadenhead, M. E. Calkins, D. J. Dobie, R. Freedman, M. F. Green, R. E. Gur, G. A. Light,

J. Mintz, K. H. Nuechterlein, A. Olincy, A. D. Radant, L. J. Seidman, L. J. Siever, J. M. Silverman, W. S. Stone, N. R. Swerdlow, D. W. Tsuang, M. T. Tsuang, B. I. Turetsky, N. J. Schork unpublished data). Numerous studies have investigated the familiality of poor performance in schizophrenia by evaluating performance of first-degree biological relatives of schizophrenia patients. The presence of increased AS error rates in relatives has been described as inconsistently demonstrated.151,192,193 Two recent meta-analyses quantitatively evaluated the magnitude of the relative-control difference. Levy et al193 reviewed selected studies (k = 9) using the standard (nonoverlap and nongap) version of the AS task and obtained a moderate mean magnitude of effect between relatives and controls (mean Cohen d = 0.43). Calkins et al159 included 17 independent groups of relatives and all AS studies regardless of AS paradigm. Meta-analysis yielded an increased AS error rate in relatives vs controls at a moderate to large magnitude of effect (mean Cohen d = 0.61). The results of both meta-analyses suggest that, on average, relatives of schizophrenia patients produce a greater number of AS errors than controls. In their review, Levy et al193 conducted moderator analyses and concluded that schizophrenia relatives appear impaired in the AS task because studies use more stringent inclusion criteria for controls than relatives, in effect leading to the spurious appearance of a deficit in relatives. However, because there are so few studies in this realm, Calkins et al159 conducted a reanalysis of primary data142 in which they varied inclusion and exclusion criteria and found impairment even in medically and psychiatrically healthy relatives who were screened comparably to controls. More recently, Ettinger et al150 compared psychiatrically healthy controls with comparably screened siblings of schizophrenia patients and obtained an effect size of 0.49. Thus, the impairment observed in relatives does not appear attributable to inclusionary criteria practices, at least in these 2 investigations. Instead, the differences across studies may lie not in the controls or their selection criteria, but in the relatives, perhaps vis--vis proband or relative inclusion criteria.159 Nonetheless, this methodological issue underscores the importance of carefully addressing and analyzing the potential impact of comorbid psychiatric and medical conditions on AS performance in both relatives and comparison subjects. A small number of studies suggest that, like schizophrenia patients, relatives tend to demonstrate longer latencies to correct trials.161 Two studies examining spatial accuracy of AS in relatives reported reduced AS gain in healthy siblings150 and in unaffected MZ cotwins of patients with schizophrenia,149 compared with healthy controls. These results are suggestive that, in addition to error rates, AS gain and latency are worthy of further investigation as candidate endophenotypes. Specific Genes Associated With AS Performance The only genetic study to include the AS task reported linkage at D22S315 on chromosome 22q1112 in 8 schizophrenia multiplex families when relatives were identified by either an AS deficit or a P50 sensory gating deficit.194 The composite endophenotype identified substantially more relatives as affected than did either of the endophenotypes alone, likely enhancing the power to detect linkage. While the linkage finding has yet to be replicated, the results are particularly notable because the linked region is the site of the catechol-Omethyltransferase (COMT) gene, variations of which have been linked to performance on

candidate endophenotypes believed to reflect PFC abilities in schizophrenia patients and their relatives.195 Given the apparent involvement of the dorsolateral prefrontal cortex in the accurate performance of the AS task, the association between AS performance (and/or P50) and chromosome 22q could be partially explicable by COMT effects. However, given the small size and lack of replication, this result must be regarded as preliminary. Previous SectionNext Section

Measures of Impaired Deviance Detection

MMN
MMN is an auditory ERP component that is elicited when a sequence of repetitive standard sounds is interrupted infrequently by deviant, oddball stimuli (eg, infrequent stimuli that differ in duration or pitch from the more frequently presented stimuli). The MMN occurs rapidly: following deviant stimuli, the response onset can be as early as 50 ms and peaks after an additional 100150 ms. Physiologically, MMN is the first measurable brain response component that differentiates between frequent and deviant auditory stimuli and reflects the properties of an automatic, memory-based comparison process.196 MMN has many advantages for psychiatric and cognitive neuroscience studies, including the exploration of the neural substrates of schizophrenia and its treatment.197199 First, MMN can be rapidly assessed and is highly stable in normal subjects.200202 In a longitudinal study of schizophrenia patients retested after 1 year, Light and Braff203 found extremely high MMN reliability coefficients (intra-class correlations ~0.90). Second, the mismatch response appears to reflect a predominantly automatic process: it is not under subject control, requires no overt behavioral response from subjects, and can be elicited while subjects perform other mental activities in parallel without apparent interaction or interference.204 In this context, well-defined MMN waveforms can be obtained from sleeping infants,205207 adults,208,209 patients with extremely severe brain injuries, and even comatose patients.210212 Because MMN occurs even in the absence of conscious and effortful attention, it appears to index a preattentive form of sensorimemory.204 While later ERP components occurring 300500 ms after stimulus presentation (eg, P3b) are also sensitive to changes in stimulus characteristics and sequencing, they are only elicited in response to attended stimuli and are therefore associated with attention-dependent and active cognitive processes. Attention-dependent cognitive functions assessed by traditional neuropsychological tests or long-latency ERP methods (eg, P3b) can be markedly influenced by motivational factors, level of task engagement, performance incentives, selfmonitoring, and emotional factors.213218 In contrast, preattentional cognitive measures such as MMN offer promise for accurately characterizing the integrity of sensory network dysfunction free of attentional or motivational artifacts in studies of neuropsychiatric patient populations.199,219 Experimental Procedures

In the prototypical MMN paradigm, an unchanging standard tone is presented repeatedly with a brief interstimulus interval (eg, 500 ms). The relatively rapid stimulus presentation ensures that the echoic memory trace of the preceding stimulus is still active when the subsequent stimulus is presented. The repeating standard tone is replaced infrequently (eg, 10% of trials) by a deviant tone that differs in one physical attribute. This is typically a change in either the pitch or the duration of the tone, though stimulus intensity has also been used to define deviance. Subjects are not instructed to attend to or respond to the tones in any way. In most cases, attention is specifically directed away from the tones through the use of a visual distracter, such as a video, or an active visual attention task. This ensures that the automatic detection of deviance at the level of echoic memory is not obscured by responses related to controlled or directed attention. Figure 4 illustrates the auditory ERP responses to the standard and pitch deviant stimuli, in patients and healthy control subjects. Measurement of MMN is carried out on the difference waveform constructed by subtracting the auditory evoked potential response to the standard tone from that of the deviant. MMN appears as a prominent negative potential on this difference waveform. For a pitch deviant, its peak latency is typically between 100 and 200 ms poststimulus, but this is more variable for a duration deviant. The amplitude of MMN is a function of the magnitude of the physical difference between the standard and deviant stimuli. Neurobiology of MMN In the auditory domain, maximal mismatch responses are evident at frontocentral scalp recording sites with phase reversal at posterior scalp electrodes (eg, mastoids).204 Magnetoenchephalography, high-density EEG, functional imaging, and studies of patients with discrete brain lesions indicate that the auditory MMN is generated within the primary and secondary auditory cortices with possible contributions from bilateral dorsolateral prefrontal cortices.220230 In addition, MMN is often utilized to probe frontotemporal brain systems across a range of developmental and neuropsychiatric disorders.199,211,231235 Previous studies have demonstrated that NMDA may play a crucial role in both the generation of MMN and the MMN deficits observed in schizophrenia (see below). NMDA receptor antagonists selectively diminish MMN generation in awake monkeys,236 and subanesthetic doses of ketamine, an NMDA antagonist, selectively decrease MMN in healthy human volunteers without affecting other ERP activity.237 Umbricht et al238 also found that lower baseline MMN was significantly associated with psychotic-like behavioral effects and experiences induced by subsequent ketamine administration. Thus, MMN may serve as a neurophysiological assay of NMDA receptor functioning in models of schizophrenia. Abnormality in Schizophrenia Deficits in MMN represent a remarkably robust finding in schizophrenia research. Shelley et al239 first identified MMN deficits in schizophrenia patients using deviant stimuli that differed in duration (ie, duration MMN) from standard stimuli. Since that time, there have been several published reports of reduced MMN in schizophrenia patients utilizing various stimulation parameters (eg, pitch, duration, and intensity stimulus manipulations) and

conditions.198,240 In a recent meta-analysis performed by Umbricht and Krljes,240 the mean effect size for the schizophrenia deficit was ~1.0a large deficit according to common standards. Also, though it was not a statistically significant difference, the effect size was approximately 40% larger for studies that used a duration deviant, compared with studies that used a frequency deviant. While the meaning of this remains unclear, it likely implicates task-specific neural mechanisms that underlie the schizophrenia deficit and is therefore a very intriguing, if still only suggestive, difference. Importantly, in contrast to most other physiological indices, MMN deficits appear to be relatively specific to schizophrenia. Bipolar, major depressive241,242 and obsessive-compulsive disorder patients243245 all have normal MMNs, though there are reports of MMN deficits among chronic alcoholics.246 Reliability There is substantial evidence to indicate that MMN has good test-retest reliability.202 In a study of 15 healthy individuals tested on 2 separate occasions 127 days apart, Tervaniemi et al247 examined the reliability of MMN for deviant stimuli that varied in duration, pitch, or intensity. Reliability was greatest for the duration deviant (r = .78) and lowest for the pitch deviant (r = .53). Kathmann et al200 reported very similar estimates from a study of 45 subjects tested 24 weeks apart. Test-retest reliability, in this case, was >0.8 for a duration deviant and ~0.5 for a pitch deviant. Escera et al248 observed reliabilities of 0.72 and 0.80 for a duration-deviant MMN, depending upon whether the peak or the mean within a defined time interval was used to measure MMN amplitude. Kujala et al201 noted test-retest correlations of 0.600.75, depending on the degree of deviance of the infrequent stimulus. Only one small study (n = 14)249 reported correlation coefficients that were described as unacceptable. Most importantly, the one study reporting the results of repeat testing in schizophrenia patients203 found intraclass correlations of ~0.90 after 1 year. Stability In schizophrenia patients, MMN deficits do not appear to be ameliorated by first-generation antipsychotic medications,250 risperidone,251 olanzapine,252 or clozapine.229,250 Similarly, clinical changes from acute to post-acute phases of illness do not correspond to a normalization of MMN deficits in chronic patients.253 In chronic schizophrenia patients, MMN deficits are highly associated with impairments in real-world functioning and level of independence in community living situation.203,254,255 Heritability There are no studies that have attempted to formally estimate the heritability of MMN. We know of no studies that have examined MZ vs DZ twin-pair correlations or considered the differences between intrafamilial and interfamilial associations. However, there are reports of specific genetic associations (see below), which indicate a degree of genetic modulation of MMN. Also, animal models of the MMN indicate NMDA-mediated differences in auditory deviance processing among genetically distinct inbred mouse strains.256 It is reasonable to expect, therefore, that the normal heritability of MMN will ultimately prove to be comparable to that of the other physiological measures considered here.

Whether or not this is true for the heritability of the schizophrenia abnormality, though, is not clear. Clinically unaffected family members of schizophrenia patients,257,258 children at risk for developing schizophrenia,259,260 and recent-onset patients261,262 have all been reported to have reduced MMN amplitudes. MMN would appear, therefore, to be a specific schizophrenia-related endophenotype8,258 for studying the complex genetics of the disorder.12,13 However, there have also been reports of normal MMNs in unaffected family members.263 Moreover, in contrast to the virtually universal finding of abnormal MMNs among chronic schizophrenia patients, MMNs have been reported to be normal in first-episode patients.262,264 Longitudinal follow-up suggests that the MMN deficit may emerge over time in concert with the progressive temporal lobe volume loss that occurs over the early course of the illness (D. F. Salisbury, personal communication). The degree of MMN impairment may also be modulated by the level of premorbid educational achievement in first-episode patients.262 Additional studies are therefore needed to clearly delineate the nature of the MMN abnormality, its prevalence among putatively prodromal or first-episode schizophrenia subjects, and its utility for predicting conversion to psychosis in individuals at genetically high risk for developing the disorder.265 Specific Genes Associated With MMN Deletions of chromosome 22q result in complex congenital syndromes that frequently include schizophrenia-like psychoses. Two studies of adolescents with 22q deletions have now demonstrated that this is associated with diminished MMN.266,267 The 22q deletion includes the COMT gene, which codes for the enzyme that deactivates DA, leading to regionally specific hyperdopaminergia. Reduced MMN was associated with the presence of the MET allele of the VAL108/158MET polymorphism of the COMT gene in the remaining copy on the unaffected chromosome.267 This suggests that genetic modulation of dopaminergic activity can affect MMN, a finding that is of obvious relevance to schizophrenia. Importantly, the limited evidence of association between COMT and schizophrenia suggests that the VAL, rather than the MET, allele may confer an increased risk of disease.195,268 However, it is difficult to make specific inferences concerning the physiological effects of the VAL/MET polymorphism in schizophrenia because this is contingent upon both the background level of dopaminergic activity and the presence or absence of other modifying genes.269 The only other genetic association study reported no relationship between ApoE allelic variation and MMN among older individuals with mild cognitive impairment.270

P300
The P300 event-related brain potential is an index of endogenous cognitive processes, typically elicited by infrequent sensory stimuli that are either task relevant or novel.271 It receives its name from its appearance as a large vertex-positive component with peak latency approximately 300 ms after stimulus presentation. Occurring after the obligate evoked potential response to the physical attributes of a stimulus, it reflects a variety of cognitive processes elicited by a change in the sensory environment. These include directed attention, the contextual updating of working memory, and the attribution of salience to a deviant stimulus. Since its discovery in 1965, it has been widely investigated, with a

multitude of studies examining the clinical and psychological correlates of P300 amplitude and latency, in both healthy and clinical populations.272 Experimental Procedures Although it can be elicited by stimuli in any sensory modality, it is the auditory P300 that has been most widely studied in schizophrenia patients. The prototypical experimental paradigm has been the oddball task in which an infrequent tone, designated as the target, is randomly interspersed within an ongoing train of a different repeating tone, designated as the standard. Subjects are instructed to indicate their perception of each target by making a button press or other response. The task is designed to be quite simple, with a relatively slow stimulus presentation rate (1- to 2-second interstimulus interval) and a large pitch difference (eg, 1000 Hz standard and 2000 Hz target). Schizophrenia patients typically achieve >90% correct target identifications. Figure 5 illustrates the auditory ERP responses to target and standard tones, in patients and healthy control subjects. A variant of the oddball task, known as the 3-tone or novelty P300 paradigm, adds an additional infrequent stimulus which is not the designated target; instead, it is distinctive, variable, and somewhat intrusive in its physical attributes but is intended to be ignored by the subject. Neurobiology of P300 It is now clearly established that the P300 is not a unitary phenomenon. Rather, it is a composite representation of the activity of temporally overlapping but anatomically and functionally distinct neural generators. Experimental task manipulations have elucidated at least 2 functionally discrete subcomponents. The P3a subcomponent, which is elicited by stimuli that are novel or unexpected (as in the 3-tone or novelty paradigm), occurs slightly earlier, has a frontocentral topographic scalp distribution and appears to reflect attentional orienting processes.273 P3b, in contrast, is elicited by stimuli that are task relevant and contextually salient (as in the oddball paradigm). It occurs later, has a parietal scalp maximum, and reflects cognitive processes associated with stimulus evaluation and response formation. Intracranial electrophysiological monitoring and fMRI studies have similarly discerned multiple sources of P300-like ERP activity, including the hippocampus,274277 thalamus,277,278 inferior parietal lobe,275,277 superior temporal gyrus, and frontal lobe.275,277,279 It is unlikely, though, that deeper sources such as the hippocampus or thalamus contribute substantially to the P300 as measured on the scalp. Convergent evidence from ERP source localization and fMRI activation studies, as well as recordings from patients with focal neurological lesions, suggests that P3b scalp activity arises primarily from the inferior parietal cortex, particularly the supramarginal gyrus, while the P3a reflects the activity of lateral prefrontal and superior temporal areas.280 However, specific neural circuits or neurotransmitters underlying the P300 response are not clearly defined. Abnormality in Schizophrenia Reduced amplitude of the auditory oddball P300 response is perhaps the most robust physiological abnormality observed in schizophrenia patients, having been replicated

repeatedly with virtually uniform consistency.272,281283 While prolonged P300 latency has also been reported,284 this appears to be a much more equivocal and less reliable finding. This may be due, in part, to differences in patient populations across studies. A recent meta-analysis of 104 studies reported a significant effect size of 0.59 for auditory P300 latency (compared with an effect size of 0.89 for amplitude).285 However, this analysis also reported that the latency effect size diminished with illness duration, making it a less reliable finding among studies of chronic patients. Investigations have now begun to move beyond the simple documentation of a cohort deficit to elucidate the clinical, familial, and neuroanatomical correlates of the amplitude decrement. There is now considerable evidence that this represents a trait abnormality that is independent of medication status, duration of illness, or symptom severity.286289 Although state-dependent relationships have been reported between P300 amplitude and measures of negative symptomatology,290 positive symptomatology,291 treatment status,292 and stage of illness,293 it is clear from both longitudinal and meta-analytic studies that P300 amplitude does not normalize in patients, even when treated with newer atypical antipsychotic agents.285,286,289,292296 Consistent with this idea of a trait abnormality, McCarley and associates have reported that the greatest P300 amplitude separation between schizophrenics and normals is observed at left temporal electrode sites291,297 and that this focal decrement is correlated with a decreased left superior temporal gyrus volume.298 Although these studies have focused primarily on the P3b subcomponent, there is some evidence to indicate that P3a is also reduced in schizophrenia patients299,300 and that this deficit is associated with decreased gray matter volume in the frontal lobe.301 It is important to note that, despite the highly reproducible and persistent nature of the schizophrenia P300 abnormality, the deficit is not specific to this disorder. Consistent with its multifactorial role in information processing and its distributed neural substrate, the P300 response is disrupted in a variety of neuropsychiatric disorders that included disturbed cognition. Reduced P300 amplitude has been observed in, among others, Alzheimer's disease,302 alcoholism,303 bipolar illness,304 and unipolar depression.305 It is notable, though, that in Alzheimer's disease the decreased amplitude is also associated with marked latency prolongation, in bipolar illness it is associated with a different scalp topography, in depression it is a state-dependent abnormality evident only during acute depressive episodes, and in alcoholism it is more abnormal in the visual than the auditory domain. These variations suggest that different neural mechanisms may underlie the deficit in different disorders. Reliability Despite its multidimensional character, scalp measurements of P300 amplitude exhibit very good test-retest reliability.296,306311 Studies of healthy control subjects with test-retest intervals of up to 2 weeks have documented reliabilities ranging from 0.81 to 0.91.296,306,307 One study of 32 subjects retested after 4.5 months reported test-retest correlations of 0.790.81.309 Two studies with even longer intertest intervals (14 and 24 months) had test-retest reliabilities of 0.59 and 0.61, respectively.310,311 In a study of both schizophrenia patients and controls tested twice over the course of 13 years, Turetsky et al289 reported reliabilities of 0.86 for controls and 0.61 for patients.

Stability As noted above, many studies have reported persistent longitudinal deficits in schizophrenia, despite active treatment and marked symptom reduction. Comparisons across sites, however, are hampered by a lack of uniformity in both the experimental protocol parameters and the methods used to measure P300 amplitude. Different laboratories focus on different electrode sites. Some measure peak amplitude at a single time point, while others use the area under the curve within a specified time interval. Still others use sophisticated decomposition strategies to estimate individual subcomponent amplitudes. As a common metric, we examined the patient/control amplitude ratio at Pz. For a large sample from our laboratory at the University of Pennsylvania, this value was 0.64. Comparable values extracted from 5 published studies were 0.59,312 0.61,304 0.69,313 0.77,294 and 0.80.314 This indicates highly consistent findings across independent laboratories. Heritability There is strong evidence of a genetic contribution to P300 amplitude among healthy individuals. The most convincing data are from a study by O'Connor et al.315 In a sample of 59 MZ and 39 same-sex DZ twin pairs, heritability was estimated to be 0.60. Consistent with this, Polich and Burns316 reported a correlation of 0.64 between MZ twin pairs, compared with 0.20 for unrelated matched pairs. A recent large-scale study of adolescent twin pairs reported that additive genetic factors accounted for 48%61% of the variance in P3 amplitude.317 A second similar study found that familial factors accounted for 30% 81% of the variance among adolescent twin pairs. In this case, the familial covariance could be attributed primarily to genetic factors among the males but to shared environmental factors among the females.318 In another study of 10 healthy families, each consisting of 2 parents and 2 children, Eischen and Polich319 reported Fisher z-transformed correlation coefficients of ~ +0.40 for within-family associations, but ~ 0.02 associations between unrelated individuals. Only one smaller study320 failed to find evidence of heritability; MZ and DZ sib-pairs had intrapair correlations, respectively, of 0.50 and 0.35, but this was a nonsignificant difference. There is also substantial evidence that the schizophrenia trait abnormality is, at least in part, genetically mediated.260,321325 Studies of individuals who share a portion of the genetic diathesis for schizophrenia, by virtue of being either the full siblings or offspring of schizophrenia patient probands, have P300 amplitude decrements that are similar to, though less severe than, those of their ill relatives.260,287,321324,326 Frangou et al,322 in the Maudsley family study, reported standardized z scores of 1.03 in 57 family members compared with healthy controls. In a study notable for its methodology of examining MZ twin pairs both concordant and discordant for schizophrenia, Weisbrod et al327 observed decreased amplitudes in both affected and unaffected cotwins of the patient probands, compared with healthy twin pairs. Only a handful of studies have considered topographic differences that reflect the relative contributions of P3a and P3b subcomponents to this familial deficit. Kimble et al325 observed z score measurements of 0.48 at Pz and 0.68 at Fz in 15 first-degree relatives. They argued that the greater frontal deficit reflected heritable impairments specifically in the attentional processes underlying P300. Another study that

deconstructed the scalp P300 into its discrete P3a and P3b subcomponents326 also found that the familial deficit was evident for the frontal P3a subcomponent (z = 0.71) but not for the parietal P3b. These 2 findings are consistent with behavioral findings from high-risk family studies, which also suggest that abnormalities in attention are indicators of biological susceptibility.328 A more recent study, however, reported that both schizophrenia patients and their unaffected siblings had increased frontal P300 amplitudes, along with the expected decrease in the parietal P300 response.329 So, although the evidence for a P300 abnormality in the unaffected first-degree relatives of patients is quite strong, the relative contributions of P3a and P3b remain unclear. Specific Genes Associated With P300 Although evidence supporting the viability of P300 as a physiological endophenotype is strong, there is only limited knowledge of specific genetic contributions to either the generation or the disruption of the ERP response. Most of what is known is derived from the Collaborative Study on the Genetics of Alcoholism studies of the visual P300 in the context of alcohol risk and may not, therefore, be applicable to schizophrenia. Nevertheless, these studies demonstrated relatively strong linkages (LOD Score > 2.3) between P300 amplitude decrements and areas of chromosomes 2, 5, 6, and 17.330,331 Of these, only the region of chromosome 6, which contains the dysbindin candidate gene, has also been implicated in schizophrenia.332 A specific association has also been reported, among children at risk for alcoholism, between reduced auditory P300 amplitude and the A1 allele of the DRD2 DA receptor on chromosome 11.333 The relationship between genetic determinants of dopaminergic function and P300 is further supported by the association between P300 amplitude and the Ser9Gly polymorphism of the DRD3 DA receptor in healthy subjects.334 These findings are not specifically linked to either schizophrenia or the schizophrenia P300 deficit. Nevertheless, the obvious importance of DA to both the symptomatology and treatment of schizophrenia makes them intriguing. The only evidence of a specific genetic association to reduced P300 amplitude in schizophrenia comes from the study of a large family pedigree with a balanced translocation of the long arm of chromosome 1 and the short arm of chromosome 11.335 This translocation disrupts the DISC1 gene at the chromosome 1 breakpoint and is strongly linked to schizophrenia (LOD Score = 3.6). Among the members of this family, those with the translocation exhibited reduced P300 amplitudes compared with both familial noncarriers and unrelated control subjects. This association was observed even among carriers of the translocation who exhibited no psychiatric symptoms, strongly implicating P300 amplitude as an endophenotypic marker of the DISC1 genetic vulnerability. Previous SectionNext Section

Conclusion
The ideal neurophysiological endophenotype is one that exhibits a robust and stable deficit in both patients and unaffected family members and shows strong evidence of both heritability and cosegregation with illness within pedigrees. It also should be easily and

rapidly measured with minimal subject demands, demonstrate excellent test-retest and across-site reliability, and, preferably, reflect a discrete neurobiological mechanism that is both informative for the pathophysiology of the disorder and regulated by a limited number of genes. Each of these 5 candidate endophenotypes has been shown to be abnormal in schizophrenia patients. For 4 of the 5, there is also strong evidence that the abnormality is heritable and present in unaffected family members of schizophrenia probands. The one exception to this is MMN, which is not unequivocally impaired in either newly diagnosed patients or unaffected first-degree relatives. It should be noted, though, that there is very little evidence that any of these measures actually cosegregate with the illness within individual pedigrees. This is a reflection of the lack of such comprehensive family studies, rather than an indication of negative findings. Of the 4 remaining measures, 2PPI and P50have the distinct advantage of being preattentive indices of relatively discrete neural mechanisms that can be assessed without any observable patient response. They, therefore, require much less motivation, cooperation, or comprehension from the subject. However, they are both influenced by state-dependent factors that add additional nongenetic noise to their measurement. The most notable of these is their tendency toward normalization by atypical antipsychotic medications, which could confound a quantitative trait linkage analysis. The 2 remaining candidate endophenotypesAS and P300both appear to be highly stable trait measures that are reliably assessed and impervious to the effects of treatment. However, these require a level of subject cooperation that presents a challenge for assessment in the most severely ill patients. Also, these are more complex behavioral tasks that rely upon a more distributed neural network and, therefore, a presumably more complex genetic architecture. It is ironic that, of all these measures, MMN perhaps best fulfills the combined criteria of simplicity, reliability, and state independence. It is therefore extremely important that the status of this deficit in unaffected family members, high-risk individuals, and newly diagnosed patients be clarified using a standardized methodology. As indicated in the introduction to this review, there is growing interest in the concept of multivariate endophenotypes. A composite endophenotype comprised of multiple measures may exhibit greater experimental stability and test-retest reliability than a single endophenotype. It may thus be a more robust marker of genetic vulnerability than any one measure. Also, to the extent that one measure can act as a surrogate for another, then the relative merits of each might allow them to be selectively applied under different circumstances. For example, one measure of inhibitory failure (eg, PPI) might be assessed in an unmotivated patient taking a typical antipsychotic, while another (eg, AS) might be measured in a cooperative patient taking an atypical agent. However, the extent to which these putative endophenotypes overlap with each other and denote the same genetic vulnerability is an issue that remains relatively unaddressed. Only rarely have multiple measures been acquired in the same patient samples. One study that assessed 4 of these endophenotypes (PPI omitted) in schizophrenia patients, relatives, and controls replicated the deficits but found no meaningful correlations across measures, with the one exception of a robust association between P50 and AS.8 Another comparably structured study, though, failed to find any association between these 2 indices.153 There are data demonstrating a similar lack of association, in schizophrenia, between PPI and AS,152 as well as both animal336 and human337,338 data suggesting a dissociation between PPI and

P50. It is telling that a recent study of P50, MMN, and P300 in healthy MZ and DZ twins9 found, once again, that each of these 3 measures was highly heritable but that they shared virtually no genetic contributions. The strong implication of these aggregation studies is that, although these measures may share a common conceptual framework (ie, inhibitory failure or impaired deviance detection), they probably reflect different neurobiological and genetic substrates. Although no one measure is an ideal physiological endophenotype neither is any one of them redundant. Rather, each is likely to denote an independent contribution to the overall genetic vulnerability to schizophrenia. In this case, individuals who are impaired on more than one measure are more likely to be those who have the highest genetic loading for the illness and to be most informative for genetic linkage and association studies.9 Conversely, individuals who are impaired on different measures may reflect different variants of genetic risk that could assist in the identification of distinct genetic subtypes of schizophrenia. Future studies should therefore focus on the assessment of multiple endophenotypic measures in the same individuals and families, despite the methodological difficulties that this would entail. Detailed investigations of the interrelatedness of these measures will enable us to better address questions regarding both the possible heterogeneity and underlying etiologic mechanisms of the disorder. Large-scale multisite investigations, such as the National Institute of Mental Healthfunded COGS, described elsewhere in this Issue,339 will be in an ideal position to perform such analyses.

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Fig. 1 The acoustic startle response to 110-dB SPL white noise burst, recorded from EMG electrodes situated over the OO muscle. The magnitude of the startle response is reduced when the startle pulse is preceded by a lower intensity auditory prepulse. In this example, an 85-dB white noise prepulse was presented 100 ms prior to the startle stimulus.

Schizophrenia patients typically exhibit less attenuation of the acoustic startle response following the prepulse.

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Fig. 2 Auditory evoked responses of 3 control subjects (left) and 3 subjects with schizophrenia (right). Stimuli were a conditioning auditory stimulus and an identical test stimulus delivered 500 ms apart. Arrows mark the location of the P50 wave in the tracings. Positive polarity is downward. Test-to-conditioning (T/C) ratio is indicated for each subject. P50 response to the second stimulus is attenuated in control subjects. As illustrated, schizophrenia patients typically exhibit less attenuation of the P50 response to this test click.

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Fig. 3

Infrared tracings of eye position during 2 trials of a prototypical AS task. The participant is asked to generate a saccade in the opposite direction of the AS cue. In the first trial (A), the participant generates a correct AS, looking away from the cue. In the second trial (B), the participant initially makes an incorrect response (prosaccade error) to the AS cue and then quickly generates a large corrective saccade to the appropriate location. Position of the AS cue varies unpredictably from trial to trial. This particular version of the task has a 200-ms overlap between central fixation and the AS cue. Schizophrenia patients typically make more of these prosaccade errors than healthy subjects.

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Fig. 4 MMN response to an auditory pitch-deviant stimulus. The MMN elicited by a 2000-Hz deviant tone is seen as a negative deflection between 100 and 150 ms poststimulus, with maximum deflection at Fz. The repeating standard, in this case, was a 1000-Hz tone presented every 500 ms, and the deviant tone comprised 5% of the stimuli. Top: grand average waveforms for 20 control subjects. Bottom: grand average waveforms for 19 patients. As shown, schizophrenia patients typically exhibit smaller MMN amplitudes than healthy subjects.

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Fig. 5 P300 response to an infrequent salient auditory stimulus. The P300 response to a target stimulus appears as a broad positive ERP component between 300 and 400 ms poststimulus, with maximum amplitude at the Pz electrode. In this example, subjects made a button press to a 2000-Hz target tone. The standard tone was 1000 Hz. Tones were presented every 1.8 seconds. Top: grand average waveforms for 38 control subjects. Bottom: grand average waveforms for 52 patients. As shown, schizophrenia patients typically exhibit smaller P300 amplitudes than healthy subjects.

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Brain volume in first-episode schizophrenia

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Systematic review and meta-analysis of Citing Articles magnetic resonance imaging studies
R. GRANT STEEN, PhD, COURTNEY MULL, MD, ROBERT MCCLURE, MD, ROBERT M. HAMER, PhD and JEFFREY A. LIEBERMAN, MD
Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, USA

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Correspondence: Dr R. Grant Steen, Articles by STEEN, R. G. Department of Psychiatry, University of North Articles by LIEBERMAN, J. A. Carolina at Chapel Hill, Campus Box 7160, Chapel Hill, North Carolina 27599-7160, USA. Search for Related Content Tel: +1 919 966 8382; e-mail: Grant_Steen@med.unc.edu PubMed Declaration of interest None. PubMed Citation Articles by STEEN, R. G. Articles by LIEBERMAN, J. A.

ABSTRACT TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

Background Studies of people with schizophrenia assessed using magnetic resonance

imaging (MRI) usually include patients with first-episode and chronic disease, yet brain abnormalities may be limited to those with chronic schizophrenia. Aims To determine whether patients with a first episode of schizophrenia have characteristic brain abnormalities. Method Systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls. Results A total of 52 cross-sectional studies included 1424 patients with a first psychotic episode; 16 longitudinal studies included 465 such patients. Meta-analysis suggests that whole brain and hippocampal volume are reduced (both P<0.0001) and that ventricular volume is increased (P<0.0001) in these patients relative to healthy controls. Conclusions Average volumetric changes are close to the limit of detection by MRI methods. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.

INTRODUCTION TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

Schizophrenia is a disabling illness that affects over 2 million people in the USA alone, but its aetiology remains poorly understood (Harrison, 1999; Siever & Davis, 2004). In past years the disorder was studied by examining pathological brain tissue samples, often derived from patients who had died after a prolonged period of illness. In recent years, with the advent of brain imaging methods such as magnetic resonance imaging (MRI), it has become possible to study patients during their first episode of psychosis, before disease effects are obscured by the confounding influences typical of cases of chronic schizophrenia. This may make it possible to test hypotheses as to which brain volumetric changes are primary to the development of schizophrenia (Shenton et al, 2001). Our goal in the study reported here is to provide an update of two excellent earlier reviews (Wright et al, 2000; Shenton et al, 2001), but with a focus specifically on patients with first-episode schizophrenia.

METHOD TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

Study selection criteria Relevant studies of patients with first-episode schizophrenia were identified in multiple searches as late as November 2004. The primary search used PubMed and the keywords SCHIZOPHRENIA and FIRST-EPISODE and MAGNETIC RESONANCE IMAGING and VOLUME, in all possible combinations. This search was repeated, substituting the keyword DRUG NAIVE for FIRST-EPISODE, and using the same search words again in all possible combinations. A secondary search was then undertaken, using each primary reference as a source. The bibliography of each source was searched for additional references that were missed by the PubMed search. In addition, the bibliographies of eight key review articles were searched (Wright et al, 2000; Konick & Friedman, 2001; Okubo et al, 2001; Shenton et al, 2001; Kasai et al, 2002; Torrey, 2002; Davidson & Heinrichs, 2003; Antonova et al, 2004) for papers relating specifically to patients with first-episode disorder. Finally, current journals were reviewed to find references too new to have been reviewed. The primary search found 75 relevant references, whereas the secondary searches found an additional 16 references. Studies were included in our analysis if brain MRI volumetric data were reported for both a population of patients with schizophrenia at first episode and a population of healthy controls evaluated concurrently. We excluded seven studies that did not report exclusively on patients with first-episode illness, and five studies that did not report concurrent data from healthy controls. Studies were also excluded if data from patients with first-episode psychosis were not separated from a larger population of patients with psychosis of some other type, or if results included patients with childhood-onset schizophrenia. We specifically excluded children younger than age 13 years from our analysis because there are rapid changes in brain volume among healthy children up to about age 9 years (Pfefferbaum et al, 1994; Giedd et al, 1999), and the young age of patients with childhoodonset illness would make it difficult to control adequately for the effects of normal brain growth. Studies were also excluded if data were reported in a format that did not enable us to calculate patient brain volume as a percentage of the control group volume. Thus, we excluded studies that used voxel-based morphometry, since our calculations are based on

volume rather than on number of pixels. We also excluded studies that reported results from a non-volumetric analysis of the data, or from a non-quantitative analysis of the data. Of the total of 91 articles that were originally identified, 26 were excluded for any of the above reasons. A total of 65 articles were evaluated (Table 1), including 52 cross-sectional and 16 longitudinal studies. Data from all 52 eligible cross-sectional studies were entered into a spreadsheet that tabulated study details, including a brief description of the study, demography of the study populations, patient medications and the statistical analyses used. For patients, additional data were entered summarising the percentage difference in structure volume relative to controls, and whether or not this difference was statistically significant according to the analysis presented in the original reference.

View this table: [in this window] [in a new Table 1 Summary of cross-sectional and longitudinal studies window] included in review

The data entry process was then repeated for all eligible longitudinal studies. If a longitudinal study reported baseline data in a format that could be analysed as a crosssectional study, this study was entered into both the cross-sectional and the longitudinal databases. The final database contained approximately 29 084 cells. Data analysis We sorted the cross-sectional database by brain structure, to determine where brain volumetric changes had been sought. Brain volume changes in the first-episode group were summarised, with respect to controls, on a structure-by-structure basis (further information available from the author upon request). We then conducted a meta-analysis of all crosssectional studies that measured whole-brain volume in the first-episode group relative to controls (Table 2). For each component study in the meta-analysis, we abstracted information about sample properties (size, mean and standard deviation) from the original paper and fitted a blocked analysis of variance model (with study as the blocking factor) to examine group differences. We additionally fitted models with the groupxtreatment interaction, to assess heterogeneity; interactions were non-significant in all cases, so we used the models without the interaction terms. We did similar meta-analyses of crosssectional studies that measured differences in hippocampal volume (Table 3) and ventricular volume (Table 4). Finally, we summarised all studies that reported longitudinal volumetric changes significant at P 0.01 (further information available from the author upon request), to address the issue of which longitudinal changes are most robust by statistical criteria.

View this table: [in this window] [in a new window] Table 2 Whole-brain volume in cross-sectional studies

View this table: [in this window] [in a new window] Table 3 Hippocampal volume in cross-sectional studies

View this table: [in this window] [in a new window] Table 4 Ventricular volume in cross-sectional studies

RESULTS TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

The primary PubMed search was able to find 75 of the 91 papers evaluated in this study, or 82% of the relevant references. This suggests that PubMed, although an effective tool, cannot be relied upon to find all relevant references.

A total of 52 studies were included in the cross-sectional analysis (Table 1), these studies involving 1424 patients with first-episode schizophrenia (30.3 patients per study, s.d.=16.5) and 1315 healthy controls (28.0 controls per study, s.d.=10.7). A total of 16 studies were included in the longitudinal analysis, these studies involving 465 patients (33.2 patients per study, s.d.=26.9) and 240 healthy controls (17.1 controls per study, s.d.=8.8). The average age of patients across all studies was 26 years. Even after excluding studies that comprised only male patients (reasoning that a study with a sample composed only of men must have made an effort to exclude women), roughly two-thirds of patients were men, suggesting that males are more common among young patients with first episodes of schizophrenia. Relatively few brain structures have been evaluated in multiple studies (further information available from the author upon request); of 14 comparisons that showed a significant volumetric decrease in grey matter of patients brains, only 6 comparisons were replicated more than three times. Most volumetric studies were small, even when the focus was a structure in which measurement error could be substantial. The total number of patients evaluated per structure, averaged across all 14 central grey matter structures, was 97.6 (s.d.=82.5), but it was only 65.5 (s.d.=47.6) if amygdala, hippocampus and the amygdala hippocampal complex were excluded. Most volumetric changes that are significant relate to grey matter, and more findings relate to central than to peripheral (cortical) grey matter. Virtually all significant volumetric differences from normal in grey matter are patient deficits in volume, compared with controls. Cross-sectional studies that measured whole-brain volume deficits in patients with firstepisode schizophrenia are summarised in Table 2. For this particular comparison there have been 21 studies, with a large number of participants (patients, n=524; controls, n=650), but only 4 studies found significance. Meta-analysis showed that the average patient brain volume was 2.7% smaller than the average control brain volume (P<0.0001). Group (patient v. control) and study differences together account for 57% of the variation in brain volume, but group differences alone were able to account for less than 1% of the variation in brain volume (P<0.0001). Thus, there was a significant variation in brain volume between studies (P<0.0001), although there was no significant study heterogeneity. There was variation in the number (and type) of covariates used in the various studies of brain volume, suggesting that it may be problematic to pool studies in a single metaanalysis. Nevertheless, the number of statistical covariates used in analysis did not seem to be related to the level of statistical significance obtained. The 4 studies that found significance had an average of 2.0 covariates, whereas the 17 non-significant studies had an average of 2.2 covariates. Cross-sectional studies that measured hippocampal volume deficits in patients with firstepisode schizophrenia are summarised in Table 3. There have been 10 separate studies of the hippocampus, with total participant numbers of 300 patients and 287 controls. Metaanalysis shows that the volume deficit in patient hippocampus is about 8% on both right and left sides (P<0.0001). This deficit is somewhat larger than the 4% volume deficit reported in a meta-analysis of hippocampal volume in patients with chronic schizophrenia (Nelson et al, 1998). Group and study differences together accounted for 64% of the variation in hippocampal volume, but group differences alone were able to account for only

2% of this variation (P<0.0001). Study-related variation in hippocampal volume was significant (P<0.0001), without significant study heterogeneity. Cross-sectional studies that measured the lateral or third ventricles in patients with firstepisode schizophrenia are also summarised (Table 4). There have been 11 studies of ventricular volume, with total participant numbers of 204 patients and 209 controls. Metaanalysis shows that the lateral ventricle volume surplus in patients is about 34% on the left side and 25% on the right side (both P<0.0001). Group and study differences together account for 31% of the variation in ventricular volume on the left side and 26% on the right side (both P<0.0001), with group differences accounting for 6% or less of the variation in ventricular volume (both P<0.0001). For third ventricle measurements, group and study differences together accounted for 68% of the variation in third ventricle volume (P<0.0001), with group differences accounting for 4% of the variation in ventricular volume. Study-related variation in ventricular volume was significant (all P<0.0001), without significant study heterogeneity. We summarised robustly significant (P 0.01) findings from longitudinal studies of brain volume change in patients (further information available from the author upon request). This compilation demonstrates that longitudinal studies are generally of recent vintage; of eight studies recorded, five were published within the past 5 years. Several longitudinal changes in the volume of the brain were robustly significant after diagnosis, including a significant decrease in volume of the whole brain after diagnosis. No significant longitudinal change was identified in white matter or cerebellum, so longitudinal changes in whole-brain volume may be limited to the grey matter.

DISCUSSION TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

Our synthesis of brain volumetric studies suggests that a great deal more work is needed. There are relatively few studies that specifically relate to patients with first episodes of schizophrenia (see Table 1); the existing studies have a rather small sample size and studies that reported a high degree of significance tended to have a smaller sample size than normal. Most significant volumetric findings are not well replicated, and few findings are robustly significant, in either cross-sectional or longitudinal studies. Studies of patients with

first episodes tend to be smaller than the average of 33 patients per study reported in a systematic review of 180 studies of patients with (mostly) chronic schizophrenia (Shenton et al, 2001). Thus, the total number of first-episode cases that have been evaluated overall is small, given the complexity of the illness. Whole-brain volume deficits Whole-brain volume differences between first-episode cases and controls are apparently quite subtle (Harrison et al, 2003). Cross-sectional studies that measured whole-brain volume reported an average volume deficit in the first-episode group of less than 3% (see Table 2), despite a large sample size. This finding agrees well with a study of brain weight at autopsy, in which 540 older patients with chronic schizophrenia were compared with 794 controls (Harrison et al, 2003). This study found that the brain weight of patients with chronic disorder was 2% less than that of healthy controls (P=0.04), but that disease-related differences were far less significant than brain weight differences attributable to either age or gender (both P<0.0001). No correlation was found between brain weight and the duration of psychosis, which may mean that brain atrophy is not progressive after diagnosis (Harrison et al, 2003). It is critically important to determine when whole-brain volume deficits in patients with schizophrenia first become significant, as this could have bearing on the aetiology of the disorder (Harrison, 1999). If whole-brain volume becomes abnormal early in childhood, this would suggest a neurodevelopmental aetiology; alternatively, if whole-brain volume becomes abnormal shortly before the onset of symptoms or even after symptoms have developed this would suggest a neurodegenerative aetiology. Population-based data suggest that head size is abnormal at birth among those who later develop schizophrenia, compared with controls (Ward et al, 1996; Harrison, 1999). Research in the offspring of people with schizophrenia, in people at high genetic risk of this disorder or in patients in its prodromal phase might help to address this aetiological question. When does volumetric change occur? Some brain structures in people with first-episode schizophrenia appear to show a volumetric deficit that is significant at diagnosis and that is also progressive over the later course of illness. For example, the lateral ventricles are significantly larger than normal at diagnosis (Table 4) and ventricular volume tends to increase significantly in longitudinal studies. Volumetric deficits at diagnosis are seen in the hippocampus (Table 3), in cortical grey matter, in Heschls gyrus, in the planum temporale and in temporal grey matter, and all of these structures also show continued volumetric loss over time (further information available from the author upon request). Some brain tissues appear to show a volumetric deficit at diagnosis, but the deficit may not progress over time. For example, there are volumetric deficits in the thalamus at diagnosis, according to four studies, but no longitudinal change has yet been described. Similarly, volume deficits in the insula are significant at diagnosis, according to two studies, but no longitudinal change has been described. This may mean that volumetric changes in the thalamus and insula are indeed not progressive, or it may mean that there are simply too few longitudinal studies to identify a progressive volume loss that is actually present in these structures.

Imaging difficulties There are a great many difficulties in measuring brain volumes of patients with schizophrenia by MRI. A major problem is that the volumetric loss in patients is no more than 4% per year (further information available upon request), which may be close to the limit of detection by MRI, given the precision of volumetric methods (Howard et al, 2003; MacFall et al, 2004). A longitudinal study of a volume phantom found that changes of up to 5% could be introduced by changes in scanner hardware or software (MacFall et al, 2004). Such machine drift can have an impact on volume measurement, as shown by a study of intracranial content in 113 healthy elderly participants (MacFall et al, 2004). Although the intracranial content cannot change after the cranial sutures close (Pfefferbaum et al, 1994; Giedd et al, 1999), error in its measurement averaged 1.5% (MacFall et al, 2004). This error could be corrected but, in the absence of correction, would confound any longitudinal measurement of brain volume (MacFall et al, 2004). In studies that control for intracranial volume, imprecision or inaccuracy may not have a major impact, but poor precision or low accuracy in even a subset of volumetric studies would lead to a lack of consensus among the various studies. Imprecision or inaccuracy in the measurement of brain volume can arise in many ways. Perhaps the most likely source of error is voxel misclassification during brain segmentation (Wang & Doddrell, 2002). Voxels classified as one tissue type could, with a relatively minor change in tissue T1 or T2, be classified as another tissue type (Steen et al, 1997). A second major issue is the familiar partial volume problem; since several tissues can occur in a volume much smaller than a typical imaging voxel, this would introduce error into the volume estimate of any tissue type (Tofts et al, 1997; Ballester et al, 2000; Wang & Doddrell, 2002), and could potentially change the proportional allocation of tissue to tissue type. A third problem is the inconspicuousness of tissue edges; this type of error is really another type of partial volume error that would primarily affect the estimate of grey matter volume, since this often has poorly defined edges with cerebrospinal fluid. Error in the measurement of grey matter volume would change the estimate of total brain volume, so controlling for brain volume would not necessarily eliminate machine drift in a longitudinal study. A fourth issue is head tilt, or angulation of the imaging slab over the brain, since different volumes of brain may be interrogated in different imaging examinations. This problem can only be overcome by striving for full brain coverage during an examination. Finally, non-systematic non-systematic errors (mistakes) can be made during the complex analytic process that is required for MRI volumetry (Haller et al, 1997). In short, because error can be substantial and because brain volumetric changes from normal in patients with first-episode schizophrenia appear to be quite small, some of the differences reported between patients and controls (Tables 2, 3, 4) are probably artefactual. Clinical difficulties A great many clinical difficulties complicate a volumetric search for the causes of schizophrenia. An enormous problem is that patients are typically treated with antipsychotic medications as soon as possible after diagnosis. Different patients may receive different medications at different dosages, and such treatment heterogeneity is almost impossible to eliminate. This makes it essential to determine whether there are acute effects of medication on total brain volume (DeLisi et al, 1991; Chakos et al, 1994; Gur et al, 1998). If brain volumetric changes in response to medication are rapid, then the length of time between

first medication and imaging evaluation could be a major confounder. Antipsychotic medication has been postulated to have an effect on basal ganglia volume in as little as 6 months (Chakos et al, 1994), and it is possible that brain volumetric change in response to medication occurs even more rapidly. A further difficulty inherent to studying first-episode cases is that some patients may have been symptomatic, but undiagnosed, for a long time. If progressive brain volume changes are rapid in the period surrounding diagnosis, then the duration of undiagnosed illness would be a serious confounder. However, since no consistent relationship has been found between duration of illness and brain volume loss (Harrison et al, 2003), this may be less likely. Recruiting patients with schizophrenia can be time-consuming, difficult and expensive, since many are unable or unwilling to comply with study requirements. Another problem is that brain structure may be weakly correlated with brain function, so that substantial variation in brain volume could be found in the absence of any variation in brain function (Uttal, 2001). These two problems together probably account for why so many studies of brain volume appear to be underpowered (Table 2). Many studies lack a sample size sufficient to test hypotheses that relate to what may be an inherently weak relationship, especially given the limitations of the methods (Haller et al, 1997; Howard et al, 2003; MacFall et al, 2004). To complicate the picture further, there may be genetic heterogeneity within the diagnosis, such that patients in a single study might actually have different diseases that converge in causing psychotic symptoms. Concluding remarks The most robust volumetric findings in patients with schizophrenia are those of grey matter volume loss (Table 3) and ventricular volume increase (Table 4), and these findings are probably linked. In monozygotic twins discordant for schizophrenia, there is a correlation between reduced left temporal grey matter volume and increased volume of cerebrospinal fluid in the left temporal horn, suggesting that loss of grey matter leads to an increase in ventricular volume (Suddath et al, 1989). Many more longitudinal studies of brain volume change in patients with first psychotic episodes are needed to determine which tissues are prone to the atrophy that manifests as ventricular volume increase. This review confirms that grey matter deficits are present in patients with first-episode psychosis (Hulshoff-Pol et al, 2001), whereas white matter changes have seldom been described (Sanfilipo et al, 2000; Hulshoff-Pol et al, 2004). Yet it is still not known whether changes in grey matter volume at first episode are associated with disease progression itself or with the many correlates of disease, including antipsychotic medication, alcoholism, drug misuse, malnutrition or even social deprivation. Both alcoholism (Joyce, 1996) and malnutrition (Swayze et al, 1996) are associated with acutely reversible changes in brain volume. Such volumetric changes are postulated to result from changes in brain water content, secondary to systemic hydration or serum protein content (Joyce, 1996; Swayze et al, 1996). Similar hydration mechanisms could be important in schizophrenia, since many patients suffer from malnutrition, dehydration and exposure (Shenton et al, 2001), so it is important to control for such environmental effects in studies. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset and manifests as progressive volumetric loss

thereafter, or whether it is better characterised as a neurodevelopmental process that results in abnormal brain volume beginning at an early age (Maynard et al, 2001).

ACKNOWLEDGMENTS TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

R.G.S. is supported by the National Alliance for Research on Schizophrenia and Depression as a Hofmann Trust Investigator. Our research was also supported by MH61603 (J.A.L.), the University of North Carolina at Chapel Hill Schizophrenia Research Center, the National Institute of Mental Health Silvio Conte Center for the Neuroscience of Mental Disorders (MH164065) and the Foundation of Hope.

REFERENCES TOP ABSTRACT INTRODUCTION METHOD RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

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Cassano GB, Rucci P, Frank E, Fagiolini A, DellOsso L, Shear MK, Kupfer DJ: The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach. Am J Psychiatry 2004; 161:12641269 Fagiolini A, Kupfer DJ: Is treatment-resistant depression a unique subtype of depression? Biol Psychiatry 2003; 53:640648 Fava M: Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53:649659

Fava M, Rankin MA, Wright EC, Alpert JE, Nierenberg AA, Pava J, Rosenbaum JF: Anxiety disorders in major depression. Compr Psychiatry 2000; 41:97102 Fochtmann LJ, Gelenberg AJ: Guideline Watch: Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 2nd Edition. Arlington, Va, American Psychiatric Association, 2005 Judd LL, Akiskal HS, Zeller PJ, Paulus M, Leon AC, Maser JD, Endicott J, Coryell W, Kunovac JL, Mueller TI, Rice JP, Keller MB: Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Psychiatry 2000; 57:375380 Kendler KS, Gardner CO, Prescott CA: Toward a comprehensive developmental model for major depression in women. Am J Psychiatry 2002; 159:11331145 Matthews JD, Fava M: Risk of suicidality in depression with serotonergic antidepressants. Ann Clin Psychiatry 2000; 12:4350 Papakostas GI, Petersen T, Mahal Y, Mischoulon D, Nierenberg AA, Fava M: Quality of life assessments in major depressive disorder: a review of the literature. Gen Hosp Psychiatry 2004; 26:1317 Rapaport MH, Judd LL, Schettler PJ, Yonkers KA, Thase ME, Kupfer DJ, Frank E, Plewes JM, Tollefson GD, Rush AJ: A descriptive analysis of minor depression. Am J Psychiatry 2002; 159:637643 Simon NM, Smoller JW, Fava M, Sachs G, Racette SR, Perlis R, Sonawalla S, Rosenbaum JF: Comparing anxiety disorders and anxiety-related traits in bipolar disorder and unipolar depression. J Psychiatr Res 2003; 37:187192 Yeung A, Chang D, Gresham RL Jr, Nierenberg AA, Fava M: Illness beliefs of depressed Chinese American patients in primary care. J Nerv Ment Dis 2004; 192:324327

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American Psychiatric Association: Practice Guideline for the Assessment and Treatment of

Patients With Suicidal Behaviors. Arlington, Va, American Psychiatric Association, 2003. Available at http://www.psych.org/psych_pract/treatg/pg/Practice%20Guidelines8904/SuicidalBehavior s.pdf American Psychiatric Association: Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 2nd ed. Washington, DC, American Psychiatric Association, 2000. Available at http://www.psych.org/psych_pract/treatg/pg/Practice%20Guidelines8904/MajorDepressive Disorder_2e.pdf Bettinger TL, Crismon ML, Trivedi MH, Grannemann B, Shon SP: Clinicians adherence to an algorithm for pharmacotherapy of depression in the Texas public mental health sector. Psychiatr Serv 2004; 55:703705 Cassano P, Fava M: Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16:1525 Dunner DL: Duration of periods of euthymia in patients with dysthymic disorder. Am J Psychiatry 1999;156:19921993 Fava M, Schmidt ME, Zhang S, Gonzales J, Raute NJ, Judge R: Treatment approaches to major depressive disorder relapse. Part 2: reinitiation of antidepressant treatment. Psychother Psychosom 2002; 71:195199 Garfield P, Kent A, Paykel ES, Creighton FJ, Jacobson RR: Outcome of postpartum disorders: a 10-year follow-up of hospital admissions. Acta Psychiatr Scand 2004; 109:434439 Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM: Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003; 361(9358):653661 Gelenberg AJ, Shelton RC, Crits-Christoph P, Keller MB, Dunner DL, Hirschfeld RM, Thase ME, Russell JM, Lydiard RB, Gallop RJ, Todd L, Hellerstein DJ, Goodnick PJ, Keitner GI, Stahl SM, Halbreich U, Hopkins HS: The effectiveness of St. Johns wort in major depressive disorder: a naturalistic phase 2 follow-up in which nonresponders were provided alternate medication. J Clin Psychiatry 2004; 65:11141119 George MS, Wassermann EM, Kimbrell TA, Little JT, Williams WE, Danielson AL, Greenberg BD, Hallett M, Post RM: Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebocontrolled crossover trial. Am J Psychiatry 1997; 154:17521756 Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, Biggs MM, OConnor K, Rasmussen K, Litle M, Zhao W, Bernstein HJ, Smith G, Mueller M, McClintock SM,

Bailine SH, Kellner CH: Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): A Consortium for Research in ECT (CORE) report. J Clin Psychiatry 2004; 65:485491 Iosifescu DV, Nierenberg AA, Alpert JE, Papakostas GI, Perlis RH, Sonawalla S, Fava M: Comorbid medical illness and relapse of major depressive disorder in the continuation phase of treatment. Psychosomatics 2004; 45:419425 Iosifescu DV, Nierenberg AA, Alpert JE, Smith M, Bitran S, Dording C, Fava M: The impact of medical comorbidity on acute treatment in major depressive disorder. Am J Psychiatry 2003; 160:21222127 Jick H, Kaye JA, and Jick SS: Antidepressants and the risk of suicidal behaviors. JAMA 2004; 292:338343 Jindal RD, Thase ME: Treatment of insomnia associated with clinical depression. Sleep Med Rev 2004; 8:1930 Jindal RD, Thase ME: Integrating psychotherapy and pharmacotherapy to improve outcomes among patients with mood disorders. Psychiatr Serv 2003; 54:14841490 Judd LL, Paulus MJ, Schettler PJ, Akiskal HS, Endicott J, Leon AC, Maser JD, Mueller T, Solomon DA, Keller MB: Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Am J Psychiatry 2000; 157:15011504 Karp JF, Buysse DJ, Houck PR, Cherry C, Kupfer DJ, Frank E: Relationship of variability in residual symptoms with recurrence of major depressive disorder during maintenance treatment. Am J Psychiatry 2004; 161:18771884 Katon W, Russo J, Frank E, Barrett J, Williams JW Jr, Oxman T, Sullivan M, Cornell J: Predictors of nonresponse to treatment in primary care patients with dysthymia. Gen Hosp Psychiatry 2002; 24:2027 Keller MB, Mccullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J, Blalock JA, Borian FE, Jody DN, Debattista C, Koran LM, Schatzberg AF, Fawcett J, Hirschfeld RMA, Keitner G, Miller I, Kocsis JH, Kornstein SG, Manber R, Ninan PT, Rothbaum B, Rush AJ, Vivian D, Rothbaum B: A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000; 342:14621470 Kennedy N, Abbott R, Paykel ES: Longitudinal syndromal and sub-syndromal symptoms after severe depression: 10-year follow-up study. Br J Psychiatry 2004; 184:330336 Kennedy N, Paykel ES: Residual symptoms at remission from depression: impact on longterm outcome. J Affect Disord 2004; 80:135144

Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, Mccullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison WM, Keller MB: Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry 2000; 157:14451452 Lenze EJ, Dew MA, Mazumdar S, Begley AE, Cornes C, Miller MD, Imber SD, Frank E, Kupfer DJ, Reynolds CF 3rd: Combined pharmacotherapy and psychotherapy as maintenance treatment for late-life depression: effects on social adjustment. Am J Psychiatry 2002; 159:466468 Leon AC, Solomon DA, Mueller TI, Endicott J, Rice JP, Maser JD, Coryell W, Keller MB: A 20-year longitudinal observational study of somatic antidepressant treatment effectiveness. Am J Psychiatry 2003; 160:727733 March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J; Treatment for Adolescents With Depression Study (TADS) Team: Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004; 292:807820 Moller HJ, Demyttenaere K, Sacchetti E, Rush AJ, Montgomery SA: Improving the chance of recovery from the short- and long-term consequences of depression. Int Clin Psychopharmacol 2003; 18:219225 Montgomery SA, Baldwin DS, Riley A: Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction. J Affect Disord 2002; 69:119140 Mueller TI, Kohn R, Leventhal N, Leon AC, Solomon D, Coryell W, Endicott J, Alexopoulos GS, Keller MB: The course of depression in elderly patients. Am J Geriatr Psychiatry 2004; 12:2229 Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH: Paroxetine for the prevention of depression induced by highdose interferon alfa. N Engl J Med 2001; 344:961966 Nemeroff CB, Heim CM, Thase ME, Klein DN, Rush AJ, Schatzberg AF, Ninan PT, McCullough JP Jr, Weiss PM, Dunner DL, Rothbaum BO, Kornstein S, Keitner G, Keller MB: Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci USA 2003; 100:1429314296 Nierenberg AA: Predictors of response to antidepressants: general principles and clinical implications. Psychiatr Clin North Am 2003; 26:345352 Papakostas GI, Petersen T, Pava J, Masson E, Worthington JJ 3rd, Alpert JE, Fava M, Nierenberg AA: Hopelessness and suicidal ideation in outpatients with treatment-

resistant depression: prevalence and impact on treatment outcome. J Nerv Ment Dis 2003; 191:444449 Reynolds CF, Frank E, Perel JM, Imber SD, Cornes C, Miller MD, Mazumdar S, Houck PR, Dew MA, Stack JA, Pollock BG, Kupfer DJ: Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA 1999; 281:3945 Rothschild AJ: Challenges in the treatment of depression with psychotic features. Biol Psychiatry 2003; 53:680690 Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G; STAR*D Investigators Group. Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Control Clin Trials 2004; 25:119142 Rush AJ, Trevedi M, Carmody TJ, Biggs MM, Shores-Wilson K, Ibrahim H, Crismon ML: One year clinical outcomes of depressed public sector outpatients: a benchmark for subsequent studies. Biological Psychiatry 2004; 56:4653 Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, Johnson CR, Seidman S, Giller C, Haines S, Simpson RK Jr, Goodman RR: Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001; 25:713728 Scott J, Teasdale JD, Paykel ES, Johnson AL, Abbott R, Hayhurst H, Moore R, Garland A: Effects of cognitive therapy on psychological symptoms and social functioning in residual depression. Br J Psychiatry 2000; 177:440446 Segal ZV, Pearson JL, Thase ME: Challenges in preventing relapse in major depression. Report of a National Institute of Mental Health Workshop on state of the science of relapse prevention in major depression. J Affect Disord 2003; 77:97108 Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, Coryell W, Warshaw M, Turvey C, Maser JD, Endicott J: Multiple recurrences of major depressive disorder. Am J Psychiatry 2000; 157:229233 Thase ME: Comparing the methods used to compare antidepressants. Psychopharmacol Bull 2002; 36(suppl 1):117

NEUROSCIENCE

Belanoff JK, Kalehzan M, Sund B, Fleming Ficek SK, Schatzberg AF: Cortisol activity and cognitive changes in psychotic major depression. Am J Psychiatry 2001;158:16121616

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Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301:386389 Drevets WC: Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 2001; 11:240 249 Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Ryan CE, Hess AL, Harrison W, Davis SM, Keller MB: Gender differences in chronic major and double depression. J Affect Disord 2000; 60:111 Lin KM: Biological differences in depression and anxiety across races and ethnic groups. J Clin Psychiarty 2001; 62(suppl 13):1319 MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT: Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA 2003; 100:13871392 Manji HK, Drevets WC, Charney DS: The cellular neurobiology of depression. Nature Med 2001; 7:541547 Meyer SE, Chrousos GP, Gold PW: Major depression and the stress system: a life span perspective. Dev Psychopathol 2001; 13:565580 Paykel ES: Stress and affective disorders in humans. Semin Clin Neuropsychiatry 2001; 6:411 Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000; 48:755756

Focus 2005 American Psychiatric Association

3:3-12

(2005)

CLINICAL SYNTHESIS

Depression: An Update for the Clinician

Andrew A. Nierenberg, M.D., Polina Eidelman, B.A., Yelena Wu, B.A., and Megan Joseph, B.A.
From the Bipolar Clinic and Research Program at Massachusetts General Hospital, Boston. Correspondence: Send reprint requests to Andrew A. Nierenberg, M.D., Massachusetts General Hospital, 15 Parkman Street, WAC 812, Boston, MA 02114; e-mail, anierenberg@partners.org.

CME Disclosure Statement Andrew A. Nierenberg, M.D., Associate Director, Depression and Clinical Research Program, Medical Director, Bipolar Programs, Massachusetts General Hospital. Consultant: Lilly, Shire, Glaxo, Innapharma, Genaissance. Grant support: Lilly, Wyeth, Glaxo, Bristol-Myers Squibb, Cyberonics, Lichtwer, Pfizer, Cederroth, Forest, Janssen. Honoraria: Lilly, Wyeth, Glaxo Polina Eidelman, B.A., Yelena Wu, B.A., Megan Joseph, B.A., Bipolar Clinic and Research Program, Massachusetts General Hospital. No disclosure of financial interests or affiliations to report. DISCLOSURE OF UNAPPROVED, OFF-LABEL, OR INVESTIGATIONAL USE OF A PRODUCT APA policy requires disclosure by CME authors of unapproved or investigational use of products discusssed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by the scientific literature and clinical experience.

CLINICAL CONTEXT

EPIDEMIOLOGY

UPDATE

The statistics for the epidemiology and course of major depressive had MDD in their lifetime and 6.6% have experienced an episode of major depression within the past year (3).

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Of those with MDD, about 90% are classified as at least moderately depresseddisorder (MDD) remain impressive. As of 2000, MDD ranked as the fourth leading cause of disability for women and seventh for men, and it is projected to be second only to cardiovascular diseases by the year 2020 (1, 2). In the United States, 16.2% of the population have . The odds ratios for women compared with men are 1.7 for lifetime MDD and 1.4 for 12month prevalence. Fifty percent of persons who have had one episode of major depression will have at least one more episode, as will 70% of those who have had two episodes and 90% of those who have had three episodes (4). About 20%25% of persons who have major depression will develop chronic depression, with the episode lasting at least 2 years (5). It has been estimated that as many as 30% of patients who present for primary care have MDD (6, 7). These epidemiological data indicate that major depressive disorder continues to be widespread, is frequently chronic and recurrent, and presents physicians of all disciplines with a substantial clinical challenge.

DIAGNOSIS
According to DSM-IV-TR (8) criteria, a diagnosis of MDD requires that at least five of nine symptoms be present (Table 1 ), although many other symptoms have been associated with the disorder (Table 2 ). However, in a key genetic epidemiological study of twins, Kendler and Gardner found that the presence of as few as four symptoms of MDD with less than severe impairment and with symptoms lasting less than 14 days in one twin was associated with a substantial risk of MDD in the co-twin (9). Dysfunction can occur with two of the nine symptoms, and functioning is unequivocally worse for patients with severe depression, defined as meeting threshold criteria for three or more of the nine symptoms (1012). With as few as two of the nine symptoms of depression associated with dysfunction, cause and effect cannot be determined (do the symptoms cause the dysfunction or does the dysfunction cause the symptoms?), leaving the threshold for treatment unclear. A full spectrum of depressive disorders has been proposed (8) (Table 3 ).

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Table 1. DSM-IV-TR Symptoms of Major Depressive Episode

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Table 2. Other Common Symptoms in Unipolar Depression

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Table 3. DSM-IV-TR Spectrum of Depressive Disorders

Minor and subsyndromal depression may precede an episode of MDD as prodromal symptoms, occur after an episode of MDD as residual symptoms, or persist without ever fully meeting the diagnostic criteria for MDD (1316). Whether or not minor and

subsyndromal depression should be treated with antidepressants is still an open question, with some studies finding no difference between active drug and placebo. For example, in a placebo-controlled study comparing paroxetine and problem-solving psychotherapy for elderly primary care patients with minor depression (17), these treatments were modestly better than placebo, but functioning improved only among participants whose functioning was the worst at baseline. Moreover, remission rates were similar for all three treatment groups: paroxetine, 53.1%; psychotherapy, 44.0%; and placebo, 49.1%. A similar study of younger primary care patients with minor depression found no differences among treatment groups receiving paroxetine, psychotherapy, or placebo (18). However, Judd and colleagues (19) found active drug to be superior to placebo in a study of fluoxetine, which was significantly more effective than placebo in improving symptoms of minor depression and improving psychosocial functioning. When minor or subsyndromal depression is the outcome of an episode of major depression, in contrast to an outcome of full remission, patients are at higher risk of relapse and recurrence (13, 20). Remission, therefore, has become the goal of treatment (21, 22). Unfortunately, only a minority of patients achieve remission with available treatments, and multimodal interventions or thoughtful polypharmacy may be necessary (6, 12). Residual symptoms have increasingly attracted the attention of researchers, and targeted interventions are under development for the management of persistent fatigue, insomnia, and amotivational states (2123). Although minor and subsyndromal depression are associated with distress and dysfunction, it is not clear when subsyndromal and minor depression should be treated: What is the threshold for treatment? In major depressive disorder, residual symptoms after a course of treatment are also associated with distress and dysfunction. In both cases, if distress and dysfunction are present, clinicians should treat their patients to remission whenever possible. One problem in practice, however, is that it can be difficult to determine when and whether remission occurs if depressive symptoms are not measured periodically. Patient rating forms provide a simple means of measuring symptoms. The Quick Inventory of Depressive SymptomatologySelf-Report version (QIDS-SR) (24) or the Beck Depression Inventory II (BDI-II) (25) can easily be incorporated into clinical practice. Patients can complete such instruments in a few minutes and help clinicians track progress (or lack thereof). Reviewing the self-report with the patient allows the clinician to have a frank and focused discussion with the patient about residual symptoms, negotiate the next steps, and evaluate the effectiveness of any interventions.

COMORBIDITY
Nearly three-quarters of persons with MDD have at least one other comorbid psychiatric disorder (3). Most common are anxiety disorders (59%), followed by impulse control disorders (30%) and substance use disorders (24%). Those with comorbid disorders seek help more often and, as would be expected, do not function as well as those without any comorbid disorders (3). One of the great paradoxes of modern clinical trials of treatments for MDD is that many studies exclude most patients with comorbid disorders, which limits the generalizability of results. Zimmerman and colleagues found that among patients treated for depression in a large outpatient clinic, only 14% would meet criteria for inclusion in

clinical trials (26). Clinicians should actively probe for comorbid anxiety, impulse, and substance use disorders and treat them accordingly. Medical comorbidity and MDD are reciprocal: Patients with medical comorbidity have higher rates of depression, and those with MDD have higher rates of some medical disorders, such as cardiovascular disease (2729). Cardiovascular outcomes have been shown to be adversely affected by MDD. For patients who have depression after myocardial infarction (MI), the risk of death is three to four times higher than for those without depression, even when the analysis is covaried by left ventricular function (3032). Research suggests that while social support may not directly affect survival, high levels of social support may act as a buffer against the high risk of death in patients with post-MI depression (33). Major depression, but not minor depression, has been found to be an independent risk factor for the development of MIand it is as strong a risk factor as impaired left ventricular function (34). The SADHART trial, although not designed to address the question of whether antidepressant treatment improves cardiovascular outcomes for patients with postMI depression, suggested that sertraline is a safe treatment for depression in these patients and that it might improve cardiovascular outcomes (35). Ongoing studies are addressing this question. When consulting with medical colleagues, it is important to avoid the mindset that some depression is normal and temporary after MI and therefore that it should not be treated. Whenever depressive symptoms are present, they should be assessed (using a patient-rated measure), treatment should be initiated, and progress should be tracked.

PATHOPHYSIOLOGY
Stress has long been implicated in the precipitation of episodes of major depression (36), but the pathophysiology of the relationship between stress and depression is quite complex. Stress has been shown in animal models to decrease gene expression of BcL-2 and BDNF (37), proteins necessary to maintain robust and healthy neurons (38). Antidepressants have been found to increase gene expression of BDNF and block the decrease precipitated by stress (39). A longitudinal study of more than 1,000 persons between ages 11 and 26 years found a gene-environment interaction that suggests that individuals with the short arm allele of the serotonin transporter gene develop depression under conditions of stressful life events or traumatic parenting, whereas those with the homozygous long arm of the gene appear protected from developing major depression (40). While stress may be a causal factor, alone it may not be sufficient to precipitate major depressive episodes. The gene-environment relationship becomes more complex when theories of neurogenesis come into play. BDNF is necessary for the generation of new neurons in the hippocampus and dentate gyrus in adults (39, 41). Because of animal models showing a decrease in BDNF with stress and an increase with antidepressants, some researchers have postulated that in human beings impaired neurogenesis may be at the heart of the pathophysiology of depression (39). Although early studies did not find a significant difference in hippocampal volume between depressed individuals and healthy control subjects (42, 43), a decrease in BDNF is consistent with more recent neuroimaging data that show decreased hippocampal volume in patients with chronic or recurrent MDD (44, 45). No actual evidence for

decreased neurogenesis in adult humans has been produced, however, nor any fundamental data on the function of new neurons and the clinical correlates of decreased neurogenesis (46). The pros and cons of these two arguments are elegantly discussed by Sapolsky (47).

TOP CLINICAL CONTEXT TREATMENT STRATEGIES AND... QUESTIONS AND CONTROVERSIES AN UPDATE ON TREATMENT-RESISTANT... CONCLUSIONS REFERENCES

TREATMENT STRATEGIES AND EVIDENCE ANTIDEPRESSANTS

The large pharmaceutical companies all advertise their antidepressants as first-line agents; but "first-line" in this context is a marketing tool, not an evidence-based concept. Instead of conceptualizing one antidepressant or another as first-line, it makes sense to tailor the treatment choices to the individual patient and, as much as clinically appropriate, involve the patient in the decision of which medication to try and which side effects to risk. In this model of shared decision making, the physician and the patient reach concordance about the best course of action (48, 49). When concordance is reached, patients are more apt to take their medication regularly than when they are merely told what to do by their physician. This model of concordance and shared decision making is new to psychiatry and still evolving in other areas of medicine (48, 50). Those interested in more detail on these issues might want to read Jay Katzs classic, The Silent World of Doctor and Patient (51), and Carl Schneiders counterargument to Katz, The Practice of Autonomy (52). Those interested in better communication of risk and negotiating around treatment choices might want to read Gerd Gigerenzers excellent book Calculated Risks (53) and Barry Schwartzs The Paradox of Choice (54) as well as Ury and Fishers classic on negotiation, Getting to Yes (55). In the past few years, the hypothesis that dual-action antidepressantsagents that inhibit reuptake of both serotonin and norepinephrineare better than single-action antidepressants has been at the center of the efficacy wars. A fundamental part of the terrain of this battleground is the emphasis on remission (becoming completely free of depression) as opposed to response (showing 50% improvement) (22). In a widely cited analysis of pooled data, Thase and colleagues found a remission rate of 45% among patients who received venlafaxine, a reuptake inhibitor of both norepinephrine and serotonin, compared with 35% for various selective serotonin reuptake inhibitors (SSRIs) and 25% for placebo (56). In contrast, Montgomery and colleagues reported that escitalopram was superior to

venlafaxine (57). Why the discrepancy? A careful look at the Thase study reveals that the SSRI in six of the eight studies analyzed used fluoxetine, an agent that has a long half-life and possibly a slower onset of action than other SSRIs, so the results of the meta-analysis may not be generalizable to other SSRIs. Also, one of the studies lasted only 6 weeks, and some of the studies may have included SSRI-resistant patients. It is essential that the treatment choices be tailored to the individual patient, typically on the basis of estimates of tolerability, possible symptom clusters, and prior treatment, and for the clinician and the patient to negotiate about a limited number of antidepressants and to share decision making.

PSYCHOTHERAPIES
The past two decades have seen the emergence of evidence-based psychotherapies, notably cognitive behavior therapy (CBT) and its variants (58) and interpersonal therapy (IPT) for depression (59). While studies with adult patients have generally found that the efficacy of these therapies can equal that of antidepressants, it is important to note that the subjects who agree to participate in clinical trials are those who are willing and able to participate in psychotherapy. Those who are too depressed to do the assignments associated with the psychotherapy obviously would not participate in the trials. Behavioral activation therapies can sometimes be helpful in these instances. Converging evidence supports the practice of combined therapy with antidepressants and targeted psychotherapies. In one key study, the combination of nefazodone and the cognitive behavioral analysis system of psychotherapy (CBASP) was superior to either treatment alone (60). Similarly, the combination of CBT and fluoxetine was better than either one alone for depression in adolescents (61). Results of a meta-analysis further support the combination of medication and targeted psychotherapy (62).

LONG-TERM

TREATMENT

Since the seminal studies by Prien et al. (63), Keller et al. (64), and the Pittsburgh group (65, 66), clinical practice has shifted from time-limited treatment for each depressive episode to long-term maintenance treatment for many patients. Guidelines suggest that all patients receive continuation treatment for 4 to 6 months after response to prevent a relapse. Patients who have had three or more lifetime episodes, those whose index episode lasted 2 years or longer, those with double depression, and those whose first onset of depression occurred at 50 years of age or later should receive indefinite maintenance treatment to prevent a recurrence of depression. Although indefinite treatment is beneficial for many patients, most stop taking their antidepressants within 6 months (67, 68). To address this reality, several sequential studies of cognitive behavior therapy have been developed that would help maintain euthymia after discontinuation of antidepressants. Paykel and colleagues found that CBT was effective for residual symptoms and prevented relapse (69). Giovanni Fava found that well-being therapy, a modification of CBT, also prevented recurrence (70). Segal and Teasdale developed a group CBT called mindfulness-based cognitive therapy (MBCT) that shows promise in this area and is being assessed for efficacy in a randomized clinical trial (71, 72).

TOP CLINICAL CONTEXT TREATMENT STRATEGIES AND... QUESTIONS AND CONTROVERSIES AN UPDATE ON TREATMENT-RESISTANT... CONCLUSIONS REFERENCES

QUESTIONS AND CONTROVERSIES RISK AND BENEFIT OF ANTIDEPRESSANTS AMONG PEDIATRIC PATIENTS
The Food and Drug Administration (FDA) held extensive hearings in September 2004 on the risk-benefit ratio of antidepressants for children and adolescents (73). An FDA advisory panel examined data from randomized clinical trials with some 5,000 pediatric subjects and found little evidence of efficacy for antidepressants in this age group and some evidence of increased suicidal thoughts. In response to the FDA hearings, the American Psychiatric Association issued a statement that access to antidepressants should be maintained and that close monitoring is needed for adolescents and children taking antidepressants (74). The American College of Neuropsychopharmacology formed its own task force to assess pediatric antidepressant use. After reviewing clinical trials, epidemiological studies, and autopsy studies, the task force concluded that SSRIs and other newer antidepressant drugs "do not increase the risk of suicidal thinking or suicide attempts" in youths (75). There are other possible explanations for increased suicidal thoughts in youths taking antidepressants, such as initial activation of psychomotorically retarded depressives (giving them the energy to act on latent impulses), precipitation of mania or panic, and induction of akathisia. In examining this controversial issue, both efficacy and the side effect of emergent suicidal ideation and behavior need to be addressed. First, randomized clinical trials of antidepressants for children and adolescents have a high placebo response rate, making it difficult to detect any therapeutic signal of the antidepressants. If one assumes that the antidepressants are ineffective for these patients, then the high placebo response rate confirms that the antidepressants do not work. On the other hand, if one assumes the opposite, that the antidepressants are effective, then the criticism is leveled at the methods used in the trials, which inflate the placebo rate. Generally, however, symptoms improve for most youths in clinical trials whether they are taking the active antidepressant or placebo. Much has been written about the placebo effect in antidepressant trials (7682). The issue is inherently complex, and it may be further complicated in the case of pediatric trials. Rater bias and competency are among the most difficult factors to assess. Baseline depression scale scores may be inflated at the start of the

trial to meet inclusion criteria, and scores may be deflated as the trial progresses with the expectation of improvement; as a result, both participants taking antidepressants and those taking placebo show improvement. Furthermore, because of safety concerns and because of volunteer bias, youths who participate in trials are moderately depressed at most, not severely depressed. With these factors combined, the results of randomized clinical trials show a minimal level of effectiveness for antidepressants that may not be generalizable to the population that will be treated (83). Parker has noted the discrepancy between patients in clinical care and subjects in clinical trials and questioned the relevance of modern clinical trials for actual practice (84). Parkers discussion refers to trials in general; the problem is compounded in pediatric studies, because parents decide whether to enroll their children in clinical trialsand parents of severely depressed youths will very likely be reluctant to have their children participate in research. Second, no suicides occurred during any of the trials, and although the relative risk ratio for active drugs compared with placebo approached 2 (indicating that about twice as many taking active drug had suicidal thoughts or behaviors), the absolute difference was about 1.5% (73). Suicidal thoughts and suicide attempts were among the events counted, but given inconsistencies in the rules and definitions, it is unclear what was actually assessed. Another consideration is that the randomized clinical trials specifically excluded subjects considered to be at risk of suicide (those who had recently attempted suicide or currently had suicidal ideation). Thus, the trials are not designed to show the efficacy of the antidepressants in reducing suicidal ideation or behavior in those who have these problems at baseline. It is likely that the analytical challenges of a high placebo response and the lack of any completed suicides in the studies led the FDA advisory panel to recommend that antidepressants carry a warning label indicating that pediatric patients be followed carefully, especially in the early stages of treatment, rather than an outright ban on prescribing antidepressants to youths. Thus, when using antidepressants to treat a depressed child or adolescent, monitor carefully for the emergence or exacerbation of suicidal thoughts (perhaps with additional measures such as the QIDS-SR or another patient-rated instrument appropriate for youths), see the patient frequently enough to detect any exacerbation, and evaluate carefully for symptoms of a bipolar disorder.

AN UPDATE ON TREATMENT-RESISTANT DEPRESSION

Because only a minority of patients achieve remission with antidepressant monotherapy, many clinicians turn to either augmentation or combination treatments for patients who have a partial response or no response to antidepressants (85). The sections below provide a brief review of what is new with these strategies.

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AUGMENTATION
Technically, augmentation in this context is the addition of a nonantidepressant medication to an antidepressant medication regimen. The oldest and most studied of such agents is lithium (8688). In a meta-analysis, Bauer and colleagues found that the average response rate with the addition of lithium was 45%, compared with 18% with placebo (86). Several other reports, however, found no significant difference between lithium and placebo augmentation (88). The only study published to date that has addressed the issue of duration of treatment with lithium augmentation found that patients who responded to and continued taking lithium in addition to their antidepressant did substantially better than those who were given placebo in addition to the antidepressant (89). Few studies have been published that examine the efficacy of lithium augmentation for SSRIs and other more recently introduced antidepressants. Thyroid hormone augmentation, specifically with T3, is the second most widely studied augmentation, but this agent, too, has not been adequately studied for augmentation of the newer antidepressants. The largest of recent studies compared lithium and thyroid augmentation of tricyclic antidepressants and found them about equally effective and better than placebo (90). One practice favored by many clinicians and slowly gaining supporting evidence from randomized controlled trials is augmentation of antidepressants with atypical antipsychotic medications for patients with nonpsychotic, treatment-resistant unipolar depression. Olanzapine (91), risperidone (92, 93), ziprasidone (94, 95), aripiprazole (96), and quetiapine (97) have been studied and found to be superior to placebo as augmentation of antidepressants for nonpsychotic depression. The long-term risks and benefits of using these medications will become clearer over time. One concern is that atypical antipsychotics have been associated with the metabolic syndrome (98, 99). Another agent favored in clinical practice that has garnered some supportive data is the addition of the antinarcolepsy agent modafinil. An initial case series supported the use of modafinil, and subsequent reports have confirmed that it might be useful for patients with residual fatigue and sleepiness (100102). Some data support the use of la-motrigine (103 106), pramipexole (107), folate (108, 109), and s-adenosylmethionine (110113), but more studies are needed to establish efficacy for these agents.

COMBINATION
Combination treatment refers to the use of two different antidepressants together. Although combination treatment is commonly used, few studies have been published. Initial case series have suggested that the combination of SSRIs and bupropion has potential (114, 115). A controlled trial of the combination of SSRIs and mirtazapine found that mirtazapine was substantially better than placebo (116).

SWITCHING
Switching within the same antidepressant class may be useful because mechanisms of action may differ across agents in the same class (117). Overall, the probability of response to a second SSRI after nonresponse to a first SSRI is about 50% (118). Reported response rates include 76% for patients who were switched from fluoxetine to citalopram (119), 63% for patients switched from sertraline to fluoxetine (120), and 50% for patients switched from one SSRI to another (121). Switching classes of antidepressant is an alternative strategy (122124). In a study of chronically depressed patients treated with imipramine or sertraline in which nonresponders were switched from one agent to the other, Thase and colleagues reported response rates of 44%60% after the switch (124). Switching from SSRIs to venlafaxine yielded response rates from 30% to 69% (123, 125127). Switching to mirtazapine, bupropion, tricyclics, and monoamine oxidase inhibitors has also been studied (128135).

STAR*D
None of the augmentation, combination, or switching options cited above, with the exception of lithium and thyroid hormone, have been evaluated in published comparison studies. To address this gap in the literature, the National Institute of Mental Health sponsored the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (136, 137), the largest clinical trial ever conducted for depression (www.star-d.org). Patients with MDD who present in either psychiatric or primary care settings are invited to participate and are treated with citalopram (open-label) at maximally tolerated doses for up to 12 weeks. Those who do not remit are randomly assigned to a second treatment through equipoise-stratified randomization (138). Equipoise-stratified randomization essentially allows the patient and the clinician to decide which group of options makes clinical sense. For example, patients who find that they are unable to tolerate citalopram would not want to opt to be randomized to an augmentation strategy, whereas those who are doing reasonably well with citalopram but fall short of remission would not want to stop citalopram treatment and start something else. Some patients may choose all options or may opt out of having cognitive behavior therapy as either an augmentation or a switch strategy. The augmentation/combination options if citalopram fails to bring a patient to remission include buspirone, bupropion, or CBT; the switch options include sertraline, bupropion, venlafaxine, or CBT. If these options fail to bring about remission, subsequent levels include augmentation with either lithium or thyroid hormone and switching to either mirtazapine or nortriptyline. Finally, if these options fail, patients are randomized to either tranylcypromine or the combination of venlafaxine and mirtazapine. Publication of results is expected to begin this year.

TOP CLINICAL CONTEXT TREATMENT STRATEGIES AND... QUESTIONS AND CONTROVERSIES AN UPDATE ON TREATMENT-RESISTANT... CONCLUSIONS REFERENCES

CONCLUSIONS
Depressive disorders, including major, minor, and subsyndromal depression, are widespread. Our understanding of the pathophysiology of these disorders is growing but far from complete. A stress-diathesis model has empirical support, but the story of the relationship between stress, genes, and neurogenesis is just beginning. Clinicians use widely different thresholds for prescribing an antidepressant, but when one is prescribed, the patient needs to be monitored carefully and systematically. Clinicians should consider using depression rating scales such as the QIDS-SR or the BDI-II. Taking the medication regularly is more important than which medication the patient takes. Comorbid conditions, especially anxiety disorders, need to be diagnosed and treated. New paradigms of shared decision making and negotiation can lead to greater concordance and improved outcomes. New psychotherapies are gaining ground, and combined treatment has increasing empirical support. Finally, treating depressed youths has become more complicated because of the controversy surrounding SSRIs and suicidality, and treatment must be delivered with great care.

TOP CLINICAL CONTEXT TREATMENT STRATEGIES AND... QUESTIONS AND CONTROVERSIES AN UPDATE ON TREATMENT-RESISTANT... CONCLUSIONS REFERENCES

REFERENCES

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115. Landen M, Bjorling G, Agren H, Fahlen T: A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry 1998; 59:664668[Medline] 116. Carpenter LL, Jocic Z, Hall JM, Rasmussen SA, Price LH: Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 1999; 60:4549[Medline] 117. Fava M: New approaches to the treatment of refractory depression. J Clin Psychiatry 2000; 61(suppl 1):2632[Medline] 118. Thase ME, Ferguson JM, Lydiard RB, Wilcox CS: Citalopram treatment of paroxetine-intolerant depressed patients. Depress Anxiety 2002; 16: 128 133[Medline] 119. Thase ME, Feighner JP, Lydiard RB: Citalopram treatment of fluoxetine nonresponders. J Clin Psychiatry 2001; 62:683687[Medline] 120. Thase ME, Blomgren SL, Birkett MA, Apter JT, Tepner RG: Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. J Clin Psychiatry 1997; 58:1621[Medline] 121. Joffe RT, Levitt AJ, Sokolov ST, Young LT: Response to an open trial of a second SSRI in major depression. J Clin Psychiatry 1996; 57:114115[Medline] 122. Kornbluh R, Papakostas GI, Petersen T, Neault NB, Nierenberg AA, Rosenbaum JF, Fava M: A survey of prescribing preferences in the treatment of refractory depression: recent trends. Psychopharmacol Bull 2001; 35(3):150 156[Medline] 123. Nierenberg AA, Feighner JP, Rudolph R, Cole JO, Sullivan J: Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 1994; 14:419 423[Medline] 124. Thase ME, Rush AJ, Howland RH, Kornstein SG, Kocsis JH, Gelenberg AJ, Schatzberg AF, Koran LM, Keller MB, Russell JM, Hirschfeld RM, LaVange LM, Klein DN, Fawcett J, Harrison W: Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry 2002; 59:233239[Abstract/Free Full Text] 125. de Montigny C, Silverstone PH, Debonnel G, Blier P, Bakish D: Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial. J Clin Psychopharmacol 1999; 19:401406[Medline] 126. Mitchell PB, Schweitzer I, Burrows G, Johnson G, Polonowita A: Efficacy of venlafaxine and predictors of response in a prospective open-label study of

patients with treatment-resistant major depression. J Clin Psychopharmacol 2000; 20:483487[Medline] 127. Saiz-Ruiz J, Ibanez A, Diaz-Marsa M, Arias F, Padin J, Martin-Carrasco M, Montes JM, Ferrando L, Carrasco JL, Martin-Ballesteros E, Jorda L, Chamorro L: Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:1129 1134[Medline] 128. Fava M, Dunner DL, Greist JH, Preskorn SH, Trivedi MH, Zajecka J, Cohen M: Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial. J Clin Psychiatry 2001; 62:413 420[Medline] 129. Stern WC, Harto-Truax N, Bauer N: Efficacy of bupropion in tricyclicresistant or intolerant patients. J Clin Psychiatry 1983; 44(5 Pt 2):148152[Medline] 130. Weintraub D: Nortriptyline in geriatric depression resistant to serotonin reuptake inhibitors: case series. J Geriatr Psychiatry Neurol 2001; 14:28 32[Abstract/Free Full Text] 131. Nierenberg AA, Papakostas GI, Petersen T, Kelly KE, Iacoviello BM, Worthington JJ, Tedlow J, Alpert JE, Fava M: Nortriptyline for treatment-resistant depression. J Clin Psychiatry 2003; 64:3539[Medline] 132. Thase ME, Rush AJ, Howland RH, Kornstein SG, Kocsis JH, Gelenberg AJ, Schatzberg AF, Koran LM, Keller MB, Russell JM, Hirschfeld RM, LaVange LM, Klein DN, Fawcett J, Harrison W: Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry 2002; 59:233239[Abstract/Free Full Text] 133. McGrath PJ, Stewart JW, Harrison W, Quitkin FM: Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull 1987; 23(1):169172[Medline] 134. Thase ME, Mallinger AG, McKnight D, Himmelhoch JM: Treatment of imipramine-resistant recurrent depression, IV: a double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry 1992; 149:195 198[Abstract/Free Full Text] 135. Fava M, McGrath PJ, Sheu WP; Reboxetine Study Group: Switching to reboxetine: an efficacy and safety study in patients with major depressive disorder unresponsive to fluoxetine. J Clin Psychopharmacol 2003; 23:365369[Medline] 136. Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ: Background

and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am 2003; 26:457494[Medline] 137. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J., Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G; STAR*D Investigators Group: Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Controlled Clin Trials 2004; 25:119142[Medline] 138. Lavori PW, Rush JA, Wisniewski S, Fava M, Kupfer DJ, Nierenberg AA, Quitkin F, Thase ME, Trivedi MH: Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry 2001; 50:792801[Medline]

Focus 2005 American Psychiatric Association

3:14-24

(2005)

REVIEW

Recent Studies of the Biology and Treatment of Depression

Alan F. Schatzberg, M.D.
From the Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, California. Correspondence: Send reprint requests to Dr. Schatzberg, Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, 401 Quarry Road, Stanford, CA 94305-5717; e-mail, afschatz@stanford.edu.

ABSTRACT

Major depression is one of the most common psychiatric disorders, with lifetime prevalence rates of over 15%. Recent research provides new insights on which brain regions are affected in the disorder, underlying biological mechanisms, and possible novel treatments. This review discusses a number of recent research advances in epidemiology, genetics, imaging, treatment, and pharmacogenetics. It also outlines issues or questions that still need to be addressed, and it begins to outline a framework for understanding why and how depression may occur.

TOP ABSTRACT EPIDEMIOLOGY AND COURSE GENETICS BRAIN IMAGING PSYCHOPHARMACOLOGY PHARMACOGENETICS SUMMARY REFERENCES

Acknowledgment This paper was supported by grant MH 50604 from the National Institute of Mental Health. CME Disclosure Statement Alan F., Schatzberg, Chairman, M.D., Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine. Consultant/Speaker: Abbott, Aventis, Bristol-Myers Squibb, Corcept, Lilly, Forest, GlaxoSmithKline, Innapharma, Janssen, Merck, Novartis, Organon, Pharmacia, Solvay, Somerset, Wyeth. Grants: Bristol-Myers Squibb, Lilly, Wyeth. Equity: Corcept, Cypress Biosciences, Elan, Merck, Pfizer. Co-founder: Corcept Therapeutics. Co-inventor: intellectual property owned by Stanford University. DISCLOSURE OF UNAPPROVED, OFF-LABEL, OR INVESTIGATIONAL USE OF A PRODUCT APA policy requires disclosure by CME authors of unapproved or investigational use of products discusssed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by the scientific literature and clinical experience. This article contains discussion of mifepristone for psychotic depression; MK-869 for major depression; selegiline patch for depression; and R121919 for depression.

EPIDEMIOLOGY AND COURSE

Depression is a common disorder. The National TOP Comorbidity Survey reported a prevalence rate of ABSTRACT 5% for current depression and a lifetime rate of EPIDEMIOLOGY AND COURSE 17% (1). Some investigators have noted that these GENETICS rates are higher than those seen in the BRAIN IMAGING Epidemiologic Catchment Area (ECA) survey (2), PSYCHOPHARMACOLOGY PHARMACOGENETICS suggesting an overinclusion of milder forms of SUMMARY depression. Indeed, a reassessment and follow-up REFERENCES study using more clinically relevant definitions of severity of illness yielded rates of depression subgroups that are more consonant with other reports as well as clinical impressions (2, 3). Still, major depression is a common disorder not only in the United States but in all societies, and even milder forms carry considerable morbidity (3). Indeed, the World Health Organization/World Bank Study ranked unipolar depression the fourth highest cause of morbidity in 1990, with the expectation that by 2020 it would become the second leading cause of disability (4, 5). Several recent studies have explored specific subtypes of depression. For example, atypical features as defined in DSM-IV-TR have been a focus of a number of epidemiological and clinical studies (6, 7). Parker and colleagues (6), in Australia, reported that the absence of mood reactivity appeared to be associated with severity of depression and that other atypical symptoms (e.g., hyperphagia) did not appear to be related to each other, raising questions about the validity of the subtype. Others, however, have observed that atypical features do coalesce (7, 8), so this issue remains subject to debate. Psychotic major depression was the focus of one analysis of a large European survey involving some 19,000 subjects in five countries (9). Psychotic features were found in nearly 19% of subjects who met criteria for a major depressive episode (MDE), a rate slightly higher than the 15% reported in the ECA study. Psychotic features were most commonly seen in individuals who endorsed eight or nine items of the criteria for major depression (33%), but they were also seen in individuals with milder forms of MDE. Alternative presentations of MDE have increasingly become a research focus, for several reasons, including the common presentation of MDE as physical complaints in primary care and the efficacy of several psychotropic agents in both mood and anxiety disorders as well as chronic pain. Many patients with MDE in primary care settings present with complaints of physical symptoms, including pain (10). Although pain is commonly observed in MDE in primary care settings, there has been considerable skepticism about the generalizability to epidemiological community samples or to psychiatric practices. In the large European sample mentioned above, chronic painful physical symptoms were observed in 16% of the general population but in 43% of subjects who met criteria for MDE (11). Less than half of the respondents who reported MDE and chronic pain symptoms had an identifiable organic cause of their pain. Headache (including neck pain), shoulder pain, and backache were the most common types of pain. Compared with DSM-IV-TR criteria for MDE, chronic painful symptoms were more commonly seen in subjects with MDE than

was guilt, and nearly as commonly as loss of energy. These data have been recently replicated in a study in California (unpublished 2004 study of M. M. Ohayon). Consideration should be given to including chronic pain symptoms in the criteria for major depression in future classification schemes. As more effective medication and psychotherapy strategies have been developed, greater attention has been given to the significance of residual symptoms that do not meet full criteria for MDE; patients with such residual symptoms have been termed partial responders and their illnesses subsyndromal disorders. Analyzing outcome data from the National Institute of Mental Health (NIMH) Collaborative Program on the Psychobiology of Depression (Collaborative Depression Study), Judd and colleagues (12, 13) reported that residual depressive symptoms are associated with a higher risk of relapse or recurrence, greater utilization of medical services, and greater risk of substance abuse. Thus, increasing attention has been given to maximizing response to both somatic and psychosocial interventions (discussed further below). A number of explanations have been proposed for the continuation of depressive symptoms despite treatment. Paykels group (14) reported a decade ago that residual physical symptoms of depression were associated with a greater likelihood of relapse or recurrence. More recently, Fava and associates (15), in a pooled analysis of studies of duloxetine (a dual norepinephrine/serotonin reuptake inhibitor), reported that remission of depressive symptoms was highly associated with improvement in pain symptoms. Thus, focusing on both physical and emotional symptoms in depression could provide added benefit. Prospective large-scale studies comparing dual uptake agents and selective serotonin reuptake inhibitors (SSRIs) in depressed patients with comorbid pain could help illuminate this area. Another area that has attracted attention is the role childhood abuse may have in adult major depression and response to treatment. Our group has reported that in chronically depressed patients with early abuse, a specialized form of psychotherapy (cognitive behavioral analysis system of psychotherapyCBASP) was more effective than nefazodone (16), whereas the opposite was seen in nonabused patients. Early abuse has also been reported to be associated with an increased risk of depression, comorbid pain, and utilization of medical services in health maintenance organization (HMO) settings (17). Thus, research data appear to be converging on an important adult medical phenomenon with roots in childhood.

GENETICS

The genetics of major depression has been a focus TOP of a great deal of research over the past several ABSTRACT decades. For much of that time, linkage studies EPIDEMIOLOGY AND COURSE failed to establish clearly any single candidate gene, GENETICS which led investigators to argue that depression BRAIN IMAGING represented a complex genetic disorder, to which PSYCHOPHARMACOLOGY PHARMACOGENETICS many different genes could potentially contribute, SUMMARY either alone or in combination with other genes or REFERENCES with environmental factors such as stress. Recently a number of interesting candidate genes have been identified, primarily from population-based or casecontrol studies. Several of these genes point to potential interactions with stress. The short form of the promoter for the serotonin (5-HT) transporter was reported a number of years ago to be associated with neurotic traits. Although subsequent studies did not find a genetic risk of depression in subjects with a short promoter (18), the short form has been associated with increased amygdala activation with stress (19). In the past few years, the short form has also been reported to predict poor response or intolerance to SSRIs in Caucasians in Europe and in the United States (see Pharmacogenetics below). In a major longitudinal study in New Zealand that followed subjects from childhood (18), the short form of the promoter by itself was again not found to be associated with increased risk of depression in the absence of stressors; similarly, stressors by themselves did not predict major depression. However, a significant gene-by-stress interaction was noted, with s/s homozygotes for the transporter promoter at greater risk of developing depression if three or more stressful life events were encountered. This could be a major lead in our understanding of the interaction between biological risk and psychosocial precipitants. Stress activates both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The ability to turn off the HPA axis via feedback mechanisms is widely believed to be a key feature of healthy adaptation, and individuals who are less able to moderate their stress response may be more prone to depression. Feedback inhibition is mediated in part via the glucocorticoid receptor in the hypothalamus, hippocampus, and pituitary. This receptor is surrounded by chaperone heat shock proteins (HSPs), one of which (HSP90) has been implicated in increasing the risk of depressive episode as well as predicting more rapid response to antidepressant treatment. Multiple single-nucleotidepolymorphism genotypes of the FKBP5 gene were explored in two German cohorts. Patients with the T/T genotype at rs1360780 demonstrated more than twice as many depressive episodes as did the C/T or C/C subtypes (20). This T/T genotype is associated with increased expression of the FKBP5 protein, which may result in glucocorticoid receptor insensitivity. However, direct study of patients with the T/T genotype did not point to their having more elevated cortisol levels, and they demonstrated more rapid responses to antidepressant treatment. Thus, although the exact role of this gene or protein in depression remains to be elucidated, the gene is clearly worthy of further study. Decreased serotonin activity has long been thought to play a key role in the pathophysiology of depression and response to treatment. Serotonin is synthesized from

tryptophan via a tryptophan hydroxylase. Recently Zhang et al. (21) and Patel et al. (22) elegantly demonstrated that neuronal synthesis of serotonin is controlled largely via tryptophan hydroxylase 2 (TPH-2) and not the 1 form, which was formerly thought to regulate synthesis in the brain but is now seen to be involved mostly in the periphery. This observation was recently supported by a report that a mutation in TPH-2 was found in some 10% of subjects with unipolar major depression, compared with 1.5% of control subjects (23). This mutation was associated with an 80% decrease in serotonin levels when expressed in a cell line. The variant was not observed in a cohort with bipolar illness. Thus, at least some depressions may be due to a gene variant associated with low serotonin activity. Whether this TPH-2 gene can be used to predict response to SSRI treatment has not yet been studied. In two of the three genes discussed above, stress could play an important role in interacting with a genetic risk to lead to a depression. In the third gene, decreased synthesis of an important brain neurotransmitter could reflect a specific genetic variant.

TOP ABSTRACT EPIDEMIOLOGY AND COURSE GENETICS BRAIN IMAGING PSYCHOPHARMACOLOGY PHARMACOGENETICS SUMMARY REFERENCES

BRAIN IMAGING STRUCTURAL IMAGING

In the past decade, hippocampal volume has become a focus of much research in MDE. The impetus has been the work of Sapolsky and of McEwen (24, 25) showing that stress and glucocorticoids could be neurotoxic and lead to hippocampal neuron loss in lower animals. A related finding is that antidepressants appear to increase neurogenesis in the hippocampus, which some have argued may be a key mechanism of action for these medications (26, 27). Smaller hippocampal volume has been reported in depressed patients in several studies (28 33) but not others (3437). A recent meta-analysis suggested that hippocampal volume is lower in depressives if one does not include the amygdala in the volume analysis (38). The findings of these various studies are summarized in Table 1 .

View this table: [in this window] [in a new window]

Table 1. Hippocampal Volume in Major Depression

A number of other factors could also affect volumetric differences. Sheline and colleagues reported a significant negative correlation between hippocampal volume and total duration of depression, but not age (39). They argued that this finding may reflect chronic exposure to stress, which is consistent with basic research suggesting that glucocorticoids could be neurotoxic. In addition, Vythilingam and colleagues reported that depressed patients with a history of early child abuse had smaller hippocampi than did healthy controls (32), which is consistent with an effect of cortisol on hippocampal volume. This hypothesis has been appealing to many investigators, but earlier data from Axelson and colleagues showed no relationship between cortisol activity and hippocampal volume (40). A number of other perspectives suggest that lower hippocampal volume could be a risk factor for depression rather than a result of it (41). For one thing, hippocampal volume is largely genetically determined (4244). Our group reported that genetics exerted a greater effect on hippocampal volume than did early stress in squirrel monkeys (42). Sullivan and colleagues (43) and Pitmans group (44) reported a significant effect of genetics on hippocampal volume in twin studies. These three studies all point to strong genetic influences on hippocampal volume. Other data point to smaller hippocampal volume presaging untoward outcomes. Firstepisode, younger depressives already had smaller hippocampi than control subjects in a German study (31). In a Veterans Administration study of posttraumatic stress disorder (PTSD) in twins (44), identical twins who were discordant for trauma exposure had similar hippocampal volumes; subjects with smaller hippocampi were more likely to develop PTSD if exposed to combat. These data all suggest hippocampal volume is related to risk of depression. Indeed, another recent study reported smaller hippocampi in depressives with l/l genotype for the 5-HT transporter (45). This finding does not entirely fit with the Caspi et al. (18) finding that the s/s form of the gene was associated with risk of depression in the face of stress. In spite of these findings suggesting that small hippocampal volume is a risk factor for MDE, depression and stress could still result in a further diminution of hippocampal size. For example, Brown and colleagues reported that medical patients taking steroids had smaller hippocampi than did medical control subjects (46). Debate in this area

is likely to continue until longitudinal studies with magnetic resonance imaging and cortisol status are undertaken with depressed subjects or their at-risk offspring.

FUNCTIONAL

IMAGING

Functional imaging studies suggest that hippocampal activity may be disordered in depression. A number of groups early on reported verbal memory impairment in the disorder (47, 48); however, my colleagues and I reported that generally nonelderly psychotic depressivesbut not nonpsychotic depressivesdemonstrated impairment in verbal memory compared with healthy controls (49). In the same study, we reported a marked impairment in an attention/response inhibition task in psychotic depressives indicative of prefrontal/anterior cingulate involvementand suggested a connection between these deficits. Bremner and colleagues (50) recently reported that verbal memory impairment in depression is associated with difficulty in activating both the hippocampus and the anterior cingulate using position emission tomography (PET). They suggested a possible circuit involving the prefrontal cortex, anterior cingulate, and hippocampus in depression (50). Decreased prefrontal activity in depression using PET is a well-established finding (5153). Of particular interest is the work of Drevets and Mayberg showing that the subgenual cortex (inferior/posterior aspect of the frontal lobe) is activated during sadness induction in depression, that it may be significantly reduced in volume, and that its activity may change in response to antidepressants (5456). This area is a focus of possible therapeutic intervention using direct activation approaches such as deep brain stimulation.

TOP ABSTRACT EPIDEMIOLOGY AND COURSE GENETICS BRAIN IMAGING PSYCHOPHARMACOLOGY PHARMACOGENETICS SUMMARY REFERENCES

PSYCHOPHARMACOLOGY
Just a few years ago my colleagues and I commented in the fourth edition of the Manual of Clinical Psychopharmacology that the horizon seemed bright for antidepressant agents with new mechanisms of action (57). However, a number of then-promising agents have not received approval from the Food and Drug Administration (FDA), and the near-term horizon seems quite a bit dimmer. Promising approaches are summarized in Table 2 .

View this table: [in this window] [in a new window]

Table 2. New Psychopharmacological Agents

DULOXETINE
The most recently approved antidepressant is duloxetine, a serotonin/norepinephrine reuptake blocker with dopamine reuptake effects as well. Duloxetine has been shown to be significantly more effective than placebo in major depression in several studies (5860). Dosages studied have ranged from 40 mg/day to 120 mg/day, and the recommended daily dose is now 60 mg/day. Duloxetines half-life is approximately 14 hours. There are no data to indicate that doses above 60 mg/day are more effective than the recommended dose. Although the package insert indicates that the dosage can be started at 60 mg/day, many clinicians have their patients start with 30 mg/day and increase the dose to 60 mg/day after approximately 1 week. This approach can help reduce the likelihood that patients will experience duloxetines most common side effect, nausea, which is seen in as many as 40% of patients begun on 60 mg/day. Accommodation to nausea often occurs by the end of the first week. Other common side effects include dry mouth, constipation, and sedation. Hypertension is seen relatively infrequently (61). As noted earlier, major depression is frequently comorbid with chronic pain, often without organic cause. Duloxetine appears to improve both depression and painful physical symptoms, particularly backache and shoulder pain. It is thought that descending norepinephrine and serotonin fibers from the brain via the spinal cord serve to dampen peripheral pain signals. Increased norepinephrine and 5-HT "tone" may thus simultaneously improve mood and comorbid pain. As mentioned above, Fava and associates (15) reported that remission of depression is more likely if pain symptoms are also markedly improved. My colleagues and I recently reported that in one study duloxetine was significantly more effective than placebo in reducing pain in depressed patients with comorbid pain but that the drug did not separate from placebo on reduction of depression (62). These data suggest that the drug can reduce chronic pain (independent of effects on depression) and are consistent with preclinical data (63). Indeed, duloxetine was the first drug approved for treatment of diabetic neuropathic pain, although it does not provide acute analgesic effects. At doses of 60120 mg/day it is significantly more effective than placebo in reducing pain in nondepressed patients.

Recently the drug has also been reported to improve pain symptoms in patients with fibromyalgia, particularly women (64). Enhanced norepinephrine/serotonin activity may improve bladder control in women with stress urinary incontinence disorder (65). Duloxetine has been approved for this use in Europe, and it is expected to receive similar approval soon in the United States. Abrupt discontinuation of antidepressants is frequently associated with rebound symptoms. This was originally reported with tricyclics, cessation of which can cause rebound peripheral cholinergic symptoms (abdominal cramping, headaches, and the like); in addition, psychiatric symptoms (hypomania and mania) were reported by our group and others in the 1980s (57, 66, 67). With the advent of the SSRIs, discontinuation symptoms were observed anew, particularly with the short-acting, more potent 5-HT reuptake blockers (68, 69). Symptoms include a flulike syndrome with vertigo, nausea, paresthesias, and mood changes. These symptoms have also been observed with the mixed reuptake blockers and have been reported in about 15% of patients treated with duloxetine in clinical trials. When discontinuing the agent, a gradual reduction from 60 mg/day to 30 mg/day for at least 1 week is recommended.

TRANSDERMAL

SELEGILINE

PATCH

Selegiline is an irreversible monoamine oxidase (MAO)-B inhibitor that has long been approved at low doses (510 mg/day orally) for the treatment of Parkinsons disease. At oral doses of 20 mg/day or higher, the drug is an effective antidepressant agent; however, at these doses it is an inhibitor of both MAO A and B and hence is prone to interactions with dietary foodstuffs (70). Delivery of selegiline via a transdermal patch avoids major inhibitory effects on intestinal MAO-A and thus obviates the need for dietary restrictions. This is particularly the case at the lower doses, such as via a 20 mg or 30 mg patch daily. At 40 mg/day an interaction is theoretically possible but highly unlikely. When delivered transdermally the drug appears to produce both MAO A and B inhibition in the brain (71), which is somewhat similar to the action of tranylcypromine. Because of its MAO A and B effects in the brain, patients need to be warned about avoiding concomitant use of other agents, such as meperidine, SSRIs, and so on, even though diet may not pose a problem. Selegiline transdermal patch has been shown to be more effective than placebo in improving depressive symptoms in patients with either typical or atypical subtypes of depression. The starting dose is 20 mg applied daily, with increases to a recommended maximum of 40 mg/day. At 20 mg/day the drug is more effective than placebo but not dramatically so (72). In a pivotal trial using flexible dosing of 2040 mg/day, more dramatic separation from placebo was seen, suggesting that higher doses may have greater efficacy. A principal side effect of selegiline is irritation at the site of application. In addition, because the drug is metabolized to amphetamine or d-amphetamine, it may be quite stimulating, and some patients have difficulty sleeping. Adjunctive hypnotics may be required. Finally, there is a small risk of orthostatic hypotension with the drug.

Selegiline transdermal patch has received an approvable letter from the FDA, and at the time of this writing final approval was pending.

APREPITANT

(MK-869)

Substance P binds to the neurokinin-1 receptor (NK-1) in brain. NK-1 receptors are distributed across regions that contain norepinephrine and 5-HT neurons. In lower animals, substance P activation has been associated with stress responses (73). Mice in which NK-1 receptors have been genetically knocked out appear less anxious (74), as do animals given an NK-1 antagonist (75). These data suggest that NK-1 antagonists may be helpful in disorders viewed as untoward stress responses, such as anxiety and depression. Aprepitant (MK-869)a Merck Laboratories substance P antagonistwas reported to be significantly more effective than placebo (and comparable to paroxetine) in reducing depression (73). A second substance P antagonist was also reported to separate from placebo in melancholic depressives (76). The manufacturer of both pursued a new formulation of MK-869, which failed to separate from placebo in five double-blind antidepressant trials (77). In three of the trials, the active comparator paroxetine did separate from placebo. Merck has halted this development program, although other companies may still be pursuing this drug class as an antidepressant. The drug has relatively little in the way of side effects and was well tolerated. In a different dosage, aprepitant is available for limited acute use (e.g., for 2 days around administration of chemotherapy) to prevent cisplatin-induced nausea and vomiting.

GEPIRONE
Gepirone is a 5-HT1A agonist that has been under study for many years as an immediaterelease formulation. Most recently, one manufacturer (Organon) was attempting to develop a long-acting formulation of the drug as an antidepressant. In one report, the drug separated from placebo on Hamilton Depression Rating Scale change scores from baseline to weeks 3 and 8 (78). In another analysis, the effects appeared to be more pronounced on symptoms of anxiety, which is consistent with previous observations (79). Side effects are generally mild and include dizziness, nausea, and insomnia. However, the file submitted to the FDA was not strong enough to win approval.

MIFEPRISTONE
Mifepristone is an antagonist for the low-affinity glucocorticoid receptor as well as a progesterone antagonist. Two decades ago my colleagues and I hypothesized that the delusions of psychotic depression and similar states were due to excessive cortisol activity (80). Clinical data suggested that at doses of 600 mg/day for 47 days, mifepristone may improve the psychotic symptoms of delusional depression (81), and two recent double-blind studies support this observation (82, 83). Mifepristone is currently in Phase III trials. The drugs side effect profile appears relatively benign; rashes are seen in 4%10% of patients.

CORTICOTROPIN-RELEASING

HORMONE

ANTAGONISTS

Several pharmaceutical companies are developing corticotropin-releasing hormone (CRH) antagonists. CRH in the brain is involved in initiating stress responses. CRH is found in the

hypothalamus, amygdala, and cortex. One CRH antagonistR121919has been reported in an open-label German study to reduce depressive symptoms in hospitalized MDE patients (84). However, the drugs development was discontinued because of laboratory test abnormalities. This remains an area of active drug development.

OLANZAPINE-FLUOXETINE

COMBINATION

The combination of olanzapine and fluoxetine has been reported to promote antidepressant responses in nonresponding depressed patients (85). The mechanism has been thought to reflect mobilization of prefrontal dopamine and norepinephrine (86). This strategy has been under further study. Thus far, the data suggest that atypical antipsychotics rapidly convert nonresponders to responders by 1 week but may not offer any advantage at 8 weeks. A combination product of olanzapine and fluoxetine has been approved for the treatment of bipolar I depression. In the pivotal trials, both olanzapine and the combination of olanzapine and fluoxetine separated from placebo (87). The combination has also been studied in psychotic or delusional depression, where it was more effective than placebo in one of two pivotal studies (88). An analysis of the combined data indicated that the combination, but not olanzapine alone, separated from placebo. However, separation from placebo occurred only after 4 weeks. At this point it is not anticipated that the combination will be developed further for delusional depression.

TOP ABSTRACT EPIDEMIOLOGY AND COURSE GENETICS BRAIN IMAGING PSYCHOPHARMACOLOGY PHARMACOGENETICS SUMMARY REFERENCES

PHARMACOGENETICS
Pharmacogenetics is becoming a major focus in psychopharmacologic research. This approach uses genetic alterationsoften single-nucleotide polymorphisms (SNPs)to assess the likelihood of response to a particular drug or class of drugs or to predict side effects. The approach has been used in various psychiatric disorders, with perhaps the strongest findings seen in depression. Findings are summarized in Table 3 .

View this table: [in this window] [in a new window]

Table 3. Pharmacogenetic Findings in Major Depression

Several years ago the Milan group reported that a short form of the serotonin transporter was associated with poor responses to specific paroxetine (89, 90). In contrast, the alternate long form predicted positive responses. This observation has been confirmed in other studies with Caucasians (91), but the opposite prediction pattern has been reported in studies with Asian populations (92). Recently our group reported that the long form of the transporter was only a mild predictor of positive response to paroxetine in geriatric patients (93). In contrast, the short form of the transporter predicted intolerance to the SSRI paroxetine but not to the 5-HT2 antagonist mirtazapine. Patients who were s/s tolerated mirtazapine much better than did l/l patients (93). Our view of previous studies has been that using last-observation-carried-forward (LOCF) approaches to analysis of patients who dropped out may have resulted in a confusion of intolerance and nonresponse in s/s patients. At any rate, the data do suggest that in Caucasians the SSRI response may not be optimal. The 102 T/C SNP of the 5-HT2A receptor has been associated with the response pattern to clozapine (94) in patients with schizophrenia. We explored whether the C/C homozygote for the receptorseen in some 25% of the populationwas associated with response to either paroxetine or mirtazapine in geriatric depressives (95). The C/C homozygocity predicted intolerance to paroxetine, with over 40% dropping out because of adverse events by 8 weeks. In contrast, the C/C form did not predict intolerance to mirtazapine. Response or remission to either drug was not predicted by the 5-HT2A variants. The s/s form of the transporter and the C/C form of the 5-HT2A receptor independently predicted intolerance to paroxetine (93). Thus, these data suggest that alterations in 5-HT reuptake or 5-HT2A postsynaptic receptor activity affect the ability to tolerate an SSRI but do not adversely affect tolerability of a postsynaptic receptor antagonist. Similarly, allelic variation of the norepinephrine transporter has been explored as a predictor of response to the selective norepinephrine reuptake inhibitor milnacipran in Japanese depressives (96). The T allele of the T-182C polymorphism of the norepinephrine transporter predicted positive response to the drug; the A/A form did not. Allelic variation for the serotonin transporter did not predict response to the norepinephrine agent. Apolipoprotein E 4 (APOE-4) has been reported to be a risk factor for Alzheimers disease. Individuals with this allele may be at increased risk of greater morbidity after surgery or after head injury and have an increased risk of obstructive sleep apnea. In our

geriatric study (97, 98), we explored the hypothesis that APOE-4 alleles were predictors of poor overall response to antidepressant therapy in geriatric patients. This prediction was not borne out, but patients with APOE-4 al-leles were dramatic responders to mirtazapine but not to paroxetine (98). The explanation is not entirely clear, but APOE status may be associated with noradrenergic dysfunction (99) or excessive cortisol activity (100), both of which are targets for mirtazapine therapy (100, 101). Glucocorticoid receptors are nuclear and are surrounded by chaperone heat-shock proteins. As discussed above, alterations in one HSP have been reported to be associated with multiple depressive episodes and rapid response to drug therapy (20). These alterations may affect the individuals ability to halt the stress response. Mirtazapine was frequently used in this study, and the prediction of rapid response may have to do with the drugs ability to lower cortisol levels (101). Further studies in other subject populations will help elucidate this issue. In regard to pharmacokinetics, two major systems have been the focus of much recent research: P450 2D6 in the liver and medication-resistant P-glycoprotein (mr-P-GP), which controls efflux of drug from the brain. P450 represents a basket of enzymes found primarily in the liver that metabolize various drugs. The best known is P450 2D6. Many drugs serve as substrates as well as inhibitors of P450 2D6, whereas some stimulate activity. There are numerous alleles for 2D6; some connote increased clearance or metabolism, whereas others connote slow metabolism. Slow metabolizers should be more likely to experience side effects. Rapid or ultrafast metabolizers may clear the drug so quickly that they fail to achieve adequate blood levels and are thus less likely to attain a drug effect. We explored whether slow metabolizers in a geriatric population were more likely to drop out because of side effects of paroxetine (a substrate and inhibitor of 2D6) or of mirtazapine (a substrate but not an inhibitor) (93, 97). We did not observe an effect of 2D6 alleles on dropouts due to adverse events from either drug, although the number of very slow metabolizers (i.e., null alleles) was small. As indicated above, we did observe pharmacodynamic predictors of SSRI response in this study (97). In the past few years greater attention has been given to mr-P-GP as a predictor of antidepressant response. In mice, knocking out the gene for the pump protein points to its role in facilitating the efflux of both cortisol and antidepressants from the brain (102105). In studies to date using knockouts, citalopram, amitriptyline, and trimipramine appear to be transported out of mouse brain by P-GP (103104). Alterations in this gene may tell us more about treatment resistance than does drug clearance via the liver. However, the significance of these observations on P-GP in lower animals to the treatment of depressed patients is unclear, since the knockout model may not be fully relevant to the clinic. Still, this is an interesting area that is fast becoming a focus of pharmacokinetic research.

SUMMARY

Recent studies point to key brain areas as having important roles in depression as well as to specific genes as risk factors for developing depression, often in interaction with environmental stress. New antidepressant strategies are being pursued, and despite some recent disappointments in this area, pharmacogenetics is pointing to potential tools for selecting drugs or deciding how to dose them.

TOP ABSTRACT EPIDEMIOLOGY AND COURSE GENETICS BRAIN IMAGING PSYCHOPHARMACOLOGY PHARMACOGENETICS SUMMARY REFERENCES

TOP ABSTRACT EPIDEMIOLOGY AND COURSE GENETICS BRAIN IMAGING PSYCHOPHARMACOLOGY PHARMACOGENETICS SUMMARY REFERENCES

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81. Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C, Schatzberg AF: An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002; 52:386392[Medline] 82. Schatzberg AF, Flores B, Keller J, Solvason HB: Antidepressant interventions on the HPA system: use of glucocorticoid antagonists. World Psychiatry 2004; 3(suppl 1):56[Medline] 83. DeBattista C, Belanoff J: A double-blind, placebo controlled trial of C-1073 (mifepristone) in the treatment of psychotic major depression. Neuropsyhopharmacology 2004; 29(suppl 1):S98 84. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F: Effects of the high-affinity corticotrophin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000; 34:171 181[Medline] 85. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY: A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158:131134[Abstract/Free Full Text] 86. Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP: Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 2000; 23:250262[Medline] 87. Tohen M, Vieta E, Calebrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evan AR, Beymer K, Dube S, Tollefson GD, Breier A: Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 60:1079 1088[Abstract/Free Full Text] 88. Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg AF, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD: A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004; 24: 365373[Medline] 89. Smeraldi E, Zanardi R, Benedetti F, DiBella D, Perez J, Catalano M: Polymorphism within the promoter of the serotonin transporter gene and antidepressant of fluvoxamine. Mol Pyschiatry 1998; 3:508511 90. Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E: Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20:105107[Medline]

91. Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ: Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23:587590[Medline] 92. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hohn CG, Carroll BJ: Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11:215219[Medline] 93. Murphy GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF: Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse effects in geriatric major depression. Arch Gen Psychiatry 2004; 61:11631169[Abstract/Free Full Text] 94. Arranz MR, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, Lesch KP, Meyer JF, Sham P, Collier DA, Murray RM, Kerwin RW: Pharmacogenetic prediction of clozapine response. Lancet 2000; 355:16151616[Medline] 95. Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF: Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 2003; 160:1830 1835[Abstract/Free Full Text] 96. Yoshida K, Takahasi H, Higuchi H, Kamata M, Ito K-I, Sato K, Naito S, Shimizu T, Itoh K, Inoue K, Suzuki T, Nemeroff CB: Prediction of antidepressant response to milnacipan by norepinephrine transporter gene polymorphisms. Am J Psychiatry 2004; 161:15751580[Abstract/Free Full Text] 97. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr; the Mirtazapine versus Paroxetine Study Group: Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry 2002; 10:541 550[Medline] 98. Murphy GM, Kremer C, Rodrigues H, Schatzberg AF; the Mirtazapine versus Paroxetine Study Group: The apolipoprotein E e4 allele and antidepressant efficacy in cognitively intact elderly depressed patients. Biol Psychiatry 2003; 54:665 674[Medline] 99. Horsburgh K, McCulloch J, Nilsen M, Roses AD, Nicoll JA: Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoformspecific, transgenic mice after global cerebral ischaemia. Eur J Neurosci 2000; 12:43094317[Medline] 100. Peskind ER, Wilkinson CW, Petrie EC, Schellenberg GD, Raskind MA: Increased CSF cortisol in AD is a function of APOE genotype. Neurology 2001; 56:10941098[Abstract/Free Full Text]

101. Schule C, Baghai T, Goy J, Bidlingmaier M, Strasburger C, Laakmann G: The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects. Psychopharmacology (Berl) 2002; 163:95101[Medline] 102. Muller MB, Keck ME, Binder EB, Kresse AE, Hagemeyer TP, Landgraf R, Holsboer F, Uhr M: ABCB1 (MDR1)-type P-glycoproteins at the blood-brain barrier modulate the activity of the hypothalamic-pituitary-adrenocortical system: implications for affective disorder. Neuropsychopharmacology 2003; 28:1991 1999[Medline] 103. Grauer MT, Uhr M: P-glycoprotein reduces the ability of amitripyline metabolites to cross the blood-brain barrier in mice after a 10-day administration of amitriptyline. J Psychopharmacol 2004; 18:6674[Abstract/Free Full Text] 104. Uhr M, Grauer MT, Holsboer F: Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry 2003; 54:840846[Medline] 105. Uhr M, Namendorf C, Grauer MT, Rosenhagen M, Ebinger M: Pglycoprotein is a factor in the uptake of dextromethorphan, but not of melperone, into the mouse brain: evidence for an overlap in substrate specificity between P-gp and CYP2D6. J Psychopharmacol 2004; 18:509515[Abstract/Free Full Text]
Focus 2005 American Psychiatric Association 3:61-68 (2005)

INFLUENTIAL PUBLICATION

The Mood Spectrum in Unipolar and Bipolar Disorder: Arguments for a Unitary Approach
Giovanni B. Cassano, M.D., Paola Rucci, D.Stat., Ellen Frank, Ph.D., Andrea Fagiolini, M.D., Liliana DellOsso, M.D., M. Katherine Shear, M.D., and David J. Kupfer, M.D.

ABSTRACT

Objective: This study examined the extent to which individuals with TOP a lifetime diagnosis of recurrent unipolar disorder endorse ABSTRACT experiencing manic/hypomanic symptoms over their lifetimes and METHOD compared their reports with those of patients with bipolar I disorder. RESULTS Method: The study group included 117 patients with remitted DISCUSSION recurrent unipolar depression and 106 with bipolar I. Subjects had CONCLUSIONS REFERENCES their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as "temperamental" features related to mood dysregulation. Results: The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. Conclusions: The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders. (Reprinted with permission from the American Journal of Psychiatry 2004; 161:1264 1269[Abstract/Free Full Text])

For most of the 20th century, depressed patients were dichotomized by using the categories "single episode" versus "recurrent" and "unipolar" versus "bipolar." There is now ample evidence that almost all depressions are recurrent to a greater or lesser degree (15). Now the question arises whether almost all recurrent depressions are bipolar to a greater or lesser degree. The distinction between bipolar and unipolar disorder served our field well in the early days of psychopharmacology. However, this distinction has been challenged in the last decades by the following: 1. Clinical studies (6, 7) showing that bipolar disorder is frequently misdiagnosed as unipolar major depressive disorder and consequently mistreated 2. Theoretical studies (8, 9) warning about limitations of the categorical diagnoses of bipolar disorder and unipolar depression

3. Epidemiological studies (10) supporting a widening of the boundaries of the bipolar spectrum to include hypomania, cyclothymia, and bipolar disorder not otherwise specified 4. Familial and genetic studies (11, 12) indicating that the familial aggregation of bipolar disorder and severe unipolar depression is at least partly due to genetic factors Despite converging evidence on its clinical validity, what has been termed "bipolar II disorder," with its requirement of discrete episodes of hypomania, has proven to be a diagnosis on which it is difficult to achieve good agreement between clinicians (13), mainly because hypomanic symptoms frequently fail to cluster in the way presumed by the diagnostic criteria that are drawn from our concept of manic episodes. Akiskal and Pinto (14) have claimed that there is a substantial proportion of unipolar patients whose mood disorder shows bipolar affinity and that such patients occupy a large terrain between the extremes of classic unipolarity and bipolarity. To address this diagnostic conundrum, he and his colleagues have proposed a number of discrete syndromes characterized by decreasing severity of mania/hypomania under a rubric of "bipolar spectrum." We agree with Akiskal and Pinto that there are large numbers of so-called unipolar patients who exhibit mild hypomanic symptoms; however, we argue that the field would benefit from a unitary and continuous approach to the assessment of both manic/hypomanic and depressive symptoms. On the basis of this unitary conceptualization of mood disorders, we hypothesized that patients with recurrent major depression without discrete lifetime hypomanic episodes would nonetheless report lifetime hypomanic/manic symptoms and that the number of lifetime hypomanic/manic symptoms would be related to the number of lifetime depressive symptoms. Finally, we hypothesized that manic/hypomanic symptoms would be associated with indicators of greater severity of depression. We tested these hypotheses in 223 patients with mood disorders who were administered a structured clinical interview for the spectrum of mood disorders (15). This instrument focuses on lifetime manic and depressive symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes and "temperamental" features related to affective dysregulation.

METHOD

STUDY

GROUP

The study group was drawn from a larger cross-sectional study, ABSTRACT described in detail by Fagiolini et al. (15) and conducted at nine METHOD Italian academic departments (Pisa, Messina, Milan, Modena, RESULTS Naples, Parma, Rome, Sassari, and Turin). In the full study, four DISCUSSION CONCLUSIONS groups of subjects were recruited: inpatients and outpatients with REFERENCES recurrent unipolar depression, inpatients and outpatients with bipolar I disorder (all of whom were currently in treatment in one of the nine departments), gastrointestinal outpatients at these same sites, and university students. Exclusion criteria were age <18 years, substance abuse, and current depressive or manic episodes. Eligible subjects of both genders were assessed initially through a clinical interview, and the resulting diagnoses were subsequently required to be confirmed by the Mini International Neuropsychiatric Interview (16). All subjects were Caucasian and Italian speaking. The patient groups included 117 subjects with recurrent unipolar depression who had recently achieved a partial or complete remission of an index episode of major depression and had no history of hypomanic episodes and 106 subjects with bipolar I disorder who had recently achieved a partial or complete remission of an index episode of major depression or mania. The comparison groups consisted of 139 university students and 114 patients being treated for gastrointestinal problems. To be included in the study, the subjects in the two comparison groups had to be without any current psychiatric diagnosis but could have a lifetime mood disorder. Eight students and nine patients with gastrointestinal problems had experienced a major depressive, manic, or hypomanic episode in the past. The group size was determined to test, by using analysis of variance (ANOVA) and post hoc pairwise comparisons between groups, the primary study hypotheses (15) that 1) bipolar patients would endorse more manic/hypomanic spectrum items than depressed patients and comparison subjects and 2) unipolar and bipolar patients would endorse more depressive spectrum items than each of the comparison groups at alpha=0.016 and a power of 80%. The present article reports secondary analyses conducted on the two patient groups. A total of 51% of the bipolar I disorder and 73% of the recurrent unipolar depression groups were women. Mean age in the two groups was, respectively, 43.7 years (SD=12.4) and 48.7 years (SD=13.9). The ethical committee of the University of Pisa approved the study procedures. All subjects entering the protocol provided written informed consent after receiving a complete description of the study and having the opportunity to ask questions.

TOP

INSTRUMENTS
Structured Clinical Interview for the Spectrum of Mood Disorders.

The Structured Clinical Interview for the Spectrum of Mood Disorders was developed simultaneously in English and Italian by capitalizing on the long-standing clinical experience of Italian and American psychiatrists and psychologists, including several of the

authors. It consists of 140 items coded as present or absent for one or more periods of at least 35 days throughout the subjects lifetime. For some questions, such as exploring temperamental features or the occurrence of specific events (for instance, suicide attempts), the duration is not specified because it would not be applicable. Items are organized into manic/hypomanic and depressive components as well as a section that assesses disturbances in rhythmicity and vegetative functions, yielding a total of seven domains. The rhythmicity and vegetative functions domain consists of 23 items, the energydepressed functions consist of nine items, the energy-manic functions of 12 items, the mood-depressed functions of 22 items, the mood-manic functions of 28 items, the cognition-depressed functions of 26 items, and the cognition-manic functions of 20 items. Symptoms are assessed by groups of statements arranged by increasing severity. For instance, suicidality is explored by questions asking whether the subject has ever experienced periods of 35 days or more when he or she 1) felt like life was not worth living, 2) hoped to die, 3) wanted to die, and 4) made suicide plans and two questions asking (5) whether he or she actually made a suicide attempt and (6) whether medical attention was required after the attempt. At the end of each domain, one question probes whether the symptoms explored caused significant impairment. The number of energy-, mood-, and cognition-depressed items endorsed by subjects makes up the "depressive component" (57 items), and the mood-, energy-, and cognition-manic items form the "manic component" (60 items). The structure of the instrument, defined a priori by the investigators on the basis of face validity, was examined by using confirmatory factor analysis, which confirmed the expected structure (P. Rucci, personal communication). The reliability of the interview proved to be excellent (15): the interrater reliability of domains ranged between 0.93 and 0.94, and the internal consistency of domains ranged between 0.79 and 0.92. In terms of discriminant validity, the mood patients had significantly higher total and domain scores than the comparison subjects, and the bipolar patients had significantly higher scores on the manic component than the patients with recurrent depression.
The Mini International Neuropsychiatric Interview.

The Mini International Neuropsychiatric Interview is a brief structured interview designed conjointly by American and European psychiatrists to diagnose axis I disorders as well as antisocial personality disorder according to DSM-IV and ICD-10 criteria. For the purposes of this study, we used the three sections of the instrument exploring current or past episodes of major depression, suicidal ideation, and current or past mania or hypomania episodes. The Mini International Neuropsychiatric Interview has been shown to be reliable in multicenter clinical trials and in epidemiological and clinical studies and is administered in a median of 15 minutes (16).

STATISTICS
The Kolmogorov-Smirnov statistic was used to test the normality of the frequency distributions of the mood scores. Pearson product-moment correlation coefficients were used to analyze the association among continuous variables. Logistic regression models were fit to analyze the relationships between the number of manic/hypomanic symptoms and some indicators of the severity of depression in the recurrent unipolar depression patients and the bipolar I disorder patients. Bonferroni correction to the alpha level

(0.05/2=0.025) was performed to adjust for multiple testing in the logistic regression. All statistical analyses were performed with SPSS, version 10.0 (SPSS, Inc., Chicago, 2000).

TOP ABSTRACT METHOD RESULTS DISCUSSION CONCLUSIONS REFERENCES

RESULTS
The mean number of mood spectrum items endorsed by the patients with recurrent unipolar depression and the patients with bipolar I disorder was 64.8 and 83.7, respectively (maximum=140) (Table 1 ). The frequency distribution of the depressive component was essentially overlapping and normal in the recurrent unipolar depression patients and the bipolar I disorder patients, while the frequency distribution of the manic/hypomanic component was normal among the bipolar patients and significantly skewed to the right among the patients with recurrent unipolar depression (Kolmogorov-Smirnov test=1.4, p=0.03).

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Table 1. Scores on the Structured Clinical Interview for the Spectrum of Mood Disorders of 117 Patients With Recurrent Depression and 106 Patients With Bipolar I Disorder

The correlation between lifetime depressive and manic component scores was similar in the bipolar I disorder (r=0.45, p<0.001) and recurrent unipolar depression (r=0.40, p<0.001) patients. An alternative way to show this relationship is to plot the mean depressive and

manic component scores versus the depressive-plus-manic score. As the latter increases, the two components increase almost linearly, both in patients with bipolar I disorder and in patients with recurrent unipolar depression (Figure 1 ). Thus, the number of depressive items endorsed, measured on a continuum, is related to the number of manic/hypomanic items endorsed. To further explore this issue, we selected psychotic and suicidality items as indicators of the severity of depression in the Structured Clinical Interview for the Spectrum of Mood Disorders. Four of these indicators, including paranoid ideation, auditory hallucinations, and suicide attempts, were significantly more common in the lifetime experience of patients with bipolar I disorder than in the patients with recurrent unipolar depression (Table 2 ). We investigated the relationship between the number of manic/hypomanic items and these indicators of the severity of depression separately in the groups with recurrent unipolar depression and bipolar I disorder by using logistic regression models. To this purpose, we combined the four indicators of suicidality and the four indicators of paranoid ideation into two composite indicators and then dichotomized these indicators as no/any symptom of suicidal ideation and no/any symptom of paranoid ideation. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of paranoid and suicidal ideation (Table 3 ). For example, we found that for each manic/hypomanic item endorsed, the likelihood of suicidal ideation was increased by 4.2% (odds ratio=1.042, 95% confidence interval 1.006 1.079, p<0.03). This odds ratio corresponds to a 42% increase in risk of suicidal ideation for a 10-item difference in the number of manic/hypomanic symptoms endorsed. Consistent with this result, we found that even the current level of suicidal risk (coded as none, low, moderate, or high in the Mini International Neuropsychiatric Interview) increased significantly with the number of lifetime mania/hypomania items endorsed (ANOVA: F=3.8, df=2, 114, p<0.03). Moreover, an earlier onset of the first depressive episode was significantly correlated with a higher number of manic/hypomanic items (r=0.32, p<0.01). Neither gender nor the number of depressive episodes was related to the number of manic/hypomanic items endorsed, the number of depressive items endorsed, or the total score on the Structured Clinical Interview for the Spectrum of Mood Disorders. To characterize the profile of manic/hypomanic features endorsed by the patients with recurrent unipolar depression, we summarized the 12 items endorsed with a frequency equal to or higher than 40% by the patients with recurrent unipolar depression (Table 4 ).

Figure 1. Relation of Scores on the Depressive and Manic Components of the Structured Clinical Interview for the Spectrum of Mood Disorders to the Combined DepressivePlus-Manic Score for 117 Patients With Recurrent Unipolar Depression and 106 Patients With Bipolar I Disorder

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Table 2. Frequency of Endorsement of Psychotic and Suicidality Items From the Structured Clinical Interview for the Spectrum of Mood Disorders by 117 Patients With Recurrent Depression and 106 Patients With Bipolar I Disorder

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Table 3. Effect of Number of Manic/Hypomanic Symptoms on Odds of Endorsing Suicidal or Paranoid Ideation for 117 Patients With Recurrent Unipolar Depression and 106 Patients With Bipolar I Disordera

window]

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Table 4. Mania/Hypomania Items From the Structured Clinical Interview for the Spectrum of Mood Disorders Endorsed by 40% of 117 Patients With Recurrent Unipolar Depression

In bipolar I disorder patients, the number of lifetime manic/hypomanic items endorsed was related to the endorsement of lifetime experiences of paranoid ideation and suicidal ideation (Table 3 ). The number of lifetime depressive episodes was not associated with the number of manic/hypomanic items endorsed, the number of depressive items endorsed, or the total score on the Structured Clinical Interview for the Spectrum of Mood Disorders. Women endorsed more depressive spectrum items than men (mean=39.1, SD=9.9, versus mean=34.9, SD=9.6) (t=2.2, df=100, p<0.05).

TOP ABSTRACT METHOD RESULTS DISCUSSION CONCLUSIONS REFERENCES

DISCUSSION

We investigated the lifetime mood spectrum characteristics of a large group of patients with recurrent unipolar depression or bipolar I disorder by using the Structured Clinical Interview for the Spectrum of Mood Disorders. Symptoms such as paranoid ideation, auditory hallucinations, and suicide attempts were significantly more frequent in bipolar patients than in unipolar patients, which is in line with findings from the literature (17). Of note, there was a linear relationship between the number of lifetime manic/hypomanic items and the number of depressive items endorsed by both the patients with bipolar I disorder and those with recurrent unipolar depression. In addition, in the patients with recurrent unipolar depression, the more manic/hypomanic items endorsed, the greater the likelihood of reporting suicidal ideation and delusions. This latter result corroborates the observation that the presence of even mild manic symptoms may change a depressive presentation into a mixed presentation and increase the likelihood of psychotic symptoms (18). Our results, indicating that the number and severity of depressive features experienced by any given mood disorder patient are related to the extent of the manic/hypomanic symptom that he or she has experienced in his or her lifetime, are in line with those of Goldberg et al. (19). They also reported that by the 15-year follow-up, 27% of the patients hospitalized for unipolar major depression eventually developed one or more distinct episodes of hypomania, and 19% had at least one episode of mania. They also showed that patients with psychotic depression are more likely than nonpsychotic patients to develop subsequent mania or hypomania at follow-up. Although psychotic symptoms were more common in the patients with bipolar I disorder, the endorsement of symptoms such as "feeling as if others were causing all of your problems," "feeling surrounded by hostility," and auditory hallucinations were related to increasing levels of mania/hypomania both in recurrent unipolar depression patients and in bipolar I disorder patients. In recurrent unipolar depression patients, an earlier onset of illness was associated with a higher frequency of endorsement of manic/hypomanic symptoms, which confirms our expectations based on the present literature (20). Although this latter result seems to foreshadow that among patients with recurrent unipolar depression, an increasing number of manic/hypomanic symptoms correlates with a higher risk of recurrences, we did not find such an association. One explanation for this seemingly paradoxical finding is the range restriction in the number of depressive episodes (median=3) in the study group, resulting from the conservative inclusion criteria we adopted. Indeed, we selected patients with two or more depressive episodes and no hypomanic episodes, therefore excluding patients with single episodes and bipolar II patients. Still, evidence from a study contrasting a large group of patients with pure unipolar depression, hyperthymic unipolar depression, bipolar I disorder, and bipolar II disorder (21) indicates that the number of depressive episodes is not significantly increased in patients with hyperthymic unipolar depression (mean=4.1) versus pure unipolar depression (mean=3.7). Cumulatively, our empirical findings support a continuous view of the mood spectrum as a unitary phenomenon that is best understood from a longitudinal perspective. Our data suggest that unipolar disorder and bipolar disorder are not two discrete and dichotomous phenomena but that mood fluctuationsup and downare common to both conditions, as

emphasized by Koukopoulos et al. (22). Indeed Swann (23), espousing the parsimonious Kraepelinian view, conceptualized recurrent affective disorders as one illness in which the apparently different bipolar and unipolar course may be determined by increased sensitization after the occurrence of a manic episode. Using a different term, Ghaemi et al. (7) proposed a view of the "affective spectrum" that spans the single depressive episode and bipolar I disorder to accommodate nonclassical parts of the bipolar spectrum, such as type II, not otherwise specified, and cyclothymia. The implications of a unitary approach to mood disorders are not only nosographic. We believe that clinical attention should be paid to sporadic manic/hypomanic manifestations in treatment planning and the prognosis of recurrent unipolar depression. Our data suggest that manic/hypomanic features, as Judd and Akiskal (24) have argued, are not "benign" because they are associated with increased lifetime and current suicidality. Our findings are in line with the results of their recent reanalysis of Epidemiologic Catchment Area data that also emphasize how even subsyndromal manic symptoms are associated with increased service use for mental health problems and the need for welfare and disability benefits. However, it must be acknowledged that only a long-term prospective follow-up study of patients assessed with the Structured Clinical Interview for the Spectrum of Mood Disorders early in their course of illness could confirm the utility of this kind of evaluation. The present study has a number of limitations. First, the Structured Clinical Interview for the Spectrum of Mood Disorders does not provide information on the frequency of occurrence of individual symptoms but only inquires whether symptoms did or did not occur for a period of at least 35 days in the subjects lifetime. Thus, the relationship we found between the number of manic/hypomanic and depressive items does not imply anything about the co-occurrence or sequence of these experiences. Also, given that the instrument assesses symptoms and behaviors retrospectively, there might be a recall bias. In this article, we assumed that the bias does not differentially affect the recall of manic/hypomanic and depressive spectrum features. Finally, caution should be used in interpreting the results because of their preliminary nature. Further analyses conducted on separate samples since the submission of this article confirmed all of the findings we report here.

CONCLUSIONS

We agree with Akiskal and Pinto (14) that a true understanding of TOP the continuum between unipolarity and bipolarity should be ABSTRACT grounded on clinical observation. On the other hand, we argue that METHOD clinical observation should be structured into an instrument with RESULTS sound psychometric properties, allowing for comparison between DISCUSSION individuals and across groups. The Structured Clinical Interview for CONCLUSIONS REFERENCES the Spectrum of Mood Disorders seems to be promising for such purposes because it provides clinicians with a conceptual frame of reference and operational criteria for diagnosing mood spectrum psychopathology and for testing research hypotheses in the context of an instrument with good psychometric properties. With this spectrum assessment, we showed that the presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional dichotomy of unipolar-bipolar disorder and bridges the gap between these two categories of mood disorders. Long-term prospective follow-up studies of patients assessed with the Structured Clinical Interview for the Spectrum of Mood Disorders early in their course of illness are warranted to confirm the utility of this kind of evaluation.

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REFERENCES
1. Keller MB, Lavori PW, Rice J, Coryell W, Hirschfeld RMA: The persistent risk of chronicity in recurrent episodes of nonbipolar major depressive disorder: a prospective follow-up. Am J Psychiatry 1986; 143:2448[Abstract/Free Full Text] 2. Judd LL: Major depressive disorder: longitudinal symptomatic structure, relapse and recovery. Acta Psychiatr Scand 2001; 104:8183[Medline] 3. Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, Solomon DA, Leon AC, Keller MB: A prospective investigation of the natural history of the longterm weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60:261269[Abstract/Free Full Text]

4. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser JD, Solomon DA, Leon AC, Rice JA, Keller MB: The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59:530 537[Abstract/Free Full Text] 5. Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, Coryell W, Warshaw M, Turvey C, Maser JD, Endicott J: Multiple recurrences of major depressive disorder. Am J Psychiatry 2000; 157:229233[Abstract/Free Full Text] 6. Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin FK: Is bipolar disorder still underdiagnosed? are antidepressants overutilized? J Affect Disord 1999; 52:135144[Medline] 7. Ghaemi SN, Ko JY, Goodwin FK: The bipolar spectrum and the antidepressant view of the world. J Psychiatr Practice 2001; 7:287297 8. Blacker D, Tsuang MT: Contested boundaries of bipolar disorder and the limits of categorical diagnosis in psychiatry. Am J Psychiatry 1992; 149:1473 1483[Abstract/Free Full Text] 9. Kendler KS, Gardner CO Jr: Boundaries of major depression: an evaluation of DSM-IV criteria. Am J Psychiatry 1998; 155:172177[Abstract/Free Full Text] 10. Angst J: The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 1998; 50:143151[Medline] 11. Duffy A, Grof P, Robertson C, Alda M: The implications of genetic studies of major mood disorders in clinical practice. J Clin Psychiatry 2000; 61: 630 637[Medline] 12. McGuffin P, Katz R: The genetics of depression and manic-depressive disorder. Br J Psychiatry 1989; 155:294304[Abstract/Free Full Text] 13. Widiger TA, Frances AJ, Pincus HA (eds): DSM-IV Sourcebook. Washington, DC, American Psychiatric Association, 1995 14. Akiskal HS, Pinto O: The soft bipolar spectrum: footnotes to Kraepelin on the interface of hypomania, temperament and depression, in Bipolar Disorders. Edited by Marneros A, Angst J. Dordrecht, the Netherlands, Kluwer Academic, 2000, pp 3762 15. Fagiolini A, DellOsso L, Pini S, Armani A, Bouanani S, Rucci P, Cassano GB, Endicott J, Maser JD, Shear MK, Grochocinski VJ, Frank E: Validity and reliability of a new instrument for assessing mood symptomatology: the Structured Clinical Interview for Mood Spectrum (SCI-MOODS). Int J Methods Psychiatr Res 1999; 8:7182

16. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC: The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(suppl 20):2233 17. Mitchell PB, Wilhelm K, Parker G, Austin MP, Rutgers P, Malhi GS: The clinical features of bipolar depression: a comparison with matched major depressive disorder patients. J Clin Psychiatry 2001; 62:212216[Medline] 18. DellOsso L, Placidi GF, Nassi R, Freer P, Cassano GB, Akiskal HS: The manic depressive mixed state: familial, temperamental and psychopathologic characteristics in 108 female inpatients. Eur Arch Psychiatry Clin Neurosci 1991; 240:234239[Medline] 19. Goldberg JF, Harrow M, Whiteside JE: Risk for bipolar illness in patients initially hospitalized for unipolar depression. Am J Psychiatry 2001; 158:1265 1270[Abstract/Free Full Text] 20. Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Keller M, Warshaw M, Clayton P, Goodwin FK: Switching from "unipolar" to bipolar II: an 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 1995; 52:114123[Abstract/Free Full Text] 21. Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G: Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J Affect Disord 1992; 26:127140[Medline] 22. Koukopoulos A, Sani G, Koukopoulos AE, Girardi P: Cyclicity and manic depressive illness, in Bipolar Disorders. Edited by Marneros A, Angst J. Dordrecht, the Netherlands, Kluwer Academic, 2000, pp 315334 23. Swann AC: "A two-illness model of bipolar disorder"RT Joffe, LT Joung, and GM McQueen: a commentary. Bipolar Disord 1999; 1:3841[Medline] 24. Judd LL, Akiskal HS: The prevalence and disability of bipolar spectrum disorders in the US population: reanalysis of the ECA database taking into account subthreshold cases. J Affect Disord 2003; 73:123131[Medline]

Focus 2005 American Psychiatric Association

3:69-75

(2005)

INFLUENTIAL PUBLICATION

The Impact of Medical Comorbidity on Acute Treatment in Major Depressive Disorder

Dan V. Iosifescu, M.D., Andrew A. Nierenberg, M.D., Jonathan E. Alpert, M.D., Megan Smith, B.A., Stella Bitran, B.A., Christina Dording, M.D., and Maurizio Fava, M.D.

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ABSTRACT
Objective: The authors investigated the impact of medical comorbidity on the acute phase of antidepressant treatment in subjects with major depressive disorder. Method: A total of 384 outpatients meeting DSM-III-R criteria for major depressive disorder enrolled in 8week open treatment with fluoxetine, 20 mg/day. The authors used the Cumulative Illness Rating Scale to measure the burden of medical comorbidity and the 17-item Hamilton Rating Scale for Depression to assess changes in depressive symptoms. The outcome measures were response to treatment ( 50% reduction in score) and clinical remission (score 7 at the end of the trial). Results: Compared to responders to fluoxetine, nonresponders had significantly higher Cumulative Illness Rating Scale scores and a greater number of Cumulative Illness Rating Scale categories were endorsed. Compared to subjects who achieved remission with antidepressant treatment, those who did not achieve remission had significantly higher Cumulative Illness Rating Scale scores and a greater number of Cumulative Illness Rating Scale categories were endorsed (i.e., more organs were affected by medical illness). The final Hamilton depression scale score was directly correlated with the total Cumulative Illness Rating Scale score and the number of Cumulative Illness Rating Scale categories endorsed. Conclusions: The total burden of medical illness and the number of organ systems affected by medical illness had a significantly negative predictive value for clinical outcome in the acute phase of treatment in major depressive disorder.

(Reprinted with permission from the American Journal of Psychiatry 2003; 160:2122 2127[Abstract/Free Full Text])

For decades, the diagnosis and treatment of depressed patients with comorbid medical illness have been controversial (1, 2). Early investigators of depression in persons with medical comorbidity judged the depression to be "reactive," i.e., a psychological consequence of having an illness and to have a less severe clinical course (3). More recently, several studies aimed at assessing the medical and social impact of major depressive disorder associated with comorbid medical illness. Most researchers have focused on the association of major depressive disorder with specific medical problems: coronary artery disease (4), congestive heart failure (5), myocardial infarct (6, 7), stroke (8), diabetes (9, 10), cancer (11), autoimmune diseases, Parkinsons disease, and dementia (12). When analyzing the overall impact of medical illness on patients with major depressive disorder, the presence of comorbid medical illness was found to be associated with a higher prevalence of major depressive disorder (1315). Other investigators found that comorbid medical illness is a risk factor for major depressive disorder (1618). However, in other studies, the severity of baseline medical comorbidity in patients with major depressive disorder did not correlate with severity of depression (19). Does the presence of comorbid medical illness have an impact on the outcome of antidepressant treatment? To this important clinical question, the answers to date have been mixed. The presence of medical comorbid disease has been associated with lower recovery rates (20) and greater chronicity of depression (21, 22). However, other researchers have reported that patients with chronic physical illness respond to antidepressants as well as those without such illness (23, 24). In the current study, we investigated further the role of comorbid medical illness on severity of depression and antidepressant treatment outcome in subjects with major depressive disorder. We hypothesized that subjects with major depressive disorder and medical comorbidity would experience more severe symptoms of depression and lower rates of response and remission compared with subjects with major depressive disorder with no medical comorbidity.

METHOD

This study was conducted at the Depression Clinical and Research ABSTRACT Program at Massachusetts General Hospital between 1992 and 1999 METHOD (25). A total of 380 subjects between the ages of 18 and 65 were RESULTS recruited through advertisements and clinical referrals in the first phase DISCUSSION REFERENCES of open-label fluoxetine treatment in a clinical study. The primary goal of the first phase was to establish prospectively nonresponse to fluoxetine. In a second phase of the study, nonresponders to fluoxetine were randomly assigned to several augmentation strategies; the results were reported elsewhere (25). Subjects were enrolled from the general population and not from a medical setting. All subjects met criteria for major depressive disorder, diagnosed by the physician-administered Structured Clinical Interview for DSM-III-RPatient Version (26). The subjects were required to have a score of 16 on the modified 17-item Hamilton Rating Scale for Depression (27) at the screening visit. Written consent was obtained from all study participants. The exclusion criteria for this study included women of child-bearing potential who were not using medically accepted means of contraception (i.e., an IUD or barrier device but not birth control pills) and women who were lactating or pregnant, had a serious suicidal risk, or a serious medical illness that was not stabilized, such as hospitalization for treatment of that illness that was likely within the next 2 weeks. Criteria also included having a seizure disorder, a history of organic mental disorders, substance use disorders, including alcohol, that were active within the last year, schizophrenia, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, mood congruent or incongruent psychotic features, or antisocial personality disorder. Subjects were also excluded if they had a history of multiple adverse drug reactions or an allergy to fluoxetine, concurrent use of psychotropic drugs, hypothyroidism, or depression that had failed in the past to respond to 6080 mg/day of fluoxetine, to a combination of fluoxetine and lithium, or to a combination of fluoxetine and desipramine. Subjects were also excluded who failed to respond to treatment during the current episode of major depressive disorder to at least one adequate antidepressant trial (e.g., 6 weeks or more of treatment with imipramine, 150 mg/day, or a monoamine oxidase inhibitor, 60 mg/day), or had a Hamilton depression scale score <16 at the screen visit or at visit 1. At the screening visit, the study physicians generated for each subject (meeting DSM-III-R criteria for major depression) a list of all existing and past medical illnesses, detailed by organ systems, and a list of current and past treatments. Each subject underwent physical examinations and screening laboratory tests. The results of these procedures and any subsequent medical workups were also incorporated in the list of medical illnesses. A trained physician (D.V.I.) reviewed the charts of all patients enrolled in the trial blind to treatment outcome and assigned a score on the Cumulative Illness Rating Scale, ranging from 0 to 4 for each of 13 organ systems, mental health excluded. The Cumulative Illness Rating Scale (28, 29) is a comprehensive recording of all comorbid diseases of a patient. It classifies comorbidities by 14 organ systems affected and rates them

TOP

according to their severity from 0 to 4. Within each category, when two diseases are present, the disease with the higher score is counted. A score of 0 represents "no problem," 1="current mild or past significant problem," 2="moderate disability requiring first-line treatment," 3="uncontrollable chronic problems or significant disability," and 4="end-organ failure requiring immediate treatment." For this study, we never assigned a score of 4, since the presence of severe/emergent medical conditions was an exclusion criterion. We generated four ratings for each patient, according to the instructions of the Cumulative Illness Rating Scale: total score, number of categories endorsed, severity index (total score/number of categories endorsed), and number of categories at level 3. The 17-item Hamilton depression scale was administered six times during the study (at screening, baseline, then every other week). We measured clinical improvement as percent of change in Hamilton depression scale score, response to treatment (defined as a 50% reduction in score from baseline to the end of trial), and clinical remission (defined as a score 7 for the last two visits of the trial). We used multiple logistic regression to test whether any of the four Cumulative Illness Rating Scale scores measuring the burden and severity of baseline medical comorbidity could predict treatment response or remission after adjusting for patient age, gender, and baseline Hamilton depression scale score. Multiple linear regressions were used to test the correlation between baseline Cumulative Illness Rating Scale score and initial, final, and percent change in Hamilton depression scale score, after adjustment for the patient age and gender. In all of our analyses, we used the last observation carried forward.

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RESULTS
Out of 384 patients, 210 (54.7%) were female. The mean age was 39.8 years old (SD=10.5); 95 subjects (24.7%) had no comorbid medical illness (i.e., their Cumulative Illness Rating Scale score was 0). The mean total Cumulative Illness Rating Scale score was 1.90 (SD=1.86). The mean number of endorsed categories was 1.62 (SD=1.41). The mean Cumulative Illness Rating Scale severity index for this population was 1.14 (SD=0.32). Table 1 presents the clinical characteristics of our patient group and the distribution of those characteristics by burden of medical illnesses (Cumulative Illness Rating Scale score).

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Table 1. Characteristics of Groups of Depressed Patients With Different Scores on the Cumulative Illness Rating Scale

Both clinical response to fluoxetine treatment and clinical remission with treatment were significantly correlated with the total Cumulative Illness Rating Scale score and the number of organ systems affected by medical illness (number of categories endorsed). Compared to responders to fluoxetine, nonresponders had significantly higher Cumulative Illness Rating Scale scores, even when adjustments were made for age, gender, and baseline Hamilton depression scale score (2.17 versus 1.68) (logistic regression coefficient=0.13; 2=4.72, df=3, p=0.03). The odds ratio was 0.88, with a 95% confidence interval (CI) between 0.78 and 0.99 (i.e., there was a 12.5% decrease in the chance of achieving response for each additional point on the total burden of disease subscale of the Cumulative Illness Rating Scale). Nonresponders also had a higher number of Cumulative Illness Rating Scale categories endorsed, adjusted for age, gender, and baseline Hamilton depression scale score (1.82 versus 1.47) (logistic regression coefficient=0.17; 2=4.18, df=4, p<0.05). The odds ratio was 0.85, with a 95% CI between 0.72 and 0.99 (i.e., there was a 15.2% decrease in the chance of achieving response for each additional organ system affected by comorbid medical illness). Similarly, after adjustment for age, gender, and baseline Hamilton depression scale score, subjects who achieved remission with antidepressant treatment had significantly lower Cumulative Illness Rating Scale scores than those not achieving remission (1.55 versus 2.10) (logistic regression coefficient=0.16; 2=5.74, df=4, p<0.02). The odds ratio was 0.85, with a 95% CI between 0.74 and 0.97 (i.e., there was a 15% decrease in the chance of remission for each additional point on the total Cumulative Illness Rating Scale score, measuring burden of disease). Subjects achieving remission also had a lower number of organ systems affected by medical illness (1.35 versus 1.79 categories endorsed) (logistic regression coefficient=0.22; 2=6.50, df=4, p<0.02). The odds ratio was 0.80, with a 95% CI between 0.68 and 0.95 (i.e., there was a 19.8% decrease in the chance of achieving remission for each additional organ system affected by comorbid medical illness). The initial severity of depression (Hamilton depression scale score) was not significantly correlated with the total Cumulative Illness Rating Scale score (linear regression coefficient=0.05; t=1.83, df=3, p<0.07), or the number of categories endorsed (linear

regression coefficient=0.04; t=1.92, df=3, p<0.06). However, after we adjusted for age and gender, the final Hamilton depression scale score was directly correlated with the total Cumulative Illness Rating Scale score (linear regression coefficient=0.03; t=2.33, df=3, p=0.02) and the number of organ systems affected by any comorbid medical illness (number of categories endorsed) (linear regression coefficient=0.02; t=2.25, df=3, p<0.03). As presented in Table 2 , Table 3 , and Table 4 , neither of the two Cumulative Illness Rating Scale scores measuring the severity of medical comorbidity (severity index and number of categories scored as 3) correlated with any of the clinical outcome measures (remission, recovery, and percent improvement in baseline or final Hamilton depression scale scores). Our study group had low scores for severity of medical illness: the mean Cumulative Illness Rating Scale severity index was 1.14 (SD=0.32), and the mean number of Cumulative Illness Rating Scale categories scored as 3 was 0.014 (SD=0.116). The majority of our subjects had stable chronic illnesses (scored as 1 or 2 on the Cumulative Illness Rating Scale). Only six subjects had medical disorders scored as 3 on the Cumulative Illness Rating Scale ("uncontrollable chronic problems or significant disability").

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Table 2. Logistic Regression Data for Prediction of Response to Treatment in 384 Depressed Patients After Treatment, Adjusted for Age, Gender, and Baseline Hamilton Depression Scale Score

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Table 3. Logistic Regression Data for Prediction of Remission in 384 Depressed Patients After Treatment, Adjusted for Age, Gender, and Baseline Hamilton Depression Scale Score

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Table 4. Linear Regression Data for Correlation of Depression Severity With Cumulative Illness Rating Scale Score in 384 Depressed Patients, Adjusted for Age and Gender

We used multiple logistic regression analysis to test whether medical illness in any of the 13 organ systems defined by the Cumulative Illness Rating Scale could predict treatment response or remission, after adjustment for age and gender. Only illnesses of the genitourinary system appeared significantly correlated with antidepressant treatment response (logistic regression coefficient=0.68; 2=5.34, df=13, p<0.03). No organ system was significantly correlated with remission status. Also, in multiple linear regression, no organ system was correlated with percent improvement in Hamilton depression scale scores (results not shown).

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DISCUSSION
In this large group of subjects with major depressive disorder, both response to fluoxetine treatment and clinical remission were significantly related to the burden of comorbid medical illness (Cumulative Illness Rating Scale scores) and the number of organ systems involved (number of categories endorsed). Also, subjects with a higher burden of medical comorbidity and greater number of organ systems involved had significantly higher

Hamilton depression scale scores (more severe depression) at the end of treatment. This is an important result, and shows that medical comorbidity can have a significant negative impact on outcome of acute treatment of depression. We did not find a correlation between the other measures of severity of medical comorbidity and clinical outcome (remission, recovery, or percent improvement of Hamilton depression scale scores). This is likely because of the low rates of severe medical illness in our study population. Our findings suggest that the overall burden of medical disease, rather than just a few specific diseases, is correlated with lower rates of remission or recovery in the acute phase of antidepressant treatment in major depressive disorder. This finding is consistent with other reports in the literature (30). Keitner and colleagues (20) found that patients whose depression was compounded by medical or psychiatric illness had lower rates of recovery than patients with pure depression (28% versus 51% at 6 months). Evans and co-workers (31, 32) presented the results of treatment with fluoxetine or placebo for a group of 62 elderly patients with major depressive disorder, 43 of whom were diagnosed with "serious physical illness" (i.e., cardiac or respiratory disease rated as moderate or severe). Although the primary analysis was a comparison between fluoxetine and placebo treatment, the tables presented results that subjects with major depressive disorder and serious physical illness had a significantly lower rate of response at 8 weeks than subjects without serious physical illness (39.5% versus 58.9%) (p<0.01). Restricting the comparison to the subjects treated with fluoxetine yielded no statistically significant difference because of the low numbers of subjects (19 subjects with serious physical illness versus 10 subjects without serious physical illness). More recently, in a group of 671 elderly subjects with major depressive disorder who were treated with multiple antidepressants, Oslin et al. (33) found that medical comorbidity, as measured with the medical illness checklist (34), predicted more severe symptoms of depression at the 3-month follow-up. The total burden of medical illness was significantly correlated (odds ratio=0.86, 95% CI=0.790.94; p=0.01), with lower rates of remission from depression at the 3-month follow-up. However, other studies are not consistent with our findings. In a large (N=671) group of depressed older patients, Small and collaborators (23) found no difference in the rates of response to antidepressants between subjects with and without chronic physical illness. However, patients were only followed for 6 weeks in their study, which may explain the lack of separation in response rates between subjects with and without chronic physical illness. Papakostas et al. (24) also reported that Cumulative Illness Rating Scale scores at baseline did not significantly predict treatment response in patients with treatment-resistant depression who were treated with nortriptyline. But for patients with treatment-resistant depression, the additional impact of medical comorbidity on treatment response may be less discernible than in our group without treatment-resistant depression. Our study was not designed to answer questions regarding the mechanism by which medical illness affects clinical response in major depressive disorder. There are, however,

several hypotheses. Ciechanowski and collaborators (34) postulated that the relationship between medical illness and depressive symptoms may be mediated by factors such as selfcare, nutrition, and adherence to treatment. Pharmacokinetic or pharmacodynamic properties of antidepressants may be changed in the context of comorbid medical illness or concurrent medications (35). Another hypothesis involves the role of cytokines, nonantibody proteins released by cells on contact with antigens. Cytokine levels are higher in a variety of infectious and noninfectious illnesses that involve activation of the immune system. Examples of chronic, noninfectious diseases associated with increased levels of cytokines include coronary artery disease (36, 37), hypertension (38), other vascular atherosclerosis (39), chronic obstructive pulmonary disease (40), diabetes (41), and arthritis and autoimmune diseases (42). Further observations have shown that administration of cytokines such as interleukin 2, tumor necrosis factor, or interferon alpha may induce depressive symptoms (42, 43). The increased production of cytokines has further impact on cortisol production and on the hypothalamic-pituitary-adrenal axis. Also, antidepressants have been shown to reduce the immune response and suppress cytokine production (42, 44). However, the association between cytokine production and response rates in major depressive disorder is still unproven. Our study has several limitations. First, since our subjects had low rates of severe medical illness, we cannot generalize our results to populations of severely medically ill subjects. Second, since our results compare response rates of a fixed dose of fluoxetine (20 mg/day), we cannot exclude the possibility that subjects with medical comorbid illness would have a greater rate of response at higher doses of fluoxetine. Third, although the Cumulative Illness Rating Scale has been used before for the measurement of the burden of medical illness in depressed subjects (45, 46), it is unclear if it is the best instrument for this purpose. The Cumulative Illness Rating Scale has been largely used in clinical series to rate medical comorbidity, and it has good interrater and test-retest reliability (47). However, since we do not understand fully the impact of medical illness on depression outcome, we do not know if comorbid diseases should be given equal weight (as in the Cumulative Illness Rating Scale) or if certain diseases and organ systems should be given more weight in calculating the burden of medical disease. Further studies are needed to elucidate the complex relationship between the burden of medical illness and the outcome of treatment in major depression. In conclusion, in this large group of patients with major depression treated with fluoxetine, the total burden of comorbid medical illness and the number of organ systems affected by medical illness had a significant negative prognostic value on clinical response and remission in the acute phase of antidepressant treatment with fluoxetine.

REFERENCES

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12. Reichman WE, Coyne AC: Depressive symptoms in Alzheimers disease and multi infarct dementia. J Geriatr Psychiatry Neurol 1995; 8:96 99[Abstract/Free Full Text] 13. Wells KB, Golding JM, Burnam MA: Psychiatric disorder in a sample of the general population with and without chronic medical conditions. Am J Psychiatry 1988; 145:976981[Abstract/Free Full Text] 14. Crum RM, Cooper-Patrick L, Ford DE: Depressive symptoms among general medical patients: prevalence and one-year outcome. Psychosom Med 1994; 56:109 117[Abstract/Free Full Text] 15. Patten SB: Long-term medical conditions and major depression in the Canadian population. Can J Psychiatry 1999; 44:151157[Medline] 16. Koenig HG, Meador KG, Cohen HJ, Blazer DG: Depression in elderly hospitalized patients with medical illness. Arch Intern Med 1988; 148:1929 1936[Abstract/Free Full Text] 17. Koenig HG, Meador KG, Shelp F, Goli V, Cohen HJ, Blazer DG: Major depressive disorder in hospitalized medically ill patients: an examination of young and elderly male veterans. J Am Geriatr Soc 1991; 39:881890[Medline] 18. Ganzini L, Smith DM, Fenn DS, Lee MA: Depression and mortality in medically ill older adults. J Am Geriatr Soc 1997; 45:307312[Medline] 19. Coulehan JL, Schulberg HC, Block MR, Madonia MJ, Rodriguez E: Treating depressed primary care patients improves their physical, mental, and social functioning. Arch Intern Med 1997; 157:11131120[Abstract/Free Full Text] 20. Keitner GI, Ryan CE, Miller IW, Kohn R, Epstein NB: 12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression). Am J Psychiatry 1991; 148:345 350[Abstract/Free Full Text] 21. Akiskal H: Factors associated with incomplete recovery in primary depressive illness. J Clin Psychiatry 1982; 43:266271[Medline] 22. Swindle RW, Cronkite RC, Moos RH: Risk factors for sustained nonremission of depressive symptoms: a 4-year follow-up. J Nerv Ment Dis 1998; 186:462 469[Medline] 23. Small GW, Birkett M, Meyers BS, Koran LM, Bystritsky A, Nemeroff CB (Fluoxetine Collaborative Study Group): Impact of physical illness on quality of life and antidepressant response in geriatric major depression. J Am Geriatr Soc 1996; 44:12201225[Medline]

24. Papakostas GI, Petersen T, Iosifescu DV, Roffi PA, Alpert JE, Rosenbaum JF, Fava M, Nierenberg AA: Axis III disorders in treatment-resistant major depressive disorder. Psychiatry Res 2003; 118:183188[Medline] 25. Fava M, Alpert J, Nierenberg A, Lagomasino I, Sonawalla S, Tedlow J, Worthington J, Baer L, Rosenbaum JF: Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol 2002; 22:379387[Medline] 26. Spitzer RL, Williams JBW, Gibbon M, First MB: Structured Clinical Interview for DSM-III-RPatient Version (SCID-P). New York, New York State Psychiatric Institute, Biometrics Research, 1989 27. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278296[Medline] 28. Linn BS, Linn MW, Gurel L: Cumulative Illness Rating Scale. J Am Geriatr Soc 1968; 16:622626[Medline] 29. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, Mulsant B, Reynolds CF III: Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41:237248[Medline] 30. Popkin MK, Callies AL, Mackenzie TB: The outcome of antidepressant use in the medically ill. Arch Gen Psychiatry 1985, 42:11601163[Abstract/Free Full Text] 31. Evans M, Hammond M, Wilson K, Lye M, Copeland J: Placebo-controlled treatment trial of depression in elderly physically ill patients. Int J Geriatr Psychiatry 1997; 12:817824[Medline] 32. Evans M, Hammond M, Wilson K, Lye M, Copeland J: Treatment of depression in the elderly: effect of physical illness on response. Int J Geriatr Psychiatry 1997; 12:11891194[Medline] 33. Oslin DW, Datto CJ, Kallan MJ, Katz IR, Edell WS, TenHave T: Association between medical comorbidity and treatment outcomes in late-life depression. J Am Geriatr Soc 2002; 50:823828[Medline] 34. Ciechanowski PS, Katon WJ, Russo JE: Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med 2000, 27; 160:32783285 35. DeVane CL: Metabolism and pharmacokinetics of selective serotonin reuptake inhibitors. Cell Mol Neurobiol 1999; 19:443466[Medline]

36. Gottsater A, Forsblad J, Matzsch T, Persson K, Ljungcrantz I, Ohlsson K, Lindgarde F: Interleukin-1 receptor antagonist is detectable in human carotid artery plaques and is related to triglyceride levels and Chlamydia pneumoniae IgA antibodies. J Intern Med 2002; 251:6168[Medline] 37. Stenvinkel P, Heimburger O, Jogestrand T: Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 2002; 39:274 282[Medline] 38. Cottone S, Mule G, Amato F, Riccobene R, Vadala A, Lorito MC, Raspanti F, Cerasola G: Amplified biochemical activation of endothelial function in hypertension associated with moderate to severe renal failure. J Nephrol 2002; 15:643648[Medline] 39. van der Meer IM, de Maat MP, Bots ML, Breteler MM, Meijer J, Kiliaan AJ, Hofman A, Witteman JC: Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study. Arterioscler Thromb Vasc Biol 2002; 22:838842[Abstract/Free Full Text] 40. Reid PT, Sallenave JM: Cytokines in the pathogenesis of chronic obstructive pulmonary disease. Curr Pharm Des 2003; 9:2538[Medline] 41. Woodman RJ, Watts GF, Puddey IB, Burke V, Mori TA, Hodgson JM, Beilin LJ: Leukocyte count and vascular function in Type 2 diabetic subjects with treated hypertension. Atherosclerosis 2002; 163:175181[Medline] 42. Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R, Shavit Y, Ovadia H, Weidenfeld J, Morag A, Newman ME, Pollmacher T: Illness, cytokines, and depression. Ann NY Acad Sci 2000; 917:478487[Medline] 43. Meyers CA: Mood and cognitive disorders in cancer patients receiving cytokine therapy, in Cytokines, Stress and Depression. Edited by Danzer R, Wollman EE, Yirmiya R. New York, Kluwer Academic/Plenum, 1999, pp 7581 44. Danzer R, Wollman E, Vitkovic L, Yirmiya R: Cytokines and depression: fortuitous or causative association. Mol Psychiatry 1999, 4:328332[Medline] 45. Lyness JM, Caine ED, Conwell Y, King DA, Cox C: Depressive symptoms, medical illness, and functional status in depressed psychiatric inpatients. Am J Psychiatry 1993; 150:910915[Abstract/Free Full Text] 46. Alexopoulos GS, Meyers BS, Robert YC, Kalayam B, Kakuma T, Gabrielle M, Sirey JA, Hull J: Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry 2000; 57:285290[Abstract/Free Full Text]

47. Extermann M: Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 2000; 35:181200[Medline]

Focus 2005 American Psychiatric Association

3:76-82

(2005)

INFLUENTIAL PUBLICATION

The Course of Depression in Elderly Patients

Timothy I. Mueller, M.D., Robert Kohn, M.D., Nina Leventhal, B.A., Andrew C. Leon, Ph.D., David Solomon, M.D., William Coryell, M.D., Jean Endicott, Ph.D., George S. Alexopoulos, M.D., and Martin B. Keller, M.D.

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

ABSTRACT
Objective: Studies on the course of major depressive disorder (MDD) among elderly persons are limited to short periods of follow-up, seldom provide comparisons with younger cohorts, and raise other methodological concerns. Methods: Utilizing 15 years of prospective data from the NIMH Collaborative Depression Study, the authors examined the index episode of MDD and the time until first observed recurrence in those who recovered for subjects in four age-groups defined by age at intake: 1730, 3150, 5164, and 6579 years. Assessments were conducted every 6 months for 5 years and annually thereafter. Survival analysis examined time until recovery and time to first recurrence. Results: Median time-to-recovery was similar for the four groups. Median time-to-first recurrence was significantly shorter for oldest versus the 5164-year-old group but not the two other groups. The oldest age-group was distinguished from the younger groups by being more likely to be divorced/widowed/separated, to have primary depression, and to have a history of medical illness, particularly cardiovascular disease or cancer. There was no difference in the generally low levels of pharmacotherapy prescribed during the index episode or the subsequent well interval. Conclusions: Elderly patients with MDD may have a greater risk

of recurrence than younger individuals. Low levels of treatment characterize the somatic treatment in all the study subjects, regardless of age-group. (Reprinted with permission from the American Journal of Geriatric Psychiatry 2004; 12:2229[Medline])

A national crisis in geriatric mental health care is looming because of the anticipated growth of the population of people over the age of 65 (1). Research on major depressive disorder (MDD) in geriatric psychiatry has lagged behind that of younger adults. The need to better address issues regarding MDD is highlighted by evidence suggesting that the point prevalence for those over the age of 65, 4.4% in women and 2.7% in men, is considerably higher than estimates from earlier epidemiological studies (24). Although MDD is highly prevalent, our knowledge about the long-term course of this disorder in elderly patients is limited, and only a few studies have examined this issue prospectively beyond 2 years. Also, less is known about how the course of MDD in elderly patients differs from that of younger adults (5). Much of the literature published between the years 1955 and 1994, on the course of MDD among elderly patients age 60 and older, with study sample sizes of at least 20 and a minimum follow-up over 12 months, was reviewed in a metaanalysis (6). Cole and Bellavances review raised serious methodological concerns about many of those studies. None of the studies described their referral patterns. Few studies defined criteria for assignment into categories of recovered or not. Most of the studies did not use systematic assessment or follow-up. The follow-up periods were typically 1 year, which limits the knowledge about the subsequent course. Many of the hospital- or clinic-based studies provided short-term follow-up data of 24 months or less (714), and six had follow-up over 2 years, but none longer than 4 years (1520). Among those six reports, 27.3% of the depressed elderly patients were well at the end of follow-up; 32.5% had a recurrence after recovery; and 14.2% remained continuously ill. Three of the five community-based studies (2125) were longer than 2 years, reporting 19% of the depressed elderly patients as being well and 27.0% remaining continuously ill (2325). Since that review, several other investigators using the criteria suggested by Cole and Bellavance have examined this issue in treated samples (2634). Only two clinically-based studies were greater than 12 months in duration. Alexopoulos et al. (27) examined recovery in individuals over the age of 63 during a 2-year period and found that 29% did not recover. Stek et al. (33) obtained follow-up data on 155 individuals discharged from a psychiatric hospital with a diagnosis of MDD; of those still living 6 to 8 years after the index episode, only 33% were described as doing well. A number of additional studies have been based on community samples, examining the course of depression in elderly patients. Three studies ranging from 2.6 to 5 years of follow-up with depressed subjects found that the rate of recovery ranged from 46% to 57% (2931). The Longitudinal Aging Study, Amsterdam has

provided data on 6 years of follow-up of a cohort of 277 depressed subjects older than 55 years (34). This study found that 32% had a severe chronic course, and 44% had a fluctuating course, on the basis of the Center for Epidemiological StudiesDepression scale (CESD) as a measure of severity and the Diagnostic Interview Schedule to confirm diagnosis. Few of these studies have included a younger cohort as a comparison group. Meats et al. (11) found that the proportion of those who were well at the end of 12 months was higher in elderly patients. Brodaty et al. (16) found that, compared with a younger group, recovery rates among depressed elderly patients continued to rise during the 45 months of follow-up. Tuma (26) and Alexopoulos et al. (27) also noted a similar outcome between older and younger patients. Our report relies on the strengths of the Collaborative Depression Study (CDS), which includes specified recruitment criteria, a wide range of subject ages, systematic assessment using standardized and well accepted instruments, up to 15 years of follow-up, and frequent short-interval prospective interviews, to examine the course of MDD in elderly patients. This study overcomes many of the methodological issues raised by earlier reviews. We examined the course of the index episode of MDD and the well period in those who recovered and the treatment received in subjects divided into four groups on the basis of their age at intake: 1730, 3150, 5164, and 6579 years of age.

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

METHODS SUBJECTS
Between the years 1978 and 1981, a total of 955 patients who sought psychiatric treatment for a major mood disorder at one of five academic medical centers in the United States (Boston, Chicago, Iowa City, New York City, and St. Louis) were entered into a prospective, observational follow-up study, the NIMH Collaborative Study on the Psychobiology of Depression (CDS). This report examines the first 15 years of follow-up data on the 431 subjects who were diagnosed with MDD at intake and who also had no previous history of mania, hypomania, schizoaffective disorder, chronic intermittent depressive disorder, or minor depression of at least 2 years duration at intake. Since the

subjects age 65 and over, who are the focus of this report, were all inpatients, we further limited the sample to only subjects who were recruited from the inpatient setting in order to limit sources of bias. This resulted in a subsample that numbered 332 subjects. We obtained written informed consent from the subjects after they received a complete description of the study.

ASSESSMENTS
The details of the assessment procedures are described elsewhere (35, 36). All subjects were interviewed at intake by trained research staff using the Schedule for Affective Disorders and Schizophrenia (SADS) (37). This information was combined with medical records to make diagnoses according to Research Diagnostic Criteria (RDC) (38). RDC criteria for MDD are essentially identical to those for DSM-IV. We have maintained RDC diagnostic categories in the CDS to maintain consistency of method over the two decades of the project. In the RDC, the primary/secondary distinction is determined solely by the chronology of onset of the illness. Primary MDD in the RDC is defined according to the Feighner criteria, which state that MDD is primary as long as it began before any one of a defined list of non-affective disorders (39). After intake, subjects were interviewed every 6 months for the first 5 years with the Longitudinal Interval Follow-up Evaluation (LIFE) (40) and every year thereafter with the Streamlined Longitudinal Interval Continuation Evaluation (SLICE). These follow-up instruments assess the level of psychopathology for each RDC major affective disorder (major depression, mania, schizoaffective mania, schizoaffective depression) on a 6-point scale called the Psychiatric Status Rating (PSR) (36). A rating of 1 denotes no symptoms of the disorders, and a 6 denotes full diagnostic criteria, with psychosis or severe impairment. In these subjects with MDD, recovery from MDD is defined as beginning with the first of 8 consecutive weeks of no or minimal symptoms (PSR 1 or 2, respectively). Until recovery occurs, a subject remains in an episode of MDD, at a level of psychopathology ranging from PSR 1 to PSR 6. The continuous string of PSR scores for MDD lasting up to 780 weeks (15 years) is the source of data for these analyses on the course of illness.

TREATMENT
Weekly somatic antidepressant treatment was assessed retrospectively by the LIFE or SLICE. These detailed records of pharmacotherapy were combined by use of a 5-point summary scale called the Composite Unipolar Antidepressant (CAD) scale, which quantifies all antidepressant somatotherapy, including electroconvulsive (ECT) and pharmacotherapy (40). Equivalent dose ranges were established for each antidepressant. A CAD score of 0 means that no antidepressant somatic treatment was provided for that week. A CAD score of 1 is equal to a daily dose of 1 mg99 mg imipramine or its equivalent. A CAD score of 2 is equal to a 100 mg199 mg imipramine-equivalent; 3 equals 200 mg299 mg imipramine-equivalent; and 4 equals 300 mg-or-more imipramine-equivalent. The study protocol did not influence the treatment provided by the patients physician. We specifically looked at the extent of "adequate pharmacotherapy" during the intake episode and first prospectively-observed well period. "Adequate pharmacotherapy" was defined as receiving treatment at a CAD level of 2. Psychotherapeutic treatments were not systematically assessed and are not included in these analyses.

STATISTICAL

METHODS

The outcomes of interest in these analyses were time-to-recovery from the intake episode of MDD and subsequent time until the occurrence (prospectively observed) of any major affective disorder (MDD, mania, schizoaffective mania, or depression). The comparisons of interest were the findings in the subsample that was 6579 years of age at intake (N=32) compared with the three other age-groups (1730 [N=119], 3150 [N=118], and 5164 [N=63]). The number of subjects in each group who, after recovery from their index episode of MDD, experienced the occurrence of a non-MDD affective disorder is small (mania 1, 1, 2, 0; schizoaffective mania: 0, 0, 0, 0; schizoaffective depression: 1, 0, 0, 0, in the 1730, 3150, 5164, and 6579 age-groups, respectively). Survival analysis was used to analyze time until recovery from the intake episode and, in those who recovered, time to first prospectively-observed recurrence during the follow-up (41). In the case of the intake episode of MDD, the survival time represents the "time until recovery," defined as the number of consecutive weeks from intake into the study during which the subject continued to show symptoms of MDD. A survival interval terminated in one of two ways: 1) an episode resolved, or 2) no resolution of episode by the time of final assessment. The latter subjects were classified as censored in the survival analysis. The Kaplan-Meier product limit was used to estimate the cumulative probability of recovery or recurrence (42). Survival analysis accounts for varying lengths of follow-up and allows us to utilize all the data collected (43). However, the analyses make no attributions about the cause of loss to follow-up status, but assumes that it was independent of the event of interest (i.e., recovery or recurrence, respectively). Pearson chi-square and one-way analysis of variance (ANOVA) were used for univariate comparisons of the age-groups on clinical and demographic features. Where the data were ordinal categories (e.g., number episodes of MDD before intake) or failed a Levine test for homogeneity of variances, a Kruskal-Wallis chi-square test was utilized. A two-tailed alpha level of 0.05 was used for each statistical test. The post-hoc procedure described by Conover (44) was used for statistically significant Kruskal-Wallis tests, whereas Bonferroni-adjusted pairwise comparisons were used for significant chi-square and log-rank tests, and where the Bonferroni denominator was equal to the number of pairwise tests.

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

RESULTS

Table 1 details the clinical and demographic characteristics of the four groups. The elderly group was significantly more likely than the younger groups to be widowed, separated, or divorced, to have three or more previous episodes compared to the youngest group, to have primary MDD (as defined in RDC as occurring before the onset of any one of a specified list of non-affective disorders, such as phobic disorder or alcoholism), and to have a history of cardiovascular and oncologic illnesses.

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Table 1. Intake Clinical and Demographic Characteristics of Four Age Groups of Collaborative Depression Study Subjects

During the intake episode of MDD after entry into the study and during the first prospectively-observed well period, the proportion of subjects who received pharmacotherapy at a level CAD 2 (100 mg199 mg imipramine-equivalents) was quite low for all groups, with no statistically significant difference in the levels of treatment received (Table 2 ). These low levels of pharmacotherapy occurred in the context of a group of people who, as a whole, had a mean of five previous episodes of MDD.

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Table 2. Pharmacotherapy Characteristics of Collaborative Depression Study Subjects During Prospective Follow-Up

COURSE

OF

MAJOR

DEPRESSIVE

DISORDER

Figure 1 and Figure 2 , respectively, present the survival curves for time-to-recovery from intake episode and time-to-recurrence in those who recovered. The median times-torecovery for the four groups (shown in Figure 2 ) are similar (log-rank[3]=2.35; p=0.50): 1730-year-old group: 28 weeks (95% confidence interval [CI]: 1638 weeks); 3150-yearold group: 28 weeks (95% CI: 1145 weeks); 5164 year old group: 29 weeks (95% CI: 1147 weeks); and 6579 year old group: 12 weeks (95% CI: 123 weeks). For the subjects who recovered from the intake episode (N=106, 104, 50, and 25, in the respective agegroups), we analyzed the time to the first prospectively observed occurrence of a major affective disorder. The median time-to-recurrence was significantly different among groups (log-rank[3]=9.88; p<0.02): 1730-year-old group: 118 weeks (95% CI: 69167 weeks); 31 50-year-old group: 112 weeks (95% CI: 51173 weeks); 5164-year-old group: 293 weeks (95% CI: 64522 weeks); and 6579-year-old group: 90 weeks (95% CI: 29151 weeks). Post-hoc analyses revealed that the only statistically significant difference was between the 5164-year-old group and those 6579 years old (log-rank[1]=10.24; p<0.008), where the older group experienced a more rapid recurrence. Examination of Figure 1 and Figure 2 provides the proportion of subjects in the respective age-groups who remained continuously ill (Figure 1 ) or continuously well, once recovered (Figure 2 ), for the entire follow-up period.

Figure 1. Survival Analysis Curve of Time-UntilRecovery From Index Episode of Major Depression

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Figure 2. Survival Analysis Curve of Time-UntilRecurrence After Recovery From Index Episode of Major Depression

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TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

DISCUSSION
This study found that elderly patients, compared with younger groups, had a similar MDD course for time until recovery from the intake episode. However, older subjects experienced a recurrence after recovery more rapidly than the cohort of subjects between the ages of 51 and 64 years. Our study incorporates many of the criteria suggested by Cole and Bellavance (6) for prospective studies examining the course of MDDin elderly patients. The CDS offers the unique advantage of a long follow-up period relative to previous work. The CDS has specified selection criteria for entry into the study, minimum severity requirements, systematically applied assessment and follow-up, and clear definitions for assignment into categories of recovered or not. Outcome measures were based on specified criteria, and all somatic treatment was recorded. Despite these advances, the study was limited by the small sample of elderly subjects enrolled at intake; this also precluded a meaningful analysis of predictors of course. Since the study sample has aged since intake, future analyses will be able to incorporate greater numbers of elderly subjects, permitting us to examine clinical and demographic

characteristics as predictors of course. Furthermore, since the study was not originally designed to examine the outcome of depression in elderly patients, measures of activities of daily-living functioning and cognitive status were not included. Evaluations of these domains are planned to be included in future assessments. Using clinical samples that are not limited to first lifetime episode has been criticized because elderly individuals with multiple recurrences will have an increased chance of being included in the study; this bias was borne out in this report. In the future, as elderly patients sample size grows, we will be able to control for this bias by including it as a variable in our predictor analyses. We looked only at people who presented to academic medical centers for treatment of moderate-to-severe MDD, and they may not represent a general group of geriatric people with MDD. All subjects in this analysis, including the elderly group, received low levels of somatic antidepressant therapy. It has been shown that adequate treatment of elderly individuals with recurrent MDD markedly decreases the risk for recurrence and that long-term maintenance treatment is superior to placebo in reducing risk of recurrence (4547). These studies and ours suggest that the long-term outcome of MDD in elderly patients, as in younger adults, has a course characterized by recovery and recurrence. Whether or not optimal somatic and psychosocial treatments would ameliorate the course of this disorder in elderly patients cannot be answered by this study. Unfortunately, this study does not provide guidance for the clinician to make decisions about the approach to a specific patient; however, the evidence for a more rapid recurrence after recovery in elderly patients, compared with a younger control group, suggests that most elderly people with MDD, similar to those who are younger, will benefit from continued attention to their mood disorder even after apparent recovery.

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

REFERENCES
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30. Henderson AS, Korten AE, Jacomb PA, et al: The course of depression in the elderly: a longitudinal community-based study in Australia. Psychol Med 1997; 27:119129[Medline] 31. Livingston G, Watkin V, Milne B, et al: The natural history of depression and the anxiety disorders in older people: the Islington community study. J Affect Disord 1997; 46:225262 32. Janzing J, Teunisse R, Bouwens P, et al: The course of depression in elderly subjects with and without dementia. J Affect Disord 2000; 57:4954[Medline] 33. Stek ML, Van Exel E, Van Tilburg W, et al: The prognosis of depression in old age: outcome six to eight years after clinical treatment. Aging Ment Health 2002; 6:282 285[Medline] 34. Beekman AT, Geerlings SW, Deeg DJ, et al: The natural history of late-life depression: a six-year prospective study in the community. Arch Gen Psychiatry 2002; 59:605611[Abstract/Free Full Text] 35. Keller MB, Lavori PW, Lewis CE, et al: Predictors of relapse in major depressive disorder. JAMA 1983; 250:32993304[Abstract/Free Full Text] 36. Mueller TI, Keller MB, Leon AC, et al: Recovery after five years of unremitted major depressive disorder. Arch Gen Psychiatry 1996; 53:794 799[Abstract/Free Full Text] 37. Endicott J, Spitzer RL: A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1978; 35:837 844[Abstract/Free Full Text] 38. Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria: rationale and reliability. Arch Gen Psychiatry 1978; 35:773782[Abstract/Free Full Text] 39. Feighner JP, Robins E, Guze SB, et al: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 1972; 26:5763[Abstract/Free Full Text] 40. Keller MB, Lavori PW, Friedman B, et al: The Longitudinal Interval Follow-up Evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987; 44:540 548[Abstract/Free Full Text] 41. Kalbfleish JD, Prentice RL: The Statistical Analysis of Failure-Time Data. New York, NY, Wiley, 1980 42. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457481

43. Leon AC, Friedman RA, Sweeney JA, et al: Statistical issues in the identification of risk factors for suicidal behavior: the application of survival analysis. Psychiatry Res 1990; 31:99108[Medline] 44. Conover WJ: Practical Nonparametric Statistics, 2nd Edition. New York, Wiley, 1980 45. Flint AJ, Rifat SL: Maintenance treatment for recurrent depression in late life: a four-year outcome study. Am J Geriatr Psychiatry 2000; 8:112116[Medline] 46. Reynolds CF III, Frank E, Perel JM, et al: Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA 1999; 281:29 45[Free Full Text] 47. Alexopoulos GS, Myers BS, Young RC, et al: Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry 2000; 57:285 289[Abstract/Free Full Text]
Focus 2005 American Psychiatric Association 3:83-97 (2005)

INFLUENTIAL PUBLICATION

Toward a Comprehensive Developmental Model for Major Depression in Women

Kenneth S. Kendler, M.D., Charles O. Gardner, Ph.D., and Carol A. Prescott, Ph.D.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

ABSTRACT
Objective: Major depression is a multifactorial disorder with many etiologic variables that

are interrelated through developmental pathways. The authors used structural equation modeling to generate a developmental model for the etiology of major depression in women. Method: Data from 1,942 adult female twins, interviewed up to four times over a 9-year period, were used to construct a developmental model to predict depressive episodes in the year before the most recent interview. Eighteen risk factors in five developmental tiers were considered: 1) childhood (genetic risk, disturbed family environment, childhood sexual abuse, and childhood parental loss), 2) early adolescence (neuroticism, self-esteem, and early-onset anxiety and conduct disorder), 3) late adolescence (educational attainment, lifetime traumas, social support, and substance misuse), 4) adulthood (history of divorce and past history of major depression), and 5) the last year (marital problems, difficulties, and stressful life events). Results: The best fitting model included six correlations and 64 paths, provided an excellent fit to the data, and explained 52% of the variance in liability to episodes of major depression. The findings suggest that the development of risk for major depression in women results from three broad pathways reflecting internalizing symptoms, externalizing symptoms, and psychosocial adversity. Conclusions: Major depression is an etiologically complex disorder, the full understanding of which will require consideration of a broad array of risk factors from multiple domains. These results, while plausible, should be treated with caution because of problems with causal inference, retrospective recall bias, and the limitations of a purely additive statistical model. (Reprinted wih permission from the American Journal of Psychiatry 2002; 159:1133 1145[Abstract/Free Full Text])

Major depression is a prototypical multifactorial disorder. An individuals probability of suffering from an episode of major depression is affected by many factors including predisposing genetic influences (13), exposure to a disturbed family environment (4, 5), childhood sexual abuse (6), premature parental loss (7), predisposing personality traits (8 10), early-onset anxiety or conduct disorder (1113), dysfunctional self-schemata (14), exposure to traumatic events and major adversities (1518), low social support (19), substance misuse (12), marital difficulties (20), a prior history of major depression (2123), and recent stressful life events and difficulties (24, 25). Several influential reviews have emphasized the importance of combining these diverse risk factor domains into an integrated etiologic model (e.g., references 2628). However, few studies have addressed the etiologic complexity that is likely realistic for major depression. Furthermore, an important goal of such models is the elucidation of the developmental pathways through which the risk factors lead to illness (29). In 1993, we published a preliminary step in this direction that used data from two waves of interviews in our ongoing longitudinal study of female-female twin pairs ascertained from the Virginia Twin Registry (30). We expand here on our previous effort by utilizing

improved statistical methods and a broader array of risk factors assessed in two additional waves of personal interviews.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

METHOD SAMPLE
The data used in this report derive from an ongoing study of Caucasian twin pairs from the Virginia Twin Registry (31, 32)a population-based register formed from a review of all birth certificates in the Commonwealth of Virginia. Female-female twin pairs born during 19331972 were initially ascertained through a questionnaire (termed FFQ) mailed to female twin pairs in the Registry in 19871988, the response to which was ~64% (N=2,354). Twins were then interviewed face-to-face in 19881989 (FF1 interview), at which time the refusal rate was ~12%. These twins completed three more telephone interviews in 19901991 (FF2), 19921994 (FF3), and 19951997 (FF4), with cooperation rates ranging from 85%93%. This report is based on data for the 1,942 twins who completed at least two interview waves, including FF4. At the FF4 interview, these subjects were a mean age of 35.8 years (SD=8.2) and had a mean of 14.3 years (SD=2.2) of education. The subjects mean time from the FF1 interview to the FF4 interview was 7.1 years (SD=1.6). To assess test-retest reliability, 190 randomly selected twins were reinterviewed a mean of 4.3 weeks (SD=1.5) after their initial interview. In addition, in 19901991, at the time of the FF2 interviews, we attempted to interview face-to-face all living biological parents of the twin pairs and succeeded in interviewing 90.2% of those who were alive and traceable (N=1,632).

OUTCOME

VARIABLE

Our goal in this model was to predict episode onset of major depression in the last year. Major depression was treated as a dichotomous variable with an assumed underlying normal liability distribution. In the FF4 interview, all twins were asked about the occurrence, at any time in the last year, of 15 individual symptoms that reflected all elements of criterion A for major depressive episode in DSM-III-R. They were then asked to aggregate these symptoms in time, to report the total number of episodes experienced and to give dates, to the nearest month, for the onset and offset of each episode. For the purposes of this study, we counted the first reported episode that met DSM-III-R criteria for

major depression unless there were multiple episodes and the first episode began in the first 2 months of the year before the interview. In that case, we counted the next reported episode.

MODEL

VARIABLES

The selection of variables began with those that had been used in our 1993 study (30), which was based on data collected at FFQ, FF1, and FF2. Several of these variables could be improved with new information obtained in later waves. We had also collected information on several key variables lacking in our earlier model, especially childhood sexual abuse, conduct disorder, and substance misuse. Finally, we included other variablesbased on the literature and their availability in our datato expand the domains examined (e.g., self-esteem to include a "self-concept" variable and early-onset anxiety because of its strong demonstrated link to risk for subsequent major depression [11]). Our final list included 18 predictor variables that we attempted to order in a tentative developmental sequence. For ease of presentation, we organized these predictors into five "tiers" that roughly approximated five developmental periods: 1) childhood (genetic risk, disturbed family environment, childhood sexual abuse, and childhood parental loss), 2) early adolescence (neuroticism, self-esteem, and early-onset anxiety and conduct disorder), 3) late adolescence (educational attainment, lifetime traumas, social support, and substance misuse), 4) adulthood (history of divorce and past history of major depression), and 5) the last year (marital problems, difficulties, and stressful life events that were either dependent on or indepen-dent of the respondents own behavior). Of these 18 predictor variables, five were latent and were constructed, by using a measurement model, from other observed variables. We here outline briefly the nature of each variable. Genetic risk was assessed by a composite measure of the lifetime history of major depression in the co-twin (assessed at FF1, FF3, and FF4) and in the mother and father (assessed in 19901991). Parents were divided into those who were affected and those who were unaffected. Co-twins were divided into four categories reflecting the number of interviews at which they received a diagnosis of lifetime major depression. To correct for varying base rates and degree of genetic relatedness in these relatives, we calculated the modified midrank score for the lifetime history of major depression and adjusted these scores to account for the varying genetic correlation with the proband twin (+1.00 for monozygotic co-twins and +0.50 for dizygotic co-twins and parents). We then took the mean of these three scores. Disturbed family environment was assessed by a measurement model with two manifest continuous variables: mean parental warmth (measured with a modified version of the Parental Bonding Instrument [33, 34]) and mean family environment score (measured by 14 items chosen from the Family Environment Scale [35]). The Parental Bonding Instrument assessed parent-child relationships up to when the twins were age 16. The Family Environment Scale reflected the general emotional tone of the home when the twins "were growing up." Mean parental warmth was calculated for each twin pair as the mean of the self-report and co-twin report of maternal and paternal warmth (assessed at FF2 and reversed-coded to reflect lack of warmth). For the family environment, we summed the

items reflecting family tension (e.g., "family members would get so angry sometimes that they would throw things or hit each other") and the reverse scoring of items reflecting family integration (e.g., "family members really helped and supported one another"). We then took the mean of the standardized scores of the twin and co-twin assessed at FF2 and the separately standardized score of mother and father assessed in 19901991. These four reports were then averaged and restandardized to create a single Family Environmental Scale score for the family. Childhood sexual abuse was a binary variable based on twin self-report at FF4 (36). Our previous analysis of these data (37) suggested that the increased risk of major depression was associated largely with the more severe forms of abuse. Therefore, in these analyses, twins were assigned a score of 1 if they reported, before the age of 16, an unwanted sexual contact with an older individual that included "touching or fondling your private parts," "making you touch them in a sexual way," or "attempting or having sexual intercourse." Validating the assessments of childhood sexual abuse is inherently problematic, but the agreement between self-report and co-twin-report in this sample far exceeded chance expectation (contingency coefficient=0.50, weighted kappa=0.40, 95% confidence interval [CI]=0.330.47). Parental loss was a binary measure scored 1 if the twin reported that one or both parents left the nuclear home due to death, divorce, or parental separation before the twin was age 17. This was assessed with high reliability (98.5% agreement between twins [38]). Neuroticism was assessed with a measurement model utilizing the short (12-item) version of the Revised Eysenck Personality Questionnaire (39) and data obtained at FFQ, FF1, and FF3. Because of the resulting J-shaped distribution, it was scored as a five-level ordinal measure. Self-esteem was assessed with a measurement model based on the full Rosenberg SelfEsteem Scale (40) by using data obtained at FF1 and FF3. Transformation was not needed because of the datas symmetric distribution. This variable was reversed so that higher scores reflected lower self-esteem. Early-onset anxiety disorder was a binary variable scored 1 for subjects with an onset before age 18 of panic disorder (data from FF1 or FF2), generalized anxiety disorder (data from FF1 or FF4), or phobia (data from FF1, FF2, or FF4). Panic disorder and generalized anxiety disorder were diagnosed with DSM-III-R criteria, except that we reduced the minimum duration of the latter disorder from 6 months to 1 month. Phobia was defined as the presence of an irrational fear that impacted in an objective and significant way on the behavior of the twin (41). Conduct disorder was treated as an ordinal variable that reflected the number of DSM-IV conduct disorder criteria met before age 18 that were endorsed at FF4. The number of years of education was treated as a continuous variable, scored from 1 to 20 at the FF4 interview. It was reverse-scored to reflect low educational attainment.

The measure of lifetime traumas was based on data from FFQ and reflected the number of 10 possible items describing traumatic events that had ever occurred in the respondents lifetime, including physical assault, unexpected death of a loved one, and abortion. The distribution was skewed so that this measure was treated as an ordinal variable. Social support was assessed by using a measurement model with information from the FF1 and FF3 interviews. We summed those dimensions of social support that related most strongly to risk for depression: problems with relatives and church and club attendance (30). This measure, which was scored to reflect lack of social support, was relatively symmetric and was treated as a continuous variable. Substance misuse was assessed with a measurement model derived from three binary manifest variables: 1) a lifetime diagnosis of DSM-III-R alcohol abuse or dependence assessed at FF3 or FF4, 2) a lifetime diagnosis of DSM-IV drug abuse or dependence at FF4 (separate assessments were made for cannabis, sedatives, stimulants, cocaine, opiates, hallucinogens, inhalants, and "over-the-counter" medications), and 3) lifetime nicotine dependence, assessed by a score of 7 on the Fagerstrom Tolerance Questionnaire (42) for the period of heaviest smoking, by using data collected at FF3 or FF4. Ever divorced was a binary measure scored 1 for women who reported a lifetime history of divorce at the FF1, FF3, or FF4 interviews. Never having been married was scored 0. Prior history of major depression was a binary measure reflecting the presence or absence of a lifetime history of DSM-III-R major depression prior to 1 year before the FF1 interview (at the mean age of 28 years). Marital problems in the last year was constructed as a three-level ordinal variable. In a piecewise regression that used seven items assessing the level of marital satisfaction in the last year from the Social Interaction Scale (43), an elevated risk for onset of major depression was associated with levels of satisfaction in the lower 20%. Those who were unmarried or not living with a partner at FF4 were assigned an intermediate risk. Thus, the variable was constructed as follows: 0=upper 80% of marital satisfaction, 1=unmarried, and 2=lower 20% of marital satisfaction. Difficulities in the last year, dependent stressful life events, and independent stressful life events were assessed by using our stressful life event measures. In the FF4 interview, each twin was systematically asked about the occurrence, at any time in the preceding 12 months, of 11 "personal" events (i.e., events occurring primarily to the informant): assault, divorce/separation, major financial problem, serious housing problems, serious illness or injury, job loss, legal problems, loss of confidant, serious marital problems, robbery, and serious difficulties at work. We also assessed four classes of "network" events: 1) serious trouble getting along with an individual in the network, 2) a serious personal crisis of someone in the network, 3) death of an individual in the network, and 4) serious illness of someone in the network. These events were presented separately for different relationships in their network (e.g., parents, siblings, offspring, etc.). Each reported event was dated to the nearest month with high interrater reliability (44, 45). The dependence of a stressful life event, reflecting the probability that the respondents own behavior contributed to the

stressful life event, was rated on a 4-point scale: clearly independent, probably independent, probably dependent, and clearly dependent, with demonstrated good interrater reliability (46). In these analyses, we dichotomized stressful life events into those clearly or probably independent versus those clearly or probably dependent. For an individual with a reported onset of major depression in the year preceding her FF4 interview, we counted, separately, the number of dependent and independent stressful life events occurring in that month and the 2 preceding monthsthe time period associated with an increased risk of depressive onset in this sample (45). If the only episode occurred in the first or second month of the year (N=14), the number of stressful life events reported was multiplied, respectively, by 3 or 1.5. For individuals reporting no depressive onset, a random 3-month window was used to assess the occurrence of stressful life events. The number of stressful life events was treated as an ordinal variable. Difficulties in the last year reflected the sum of all stressful life events reported at other times during the year before the FF4 interview.

STATISTICAL

METHODS

Our structural equation model consisted of two parts: 1) a measurement model that consisted of factor loadings for the observed variables that index the five latent variables and 2) a structural model that consisted of path and correlation coefficients connecting the five latent and the 14 observed variables of the model proper. Model fitting was done by using Mplus, version 2 (47), because of its ability to combine categorical, ordinal, and continuous data. The fit function was weighted least squares. As in most longitudinal studies, missing data were a major problem. Excluding data from all subjects for whom one or more data points were missing would have resulted in unacceptable sample shrinkage. Therefore, the raw data was first put through multiple imputation by using IVEware (48), which utilizes a multivariate sequential regression approach encompassing linear regression for continuous variables, Poisson regression for count variables (e.g., numbers of stressful life events, symptoms of conduct disorder), and logistic regression for ordinal and binary variables (49). Five imputed data sets were created and then combined for analysis in Mplus, each being treated as one group in a multigroup analysis. The measurement model was not constrained across groups, and we did not attempt to simplify it in any way. For the structural model, we began with a fully saturated model and used a combination of four approaches to produce a model with the optimal balance of explanatory power and parsimony. First, observing the significance levels of individual paths, we fixed sets of paths to zero when the associated z value was <1.96. Second, because our sample size was so large, some paths that remained significant were, in our judgment, too small to be meaningful. Therefore, our second step was to set all paths to zero with a value of <0.05, regardless of z value. In our third step, we further "trimmed" our model by setting paths to zero and looking for those where the increase in the model chi-square value was less than 3.84. As a last check, taking final results from an earlier iteration of the model, we added and subtracted a number of paths that were marginal by significance and/or magnitude to

see if we could arrive at a better overall fit and indeed produced a modest improvement in fit and explanatory power. We utilized three fit indices that reflect, in different ways, the success of the model in balancing explanatory power and parsimony: the Tucker-Lewis index (50), the comparative fit index (51), and the root mean square error of approximation (52). For the Tucker-Lewis index and comparative fit index, values between 0.90 and 0.95 are considered acceptable and values 0.95 as good. For the root mean square error of approximation, good models have values 0.05, while values >0.10 are considered poor.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

RESULTS MODEL FITTING

Of the 1,942 female twins who participated in the fourth interview wave, 176 (9.1%) reported a depressive episode meeting DSM-III-R criteria in the last year. The best fitting model predicting the occurrence of these episodes (fit to five replicates) produced a chisquare of 5,074.4 with 1,603 degrees of freedom. This model, which accounted for 52.1% of the variance in liability to major depression in the last year, produced the following fit indices: comparative fit index=0.951, Tucker-Lewis index=0.950, and root mean square error of approximation=0.033.

PARAMETER

ESTIMATES

As seen in Table 1 , the loadings of the different manifest measures on each of the five latent variables were similar, ranging from 0.73 to 0.87. The parameter estimates of the best-fit structural model are depicted in Figure 1 , and the expected correlations among the 19 variables are shown in Table 2 . We review the results of this model one variable at a time. In this model, the predicted path coefficients reflect the unique relationship between variables adjusting for all the other possible relationships through other parameters in the model.

View this table: [in this window] [in a new window]

Table 1. Mean Factor Loadings for Observed Measures of Five Latent Predictor Variables for an Episode of Major Depression in the Last Year in 1,942 Female Twinsa

Figure 1. Path and Correlation Estimates of the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twinsa a Two-headed arrows represent correlation coefficients, and one-headed arrows represent path coefficients or standardized partial regression coefficients. Latent variablesindexed by observed variables in a measurement modelare depicted in ovals, and observed variables are depicted in rectangles. All variables have estimated residual variance that is not depicted in the figure. See text for a description of each variable.

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Table 2. Correlation Matrix for Variables in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twinsa

window]

CHILDHOOD

RISK

FACTORS

Substantial interfactor correlations were seen between the four childhood risk factors. In particular, high genetic risk for major depression was associated with increased levels of disturbed family environment, childhood sexual abuse, and childhood parental loss. As seen in Figure 2 , high genetic risk for major depression was uniquely predictive of elevated levels of neuroticisma key "temperamental" risk factor for later depression substance misuse, and exposure to lifetime traumas and divorce. The level of genetic risk for major depression also uniquely predicted both a past history of major depression and the probability of a depressive episode in the last year.

Figure 2. Paths and Correlations Involving Genetic Risk for Major Depression in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twins

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A disturbed family environment uniquely predicted all four early adolescent risk factors, with the strongest effect on conduct disorder, followed by neuroticism (Figure 1 ). Disturbed family environment strongly predicted level of social support. Controlling for other variables in the model, disturbed family environment also increased the probability of

exposure to three "environmental" risk factors: lifetime trauma, marital problems in the last year, and difficulties in the last year. Childhood sexual abuse uniquely predicted three of the four early adolescent and three of the four late adolescent risk factors, with its strongest effects on conduct disorder and lifetime trauma. In addition, childhood sexual abuse was associated with both difficulties and independent stressful life events in the last year. Controlling for other variables in the model, childhood parental loss uniquely predicted only low educational attainment.

RISK

FACTORS

OF

EARLY

ADOLESCENCE

Neuroticism had a particularly strong relationship with low self-esteem and early-onset anxiety disorders. High levels of neuroticism also predicted low levels of social support and marital problems in the last year. After the two classes of stressful life events, neuroticism was the strongest predictor of risk of onset of major depression. Low self-esteem had a substantial influence on low educational attainment as well as predicting marital difficulties in the last year. Early-onset anxiety disorder increased the risk for conduct disorder, low social support, and substance misuse, as well as exposure to lifetime trauma and independent stressful events in the last year. Along with the measured genetic risk factors, early-onset anxiety disorder was the only variable to uniquely predict risk both for past history of major depression and for depressive episodes in the last year. Conduct disorder symptoms increased the risk for lifetime traumas, low social support and, especially strongly, substance use. In addition, a history of conduct disorder was a direct and independent risk factor for the onset of major depression in the past year.

RISK

FACTORS

OF

LATE

ADOLESCENCE

Low educational attainment uniquely predicted lifetime traumas, substance misuse, and the risk for divorce. Lifetime trauma also predicted divorce, past history of major depression, and difficulties and independent stressful life events in the last year. Low social support was a unique predictor only of substance misuse. Substance misuse, the most "connected" variable in the model, was the second strongest predictor of a history of major depression and predicted exposure to three "environmental" risk factors: history of divorce, last year difficulties, and dependent stressful life events.

ADULT

RISK

FACTORS

Ever being divorced and past history of major depression were both predicted by an array of upstream variables. Ever being divorced uniquely predicted only past history of major depression and last-year marital problems, while past history of major depression predicted last-year dependent stressful life events and risk for an episode of major depression in the last year.

LAST-YEAR

RISK

FACTORS

Our model included four measures of environmental adversity in the last year. Two represented difficulties and were not timed relative to episode onset. In contrast, two represented stressful life events that had to occur in temporal proximity to the onset of major depression. All four of these risk factors were uniquely related to risk for major depression, with the impact of events being stronger than difficulties.

EPISODE

OF

MAJOR

DEPRESSION

IN

THE

LAST

YEAR

As depicted in Figure 3 , the unique influences on risk for major depression are diverse and include genetic risk, three risk factors from early adolescence, past history of major depression, and all four last-year risk factors. Quantitatively, the three strongest risk factors were dependent and independent stressful life events in the last year and neuroticism.

Figure 3. Paths Involving Episode of Major Depression in the Last Year in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twins

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DISCUSSION

The goal of this report was to derive empirically an integrated, TOP developmental model for the etiology of major depression in women ABSTRACT that improved in several significant ways on the model presented in our METHOD previous report (30). Given the sample size and the complexity of our RESULTS model, its fit, as assessed by three different indices, was quite good. DISCUSSION These results suggested that we succeeded in our attempt to identify a REFERENCES model with a good balance of parsimony and explanatory power. It is relatively rare in the human behavioral literature to explain more than 50% of the variance for an outcome such as major depression, especially when it is assessed over as short an interval as 1 year.

METHODOLOGIC

LIMITATIONS

Our efforts should, however, be interpreted in the context of six potentially critical methodologic limitations. First, our analytic model assumed a causal relationship between predictor variables (at the top of arrows) and dependent variables (at the bottom of arrows). The probable validity of this assumption varies across our model. For example, the path from genetic risk to neuroticism could only plausibly go in one direction. By contrast, the relationship between low self-esteem and low educational attainment or between divorce and past history of major depression is likely bidirectional. In some instances, the temporal ordering of our assessments over the four waves of interviews provided some confidence in our causal assumptions. Furthermore, after the completion of our model, we experimented with shifting the order of variables. The overall fit of the model consistently declined, and little change was seen in path estimates. It is unlikely that our parameter estimates are far off because of assumptions of directions of causality. However, it is probable that in some parts of our model, intervariable relationships that we assume take the form of A B may be truly either A B or, more likely, A B. Second, some variables were assessed by long-term retrospective recall. Numerous studies have suggested that such data are subject to recall bias that is more likely to overestimate than to underestimate causal relationships (5355). Ideally, this study should have been done prospectively with a twin cohort followed from birth, but this strategy was not feasible. Within the limits of a longitudinal design beginning with a cohort in early to midadulthood, we did several things to minimize this problem. We combined reports across raters (including parents for the key variable of disturbed family environment), thereby reducing the impact of individual rater bias. Many variables were assessed in a prospective fashion, i.e., we asked about the variables during the interviews that occurred before the interview at which the prevalence of major depression in the last year was assessed. This strategy should have reduced some aspects of reporting bias. The reference period for several key variables was the last year, keeping the time frame of recall to a minimum. For stressful life events, individual dates were required, which may have improved recall. Three key variables (childhood parental loss, educational attainment, and history of divorce) were relatively objective and probably subject to less recall bias. Finally, many important variables such as neuroticism and social support were assessed at multiple waves, thereby reducing the bias expected from any one time of reporting.

Third, the models we employed assumed that multiple independent variables act additively and linearly in their impact on a dependent variable. This is unlikely to be true for the etiology of major depression (e.g., 24, 44, 56). Although we could have included interactions in our model, the analysis and subsequent interpretation of the very large number of such possible interactions among these variables is daunting. Fourth, the subjects consisted of epidemiologically sampled adult white female twins born in the Commonwealth of Virginia. We (57, 58) and others (59) have found that, with respect to the rates of psychopathology, including depressive symptoms and major depression, twins are representative of the general population. Furthermore, the 1-year prevalence of major depression in our study (mean=9.1%, SD=0.7%) is in the range of rates reported for women in two previous large U.S. national studies (5.0% [60] and 12.9% [61]) and nearly identical to that recently reported in a general population study of women in Norway (mean=9.7%, SD=0.9%) (62). It is likely that our sample is broadly representative of white North American and perhaps Northern European women. However, the results for men or women from other ethnic groups might differ substantially. Fifth, our model is likely to underestimate the impact of genetic factors on the etiology of major depression in two ways. First, our measure of genetic risk for major depression was indirect and did not incorporate the most powerful use of the twin modelthe direct comparison of correlations between monozygotic and dizygotic twins. Second, we did not include in our model the well-known genetic influences on neuroticism (63, 64), anxiety disorders (65), conduct disorder (66, 67), or substance use (32, 68, 69). Sixth, in the evaluation of direct paths to last-year depression, a model of this complexity has a built-in bias. Upstream variables, such as childhood risk factors, have many more possible indirect pathways to risk for major depression than do downstream variables. Thus, all other factors being equal, direct paths will tend to be weaker for upstream variables and become progressively stronger for downstream variables closer in the model to the depressive onsets.

SUMMARY

AND

IMPLICATIONS

OF

FINDINGS

These results, which strongly support previous work suggesting that major depression is a complex, multifactorial disorder, suggest three major pathways to major depression: internalizing (Figure 4 ), externalizing (Figure 5 ), and adversity (Figure 6 ). The internalizing pathway is anchored by two variables: neuroticism and early-onset anxiety disorders. The externalizing pathway is similarly anchored by two variables: conduct disorder and substance misuse. The adversity pathway is more extensive, beginning with the three childhood risk factors of disturbed family environment, childhood sexual abuse, and parental loss, flowing through low educational attainment, lifetime trauma, and low social support to ever divorced and then influencing all four last-year environmental risk factors. This last pathway might be better termed "adversity-interpersonal difficulties," as many of the depressogenic consequences of the earlier adversities appear to be in the realm of troubled interpersonal relationships.

Figure 4. Paths Reflecting a Broad Internalizing Pathway to Major Depression in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twins

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Figure 5. Paths Reflecting a Broad Externalizing Pathway to Major Depression in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twins

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Figure 6. Paths Reflecting a Broad Adversity/Interpersonal Difficulty Pathway to Major Depression in the Best-Fitting Model for Predicting an Episode of Major Depression in the Last Year in 1,942 Female Twins

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These three pathways are interlinked in four important ways. First, genetic risk factors for major depression contribute to all three pathways. Second, childhood adversities are strong risk factors for externalizing disorders. Third, externalizing disorders are substantial predictors for later adversity. Finally, to a more modest extent, internalizing variables also predispose to future adversity. Of the many points that could be emphasized in this rich set of results, we specifically comment on eight. First, this model illustrates the problem that in studying nuclear families, genetic and environmental risk factors for major depression are confounded. Substantial correlations were seen between measures of genetic risk and indices of childhood environmental adversity. Second, our model accounted for 52% of the variation in liability to onset of major depression in a 1-year period. Although this result reflects a high level of predictability for the behavioral sciences, it can be legitimately asked why the model did not account for more variance. One reason is that major depression was not diagnosed with perfect accuracy. In our short-term test-retest sample, the kappa coefficient (70) and the tetrachoric correlation for diagnosis of major depression were 0.60 (SD=0.09) and 0.86 (SD=0.06), respectively, suggesting that about 15% of the variance in liability to major depression was measurement error. Many of our predictor variables themselves contained error, and our list

of such variables was hardly exhaustive. For example, neuroticism and self-esteem are unlikely to capture fully the temperamental and cognitive substrates of liability to major depression. We had no measures of defense styles, coping strategies, or biological markers of vulnerability. Some of the unexplained variance in liability could result from interactions between risk factors that were not captured in our additive model. A year is a relatively short sampling period, and our predictability might increase if we examined a longer time period. Third, our results illustrate the probable intricacy of the "gene-to-phenotype" pathway for complex psychiatric disorders such as major depression. Of the nine paths from genetic risk factors in our model, three involved correlations with key childhood environmental adversities. These relationships could be mediated through the genotype of the parents or the genotype of the twin. In the former, parents of affected twins would, on average, have high liability to major depression, which would predispose directly to family discord and divorce. In the latter, the twins own childhood temperament, influenced by genetic factors, would directly contribute to familial disturbances. Two of the nine paths involve more unambiguously what we have previously termed "genetic control of exposure to the environment" (71), in which individuals at high genetic risk for major depression select themselves into lifetime traumas and divorce, which in turn increase the risk for depressive episodes. Consistent with prior work (72), one path suggests that genetic risk factors for major depression act in part by influencing personality. Substance misuse was also an important intervening variable between genes and major depression in our model. Finally, in addition to having an indirect influence on these pathways, genetic risk factors directly increase the probability for both prior and last-year episodes of major depression. Genetic factors were the only childhood risk factor to directly influence the latter outcome. Fourth, consistent with prior results (37), childhood sexual abuse in women had a unique, diverse, and substantial impact on a wide range of risk factors for major depression that could not be accounted for by the observed positive correlations with disturbed family environment, parental loss, or genetic risk. It is noteworthy that, unlike disturbed family environment, childhood sexual abuse uniquely contributed to lower educational attainment and substance misuse. Fifth, several negative results are worthy of comment. When the analysis controlled for level of neuroticism, low self-esteem was not a major predictor of other risk factors or of major depression itself. In this data set, stable negative self-schemata were not a potent unique risk factor for major depression. Neither educational status, used partly as a proxy for social class, nor social support had more than a modest and indirect effect on risk for major depression. Sixth, consistent with prior findings (11), early-onset anxiety disorder in women was a unique and potent risk factor for both past history and last-year major depression, independent of the trait neuroticism with which it was highly correlated. Given prior results in this sample, we were surprised that the final model did not include a direct path from genetic risk factors to early-onset anxiety. This path was present in early versions of the model, but in the reduced version it was subsumed into the indirect path from genetic risk to neuroticism to early-onset anxiety.

Seventh, as shown previously (30), in the prediction of episodes of major depression over short time periods, recent environmental adversity remained the strongest risk factor. However, the probability of exposure to stressful life events was in turn at least weakly predicted by a range of upstream variables in the model. Last, although several prior twin analyses with this sample showed no evidence for a familial-environmental contribution to the etiology of major depression (31, 73, 74), the present results suggest that a disturbed family environment may play an important role in the developmental cascade leading to depression. Two possible explanations for this apparent discrepancy are noteworthy. First, family environment in twin studies is defined as those environmental factors that impact on liability equally in both members of the twin pair. As Plomin and colleagues (75, 76) have pointed out, many aspects of the family are likely to impact differently on different children, either because one child is singled out or because the children react differently to the same stressor owing to differences in temperament or maturity. Furthermore, we found only modest twin concordance for childhood sexual abuse in this sample (37), suggesting that this key risk factor willfrom the perspective of twin modelingcontribute more to individual-specific than to familialenvironmental effects. Second, twin modeling for dichotomous traits with realistic sample sizes is a blunt tool. Power analyses showed that, in our female-female twin cohort, given the presence of substantial genetic effects, we could easily miss familial-environmental factors that could account for up to 20% of the variance in liability (77).

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

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Focus 2005 American Psychiatric Association

3:98-105

(2005)

INFLUENTIAL PUBLICATION

A Descriptive Analysis of Minor Depression

Mark Hyman Rapaport, M.D., Lewis L. Judd, M.D., Pamela J. Schettler, Ph.D., Kimberly Ann Yonkers, M.D., Michael E. Thase, M.D., David J. Kupfer, M.D., Ellen Frank, Ph.D., John M. Plewes, M.D., Gary D. Tollefson, M.D., Ph.D., and A. John Rush, M.D.

ABSTRACT

Objective: The authors provide a detailed clinical description of minor TOP depression: its symptoms, level of disability, stability, and relationship ABSTRACT to patient and family history of major depressive disorder. Method: METHOD Rigorous criteria for minor depression, including functional disability, RESULTS were used to identify 226 individuals for a three-phase treatment study. DISCUSSION This report presents data obtained on that study group during the first REFERENCES study phase, a 4-week placebo lead-in period. Results: One hundred sixty-two subjects (72% of the initial study group) remained in the study for 4 weeks and continued to meet criteria for minor depression. Minor depression in these subjects was primarily characterized by mood and cognitive symptoms, not the classical neurovegetative signs and symptoms of depression. Approximately one-third of the subjects with minor depression had a past history of major depressive disorder, and nearly half had a family history of unipolar depressive disorder; however, neither factor affected the severity or quality of minor depressive symptoms. Conclusions: These data suggest that 1) minor depression is not evanescent; 2) minor depression is characterized by mood and cognitive symptoms rather than neurovegetative symptoms; 3) minor depression may occur either independently of a lifetime history of major depressive disorder or as a stage of illness in the course of recurrent unipolar depressive disorder; and 4) depressive disorders should be conceptualized as a continuum of severity. (Reprinted with permission from the American Journal of Psychiatry 2002; 159:637 643[Abstract/Free Full Text])

The term "minor depression" has been used to describe depressive conditions that are not of sufficient severity and duration to meet criteria for a major depressive episode (16). DSMIII included a chronic form of minor depression as a diagnostic category (dysthymia), but minor depression lasting less than 2 years was folded in with atypical depression, identified as depressive disorder not otherwise specified in DSM-III-R. In DSM-IV, minor depressive disorder was identified as a potential diagnostic category that requires empirical validation. The proposed diagnostic criteria for minor depressive disorder required the presence of two to four symptoms of depression lasting for at least 2 weeks and excluded individuals with a previous history of major depressive disorder. Epidemiologic studies, primarily based on the Epidemiologic Catchment Area (ECA) and National Comorbidity Survey databases, document the prevalence, societal costs, functional disability, and long-term consequences of minor depression (39). Although investigators have used a variety of definitions and analytic strategies, the overarching findings from these studies are as follows: 1) Minor depression has a point prevalence rate of 2%5%. 2) Minor depression is associated with functional impairment and greater service utilization. 3) Minor depression is associated with a greater risk of developing major depressive disorder. 4) The presence of depressed mood or anhedonia (the "A criterion") is associated

with even greater dysfunction and risk of developing a future episode of major depressive disorder. 5) The greater the number of symptoms of depression, the greater the number of episodes, length of longest episode, degree of impairment, and likelihood of having a comorbid diagnosis and family history of psychiatric disorders. 6) Individuals with a history of major depressive disorder freely traverse between major depressive disorder, minor depression, and subsyndromal depressive symptoms (35, 814). The most common symptoms reported for individuals with minor depression in the ECA data set are recurrent thoughts of death, insomnia, feeling tired all the time, trouble concentrating, poor appetite, and feelings of worthlessness (4). These data, as well as analyses of other large data sets (15, 16), suggest that we need to broaden our conceptualization of depressive disorders. Kendler and Gardners 1998 longitudinal analysis of the Virginia Twin Registry (16) demonstrated that the presence of five or more symptoms of depression was not a more accurate harbinger of depression at 1year follow-up than the presence of three or four symptoms. Data from the NIMH Collaborative Study on Depression (15) demonstrated that, following an entry episode of major depressive disorder, patients spent an average of 58% of the weeks during the next 9 years experiencing major depressive disorder (15% of the weeks), minor depression (27% of the weeks), or subsyndromal depressive symptoms (16% of the weeks). The confluence of these findings suggests that there may be value in considering depression as a spectrum of disorders rather than a single categorical disorder. Despite considerable evidence of the prevalence and disability associated with minor depression, many questions remain. Is minor depression an evanescent phenomenon or an enduring and disabling condition? What is the nature of the relationship between minor depression and an individuals personal or family history of major depressive disorder? Do these factors influence the qualitative presentation of minor depression? In this article we address the following hypotheses: 1) Minor depression is not evanescent. 2) There is a strong family history of unipolar disorder associated with minor depression. 3) A substantial number of individuals with minor depression previously have had episodes of major depressive disorder. 4) Minor depression shares mood and cognitive symptoms with major depressive disorder but not the neurovegetative and reverse neurovegetative symptoms of depression. 5) One cannot differentiate individuals with minor depression from one another on the basis of past history of major depression or family history of depression.

METHOD

OVERVIEW

OF

THE

STUDY

Data for this report are derived from a comprehensive study of the diagnosis and treatment of minor depression. The study had three distinct phases: 1) an initial diagnostic evaluation followed by a 4week single-blind placebo lead-in period; 2) a 12-week double-blind, placebo-controlled treatment phase; and 3) a 24-week randomized crossover continuation phase. In-depth discussion of the acute and continuation treatment study design and results will be presented elsewhere.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

This descriptive report of minor depression is based on data from the placebo lead-in phase of the study. Demographic and clinical ratings presented here were obtained at the initial study visit. Data pertaining to the stability of symptoms and overall criteria for minor depression were obtained during the subsequent four weekly visits constituting the placebo lead-in period.

SUBJECT

RECRUITMENT

The subjects were recruited at three sites (University of California, San Diego; University of Pittsburgh; and University of Texas, Southwestern Medical Center) primarily by means of advertisements in local newspapers. Some subjects were referred to the study by psychiatrists and family practitioners in the local community. A few subjects entered the study through referral from subjects already involved in research at the institution. After telephone screening, subjects were invited in for a diagnostic evaluation. Subjects who were invited in for a diagnostic interview participated in the process of informed consent before this interview. Informed consent involved the subjects reviewing a written document describing the study with the principal investigators staff, who answered any questions before the subject signed the consent form. All subjects were at least 18 years of age, conversant in English, and willing to be available for participation in the 40-week study.

EVALUATION

OF

SUBJECTS

Measures used for the initial evaluation of subjects included the Structured Clinical Interview for DSM-IV (SCID) (17); the depression module of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) (18); the Medical Outcomes Study 36item Short-Form Health Survey (19); the 28-item version of the Hamilton Depression Rating Scale, which was also scored for the 17-item and 21-item versions (2022); the Hamilton Anxiety Rating Scale (23); the 30-item version of the clinician-rated Inventory for Depressive Symptomatology (24); the Beck Depression Inventory (25); the HSCL (26); and the Clinical Global Impression (CGI) severity scale (27). The extensive demographic evaluation of the subjects included determination of Research Diagnostic Criteria family history diagnoses. Subjects had to have normal physical examination and laboratory results, including a complete blood count, urine toxicology screen, urine analysis, and serum chemistries for hepatic and renal function.

Subjects were reevaluated weekly for the 4 weeks after study entry with the DIS depression section, Hamilton depression scale, Inventory for Depressive Symptomatology, Short-Form Health Survey, Global Assessment of Functioning Scale (DSM-III, p. 122), CGI severity scale, and CGI improvement scale.

DIAGNOSTIC

CRITERIA

FOR

MINOR

DEPRESSION

In defining minor depression for this study, we made several methodological and conceptual decisions. First, at the inception of this study in 1992, the majority of available data regarding minor depression resulted from ECA analyses, which used the depression section of the DIS; therefore, we adopted the DIS as our primary diagnostic tool for defining minor depression. Second, anticipating concerns that minor depression might be perceived as trivial, we required that functional disability be evident according to scores on both the Global Assessment of Functioning Scale and at least one of two Short-Form Health Survey subscales. Third, we included subjects with a past history of major depressive disorder or dysthymia so that our study group would be more representative of the larger group of patients with minor depressive symptoms. However, to eliminate the possibility that the minor depression was a residual phase of another type of depressive episode, we did not include subjects who had experienced major depression or dysthymia within the last 2 years. Fourth, because the antidepressants used in treatment phases of this trial (serotonin reuptake inhibitors) are effective treatments for a variety of psychiatric disorders, we excluded individuals with any current axis I disorder. To qualify as having "confirmed" minor depression, subjects in this study had to meet the following three criteria at the initial diagnostic visit and at least three of the four subsequent visits, including those during the last 2 weeks of the single-blind study period: 1. At least 2 weeks of depressed mood/dysphoria/sadness (DIS item 1) and pervasive loss of interest/pleasure in all or almost all activities (DIS item 2) and at least one additional depressive symptom group from the DIS or at least 2 weeks of depressed mood/dysphoria/sadness (DIS item 1) or pervasive loss of interest/pleasure in all or almost all activities (DIS item 2), but not both of these, and at least two additional depressive symptom groups from the DIS. 2. A Global Assessment of Functioning Scale score of 70 or less for the last month. (The time frame was decreased to the last week during the 4 weeks of single-blind evaluation.) 3. A score of 75 or less on the social role function scale or a score of 67 or less on the emotional role function scale of the Short-Form Health Survey for a time period including the last month. Subjects who had developed five or more symptoms of major depressive disorder when they were interviewed with the DIS depression section were interviewed with the depression module of the SCID to determine whether their minor depression had progressed to major depressive disorder.

EXCLUSION

CRITERIA

Exclusion criteria for the study were current major depressive disorder or dysthymia; major

depressive disorder or dysthymia within the last 2 years; major depressive disorder in partial remission; loss of a loved one or significant other within the past year; serious suicidal risk; substance or alcohol abuse or dependence within the last year; a current diagnosis of any axis I disorder; a lifetime diagnosis of bipolar disorder (type I), borderline personality disorder, antisocial personality disorder, psychotic disorder, organic mood disorder, organic psychotic disorder, or schizophrenia; use of any psychotropic drug except chloral hydrate within 7 days or a monoamine oxidase inhibitor within 14 days of starting active treatment; the presence of a serious medical condition that was not currently stabilized; seizure disorder within the last year; a history of severe allergies or multiple adverse drug reactions; previous nonresponse or adverse reaction to fluoxetine; or previous participation in a fluoxetine study.

STATISTICAL

ANALYSES

Descriptive statistics are presented for key demographic and clinical characteristics of the study group. After evaluating continuous data for homogeneity of variance and normal distribution, we compared different study subgroups using t tests. Chi-square tests or Fishers exact tests were used to compare groups on categorical variables, and Wilcoxon rank sum tests were used for measures with ordinal values such as CGI and Short-Form Health Survey scales. A probability level of p=0.05 (two-tailed) was used to determine statistical significance of group differences. Group sizes for the two comparisons of interest (positive versus negative patient history of major depressive disorder and positive versus negative family history of depression) were considered sufficiently large to detect group differences. Since this is a descriptive report, statistics and resulting probability values are to be taken as descriptive indicators, not inferential ones.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

RESULTS
Of the 226 subjects who met criteria for minor depression at initial screening, 64 did not complete the 4-week lead-in phase of the study for the following reasons: adverse effects (N=4), lack of efficacy (N=5), withdrew consent or declined further participation (N=17), had contraindicated medical conditions (N=10), other protocol violations (N=3), were lost to follow-up (N=6), developed major depressive disorder (N=5), or no longer met criteria for minor depression (N=14). The 162 individuals (72% of the initial sample) who

remained in the study for 4 weeks and continued to meet criteria for minor depression constitute the study group of subjects with confirmed and nontransient minor depression who are the focus of this report. As shown in Table 1 , 59% of subjects with confirmed minor depression were women, 90% were Caucasian, and their mean age was 43.5 years. Overall, the 64 subjects excluded from the analyses did not differ significantly from the 162 patients with confirmed minor depression with respect to sex, race, age, family history of affective disorders, or initial symptom rating scale scores; however, they were significantly less likely to have a past history of major depressive disorder (Table 1 ). The subgroups of subjects who withdrew, were excluded, or changed diagnostic status were fairly heterogeneous and too small for meaningful statistical comparison. The 14 subjects who spontaneously recovered from minor depression during the 4-week placebo lead-in phase tended to be the least severely ill on all clinical measures. The five subjects who developed major depressive disorder had clinical ratings similar to the top third of patients with confirmed minor depression. Patients who dropped out (N=17) or were lost to follow-up (N=6) constituted heterogeneous groups encompassing a wide range of depressive severity.

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Table 1. Characteristics of 226 Subjects Whose Screening Diagnosis of Minor Depression Was or Was Not Confirmed

Thirty-two percent of the subjects with minor depression had a past history of major depressive disorder (Table 1 ). They did not differ from the subjects without a past history of major depressive disorder on any demographic characteristic, family history variable, or clinical rating of severity or dysfunction. Forty-six percent of the subjects with minor depression had a first-degree relative who had suffered from unipolar depression (major depressive disorder or dysthymia), and 6% had a first-degree relative with bipolar disorder (Table 1 ). A positive family history of depression was associated with a higher total 17-item Hamilton depression scale score (mean=12.5, SD=3.0, versus mean=11.4, SD=3.1) (t=2.16, df=150, p=0.03). (A difference of 1.1 on the 17-item Hamilton depression scale usually is not clinically significant.)

Table 2 demonstrates that baseline clinical ratings for the subjects with confirmed minor depression encompass a broad range of depressive severity, from mild symptoms to moderately severe symptoms, which overlap with scores observed in outpatients with major depressive disorder.

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Table 2. Clinical Rating Scale Scores at Visit 1 for 162 Subjects With Confirmed Minor Depression

Table 3 presents the scores on the Short-Form Health Survey subscales for our subjects with minor depression, compared with data reported in previous studies of patients with major depressive disorder and normal subjects (14). Our subjects with minor depression were more impaired than normal subjects on most measures and were at least as impaired as patients with major depressive disorder on many measures.

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Table 3. Psychosocial Functioning at Visit 1 for 162 Subjects With Confirmed Minor Depression, 502 Subjects With Major Depressive Disorder, and 2,474 Normal Subjects

Seven DIS symptoms were frequently endorsed at the initial evaluation of our study group: feeling sad or depressed nearly every day (an inclusion criterion) (N=179 [79%]), fatigue (N=163 [72%]), trouble thinking or concentrating (N=145 [64%]), sleep disturbance (N=140 [62%]), feelings of worthlessness (N=118 [52%]), loss of interest in things usually enjoyed (N=108 [48%]), and loss of interest in sex and/or other people (N=99 [44%]).

Between 60% and 71% of the subjects endorsing those symptoms at entry into the study continued to report them at all of the next four visits, while they were taking placebo (single-blind). By contrast, those symptoms with low rates of initial endorsementappetite disturbance (16% [N=36]), slow or restless/fidgety (9% [N=20]), and thoughts of death/suicide (9% [N=20])were highly unstable over the next four visits. Table 4 reports the frequency of endorsements of individual items of the clinician-rated Inventory for Depressive Symptomatology in our study group. The 11 most frequently endorsed items at the initial visit were sad mood (93%), lack of involvement (91%), quality of mood distinctly different from bereavement (85%), irritable mood (85%), lack of pleasure and enjoyment (an inclusion criterion) (83%), problems concentrating and making decisions (83%), having a pessimistic outlook for the future (83%), fatigue (82%), anxious mood (80%), increased interpersonal sensitivity (71%), and increased mood reactivity (70%). Table 4 also shows the persistence of symptoms during weekly evaluations, again demonstrating considerable stability among the frequently endorsed symptoms.

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Table 4. Scores of 162 Subjects With Confirmed Minor Depression on the Clinician-Rated Inventory for Depressive Symptomatology at Baseline and Over a 4-Week Placebo Lead-In Period

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

DISCUSSION

We believe that the data from this study support four conclusions, each with important implications for the conceptualization and clinical management of minor depression. First, minor depression with functional disability is not evanescent. The majority of individuals initially meeting our rigorous criteria for minor depression had persistent depressive symptoms and disability throughout a subsequent 4-week period. Of the 226 individuals who met criteria at intake, only five (2.2%) developed major depressive disorder and 14 (6.2%) spontaneously recovered during the 4-week placebo period. Our second conclusion is that minor depression is characterized by affective and cognitive symptoms: sadness, loss of pleasure/enjoyment, irritable mood, anxious mood, pessimism, difficulty concentrating, lack of involvement, and fatigue. It is distinguished from more severe forms of depression by the infrequent occurrence of the classical neurovegetative and reverse neurovegetative signs and symptoms of depression. In contrast, individuals with minor depression in the ECA database endorsed more of the classic neurovegetative signs of depression. (The ECA is an epidemiological survey and may have included subjects with mild major depressive disorder in the minor depression group.) An additional important finding is that highly endorsed symptoms of depression at the initial interview continued to be endorsed consistently throughout 4 weeks of observation. Our third conclusion from this study is that minor depression may occur either 1) independently of a history of major depressive disorder, 2) as a less severe but stable episode of major depressive disorder for individuals who have experienced past episodes, or 3) as a transitional state for individuals traversing between euthymia and more severe forms of depression. In our study group of 162 subjects with stable minor depression, 52 (32%) had a history of past major depression, which suggests that it may not be appropriate to use a past history of major depressive disorder as an exclusion criterion for minor depression. In our study, individuals with and without past major depression were nearly identical in age, which argues against the conceptualization of minor depression as simply a stage in the lifetime emergence of major depressive disorder. Patients with and without past major depressive disorder also did not differ in clinical measures of depressive severity or functional disability. Only 2.2% of subjects initially meeting criteria for minor depression in this study went on to develop episodes of major depressive disorder during the next 4 weeks, suggesting that minor depression may be a transitional state for a minority of individuals. The fourth and broadest conclusion from our study is that minor depression and major depressive disorder should be considered part of a spectrum of severity rather than as two discrete disorders. Several lines of evidence support this conceptualization. First, subjects meeting our rigorous criteria for minor depression over a 4-week period had scores on clinical rating scales for depression indicating a broad spectrum of severity from a mild level to a level approaching the threshold for major depressive disorder. Second, individuals with and without a previous history of major depressive disorder had similar rates of family history of mood disorders, suggesting that minor depression, in some instances, may be part of a spectrum of mood disorders inherited within a family. In our clinical study group, 47 (43%) of the 110 subjects with minor depression who did not have a previous history of

major depressive disorder and 27 (52%) of the 52 subjects who did have such a history had a first-degree relative with unipolar mood disorder. This is consistent with findings from epidemiologic studies indicating that the presence of minor depression carries a greater vulnerability for depression in family members, similar to that seen in major depressive disorder (2, 4, 8, 16). Further support for the spectrum concept of depressive disorders comes from our finding that five out of 226 subjects with minor depression developed major depressive disorder and 14 fell below the threshold for minor depression during a 1month period. Epidemiologic and clinical studies (6, 12, 15) clearly demonstrate fluidity among major depressive disorder, minor depression, recurrent brief depression, and depressive symptoms, with many patients traversing a variety of states of severity of depression over time. There are limitations to this analysis that need to be acknowledged. First, this study group is derived from respondents to advertisements and from clinician referrals for subjects to participate in a pharmacological treatment trial of minor depression. Second, raters were not blind to randomization criteria, creating a potential bias to keep people in the study. Third, our requirement that subjects maintain functional disability throughout the 4-week lead-in phase may mean that we have identified a subset of subjects who are less likely to have an evanescent condition. We believe that substantial dysfunction or disability is a necessary requirement for defining a physical or mental condition that merits treatment. Despite these limitations, we believe that the data presented here provide important information about a group of subjects with nontransient and disabling depressive symptoms. In conclusion, using a very rigorous set of criteria for minor depression, we have presented evidence that minor depression is stable, is characterized by mood and cognitive symptoms of depression, occurs independently of a previous personal or familial history of major depressive disorder, is disabling, and should be conceptualized as part of the continuum of severity of depressive disorders. This research suggests that we need to evaluate minor depression in other types of clinical settings and investigate the impact that treatment might have on the course of minor depression.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

REFERENCES

1. United States Depression Guideline Panel: Depression in Primary Care, vol 5. Rockville, Md, US Department of Health and Human Services, Agency for Health Care Policy and Research, 1993 2. Parker G: Classifying depression: should paradigms lost be regained? Am J Psychiatry 2000; 157:11951203[Abstract/Free Full Text] 3. Broadhead WE, Blazer DG, George LK, Tse CK: Depression, disability days, and days lost from work in a prospective epidemiologic survey. JAMA 1990; 264:2524 2528[Abstract/Free Full Text] 4. Judd LL, Rapaport MH, Paulus MP, Brown JL: Subsyndromal symptomatic depression: a new mood disorder? J Clin Psychiatry 1994; 55(April suppl):1828 5. Johnson J, Weissman MM, Klerman GL: Service utilization and social morbidity associated with depressive symptoms in the community. JAMA 1992; 267:1478 1483[Abstract/Free Full Text] 6. Angst J, Merikangas K: The depressive spectrum: diagnostic classification and course. J Affect Disord 1997; 45:3139[Medline] 7. Kessler RC, Walters EE: Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety 1998; 7:314[Medline] 8. Kessler RC, Zhao S, Blazer DG, Swartz M: Prevalence, correlates, and course of minor depression and major depression in the National Comorbidity Survey. J Affect Disord 1997; 45:1930[Medline] 9. Skodol AE, Schwartz S, Dohrenwend BP, Levav I, Shrout PE: Minor depression in a cohort of young adults in Israel. Arch Gen Psychiatry 1994; 51:542 551[Abstract/Free Full Text] 10. Lyness JM, King DA, Cox C, Yoediono Z, Caine ED: The importance of subsyndromal depression in older primary care patients: prevalence and associated functional disability. J Am Geriatr Soc 1999; 47:647652[Medline] 11. Romanoski AJ, Folstein MF, Nestadt G, Chahal R, Merchant A, Brown CH, Gruenberg EM, McHugh PR: The epidemiology of psychiatrist-ascertained depression and DSM-III depressive disorders: results from the Eastern Baltimore Mental Health Survey Clinical Reappraisal. Psychol Med 1992; 22:629 655[Medline] 12. Maier W, Gansicke M, Weiffenbach O: The relationship between major and subthreshold variants of unipolar depression. J Affect Disord 1997; 45:41 51[Medline]

13. Beekman AT, Deeg DJ, Braam AW, Smit JH, van Tilburg W: Consequences of major and minor depression in later life: a study of disability, well-being and service utilization. Psychol Med 1997; 27:13971409[Medline] 14. Sherbourne CD, Wells KB, Hays RD, Rogers W, Burnam MA, Judd LL: Subthreshold depression and depressive disorder: clinical characteristics of general medical and mental health specialty outpatients. Am J Psychiatry 1994; 151:1777 1784[Abstract/Free Full Text] 15. Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL, Leon AC, Mueller TI, Rice JA, Keller MB: A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 1998; 55:694 700[Abstract/Free Full Text] 16. Kendler KS, Gardner CO Jr: Boundaries of major depression: an evaluation of DSM-IV criteria. Am J Psychiatry 1998; 155:172177[Abstract/Free Full Text] 17. First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), version 2. New York, New York State Psychiatric Institute, Biometrics Research, 1995 18. Robins LN, Helzer JE, Croughan J, Ratcliff KS: The National Institute of Mental Health Diagnostic Interview Schedule: its history, characteristics, and validity. Arch Gen Psychiatry 1981; 38:381389[Abstract/Free Full Text] 19. Ware JE, Snow KK, Kosinski M, Gandek B: SF-36 Health Survey: Manual and Interpretation Guide. Boston, New England Medical Center, Health Institute, 1993 20. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:5662[Free Full Text] 21. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278296[Medline] 22. Williams JB: A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 45:742747[Abstract/Free Full Text] 23. Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:5055[Medline] 24. Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C: The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Res 1986; 18:6587[Medline]

25. Beck AT, Beamesderfer A: Assessment of depression: the Depression Inventory. Mod Probl Pharmacopsychiatry 1974; 7:151169[Medline] 26. Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L: The Hopkins Symptom Checklist (HSCL): a measure of primary symptom dimensions. Mod Probl Pharmacopsychiatry 1974; 7:4345 27. Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department of Health, Education, and Welfare, 1976, pp 218222
Focus 2005 American Psychiatric Association 3:106-113 (2005)

INFLUENTIAL PUBLICATION

A 20-Year Longitudinal Observational Study of Somatic Antidepressant Treatment Effectiveness

Andrew C. Leon, Ph.D., David A. Solomon, M.D., Timothy I. Mueller, M.D., Jean Endicott, Ph.D., John P. Rice, Ph.D., Jack D. Maser, Ph.D., William Coryell, M.D., and Martin B. Keller, M.D.

TOP ABSTRACT METHOD ASSESSMENTS RESULTS DISCUSSION REFERENCES

ABSTRACT
Objective: This observational study examined the effectiveness of somatic antidepressant treatments as administered in the community. Method: The study group consisted of 285 subjects with an intake diagnosis of major depressive disorder who had entered the National Institute of Mental Health Collaborative Depression Study as early as 1978, had at least one additional affective episode, and had been followed for up to 20 years, as recently as 1999. The characteristics that distinguished subjects receiving various levels of somatic

antidepressant treatment were accounted for in what was called a propensity for treatment intensity model. The effectiveness of somatic antidepressant treatment during major affective episodes was then examined. Results: Those who received higher levels of antidepressant treatment tended to have more prior episodes, more severe depressive symptoms, and more intensive somatic therapy during prior episodes and prior well intervals than those who received lower levels. Treatment effectiveness analyses that were stratified by propensity for treatment intensity demonstrated that those who received higher levels of antidepressant treatment were significantly more likely to recover from affective episodes. In contrast, those treated with lower levels were no more likely to recover than those who did not receive somatic treatment. Conclusions: Despite the indications of more severe depressive illness, those who received higher levels of somatic antidepressant treatment were more likely to recover from recurrent affective episodes. Results from this observational study extend the generalizability of reports from randomized clinical trials of antidepressants to a wider, more representative group of individuals who suffer from major depression. (Reprinted with permission from the American Journal of Psychiatry 2003; 160:727 733[Abstract/Free Full Text])

Numerous randomized clinical trials have demonstrated the efficacy of somatic antidepressant therapy for major depressive disorder (17). These studies, as with randomized clinical trials in general, were designed to evaluate the benefits of treatment in tightly controlled settings measured under ideal circumstances among relatively homogeneous groups of subjects (8). Randomized clinical trials have been an indispensable source of information about efficacy. Protocols for randomized clinical trials include proscribed treatment decisions, a defined duration of treatment, limited choices of interventions (including placebo), and strict inclusion and exclusion criteria. For instance, protocols tend to exclude the mild to moderately depressed (e.g., Hamilton Depression Rating Scale score <18) and, for both ethical and legal reasons, the acutely suicidal or psychotic patients, a group in most need of treatment. Patients taking other medications and those with comorbid psychiatric or other medical illnesses are also often excluded. As a consequence, randomized clinical trials have informed clinical practice about the monotherapeutic treatment of nonsuicidal patients with minimal comorbid illnesses. Taken as a whole, these criteria very likely increase the drug-placebo differences. Yet, randomized clinical trial results do not apply to a substantial proportion of individuals who suffer from depressive disorders (9, 10). In contrast, effectiveness studies are designed to evaluate treatments among a more inclusive group of patients in settings more similar to those seen in clinical practice. Effectiveness studies are far less common than randomized clinical trials in medicine in general and in psychiatry in particular.

An observational study of affective disorders can be used to examine the association between treatments as administered in the community and a range of psychopathology among a heterogeneous group of subjects. Yet by design, such a study observes but does not manipulate the treatment received by subjects. As a consequence, the causal path between treatment and level of psychopathology is often ambiguous. For example, some subjects are asymptomatic because they receive treatment, whereas others receive treatment because their symptoms are exacerbated. Without experimental control over treatment decisions, the direction of the causality is not clear. Thus, observational evaluations of treatment effectiveness are less useful for treatment evaluation than randomized clinical trials because of the confounding variable of recent symptoms, which are related to both the intervention and the outcome. Cochran (11) proposed the method of subclassification, an approach that can be applied to reduce bias in estimates of treatment effectiveness. The fundamental premise of this approach is that analyses that are stratified by a confounding variable remove the influence of that variable. That is, separate analyses of subjects with and without the characteristic of interest hold constant what otherwise confounds the relation between the intervention and the outcome. The simplicity of stratification is appealing. However, the mechanism that drives individuals to seek treatment probably consists of more than one variable (e.g., health insurance, treatment history, and comorbidity). Analyses that require multiple strata to account for numerous confounding variables are unwieldy and difficult to interpret. The propensity adjustment (1215) is a univariate alternative to multivariable stratification in that a linear combination of variables related to the likelihood of treatment seeking comprise a propensity score. In the context of antidepressant treatment effectiveness, the propensity model can examine clinical and demographic predictors of receiving treatment. The multifaceted treatment-seeking mechanism is then incorporated by stratifying effectiveness analyses by the propensity score. That is, separate effectiveness analyses are conducted for subjects who are least likely to seek treatment (i.e., those with low propensity scores), those somewhat more likely (i.e., those with moderate propensity scores), and those most likely to seek treatment (i.e., those with high propensity scores). Although the propensity adjustment reduces the bias in the estimates of treatment effectiveness associated with variables in the propensity model, unmeasured or hidden sources of bias remain (16, 17). In contrast, with randomization, both observed and hidden sources of bias tend to be removed from estimates of efficacy. We applied the propensity methodology to the National Institute of Mental Health (NIMH) Collaborative Depression Study, a longitudinal observational study of affective illness that includes subjects with a range of illness severity and complexity. Our objectives were twofold. First, we examined features that distinguished those who received varying levels of somatic antidepressant treatment and incorporated those in estimates of the propensity for treatment intensity. Second, we evaluated treatment effectiveness in analyses that were stratified by the propensity for treatment intensity.

TOP ABSTRACT METHOD ASSESSMENTS RESULTS DISCUSSION REFERENCES

METHOD SUBJECTS
From 1978 through 1981, the NIMH Collaborative Depression Study recruited 955 subjects who sought treatment for one of the major affective disorders (major depressive disorder, mania, or schizoaffective disorder) at one of five academic medical centers in the United States (located in Boston, Chicago, Iowa City, New York, and St. Louis). All subjects were at least 17 years of age, English speaking, and Caucasian. Each subject provided written informed consent. The objectives and design of the NIMH Collaborative Depression Study have been described previously (18). The NIMH Collaborative Depression Study follow-up is ongoing, and the current analyses include up to 20 years of follow-up data. The patient group examined in these analyses was derived from the 431 subjects who met criteria for major depressive disorder at intake, had no underlying minor or intermittent depression of at least 2 years duration, and had no history of mania, hypomania, or schizoaffective disorder (19). Neither alcohol nor substance abuse was an exclusion criterion. Of these 431 subjects, the study group was limited to the 285 subjects who recovered from their intake episode and then had at least one recurrent affective episode over the course of the follow-up period. This was done because 1) the variables in the propensity model (described in the Data Analyses section) include clinical characteristics such as treatment during the prior episode and prior well interval, and 2) detailed clinical information on prior treatment was only available on episodes that commenced after intake into the NIMH Collaborative Depression Study.

ASSESSMENTS

The Schedule for Affective Disorders and Schizophrenia (20) and TOP clinical records were used for diagnostic assessment according to ABSTRACT Research Diagnostic Criteria (RDC) (21). The Longitudinal Interval METHOD Follow-Up Evaluation (22) was administered by trained, wellASSESSMENTS supervised raters for assessment of psychopathology, functional RESULTS impairment, and dose and duration of somatic treatment. Patients DISCUSSION REFERENCES were assessed with this semistructured interview semiannually for the first 5 years of the follow-up period and annually thereafter. The specific wording of the Longitudinal Interval Follow-Up Evaluation items, rater qualifications, and interrater reliability of the ratings have been reported previously (22). For instance, the intraclass correlation coefficient for week of recovery was 0.95. Severity of symptoms of major affective disorders (i.e., major depressive disorder, mania, schizoaffective depression, and schizoaffective mania) was recorded by using the Longitudinal Interval Follow-Up Evaluation psychiatric status ratings, which range from 1 (no symptoms) to 6 (severe symptoms). Information regarding somatic treatment collected during Longitudinal Interval Follow-Up Evaluation interviews was corroborated with available clinical records. During each interview, the rater assigned Longitudinal Interval Follow-Up Evaluation ratings for each week that had elapsed since the prior interview. To do so, the rater identified chronological anchor points (e.g., holidays) to assist the subject in recalling when significant clinical improvement or deterioration took place. The NIMH Collaborative Depression Study developed composite ratings to quantify treatments appropriate for unipolar depression, psychotic depression, and bipolar disorder (23). The unipolar composite antidepressant rating is a summary measure of the intensity of somatic antidepressant treatment. The rationale and method for deriving the unipolar composite antidepressant rating have been described previously (23). The unipolar composite antidepressant rating algorithms continue to be revised with the introduction of new medications and further clinical experience with existing medications. A panel of experts, drawn from NIMH Collaborative Depression Study investigators, bases the approximations of dose equivalents largely on clinical experience, since there is limited randomized clinical trial literature that provides comparisons across graduated doses of the wide variety of medications included in the unipolar composite antidepressant rating. Daily doses of different classes of somatic antidepressant therapies are rated on a scale designed to reflect the overall commitment to somatic antidepressant treatment or intensity of treatment (examples are presented in Table 1 ). The algorithms include rules for increased treatment intensity associated with the use of medication for augmentation. Tests of plasma levels are not incorporated in the algorithms. The unipolar composite antidepressant rating does not purport to represent biologically equivalent doses. Instead, it is an ordinal scale of treatment intensity ranging from 0 to 4. A unipolar composite antidepressant rating of 0 indicates no somatic treatment, and unipolar composite antidepressant ratings of 1 to 4 represent progressively larger doses. We acknowledge that this scale is somewhat coarse. The analyses compare broad classes of treatment intensity and are not meant for inferences regarding differences in effectiveness of two medications or two doses of any one specific medication.

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Table 1. Intensity Ratings for Somatic Treatment Received by Subjects in the NIMH Collaborative Depression Study (N=285)a

DATA

ANALYSES

The analyses were conducted in two stages. First, analysis of the propensity for treatment intensity examined characteristics that distinguished among those receiving various levels of somatic antidepressant treatment. A dynamic adaptation of the propensity adjustment for ordinal doses (24) was employed in a mixed-effect ordinal logistic regression model (25); MIXOR software (26) was used for this model. Unipolar composite antidepressant rating was the ordinal dependent variable, and fixed effects included several demographic and clinical variables that were hypothesized to be associated with treatment intensity, such as gender, site, socioeconomic status, age, number of prior affective episodes, and treatment intensity during the most recent prior episode and prior well period. In addition, both symptom severity (mean psychiatric status rating in the 8 weeks before commencing treatment) and trajectory of symptom severity in the 8 weeks before the change in treatment (i.e., whether psychiatric status ratings were increasing, stable, or decreasing) were entered into the model. The significance of each variable was evaluated based on 2 log likelihood difference between models with and without the additional variable. A linear combination of these variables, called the propensity score, was derived on the basis of the results of the logistic model. A subject-specific intercept was included as a random effect to account for within-subject clustering. Treatment effectiveness analyses were then conducted with a mixed-effect grouped-time survival model (27) of the time from the start of the course of a particular intensity of treatment until recovery from major affective episode; MIXGSUR software (28) was used for these analyses. Survival time represented the "time until recovery," defined as the number of consecutive weeks during which treatment remained at one level of intensity during an affective episode. A survival interval terminated in one of three ways: 1) resolving of an episode, 2) a change in antidepressant treatment intensity, or 3) end of follow-up. The latter two were classified as censored and were assumed to be unrelated to time until recovery. Recovery from an episode was the target "terminal" event that ended a survival interval and was defined according to RDC as 8 consecutive weeks of no more than minimal symptoms. Thus, the survival chronometer started over with each new episode and each change in level of treatment. A subject accumulated additional survival intervals,

hereafter referred to as "treatment intervals," with each new episode and each change in treatment intensity while in an episode. The unit of analysis for both the propensity and effectiveness models was treatment interval. A separate propensity score was calculated for each treatment interval. The treatment effectiveness analyses, which included fixed effects of treatment levels and a random effect for the subject-specific intercepts, were stratified by propensity score quintile, as recommended by Rosenbaum and Rubin (12). Thus, separate effectiveness analyses were conducted for those least likely to get aggressive somatic treatment, those somewhat more likely to get aggressive treatment, and so on. These stratified results were then pooled by using the Mantel-Haenszel procedure (described by Fleiss [29]) after evaluating the appropriateness of combining results across strata. Most important, stratumspecific results cannot be pooled if there is a significant propensity-by-treatment interaction because such an interaction would indicate that treatment effects vary across groups defined by their propensity for treatment. Mixed-effect models were used for both stages of analyses, since many subjects had multiple episodes and multiple treatment intervals within episodes. This approach allowed for within-subject variation in treatment intensity and propensity scores across treatment intervals. A two-tailed alpha level of 0.05 was used for each statistical test. According to the statistical power algorithm from Diggle et al. (30), the group size was sufficient to detect differences in response rates of about 10%15%, with statistical power of 0.80 and a two-tailed alpha level of 0.05.

TOP ABSTRACT METHOD ASSESSMENTS RESULTS DISCUSSION REFERENCES

RESULTS
Demographic and clinical characteristics are presented for the 285 subjects who met criteria for major depressive disorder at intake into the NIMH Collaborative Depression Study and had at least one prospectively observed episode (Table 2 ). Many of these subjects would likely have been excluded from randomized clinical trials. For instance, 15.4% had a history of serious suicide attempts, and 14.0% (N=40) were over 65 years old during the final treatment interval examined in these analyses. Among these subjects, the number of affective episodes that commenced after intake into the NIMH Collaborative Depression Study ranged from 1 to 18 (mean=3.2, median=2.0, SD=2.9).

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Table 2. Demographic and Clinical Characteristics of Subjects in the NIMH Collaborative Depression Studya

The demographic and clinical characteristics of these 285 subjects were compared with the 146 subjects who presented with major depressive disorder at intake into the NIMH Collaborative Depression Study but were excluded from the analyses because they did not have at least two prospectively observed episodes. Those who were included were younger than those excluded (mean=37.2 [SD=14.7] versus 41.3 [SD=15.1] years, respectively) (t=2.40, df=429, p<0.02), and the included group was overrepresented by women (64.2% versus 53.4%) ( 2=4.26, df=1, p<0.04). However, included and excluded subjects did not differ with regard to marital status ( 2=4.42, df=2, p=0.11), site ( 2=4.75, df=4, p=0.31), social class (Mann-Whitney p=0.53), inpatient status ( 2=0.38, df=1, p=0.54), intake Global Assessment Scale score (t=0.45, df=425, p=0.66), or intake Hamilton depression scale score (t=0.31, df=414, p=0.76). Since either a new episode or a change in treatment intensity while in an episode designated a new treatment interval, the number of treatment intervals (mean=11.0 [SD=11.6], median=8.0, range=165) almost always exceeded the number of affective episodes for each subject. The propensity and effectiveness analyses included 3,141 observations (i.e., treatment intervals) for these 285 subjects. The median follow-up time was 17 years (mean=14.3, SD=5.4) and ranged from 6 months to 20 years after intake into the NIMH Collaborative Depression Study. The data span from 1978 through 1999.

PROPENSITY FOR ANTIDEPRESSANT TREATMENT INTENSITY

The results of the propensity for treatment intensity model indicate that those who were more severely ill and those who had received more intensive treatment earlier tended to receive more intensive somatic antidepressant therapy (Table 3 ). For instance, the odds ratios revealed that those with worsening symptoms in the 8 weeks before commencing treatment (i.e., an increasing trajectory for psychiatric status ratings) were 62% more likely to receive higher levels of somatic antidepressant treatment than those whose symptom severity remained stable. Similarly, those with more severe symptoms immediately before treatment commenced were 24% more likely to receive more intensive somatic treatment (i.e., a 24% increase with each additional psychiatric status rating point). Furthermore, those with more prior affective episodes or more intensive treatment in either their prior

episode or their prior well interval tended to receive more aggressive treatment during their current affective episode. These results underscore the need to account for various aspects of the course and treatment of affective illness in the effectiveness analyses. Demographic factors were not even marginally significant and thus not included in the model (gender: 2 log likelihood=0.001, df=1, p=0.98; site: 2 log likelihood=4.71, df=4, p=0.32; socioeconomic status: 2 log likelihood=1.50, df=4, p=0.83; age: 2 log likelihood=2.46, df=4, p=0.65).

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Table 3. Effect of Illness and Treatment Variables on Propensity for Treatment Intensity for Subjects in the NIMH Collaborative Depression Study (N=285)a

After developing a propensity for treatment intensity model, and as a prerequisite to the treatment effectiveness evaluation, we determined whether all levels of treatment intensity were represented in each of the propensity quintiles (Table 4 ). As expected, those in the lowest propensity for treatment intensity quintile were overrepresented among those receiving lower levels of treatment. Similarly, those in the highest propensity for treatment intensity quintile were disproportionately represented among those receiving high levels of treatment. Nevertheless, because all four levels of treatment were well represented in each of the five quintiles of treatment intensity, the effectiveness evaluation proceeded as described.

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Table 4. Treatment Intensity by Propensity Score Quintile for Subjects in the NIMH Collaborative Depression Study (N=285)a

TREATMENT

EFFECTIVENESS

Mixed-effect grouped-time survival analyses of time until recovery were used to examine treatment effectiveness. Separate analyses were conducted for each of the propensity quintiles, and the results were then pooled by using the Mantel-Haenszel procedure. (Before pooling the quintile-specific results, one model that included all observations examined the propensity-by-treatment interaction, which was nonsignificant [2 log likelihood=5.817, df=12, p<0.93]. Thus, pooling of results was indicated.) The pooled results indicated that when treated with higher levels of somatic antidepressant therapy, subjects were nearly twice as likely to recover as those who received no somatic treatment (odds ratio=1.86, 95% CI=1.272.72; z=3.17, p=0.002) after we controlled for propensity for treatment intensity. In contrast, neither low levels of antidepressant treatment (odds ratio=0.86, 95% CI=0.55 1.23; z=0.93, p<0.35) nor moderate levels (odds ratio=1.13, 95% CI=0.791.63; z=0.67, p<0.51) were associated with a significant increase in the likelihood of recovery. Furthermore, although higher levels of antidepressant treatment were significantly superior to lower levels, overlapping confidence intervals signified that there was no significant difference between high and moderate levels of antidepressant treatment.

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DISCUSSION
The effectiveness of somatic antidepressant treatment was examined in a longitudinal observational study of subjects who met criteria for unipolar major depressive disorder at intake into the NIMH Collaborative Depression Study. Those who received higher levels of treatment tended to be more ill as measured by more severe symptoms and worsening symptoms. They also had more prior episodes and a history of more aggressive treatment in both their prior episode and prior well interval. Nevertheless, in analyses that controlled for these differences through stratification, those who received higher levels of antidepressant treatment were significantly more likely to recover from a major affective episode than those who received no somatic treatment. In contrast, those receiving lower levels were no more likely to recover than those who were untreated.

This study extends the generalizability of reports from randomized clinical trials in which the baseline level of illness, as well as the dose and duration of pharmacologic interventions, have been carefully controlled. In contrast to subjects in randomized clinical trials, subjects in the NIMH Collaborative Depression Study received a variety of antidepressant medications, both alone and in combination, that were rated on a scale of treatment intensity. Furthermore, unlike most randomized clinical trials, we included elderly subjects, subjects with comorbid medical illnesses, and subjects with a history of serious suicide attempts. Finally, randomized clinical trials typically evaluate the efficacy of a medication relative to placebo or another active agent. In this observational study, a substantial proportion of depressive episodes received no somatic treatment (30%, N=946 of 3,141 [Table 4 ]). Accordingly, we have compared the effectiveness of various intensities of somatic antidepressant treatments to no somatic treatment, allowing us to remove much of the "package of placebo effects" (32) from the efficacy estimates that are reported in placebo-controlled randomized clinical trials. The analyses presented here proceeded in two stages. Initially, we used a propensity for treatment intensity model to examine differences among patients who received various intensities of antidepressants. Then, after we controlled for those differences through stratification, treatment effectiveness analyses were conducted. In standard covariateadjusted analyses of treatment effectiveness, it would have been unwieldy, at best, to verify the representativeness of the treatment levels across the hundreds of combinations of levels of these five covariates. However, using the propensity approach of Rosenbaum and Rubin (1215), we verified that each treatment level was well represented within each propensity quintile. Most important, beneficial effects of higher doses of somatic antidepressant therapy were detected in this observational study. Furthermore, because a mixed-model approach was used, multiple episodes within-subject and multiple treatment intervals within-episode were included in the analyses, and the analyses accounted for the varying duration of both episodes and treatment intervals. There are several limitations of this observational study. First, although the propensity adjustment reduces bias associated with variables in the propensity model, other sources of bias can remain. In fact, the propensity adjustment removed or greatly reduced treatment group differences on all of the propensity components (data not shown). Second, the treatment intensity data are based on Longitudinal Interval Follow-Up Evaluation interviews. Although this was verified with clinical records whenever possible, availability and quality of records were highly variable. Moreover, we do not have blood levels to confirm the treatment data. Third, treatment intensity is defined on a composite antidepressant scale. We acknowledge that this scale has broad classes of treatment intensity, based on consensus judgment among clinical researchers. Fourth, the scale does not include other psychotropic medications such as neuroleptics or psychotherapy, which for that reason, have been ignored in these analyses. Fifth, the analyses did not examine side effects or toxicity of antidepressants because such data were not available. Finally, the analyses focused on recurrent affective episodes and did not include the intake depressive episode. This was done for a variety of reasons. All subjects were recruited into the study when seeking treatment. In these analyses, we sought to compare a wide range of antidepressant treatment levels, including no somatic treatment. Furthermore, recruitment

into the NIMH Collaborative Depression Study took place at varying points in the course of the subjects episodes, not strictly as the episode commenced. Thus, the results that are reported are based on all prospectively observed major affective episodes that began after intake into the NIMH Collaborative Depression Study. This allowed the propensity for treatment intensity model to include comprehensive information on treatment in prior well intervals and prior depressive episodes. It also permitted us to examine treatment effectiveness in a context that most closely mirrors community practice not influenced by clinical research, since the first prospective episode of depression occurred on average 20 months (median) after remission of the intake episode. In conclusion, this study provides evidence of the effectiveness of higher levels of somatic antidepressant therapy in a more inclusive group of subjects than is generally included in a randomized clinical trial. These findings indicate that clinicians should try to administer higher antidepressant doses and work with patients to overcome obstacles such as side effects, financial costs, and lack of motivation. The results from this observational study extend the generalizability of reports from randomized clinical trials of antidepressants to a wider, more representative group of individuals who suffer from major depressive disorder.

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REFERENCES
1. Bech P, Cialdella P, Haugh MC, Birkett MA, Hours A, Boissel JP, Tollefson GD: Meta-analysis of randomised controlled trials of fluoxetine v placebo and tricyclic antidepressants in the short-term treatment of major depression. Br J Psychiatry 2000; 176:421428[Abstract/Free Full Text] 2. Claghorn JL, Earl CQ, Walczak DD, Stoner KA, Wong LF, Kanter D, Houser VP: Fluvoxamine maleate in the treatment of major depression: a single-center, doubleblind, placebo-controlled comparison with imipramine in outpatients. J Clin Psychopharmacol 1996; 16:113120[Medline] 3. Cohn JB, Crowder JE, Wilcox CS, Ryan PJ: A placebo- and imipramine-controlled study of paroxetine. Psychopharmacol Bull 1990; 26:185189[Medline]

4. Feighner JP, Boyer WF: Paroxetine in the treatment of depression: a comparison with imipramine and placebo. J Clin Psychiatry 1992; 53(Feb suppl):44 47[Medline] 5. Feighner JP, Overo K: Multicenter, placebo-controlled, fixed-dose study of citalopram in moderate-to-severe depression. J Clin Psychiatry 1999; 60: 824 830[Medline] 6. Lydiard RB, Stahl SM, Hertzman M, Harrison WM: A double-blind, placebocontrolled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression. J Clin Psychiatry 1997; 58:484491[Medline] 7. Mendels J, Kiev A, Fabre LF: Double-blind comparison of citalopram and placebo in depressed outpatients with melancholia. Depress Anxiety 1999; 9:54 60[Medline] 8. Meinert CL: Clinical Trials Dictionary: Terminology and Usage Recommendations. Baltimore, Harbor Duvall Graphics, 1996 9. Zimmerman M, Mattia JI, Posternak MA: Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? Am J Psychiatry 2002; 159:469473[Abstract/Free Full Text] 10. Partonen T, Sihvo S, Lonnqvist JK: Patients excluded from an antidepressant efficacy trial. J Clin Psychiatry 1996; 57:572575[Medline] 11. Cochran WG: The effectiveness of adjustment by subclassification in removing bias in observational studies. Biometrics 1968; 24:295313[Medline] 12. Rosenbaum P, Rubin DB: The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70:4155[Abstract/Free Full Text] 13. Rosenbaum PR, Rubin DB: Reducing bias in observational studies using subclassification on the propensity score. J Am Statistical Assoc 1984; 79:516524 14. Rubin DB, Rosenbaum PR: Constructing a control group using multivariate matched sampling methods that incorporate the propensity score. Am Statistician 1985; 39:3338 15. Rubin DB: Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997; 127:757763[Abstract/Free Full Text] 16. Rosenbaum PR: Discussing hidden bias in observational studies. Ann Intern Med 1991; 115:901905[Medline] 17. Rosenbaum PR: Observational Studies. New York, Springer-Verlag, 1995

18. Katz MM, Klerman GL: Introduction: overview of the clinical studies program. Am J Psychiatry 1979; 136:4951[Free Full Text] 19. Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RMA, Shea T: Time to recovery, chronicity and levels of psychopathology in major depression: a prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992; 49:809 816[Abstract/Free Full Text] 20. Endicott J, Spitzer RL: A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1978; 35:837 844[Abstract/Free Full Text] 21. Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria: rationale and reliability. Arch Gen Psychiatry 1978; 35:773782[Abstract/Free Full Text] 22. Keller MB, Lavori PW, Friedman B, Nielsen E, Endicott J, McDonald-Scott P, Andreasen NC: The Longitudinal Interval Follow-Up Evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987; 44:540548[Abstract/Free Full Text] 23. Keller MB: Undertreatment of major depression. Psychopharmacol Bull 1988; 24:7580[Medline] 24. Leon AC, Mueller TI, Solomon DA, Keller MB: A dynamic adaptation of the propensity score adjustment for effectiveness analyses of ordinal doses of treatment. Stat Med 2001; 20:14871498[Medline] 25. Hedeker D, Gibbons RD: A random-effects ordinal regression model for multilevel analysis. Biometrics 1994; 50:933944[Medline] 26. Hedeker D, Gibbons RD: MIXOR: a computer program for mixed-effects ordinal regression analysis. Comput Methods Programs Biomed 1996; 49:157 176[Medline] 27. Hedeker D, Siddiqui O, Hu FB: Random-effects regression analysis of correlated grouped-time survival data. Stat Methods Med Res 2000; 9:161 179[Abstract/Free Full Text] 28. Hedeker D: MIXGSUR: A Computer Program for Mixed-Effects Grouped-Time Survival Analysis: Technical Report. Chicago, University of Illinois at Chicago, 1998 29. Fleiss JL: Statistical Methods for Rates and Proportions, 2nd ed. New York, John Wiley & Sons, 1981

30. Diggle PJ, Liang K-Y, Zeger SL: Analysis of Longitudinal Data. Oxford, UK, Oxford University Press, 1994 31. Endicott J, Cohen J, Nee J, Fleiss JL, Serantakos: Hamilton Depression Rating Scale: extracted from regular and change versions of the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1981; 38:98 103[Abstract/Free Full Text] 32. Klerman GL: Scientific and ethical considerations in the use of placebo controls in clinical trials in psychopharmacology. Psychopharmacol Bull 1986; 22:25 29[Medline]

Focus 2005 American Psychiatric Association

3:114-121

(2005)

INFLUENTIAL PUBLICATION

Integrating Psychotherapy and Pharmacotherapy to Improve Outcomes Among Patients With Mood Disorders
Ripu D. Jindal, M.D., and Michael E. Thase, M.D.

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ABSTRACT
A number of studies have demonstrated comparable benefits of psychosocial interventions and pharmacologic treatments in subgroups of patients with mood disorders. The two

treatment modalities are often combined in clinical practice. However, concerns about the costs of health care are paramount. For the optimum but judicious use of resources, it is valuable for mental health professionals to know the indications for and evidence pertaining to the efficacy of combined treatment. The authors demonstrate that a reexamination of existing research data in light of the recent advances in understanding of the design of clinical trials reveals a systematic underestimation of the benefits of combined treatment for certain subgroups of patients. Existing studies of combined treatments need to be reexamined in light of information about design sensitivity, ceiling effects, and nonspecific placebo effects. The authors summarize by arguing for a new generation of adequately powered investigations of efficacy, which they believe is necessary before the issue of costeffectiveness can be properly addressed. (Reprinted with permission 2003[Abstract/Free Full Text]) from Psychiatric Services 54:14841490,

During the past three decades, treatment standards and practices for mood disorders have undergone enormous changes. As a result of rapid increases in the quality and quantity of empirical data, newer forms of treatment have come into use while others have fallen out of favor. A number of studies have demonstrated comparable benefits for psychosocial interventions and pharmacologic treatments in subgroups of patients. However, with only a few exceptions, these "horse races" did not have the statistical power to detect modestbut still clinically meaningfuldifferences between treatments, and relatively few studies have examined the treatments factoriallythat is, singly and in combination. In our quest to provide the best possible symptom relief to our patients in the quickest possible time, it makes intuitive sense to combine both treatment modalities. Moreover, combined treatments generally receive high marks from consumers (1) and have been recommended by expert consensus panels that reviewed therapeutics for depression (2, 3). However, at the beginning of the 21st century, concerns about the costs of health care are paramount, and routinely providing combined treatment to everyone seeking care would likely overwhelm the capacities of existing health services. Therefore, for the optimum but judicious use of resources, it is valuable for mental health professionals to know the indications for and evidence pertaining to the efficacy of combined treatment. A philosophic switch to evidence-based medicine conveys the need to look for convincing evidence that combined treatment is superior before that approach can be recommended. In some areas, the current weight of empirical evidence does not clearly establish the superiority of combination treatments. Before it can be assumed that these studies have established a lack of additive value of combined treatmentsas opposed to trials that resulted in false-negative resultsthere is a need to evaluate the research methods used in these studies. As we demonstrate in this article, a reexamination of research in light of the recent advances in understanding of clinical trial design reveals a systematic

underestimation of the benefits of combined treatment for certain subgroups of patients. We summarize by arguing for a new generation of adequately powered investigations of efficacy, which is necessary before the issue of cost-effectiveness can be properly addressed.

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THE RATIONALE FOR COMBINED PSYCHOTHERAPY AND PHARMACOTHERAPY

Although combined treatment approaches have found acceptance from a large proportion of mental health professionals, concerns persist that alleviation of symptoms with medication in the absence of the necessary lifestyle changes is a "bandage" rather than a sustainable "cure" (46). However, with time, pharmacotherapy began to be viewed more favorably as a way of hastening recovery and helping patients make better use of psychotherapy (5). Clinical trials of combined treatments were not showing any evidence of a negative effect of combining treatment modalities as had been feared by some (7). Moreover, awareness was increasing of the limitations of psychotherapy as the only treatment. For example, it was becoming clear that psychotherapy alone would be ineffective for mania and depression with psychotic features. The paradigm shift was also aided by the availability of better tolerated medications. Evidence simultaneously accumulated to show that pharmacotherapy alone was insufficient in many cases. Despite effective treatment with medication, patients continued to have interpersonal difficulties, vocational impairment, and poor problem-solving skills. Compared with medication alone, combined treatments were also expected to convey additional benefits over time by reducing demoralization, improving methods of coping with adverse life events, and increasing adherence to medication regimens.

TOP ABSTRACT THE RATIONALE FOR COMBINED... USE OF STATISTICS TO... PRACTICAL ISSUES IN INTEGRATING... RESEARCH FINDINGS CONCLUSIONS REFERENCES

USE OF STATISTICS TO DETECT ADDITIVE EFFECTS

Nevertheless, the primary rationale for combining treatments is to obtain truly additive effects. Theoretically, a synergistic interaction between the treatments used in a combinationfor example, .4 + .3=.9is possible. Unfortunately, such synergy has not been evident in studies of combined treatment for mood disorders (8). In fact, the greatest effect size ever observed in favor of combined treatment was rather modest: .5 + .5=.8 (9). One of the reasons for "incomplete summation" of additive effects is the progressive loss of measurement sensitivity as improvements in symptoms evolve over timethe so-called ceiling effect. This ceiling might be raised if indicators of wellnessfor example, endurance, equanimity, levity, composure, flexibility, reciprocity, creativity, and patience were added to measures of symptom severity to assess outcomes. Reliable measurement of such indicators of "above-average" functioning remains a challenge for researchers who are interested in measuring quality of life. The ceiling effect also results from the fact that a fair proportion of patients with treatmentresistant illness are included in any clinical trial. For example, among approximately 10 to 20 percent of participants in depression studies, depression proves to be refractory to multiple courses of treatment (10). High symptom scores among these nonresponders not only increase the mean scores on key outcome measures but also inflate the standard deviations of the outcome measures. Specifically, the standard deviations of measures such as the Hamilton (11), Beck (12), and Young rating scales (13) typically double across an eight-week randomized controlled trial. Given that effect size is based on the difference between treatments by the standard deviation on that dependent measure, the sensitivity for detecting small to moderate differences in symptom ratings is reduced. This problem is amplified when the lastobservation-carried-forward (LOCF) method is used to impute the outcomes of patients who drop out of the study (14). Although an intent-to-treat approach to data analysis is preferred, the assumption that those who drop out have the same high scores across multiple time points further distorts the variance structure of a longitudinal data set. A second factor that adversely affects design sensitivity is the so-called placebo effect. The placebo effect encompasses spontaneous remission (the probability of improvement within

a fixed period without any intervention), reactivity to repeated measurement, and the beneficial effects of a helping, professional relationship (15). In contemporary randomized controlled trials of antidepressant medications, placebo effects consistently account for between 60 and 80 percent of the response to pharmacotherapy (1517). In all likelihood, such nonspecific effects similarly account for a large amount of the action of the depression-focused psychotherapies (18, 19). For example, in one randomized controlled trial, a measure of the strength of the helping alliance was as predictive of success with pharmacotherapy, either with imipramine or placebo, as it was of success with cognitive and interpersonal psychotherapies (20). It therefore is important to keep in mind that when two treatments are combined it is likely that there is a common placebo-response component that is not additive. Existing studies of combined treatments need to be reexamined in light of this information about design sensitivity, ceiling effects, and nonspecific placebo effects. When these considerations are taken into account, it becomes clear that the study by Keller and colleagues (9), cited above as an example of incomplete summation, found additive or even synergistic effects. On the basis of previous studies (21, 22), at least 30 percent of the patients in the study would have responded to a credible placebo-expectancy intervention. With the active components of pharmacotherapy and psychotherapy each delivering about a 20 percent "specific" response rate (50 percent total response rate minus 30 percent placebo-expectancy rate), an additive effect of 70 percent would be expected (30 percent plus 20 percent plus 20 percent). In fact, the investigators observed a 72 percent intent-totreat response rate in the group that received combined therapy. Once it has been recognized that the specific effects of antidepressant interventions are small, it is imperative to pay close attention to the concept of statistical power. At least 250 patients need to be enrolled in each study group to provide 80 percent power to detect a 15 percent difference in response rates (23). If an even more modest difference of 10 percent is anticipated, at least 500 patients will be needed in each group (24).

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PRACTICAL ISSUES IN INTEGRATING TREATMENT

Combined treatment is provided in two different models: the single-provider model (for example, a psychiatrist or selected nurse practitioners), and a split-treatment model, in which a psychotherapist collaborates with a primary care physician or a psychiatrist. We are not aware of any controlled studies that have established the superiority of one approach over the other. Proponents of an integrated model contend that a single provider is more likely to impart clear, nonconflicting information about the treatment plan than a pair of providers, and they highlight the possibility of splitting of communication. However, the evidence supporting disruption of care as a result of splitting of communication is purely anecdotal. Most community mental health centers and managed care organizations favor a splittreatment model as a way of reducing costs. In base terms, the hourly fee of a psychiatrist is higher than that of other mental health providers. Whether split care does in fact reduce costs is still open to some debate. Compared with nonmedical therapists, psychiatrists tend to treat patients who are more severely ill (25), and, after case complexity is controlled for, the presumed cost differential disappears (26). In fact, Dewan (27), demonstrated that integrated care by a psychiatrist was somewhat less costly than split treatment in analysis of an insurance database. Nevertheless, even if an integrated model proved to be both superior in efficacy and no more costly, there are simply not enough psychiatrists to treat all the patients who might benefit from combined therapy. Service use data reveal that psychiatrists provide no more than 10 percent of psychotherapy and only about 35 percent of the pharmacotherapy provided to patients with mental disorders in the United States (25, 28). These percentages may be even lower for patients with depressive disorders. Another way of reducing costs is to have a primary care physician handle the prescribing. To our knowledge, no randomized comparative studies have been conducted of the outcomes of pharmacotherapy by psychiatrists and by primary care physicians. In one study, pharmacotherapy provided by psychiatrists was markedly more effective than pharmacotherapy provided by primary care physicians (29). However, the patients were not randomly assigned to the two treatment settings. In two other studies, the outcomes of treatment as usual provided by primary care physicians were poor (30, 31). However, in the latter study, advanced training and the use of a carefully outlined pharmacotherapy protocol greatly improved the outcomes of patients who were treated by primary care physicians. Even in the absence of sufficient controlled data, it seems reasonable to say that patients with a complex mood disorderfor example, comorbid agoraphobia, posttraumatic stress disorder, and substance abusewould be better served through combined treatment provided by a psychiatrist.

RESEARCH FINDINGS

MAJOR DISORDER

DEPRESSIVE

Controlled clinical studies show that 40 to 70 percent of patients with major depressive disorder (nonpsychotic nonmelancholic subtype) obtain a satisfactory response with either an antidepressant or one of the newer procedurally specified psychotherapies, such as cognitive-behavioral therapy or interpersonal therapy alone. Such success rates are clearly higher than the spontaneous remission rates observed in control groups of patients on waiting lists and surpass the gains observed in placebo groups or in pseudotherapy attentional control groups about 50 percent of the time. There is a paucity of data on more eclectic psychotherapies, and evidence gathered from randomized controlled trials of well-specified therapies may or may not be applicable. Meta-analyses of early randomized controlled trials among outpatients with depression have shown relatively small additive effect sizes (3, 32). Most of the early studies that used cognitive or behavioral therapies did not detect a statistically significant additive benefit of combined treatment (3336). However, as noted above, interpretation based on these studies must be tempered by concerns about research methods and design sensitivity. More recently, a pooled analysis of nearly 600 outpatients with depression (37) revealed that a combination of pharmacotherapy and interpersonal therapy was associated with remission rates that were about 15 percent higher than those associated with psychotherapy alone among patients with milder major depressive episodes. Although this is a modest effect, it would nevertheless have significant public health implications. Moreover, combined treatment was associated with a more substantial additive effect in a subgroup of patients with severe, recurrent depressive episodes. The major shortcoming of the study was the absence of a group that received pharmacotherapy alone. In perhaps the most influential early study, DiMascio and colleagues (38) studied outcomes with interpersonal therapy and amitriptyline, singly and in combination, compared with a low-contact control condition ("treatment on demand"). In terms of symptom measures, the two component monotherapies were superior to the control condition, and the combination was superior to monotherapies. Results of a secondary analysis of the same data (39) suggested that the three active treatment groups were comparably effective for the subgroup of patients who met research diagnostic criteria (40) for situational, nonendogenous major depressive disorder. By contrast, combined treatment was superior to both monotherapies among the patients with nonsituational, endogenous depression. These findings essentially mirror those observed in the pooled analysis referred to above (37). Thus it appears that a severity (endogenous) grouping can be used to select patients for whom combined treatment is likely to be more cost-effective than either pharmacotherapy or psychotherapy alone.

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In another recent randomized study of outpatients with major depression, combined treatment was found to be more acceptable to patients and was associated with a significantly lower dropout rate and a significantly higher remission rate than medication alone (41). The study used short-term psychodynamic supportive psychotherapy and a three-step successive medication regimenfluoxetine, amitriptyline, and moclobemide, in that order, depending on intolerability or inefficacyas pharmacotherapy. Two small studies of hospitalized patients with depression produced evidence favoring a combined strategy over medication management (42, 43). In a secondary analysis, Miller and colleagues (44) observed a particularly large additive effect for combined treatment among patients with high levels of dysfunctional attitudes. Because patients with this pattern of negative thinking also tend to respond less favorably to cognitive-behavioral therapy alone (45), one would presume that the advantage of combined treatment over psychotherapy alone would be evident. Although the data from controlled trials are sparse, it appears that the combination of cognitive-behavioral therapy and pharmacotherapy may be especially useful for patients with depression during and after an acute psychiatric hospitalization. Three randomized controlled trials have been published of combined treatment among chronically depressed outpatients. Ravindran and colleagues (21) found no additive benefit of a combination of group cognitive-behavioral therapy and sertraline in a study of 97 outpatients with dysthymia. The group cognitive-behavioral therapy was no more effective than placebo, which calls into question the efficacy of the psychosocial intervention. Browne and associates (46) conducted a randomized controlled trial among 707 patients with chronic depression who were randomly assigned to one of three treatment groups: interpersonal therapy alone, sertraline therapy alone, and a combination of sertraline and interpersonal therapy. Although all treatment modalities proved to be reasonably effective over a two-year period, sertraline alone or in combination was more effective than interpersonal therapy alone. The major finding in support of combined treatment was that patients had lower overall health and social service costs than patients receiving monotherapies. In a multicenter trial of more than 650 patients with chronic depression (9), combined treatment was associated with substantially better response and remission rates than both monotherapies, which had virtually identical outcomes. The study used the cognitivebehavioral analysis system of psychotherapy, an individual therapy specifically developed for the treatment of chronic depression (47), as the psychotherapeutic intervention and nefazodone as pharmacotherapy. The longer term effects of combined treatment have been documented in three studies. In the first study of continuation therapy, Klerman and colleagues (48) did not detect significant benefits of combined treatment over pharmacotherapy alone in preventing relapses. However, there was a later emerging trend of a higher level of social adjustment in a subgroup of patients who received individual psychotherapy. Moreover, the study may have underestimated the benefit of the psychotherapeutic intervention, because all the

patients had responded to amitriptyline before they began psychotherapy. (The study group was preselected for responsiveness to pharmacotherapy, not psychotherapy.) Two more recent studies have evaluated the efficacy of combined treatment in the maintenance phase of recurrent depression. In both these studies, all patients received combined treatment during the acute and continuation phases. In the first study (49), which involved 125 outpatients with highly recurrent major depression who were between the ages of 19 and 65 years, combined maintenance phase treatmentinterpersonal therapy sessions plus imipraminewas not associated with better prophylaxis than imipramine alone during a 36-month blinded maintenance phase. In the second study, 107 depressed outpatients aged 60 or older who had stabilized during the acute and continuation phases of treatment with nortriptyline and interpersonal therapy participated in a double-blind, placebo-controlled maintenance-phase study (50). The patients who continued to receive combination treatment were less likely to have a recurrence than were those in either of the monotherapy conditions. Interestingly, the outcome of pharmacotherapy alone in that study was less robust than the results of Frank and colleagues (49), which probably points to the relatively greater advantage of combined therapy when patients have higher inherent risk of recurrent depression. Sequential treatment strategies have also been investigated. In one study, a three-month course of cognitive-behavioral therapy among 40 patients who had responded to pharmacotherapy but whose illness was not in remission was shown to have additive effects on residual depressive symptoms (51). In follow-up reports, the group that received cognitive-behavioral therapy had a significantly better chance of discontinuing medication without relapse (52) as well as a sustained decrease in the risk of recurrence (53). Paykel and colleagues (54) replicated these findings in a larger two-center study of 158 patients with incomplete remission who were taking antidepressants. The patients received 18 sessions of individual cognitive-behavioral therapy. The group that received cognitivebehavioral therapy in addition to pharmacotherapy had about a 50 percent reduction in relapse risk. A third study investigated the efficacy of sequential cognitive-behavioral therapy treatment during the maintenance phase (55). In that study, 40 patients whose illness was in full remission and who had a history of highly recurrent depression were randomly assigned to receive either 14 sessions of cognitive-behavioral therapy or supportive medication management during withdrawal of antidepressant pharmacotherapy. Again, the addition of cognitive-behavioral therapy was associated with a significantly reduced risk of recurrence over the next two years.

BIPOLAR

DISORDER

There is a broad consensus that mania should not be treated with psychotherapy alone (56). Specifically, the efficacy of several types of pharmacotherapy has been established for mania, whereas there is virtually no evidence that psychotherapy alone is effective. An exception may be made if a manic patient refuses pharmacotherapy. Even then, the ability of a manic individual to make informed treatment choices is always worrisome. In such

cases, involuntary treatment, guardianship procedures, and mental health advance directivesdepending on the jurisdictionare some of the options. Some of the information discussed in another paper in this issue of Psychiatric Services (57), about combined treatment for schizophrenia, could also be relevant to mania. Perhaps surprisingly, combined treatments for mania have received much less systematic inquiry than have those for schizophrenia, possibly because the therapeutic benefits of pharmacotherapy were overvalued until the early 1990s (58). Eventually, it became clear that bipolar disorder is more often than not a recurrent and life-disrupting severe mental illness associated with profound morbidity and elevated mortality (59). Furthermore, evidence of the effects of psychosocial factors such as stressful life events (60), high levels of expressed emotion (61), marital discord (62), and social support (63) on relapse rates among patients with mania led to the studies of various modalities of psychosocial interventions in relapse prevention. In the first large study of combined treatment, Perry and associates (64) evaluated a brief individual psychoeducation intervention (average duration of seven sessions). Apart from the information about the disorder and its treatment, patients were informed of the early warning signs of impending relapse and were provided assistance in developing relapse prevention plans. Compared with treatment as usual, the additional psychoeducational sessions were associated with significantly lower rates of relapses of manic episodes. The second study (65) evaluated a longer term model of family-focused therapy provided soon after discharge from inpatient treatment. All participants received pharmacotherapy as part of the study and were randomly assigned to receive either clinical management (N=70) or 21 sessions of family-focused therapy over a nine-month period (N=31). A preliminary report on the outcomes of nine patients who received family-focused therapy yielded promising resultsone relapse, or 11 percent, compared with 14 relapses in a historical control group of 23, or 61 percent. Results of the prospective study confirmed the benefit of family-focused therapy over the comparison condition for the first year, in terms of both fewer depressive relapses and lower levels of depressive symptoms. No significant association with risk of manic relapse was found. Adherence to medication regimens and reduced levels of expressed emotion were associated with outcome independent of treatment assignment. Thus, it seems that improved outcome with family-focused therapy was not mediated by medication adherence or lower levels of expressed emotion. However, the advantage of family-focused therapy was most pronounced among patients who lived in households with high levels of expressed emotions, particularly if the patient had not fully recovered from the index episode. The third study examined a modified form of interpersonal therapy, adapted to help patients develop more stable social rhythms, known as interpersonal social rhythms therapy (IPSRT) (66). All patients received appropriate pharmacotherapy for their index episodes. In addition, the study used a 2 x 2 sequential design for psychosocial intervention; half the patients received IPSRT for acute-phase management, and the other half received clinical management. During the maintenance phase of the study, half the patients in remission in

each group continued to undergo the same treatment strategy, and half switched treatment strategiesthat is, from IPSRT to clinical management or vice versa. As expected, IPSRT was not significantly associated with enhancement of patients lifestyle regularity (67). Moreover, the patients who received maintenance IPSRT experienced a significant reduction in depressive symptoms and an increase in the number of euthymic days (68). However, IPSRT was not associated with improvement in acute-phase treatment outcomes or time to remission (69, 70). Furthermore, discontinuation of acute-phase IPSRT was associated with an increase in risk of relapse, whereas the addition of maintenance IPSRT was not associated with a lower risk of relapse (71). Individual and group cognitive therapy also are being investigated as adjunctive treatments for bipolar disorder (72, 73). Although results of controlled studies are pending, the results of preliminary studies suggest that these modalities have antidepressant effects (74) and are likely to lower the risk of relapse among patients with mania (7577). Taken together, the results of these studies provide support for the addition of focused psychosocial treatment for patients receiving pharmacotherapy for bipolar disorder. Familyfocused and interpersonal therapeutic interventions appear to help with depressive symptoms. Psychoeducation and relapse prevention training may even reduce the risk of manic relapse.

TOP ABSTRACT THE RATIONALE FOR COMBINED... USE OF STATISTICS TO... PRACTICAL ISSUES IN INTEGRATING... RESEARCH FINDINGS CONCLUSIONS REFERENCES

CONCLUSIONS
Sufficient evidence now exists that focused psychosocial interventions have significant benefit when combined with pharmacotherapy for some patients. The added benefit of combined treatment is best established for severe, recurrent, and chronic major depressive disorder and bipolar affective disorder. It is possible that the added benefits of psychotherapy are nonspecificfor example, mediated by low levels of expressed emotion in a household or improved medication adherence. It remains to be seen whether there are also therapy-specific outcomes.

Little evidence exists that combined psychotherapy and pharmacotherapy should be considered a routine standard of care for less pervasive or milder depression. On the basis of this evidenceor lack thereofit seems reasonable that patients with these forms of depression should receive one of the monotherapies first, based on availability and patient preference, and the alternative strategy considered in sequence or in combination for patients who are less responsive to treatment. Resolution of several issues calls for future research. One such issue is determination of whether combined treatment by a single provider offers additional advantages. Another is replication of findings from specialty research clinics to everyday practice settings. Treatments that convey only benefit when provided by highly skilled expert therapists in tertiary care settings may not be the same as the ones provided to patients who are treated in busy urban clinics or community mental health centers. Much work remains to be done before we can truly make informed choices.

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INFLUENTIAL PUBLICATION

Effects of Cognitive Therapy on Psychological Symptoms and Social Functioning in Residual Depression
Jan Scott, F.R.C.Psych., John D. Teasdale, Ph.D., Eugene S. Paykel, F.R.C.Psych., Anthony L. Johnson, C.Stat., Rosemary Abbott, Ph.D., Hazel Hayhurst, Ph.D., Richard Moore, Ph.D., and Anne Garland, B.A.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

ABSTRACT
Background: About 30% of psychiatric out-patients with major depression demonstrate partial remission. Aims: To explore whether the addition of cognitive therapy (CT) had any differential effect on residual symptoms or social adjustment. Method: Patients with residual symptoms of major depression (n=158) were randomised to receive clinical management (CM) alone, or CM plus 18 sessions of CT. Subjects depressive symptoms and social functioning were assessed regularly over 16 months. Results: The addition of CT produced statistically significant differential effects on: two out of four measures of overall severity of depression; specific psychological symptoms (guilt, self-esteem and hopelessness); and social functioning (including dependency, interpersonal behaviour and friction). Conclusions: In patients showing only partial response to antidepressants, the

addition of CT produced modest improvements in social and psychological functioning. The implications for research on the mechanisms of action of CT are discussed. (Reprinted with permission from the British Journal of Psychiatry 2000; 177:440446)

About 30% of psychiatric out-patients report residual depressive symptoms following treatment for acute depression (Paykel et al, 1995). These symptoms are frequently drug refractory (Cornwall & Scott, 1997). Our recent large, randomised controlled trial of 18 sessions of cognitive therapy (CT) with clinical management (CM) versus clinical management alone in 158 subjects with residual depressive symptoms who were receiving antidepressants (Paykel et al, 1999) demonstrated that remission rates at 20 weeks were significantly greater in the CT plus CM group (24%) than in the CM alone group (11%). Cumulative rates of persistent symptoms or relapse were also significantly lower in the CT that in the control group: 10% v. 18% at 20 weeks, 24% v. 40% at 44 weeks, and 29% v. 47% at 68. This study explores whether the addition of CT to CM plus medication has any differential effects on the psychological and social functioning of individuals with residual depression and how any changes relate to the reduced relapse rates.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

METHOD
The methodology has been described in detail by Paykel et al (1999). Key aspects are highlighted here.

SUBJECTS
Subjects were psychiatric out-patients aged 2165 years, who had satisfied DSM-III-R (American Psychiatric Association, 1987) criteria for major depression within the last 18

months. At randomisation, subjects were required to have current residual symptoms of at least 8 weeks duration. At entry, these symptoms needed to reach both: (a) a score of eight or more on the 17-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967) and (b) nine or more on the Beck Depression Inventory (BDI; Beck et al, 1961). These criteria were modified from Frank et al (1991). Patients were excluded if they had a history of manic episodes, cyclothymia, schizoaffective disorder, definite drug or alcohol dependence, persistent antisocial behaviour or organic brain damage and where any other Axis I disorder was primary at the time of the index illness. Also excluded were patients meeting DSM-III-R criteria for borderline personality disorder, patients who persistently repeated self-harm, those with learning disabilities (IQ estimated clinically to be below 70), or other intellectual or linguistic factors precluding participation in the study and patients currently receiving formal psychotherapy. Patients who had previously received CT for more than five sessions were also excluded. Patients with DSM-III-R dysthymia were included, provided that the criteria for major depression were satisfied and the onset of dysthymia was not before age 20 years. Patients were required to have been taking antidepressant medication for at least the previous 8 weeks, with at least 4 weeks at an adequate dose, defined as a minimum equivalent to 125 mg per day of amitriptyline and to have definite current side-effects, or to have refused explicitly to increase the dose of medication. Most doses and lengths of treatment were far in excess of this.

STUDY

DESIGN

The study was a parallel two group trial employing 20 weeks treatment and 1-year followup. The treatment phase comprised 20 weeks of randomised treatment, during which all patients received drug continuation and CM, and one group received additional CT. Following this was a followup phase of 48 weeks, during which antidepressants, CM and rating procedures were continued. After written informed consent, patients provided a full set of baseline ratings and were then randomised. Assignments in consecutively numbered sealed envelopes were prepared by the trial statistician (A.L.J.) stratified by centre, previous major depressive episodes (two or more v. fewer); length of present illness, including both index major depression and residual symptoms (1 year or more v. less); and severity of index major depression (global ratings of mild or moderate v. severe or psychotic). The pre-set sample size was 160 subjects (80 per treatment group), which gave 80% power to detect by the log-rank test at P=0.05 (two-tailed) a 50% reduction in relapse rates for 40 to 20% and an effect size of 0.45 in two-tailed parametric tests of continuous measures.

TREATMENT
Drug continuation and CM involved sessions of about 30 minutes each with a study psychiatrist every 4 weeks during the treatment phase, and every 8 weeks during the followup phase. The content of interviews was modified from Elkin et al (1989). In our model,

symptoms were rated, limited support provided and drugs prescribed. Use of specific cognitive and behavioural techniques was not allowed. Patients were continued on the same anti-depressant as at inclusion, but a dosage increase was permitted to 30% greater than at the point of inclusion and up to a total of two consecutive extra out-patient sessions once weekly. No formal psychotherapy was permitted without withdrawal from the study. Sessions were audiotaped and monitored to ensure protocol compliance and absence of cognitive therapy. Patients allocated to CT in addition to CM plus medication were seen for 16 CT sessions over 20 weeks plus two booster sessions at approximately Week 26 and Week 32. The therapy was modified from Becks original model (Beck et al, 1979) and a manual was used (Scott, 1998). Therapists were already trained and experienced in CT and during the study there was regular joint supervision of the two therapists by J.S. Sessions were audiotaped and assessed by an independent rater to ensure therapist competency and fidelity to the CT.

ASSESSMENTS
Subjects were assessed every 4 weeks until Week 20 and every 8 weeks thereafter by the study psychiatrist, and at baseline, 8, 20 and 68 weeks by a research assistant. Both were blind to treatment group and patients were requested not to reveal any details that might prejudice blindness. As total blindness is difficult to achieve, we incorporated three additional strategies. First, we gave subjects clear instructions that they should try to avoid revealing information about which group they had been allocated to. Second, we asked the raters to make guesses of group allocation. Third, all potential cases of relapse or withdrawal from the study were subjected to independent rating by a rater who was blind to treatment. Baseline clinical assessments are described in detail elsewhere (Paykel et al, 1999), and included: history of present and previous episodes; personal history; premorbid personality functioning (including the Eysenck Personality Inventory); Schedule for Affective Disorders and Schizophrenia modified for DSM-III-R criteria; treatments received and levels of adherence. The symptom measures described below were rated at baseline and at follow-up assessments. Ratings on the HRSD and BDI were used to categorise subjects into pre-defined remission, persistent symptoms and relapse groups in our previous paper (see Paykel et al, 1999), but group mean scores over time were not described. As these scales are the most widely used observer and self-rating measures of depression, the repeated ratings are reported here. The other repeated ratings included the following. Raskin Depression Scale (Raskin et al, 1970) The Raskin Depression Scale (RDS) was used as a global rating of depression severity. It explores the extent to which an individual demonstrates depression on three sub-scales (rated 15): verbal self-report, behaviour and secondary symptoms of depression. Scores range from 315, with higher scores indicating greater severity.

Clinical Interview for Depression (Paykel, 1985) The Clinical Interview for Depression (CID) is a 36-item scale which also provides separate total scores for anxiety (four items) and depression (10 items). The CID was used as it is particularly useful for discriminating between treatment effects on individual symptoms. Each item is rated on a seven-point scale (1, absent; 7, severe) making the CID more sensitive than other depression rating scales. The items included in the depression rating were: depressed mood, depressed appearance, guilt and self-esteem, hopelessness and pessimism, suicide risk, work interests, anorexia, delayed insomnia, retardation and agitation. We also included initial insomnia as this may be important in residual depression (Paykel et al, 1995; Fava, 1999). Social Adjustment Scale (Weissman & Paykel, 1974) The Social Adjustment Scale (SAS) was rated less frequently (at Week 0, 20 and 68). The SAS is an established measure of social and vocational functioning, using a semi-structured interview to assess areas such as work and leisure activities as well as assessing behaviours across these different domains such as dependency, interpersonal interactions and friction in relationships. Each item is rated on a five-point scale. Mean sub-scale scores were derived by summing scores on each relevant item and then dividing by the number of items rated. Scores ranged from 1 to 5, with lower scores indicating a higher level of functioning. An overall social adjustment rating is derived from the scores on each of the nine sub-scales.

DATA

ANALYSIS

An intention to treat analysis (including all randomised patients) was undertaken. Repeated measures analysis included as covariates the five stratification variables used in randomisation, and five additional variables considered possibly important: HRSD at entry, Eysenck Personality Inventory, neuroticism sub-scale (EPI-N) score, age at entry, gender and presence of melancholia at index major depressive episode. In addition, initial ratings on the specific item being analysed were included as a covariate. Initially, for each of the five assessment scales (HRSD, BDI, RDS, CID, SAS) plots of standard deviation against mean for each group at each visit were produced to assess the relationship between the two. In most instances these plots indicated that analysis of raw (untransformed) data was appropriate; others, however, required log transformation. Repeated measures analyses of variance of the separate assessment scales of depressive symptoms were carried out in SAS version 3.2 for Windows using a mixed model (PROC MIXED) which can cope with the unbalanced effect that arises from missing observation. The analysis incorporated two between-subject effects (between groups and between subjects within groups) and three within-subject effects (between times, group by time interactions and random variation). The time effect and its interaction with group were broken down into linear, quadratic and cubic components. The advantages of using mixed models for the analysis of repeated measures with missing data over the more traditional approaches using general linear models have recently been documented (Cnann et al, 1997; Everitt, 1998; Albert, 1999). The mixed model also requires specification of the withinsubject covariance structure, that is, the way in which both the variation within subjects and the correlation between measures assessed at different time points change with time. To assess this, analyses were produced using three separate structures: compound symmetric,

where the variation between subjects (within treatment groups) at each time point and the correlation between measures at different time points (irrespective of the interval between them) are both constant; first-order autoregressive (AR(1)), where the variation within subjects at each time point is constant and the correlation between measures at two different time points decays (in a structured way) with separation; and unstructured, where no pattern is imposed. Type III hypotheses for fixed effects were incorporated to ensure that all baseline covariates were adjusted for simultaneously. Nominal study weeks were used as the measure of time, with the initial interview taken as baseline. Comparative runs were undertaken for the treatment phase (Weeks 420), followup phase (Weeks 2868) and whole study (Weeks 468). As social adjustment was assessed on only three occasions, two separate analyses of variance were used to assess changes in ratings by group and time (at Week 20 and Week 68 with baseline ratings as a covariate). One subject from the control group was excluded from all analyses because of insufficient baseline data. In all other cases, missing baseline values were replaced by treatment group means. The 5% level was used for deciding statistical significance.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

RESULTS STUDY FLOW AND DROP-OUT

Two hundred and thirty patients appeared to meet criteria for the study, but 72 individuals refused full assessment or randomisation. Of the 158 subjects who agreed to participate, 78 subjects were randomised to CM alone and 80 to CT plus CM. In the CM only group 66 subjects (85%) adhered to protocol until the end of the study or until relapse, while 61 of the CT plus CM group (76%) did so. Full or fairly complete ratings to relapse or end of study were obtained for all except six subjects in the CM and 10 in the CT plus CM groups (see Paykel et al, 1999).

INITIAL

CHARACTERISTICS

OF

TREATMENT

GROUPS

Initial characteristics of the two treatment groups demonstrated that they were closely

comparable on key variables (see Table 1 ). Subjects had a mean age of 43 years and, unusually for a depression study, about 50% were male. The majority of index episodes (including residual symptoms) were over 1 year in duration, and the index major depressive episodes were rated as severe in over 50% of cases. Two-thirds of subjects had a history of depression. Mean symptom ratings at baseline were in the middle of the residual depression range (Paykel et al, 1995): HRSD (12.2; s.d.=2.8), BDI (22.1; s.d.=7.9), RDS (6.4; s.d.=1.4) and CID depression total (25.0; s.d.=3.7) respectively. The mean CID anxiety score was 9.6 (s.d.=3.8). The mean SAS score was 2.1 (s.d.=0.5), suggesting moderate levels of social impairment.

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Table 1. Baseline Characteristics

CHANGES

IN

DEPRESSION

Over the 20-week acute treatment phase, the HRSD, BDI, RDS, CID depression and CID anxiety scores fell by about 20% (see Table 2 ). There were no statistically significant between-group differences or group by time interactions.

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Table 2. Repeated Measures Analysis of Depression Ratings

Throughout the treatment and follow-up phases, there was a non-significant trend toward

lower HRSD, BDI and CID anxiety scores in the CT plus CM group as compared with the CM only group (see Fig. 1 ).

Figure 1. Mean Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory (BDI) Scores Over Time by Group

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Over the whole study period there were significant group by time interactions for CID depression (F=4.6; d.f.=1323; P=0.03) and RDS scores (F=4.4; d.f.=1319; P=0.04) and two individual CID items measuring key psychological symptoms of depression (see Table 2 ). The first item assessed guilt and self-esteem (F=6.6; d.f.=1323; P=0.01), and the second item assessed hopelessness and pessimism (F=6.8; d.f.=1323; P=0.01). As shown in Fig. 2 , differences between groups were most marked on all ratings in the first 6 months of follow-up (Weeks 2044), but then converged by final follow-up (at Week 68). At Week 44 the mean difference between groups was 0.44 (95% CI 0.050.83) for guilt and self-esteem, and 0.65 (95% CI 0.281.01) for hopelessness and pessimism. There were no statistically significant between-group differences or group by time interactions for the other CID depression items.

Figure 2. Mean Clinical Inventory for Depression Score Over Time by Group: (a) Depression Total; (b) Individual Item Score for Guilt and Self-Esteem; (c) Individual Item Score for Hopelessness and Pessimism

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CHANGES

IN

SOCIAL

ADJUSTMENT

The total SAS score and all sub-scale scores changed over time between baseline assessment and Week 20 and between baseline and Week 68. As shown in Table 3 , significant between-group differences emerged by the end of the acute treatment phase for total SAS score (F=7.6; d.f.=1129; P=0.01) and for four of the sub-scale scores: dependency (F=4.2; d.f.=1127; P=0.04), friction (F=5.25; d.f.=1128; P=0.02), interpersonal behaviour (F=4.7; d.f.=1128; P=0.03) and interaction with extended family (F=4.1; d.f.=1123; P=0.04).

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Table 3. Comparison of Social Functioning Between Groups

By Week 68 these between-group differences were no longer apparent. Neither group had

returned to the baseline level of functioning. However, group means converged between Weeks 20 and 68.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

DISCUSSION
We have demonstrated that, in comparison with CM alone, CT plus CM may have a particular role in the prevention of relapse in subjects with residual depression (Paykel et al, 1999). This paper shows that CT plus CM has statistically significant differential effects on some drug-refractory residual symptoms. Taken together, these data allow an exploration of how CT reduces relapse rates. There appear to be three potential mechanisms of relapse prevention: overall reduction in levels of depressive symptoms or social impairment, changes in specific symptoms associated with relapse, and changes in individual coping skills.

OVERALL

REDUCTION

IN

DEPRESSIVE

SYMPTOMS

Both the CM only and the CT plus CM groups showed statistically significant changes in overall levels of depressive symptoms and social adjustment over time. However, there were relatively few significant between-group differences in depressive symptom ratings and these only became significant when assessed over the 68-week study period. In comparison with control subjects, CT subjects showed greater reductions in RDS score and CID total depression score. While these differences were statistically significant, the actual differences in mean scores between groups were modest. Furthermore, similar trends on the HRSD and BDI scores did not reach statistical significance. It is feasible, but not proven, that there was less possibility of demonstrating treatment effects because patients had lower levels of baseline symptomatology than those reported in acute treatment studies. However, our findings do not demonstrate with any certainty that overall reduction in level of residual depressive symptoms is a clinically meaningful explanation of reduced relapse rates. Significant between-group differences in social adjustment were most marked during the acute treatment phase. Improving social adjustment is important given the 6080% prevalence of subjective impairment in partially remitted depression and its association with subsequent relapse (Mintz et al, 1992; Fava, 1999). The changes in SAS sub-scale scores may reflect the specific targeting with CT of certain personality traits that are often

associated with persistent depression (e.g. dependency), while changes in interpersonal behaviour and reduced friction in relationships may reflect more explicit emphasis on interpersonal context when using CT in chronic affective disorders (Markowitz, 1994; Scott, 1995). However, by Week 68 there were no significant between-group differences on any SAS sub-scale score.

CHANGES

IN

SPECIFIC

SYMPTOMS

The second hypothesis is that changes in specific symptomatology are critical in relapse prevention. The findings that there were significant group by time interactions for changes in CID item scores for guilt and self-esteem, and hopelessness and pessimism, replicate previous research. In one of the earliest studies, Rush et al (1981) reported that CT was particularly associated with changes in mood, views of self and hopelessness. Furthermore, CT was associated with greater reductions in hopelessness and improvements in self-esteem than antidepressant medication (Rush et al, 1982). Later studies comparing CT with medication that controlled for initial severity and/or chronicity of symptoms (e.g. Imber et al, 1990) failed to find any mode-specific effects for the psychological and pharmacological interventions employed. However, none of the studies was of similar statistical power to the present one. Given the explicit targeting in CT of symptoms such as low self-esteem and hopelessness (and of interpersonal problems in chronic depression), the specific symptom changes noted above are not unexpected. However, there is only limited evidence to support the view that low self-esteem and feelings of hopelessness predict future depressive relapse (e.g. Evans et al, 1992; Paykel et al, 1995). The known association between expressed emotion, marital dissatisfaction and depressive relapse (e.g. Hooley & Teasdale, 1986) may mean that reducing friction in relationships was particularly beneficial. Interestingly, Hayhurst et al (1997) noted higher levels of criticism when one partner had residual depressive symptoms. The most frequently reported critical comments were about depression and depressed mood in general (39%) and dependency in particular (15%).

CHANGES

IN

INDIVIDUAL

COPING

SKILLS

The final hypothesis takes into account that changes in residual symptoms alone may not be a sufficient explanation of the changes in relapse rates. In studies of the use of CT in panic disorders it has been demonstrated that, although CT reduces the risk of relapse, individuals are often left with substantial levels of residual symptoms of anxiety. It is suggested that CT may prevent relapse primarily by preventing the escalation of these anxiety symptoms to panic in response to internal or external stressors. Our data also appear to show that relapse rates can be significantly reduced without gross changes in depressive symptoms. In a comprehensive theoretical review, Persons (1993) suggested that one mechanism of action of CT was that it taught people compensatory skills that allowed them to manage their symptoms and problems more effectively. In our studies, the significant association between CT and relapse prevention in the absence of a strong association between CT and symptom reduction suggests that, in residual depression at least, patients are learning how to cope with persistent symptoms so that they are less likely to escalate to relapse.

CLINICAL IMPLICATIONS The reduced risk of relapse with cognitive therapy (CT) plus clinical management (CM) as compared with clinical management alone is clinically worthwhile, but there is a less marked effect of CT plus CM on symptom ratings. The differential effect of CT plus CM on specific symptoms such as guilt, selfesteem, hopelessness and pessimism replicates the patterns of change seen in other CT studies of acute depression. The study offers evidence that the mechanism of action of CT in residual depression may be to change coping skills rather than to ameliorate all depressive symptoms. LIMITATIONS Given the low levels of symptoms reported at baseline assessment, it is difficult to demonstrate large differential treatment effects on individual symptoms. It can be argued that the statistically significant differences in symptom ratings reported may not be clinically significant. Pharmacotherapists and cognitive therapists respectively may argue that the dose and/or duration of the antidepressant medications or the CT were sub-optimal.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

REFERENCES
Albert, P. (1999) Longitudinal data analysis (repeated measures) in clinical trials. Statistics in Medicine, 1817071731.[Medline] American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders (3rd edn, revised) (DSM-III-R). Washington, DC: APA.

Beck, A. T., Ward, C. H., Mendelson, M., et al (1961) An inventory for measuring depression. Archives of General Psychiatry, 4561571.[Abstract/Free Full Text] Beck, A. T., Rush, A. J., Shaw, B. F., et al (1979) Cognitive Therapy of Depression. New York: John Wiley. Cnann, A., Laird, N. M. & Slasor, P. (1997) Tutorial in biostatistics, using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. Statistics in Medicine, 1623492380.[Medline] Cornwall, P. & Scott, J. (1997) Partial remission in depressive disorders. Acta Psychiatrica Scandinavica, 95265271.[Medline] Elkin, I., Shea, M. T., Watkins, J. T., et al (1989) National Institute of Mental Health Treatment of Depression Collaborative Research Program: general effectiveness of treatment. Archives of General Psychiatry, 46971 982.[Abstract/Free Full Text] Evans, M. D., Hollon, S. D., De Rubeis, R. J., et al (1992) Differential relapse following cognitive therapy and pharmacotherapy for depression. Archives of General Psychiatry, 49802808.[Abstract/Free Full Text] Everitt, B. S. (1998) Analysis of longitudinal data: Beyond MANOVA. British Journal of Psychiatry, 172710.[Abstract/Free Full Text] Fava, G. (1999) Subclinical symptoms in mood disorders: pathophysiological and therapeutic implications. Psychological Medicine, 294761.[Medline] Frank, E., Prien, R. F., Jarrett, R. B., et al (1991) Conceptualisation and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse and recurrence. Archives of General Psychiatry, 48851 855.[Abstract/Free Full Text] Hamilton, M. (1967) Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology, 6278296. Hayhurst, H., Cooper, Z., Paykel, E., et al (1997) Expressed emotion and depression. British Journal of Psychiatry, 171439443.[Abstract/Free Full Text] Hooley, K. & Teasdale, J. (1986) Predictors of relapse in unipolar depressives: expressed emotion, marital distress and perceived criticism. Journal of Abnormal Psychology, 98229235. Imber, S., Pilkonis, P., Sotsky, S., et al (1990) Modespecific effects among three treatments of depression. Journal of Consulting and Clinical Psychology, 58352 359.[Medline]

Markowitz, J. (1994) Psychotherapy for dysthymia. American Journal of Psychiatry, 151114121. Mintz, J., Mintz, L., Arruda, M., et al (1992) Treatment of depression and functional capacity to work. Archives of General Psychiatry, 49761 768.[Abstract/Free Full Text] Paykel, E. S. (1985) The clinical interview for depression. Development, reliability and validity. Journal of Affective Disorders, 98596.[Medline] Paykel, E. S., Ramana, R., Cooper, Z., et al (1995) Residual symptoms after partial remission: an important outcome in depression. Psychological Medicine, 251171 1180.[Medline] Paykel, E. S., Scott, J., Teasdale, J., et al (1999) Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Archives of General Psychiatry, 56829835.[Abstract/Free Full Text] Persons, J. (1993) The process of change in cognitive therapy: schema change or acquisition of compensatory skills? Cognitive Therapy and Research, 17123137. Raskin, A., Schulterbrandt, J., Reatig, N., et al (1970) Differential response to chlorpromazine, imipramine and placebo. A study of subgroups of depressed patients. Archives of General Psychiatry, 23164173.[Abstract/Free Full Text] Rush, A., Kovacs, M., Beck, A., et al (1981) Differential effects of cognitive therapy and pharmacotherapy on depressive symptoms. Journal of Affective Disorders, 3221229.[Medline] Rush, A., Beck, A. T., Kovacs, M., et al (1982) Comparison of the effects of cognitive therapy and pharmacotherapy on hopelessness and self-concept. American Journal of Psychiatry, 139862866.[Abstract/Free Full Text] Scott, J. (1995) Psychological treatments of depression: an update. British Journal of Psychiatry, 167289292.[Free Full Text] Scott, J. (1998) Where theres a will...cognitive therapy for chronic depression. In Cognitive Therapy for Complex Cases (eds N. Tarrier, G. Haddock & A. Wells). London: John Wiley & Sons. Weissman, M. & Paykel, E. S. (1974) The Depressed Woman: Study of Social Relationships. Chicago, IL: University of Chicago Press.
Focus 2005 American Psychiatric Association 3:131-135 (2005)

INFLUENTIAL PUBLICATION

Differential Responses to Psychotherapy Versus Pharmacotherapy in Patients With Chronic Forms of Major Depression and Childhood Trauma
Charles B. Nemeroff, Christine M. Heim, Michael E. Thase, Daniel N. Klein, A. John Rush, Alan F. Schatzberg, Philip T. Ninan, James P. McCullough, Jr., Paul M. Weiss, David L. Dunner, Barbara O. Rothbaum, Susan Kornstein, Gabor Keitner, and Martin B. Keller

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

ABSTRACT
Major depressive disorder is associated with considerable morbidity, disability, and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy, or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma. (Reprinted with permission from the Proceedings of the National Academy of Sciences of the United States of America 2003; 100:1429314296[Abstract/Free Full Text]. Copyright 2003 National Academy of Sciences, U.S.A.)

Mood disorders are common illnesses, and major depression is the most common, affecting 17% of the population in the United States in their lifetime, with women (21.3%) having a higher prevalence rate than men (12.7%) (1). Depression is associated with significant morbidity, disability (loss of work days, reduced quality of life), increased medical comorbidity (cardiovascular disease and stroke), and mortality (increased risk for suicide and death from comorbid medical disorders) (24). Effective treatments for depression are available, including a variety of antidepressants, electroconvulsive therapy, and certain types of targeted psychotherapy such as cognitive-behavioral and interpersonal therapy (5). Research comparing antidepressant medication to cognitive-behavioral and interpersonal psychotherapy has generally found that both are equally effective for nonpsychotic forms of depression (6, 7). The combination of antidepressant medication and psychotherapy seems to provide only a modest increment in efficacy, although there may be some patients for whom combination therapy is more effective than medication or psychotherapy alone (8, 9). Unfortunately, there are few predictors of response to any particular treatment, leaving both patients and clinicians to engage in often multiple trial and error attempts to identify the preferred treatment. In general, constellations of particular symptoms, such as the presence of a sleep disturbance or anxiety, have not proved helpful in predicting response to one or another pharmacological or psychotherapeutic treatment (10). One notable exception is the clear demonstration that major depression with psychotic features requires treatment with a combination of both antidepressant and antipsychotic medications or electroconvulsive therapy (11). Another exception is the superior efficacy of monoamine oxidase inhibitors (MAOIs) in the treatment of depression with atypical features, e.g., hypersomnia, hyperphagia, mood reactivity, interpersonal rejection sensitivity, leader limb paralysis, and reverse diurnal mood variation. When to recommend psychotherapy, antidepressant medication, or the combination for a given patient with nonpsychotic depression remains unclear. In a large, multicenter study comprised of 681 patients, Keller et al. (8) reported that 12-week treatment with the combination of an antidepressant, nefazodone, and Cognitive Behavioral Analysis System of Psychotherapy (CBASP) was superior in efficacy to either monotherapy in the treatment of chronic forms of major depression, i.e., Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; ref. 12) criteria for a current episode of chronic major depressive disorder (MDD), MDD superimposed on a preexisting dysthymic disorder, or recurrent MDD with incomplete remissions and a total duration of illness of at least 2 years. CBASP is a structured, timelimited psychotherapy specifically developed to treat chronic depression that includes elements of traditional cognitive-behavioral therapy and interpersonal therapy. It utilizes a technique called situational analysis to help patients understand the consequences of their behavior and interactions with others, alter patterns of coping, and improve interpersonal skills (13). Several well established risk factors increase an individuals likelihood of developing depression, including female gender, family history for depression, past personal history of

depression, and early life trauma (14). Indeed, exposure to extraordinary life stressors in the prepubertal period, such as loss of parents or sexual or physical abuse has been well documented to increase the risk for depression and suicide (1517). Whether depression associated with the presence of one or more of these risk factors responds preferentially to one or another effective treatment for depression has been little studied, although some evidence suggests that women and men may differ in their response to tricyclic antidepressants compared to the selective serotonin reuptake inhibitors (SSRIs) (18). No data exist as to whether a positive family history of depression, one of the major risk factors for depression, is associated with a better response to one of the available effective treatments for depression. In this retrospective analysis of the large chronic-depression study cited above (8) comparing an antidepressant (nefazodone), a form of psychotherapy (CBASP), and their combination, we report that patients with chronic depression responded differently to the treatments depending on the presence or absence of early life trauma.

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

METHODS
The large, multicenter study on treatment responses in chronic depression was previously described in detail by Keller et al. (8). We used the identical sample for the present investigation. A total of 681 patients, 18 to 75 years of age, with chronic forms of MDD, i.e., Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (12) criteria for a current episode of chronic MDD, MDD superimposed on a preexisting dysthymic disorder, or recurrent MDD with incomplete remissions and a total duration of illness of at least 2 years, were randomly assigned to 12 weeks of treatment with nefazodone, CBASP, or their combination. The Childhood Trauma Scale (19), administered at baseline, was used to assess the presence of early life adverse events. This scale quantifies childhood adverse experiences in the following categories: parental loss, physical abuse, sexual abuse and neglect, and any trauma. The 24-item Hamilton Rating Scale for Depression (HRSD24), a standard method to measure depression severity, obtained both at baseline and after 12 weeks of treatment, was the main depression-severity treatment-outcome measure. We evaluated the effect of the presence or absence of histories of childhood adversity (parental loss, physical abuse, sexual abuse, neglect) on delta HRSD24 scores (baseline minus exit score) in a completer analysis by using a general linear model with two factors (treatment

and childhood adverse experience). Results were controlled for effects of age, sex, race, and depression severity at baseline. Last Observation Carried Forward (LOCF) analysis was used to evaluate the effect of presence or absence of histories of childhood adversity on remission rates, in addition to logistic modeling in completers. Odds ratios for achieving remission were calculated as a function of childhood adversity based on the LOCF data. Remission was defined as an exit HRSD24 score of 8, which is generally considered to represent complete recovery from depression with minimal, if any, residual symptoms (20).

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

RESULTS
The treatment group prevalence of traumatic child abuse experiences in our sample of patients with chronic depression is presented in Table 1 . In this population of patients with chronic forms of depression, approximately one-third experienced parental loss before age 15 years, 45% experienced childhood physical abuse, 16% experienced childhood sexual abuse, and 10% experienced neglect. These findings alone highlight the remarkably high prevalence rate of early life trauma in patients with chronic forms of major depression. Patients with early life adverse experiences did not differ from patients without early life trauma in drop-out rates during the study.

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Table 1. Description of Childhood Adverse Experiences of Subjects Stratified by Treatment Group

Results regarding treatment responses differed dramatically from those initially reported by Keller et al. (8), when groups were stratified according to the presence or absence of childhood trauma. There were significant interactions of effects of treatment type and parental loss (F=4.46, df=1,495, P=0.0121), physical abuse (F=3.25, df=1,495, P=0.03), neglect (F=4.82, df=1,495, P=0.0084), and any trauma (F=3.13, df=1,495, P=0.0446). Specifically, among patients with no history of childhood abuse/early trauma, there was a clear-cut stepwise order of treatment efficacy (combination > nefazodone CBASP). In contrast, patients who reported early life trauma exhibited a superior antidepressant response to psychotherapy (with or without nefazodone) when compared with those treated with antidepressant alone (shown in Fig. 1A ). Moreover, the advantage of the combination of pharmacotherapy and psychotherapy (relative to psychotherapy alone) was modest and did not attain statistical significance in the subgroup of patients with early life trauma. The superiority of psychotherapy (with or without nefazodone) for patients reporting early life trauma persisted when the analyses were controlled for gender, age, race, and depression severity at baseline. Fig. 1B reveals similar findings with remission of depression, the most stringent criterion for treatment response as the end point. For patients with chronic forms of depression and early life trauma who completed the study, remission was attained in 48.3% of the patients treated with CBASP, 32.9% treated with the antidepressant, and 53.9% treated with combination therapy. In these patients, but not in patients with chronic depression and no childhood trauma, the remission rate was significantly higher with psychotherapy compared to antidepressant treatment (Wald 2=6.8912, df=1, P= 0.0087). The effect was confirmed when LOCF analysis was performed (Wald 2=6.5315, df=1, P=0.0106). Based on the LOCF data, the likelihood of achieving remission in patients with chronic forms of major depression and any early adverse life event was estimated to be twice as high after treatment with psychotherapy when compared to antidepressant therapy (odds ratio=2.322, 95% confidence interval=1.2254.066). Further analysis of type of early trauma indicates that this effect was particularly prominent in patients with chronic forms of depression and parental loss (odds ratio for remission after psychotherapy versus antidepressant=2.7857, 95% confidence interval=1.2956.182).

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Figure 1. (A) Response to antidepressant (nefazodone), psychotherapy (CBASP), and the combination (nefazodone and CBASP) as a function of treatment type and early adverse life events in patients with chronic forms of major depression. In this completer analysis, the effect of the presence or absence of histories of childhood adversity (parental loss, physical abuse, sexual abuse, neglect) on

HRSD24 scores was evaluated. A general linear model with two factors (treatment and childhood adverse experience) was computed. *, There was a significant interaction of effects of treatment type and parental loss (F=4.46, df=1,495, P=0.0121), physical abuse (F=3.25, df=1,495, P=0.03), neglect (F=4.82, df=1,495, P=0.0084), and any trauma (F=3.13, df=1,495, P=0.0446). The patients with any early life trauma responded well to psychotherapy alone or the combined treatment but not to antidepressant alone. Patients with chronic depression with early life trauma responded equally well to antidepressant and CBASP. (B) Remission rates as a function of treatment type and early adverse life events in patients with chronic forms of major depression. Remission was defined as HRSD24 score 8. *, Completer analysis using logistic modeling revealed a significantly higher remission rate in the patients with chronic forms of major depression and early life trauma treated with psychotherapy compared to antidepressant treatment (Wald 2=6.8912, df=1, P=0.0087). The effect was confirmed in the LOCF analysis (Wald 2=6.5315, df=1, P=0.0106). The likelihood of achieving remission in patients with chronic forms of major depression and any early adverse life event was twice as high after treatment with psychotherapy when compared to antidepressant therapy (odds ratio=2.322, 95% confidence interval=1.2254.066). Further analysis of type of early trauma indicates that this effect was particularly prominent in patients with chronic forms of depression and parental loss (odds ratio for remission after psychotherapy versus antidepressant=2.7857, 95% confidence interval=1.2956.182).

DISCUSSION

These findings have significant implications for research on the TOP pathophysiology of chronic forms of major depression and for the ABSTRACT treatment of chronic depression. The differential response of chronic METHODS depression to CBASP psychotherapy versus pharmacotherapy as a RESULTS function of the presence of early life trauma suggests that there may be DISCUSSION important differences in the etiology and pathogenesis of depression in REFERENCES individuals with and without history of early trauma. Taking this finding into account may reduce the often observed heterogeneity in biological studies of depressed patients. Indeed, we recently demonstrated that the widely replicated finding of reduced hippocampal volume in patients with major depression is largely due to the subgroup of patients with early life trauma (21). Future studies are needed to determine the generalizability of our findings. In particular, we examined only one form of psychotherapy and one antidepressant medication. It is important to compare the effectiveness of CBASP to cognitive-behavioral therapy, interpersonal therapy, and both long- and short-term psychodynamic psychotherapy in the treatment of patients with chronic forms of major depression and early life trauma to identify the elements of psychotherapy that are most critical to antidepressant response. It is also important to determine whether the relatively poor treatment response of patients with chronic depression and early life trauma to nefazodone alone is also true of other antidepressants, including the very commonly prescribed selective serotonin reuptake inhibitors, e.g., paroxetine, sertraline, fluoxetine, escitalopram, and citalopram; dual serotonin/norepinephrine reuptake inhibitors, e.g., venlafaxine, milnacipran, and duloxetine; or antidepressants that act by other mechanisms of action, e.g., mirtazepine and bupropion.

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REFERENCES
1. Kessler, R. C., McGonagle, S., Zhao, C. B., Nelson, M., Hughes, S., Eshleman, S., Wittchen, H. U. & Kendler, K. S. (1994) Arch. Gen. Psychiatry 51, 8 19.[Abstract/Free Full Text] 2. Musselman, D. L., Evans, D. L. & Nemeroff, C. B. (1998) Arch. Gen. Psychiatry 55, 580592.[Abstract/Free Full Text]

3. Nemeroff, C. B., Compton, M. T. & Berger, J. (2001) Ann. N.Y. Acad. Sci. 932, 1 23.[Medline] 4. Hays, R. D., Wells, K. B., Sherbourne, C. D., Rogers, W. & Spritzer, K. (1995) Arch. Gen. Psychiatry 52, 1119.[Abstract/Free Full Text] 5. Nemeroff, C. B. & Schatzberg, A. F. (2002) in A Guide to Treatments That Work, eds. Nathan, P. E. & Gorman, J. M. (Oxford Univ. Press, New York), pp. 229261. 6. Hollon, S. D., Thase, M. E. & Markowitz, J. C. (2002) Psychol. Sci. Publ. Interest 3, 3977. 7. Rush, A. J. & Thase, M. E. (1998) in WPA Series: Evidence and Experience in Psychiatry, eds. Maj, M. & Sartorius, N. (Wiley, Chichester, U.K.), 2nd Ed., Vol. 1, pp. 161206. 8. Keller, M. B., McCullough, J. P., Klein, D. N., Arnow, B., Dunner, D. L., Gelenberg, A. J., Markowitz, J. C., Nemeroff, C. B., Russell, J. M., Thase, M. E., et al. (2000) N. Engl. J. Med. 342, 14621470.[Medline] 9. Thase, M. E., Greenhouse, J. B., Frank, E., Reynolds, C. F., III, Pilkonis, P. A., Hurley, K., Grochocinski, V. & Kupfer, D. J. (1997) Arch. Gen. Psychiatry 54, 10091015.[Abstract/Free Full Text] 10. Esposito, K. & Goodnick, P. (2003) in The Psychiatric Clinics of North America Drug Therapy: Predictors of Response, eds. Rosenbaum, J. F. & Dunner, D. L. (Saunders, Philadelphia), Vol. 26, pp. 353366. 11. Rothschild, A. J. & Duval, S. E. (2003) J. Clin. Psychiatry 64, 390396.[Medline] 12. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Am. Psych. Assoc., Washington, DC). 13. McCullough, J. P., Jr. (2000) Treatment for Chronic Depression: Cognitive Behavioral Analysis System of Psychotherapy (CBASP) (Guilford, New York). 14. Hirschfeld, R. M. & Goodwin, F. K. (1988) in Textbook of Psychiatry, eds. Hales, R. E. & Yudofsky, S. (Am. Psychiat. Press, Washington, DC), pp. 403441. 15. Kendler, K. S., Kessler, R. C., Walters, E. E., MacLean, C., Neale, M. C., Heath, A. C. & Eaves, L. J. (1995) Am. J. Psychiatry 152, 833842.[Abstract/Free Full Text] 16. Heim, C. M. & Nemeroff, C. B. (2001) Biol. Psychiatry 49, 10231039.[Medline] 17. Dube, S. R., Anda, R. F., Velitti, V. J., Chapman, D. P., Williamson, D. F. & Giles, W. H. (2001) J. Am. Med. Assoc. 286, 30893096.[Abstract/Free Full Text]

18. Kornstein, S. G., Schatzberg, A. F., Thase, M. E., Yonkers, K. A., McCullough, J. P., Keitner, G. I., Gelenberg, A. J., Davis, S. M., Harrison, W. M. & Keller, M. B. (2000) Am. J. Psychiatry 157, 14451452.[Abstract/Free Full Text] 19. Lizardi, H., Klein, D. N., Ouimette, P. C., Riso, L. P., Anderson, R. L. & Donaldson, S. K. (1995) J. Abnorm. Psychol. 104, 132139.[Medline] 20. Thase, M. E., Entsuah, A. R. & Rudolph, R. L. (2001) Br. J. Psychiatry 178, 234 241.[Abstract/Free Full Text] 21. Vythilingam, M., Heim, C., Newport, D. J., Miller, A. H., Anderson, E., Bronen, R., Brummer, M., Staib, L., Vermetten, E., Charney, D. S., et al. (2002) Am. J. Psychiatry 159, 2072 2080.[Abstract/Free Full Text]
Focus 3:140-145 2005 American Psychiatric Association (2005)

22.

INFLUENTIAL PUBLICATION

Hopelessness and Suicidal Ideation in Outpatients With Treatment-Resistant Depression: Prevalence and Impact on Treatment Outcome
George I. Papakostas, M.D., Timothy Petersen, Ph.D., Joel Pava, Ph.D., Ella Masson, B.A., John J. Worthington, III, M.D., Jonathan E. Alpert, M.D., Ph.D., Maurizio Fava, M.D., and Andrew A. Nierenberg, M.D.

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ABSTRACT

Depression and hopelessness are risk factors for suicide. The purpose of this study was to examine the extent of suicidal ideation and hopelessness in outpatients with treatmentresistant depression (TRD) and to study the impact of suicidal ideation and hopelessness on treatment with nortriptyline (NT). The degree of suicidal ideation and hopelessness was assessed during the screen visit with the use of items #3 and #30 of the Hamilton Depression Rating Scale (HAM-D) in 89 patients with TRD who entered a 6-week open trial of NT. Forty of these patients also completed the Beck Hopelessness Index (BHI) during the screen visit. In separate logistic regressions, the scores from the BHI and the two HAM-D items were then tested as predictors of clinical response to the 6-week trial with NT, controlling for the severity of depression. More than half of patients reported thoughts or wishes of death to self and significant hopelessness. A greater degree of hopelessness before treatment in completers, reflected by the score on the HAM-D item #30, predicted response to NT. More than half of patients with prominent hopelessness who completed the trial responded. Patients with TRD are more likely than not to report prominent suicidal ideation and hopelessness. Furthermore, a full 6-week trial of NT, a relatively noradrenergic tricyclic antidepressant, may be particularly useful in patients who have failed to respond to several antidepressants and also report significant hopelessness. (Reprinted with permission from the Journal of Nervous and Mental Disease 2003; 191:444449[Medline])

Suicide is a major public health concern (Weller et al., 2001). Currently, suicide ranks as the third leading cause of death in adolescents, representing 12% of deaths (American Academy of Child and Adolescent Psychiatry, 2001). Both depression (Bostwick and Pankratz, 2000) and hopelessness (Beck et al., 1989) are risk factors for suicidal ideation and suicide. A study of 4000 patients reveals that in depression, the standardized mortality rate is double for all causes of death and 26-fold for death from suicide (Newman and Bland, 1991). Overall, the lifetime risk for suicide in depressed patients has been estimated at 2.2% (Bostwick and Pankratz, 2000). In addition to suicide, hopelessness has also been shown to predict a variety of other adverse health outcomes in large epidemiological studies, such as incidents of myocardial infarctions, hypertension, cancer, and an increase in all-cause mortality (Everson et al., 1996; Everson et al., 2000; Stern et al., 2001). In fact, the relationship between hopelessness and these adverse outcomes remains significant even after adjusting for other biological, socioeconomic, or behavioral risk factors such as depression, smoking, perceived health, or social support (Everson et al., 1996; Everson et al., 2000; Stern et al., 2001). In addition, patients with a high degree of hopelessness may also receive suboptimal care; the results of one study indicate that hopeless patients overestimate the risks and underestimate the benefits of potentially life-saving treatments (Ganzini et al., 1994). This finding is particularly important for patients with treatment-resistant depression (TRD),

who have not responded to previous antidepressant treatments and typically require higher doses of medication, more aggressive treatment, or both in order to respond. In addition, after protracted treatment courses, TRD patients may experience an even greater tendency to underestimate the benefits of the next treatment. It appears that 29% to 46% of depressed patients show only partial or no response to antidepressants (Fava and Davidson, 1996). TRD, which represents a more chronic and severe form of major depressive disorder (Kornstein and Schneider, 2001), is associated with higher disability, morbidity, and mortality (Greden, 2001). However, hopelessness or suicidal ideation has never been assessed systematically among patients with TRD in relationship to treatment outcome. Studying the extent of hopelessness or suicidal ideation in this population may help identify risk factors that would place these patients at higher risk for disability or death and help guide clinicians and their patients in their treatment decisions (Nierenberg and Amsterdam, 1990). The purpose of this study was to examine suicidal ideation and hopelessness in depressed patients who had not responded to one to five adequate antidepressant trials during the current depressive episode, and the relationship between these two symptoms of depression and treatment outcome.

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METHODS
Subjects were recruited at the Massachusetts General Hospital Depression Clinical and Research Program for the purposes of an outpatient clinical trial to assess the efficacy of lithium versus placebo augmentation of nortriptyline (NT) for subjects with TRD who had previously failed to respond to an open clinical trial of NT. This report is on the open phase of the study. Inclusion criteria were as follows: men and women age 18 to 70 years with MDD as diagnosed using the Structured Clinical Interview for DSM-III-Rpatient edition (SCID-P; Spitzer et al., 1989) and a score on the 17-item Hamilton Depression Rating Scale (HAM-D-17; Hamilton, 1960) greater than or equal to 18. Treatment resistance was defined as at least one but no more than five adequate failed trials during the current episode. The adequacy of a trial was assessed using the Harvard Antidepressant Treatment History form (Nierenberg et al., 1991), which provides criteria specific to each antidepressant in terms of dose and duration for a trial to be considered adequate. Exclusion criteria for this trial were defined as follows: bipolar I or II disorder, psychotic disorders, a history of organic mental

or seizure disorder, serious or unstable medical illness, substance abuse or dependence disorders active within the past 12 months, lactation, pregnancy, history of adverse reaction or allergy to the study medications, concomitant use of psychotropic medications, and clinical or laboratory evidence of thyroid abnormalities. Patients who were found to be imminently suicidal and in need of immediate containment, as assessed through clinical interview and using HAM-D-17 item #3 (score of 4), were excluded from the study. The presence and extent of hopelessness during the screen visit were assessed with the Beck Hopelessness Inventory (BHI; Beck and Steer, 1988). Forty patients completed the BHI during the screen visit. Because of the relatively small sample size of those administered this instrument, the degree of hopelessness was also assessed during the screen visit with item #30 of the 31-item Hamilton Depression Rating Scale (HAM-D-31). Suicidal ideation was assessed during the screen visit with the use of item #3 of the HAMD-31. A total of 92 outpatients were enrolled. We were able to locate the screen HAM-D-31 scales for all but three of these patients. The HAM-D item #3 asks, "During the course of the past week, have you ever had any thoughts that life is not worth living, or that youd be better off dead? What about thoughts of killing yourself?" and is rated as follows: 0, suicidal ideation is "absent"; 1, patient "feels that life is not worth living"; 2, patient "wishes he/she were dead or any thoughts of possible death to self"; 3, patient has "suicidal ideas or gesture"; 4, patient has "attempted suicide." The HAM-D item #30 asks, "Over the last week, do you feel hopeful that you will get better? Are you experiencing discouragement, despair, pessimism about the future?" and is rated as follows: 0, hopelessness is not present; 1, the patient has intermittent doubts that "things will improve" but can be reassured; 2, the patient consistently feels "hopeless" but accepts reassurances; 3, the patient expresses feelings of discouragement, despair, pessimism about future, which cannot be dispelled; and 4, the patient spontaneously and inappropriately perseverates, "Ill never get well," or its equivalent. Participants in this study signed an Institutional Review Board-approved informed consent form during the screen visit. Subjects returned 1 week later (baseline visit) and then started on 25 mg of NT. The NT dose was increased by 25 mg per day until an initial daily dose of 100 mg was reached, unless patients were unable to tolerate the dose increase because of side effects. Blood levels of NT were obtained at weeks 2 and 6, and dose adjustments were made after the second week if blood levels were 100 ng/ml or less. Subjects were then kept on their dose of NT for 6 weeks. Study visits occurred at screen, at baseline, and then weekly for 6 weeks. The HAM-D-31, which allows the scoring of the HAM-D-17, was administered during the screen and baseline visits and at each study visit by experienced psychiatrists and psychologists. In our group, training in the use of instruments such as the HAM-D-17 and SCID-P is performed by peer review of videotaped interviews. Our interrater reliability for the use of the SCID-P was recently estimated as Kappa=.80 (Fava et al., 2000).

DEFINITION OF CLINICAL RESPONSE AND STATISTICAL TESTS USED

Response was measured by examining the change in HAM-D-17 score between baseline and week 6. Clinical response was defined as a 50% or greater reduction in the total HAMD-17 score (baselineendpoint). A completer analysis and an intent-to-treat (ITT) analysis were used. In the former, the analysis was limited to patients who completed the study. In the latter, the last recorded HAM-D-17 score substituted for the score at week 6 for patients who prematurely discontinued the study. Three separate multiple regressions were then performed to test whether the HAM-D items #3 and #30 or the BHI scores at screening predicted the severity of depression at screening, as reflected by the HAM-D-17. Three separate logistic regressions were performed to test whether any of these four scores predicted clinical response to NT in the completer analysis, controlling for depression severity during the screen visit, as reflected by the HAM-D-17 total score. Three separate logistic regressions were then performed to test whether any of these four scores predicted clinical response to NT in the ITT analysis, controlling for depression severity during the screen visit, as reflected by the HAM-D-17 total score. Paired t-tests were used to test whether there was a statistically significant difference in the change in HAM-D item #30 or item #3 during the course of the trial (endpointscreen) between responders and nonresponders in the completer analysis and the ITT analysis.

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

RESULTS
Ninety-two patients were enrolled in the trial. None of the patients screened were excluded because of a HAM-D item #3 score of 4. We were able to locate the screen HAM-D-31 scales for all but three of these patients. The results of the open NT trial are reported elsewhere (Nierenberg et al., In Press). Briefly, the mean age of our sample was 41.111.7 years, and 50% were females. The mean age of onset of depression was 22.414.1 years, the mean duration of the current major depressive episode was 96.2114.4 months, and the mean HAM-D-17 score during the screen visit was 21.33.9. For our sample, the mean number of failed trials during the current depressive episode was 2.31.5. Thirty-one patients had failed to respond to one medication, 18 had failed to respond to two, 15 had failed to respond to three, 16 had failed to respond to four, and 12 had failed to respond to

five. There were no significant differences in the NT dosage or level between responders and nonresponders at week 6. Only five patients with blood NT levels less than 100 ng/ml at week 2 could not tolerate the minimal target NT daily dose of 100 mg because of side effects. Two of these patients responded to NT. The mean BHI score during the screening visit was 13.05.0 (N=40). Furthermore, during screening, 27 (30.3%) patients scored 0 on item 3 of the HAM-D, 15 (16.8%) scored 1, 19 (21.3%) scored 2, and 28 (31.4%) scored 3. Of the patients, 52.7% reported significant suicidal ideation, defined as a score of 2 or greater on this item. Also during this visit, 28 (31.4%) patients scored 0 on item 30 of the HAM-D, 13 (14.6%) scored 1, 14 (15.7%) scored 2, and 34 (38.2%) scored 3. Of the patients, 53.9% reported significant hopelessness, defined as a score of 2 or greater on this item. None of these three scores (BHI and HAM-D-31 items #3 and #30) predicted depression severity during the screen visit (p ranged from .5 to .6). In addition, we did not find the degree of suicidal ideation during the screen visit, as reflected by the score on the HAM-D item #3, to predict clinical response to NT in the completer or ITT analyses (p>.05). However, scores on the HAM-D item #30 during the screen visit did predict clinical response, with higher scores predicting good response in the completer analysis (p=.03, chisquare=4.9, odds ratio=2.2, 95% confidence interval=1.1 to 2.3). With respect to completers, approximately 23.5% (4/17) with a HAM-D item #30 score of 0 during screening responded, 33.3% (3/9) with a score of 1 responded, 55.5% (5/9) with a score of 2 responded, and 50.0% (13/26) with a score of 3 responded. Furthermore, there was a trend toward statistical significance for the BHI score during the screen visit to predict clinical response in the completer analysis (p=.09, chi-square=2.7, odds ratio=1.6, 95% confidence interval=1.0 to 1.4), with higher scores predicting a higher likelihood of response in the completer analysis. The mean HAM-D item #30 scores during the screen visit for responders and nonresponders in the completer analysis were 2.11.3 and 1.41.7, respectively. The mean BHI scores during the screen visit for responders and nonresponders in the completer analysis were 15.524.0 and 12.225.8, respectively. Scores on the HAM-D scale item #30 during the screen visit or scores on the BHI during the screen visit did not significantly predict treatment response in the ITT analysis (p>.05). With respect to all patients (ITT), approximately 40.7% (11/27) with a HAM-D item #30 score of 0 during screening responded, 53.3% (8/15) with a score of 1 responded, 31.6% (6/19) with a score of 2 responded, and 39.3% (11/28) with a score of 3 responded. When completers alone were examined, there was a statistically significant difference in the change in HAM-D item #30 at week 6 compared with the screen visit between responders and nonresponders (1.500 vs. .176, p=.0001). Specifically, responders experienced a mean decrease in HAM-D item #30 scores, whereas nonresponders experienced a mean increase. For completers, there was also a statistically significant difference in the change in HAM-D item #3 at week 6 compared with the screen visit between responders and nonresponders ( 1.250 vs. 0.083, p=.004). Although both groups experienced a mean decrease in HAM-D item #3 scores during treatment, responders experienced a greater mean decrease in scores than nonresponders. When all patients were examined (ITT), there was a statistically significant difference in the change between HAM-D item #30 during the last recorded visit

compared with the screen visit between responders and nonresponders (1.308 vs. .229, p=.0004). Again, responders experienced a mean decrease in HAM-D item #30 scores, whereas nonresponders experienced a mean increase. For all patients (ITT), there was also a statistically significant difference in the change in HAM-D item #3 at endpoint compared with the screen visit between responders and nonresponders (1.212 vs. 0.023, p<.001). Although both groups experienced a mean decrease in HAM-D item #3 scores during treatment, responders experienced a greater mean decrease in scores than nonresponders.

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

DISCUSSION
The results of the present study indicate that more than half of patients with TRD reported thoughts of death to self, whereas approximately one third reported significant suicidal ideas or gestures. At the same time, more than half of TRD patients reported significant hopelessness or despair, whereas more than one third expressed despair and could not be reassured. Furthermore, we found that a greater degree of hopelessness predicted a favorable response to NT in patients who received the full 6 weeks of treatment, and this response was independent of the severity of the depressive episode. In fact, approximately half of patients reporting significant hopelessness who completed the trial responded. Although we did not find that hopelessness scores during the screen visit predicted response to the ITT analysis, this result may have been caused by the greater likelihood of hopeless patients to discontinue the study prematurely. In fact, Rifai et al. (1994) have reported that depressed patients with prominent hopelessness were more likely to discontinue treatment with NT prematurely. With respect to suicide, our results are significant in that the presence and extent of suicidal thoughts have been shown to have a negative impact on the course of depression in a number of studies. A suicide attempt is a strong predictor of future suicidal behavior among patients with mood disorders (Nordstrom et al., 1995), whereas depressed patients with suicidal ideation are at higher risk of relapse (Szanto et al., 2001), of discontinuing treatment (Rifai et al., 1994), of experiencing a chronic course of illness (Moos and Cronkite, 1999), and of scoring lower on quality of life measures (Goldney et al., 2001), and are more likely to make use of mental health services than depressed patients without suicidal ideation (Pirkis et al., 2001).

The impact of hopelessness on the presentation, treatment, and course of major depressive disorder, however, is relatively understudied. In a study of 107 depressed adolescents who underwent a brief trial of psychotherapy, higher levels of hopelessness predicted persistence of depression after treatment (Brent et al., 1998). In a similar fashion, results of a multicenter study involving 293 depressed outpatients randomized to a 16-week trial of interpersonal psychotherapy, cognitive behavioral therapy, imipramine, or placebo revealed that a higher degree of expectation of improvement predicted clinical response in the placebo and imipramine groups and across all treatment groups (Sotsky et al., 1991). These last findings contrast with the present results, which report a favorable outcome in hopeless patients who complete the trial. A possible reason for the discrepancy is the difference in the populations studied. Hope and the expectation of improvement are features that increase the likelihood of a patient experiencing a placebo response (Brown, 1994). However, patients with TRD have been reported to have low placebo response rates compared with non-TRD patients, which some estimate as low as 10% (Thase et al., 1992). The inherently low placebo response rate in our sample may explain why the traditional relationship between expectation of improvement, by way of the degree of hopelessness, and placebo response is not seen. Hopelessness per se may be a marker of an underlying biological process, and the low placebo response rates in TRD would be less likely to obscure an effect of NT on an underlying biological process. In a study of suicidal inpatients, for instance, Russ et al. (2000) report that the genotype frequency for the serotonin transporter (5HTT) was significantly related to BHI scores at screening. Specifically, patients with high BHI scores were more likely to have the long allele of 5HTT (5HTT-l), which has a higher transcriptional activity than the short allele (5HTT-s). The latter allele has been found to predict poor response to treatment with selective serotonin reuptake inhibitors (SSRIs) in MDD (Zanardi et al., 2001), whereas depressed patients homozygous for the 5HTT-l allele may respond sooner than those possessing a 5HTT-s allele (Pollock et al., 2000). Unfortunately, no studies have been published focusing on the role of the 5HTT alleles in predicting clinical response to agents that have a significant effect on the noradrenergic system; such studies would aid in confirming this relationship for NT. Alternatively, there is some evidence to suggest that tricyclic antidepressants (TCAs) may actually be more effective than SSRIs in the treatment of certain depressive subtypes, such as melancholic and poststroke depression (Georgotas et al., 1986; Perry et al., 1996; Robinson et al., 2000; Roose et al., 1994). Patients with endogenous depression respond preferentially to clomipramine compared with SSRIs, a finding that may be caused by the dual effect of clomipramine on both the noradrenergic and the serotonergic systems (Danish University Antidepressant Group, 1986; Danish University Antidepressant Group, 1990). Similar to clomipramine, NT also has a significant effect on the noradrenergic system (Nyback et al., 1975). Thus, it is quite possible that patients with a greater degree of hopelessness who completed the 6-week trial were more likely to respond to treatment because of the use of TCA. In addition, it is also possible that clinicians were inadvertently more encouraging or supportive to very hopeless or suicidal patients, although the effect of support and encouragement on clinical response would have been rather small given the low placebo response rate in this population. In addition, this open trial was designed to generate nonresponders for the second phase of the study (placebo-controlled trial of

lithium augmentation); if any bias were present, it would be toward minimizing response to NT to generate more subjects for the second phase of the study.

LIMITATIONS
Although the relationship between hopelessness and response to NT in TRD may represent a chance finding, the degree of significance (p=.02) and the fact that there was a similar trend when a second, independent measure of hopelessness was used (BHI) make this seem unlikely. One limitation of our study is the use of a dichotomous classification of clinical response. Another limitation is that of sampling bias. Clinical trials have a number of inclusion and exclusion criteria, and as a result, patients in clinical trials do not directly reflect the typical outpatient population with MDD. This factor is particularly important for the present study, because depressed patients who were imminently suicidal were excluded. Thus, it would be difficult to generalize the present findings to patients with chronic and severe suicidal ideation. In addition, our study did not involve a placebo arm, which would have afforded us the opportunity to compare the effect of hopelessness on treatment response in both the active drug and placebo groups. Finally, our assessment of hopelessness during the screen visit, pertaining to the week immediately before the screen visit, provides a cross-sectional measure of severity and is not informative about possible heterogeneous patterns of hopelessness during the course of illness. There may be patients whose level of hopelessness is static, for example, and others whose level of hopelessness fluctuates frequently according to life events. Our results do not address the relative likelihood of NT response for patients in these two hypothetical groups. Future studies addressing these limitations are necessary to shed light on the relationship among suicidal ideation, hopelessness, and treatment response in MDD.

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

CONCLUSIONS
Our findings demonstrate that in a sample of outpatients with well characterized TRD, patients are more likely than not to report prominent suicidal ideation and hopelessness. In addition, for patients with TRD prospectively treated with open-label NT who completed the trial, the presence of hopelessness appeared to be associated with a significantly greater chance of response to antidepressant treatment. In fact, approximately half of these patients with prominent hopelessness responded. The degree of expectation of improvement,

indirectly measured by the degree of hopelessness, has traditionally been thought to be related to the placebo response. A possible reason for our finding may include the low placebo response rates in TRD, which would be less likely to obscure an effect of NT on an underlying biological process in patients with TRD and a greater degree of hopelessness. These results suggest that a full, 6-week trial of NT, a relatively noradrenergic TCA, may be particularly useful among patients who have failed to respond to several antidepressants and also present with significant hopelessness.

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REFERENCES
American Academy of Child and Adolescent Psychiatry (2001) Practice parameter for the assessment and treatment of children and adolescents with suicidal behavior. J Am Acad Child Adolesc Psychiatry 40: 24s51s. Beck AT, Brown G, Steer RA (1989) Prediction of eventual suicide in psychiatric inpatients by clinical ratings of hopelessness. J Consult Clin Psychol 57: 309 310.[Medline] Beck AT, Steer RA (1988) Manual for the Beck Hopelessness Scale. San Antonio: Psychological Corp. Bostwick JM, Pankratz VS (2000) Affective disorders and suicide risk: A reexamination. Am J Psychiatry 157: 19251932.[Abstract/Free Full Text] Brent DA, Kolko DJ, Birhamer B, Baugher M, Bridge J, Roth C, Holder D (1998) Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. J Acad Child Adolesc Psychiatry 37: 906914. Brown WA (1994) Placebo as a treatment Neuropsychopharmacology 10: 265269.[Medline] for depression.

Danish University Antidepressant Group (1986) Citalopram: Clinical effect profile in comparison with clomipramine: A controlled multicenter study. Psychopharmacol (Berl) 90: 131138.[Medline] Danish University Antidepressant Group (1990) Paroxetine: A selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord 18: 289 299.[Medline] Everson SA, Goldberg DE, Kaplan GA, Cohen RD, Pukkala E, Tuomilehto J, Salonen JT (1996) Hopelessness and risk of mortality and incidence of myocardial infarction and cancer. Psychosom Med 58: 113121.[Abstract/Free Full Text] Everson SA, Kaplan GA, Goldberg DE, Salonen JT (2000) Hypertension incidence is predicted by high levels of hopelessness in Finnish men. Hypertension 35: 561 567.[Abstract/Free Full Text] Fava M, Alpert JE, Nierenberg AA, Russell J, OBoyle M, Camillieri A, Harrison W (May 2000) A validation study of a computerized management system for the diagnosis and treatment of depression. Report Presented at the American Psychiatric Association Annual Meeting. Fava M, Davidson KG (1996) Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 19: 179200.[Medline] Ganzini L, Lee MA, Heintz RT, Bloom JD, Fenn DS (1994) The effect of depression treatment on elderly patients preference for life-sustaining medical therapy. Am J Psychiatry 151: 16311636.[Abstract/Free Full Text] Georgotas A, McCue RE, Hapworth W, Friedman E, Kim MO, Welkowitz J, Chang I, Cooper TB (1986) Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly. Biol Psychiatry 21: 11551166.[Medline] Goldney RD, Fisher LJ, Wilson DH, Cheok F (2001) Suicidal ideation and healthrelated quality of life in the community. Med J Aust 175: 546549.[Medline] Greden JF (2001) The burden of disease for treatment-resistant depression. J Clin Psychiatry 62(suppl 16): 2631. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 5662.[Free Full Text] Kornstein SG, Schneider RK (2001) Clinical features of treatment-resistant depression. J Clin Psychiatry 62(suppl 16): 1825.

Moos RH, Cronkite RC (1999) Symptom-based predictors of a 10-year chronic course of treated depression. J Nerv Ment Dis 187: 360368.[Medline] Newman SC, Bland RC (1991) Suicide risk varies by subtype of depressive disorder. Acta Psychiatr Scand 83: 420426.[Medline] Nierenberg AA, Amsterdam JD (1990) Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry 51(suppl): 3947.[Medline] Nierenberg AA, Keck PE, Samson J, Rothschild AJ, Schatzberg AF (1991) Methodologic considerations for the study of treatment-resistant depression. In JD Amsterdam (Ed), Refractory depression (pp 112). New York: Raven Press. Nierenberg A, Papakostas GI, Petersen T, Worthington JJ III, Tedlow J, Alpert JE, Fava M (2003) Nortriptyline for Treatment Resistant Depression. J Clin Psychiatry 64: 3539.[Medline] Nordstrom P, Asberg M, Aberg-Wistedt A, Nordin C (1995) Attempted suicide predicts suicide risk in mood disorders. Acta Psychiatr Scand 92: 345 350.[Medline] Nyback HV, Walters JR, Aghajanian GK, Roth RH (1975) Tricyclic antidepressants: Effects on the firing rate of brain noradrenergic neurons. Eur J Pharmacol 32: 302312.[Medline] Perry PJ (1996) Pharmacotherapy for major depression with melancholic features: Relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants. J Affect Disord 39: 16.[Medline] Pirkis JE, Burgess PM, Meadows GN, Dunt DR (2001) Suicidal ideation and suicide attempts as predictors of mental health service use. Med J Aust 175: 542 545.[Medline] Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirschner RA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23: 587590.[Medline] Rifai AH, George CJ, Stack JA, Mann JJ, Reynolds CF III (1994) Hopelessness in suicide attempters after acute treatment of major depression in late life. Am J Psychiatry 151: 16871690.[Abstract/Free Full Text] Robinson RG, Schultz SK, Castillo C, Kopel T, Kosier JT, Newman RM, Curdue K, Petracca G, Starkstein SE (2000) Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: A placebo-controlled double blind study. Am J Psychiatry 157: 351359.[Abstract/Free Full Text]

Roose SP, Glassman AH, Attia E, Woodring S (1994) Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 151: 17351739.[Abstract/Free Full Text] Russ MJ, Lachman HM, Kashdan T, Saito T, Bajmakovic-Kacila S (2000) Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide. Psychiatry Res 93: 7378.[Medline] Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF, Elkin I, Watkins JT, Imber SD, Leber WR, Moyer J (1991) Patient predictors of response to psychotherapy and pharmacotherapy: Findings in the NIMH Treatment of Depression Collaborative Research Program. Am J Psychiatry 148: 997 1008.[Abstract/Free Full Text] Spitzer RL, Williams JBW, Gibbon M, First MB (1998) Structured clinical interview for DSM-III-R-patient edition (SCID-P). New York Biometrics Research Department, New York State Psychiatric Institute. Stern SL, Dhanda R, Hazuda HP (2001) Hopelessness predicts mortality in older Mexican and European Americans. Psychosom Med 63: 344 351.[Abstract/Free Full Text] Szanto K, Mulsant BH, Houck PR, Miller MD, Mazumdar S, Reynolds CF III, (2001) Treatment outcome in suicidal vs. non-suicidal elderly patients. Am J Geriatr Psychiatry 9: 261268.[Medline] Thase ME, Frank E, Mallinger AG, Hamer T, Kupfer DJ (1992) Treatment of imipramine-resistant recurrent depression III: Efficacy of monoamine oxidase inhibitors. J Clin Psychiatry 53: 511.[Medline] Weller EB, Young KM, Rohrbaugh AH, Weller RA (2001) Overview and assessment of the suicidal child. Depress Anxiety 14: 157163.[Medline] Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E, Dotoli D, Smeraldi E (2001) Factors affecting pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 50: 232330.[Medline]

Focus 2005 American Psychiatric Association

3:146-155

(2005)

INFLUENTIAL PUBLICATION

Course of Illness, Hippocampal Function, Hippocampal Volume in Major Depression

and

Glenda M. MacQueen, Stephanie Campbell, Bruce S. McEwen, Kathryn Macdonald, Shigeko Amano, Russell T. Joffe, Claude Nahmias, and L. Trevor Young

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

ABSTRACT
Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multipleepisode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset. (Reprinted with permission from the Proceedings of the National Academy of Sciences of the United States of America 2003; 100:13871392.[Abstract/Free Full Text] Copyright 2003 National Academy of Sciences, U.S.A.)

The importance of the hippocampus in the pathophysiology of major depressive disorder (MDD) is supported by a substantial body of evidence from basic and clinical studies. Studies using magnetic resonance imaging (MRI) have reported that hippocampal (HC) volume is reduced in patients with MDD (1). Sheline and colleagues (2, 3) reported bilateral HC volume reductions in women with MDD. Three studies reported that patients with depression have smaller left HC volumes than control subjects (46), with the reductions restricted to men in one study (6); another study found right HC volume reductions (7). Several investigators have not found reductions in HC volume in depressed patients (810) including those that have assessed combined volumes of the amygdalaHC complex as one (1114). Most of the studies that have found reduced HC volume examined older depressed subjects (2, 3, 7). Age itself does not predict HC volume in depressed subjects, but rather it may be predicted by length of illness and other variables associated with past burden of illness (3). Although past illness may be particularly important in accounting for variations in hippocampus size, patients studied to date are heterogeneous with respect to this variable. Sheline et al. (3) reported that past illness predicted HC volume reduction; others reported that volumetric reductions were greatest in patients with a chronic course and large number of weeks ill than in those who recovered fully with shorter overall illness duration (4). In contrast, one group found that patients with an older age at onset had smaller HC volumes, and number of depressive episodes was unrelated to HC volume (7). In another study, there was no evidence for an association between HC volume and number of depressive episodes, weeks in remission, or number of past hospitalizations (5). Thus it has not been established whether patients have HC abnormalities that antedate depression or whether accrual of depressive episodes results in altered HC morphology. Although the studies demonstrating an association between duration of illness and HC volume loss suggest the latter, it remains possible that patients may be predisposed to a more refractory course of illness as the result of abnormal HC morphology. To date, this critical variable has not been studied in subjects selected for either minimal or extensive past exposure to depressive episodes and when older subjects are excluded from the analysis. The relation between HC morphology and function as assessed by tasks that are specific to the HC such as recollection memory performance has not been examined adequately. HCdependent recollection memory deficits are amongst the most reliably reported neuropsychological changes in patients with MDD (1519), and these findings provide support for the hypothesis that the hippocampus is abnormal in MDD. An association between HC volume and global cognitive performance in elderly depressed subjects has been reported (14), and one study found an association between left HC gray-matter density and verbal recognition (4). Whether memory deficits occur only in patients with morphological changes is not established. To address these questions regarding the relation between depressive episodes and HC function and morphology, measures were obtained from groups of never treated, postpubertal patients in a first episode (FE) of depression and from a sample of relatively

young patients with a similar age of onset but a substantial past illness burden. These groups were chosen specifically to assess the effect of course of illness not confounded by age.

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

MATERIALS AND METHODS SUBJECTS

Twenty subjects (7 men and 13 women) with a FE of nonpsychotic, unipolar depression, diagnosed by the Structured Clinical Interview for DSM-IV (SCID; ref. 20) comprised the FE group. No subjects had ever received pharmacological or psychotherapeutic treatment for a psychiatric illness, and all endorsed the current episode as their first of depression. Collaborative history from families and family physicians corroborated the self-reports of the patients. Patients completed the initial assessment including memory testing free of medication. Antidepressant medication was initiated in some cases before scanning. Twenty age-, sex-, and premorbid IQ-matched subjects with no history of psychiatric illness by SCID were included as control subjects. Control subjects had no known first-degree relative with depression. Seventeen subjects (11 women and 6 men) with confirmed multiple past episodes (MEs) of depression, as determined by both patient report and chart history, were included as the group with a high past total burden of illness. Patients had an average of six past episodes of depression and 10 years of illness. All patients in the ME group had received at least a trial of a serotonergic antidepressant with an average of three trials of medication per patient. Several ME patients had multiple antidepressant trials that included serotonergic, tricyclic, and novel agents as well as monoamine oxidase inhibitors. No patients were receiving atypical antipsychotics, lithium, or other mood stabilizers during any phase of the procedure. Four patients in the ME group had received past treatment with electroconvulsive therapy; none had received electroconvulsive therapy in the year before assessment. Seventeen age-, sex-, and premorbid IQ-matched individuals with no history of psychiatric illness served as control subjects for this group. Exclusion criteria for all patients and controls included (i) substance-related disorder within the past 6 months as determined by the SCID; (ii) lifetime history of substance dependence

as measured by the SCID; (iii) any anxiety disorder including posttraumatic stress disorder as determined by the SCID; (iv) use of alcohol or illicit psychoactive substance within 48 h of cognitive testing; (v) untreated medical illness such as uncontrolled diabetes or other endocrine disorders; (vi) history of head injury with loss of consciousness; (vii) history of neurological disease; and (viii) treatment with electroconvulsive therapy within 12 months before assessment. All subjects provided written informed consent and completed the questionnaires and memory assessment on the same day. The study was approved by the ethics boards of St. Josephs Hospital (Ontario, Canada) and Hamilton Health Sciences Corporation (Ontario, Canada).

DIAGNOSTIC

AND

SYMPTOM

QUESTIONNAIRES

Subjects received the SCID for diagnostic clarification and to rule out comorbidity. Information from the SCID was used in conjunction with clinical records and family interviews where possible to ascertain number of past depressive episodes. The National Adult Reading Test (21) was administered as an index of premorbid IQ. On the day of cognitive assessment, subjects received the 21-item Hamilton Depression Rating Scale (Ham-D; ref. 22) and the Beck Depression Inventory II (BDI-II; ref. 23); the Global Assessment of Function Scale (GAF; ref. 24) and Clinical Global Impression of Illness Scale (CGI) also were completed.

MEMORY

ASSESSMENT

Subjects completed the Cognitive Failures Questionnaire (CFQ; ref. 25), a measure of individual self-perception of memory impairment. High scores on the CFQ indicate a greater degree of perceived memory impairment, and we have shown previously that subjects with a history of depression have elevated CFQ scores that are not a function of current mood state (16). The California Verbal Learning Test was used as a standard neuropsychological tool to assess immediate and delayed verbal memory; deficits on verbal list learning have been shown previously to be associated with MDD (3). In addition we used a computerized task, the process dissociation task, to examine recollection and habit memory integrity within a single task (26). This task has been recognized as a valid method of examining recollection memory (hippocampus-dependent) processes independent of habit memory (hippocampus-independent) within a single paradigm (27). In contrast to list learning and other tasks that can depend heavily on the ability to categorize information or strategies for learning, this task does not access functions that may depend heavily on frontal lobe integrity. This is important, given recent studies reporting dysfunction in frontal lobe-dependent executive tasks in MDD (28, 29). The task is sensitive to recollection memory impairment in unipolar subjects across a variety of mood states (16) and uses stimuli that have been studied extensively in nonpsychiatric populations (30). Eighteen stimulus words are paired with two associative responses that occurred with equal frequency in published norms (e.g., door-knobs, doorknock). Stimuli are presented on an IBM-compatible computer monitor using Microexperimental software (31). Character size is 3 x 4 mm, and subjects sat 75 cm from the monitor.

The first phase of the procedure consists of training, during which a habit is created by repeated association of the word pairs. Word pairs are presented every 2 sec as an incomplete pair (door-kno_ _), then for 1 sec as the complete pair (door-knobs). Subjects guess completions that are semantically related to the stimulus word. Unknown to the subjects, the word pairs occur with specific frequencies; one pair (e.g., door-knobs) is presented as the correct response in 67% of trials, whereas the other word pair (e.g., doorknock) is presented as the correct response in 33% of trials. Word pairs are presented in random order with the exception that no word pair occurred on more than three consecutive trials. The word pairs that are presented at high or low frequency are counterbalanced across subjects. After this training phase, subjects immediately proceed to a phase consisting of the presentation of 18 successive study-test lists of eight of the word pairs presented during training. Subjects read the word pairs and are told to remember them for a test that will follow. A mathematical distractor task is presented after presentation of the study list. The key test occurs immediately after the mathematical task when incomplete word pairs appear on the screen at the rate of one pair every 3 sec (door-kno_ _). Subjects complete the pair with the word on the immediately preceding study list, and are told to guess if they do not remember. Recollection scores are obtained by subtracting the incongruent trial (when study-list pairs were the same as the low-frequency pair during training) probability from the congruent trial (where study-list pairs were the same as the high-frequency pair during training) probability. An estimate of habit is obtained by the formula habit = incongruent probability/1 recollection (26).

IMAGE

ACQUISITION

AND

ANALYSIS

Images were obtained on a 1.5-T Sigma GE Genesis-based Echo-Speed scanner running version 5.7 software (General Electric Medical Systems, Milwaukee, WI) using a standard 30-cm circularly polarized head coil. Sagittal anatomic images were acquired by using: a 3D/FSPGR/20 sequence; flip angle, 8; echo delay time in-phase, 3.9 msec; repetition time, 21.2 msec; inversion recovery, 300 msec; matrix, 512 x 256; field of view, 23 x 17 cm; scan thickness, 1.2 mm. Image processing was performed by using the software of the magnetic resonance workstation manufacturer. Two raters (S.C. and S.A.) measured unilateral HC gray-matter volume based on stereological estimation methods that have been used for both magnetic resonance volumetry and microscopy. Interrater reliabilities for right and left HC were calculated to be 0.83 and 0.87, respectively. Measurements were taken starting from the optical section lateral extreme of the hippocampus and working medially. On each, the gray-matter region comprising the HC was outlined manually, and the area within was calculated.

ANATOMIC

DEFINITION

OF

THE

HIPPOCAMPUS

The HC is primarily a gray-matter complex, bordered superiorly by the fornixfimbria white-matter junction, inferiorly by para-HC gyrus white matter, anteriorly by white matter separating the HC from the amygdalar nuclei, posteriorly by the lateral ventricle, medially

by subarachnoid spaces of various cisterns, and laterally by the white matter of the corona radiata from the temporal gray matter. The indusium griseum, fornix fimbria white-matter complex, alveus, and white matter of the para-HC gyrus were excluded from the area measured, as were the amygdala proper and the white-matter border, which separates the hippocampus from the amygdala. Included were the cornu ammonis and dentate gyrus; because no clear gross anatomic distinction exists between the hippocampus and the subiculum, presubiculum, or parasubiculum, these structures were also included (see Fig. 1 ).

Figure 1. Saggital MRI of the Hippocampus. The HC gray matter was selected to be measured. Included were the cornu ammonis, dentate gyrus, and subiculum. Excluded were the indusium griseum, amygdalar nuclei, alveus, fimbria, and surrounding white-matter structures.

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ANATOMIC

DEFINITION

OF

TOTAL

CEREBRAL

VOLUME

Total cerebral volume included gray and white matter of both hemispheres and the midbrain superior to the pons, with this border used as the demarcation point because it is identified easily.

STATISTICAL

ANALYSES

Absolute left and right HC volumes as well as volumes corrected for total cerebral volume were examined by using between-within subjects analyses of variance (ANOVAs). The within-group factor included depressed subjects and their age-, sex-, and IQ-matched controls, whereas the between-group factor was FE versus ME patients. This method of analysis was chosen such that these two patient groups could be compared with both their controls and each other within the same analysis. Post hoc analyses were conducted by using the conservative Scheff test.

Where there was a linear relation between variables, the Pearson correlation was used to determine the significance of relations among volumetric changes, clinical variables, and performance on neuropsychological measures. Curve-fitting analysis that included logarithmic, exponential, power, and quadratic functions was conducted to assess for nonlinear associations between variables. The equation that best described the relation between volumetric and clinical variables was reported if significant.

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

RESULTS DEMOGRAPHIC AND CLINICAL DATA

Demographic and clinical variables for patient and control groups are summarized in Table 1 . FE or multiple-episode patients did not differ from controls on the matched variables of age, sex, and full-scale IQ. One patient in the FE group had well controlled diabetes mellitus, and one in the multiple-episode group had a history of hypothyroidism and was on replacement with normal thyroid indices at the time of assessment. No other patients had a history of significant medical illness. Two patients in each depressed group had remote histories consistent with substance abuse, although not substance dependence, and control subjects were matched for an equal frequency of remote substance abuse. The patient and control groups differed significantly on clinical measures such as Ham-D, BDI-II, CGI, and GAF, but the patient groups did not differ from each other on CGI [df(35), t=0.98, P=0.33], BDI-II [df(35), t=1.1, P=0.26], or Ham-D [df(35), t=0.89, P=0.38] scores. FE patients had lower GAF scores than ME patients despite equivalent symptom scores on the Ham-D [df(35), t=2.01, P=0.05]. Although ME patients were older than FE patients at the time of assessment [df(35), t=2.1, P=0.046], the patient groups had a similar age of first illness onset [df(35), t=0.38, P=0.70].

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Table 1. Demographic and Clinical Variables of the Patients and

[in this window] [in a new window]

Matched Controls

MEMORY

PERFORMANCE

Recollection memory was impaired in both patient groups compared with controls on the process dissociation task [Table 2 ; df(1,35), F=15.9, P<0.001]. The patient groups did not differ from each other [df(1,35), F=1.2, P= 0.28]. FE and ME patients performed at the level of control subjects on the measure of habit memory [df(1,35), F=0.007, P=0.93] and showed no differential tendency to guess when compared with control subjects [df(1,35), F=0.1, P=0.71]. There were no associations between Ham-D score at the time of assessment and recollection memory performance (rsq=0.001, df(35), F=0.03, P=0.87).

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Table 2. Hippocampus-Dependent Recollection Memory Function, Perceived Memory Impairment (CFQ), and Hippocampus Volumes

There was also a significant difference between patients and controls on verbal memory as assessed by total number of words correct on the California verbal learning test [df(1,35), F=7.0, P=0.01] but no interaction to suggest that ME patients were relatively worse than controls compared with FE patients [df(1,35), F=1.9, P=0.17]. Patients rated their memory performance as worse than controls on the CFQ [df(1,35), F=33.4, P<0.001]. On post hoc analyses, the patient groups did not differ from each other (P=0.16).

VOLUMETRIC

DATA

Patients with multiple episodes of depression had HC volumes that were significantly smaller than both healthy controls and patients in a FE of depression (Figs. 2 and 3 ).

There was a significant interaction between patients and controls [df(1,35), F=6.4, P=0.016]. In post hoc analyses, ME patients had smaller left HC volumes compared with matched controls (P=0.04) and FE patients (P=0.009). FE patients did not differ from their matched controls (P=0.99). Right HC volumes were also decreased only in the ME group, with a similar significant interaction between patient groups compared with controls [df(1,35), F=7.5, P=0.01]. In post hoc analyses, ME patients had smaller right HC volumes than controls (P=0.04), whereas FE patients did not differ from controls (P=0.99). ME patients also had smaller right HC volumes than FE patients (P=0.001).

Figure 2. HC Volumes of ME Patients and Matched Control (CTL) Subjects. ME patients show significantly smaller HC volumes (in mm3) than age-, sex-, and IQ-matched healthy controls (left HC, P=0.04; right HC, P=0.01).

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Figure 3. HC Volumes of FE Patients and Matched Control (CTL) Subjects. No significant difference in HC volume (in mm3) is seen between FE patients and age-, sex-, and IQmatched healthy controls (left HC, P=0.99; right HC, P=0.99).

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Total cerebral volumes did not differ between groups [df(1,35), F=1.2, P=0.27]. Consequently, the pattern of results did not change when HC volumes were examined after correcting for total cerebral volume. Left and right corrected HC volumes remained smaller when compared with controls in ANOVAs [left: df(1,35), F=15.4, P<0.001; right: df(1,35), F= 11.8, P=0.002]; post hoc analyses revealed that ME patients had significantly smaller corrected HC volumes than controls (left, P=0.03; right, P=0.03). Left or right corrected volumes for FE groups did not differ when compared with controls (left, P=0.56; right, P=0.71). In contrast to one recent report of FE subjects (6) but consistent with studies examining depressed subjects with varied illness backgrounds (7, 8, 11, 14), we found no gender by group interaction for HC volumes in FE patients [left: F(1,18)=0.03, P=0.86; right: F(1,18)=1.54, P=0.23] or ME patients [left: F(1,15)=0.33, P=0.573; right: F(1,15)=0.79, P=0.39]. When men and women were examined in separate analyses comparing HC volumes in FE men with controls, there were no differences between gender-specific FE patient groups and healthy controls [men, left HC: F(1,6)=0.12, P=0.74; men, right HC: F(1,6)=1.11, P=0.33; women, left HC: F(1,12)=0.005, P=0.94; women, right HC: F(1,12)=0.61, P=0.45].

RELATIONS BETWEEN HC VOLUMES AND ILLNESS VARIABLES

There were trends toward a linear association between length of illness and right and left HC volumes (right: r2=0.29, P=0.08; left: r2=0.29, P=0.08). We examined nonlinear equations that might describe the association between length of illness and HC volumes, because we have shown previously that the association between illness burden and outcome may be nonlinear (32). In fact, the relation between length of illness and HC volumes was

described best by a logarithmic function that was significant for both the left and right HC volumes [left HC: rsq=0.11, df(35), F=4.4, P=0.04; right HC: rsq=0.16, df(35), F=6.8, P=0.03] (see Fig. 4 ). Fig. 4 illustrates the flattening in the curve describing the relation of HC volumes and length of illness later in the course of illness. Curve-fitting analysis did not reveal any relations between total cerebral volume and duration of illness or number of past episodes.

Figure 4. Relation of HC Volumes to Length of Illness. A logarithmic relation describes the association between duration of illness (in years) and HC volume (in mm3) for both left and right HC volumes.

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Neither linear nor nonlinear equations described a relation between depressive severity as assessed by the Ham-D or BDI-II and recollection memory function or HC volumes.

DISCUSSION

This study examines HC function and morphology in ABSTRACT never-treated patients experiencing a FE of depression MATERIALS AND METHODS and in those chosen specifically for multiple past RESULTS episodes of illness in early and middle adulthood. The DISCUSSION REFERENCES results confirm that HC volume reductions associated with MDD are present in patients with significant past illness and suggest furthermore that such morphological changes are not detectable in adult patients with a FE of depression. Because the oldest patient in the ME group was 51 years old, these changes are not accounted for by increasing age. Both patient groups reported cognitive difficulties and had impairment on list learning and a specific recollection task. A logarithmic function best described the association between illness burden as measured by duration of illness and HC volumes and suggests that volume reductions occur early in the course of illness but not before first presentation of depression. Taken together, these data highlight the critical interaction between course of illness and HC pathology in MDD. The observed decreases in HC volume might be due to remodeling of key cellular elements involving retraction of dendrites, decreased neurogenesis in the dentate gyrus, and loss of glial cells (3338). Potentially reversible remodeling and irreversible cell death are likely caused by dysregulation of glucocorticoid secretion and elevated activity of excitatory amino acid neurotransmitters (39). Indeed, elevated glucocorticoid levels are associated with HC atrophy in rats (39) and primates (40). Patients with MDD have demonstrated abnormalities of the hypothalamic pituitary adrenal (HPA) axis; among the most reproducible findings in patients with MDD is nonsuppression of the HPA axis by dexamethasone, a marker of HPA axis overactivation, along with elevated evening levels of cortisol (41). Because the hippocampus is a major site in the glucocorticoid negative feedback circuit, remodeling or neuronal damage and death may lead to less efficient inhibitory control of the corticotrophin-releasing hormone-producing cells of the hypothalamus, resulting in increased glucocorticoids and worsening of the process (39). A decrease in neurotrophic factors such as brain-derived neurotrophic factor could lead to low HC volume and vulnerability to subsequent episodes of depression, a result of decreased neurogenesis, increased remodeling of dendrites, and loss of glial cells or increased excitotoxicity (42, 43). Repeated exposure to and then withdrawal from antidepressant medication could also contribute to the excitotoxic damage that may underlie the volume reductions in the ME patients. Abrupt withdrawal of the antidepressant imipramine leads to a rapid increase in glutamate activity (44) in animal models, and patients abruptly withdrawn from the serotonergic antidepressant paroxetine have activation of the sympathetic and hypothalamicpituitary-growth systems (45). Morphological changes in the hippocampus were not evident in patients in a FE of depression. These data differ somewhat from a recent study in which HC volume reductions were reported in men but not women in the FE of depression (6). These differences may reflect differences in the age of patients at the time of study. The FE subjects in our study were younger than others studied who had an average age of 40 and included patients up to age 58 (6). The younger age of onset in our sample is more typical of large-scale epidemiological studies (46); older age at first presentation may be associated with greater

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exposure to subthreshold depression or to depression associated with vascular or other neurological diseases. These results have clinical significance in suggesting that morphological changes associated with depression are not present early in illness; consequently, there may be a window of time in which it is possible to arrest or delay progression of the morphological changes associated with MDD. The logarithmic equation that described the association between HC volumes and illness duration further supports the notion that such intervention is crucial in the early stages of illness. This relation implies a relatively rapid decrease in HC volumes across the first few years of illness followed by a flattening of the curve, suggesting that after several years of illness, there is, on average, little further decline in HC volumes. Whether treatment in the early years of illness may ultimately change the clinical course of illness expression and rate of HC volume loss is not known. The ME patients averaged over three lifetime trials of different antidepressants, and some had many years of treatment with up to a dozen different agents, yet they still displayed the observed morphological and functional abnormalities. This may be because, despite extensive pharmacological treatment histories, they were not treated adequately during the FEs of illness. Alternatively, it is possible that antidepressants, although improving symptoms, do little to prevent the pathophysiological processes associated with chronic, recurrent depression. The long-term benefits of these medications remain to be established, and new agents may need to be developed that interfere with the HC remodeling that occurs as a consequence of repeated stress (38). Although morphological changes were not apparent in FE patients, recollection memory impairment was detectable, which implicates HC dysfunction in these patients and suggests that the dysfunction predates measurable morphological changes. Recollection memory performance was not predicted by Ham-D or BDI-II scores in this study, and using the process dissociation task in a separate group of individuals with current or remitted depression we previously found recollection memory impairment after remission of depressive symptoms (16). These data are consistent with previous work of Sheline et al. (3), which demonstrated list-learning deficits in patients in remission, and other recent reports of memory impairment persisting into the euthymic period (47, 48). Whether these deficits ultimately resolve remains to be established. Thus it seems that detectable morphological changes are not required before significant memory abnormalities are detectable, and hippocampus dysfunction, as assessed by recollection memory performance, may be a better marker of the early effects of MDD than structural analyses. The logarithmic association between decreased HC size and length of illness found in this study supports the importance of illness course variables in emergent morphological abnormalities. The fact that the relation between illness duration and HC volumes was not statistically significant when modeled by a linear curve may explain why other studies that tested only for a linear association could not detect relations between illness burden and HC volumes. Association between illness burden and HC volumes could also be obscured if only patients with a long duration of illness are included in the sample, because these patients might be expected to fall only within the flat tail of the curve. Several factors need to be considered when interpreting the data. First, none of our patients had a prepubertal age of depression onset, nor were they required to have a positive family

history of depressive disorder. Selected samples of individuals with childhood-onset depression (49) or strong family histories (50) might represent samples enriched for genetic vulnerability that may be more likely to have abnormal HC morphology at the time of illness onset (51). We focused on patient samples with postpubertal, adolescent, or adult onset of first depression, and these data may not be applicable to all FE patients. Second, it is possible that a greater degree of anatomic resolution would have detected early evidence of morphometric changes in some HC regions. FE patients and the matched control subjects had right and left HC volumes that differed by only 12% in contrast to the 13% observed in ME patients, however, suggesting that further increasing the sample size would have been unlikely to uncover a real difference between FE patients and their matched controls. Third, the ME patients had variable exposure to antidepressants and benzodiazepines. Although both classes of drugs may have beneficial effects in animal models of depression and chronic stress, respectively, at least in this sample of patients who were currently symptomatic past exposure to these medications did not prevent or reverse the appearance of HC damage. In summary, these data confirm that relatively young adults with multiple episodes of depression have bilateral HC volume reductions. The association between HC volume reduction and length of illness was best described by a logarithmic function. Morphological changes were not apparent in patients with a postpubertal FE of depression. Hippocampus dysfunction, as reflected in hippocampus-dependent recollection memory impairment, was apparent in patients with first or multiple episodes of depression and thus seems to affect patients before the emergence of significant HC volume reductions. Treatment early in disease progression may reduce or eliminate the volumetric reductions associated with multiple episodes of illness. Longitudinal studies of patients from early in illness will ultimately be required to evaluate this hypothesis.

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

REFERENCES
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3. Sheline, Y. I., Sanghavi, M., Mintun, M. A. & Gado, M. H. (1999) J. Neurosci. 19, 50345043.[Abstract/Free Full Text] 4. Shah, P. J., Ebmeier, K. P., Glabus, M. F. & Goodwin, G. M. (1998) Br. J. Psychiatry 172, 527532.[Abstract/Free Full Text] 5. Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L. & Charney, D. S. (2000) Am. J. Psychiatry 157, 115117.[Abstract/Free Full Text] 6. Frodl, T., Meisenzahl, E. M., Zetzsche, T., Born, C., Groll, C., Jager, M., Leinsinger, G., Bottlender, R., Hahn, K. & Moller, H. J. (2002) Am. J. Psychiatry 59, 11121118. 7. Steffens, D. C., Byrum, C. E., McQuoid, D. R., Greenberg, D. L., Payne, M. E., Blitchington, T. F., MacFall, J. R. & Krishnan, K. R. (2000) Biol. Psychiatry 48, 301309.[Medline] 8. Vakili, K., Pillay, S. S., Lafer, B., Fava, M., Renshaw, P. F., Bonello-Cintron, C. M. & Yurgelun-Todd, D. A. (2000) Biol. Psychiatry 47, 10871090.[Medline] 9. Rusch, B. D., Abercrombie, H. C., Oakes, T. R., Schaefer, S. M. & Davidson, R. J. (2001) Biol. Psychiatry 50, 960964.[Medline] 10. von Gunten, A., Fox, N. C., Cipolotti, L.&Ron, M. A. (2000) J. Neuropsychiatry Clin. Neurosci. 12, 493498.[Abstract/Free Full Text] 11. Axelson, D. A., Doraiswamy, P. M., McDonald, W. M., Boyko, O. B., Tupler, L. A., Patterson, L. J., Nemeroff, B., Ellinwood, E. H., Jr., & Krishnan, K. R. (1993) Psychiatry Res. 47, 163173.[Medline] 12. Pantel, J., Schroder, J., Essig, M., Popp, D., Dech, H., Knopp, M. V., Schad, L. R., Eysenbach, K., Backenstrass, M. & Friedlinger, M. (1997) J. Affect. Disord. 42, 6983.[Medline] 13. Coffey, C. E., Wilkinson, W. E., Weiner, R. D., Parashos, I. A., Djang, W. T., Webb, M. C., Figiel, G. S. & Spritzer, C. E. (1993) Arch. Gen. Psychiatry 50, 7 16.[Abstract/Free Full Text] 14. Ashtari, M., Greenwald, B. S., Kramer-Ginsberg, E., Hu, J., Wu, H., Patel, M., Aupperle, P. & Pollack, S. (1999) Psychol. Med. 29, 629638.[Medline] 15. Zakanzis, K. K., Leach, L. & Kaplan, E. (1998) Neuropsychiatry Neuropsychol. Behav. Neurol. 11, 111119.[Medline] 16. MacQueen, G. M., Young, T. L., Marriott, M., Robb, J., Begin, H. & Joffe R. T. (2002) Acta Psychiatr. Scand. 105, 414418.[Medline]

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33. Czeh, B., Michaelis, T., Watanabe, T., Frahm, J., de Biurrun, G., van Kampen, M., Bartolomucci, A. & Fuchs, E. (2001) Proc. Natl. Acad. Sci. USA 98, 12796 12801.[Abstract/Free Full Text] 34. Magarinos, A. M., Deslandes, A. & McEwen, B. S. (1999) Eur. J. Pharmacol. 371, 113122.[Medline] 35. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. (2000) J. Neurosci. 20, 91049110.[Abstract/Free Full Text] 36. Rajkowska, G. (2000) Biol. Psychiatry 48, 766777.[Medline] 37. Sousa, N., Lukoyanov, N. V., Madeira, M. D., Almeida, O. F. X. & Paula-Barbosa, M. M. (2000) Neuroscience 97, 253266.[Medline] 38. McEwen, B. S. (1999) Annu. Rev. Neurosci. 22, 105122.[Medline] 39. Sapolsky, R. M. (2000) Biol. Psychiatry 48, 755765.[Medline] 40. Sapolsky, R. M., Uno, H., Rebert, C. S. & Finch, C. E. (1990) J. Neurosci. 10, 28972902.[Abstract] 41. Young, E. A., Haskett, R. F., Grunhaus, L., Pande, A., Weinberg, M., Watson, S. J. & Akil, H. (1994) Arch. Gen. Psychiatry 51, 701707.[Abstract/Free Full Text] 42. Dowlatshahi, D., MacQueen, G. M. & Wang, J. F. (1998) Lancet 352, 1754 1755.[Medline] 43. Chen, B., Dowlatshahi, D. & MacQueen, G. M. (2001) Biol. Psychiatry 50, 260 261.[Medline] 44. Harvey, B. H., Jonker, L. P., Brand, L., Heenop, M. & Stein, D. (2002) Life Sci. 71, 4354.[Medline] 45. Michelson, D., Amsterdam, J., Apter, J., Fava, M., Londborg, P., Tamura, R. & Pagh, L. (2000) Psychoneuroendocrinology 25, 169177.[Medline] 46. Wittchen, H. U., Knauper, B. & Kessler, R. C. (1994) Br. J. Psychiatry Suppl. 26, 1622. 47. Reischies, F. M. & Neu, P. (2000) Eur. Arch. Psychiatry Clin. Neurosci. 250, 186 193.[Medline] 48. Grant, M. M., Thase, M. E. & Sweeney, J. A. (2001) Biol. Psychiatry 50, 35 43.[Medline]

49. Steingard, R. J., Renshaw, P. F., Yurgelun-Todd, D., Appelmans, K. E., Lyoo, I. K., Shorrock, K. L., Bucci, J. P., Cesena, M., Abebe, D., Zurakowski, D., et al. (1996) J. Am. Acad. Child Adolesc. Psychiatry 35, 307311.[Medline] 50. Drevets, W. C. (2000) Biol. Psychiatry 48, 813829.[Medline] 51. Kaufman, J., Martin, A., King, R. A. & Charney, D. (2001) Biol. Psychiatry 49, 9801001.[Medline]
Focus 2005 American Psychiatric Association 3:156-160 (2005)

INFLUENTIAL PUBLICATION

Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

Avshalom Caspi, Karen Sugden, Terrie E. Moffitt, Alan Taylor, Ian W. Craig, HonaLee Harrington, Joseph McClay, Jonathan Mill, Judy Martin, Antony Braithwaite, and Richie Poulton

TOP ABSTRACT REFERENCES AND NOTES

ABSTRACT
In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HTT promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individuals response to environmental insults is moderated by his or her genetic makeup.

(Reprinted with permission from Science 2003 301(5631):386 389.[Abstract/Free Full Text] Copyright 2003 American Association for the Advancement of Science) Supporting online www.sciencemag.org/cgi/content/full/301/5631/386/DC1 Materials and Tables S1 to S5 material Methods

Depression is among the top five leading causes of disability and disease burden throughout the world (1). Across the life span, stressful life events that involve threat, loss, humiliation, or defeat influence the onset and course of depression (25). However, not all people who encounter a stressful life experience succumb to its depressogenic effect. Diathesis-stress theories of depression predict that individuals sensitivity to stressful events depends on their genetic makeup (6, 7). Behavioral genetics research supports this prediction, documenting that the risk of depression after a stressful event is elevated among people who are at high genetic risk and diminished among those at low genetic risk (8). However, whether specific genes exacerbate or buffer the effect of stressful life events on depression is unknown. In this study, a functional polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) was used to characterize genetic vulnerability to depression and to test whether 5-HTT gene variation moderates the influence of life stress on depression. The serotonin system provides a logical source of candidate genes for depression, because this system is the target of selective serotonin reuptakeinhibitor drugs that are effective in treating depression (9). The serotonin transporter has received particular attention because it is involved in the reuptake of serotonin at brain synapses (10). The promoter activity of the 5-HTT gene, located on 17q11.2, is modified by sequence elements within the proximal 5 regulatory region, designated the 5-HTT gene-linked polymorphic region (5-HTTLPR). The short ("s") allele in the 5-HTTLPR is associated with lower transcriptional efficiency of the promoter compared with the long ("l") allele (11). Evidence for an association between the short promoter variant and depression is inconclusive (12). Although the 5-HTT gene may not be directly associated with depression, it could moderate the serotonergic response to stress. Three lines of experimental research suggest this hypothesis of a gene-by-environment (G x E) interaction. First, in mice with disrupted 5-HTT, homozygous and heterozygous (5-HTT / and +/) strains exhibited more fearful behavior and greater increases in the stress hormone (plasma) adrenocorticotropin in response to stress compared to homozygous (5-HTT +/+) controls, but in the absence of stress no differences related to genotype were observed (13). Second, in rhesus macaques, whose length variation of the 5-HTTLPR is analogous to that of humans, the short allele is associated with decreased seroto-nergic function [lower

cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid concentrations] among monkeys reared in stressful conditions but not among normally reared monkeys (14). Third, human neuroimaging research suggests that the stress response is mediated by variations in the 5HTTLPR. Humans with one or two copies of the s allele exhibit greater amygdala neuronal activity to fearful stimuli compared to individuals homozygous for the l allele (15). Taken together, these findings suggest the hypothesis that variations in the 5-HTT gene moderate psychopathological reactions to stressful experiences. We tested this G x E hypothesis among members of the Dunedin Multidisciplinary Health and Development Study (16). This representative birth cohort of 1037 children (52% male) has been assessed at ages 3, 5, 7, 9, 11, 13, 15, 18, and 21 and was virtually intact (96%) at the age of 26 years. A total of 847 Caucasian non-Maori study members, without stratification confounds, were divided into three groups on the basis of their 5-HTTLPR genotype (11): those with two copies of the s allele (s/s homozygotes; n=147; 17%), those with one copy of the s allele (s/l heterozygotes; n=435; 51%), and those with two copies of the l allele (l/l homozygotes; n=265; 31%). There was no difference in genotype frequencies between the sexes [ 2(2<)=0.02, P=0.99]. Stressful life events occurring after the 21st birthday and before the 26th birthday were assessed with the aid of a life-history calendar (17), a highly reliable method for ascertaining life-event histories (18). The 14 events included employment, financial, housing, health, and relationship stressors. Thirty percent of the study members experienced no stressful life events; 25% experienced one event; 20%, two events; 11%, three events; and 15%, four or more events. There were no significant differences between the three genotype groups in the number of life events they experienced, F(2,846)=0.56, P=0.59, suggesting that 5-HTTLPR genotype did not influence exposure to stressful life events. Study members were assessed for past-year depression at age 26 with the use of the Diagnostic Interview Schedule (19), which yields a quantitative measure of depressive symptoms and a categorical diagnosis of a major depressive episode according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria (20). 17% of study members (58% female versus 42% male; odds ratio=1.6; 95% confidence interval from 1.1 to 2.2) met criteria for a past-year major depressive episode, which is comparable to age and sex prevalence rates observed in U.S. epidemiological studies (21). In addition, 3% of the study members reported past-year suicide attempts or recurrent thoughts about suicide in the context of a depressive episode. We also collected informant reports about symptoms of depression for 96% of study members at age 26 by mailing a brief questionnaire to persons nominated by each study member as "someone who knows you well." We used a moderated regression framework (22), with sex as a covariate, to test the association between depression and (i) 5-HTTLPR genotype, (ii) stressful life events, and (iii) their interaction (table S1). The interaction between 5-HTTLPR and life events showed that the effect of life events on self-reports of depression symptoms at age 26 was significantly stronger (P=0.02) among individuals carrying an s allele than among l/l homozygotes (Fig. 1A ). We further tested whether life events could predict withinindividual increases in depression symptoms over time among individuals with an s allele by statistically controlling for the baseline number of depressive symptoms they had before

the life events occurred (table S1). The significant interaction (P=0.05) showed that individuals carrying an s allele whose life events occurred after their 21st birthday experienced increases in depressive symptoms from the age of 21 to 26 years (b=1.55, SE=0.66, t=2.35, P=0.02 among s/s homozygotes and b=1.25, SE=0.34, t=3.66, P<0.001 among s/l heterozygotes) whereas l/l homozygotes did not (b=0.17, SE=0.41, t=0.41, P=0.68).

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Figure 1. Results of multiple regression analyses estimating the association between number of stressful life events (between ages 21 and 26 years) and depression outcomes at age 26 as a function of 5-HTT genotype. Among the 146 s/s homozygotes, 43 (29%), 37(25%), 28 (19%), 15 (10%), and 23 (16%) study members experienced zero, one, two, three, and four or more stressful events, respectively. Among the 435 s/l heterozygotes, 141 (32%), 101 (23%), 76 (17%), 49 (11%), and 68 (16%) experienced zero, one, two, three, and four or more stressful events. Among the 264 l/l homozygotes, 79 (29%), 73 (28%), 57 (21%), 26 (10%), and 29 (11%) experienced zero, one, two, three, and four or more stressful events. (A) Self-reports of depression symptoms. The main effect of 5-HTTLPR (i.e., an effect not conditional on other variables) was marginally significant (b=0.96, SE=0.52, t=1.86, P=0.06), the main effect of stressful life events was significant (b=1.75, SE=0.23, t=7.45, P<0.001), and the interaction between 5-HTTLPR and life events was in the predicted direction (b=0.89, SE=0.37, t=2.39, P=0.02). The interaction showed that the effect of life events on self-reports of depression symptoms was stronger among individuals carrying an s allele (b=2.52, SE=0.66, t=3.82, P<0.001 among s/s homozygotes, and b=1.71, SE=0.34, t=5.02, P<0.001 among s/l heterozygotes) than among l/l homozygotes (b=0.77, SE=0.43, t=1.79, P=0.08). (B) Probability of major depressive episode. The main effect of 5HTTLPR was not significant (b=0.15, SE=0.14, z=1.07, P=0.29), the main effect of life events was significant (b=0.37, SE=0.06, z=5.99, P<0.001), and the G x E was in the predicted direction (b=0.19, SE=0.10, z=1.91, P=0.056). Life events predicted a diagnosis of major depression among s carriers (b=0.52, SE=0.16, z=3.28, P=0.001 among s/s homozygotes, and b=0.39, SE=0.09, z=4.24, P<0.001 among s/l heterozygotes) but not among l/l homozygotes (b=0.16,

SE=0.13, z=1.18, P=0.24). (C) Probability of suicide ideation or attempt. The main effect of 5-HTTLPR was not significant (b= 0.01, SE=0.28, z=0.01, P=0.99), the main effect of life events was significant (b=0.51, SE=0.13, z=3.96, P<0.001), and the G x E interaction was in the predicted direction (b=0.39, SE=0.20, t=1.95, P=0.051). Life events predicted suicide ideation or attempt among s carriers (b=0.48, SE=0.29, z=1.67, P=0.09 among s/s homozygotes, and b=0.91, SE=0.25, z=3.58, P<0.001 among s/l heterozygotes) but not among l/l homozygotes (b=0.13, SE=0.26, z=0.49, P=0.62). (D) Informant reports of depression. The main effect of 5-HTTLPR was not significant (b=0.06, SE=0.06, t=0.98, P=0.33), the main effect of life events was significant (b=0.23, SE=0.03, t=8.47, P<0.001), and the G x E was in the predicted direction (b=0.11, SE=0.04, t=2.54, P<0.01). The effect of life events on depression was stronger among s carriers (b=0.39, SE=0.07, t=5.23, P<0.001 among s/s homozygotes, and b=0.17, SE=0.04, t=4.51, P<0.001 among s/l heterozygotes) than among l/l homozygotes (b=0.14, SE=0.05, t=2.69, P<0.01).

The G x E interaction also showed that stressful life events predicted a diagnosis of major depression among carriers of an s allele but not among l/l homozygotes (P=0.056, Fig. 1B ). We further tested whether life events could predict the onset of new diagnosed depression among carriers of an s allele (table S1). We excluded from analysis study members who were diagnosed with depression before age 21. The significant interaction (P=0.02) showed that life events occurring after their 21st birthdays predicted depression at age 26 among carriers of an s allele who did not have a prior history of depression (b=0.79, SE=0.25, z=3.16, P=0.002 among s/s homozygotes and b=0.41, SE=0.12, z=3.29, P=0.001 among s/l heterozygotes) but did not predict onset of new depression among l/l homozygotes (b=0.08, SE=0.20, z=0.42, P=0.67). Further analyses showed that stressful life events predicted suicide ideation or attempt among individuals carrying an s allele but not among l/l homozygotes (P=0.05, Fig. 1C ). The hypothesized G x E interaction was also significant when we predicted informant reports of age-26 depression (P<0.01), an analysis that ruled out the possibility of self-report bias (Fig. 1D ). The interaction showed that the effect of life events on informant reports of depression was stronger among individuals carrying an s allele than among l/l homozygotes. These analyses attest that the 5-HTT gene interacts with life events to predict depression symptoms, an increase in symptoms, depression diagnoses, new-onset diagnoses, suicidality, and an informants report of depressed behavior. This evidence that 5-HTTLPR variation moderates the effect of life events on depression does not constitute unambiguous evidence of a G x E interaction, because exposure to life

events may be influenced by genetic factors; if individuals have a heritable tendency to enter situations where they encounter stressful life events, these events may simply be a genetically saturated marker (23, 24). Thus, what we have identified as a gene x environment interaction predicting depression could actually reflect a gene x "gene" interaction between the 5-HTTLPR and other genes we did not measure. We reasoned that, if our measure of life events represents merely genetic risk, then life events would interact with 5-HTTLPR even if they occurred after the depression episode. However, if our measure of life events represents environmental stress, then the timing of life events relative to depression must follow cause-effect order and life events that occur after depression should not interact with 5-HTTLPR to postdict depression. We tested this -hypothesis by substituting the age-26 measure of depression with depression assessed in this longitudinal study when study members were 21 and 18 years old, before the occurrence of the measured life events between the ages of 21 and 26 years. Whereas the 5-HTTLPR x life events interaction predicted depression at the age of 26 years, this same interaction did not postdict depression reported at age 21 nor at the age of 18 years (table S2), indicating our finding is a true G x E interaction. If 5-HTT genotype moderates the depressogenic influence of stressful life events, it should moderate the effect of life events that occurred not just in adulthood but also of stressful experiences that occurred in earlier developmental periods. Based on this hypothesis, we tested whether adult depression was predicted by the interaction between 5-HTTLPR and childhood maltreatment that occurred during the first decade of life (16, 25). Consistent with the G x E hypothesis, the longitudinal prediction from childhood maltreatment to adult depression was significantly moderated by 5-HTTLPR (table S3). The interaction showed (P=0.05) that childhood maltreatment predicted adult depression only among individuals carrying an s allele but not among l/l homozygotes (Fig. 2 ).

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Figure 2. Results of regression analysis estimating the association between childhood maltreatment (between the ages of 3 and 11 years) and adult depression (ages 18 to 26), as a function of 5-HTT genotype. Among the 147s/s homozygotes, 92 (63%), 39 (27%), and 16 (11%) study members were in the no maltreatment, probable maltreatment, and severe maltreatment groups, respectively. Among the 435 s/l heterozygotes, 286 (66%), 116 (27%), and 33 (8%) were in the no, probable, and severe maltreatment groups. Among the 265 l/l homozygotes, 172 (65%), 69 (26%), and 24 (9%) were in the no, probable, and severe maltreatment groups. The main effect of 5-

HTTLPR was not significant (b=0.14, SE=0.11, z=1.33, P=0.19), the main effect of childhood maltreatment was significant (b=0.30, SE=0.10, z=3.04, P=0.002), and the G x E interaction was in the predicted direction (b=0.33, SE=0.16, z=2.01, P=0.05). The interaction showed that childhood stress predicted adult depression only among individuals carrying an s allele (b=0.60, SE=0.26, z=2.31, P=0.02 among s/s homozygotes, and b=0.45, SE=0.16, z=2.83, P=0.01 among s/l heterozyotes) and not among l/l homozygotes (b=0.01, SE=0.21, z=0.01, P=0.99).

We previously showed that variations in the gene encoding the neurotransmittermetabolizing enzyme monoamine oxidase A (MAOA) moderate childrens sensitivity to maltreatment (25). MAOA has high affinity for 5-HTT, raising the possibility that the protective effect of the l/l allele on psychiatric morbidity is further augmented by the presence of a genotype conferring high MAOA activity (13, 26). However, we found that the moderation of life stress on depression was specific to a polymorphism in the 5-HTT gene, because this effect was observed regardless of the individuals MAOA gene status (tables S4 and S5). Until this studys findings are replicated, speculation about clinical implications is premature. Nonetheless, although carriers of an s 5-HTTLPR allele who experienced four or more life events constituted only 10% of the birth cohort, they accounted for almost onequarter (23%) of the 133 cases of diagnosed depression. Moreover, among cohort members suffering four or more stressful life events, 33% of individuals with an s allele became depressed, whereas only 17% of the l/l homozygotes developed depression (Fig. 3 ). Thus, the G x Es attributable risk and predictive sensitivity indicate that more knowledge about the functional properties of the 5-HTT gene may lead to better pharmacological treatments for those already depressed. Although the short 5-HTTLPR variant is too prevalent for discriminatory screening (over half of the Caucasian population has an s allele), a microarray of genes might eventually identify those needing prophylaxis against lifes stressful events (27).

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Figure 3. The percentage of individuals meeting diagnostic criteria for depression at age 26, as a function of 5-HTT genotype and number of stressful life events between the ages of 21 and 26. The figure shows individuals with either one or two copies of the short allele (left) and individuals homozygous for the long allele (right). In a hierarchical logistic regression model, the main effect of genotype (coded as s group=0 and l group=1) was not significant, b=0.15, SE=0.21, z=0.72, P=0.47; the main effect of number of life events was significant, b=0.34, SE=0.06, z=5.70, P<0.001; and the interaction between genotype and number of life events was significant, b=0.30, SE=0.15, z=1.97, P=0.05.

Evidence of a direct relation between the 5-HTTLPR and depression has been inconsistent (12), perhaps because prior studies have not considered participants stress histories. In this study, no direct association between the 5-HTT gene and depression was observed. Previous experimental paradigms, including 5-HTT knockout mice (13), stress-reared rhesus macaques (14), and human functional neuroimaging (15), have shown that the 5HTT gene can interact with environmental conditions, although these experiments did not address depression. Our study demonstrates that this G x E interaction extends to the natural development of depression in a representative sample of humans. However, we could not test hypotheses about brain endophenotypes (28) intermediate between the 5-HTT gene and depression because of the difficulty of taking CSF or functional magnetic resonance imaging measurements in an epidemiological cohort. Much genetic research has been guided by the assumption that genes cause diseases, but the expectation that direct paths will be found from gene to disease has not proven fruitful for complex psychiatric disorders (29). Our findings of G x E interaction for the 5-HTT gene and another candidate gene, MAOA (25), point to a different, evolutionary model. This model assumes that genetic variants maintained at high prevalence in the population probably act to promote organisms resistance to environmental pathogens (30). We extend the concept of environmental pathogens to include traumatic, stressful life experiences and propose that the effects of genes may be uncovered when such pathogens are measured (in naturalistic studies) or manipulated (in experimental studies). To date, few linkage studies detect genes, many candidate gene studies fail consistent replication, and genes that replicate account for little variation in the phenotype (29). If replicated, our G x E findings will have implications for improving research in psychiatric genetics. Incomplete gene penetrance, a major source of error in linkage pedigrees, can be explained if a genes effects

are expressed only among family members exposed to environmental risk. If risk exposure differs between samples, candidate genes may fail replication. If risk exposure differs among participants within a sample, genes may account for little variation in the phenotype. We speculate that some multifactorial disorders, instead of resulting from variations in many genes of small effect, may result from variations in fewer genes whose effects are conditional on exposure to environmental risks.

TOP ABSTRACT REFERENCES AND NOTES

REFERENCES AND NOTES

1. C. J. Tang, A. D. Lopez, Lancet 349, 1498 (1997).[Medline] 2. G. W. Brown, Soc. Psychiatry Psychiatr. Epidemiol. 33, 363 (1998). 3. K. S. Kendler, L. M. Karkowski, C. A. Prescott, Am. J. Psychiatry 156, 837 (1999).[Abstract/Free Full Text] 4. R. C. Kessler, Annu. Rev. Psychol. 48, 191 (1997).[Medline] 5. D. S. Pine, P. Cohen, J. G. Johnson, J. S. Brook, J. Affect. Disorders 68, 49 (2002).[Medline] 6. E. J. Costello et al., Biol. Psychiatry 52, 529 (2002).[Medline] 7. S. M. Monroe, A. D. Simons, Psychol. Bull. 110, 406 (1991). 8. K. S. Kendler et al., Am. J. Psychiatry 152, 833 (1995).[Abstract/Free Full Text] 9. C. A. Tamminga et al., Biol. Psychiatry 52, 589 (2002).[Medline] 10. K. P. Lesch, M. D. Greenberg, J. D. Higley, A. Bennett, D. L. Murphy, in Molecular Genetics and the Human Personality, J. Benjamin, R. P. Ebstein, R. H. Belmaker, Eds. [American Psychiatric Association (APA), Washington, DC, 2002], pp. 109136. 11. K. P. Lesch et al., Science 274, 1527 (1996).[Abstract/Free Full Text]

12. K. P. Lesch, in Behavioral Genetics in the Postgenomics Era, R. Plomin, J. C. DeFries, I. W. Craig, P. McGuffin, Eds. (APA, Washington, DC, 2003), pp. 389 424. 13. D. L. Murphy et al., Brain Res. Bull. 56, 487 (2001).[Medline] 14. A. J. Bennett et al., Mol. Psychiatry 7, 188 (2002). 15. A. R. Hariri et al., Science 297, 400 (2002).[Abstract/Free Full Text] 16. Materials and methods are available as supporting material on Science Online. 17. A. Caspi et al., Int. J. Methods Psychiatr. Res. 6, 101 (1996). 18. R. F. Belli, W. L. Shay, F. P. Stafford, Public Opin. Q. 65, 45 (2001).[Abstract] 19. L. N. Robins, L. Cottler, K. Bucholtz, W. Compton, Diagnostic Interview Schedule for DSM-IV (Washington University, St. Louis, MO, 1995). 20. APA, Diagnostic and Statistical Manual of Mental Disorders (APA, Washington, DC, ed. 4, 1994). 21. R. C. Kessler, K. A. McGonagle, M. Swartz, D. G. Blazer, C. B. Nelson, J. Affect. Disorders 29, 85 (1993).[Medline] 22. L. S. Aiken, S. G. West, Multiple Regression: Testing and Interpreting Interactions (Sage, Thousand Oaks, CA, 1991). 23. K. S. Kendler, L. Karkowski-Shuman, Psychol. Med. 27, 539 (1997).[Medline] 24. R. Plomin, C. S. Bergeman, Behav. Brain Sci. 14, 373 (1991). 25. A. Caspi et al., Science 297, 851 (2002).[Abstract/Free Full Text] 26. N. Salichon et al., J. Neurosci. 21, 884 (2001).[Abstract/Free Full Text] 27. W. E. Evans, M. V. Relling, Science 286, 487 (1999).[Abstract/Free Full Text] 28. I. I. Gottesman, T. D. (2003).[Abstract/Free Full Text] Gould, Am. J. Psychiatry 160, 636

29. D. Hamer, Science 298, 71 (2002).[Free Full Text] 30. A. V. S. Hill, Br. Med. Bull. 55, 401 (1999).[Abstract/Free Full Text]

31. We thank P. Silva, founder of the Dunedin Multidisciplinary Health and Development Study, Air New Zealand, and the study members, their families, and their friends. Supported by the Health Research Council of New Zealand and the University of Wisconsin Graduate School and by grants from the U.K. Medical Research Council, the William T. Grant Foundation, and the U.S. National Institute of Mental Health (MH49414 and MH45070). T.E.M. is a Royal SocietyWolfson Research Merit Award holder. The study protocol was approved by the institutional review boards of the participating universities.
Focus 2005 American Psychiatric Association 3:161-169 (2005)

INFLUENTIAL PUBLICATION

Relationship of Variability in Residual Symptoms With Recurrence of Major Depressive Disorder During Maintenance Treatment
Jordan F. Karp, M.D., Daniel J. Buysse, M.D., Patricia R. Houck, M.S.H., Christine Cherry, M.S., David J. Kupfer, M.D., and Ellen Frank, Ph.D.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

ABSTRACT
Objective: To investigate how residual symptoms from an index episode of major depressive disorder may be associated with recurrence, the authors conducted a trial involving four maintenance treatment approaches and examined 1) whether the level and variability of residual symptoms differed among the maintenance treatment conditions and 2) whether greater symptom variability is associated with a higher likelihood of recurrence and more rapid recurrence. Method: Patients enrolled in a maintenance treatment study (N=114) were randomly assigned to one of four maintenance treatment conditions: imipramine plus interpersonal psychotherapy, imipramine alone, interpersonal

psychotherapy alone, or no active treatment. Residual symptoms were characterized both as continuous variables (mean values and coefficients of variation for Hamilton Depression Rating Scale and Global Assessment Scale [GAS] scores) and as a categorical variable, the percentage of maintenance evaluations with a Hamilton depression scale score 8 (e.g., with a symptom peak). Results: Analysis of variance revealed no differences among the four treatment conditions in patients levels of residual symptoms or symptom variability assessed as a continuous variable, but patients in the combined treatment group had fewer symptom peaks, compared to those in the placebo and interpersonal psychotherapy groups. Cox proportional hazards modeling showed that higher coefficients of variation for both the Hamilton depression scale and the GAS scores and a greater percentage of evaluations with symptom peaks were associated with shorter survival times. Conclusions: A higher level of symptom variability during maintenance treatment is associated with higher risk for recurrence of depression and may provide a specific target for maintenance treatments. (Reprinted with permission from the American Journal of Psychiatry 2004; 161:1877 1884[Abstract/Free Full Text])

Over the last 20 years increasing focus has been placed on continuation and maintenance treatment of depression (13), and parameters have been adopted for defining relapse and recurrence (4). Treatments for these empirically defined features of the natural history of depression have also been described (1, 57). Most studies have used dichotomous measures of acute treatment outcome defined by symptoms on the Hamilton Depression Rating Scale (8), Beck Depression Inventory (9), and the Global Assessment Scale (GAS) (10). However, some level of symptoms often persists even after a patient has been determined to be "well," according to scores on these measures. This phenomenon may be related to both the varied natural history and the multifactorial etiology of depression, which includes biological predispositions (11), vulnerable cognitive processes (12), and environmental stressors such as significant life events and long-term stressors (13). Indeed, Paykel (14) noted, "Failure to remit, delayed remission, partial remission with considerable residual symptoms, relapse and recurrence are common outcomes of the depressive illness." The subclinical nature of persistent symptoms may not warrant a diagnosis of either an incompletely treated or new episode of major depression, of dysthymic disorder, or of personality disorder. Nonetheless, residual symptoms may continue to cause significant subjective distress (15) and may, in fact, be risk factors for subsequent episodes of depression (14). The purpose of this report is to extend previous findings by describing the quality of remission with different maintenance treatments in a group of patients with recurrent depression. We also sought to determine whether recurrence of depression was related to the level or variability of persistent symptoms during maintenance treatment. The studies mentioned earlier defined residual symptoms as depression severity or global functioning symptoms in excess of the threshold criterion for recovery. In this study, we examined

residual symptoms in two ways: first, on a continuous scale of symptom severity and variability and, second, on the basis of a threshold criterion for symptom exacerbations (symptom peaks). We hypothesized that 1) the level and variability of residual symptoms would differ among four maintenance treatment conditions (medication, maintenance interpersonal psychotherapy, medication plus maintenance interpersonal psychotherapy, and placebo) and 2) patients with greater variability in depression and global functioning ratings would experience more rapid recurrences during maintenance treatment.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

METHOD PATIENTS
Methods and study design have been described in detail elsewhere (1) but will be briefly reviewed. The original protocol from which the subjects were drawn was designed to explore the relative efficacy of five maintenance treatment strategies in preventing or delaying recurrences in a group of patients with high rates of recurrence of unipolar depression (1, 6). To enter the original protocol, subjects between ages 21 and 65 years were required to have a minimum of a 10-week remission period between the index episode and the immediately prior episode, according to Research Diagnostic Criteria (RDC) (16). A minimum Hamilton depression scale score of 15 and a minimum score of 7 on the Raskin Severity of Depression Scale (17) were also required for study participation. Eligible patients were then evaluated with the Schedule for Affective Disorders and Schizophrenia (18). Patients who met both the RDC for a major depressive episode and the historical requirements for previous episodes and clear remissions were entered into the protocol. After complete description of the study to the subjects, written informed consent was obtained. Before entering the maintenance phase of the study, all patients (N=230) received acute treatment consisting of a combination of imipramine hydrochloride (150300 mg/day) and interpersonal psychotherapy (19). Treatment sessions were scheduled weekly for 12 weeks, then biweekly for 8 weeks, and then monthly. After achieving a Hamilton depression scale score 7 and a Raskin Severity of Depression Scale score 5 for 3 consecutive weeks in acute treatment, patients entered the continuation phase of the study, which lasted an additional 17 weeks. To remain in the continuation phase of treatment, patients were

required to have stable Hamilton depression scale and Raskin Severity of Depression Scale scores and a stable imipramine dose. At the patients entrance into the continuation phase, their personality pathology was assessed with the Personality Assessment Form (20). At the end of the 17 weeks, symptomatically stable patients were evaluated once again with the Personality Assessment Form and were randomly assigned to one of five maintenance treatments for a period of 3 years or until they experienced a recurrence of illness. The original five treatments were 1) a maintenance form of interpersonal psychotherapy (21, 22) offered alone, 2) maintenance interpersonal psychotherapy with active imipramine therapy continued at the acute treatment dose, 3) maintenance interpersonal psychotherapy with placebo, 4) medication clinic visits with active imipramine therapy, and 5) medication clinic visits with placebo. For the purposes of the present report, we combined two of the treatment groups, both of which received maintenance interpersonal psychotherapy as the primary modality of treatment. All previous analyses found these groups to be equivalent. Thus, the four treatments we compared were 1) medication clinic visits with placebo (N=19), 2) medication clinic visits with active imipramine therapy (N=23), 3) maintenance interpersonal psychotherapy alone or with placebo (N=47), and 4) maintenance interpersonal psychotherapy with active imipramine therapy continued at the acute treatment dose (N=25). During maintenance therapy, patients had monthly contact with their assigned therapist and psychiatrist. Of the 128 patients who ultimately entered the maintenance therapy phase and were followed for 3 years, 114 met the additional requirement for this report of having at least two office contacts with their treatment team and two independent evaluators during the maintenance phase. Of the 14 patients who did not meet this criterion, 11 experienced a recurrence, and three were dropouts (one found the clinic schedule inconvenient, one was nonadherent with medication treatment, and one died in a house fire). Among the 14 patients who were not included, five were receiving interpersonal psychotherapy alone or interpersonal psychotherapy with placebo, five were receiving active medication therapy alone, and four were receiving placebo. All of the patients who were receiving maintenance interpersonal psychotherapy with active imipramine therapy had at least two office contacts during maintenance therapy. If a patient presented with substantial clinical worsening or called the clinic to report such worsening, the clinician evaluated the patient twice during a 7-day period. Onset of a recurrence of depression during maintenance therapy was identified by agreement of two evaluatorsan independent clinical evaluator and a senior psychiatrist not affiliated with the studywho determined that the patient met the criteria for an episode of major depression. For patients with recurrence of depression, the last two Hamilton depression scale scores, which contributed to the identification of recurrence, were not included in the current analyses, because inclusion of these scores would have artificially increased the level and variability of symptoms.

STATISTICAL

METHODS

The time spent in maintenance treatment for these 114 patients was compared across the four treatment groups by using Cox proportional hazards analysis. This analysis was performed primarily to confirm our previous findings about the treatments efficacy in preventing recurrences (1).

To determine the effect of residual symptom severity and variability on recurrence, we first examined these measures as continuous variables. The mean, standard deviation, and coefficient of variation of the Hamilton depression scale and GAS scores during maintenance treatment were determined for each patient. The coefficient of variation expresses the standard deviation of the individuals score as a percentage of the mean (coefficient of variation=standard deviation/mean x 100). This measure is useful for examining the size of the variation relative to the size of the observation and also allows for independence from the units of observation. Mean values for each measure were compared across treatment groups with analysis of variance (ANOVA). The risk of recurrence as a function of residual symptom level and variability was determined by Cox proportional hazards analysis with a stepwise selection model. Treatment assignment, which had been shown to influence recurrence rates, was entered first into the model. Residual symptom levels and variability were entered next and were considered to be significant if the coefficient was associated with a probability of <0.05. Hazard ratios and 95% confidence intervals (CIs) are reported for the variables in the models. In the second type of analysis, we considered the percentage of Hamilton depression scale scores 8 (symptom peak) during maintenance treatment. We selected this level because Hamilton depression scale scores 7 were used to define recovery. A t test was performed to compare data for patients with and without symptom peaks to determine if there was a difference in total number of contacts with clinicians during maintenance treatment. This type of analysis parallels those reported by Paykel et al. (23) and focuses on the amount of time spent above a predefined criterion level of symptom severity. ANOVA was used to contrast the percentage of maintenance treatment scores 8 among the four maintenance treatment groups. We used Cox proportional hazards modeling, as described earlier, to determine the effect of the number of symptomatic peaks on recurrence. Finally, we examined scores for each item of the Hamilton depression scale to determine if some items had a greater degree of variability and therefore had greater influence on overall symptom variability. This analysis was done by dividing the observed range of scores for each item by the possible range of scores for that item in each subject, and then calculating the group mean.

RESULTS

The demographic and clinical characteristics of the 128 patients entering the maintenance phase of treatment have been described elsewhere (1). Among the 114 subjects included in our analyses, the four treatment groups (measured at baseline) were equivalent with respect to age, Raskin Severity of Depression Scale score, 17-item and 25-item Hamilton depression scale score, and GAS score at entry into the study. The groups were also similar in duration of the index episode, number of previous episodes, and age at onset of first depressive episode (Table 1 ).

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

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Table 1. Baseline Demographic Characteristics of Patients With Major Depressive Disorder Randomly Assigned to Four Maintenance Treatment Conditions

Statistically significant differences in time to recurrence were found among the four groups, as determined by Cox proportional hazards analysis (p 0.0001). The results are similar to those of our previous study (1), in which we found that patients who received imipramine as part of their treatment regimen experienced longer recurrence-free intervals. We note these findings simply to illustrate the difference in time to recurrence among the four treatment modalities.

RECURRENCE
Continuous definition of

OF
symptom severity

DEPRESSION
and variability.

To identify differences in the quality of remission among the groups, we used ANOVA to compare the mean, standard deviation, and coefficient of variation of the Hamilton depression scale and GAS scores. There were no statistically significant differences among the treatment groups with respect to level or variability of residual symptoms (Table 2 ).

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this

table: [in this window] [in a new window]

Table 2. Measures of Variability of Residual Symptoms in Patients With Major Depressive Disorder Randomly Assigned to Four Maintenance Treatment Conditions

Relative to survival time for the placebo group, survival time was significantly higher for the combined treatment group (hazards ratio=0.15, 95% CI=0.060.41, p=0.0002) and the imipramine only group (hazards ratio=0.12, 95% CI=0.040.35, p=0.0002) but not for the interpersonal psychotherapy only group (hazards ratio=0.59, 95% CI=0.301.16, p=0.13). Cox proportional hazards modeling was used to examine the length of time to recurrence in relation to symptom variability. This analysis, which utilized stepwise selection and included the four treatment groups in the model, indicated that higher coefficients of variation for both the Hamilton depression scale (relative risk=1.01, 95% CI=1.001.02, p 0.05) and the GAS (relative risk=1.154, 95% CI=1.081.23, p 0.0001) were significantly associated with lower survival times. No additional variables met the 0.05 significance level for entry into the model. The difference between groups in mean scores was not significant for the Hamilton depression scale ( 2=0.64, df=1, p=0.43) or the GAS ( 2=0.34, df=1, p=0.56). The difference between the standard deviations for the Hamilton depression scale ( 2 =2.68, df=1, p=0.10) and the GAS ( 2<0.01, df=1, p=0.95) was also not significant. Figure 1 shows a graphical display of the results of a Cox regression analysis of predicted survival curves for low and high levels of variability for each treatment, as determined by the 25th and 75th percentiles of the coefficients of variation for the Hamilton depression scale and GAS scores. Subjects with low variability had a longer survival course for each of the treatments, compared to their respective high-variability counterparts within that treatment group.

Figure 1. Cox Proportional Hazards Analysis Predicting the Proportion of Patients Without Recurrence of Major Depressive Disorder in Four Maintenance Treatment Conditions, by Low and High Levels of Symptom Variabilitya a Low symptom variability was indicated by coefficients of variation below the 25th percentile (coefficients of variation of 61 for the Hamiltion Depression Rating Scale and 7 for the Global Assessment Scale [GAS]); high symptom variability was indicated by coefficients of variation above the 75th percentile (coefficients of variation of 99 for the Hamilton depression scale and 12 for the GAS).

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Categorical

definition

of

residual

symptom

variability.

Before performing similar analyses on the categorical (symptom peak) data, we used a t test to determine if there was a difference in the number of recorded Hamilton depression scale scores between patients who did not experience any symptom peaks and patients who had one or more symptom peaks. This analysis was done to confirm that patients who had at least one symptom peak were not underrepresented in the analysis because of early relapse or dropout. No difference was found in the number of Hamilton depression scale scores between the patients with no symptom peaks and those with one or more symptom peaks (t=0.66, df=112, p=0.51). Treatment group was significantly related to outcome. Relative to survival time for the placebo group, survival time was significantly higher for the combined treatment group (hazard ratio=0.20, 95% CI=0.070.53, p=0.001) and the imipramine only group (hazard ratio=0.14, 95% CI=0.050.43, p=0.0006) and was nonsignificantly higher for the interpersonal psychotherapy only group (hazard ratio=0.57, 95% CI=0.301.09, p=0.09). To identify differences in the quality of remission among the groups according to the categorical model, ANOVA was used to compare the percentage of Hamilton depression scale scores 8 across the four groups. A statistically significant difference between the groups was identified (F=3.27, df=3, 110, p<0.03). Post hoc tests revealed a significantly lower percentage of symptom peaks in the combination treatment group, compared to the placebo and interpersonal psychotherapy only groups. Given the waxing and waning nature of these symptom peaks, we feel they represent a true measure of variability.

Cox proportional hazards modeling was again used to examine the relationship between symptom peaks and time to recurrence. This analysis, which used stepwise selection and included the four treatment groups in the model, indicated that an increased percentage of symptom peaks during maintenance treatment was significantly associated with decreased survival time (relative risk=1.02, 95% CI=1.011.03, p 0.005).

CLINICAL

CORRELATIONS

We computed correlation coefficients between the values for the patients demographic and clinical characteristics and the coefficients of variation of the Hamilton depression scale and GAS scores. None of these variables was significantly correlated with either coefficient of variation. We also examined correlations of the scores on the Personality Assessment Form at recovery with the coefficients of variation and standard deviations. This analysis was done for the total Personality Assessment Form score as well as for the scores on the three dimensions of the Personality Assessment Form: odd/eccentric, dramatic, and anxious/fearful personality subtypes. Earlier studies showed good stability between continuation and premaintenance evaluations for the clinician-rated Personality Assessment Form, with correlation coefficients ranging from 0.56 to 0.89 for specific diagnoses and even higher correlations for the three clusters (24). Our analysis revealed a significant correlation between the Personality Assessment Form total score and the standard deviation of the Hamilton depression scale scores (r=0.23, df=111, p<0.02). We also found statistically significant correlations with the standard deviation of the Hamilton depression scale score for both cluster B (dramatic) (r=0.20, df=111, p<0.03) and cluster C (anxious/fearful) (r=0.25, df=111, p<0.008) scores. In other words, personality disorder features were positively associated with variability in Hamilton depression scale scores.

DESCRIPTIVE

ANALYSIS

Finally, we performed a descriptive analysis for each item of the Hamilton depression scale to determine which items showed the greatest variability during maintenance treatment. For each patient, the observed range of scores for each item was divided by the possible range; and the mean for this value across all patients was then calculated. The seventeen items of the Hamilton depression scale are listed in descending order of variability in Table 3 . The items with the greatest variability were anergia; loss of libido; initial, middle, and delayed insomnia; psychological and somatic anxiety; depressed mood; and weight loss.

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Table 3. Rank Order of 17-Item Hamilton Depression Rating Scale Items by Measures of Symptom Variability Among Patients With Major Depressive Disorder (N=114) in a Maintenance Treatment Study

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

DISCUSSION
We were interested in determining whether the level of variability of Hamilton depression scale and GAS scores was related to the type of maintenance treatment and whether variability influenced time to recurrence in patients with recurrent major depressive disorder. Our findings show that the four treatment conditions we studied differed in terms of the percentage of residual symptom peaks, but they did not differ in terms of residual symptoms considered on a continuous scale. Second, compared with patients who remained well, patients who had recurrences had higher levels of symptoms and greater symptom variability, illustrated by an increase in percentage of symptom peaks. Third, we found that a higher coefficient of variation for both the Hamilton depression scale and the GAS scores was associated with significantly shorter survival time. Finally, a higher level of symptom variability was related to higher levels of personality pathology. These findings suggest that, independent of the type of treatment that a patient is receiving, a higher level of variability of depressive symptoms and functioning are associated with a higher risk of recurrence. The findings of minor differences in residual symptoms among the four treatment conditions is somewhat surprising because there was a dramatic difference in survival among the four groups (1), i.e., the groups treated with active medication remained well significantly longer than their nonmedicated counterparts. This finding would lead one to predict that the quality as well as the "quantity" (i.e., survival time) of the weeks spent in maintenance therapy would also be superior for the more aggressively treated groups. The patients who received the combination of imipramine and interpersonal psychotherapy had fewer symptom peaks than the patients who received placebo or interpersonal psychotherapy alone, but the groups did not differ when residual symptoms were defined by standard deviation, coefficient of variation, or mean level. Thus, the specific effect of pharmacotherapy on residual symptoms appears to be small. However, it is possible that active medication treatment stabilized those symptoms that were more variable, i.e., the neurovegetative symptoms. Psychological therapies may not adequately address these features of recurrent depression, and this lack of adequate effects may have resulted in the differences in symptom peaks. It should be noted that all of the patients who received combination maintenance interpersonal psychotherapy and imipramine had at least two

office contacts during maintenance therapy. This pattern of office contacts is in contrast to those of the other three treatment groups, which each had an equal number of subjects excluded from this analysis because they either had a recurrence or dropped out. Thus, the combination of psychotherapy and active medication or of not changing the treatment regimen (all patients received combination therapy in the acute and continuation phases) on the number of symptom peaks may protect patients against early relapse as well as recurrence. It is likely that factors other than random treatment assignment were more strongly related to symptom variability during maintenance treatment. As discussed later in this section, personality features may be one such factor. Higher levels of symptom variability may also be a trait that is present only in certain individuals, as suggested by the absence of treatment group differences in variability. An alternate hypothesis is that different treatment conditions may produce different sources of symptom variability, which nonetheless lead to the same outcome, recurrence. For example, earlier reports have shown that interpersonal psychotherapy patients who had a recurrence tended to be less able to focus on interpersonal themes during therapy (21, 22, 25), whereas imipramine treated patients who had a recurrence tended to have poorer medication compliance (26). There is a large body of evidence concerning the chronicity of major depression (2732), and the literature describing residual symptoms of depression and their clinical significance continues to grow. Studies published by Fava and colleagues (33, 34), Judd et al. (35, 36), and other thought leaders in this area (37) have found that patients with residual subthreshold depressive symptoms during recovery had significantly more severe and chronic future courses of depression. Paykel et al. (23) also examined residual symptoms after partial remission from depression. The only significant predictor of residual symptoms in that study was a more severe initial illness. However, residual symptoms were strong predictors of early relapse, which occurred in 76% (13 of 17 patients) of those with residual symptoms and 25% (10 of 40 patients) of those without residual symptoms. Paykel et al. did not examine the effect of different treatments on level of residual symptoms. In practical terms, recovered patients with more variability in symptoms, especially neurovegetative symptoms, may need closer surveillance for relapses or recurrences. Frank et al. (5) analyzed the quality of remission during the continuation phase of treatment in the same patient group described in this paper. Eighty-one (63%) of the 128 patients never experienced a Hamilton depression scale score >9 during the 20-week continuation period. Twenty-six patients (20%) experienced at least one symptomatic "blip" (Hamilton depression scale score >10), and 21 patients (16%) experienced two or more blips. While Frank et al. found these residual symptoms (blips) to be related to poor treatment outcome during the continuation phase of treatment, we found residual symptoms (defined as both increased symptom variability and increased percentage of blips during maintenance therapy) to be a risk factor for disease recurrence during maintenance treatment. This finding reinforces the potential importance of the relationship between residual symptoms and outcome during different phases of depression treatment. In addition, this finding is supported by a recent meta-analysis by Geddes et al. (38), who found that continuing

treatment with antidepressants reduces the risk of relapse by 70%, compared with treatment discontinuation, and appears to benefit many patients with recurrent depressive disorder. Our results showed a statistically significant correlation between the standard deviation of the Hamilton depression scale score and cluster B, cluster C, and total scores on the Personality Assessment Form. Other studies have examined the relationship between personality pathology and time to remission (24, 39, 40). Personality traits and disorders, long a controversial variable with respect to the etiology of depression and its failed treatment, may play a significant role in residual symptoms (41, 42). For example, "character spectrum disorder," identified by Akiskal (41), is marked by unstable traits such as dependent, histrionic, antisocial, and schizoid features, as well as irritable dysphoria and substance abuse, and is thought to be secondary to unstable and chaotic developmental experiences. In patients with character spectrum disorder, depression is viewed as secondary to personality pathology and is, in fact, distinct from true affective disorder. The traits identified by Akiskal were largely replicated in our study: specifically cluster B (dramatic) and cluster C (anxious/fearful) scores on the Personality Assessment Form were significantly associated with the standard deviation of the Hamilton depression scale score, and the standard deviation of the Hamilton depression scale score was in turn a significant risk factor for recurrence. One limitation of our study is that patients with severe clinical features of personality disorders, particularly cluster A and B disorders, were excluded from study participation. The limitations of the current study include the post hoc nature of the analyses, the limited temporal resolution of symptom measures, and the fact that subjects with the most rapid recurrence (e.g., less than two office visits) were not included. It should also be remembered that patients were seen only once a month unless symptoms appeared, and thus some symptom peaks may have been missed. In addition, the size of the observed effects for symptom variability on recurrence was modest. Finally, it should be noted that the medication used in the study, imipramine, is not currently a first-line choice of antidepressant. It would be ideal to replicate this study with a selective serotonin reuptake inhibitor or a newer dual-mechanism antidepressant to see if outcomes or tolerability were comparable. Nevertheless, our findings suggest that variability of residual symptoms, as well as the actual level of residual symptoms, may constitute a new target for the maintenance treatment of recurrent depression. In addition, while a literature about subsyndromal symptomatic depression exists (43, 44), there has been no research to our knowledge on residual symptoms during an index episode. While these two phenomena are related across the spectrum of depressive illnesses, our findings suggest that minimizing the variability of residual symptoms during maintenance treatment may help to prevent recurrences.

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2007 American Psychiatric Association
relevance focus

47. Bibliography BIPOLAR DISORDER

48. This section contains a compilation of recent publications that have shaped the thinking in the field as well as classic works that remain important to the subject reviewed in this issue. This bibliography has been compiled by experts in the field and members of the editorial and advisory boards. Entries are listed chronologically and within years by first author. Articles from the bibliography that are reprinted in this issue are in bold type. 49. Papadimitriou GN, Dikeos DG, Full Text (PDF) Soldatos CR, Calabrese JR: Non- Role of Psychotherapy in the pharmacological treatments in the Management of Bipolar Disorder of Bipolar management of rapid cycling bipolar Pharmacotherapy Depression disorder. J Affect Disord 2007; 98:1 Citation Map 10[Medline] 50. Albanese MJ, Clodfelter RC Jr, Pardo TB, Ghaemi SN: Underdiagnosis of bipolar disorder in men with substance use disorder. J Psychiatr Pract 2006; 12:124127[Medline] Email this article to a Colleague 51. Altman S, Haeri S, Cohen LJ, Ten A, Similar articles in this journal Barron E, Galynker II, Duhamel KN: Alert me to new issues of the journal Predictors of relapse in bipolar Add to My Articles & Searches disorder: a review. J Psychiatr Pract Download to citation manager 2006; 12:269282[Medline] 52. Altshuler LL, Post RM, Black DO, Keck PE, Nolen WA, Frye MA, Suppes T, Grunze H, Kupka RW, Leverich GS, McElroy SL, Walden J, Mintz J: Subsyndromal depressive Citing Articles via Google Scholar symptoms are associated with functional impairment in patients with bipolar disorder: results of a large, multisite study. J Clin Psychiatry 2006; 67:15511560[Medline] Search for Related Content 53. Altshuler LL, Suppes T, Black DO, Nolen WA, Leverich G, Keck PE Jr, Frye MA, Kupka R, McElroy SL, Grunze H, Kitchen CM, Post R: Lower

switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants. Am J Psychiatry 2006; 163:313315[Abstract/Free Full Text] 54. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J: Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006; 8:625639[Medline] 55. Ball JR, Mitchell PB, Corry JC, Skillecorn A, Malhi GS: A randomized controlled trial of cognitive therapy for bipolar disorder: focus on long-term change. J Clin Psychiatry 2006; 67: 277286[Medline] 56. Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Keller M: Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006; 63: 175 183[Abstract/Free Full Text] 57. Bowden CL, Calabrese JR, Ketter TA, Sachs GS, White RL, Thompson TR: Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Am J Psychiatry 2006; 163:11991201[Abstract/Free Full Text] 58. Findling RL, McNamara NK, Stansbrey R, Gracious BL, Whipkey RE, Demeter CA, Reed MD, Youngstrom EA, Calabrese JR: Combination lithium and divalproex sodium in pediatric bipolar symptom re-stabilization. J Am Acad Child Adolesc Psychiatry 2006;45:142148[Medline] 59. Frye MA, Calabrese JR, Reed ML, Hirschfeld RM: Healthcare resource utilization in bipolar depression compared with unipolar depression: results of a United States population-based study. CNS Spectr 2006; 11: 704710[Medline] 60. Gitlin M: Treatment-resistant bipolar disorder. Mol Psychiatry 2006; 11:227 240[Medline] 61. Green EK, Raybould R, Macgregor S, Hyde S, Young AH, ODonovan MC, Owen MJ, Kirov G, Jones L, Jones I, Craddock N: Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disordercase-control study of over 3000 individuals from the UK. Br J Psychiatry 2006; 188: 2125[Abstract/Free Full Text] 62. Ketter TA, Houston JP, Adams DH, Risser RC, Meyers AL, Williamson DJ, Tohen M. Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. J Clin Psychiatry 2006; 67:95101[Medline] 63. Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE Jr, Kupka RW, Denicoff KD, Nolen WA, Grunze H, Martinez MI, Post RM: Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry 2006; 163:232 239[Abstract/Free Full Text] 64. Miklowitz DJ: An update on the role of psychotherapy in the management of bipolar disorder. Curr Psychiatry Reports 2006; 8:498503 Role of Psychotherapy in the Management of Bipolar Disorder ONLINE EXCLUSIVE: Full text of article as it originally appeared. 65. Nierenberg AA, Ostacher MJ, Calabrese JR, Ketter TA, Marangell LB, Miklowitz DJ, Miyahara S, Bauer MS, Thase ME, Wisniewski SR, Sachs GS: Treatmentresistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of

antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry 2006; 163:210216[Abstract/Free Full Text] 66. Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, Ketter TA, Miklowitz DJ, Otto MW, Gyulai L, Reilly-Harrington NA, Sachs GS, Thase ME: Predictors of recurrence in bipolar disorder: primary outcomes from the systematic treatment enhancement program for bipolar disorder. Am J Psychiatry 2006; 163:217224. Reprinted in FOCUS 2006; 4:553561[Abstract/Free Full Text] 67. Perlis RH, Welge JA, Vornik LA, Hirschfeld RM, Keck PE Jr: Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebocontrolled trials. J Clin Psychiatry 2006; 67:509516[Medline] 68. Post RM, Altshuler LL, Leverich GS, Frye MA, Nolen WA, Kupka RW, Suppes T, McElroy S, Keck PE, Denicoff KD, Grunze H, Walden J, Kitchen CM, Mintz J: Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry 2006; 189:124 131[Abstract/Free Full Text] 69. Post RM, Leverich GS: The role of psychosocial stress in the onset and progression of bipolar disorder and its comorbidities: the need for earlier and alternative modes of therapeutic intervention. Dev Psychopathol 2006; 18:11811211[Medline] 70. Scott J: Psychotherapy for bipolar disordersefficacy and effectiveness. J Psychopharmacol 2006; 20(2 suppl):4650[Abstract/Free Full Text] 71. Scott J, Paykel E, Morriss R, Bentall R, Kinderman P, Johnson T, Abbott R, Hayhurst H: Cognitive-behavioural therapy for severe and recurrent bipolar disordersrandomised controlled trial. Br J Psychiatry 2006; 188:313 320[Abstract/Free Full Text] 72. Simon GE, Ludman EJ, Bauer MS, Unutzer J, Operskalski B: Long-term effectiveness and cost of a systematic care program for bipolar disorder. Arch Gen Psychiatry 2006; 63:500508[Abstract/Free Full Text] 73. Thase ME: Bipolar depression: Diagnostic and treatment considerations. Dev Psychopathol 2006; 18:12131230[Medline] 74. Thase ME: Pharmacotherapy of bipolar depression: an update. Curr Psychiatry Rep 2006; 8:478488[Medline] Pharmacotherapy of Bipolar Depression ONLINE EXCLUSIVE: Full text of article as it originally appeared. 75. Tohen M, Calabrese JR, Sachs GS, Banov MD, Detke HC, Risser R, Baker RW, Chou JCY, Bowden CL: Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry 2006; 163: 247 256[Abstract/Free Full Text] 76. Weisler RH, Cutler AJ, Ballenger JC, Post RM, Ketter TA: The use of antiepileptic drugs in bipolar disorders: a review based on evidence from controlled trials. CNS Spectr 2006; 11:788799[Medline] 77. Bowden CL, Collins MA, McElroy SL, Calabrese JR, Swann AC, Weisler RH, Wozniak PJ: Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo. Neuropsychopharmacology 2005; 30:19321939[Medline] 78. Bowden CL, Grunze H, Mullen J, Brecher M, Paulsson B, Jones M, Vagero M, Svensson K: A randomized, double-blind, placebo-controlled efficacy and safety

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ABSTRACT
This section contains a compilation of recent publications that have shaped the thinking in

the field as well as classic works that remain important to the subject reviewed in this issue. This bibliography has been compiled by experts in the field and members of the editorial and advisory boards. Entries are listed chronologically and within years by first author. Articles from the bibliography that are reprinted in this issue are in bold type.

TOP ABSTRACT REFERENCES

REFERENCES
Green MF, Nuechterlein KH, Kern RS, Baade LE, Fenton WS, Gold JM, Keefe RS, Mesholam-Gately R, Seidman LJ, Stover E, Marder SR. Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study. Am J Psychiatry 2008; 165:221 228[Abstract/Free Full Text] Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull2007; 33:2132 Available online at http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/33/1/21[Abstract/Fre e Full Text] Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA. Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 2007; 33:1120 1130[Abstract/Free Full Text] Cooper D, Moisan J, Gregoire JP. Adherence to atypical antipsychotic treatment among newly treated patients: a population-based study in schizophrenia. J Clin Psychiatry 2007; 68:815825 Craddock N, O'Donovan MC, Owen MJ. Phenotypic and genetic complexity of psychosis. Invited commentary on... Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 2007; 190:200203[Abstract/Free Full Text] Elkis H. Treatment-resistant schizophrenia. Psychiatr Clin North Am 2007; 30:511 33[Medline]

Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA (CATIE Investigators; Neurocognitive Working Group). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64:633647[Abstract/Free Full Text] Keefe RS, Sweeney JA, Gu H, Hamer RM, Perkins DO, McEvoy JP, Lieberman JA. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 2007; 164:10611071[Abstract/Free Full Text] Kreyenbuhl J, Marcus SC, West JC, Wilk J, Olfson M. Adding or switching antipsychotic medications in treatment refractory schizophrenia. Psychiatr Serv 2007; 58:983990[Abstract/Free Full Text] Malik P. Sexual dysfunction in schizophrenia. Curr Opin Psychiatry 2007; 20:138 142[Medline] McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D, Olexy C, Weiden P, Strakowski SD. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 2007; 164:1050 1060[Abstract/Free Full Text] McGurk SR, Twamley EW, Sitzer DI, McHugo GJ, Mueser KT. A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry 2007; 164:1791 1802[Abstract/Free Full Text] Stover EL, Brady L, Marder SR. New paradigms for treatment development. Schizophr Bull 2007; 33:10931099 Available online at http://schizophreniabulletin.oxfordjournals.org/cgi/content/abstract/33/5/1093[Abstr act/Free Full Text] Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Capuano GA, Rosenheck RA, Keefe RS, Miller AL, Belz I, Hsiao JK (CATIE Investigators). Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. Am J Psychiatry 2007; 164:415427[Abstract/Free Full Text] Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, Reimherr F, McGee MF, Keefe RS, McEvoy JP, Hsiao JK, Lieberman JA (CATIE Investigators). Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry 2007; 164:428436[Abstract/Free Full Text]

Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull 2007; 33:6994[Abstract/Free Full Text] Weiden PJ, Buckley PF, Grody M. Understanding and treating "first-episode" schizophrenia. Psychiatr Clin North Am 2007; 30:481510[Medline] Brown AS: Prenatal infection as a risk factor for schizophrenia. Schizophr Bull2006; 32:200202 Available online at http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/32/2/200[Abstract/F ree Full Text] Fenton WS, Chavez MR. Medication-induced weight gain and dyslipidemia in patients with schizophrenia. Am J Psychiatry 2006; 163:16971704[Free Full Text] Green AI, Lieberman JA, Hamer RM, Glick ID, Gur RE, Kahn RS, McEvoy JP, Perkins DO, Rothschild AJ, Sharma T, Tohen MF, Woolson S, Zipursky RB (HGDH Study Group). Olanzapine and haloperidol in first episode psychosis: twoyear data. Schizophr Res 2006; 86:234243[Medline] Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn R (Clozapine and Risperidone Enhancement (CARE) Study Group). Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006; 354:472482[Medline] Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63:10791087[Abstract/Free Full Text] Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32:214 219[Free Full Text] Marder SR. Initiatives to promote the discovery of drugs to improve cognitive function in severe mental illness. J Clin Psychiatry 2006; 67:e03[Medline] McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK (CATIE Investigators). Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163:600 610[Abstract/Free Full Text]

Miller BJ, Paschall CB 3rd, Svendsen DP. Mortality and medical comorbidity among patients with serious mental illness. Psychiatr Serv 2006; 57:1482 1487[Abstract/Free Full Text] Murphy BP, Chung YC, Park TW, McGorry PD. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res 2006; 88:525[Medline] Newcomer JW, Haupt DW: The metabolic effects of antipsychotic medications. Can J Psychiatry 2006; 51:480491[Medline] Norton N, Williams HJ, Owen MJ. An update on the genetics of schizophrenia. Curr Opin Psychiatr. 2006; 19:158164[Medline] Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry 2006; 63:679685[Abstract/Free Full Text] Robinson DG, Woerner MG, Napolitano B, Patel RC, Sevy SM, Gunduz-Bruce H, Soto-Perello JM, Mendelowitz A, Khadivi A, Miller R, McCormack J, Lorell BS, Lesser ML, Schooler NR, Kane JM. Randomized comparison of olanzapine versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes. Am J Psychiatry 2006; 163:20962102[Abstract/Free Full Text] Shad MU, Tamminga CA, Cullum M, Haas GL, Keshavan MS. Insight and frontal cortical function in schizophrenia: a review. Schizophr Res 2006; 86:54 70[Medline] Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in firstepisode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry 2006; 188:510518[Abstract/Free Full Text] Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK (CATIE Investigators). Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163:611622[Abstract/Free Full Text] Tamminga CA. The neurobiology of cognition in schizophrenia. J Clin Psychiatry 2006; 67:e11[Medline] Turkington D, Kingdon D, Weiden PJ. Cognitive behavior therapy for schizophrenia. Am J Psychiatry 2006; 163:365373[Abstract/Free Full Text]

Andreasen N, Carpenter W, Kane J, Lasser R, Marder S, Weinberger D. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162:441449[Abstract/Free Full Text] Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC, Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005; 31:519[Abstract/Free Full Text] Craddock N, O'Donovan MC, Owen MJ. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42:193 204[Abstract/Free Full Text] Elbogen EB, Swanson JW. Swartz MS, Van Dorn R. Medication nonadherence and substance abuse in psychotic disorders: impact of depressive symptoms and social stability. J Nerv Ment Dis 2005; 193:673679[Medline] Jablensky AV, Morgan V, Zubrick SR, Bower C, Yellachich L-A. Pregnancy, delivery and neonatal complications in a population cohort of women with schizophrenia and major affective disorders. Am J Psychiatry 2005; 162:79 91[Abstract/Free Full Text] Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:12091223[Medline] McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, Meltzer HY, Hsiao J, Scott Stroup T, Lieberman JA. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80:19 32[Medline] Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19(suppl 1):193[Medline] Penn DL, Waldheter EJ, Perkins DO, Mueser KT, Lieberman JA. Psychosocial treatment for first-episode psychosis: a research update. Am J Psychiatry 2005; 162:22202232[Abstract/Free Full Text] Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005; 162:17851804[Abstract/Free Full Text]

Schooler N, Rabinowitz J, Davidson M, Emsley R, Harvey PD, Kopala L, McGorry PD, Van Hove I, Eerdekens M, Swyzen W, De Smedt G (Early Psychosis Global Working Group). Risperidone and haloperidol in first episode psychosis: a longterm randomized trial. Am J Psychiatry 2005; 162:947 953[Abstract/Free Full Text] Asarnow JR, Tompson MC, McGrath EP: Annotation: childhood onset schizophrenia: clinical and treatment issues. J Child Psychol Psychiatry 2004; 45:180194[Medline] Correll CU, Leucht S, Kane JM. Lower risk of tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161:414425[Abstract/Free Full Text] Marder SR, Essock SM, Miller AL, Buchanan RW, Casey DE, Davis JM, Kane JM, Lieberman JA, Schooler NR, Covell N, Stroup S, Weissman EM, Wirshing DA, Hall CS, Pogach L, Pi-Sunyer X, Bigger JT Jr, Friedman A, Kleinberg D, Yevich SJ, Davis B, Shon S. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:13341349[Abstract/Free Full Text] Newcomer JW, Nasrallah HA, Loebel AD. The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol 2004; 23(5, suppl 1):S1S6 Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S. The role of the medial frontal cortex in cognitive control. Science 2004; 306:443 447[Abstract/Free Full Text] Ridderinkhof KR, van den Wildenberg WP, Segalowitz SJ, Carter CS. Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain Cogn 2004; 56:129140[Medline] Robinson DG, Woerner MG, McMeniman M, Mendelowitz A, Bilder RM. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 2004; 161:473 479[Abstract/Free Full Text] Vauth R, Loschmann C, Rusch N, Corrigan PW. Understanding adherence to neuroleptic treatment in schizophrenia. Psychiatry Res 2004; 126:4349[Medline] Hyman SE, Fenton WS. Medicine: what are the right targets psychopharmacology? Science 2003; 299:350351[Abstract/Free Full Text] for

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Howard P, Rabins PV, Seeman MV, Jeste DP (International Late-Onset Schizophrenia Group): Late-onset schizophrenia and very late-onset schizophrenialike psychosis: an international consensus. Am J Psychiatry 2000; 157:172 178[Abstract/Free Full Text] Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW: Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 1999; 20:106 118[Medline] Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153:321330[Abstract/Free Full Text] Liddle PF. The symptoms of chronic schizophrenia: A re-examination of the positive and negative dichotomy. Br J Psychiatry 1987; 151:145 151[Abstract/Free Full Text]

III.- TRASTORNOS Ansiosos y OBSESIVOS COMPULSIVOS Vision de conjunto

La ansiedad, fenmeno central en la historia humana, se extiende en el tiempo y la cultura de manera universal. Sin embargo, su estudio sistematico en psiquiatria clinica es reciente. Su prevalencia en la comunidad es alta y los costos asociados a su tratamiento ocupa el tercio del gasto total en servicios de salud mentals. Pese a ello, los cuadros ansiosos son a menudo mal diagnosticados y tratados en la practica medica psiquiatrita y psicologica general. En la actualidad, el campo de la investigacin clinica y neurobiologica de la ansiedad es uno de los mas interesantes y abarca aspectos dispares, desde la genetica hasta las disfunciones cognitivas, pasando por la neuroquimica, la anatomia y las contribuciuones del medio ambiente en cada uno de los trastornos ansiosos que se encuentran en el DSM IV-TR, marco de referencia para su anlisis psicopatologico en este texto. Por otro lado, el desarrollo de las tecnicas de imagen cerebral ha permitido conocer el funcionamiento cerebral y la accion de la farmacoterapia y psicoterapia en la normalizacion de la neuroanatoma funcional de los sujetos, ofreciendo un campo de reflexion y analisis muy interesante de los vinculos mente-cuerpo, tradicionalmente separados en la practica psiquiatrita de orientacin meramente biologica. Los trastornos ansiosos constituyen la patologa psiquitrica-psicologica mas frecuente en la poblacin causando malestar importante y deterioro social y laboral, y a menudo constituye un factor de riesgo para el desarrollo de alcoholismo, otras

patologas adictivas y trastornos alimentarios. A menudo se presenta en comorbilidad con otras patologas tales como depresiones y otras patologis ansiosas

Breve historia de la neurosis Ansiedad y angustia Modificaciones del DSM Cuadros clinicos segn DSM IV TR: TAG, Trastorno panico, etc

Focus 6:431-437, 2008 American Psychiatric Association

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2008

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CLINICAL SYNTHESIS

Update on the Assessment, Diagnosis, and Treatment of Individuals with Social Anxiety Disorder
Hannah Delong, B.A., and Mark H. Pollack, M.D.
Correspondence: Address correspondence to Mark H. Pollack, M.D., The Center for Anxiety and Traumatic Stress Disorders Program, Massachusetts General Hospital, 185 Cambridge, Suite 2200, 2nd Floor, Boston, MA 02114; email: mpollack@partners.org.

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ABSTRACT
Social anxiety disorder, also called social phobia, is a disorder characterized by extreme fear and/or avoidance of social or performance situations that involve evaluation or possible scrutiny by others. This disorder encompasses both isolated performance anxiety and generalized fears of many social encounters, leading to significant impairment and dysfunction in social, family, educational, and occupational functioning. It is often complicated by the presence of comorbid mood disorders, such as depression, and alcohol and substance use disorders. This article reviews the epidemiology, associated impairment, comorbidity, and treatment of social anxiety disorder, including pharmacotherapy and psychosocial therapies.

TOP ABSTRACT DEFINITION PREVALENCE COMORBIDITY TREATMENT CONCLUSION REFERENCES

DEFINITION
Social anxiety disorder (SAD), also called social phobia, is characterized by marked and persistent fear of embarrassment or humiliation in situations involving performance or interaction with or scrutiny by others (see Table 1 for DSM-IV criteria). The situation(s) are either avoided or endured with marked distress. The affected individual will often experience marked anticipatory anxiety before a feared interactional or performance situation and may experience a panic attack during the exposure. This anticipatory anxiety, avoidance, or distress in the social situation has a negative effect on the individual's social, academic, or occupational function and interpersonal relationships and/or causes marked distress.

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Table 1. DSM-IV Diagnostic Criteria for Social Anxiety Disorder

The true extent of the impairment and dysfunction associated with SAD may have been unrecognized in earlier years because the diagnostic term "social phobia" tended to conflate individuals with both subtypes of the disorder: those with nongeneralized or performance anxiety and those with the more impairing generalized subtype, in which the severity of symptoms and extent of impairment in function and quality of life are amplified (1, 2).

GENERALIZED

SOCIAL

ANXIETY

DISORDER

Generalized social anxiety disorder (GSAD) accounts for two-thirds of individuals with SAD (2) and is characterized by fear and avoidance of numerous interactional as well as performance social situations. Compared with the nongeneralized subtype, GSAD is more pervasive and is associated with greater distress and dysfunction in affected individuals, increased alcohol and drug abuse, depression, suicide attempts, poor marital functioning, vocational impairment, financial dependence, increased utilization of health care resources, and decreased educational attainment (38).

NONGENERALIZED

SOCIAL

ANXIETY

DISORDER

Nongeneralized SAD or "performance anxiety" refers to marked anticipatory anxiety, distress, and avoidance associated with public speaking or other performance-type situations. Although it is less pervasive and generally considered less disabling than the generalized subtype (4), nongeneralized SAD may result in significant impairment and underachievement at school and work as well (9). Most individuals with GSAD also experience performance anxiety.

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PREVALENCE
A number of both national and international epidemiologic studies suggest that SAD is a common psychiatric disorder (10). Recently, the National Comorbidity Survey (NCS) Replication documented that SAD has a lifetime prevalence of 12.1%, making it the fourth most common psychiatric condition in the United States behind major depressive disorder, alcohol abuse, and specific phobias (11). A more stringent reanalysis of data from the

Epidemiological Catchment Area Study and the NCS included the requirement that the disorder be clinically significant, defined as requiring treatment or causing impairment. Even with this more rigorous assessment, the disorder remained relatively common with a reported 12-month prevalence of 3.7% (12).

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COMORBIDITY
SAD frequently presents comorbidly with other psychiatric disorders including other anxiety disorders, major depressive disorder, bipolar disorder, and alcohol and substance use. The NCS documented that 81% of individuals with SAD report at least one other lifetime DSM-III-R psychiatric diagnosis (5). Not surprisingly given its overall greater severity, GSAD was more commonly associated with comorbid psychiatric illnesses than was the nongeneralized subtype (1, 2). The onset of SAD frequently precedes and may in fact be a risk factor for the development of other comorbid disorders such as major depressive disorder (5, 6, 13, 14). In the NCS, secondary major depressive disorder was present in 37% of those with SAD (15); the lifetime rate of comorbid major depressive disorder was reported to be near 60% in clinical samples (16). Similarly, 22% of patients from a large study of bipolar disorder had SAD (17). Comorbid anxiety disorders including panic disorder, posttraumatic stress disorder, generalized anxiety disorder, and obsessive-compulsive disorder are also relatively common among individuals with SAD. For instance, in the NCS, a lifetime history of posttraumatic stress disorder was present in 16% of individuals with SAD, panic disorder was present in 11%, and generalized anxiety disorder was present in 13% (5). Individuals with SAD also have an increased risk for alcohol abuse and dependence and other substance abuse disorders. Socially anxious individuals may use alcohol in an attempt to decrease anticipatory anxiety and reduce avoidance of feared social and/or performance situations. In the NCS, the lifetime prevalence rate of alcohol dependence was 24% among those with social phobia (5); thus, individuals with SAD have a two- to threefold increased risk of developing alcohol abuse or dependence compared with the general population. As

with other comorbidities, SAD onset typically precedes that of alcohol abuse; in a prospective study of individuals with social phobia or subclinical social fears, the risk of the developing alcohol abuse or dependence was more than twice that of the general population without such fears (18). The rate of alcohol abuse among those with social phobia in the clinical setting approaches 40% (19).

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TREATMENT
The aim of treatment of SAD is to ultimately eliminate the patient's anticipatory and phobic anxiety around social interaction and performance situations, eradicating attendant avoidance behavior, and improving overall quality of life and function.

PHARMACOTHERAPY
A variety of pharmacologic agents have demonstrated efficacy for the treatment of SAD (Table 2).

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Table 2. Pharmacotherapy Agents, Dosing and Side Effects for Social Anxiety Disorder

Serotonin selective and serotonin-norepinephrine reuptake inhibitors. The serotonin selective reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have become first-line pharmacotherapy for the treatment of SAD because of their demonstrated efficacy for SAD and for major depressive disorder as well as other anxiety disorders that may often present comorbidly. In addition, they have a more favorable tolerability and safety profile than the monoamine oxidase inhibitors (MAOIs), which were the former "gold standard" agents for SAD and are not associated with the potential for abuse and dependence or ineffectiveness for comorbid major depressive disorder that complicates treatment with benzodiazepines. The SSRIs paroxetine, sertraline, and fluvoxamine (controlled release) and the SNRI venlafaxine (extended release) have received Food and Drug Administration approval for the SAD indication. Other agents from this class also have demonstrated efficacy in randomized placebo-controlled studies and are likely effective as well, although differences in side effect profiles may be clinically relevant in some cases (20). Administration of SSRIs and SNRIs may be associated with a variety of side effects including sexual dysfunction, weight gain, increased anxiety, sedation, dizziness, headache, and gastrointestinal distress, as well as hypertension with venlafaxine and urinary retention with duloxetine. The onset of therapeutic effects usually takes at least 23 weeks, with greater benefits accruing over weeks or months as patients begin to expose themselves to previously feared situations. Roughly one-half to two-thirds of patients respond in acute treatment trials, with about one-half of these experiencing remission. Although the benefits of acute treatment are maintained in long-term follow-up (21), a substantial number of patients remain at least somewhat symptomatic over time (22). Given that most large randomized controlled trials (RCTs) often exclude patients with significant psychiatric or medical comorbidity as well as other complicating factors, it is likely that response and remission rates in clinical practice are even lower, underscoring the need to develop more effective treatment paradigms. -Blockers. -Blockers, such as propranolol (1080 mg/day) and atenolol (50150 mg/day) are effective for performance anxiety regarding public speaking or other performance situations (23, 24). They are typically administered on an "as needed" basis 12 hours before a performance situation, although some patients facing frequent performance challenges take them on a more routine basis. -Blockers seem to reduce anxiety in performance situations by blunting the symptoms of physiological arousal such as tachycardia and tremor that are often an individual's focus when performing and drive an escalating cycle of fear and further anxiety. However, given their relatively short duration of action and lack of effect on the emotional and cognitive (relative to physiological) symptoms of social anxiety, these agents have not been considered to be first-line agents for GSAD (25). Side effects of blockers include lightheadedness, bradycardia, sedation, and nausea. Of interest, pindolol, a -blocker with serotonin type 1A (5-HT1A) autoreceptor antagonist properties, which may accelerate or augment responses to antidepressants for major depressive disorder (26) and panic disorder (27), was ineffective in a placebo-controlled randomized augmentation trial in social phobics.

Monoamine oxidase inhibitors. Until supplanted by the better tolerated and safer SSRIs and SNRIs, the monoamine oxidase inhibitors (MAOIs), including phenelzine and tranylcypromine, were the gold standard pharmacotherapy for SAD (25, 28). Early observations of the efficacy of MAOIs in atypical major depressive disorder, a syndrome characterized by marked sensitivity to rejection evocative of the focus of anxiety in those with social phobia (29), led to the use of the these agents in SAD and subsequent demonstration of efficacy in RCTs (25). However, the association of MAOI administration with troubling side effects including orthostatic hypotension, paresthesias, weight gain, and sexual dysfunction, as well as the need for proscribed dietary intake of tyramine-containing foods and sympathomimetic medication because of risk of potentially fatal hypertensive and serotonergic syndromes, has limited the widespread use of these agents and they are now generally reserved for use in refractory cases. Benzodiazepines. Benzodiazepines appear to be effective in SAD, with studies in nondepressed individuals treated with clonazepam and alprazolam suggesting efficacy beginning within 2 weeks (3, 30, 31). In addition to rapid onset of effect relative to other classes of effective agents, benzodiazepines have a favorable side effect profile and the flexibility to be used on an asneeded basis for situational anxiety. In addition, they can be used to augment the efficacy of antidepressants for generalized SAD. Data from a double-blind, randomized, placebocontrolled study demonstrated that the addition of clonazepam to paroxetine improved outcome compared with the SSRI alone (32). Adverse effects associated with benzodiazepine administration include sedation, ataxia, and cognitive and psychomotor impairment; further, physiological dependence may develop with regular use. In addition, it is important to recognize that benzodiazepines as monotherapy are generally not effective for the depressive disorders that commonly present comorbidly with SAD and in fact may lead to worsened mood. The abuse liability of benzodiazepines is generally limited to those with a predisposing diathesis or history of alcohol or substance abuse, although given the relatively high rates of concurrent alcohol or substance abuse in SAD, their abuse potential should be taken into account when a treatment plan for comorbidly affected individuals is developed and alternative therapeutic interventions should be used when possible. Other medications. Although not subjected to extensive testing for this indication, the tricyclic antidepressants seem to lack efficacy for SAD (33), whereas there is evidence from a small open trial suggesting potential efficacy for bupropion (34) and a small controlled study with mirtazapine that showed positive results (35). The azapirone buspirone, a 5-HT1A partial agonist, has not demonstrated efficacy for SAD as a monotherapy, although it may be useful for augmentation in patients incompletely responsive to SSRI therapy (36). Although small studies suggest the potential efficacy of atypical antipsychotic drugs including olanzapine (37), risperidone (38), aripiprazole (39), and quetiapine (40), they have not been tested in large RCTs in SAD, and given concerns about associated metabolic syndrome, weight gain, and extrapyramidal effects, their use is best reserved for patients remaining symptomatic despite standard interventions.

The anticonvulsants gabapentin, an 2 calcium channel antagonist, and a related compound pregabalin demonstrated efficacy for social phobia in RCTs (41, 42). An open trial of valproic acid suggested potential efficacy for SAD (43), whereas results in small studies with levetiracetam have been mixed (44, 45) and results of a larger RCT with that agent were negative (Stein MB, Ravindran L, Simon NM, Khan A, Liebowitz M, BrawmanMintzer O, Lydiard RB, Pollack MH: A Multicenter, Randomized, Double-Blind, PlaceboControlled, Parallel-Group Study to Assess the Efficacy and Safety of Levetiracetam for Treatment of Generalized Social Anxiety Disorder. Submitted for publication, 2008.).

COGNITIVE

BEHAVIORAL

THERAPY

Cognitive behavioral therapy (CBT) is typically a time-limited psychosocial intervention, administered either in individual or group settings, that has demonstrated clear efficacy for the treatment of SAD (46, 47). Typical components of CBT include psychoeducation, somatic management techniques such as muscle relaxation, in vivo and imaginal exposure, video feedback, cognitive restructuring, and social skills training (46, 48). CBT has demonstrated efficacy comparable to that of pharmacotherapy, with a slightly slower onset of therapeutic effect but greater persistence of benefit after treatment discontinuation (31, 4952). Although combined pharmacotherapy and CBT may be presumed to be more effective than either intervention administered individually, evidence from one large RCT with fluoxetine and CBT did not demonstrate a significant advantage for the combined intervention over each effective monotherapy (53). This finding suggests that it would be reasonable to initiate treatment with either intervention alone and consider adding the alternative intervention for individuals who do not show a satisfactory response to the single intervention, although there are few systematic data addressing this hypothesis. Recently, another paradigm for combining pharmacological and CBT interventions has emerged, with the aim of using pharmacotherapy to enhance the effects of exposure-based treatment. This approach is based on translational research derived from preclinical work on the neural circuitry underlying fear extinction, demonstrating the importance of the Nmethyl-D-aspartate (NMDA) receptor within the amygdala for fear extinction and the effect of NMDA partial agonists administered systemically or in the amygdala to facilitate extinction (54, 55). Subsequent work in humans demonstrated that administration of the antibiotic d-cycloserine (DCS), an NMDA receptor partial agonist, before a CBT session, enhanced its efficacy for acrophobia (56, 57). More recently, DCS demonstrated efficacy for the enhancement of CBT in the treatment of SAD as well (58). If these early findings are confirmed, DCS and other agents active at the NMDA receptor and glutamatergic system may be routinely administered to enhance the effectiveness of exposure-based treatment of SAD and other phobic disorders.

CONCLUSION

Over the last two to three decades, advances in our understanding of SAD have been spurred by the growing recognition of its prevalence, early onset, chronicity, and morbid impact. Although currently available pharmacotherapies and CBT are clearly effective for the treatment of SAD, many of those treated remain symptomatic or fail to respond at all, and there is a significant unmet need to discover ways to optimize the use of currently available interventions and to develop novel therapies. Translational research derived from growing understanding of the underlying neurobiology of fear-based disorder offers the promise of improving outcomes for the treatment of SAD.

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FOOTNOTES
CME Disclosure Hannah Delong, B.A., The Center for Anxiety and Traumatic Stress Disorders Program, Massachusetts General Hospital, Boston No relevant financial relationships to disclose. Mark H. Pollack, M.D, The Center for Anxiety and Traumatic Stress Disorders Program, Massachusetts General Hospital, Boston Dr. Pollack is a consultant and on the advisory board for AstraZeneca, Brain Cells Inc, Bristol Myers Squibb, Cephalon, Dov Pharmaceuticals, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Eli Lilly & Co, Medavante, Neurocrine, Neurogen, Novartis, Otsuka Pharmaceuticals, Pfizer, Predix, Roche Laboratories, Sanofi, Sepracor, Solvay, Tikvah Therapeutics, Transcept Inc, UCB Pharma, Wyeth, he receives grant support from Astra-Zeneca, Bristol Myers Squibb, Cephalon, Cyberonics, Forest Laboratories, GlaxoSmithKline, Janssen, Eli Lilly, NARSAD, NIDA, NIMH, Pfizer, Roche Laboratories, Sepracor, UCB Pharma, Wyeth, he is a speaker for Bristol Myers Squibb, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Pfizer, Solvay, Wyeth. In addition, Dr Pollack has equity with Medavante, Mensante Corporation and has the following royalty/patent: SIGH-A, SAFER.

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45. Zhang W, Connor KM, Davidson JR: Levetiracetam in social phobia: a placebo controlled pilot study. J Psychopharmacol 2005; 19:551 553[Abstract/Free Full Text] 46. Heimberg, RG, Jester, HR: Cognitive behavioral treatments: literature review, in Social Phobia: Diagnosis, Assessment and Treatment. Edited by Heimberg, RG, Liebowitz, MR, Hope, DA, Schneier, FR. New York, Guilford Press, 1995 47. Heimberg RG: Cognitive-behavioral therapy for social anxiety disorder: current status and future directions. Biol Psychiatry 2002; 51:101108[Medline] 48. Gould RA, Pollack MH, Yap L: Cognitive-behavioral and pharmacological treatment for social phobia: a meta-analysis. Clin Psychol Sci Pract 1997; 4:291 306 49. Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, Juster HR, Campeas R, Bruch MA, Cloitre M, Fallon B, Klein DF: Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry 1998; 55:11331141[Abstract/Free Full Text] 50. Liebowitz MR, Heimberg RG, Schneier FR, Hope DA, Davies S, Holt CS, Goetz D, Juster HR, Lin SH, Bruch MA, Marshall RD, Klein DF: Cognitive-behavioral group therapy versus phenelzine in social phobia: long-term outcome. Depress Anxiety 1999; 10:8998[Medline] 51. Heimberg RG: Specific issues in the cognitive-behavioral treatment of social phobia. J Clin Psychiatry 1993; 54, (suppl):3645[Medline] 52. Taylor S: Meta-analysis of cognitive-behavioral treatments for social phobia. J Behav Ther Exp Psychiatry 1996; 27:19[Medline] 53. Foa EB, Franklin ME, Moser J: Context in the clinic: how well do cognitivebehavioral therapies and medications work in combination? Biol Psychiatry 2002; 52:987997[Medline] 54. Davis M: Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur J Neurosci 2002; 16:395 398[Medline] 55. Ledgerwood L, Richardson R, Cranney J: Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci 2003; 117:341349[Medline] 56. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M: Cognitive enhancers as adjuncts to psychotherapy: use of Dcycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004; 61:11361144[Abstract/Free Full Text]

57. Davis M, Ressler K, Rothbaum BO, Richardson R: Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 2006; 60:369375[Medline] 58. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW: Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry 2006; 63:298 304[Abstract/Free Full Text]

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Assessment of Panic Disorder Across the Life Span

Citing Articles via Google Scholar Vishal Madaan, M.D., M.B.B.S.
Correspondence: Address correspondence to Vishal Madaan, M.D., Department of Psychiatry and Child Psychiatry, Creighton University/University of Nebraska Medical Center, 3528 Dodge St., Omaha, NE 68131; e-mail: vishalmadaan@creighton.edu.

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TOP ABSTRACT ASSESSMENT IN CHILDREN AND... ASSESSMENT IN THE ADULT... ASSESSMENT IN THE ELDERLY CONCLUSIONS REFERENCES

ABSTRACT
Panic disorder is a relatively common anxiety disorder that is often disabling. It may or may not be associated with agoraphobia. Panic disorder can be imitated by various medical illnesses, which, even when treated, can get cued with panic symptoms. It is also frequently comorbid with other psychiatric disorders including depression, generalized anxiety disorder, and substance use disorders. Although often initially seen in early adulthood, panic disorder can also present in childhood or in the geriatric population. Clinicians should thus be aware of the variability in clinical presentations that may be associated with both the pediatric and geriatric age groups. This article provides a broad overview of various screening and assessment tools used to evaluate panic disorder across the lifespan. The

article also highlights some of the developmental differences and variability in the clinical presentation of pediatric and geriatric panic disorder.

Panic disorder is a common psychiatric disorder that affects up to 5% of the population at some point in their lifetime (1). The essential features of panic disorder include recurrent, often unexpected, panic attacks followed by at least 1 month of persistent concern about having another panic attack, worry about the possible implications or consequences of the panic attacks, or a significant behavioral change related to the attacks (2). Panic attacks are discrete episodes associated with an intense fear or discomfort and accompanied by at least 4 of the 13 somatic or cognitive symptoms listed in the DSM-IV-TR: accelerated heart rate, shortness of breath, chest pain, choking sensations, hot/cold flashes, sweating, trembling, nausea, depersonalization/derealization, fear of dying, fear of going crazy, and fear of losing control (Table 1) (3). Panic attacks usually have an abrupt onset and last from 10 to 45 minutes (4). Many times, these may result in behavioral modifications in daily routine. Although panic attacks can occur in associated anxiety disorders including phobias and social anxiety disorder, panic attacks associated with panic disorder are unique as they occur spontaneously without an environmental trigger. Panic disorder may be associated with agoraphobia if the individual avoids places or situations from which escape may be difficult (5).

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Table 1. Panic Attacks and Panic Disorder

Panic disorder must be distinguished from various psychiatric disorders and physical conditions that can have associated panic symptoms. Some of these conditions include other anxiety disorders (including specific phobias and posttraumatic stress disorder), substance use disorders (including stimulant abuse or withdrawal from sedative agents), or medical conditions, including hyperthyroidism (6). Furthermore, the clinical presentation of panic

disorder may vary depending on the age of presentation and may make it difficult for the clinician to assess and ascertain the significance of such symptoms (7). This article focuses on the distinct diagnostic dilemmas and assessment tools used in the evaluation of panic disorder across the lifespan. A discussion of treatment approaches for panic disorder is beyond the scope of this article, and the reader is referred elsewhere for such a discussion (8). The paucity of literature on this subject in both extremes of ages further limits the evidence base in these age groups. As a result, there are a few instances in this article where the author has to refer to a more general term, "anxiety disorder," instead of panic disorder specifically.

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ASSESSMENT IN CHILDREN AND ADOLESCENTS

Although panic disorder is believed to emerge in late adolescence or early adulthood, adults with panic disorder often report having had panic symptoms starting in childhood or early adolescence (9). In most such individuals panic disorder may have either been misdiagnosed or not come to clinical attention. Epidemiological studies have reported that panic attacks may not be rare in the community samples of adolescents, although panic disorder may not be commonly reported. For instance, Goodwin and Gotlib (10) reported a prevalence of 3.3% of panic attacks from among 1,285 youth, aged 917 years, whereas Whitaker et al. (11) reported lifetime prevalence of panic disorder to be 0.6% using a structured interview with 5,000 students aged 1417 years. A much higher prevalence of panic disorder has, however, been reported in the clinical samples. Biederman et al. (12) reported that 6% of the children and adolescents consecutively referred to their pediatric psychopharmacology clinic met the criteria for panic disorder. Similarly, Masi et al. (13) found that 10.4% of their consecutive outpatients referred to a mood and anxiety service had panic disorder. Clinical presentation of panic symptoms in younger children compared with that in adolescents can be intriguing (14). Such a presentation can be manifested by the presence of atypical symptoms including "hyperventilation syndrome," nocturnal occurrences, and fewer somatic and cognitive symptoms (15). Still, some of the common symptoms in younger children include palpitations, shortness of breath, sweating, faintness, and weakness (16). Among adolescents, symptoms such as chest pain, trembling, headache, and

vertigo are reported (17). Another interesting developmental difference between the two age groups is that children and younger adolescents may attribute their symptoms to the external environment compared with older adolescents. Older adolescents are more competent of internal attributions that are more typically seen with panic disorder. Furthermore, cognitive symptoms appear only among adolescents (18). Interestingly, the fear of dying has been reported to be the earliest cognitive symptom whereas feelings of losing control and symptoms of depersonalization and derealization appear later (15, 17). Given the complexity of establishing a diagnosis of panic disorder in this population, the clinician may benefit by using brief self-reports and rating scales for anxiety disorders, some of which are even available for the preschool child. Table 2 lists some of the freely available assessment tools that include self-report, parent, and clinician versions.

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Table 2. Commonly Used Instruments to Assess Anxiety in Children and Adolescents

Another interesting aspect in this age group is the association of panic symptoms with comorbid anxiety disorders including separation anxiety disorder and generalized anxiety disorder (27, 28). Separation anxiety disorder has been reported to be associated with earlyonset panic disorder but not necessarily with adult onset panic disorder (29). Similarly, agoraphobia has been reported more frequently in younger-onset panic disorder (30). Furthermore, mitral valve prolapse has also been associated with a higher incidence of panic disorder in the adolescent population (31). The clinician should also rule out any medical causes (such as pheochromocytoma and thyroid disease) and substance use disorders, both of which are well known to imitate panic disorder. More details are considered in the next section. Along with these comorbidities, a strong family history of panic disorder should cue the clinician to perform a detailed assessment for panic disorder in the child. Awareness of early-onset panic disorder and a detailed assessment can potentially improve diagnosis and treatment and thus decrease impairment and improve quality of life for these patients. The American Academy of Child and Adolescent Psychiatry practice parameter for anxiety disorders also provides recommendations for assessment of various anxiety disorders. Although not specifically discussing panic disorder, the practice parameter recommends

that clinicians routinely include screening questions about anxiety symptoms and that the questions should use developmentally appropriate language based on DSM-IV-TR criteria. If the screening indicates significant anxiety, the clinician should thoroughly evaluate the patient to determine the type, nature, frequency, and severity of the anxiety disorder and assess the functional impairment caused by it. Clinicians may also find it beneficial to use sections of the available diagnostic interviews such as the Anxiety Disorders Interview Schedule for DSM-IV-Child Version (ADIS). The ADIS has a Feelings Thermometer (ratings from 0 to 8) that may help children quantify and self-monitor ratings of fear and interference with functioning. Younger children may use more developmentally appropriate visual analogs such as smiley faces and upset faces to rate severity and interference (32).

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ASSESSMENT IN THE ADULT POPULATION

As discussed initially, the DSM-IV-TR defines panic disorder as comprising discrete episodes of marked autonomic arousal that are accompanied by catastrophic thinking and are not directly caused by substance use or a medical condition. The DSM-IV-TR requires recurrent unexpected panic attacks plus at least 1 month of persistent concern about experiencing additional attacks, worry about the implications or consequences of attacks, or a significant change in behavior related to attacks to establish the diagnosis of panic disorder. The DSM-IV-TR criteria require that at least 4 of 13 criteria must be present to diagnose a "full" panic attack. When fewer than 4 of the 13 symptoms of a panic attack are present, this is referred to as "limited symptom attack." Agoraphobia is a fear of places or situations from which escape might be difficult or in which help may be unavailable in the event of a panic attack or panic symptoms. The ICD-10 criteria for panic disorder are similar to the DSM criteria but do not specify a threshold beyond recurrent attacks (33). This section addresses three important areas for the clinician when assessing panic disorder: screening and assessment tools, comorbid psychiatric disorders, and associated medical conditions.

SCREENING

AND

ASSESSMENT

TOOLS

The diagnosis of panic disorder is largely clinical in nature; yet the clinician may find some of the following screening and assessment tools useful and practical in the clinical setting. In the primary care setting, screening may be initiated with the two questions related to

panic disorder from the five-question Anxiety and Depression Detector (34). These questions are: In the last 3 months 1. "Did you ever have a spell or an attack when all of a sudden you felt frightened, anxious or very uneasy?" and 2. "Would you say that you have been bothered by nerves or feeling anxious or on edge?" These two questions have been reported to yield a high sensitivity and modest specificity and can be used for screening. The Anxiety Disorder Association of America has posted an online panic disorder self-test based on DSM-IV that can be used for self-report (35). In the psychiatric setting, assessment tools such as the Beck Anxiety Inventory may also be used for similar initial assessment. An online free html version is available (36). Although this is not a specific tool for assessment of panic disorder, it can point toward the severity of anxiety symptoms in the patient. Apart from monitoring the frequency and severity of panic attacks, the severity of agoraphobic avoidance and anticipatory anxiety may also be evaluated. The Panic Disorder Severity Scale (PDSS) and the Panic and Agoraphobia Scale (PAS) can be used to monitor the frequency and severity of panic attacks (37, 38). The Panic Disorder Severity Scale is a seven-item, interview-based scale for assessing the severity of panic disorder. Although not a diagnostic instrument, the PDSS provides a simple and efficient way to monitor panic disorder severity in patients in research and clinical settings for whom a diagnosis has been established (37). A self-report version of the scale has recently been tested and found to be reliable (39). More recently, another selfreport scale, the Panic Disorder Self-Report has also been found to be valid and reliable (40). Structured instruments such as the Structured Clinical Interview for DSM-IV (SCIDIV) are often used in research settings (41).

ASSESSMENT

OF

MEDICAL

CONDITIONS

Medical conditions may be associated with panic and other anxiety symptoms and need to be explored. Some of these disorders are pheochromocytoma, hyperthyroidism, supraventricular tachycardia, and Mnire's disease, among others (42). Both hyper- and hypothyroidism can be associated with anxiety unaccompanied by other signs or symptoms. For this reason, it is imperative that all patients complaining of anxiety undergo routine thyroid function tests, including the evaluation of the level of thyroidstimulating hormone. It is also important to note that thyroid disorders may initiate or trigger panic attacks. More importantly, as these panic attacks may get cued to other stimuli, even after the primary thyroid disease is corrected, panic attacks may continue unless treated specifically. Hyperparathyroidism can also present with anxiety symptoms and thus obtaining a serum calcium level may be desired (6, 43). Cardiac conditions such as paroxysmal atrial tachycardia can be ruled out using an electrocardiogram (ECG) or, at times, 24-hour monitoring, if required. Similarly, over the years, there has been a lot of interest in the relationship of mitral valve prolapse to panic

disorder. Although patients with mitral valve prolapse may complain of palpitations, chest pain, and lightheadedness, symptoms of a full-blown panic attack are rare. There have been reports of an underlying autonomic nervous system dysfunction or intermittent high catecholamine levels in patients with both mitral valve prolapse and panic disorder that may further highlight this connection. Interestingly, however, screening of patients with mitral valve prolapse has not revealed an increase in frequency of panic disorder compared with that in the general population (6, 43). Pheochromocytoma is a rare tumor of the adrenal medulla that results in episodic bursts of catecholamines. These bursts are associated with intermittent elevated blood pressures, anxiety, flushing, and tremulousness. If suspected, a 24-hr urine sample should be collected and evaluated for catecholamine metabolites. Vestibular nerve disorders can also be associated with episodic vertigo, lightheadedness, and anxiety and may warrant a consultation with an ear, nose, and throat specialist or a neurologist (6, 43).

ASSESSMENT

OF

COMORBID

PSYCHIATRIC

CONDITIONS

Apart from a thorough assessment of comorbid medical disorders that may imitate panic or anxiety symptoms, various psychiatric disorders with predominant anxiety symptoms need to be distinguished from panic disorder for appropriate management. One of the common clinical conundrums is the association of panic-like symptoms with depression (44). Patients with depression can have frank panic attacks and thus manifest with symptoms and signs of anxiety. Similarly, patients who have a long-standing untreated or inadequately treated panic disorder have a poor quality of life and can become depressed over time. Although both these disorders can often be comorbid, the clinician may find it helpful to differentiate between the two. Some of the key points that may be helpful in such an assessment include the following:

Patients with predominant anxiety symptoms may not have the all of the vegetative symptoms seen in depressionthey may have initial insomnia but not early morning awakening, they may not lose their appetite, and they may have minimal diminution in interest in activities (6, 44). The temporal onset of symptoms is also differentin patients with predominant panic disorder, anxiety attacks may be recalled initially followed by a feeling of depression; in contrast, primarily depressed patients will have an initial onset of depressive symptomatology that will be followed by anxiety. Furthermore, it has also been reported that patients suffering from atypical depression commonly have panic attacks although it is rarely associated with agoraphobia. Patients with symptoms of posttraumatic stress disorder can be distinguished from those with panic disorder by the presence of a preexisting trauma and association with symptoms of avoidance, reexperiencing, and hyperarousal (45). Patients with somatization disorder present with predominantly somatic symptoms that are persistently reported compared with the episodic nature of symptoms in panic disorder (43). Patients with comorbid agoraphobia may present with fears of leaving home; they can be distinguished from those with paranoia and frank psychosis by the absence of positive psychotic symptoms and formal thought disorder (6, 43).

Also, as mentioned previously, substance abuse or withdrawal symptoms can also present with sudden onset of anxiety or panic symptoms. These can be distinguished by a temporal association between the substance abuse/withdrawal and onset of symptoms (6, 46).

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ASSESSMENT IN THE ELDERLY

There is very limited literature on the subject of panic disorder in the geriatric population. As a result, most recommendations regarding assessment of panic disorder are derived and extrapolated from the adult literature. Flint et al. (47) have reported a decline in panic attacks in elderly individuals; however, it is important not to dismiss the significance of such anxiety symptoms in this population. Although the diagnostic criteria of panic disorder are similar to those in the general adult population, its presentation may vary in elderly individuals. Panic attacks in this population may be more reactive to transient situations or life changes (48). Many times elderly individuals may not complain of anxiety symptoms but focus on physical symptoms (49). They may not elaborate on their subjective apprehensive states but rather discuss bodily dysfunction. These complaints can force the clinician to delve into extensive medical investigations when the etiology may be more functional. On the contrary, because elderly individuals are more predisposed to having a medical comorbidity, it is imperative not to dismiss their physical complaints either. As a result, panic disorder has not been very well studied and more research on the subject is needed. Apart from the variability in quality of symptoms for panic disorder in this population, the frequency and severity of reporting of symptoms may vary as well. Sheikh et al. (50) reported that elderly individuals with panic disorder report less severe and fewer panic symptoms, less anxiety and arousal, and higher levels of functioning compared to middleaged patients with panic disorder. Furthermore, elderly patients with late-onset panic disorder may report less distress with panic symptoms compared with older patients with early-onset panic disorder (50). It may take quite a few panic attacks along with insignificant laboratory results in elderly patients to lead to a diagnosis of panic disorder. The medical comorbidities that may present with panic-like symptoms are similar to those

mentioned in the adult population as listed in Table 3 and should be thoroughly assessed, especially in this older population.

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Table 3. Medical Conditions and Panic Disorder

To the best of the author's knowledge, there are no specific rating scales available for assessment of severity and diagnosis of panic disorder in the geriatric population, especially because panic disorder has not been very well studied in this age group and possibly also owing to a decline in panic attacks in the population. One of the newly developed scales, the Geriatric Anxiety Inventory (GAI) has recently been shown to measure common symptoms of anxiety in older adults. It consists of 20 items that can be answered in a dichotomous manner, which is "agree/disagree." The GAI can be self-rated or administered by a trained health professional. The GAI, however, was not designed to diagnose specific anxiety disorders but rather to assess the severity of anxiety symptoms across a range of presentations in older adults (51). Clinicians also use some other assessment tools such as the Hamilton Anxiety Scale and Beck Anxiety Inventory for monitoring the anxiety symptoms that are often comorbid with both psychiatric and medical conditions. It is important to recognize and treat such comorbid anxiety disorders as they can have a significant impact on the quality of life in this population. In fact, it has been reported that such patients may also have a much increased risk of both suicidal attempts and completed suicides (52). In addition, there is also some evidence to suggest that late-onset panic attacks may be due to preexisting depression (48). Furthermore, anxiety may also be a predictor of decline in cognitive functions, which should be simultaneously evaluated (53). The diagnosis of panic disorder is based on a thorough history (from both the patient and the patient's family or caregivers), mental state examination, physical examination, and investigations selected to screen for medical etiology that could be contributing to symptoms. Initial screening investigations may include a complete blood count, fasting serum glucose level, serum calcium level, thyroid function tests, and an ECG. Physicians should have a high index of suspicion for panic attacks in older patients with multiple episodic physical symptoms that are not explained by physical examination and

investigations. In addition, symptoms such as derealization, depersonalization, and fear of losing control should also alert the clinician to the possibility of panic disorder.

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CONCLUSIONS
Panic disorder is a common, often impairing, anxiety disorder that usually presents in late adolescence or early adulthood. However, an onset in childhood or in the geriatric age group should not be discounted without an adequate and thorough assessment. Clinicians should always screen their patients in all age groups for panic disorder, using some of the DSM-IV-TR-based screening aids. Patients with panic disorder should always be assessed for comorbid psychiatric disorders and causative medical illnesses that may present as panic attacks. Clinicians should also be aware of the variability in clinical presentations that may be associated with both the pediatric and geriatric age groups.

FOOTNOTES
CME Disclosure Vishal Madaan M.D., M.B.B.S., Department of Psychiatry & Child Psychiatry, Creighton University/Univ of Nebraska Medical Center, 3528 Dodge St., Omaha, NE 68131 Reports no conflict of interest

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28. Masi G, Mucci M, Millepiedi S, Poli P, Bertini N, Akiskal HS: Generalized anxiety disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 2004; 43:752760[Medline] 29. Masi G, Mucci M, Millepiedi S: Separation anxiety in children and adolescents: epidemiology, diagnosis and management. CNS Drugs 2001; 15:93104[Medline] 30. Battaglia M, Bertella M, Politi E, Bernardeschi L, Perna G, Gabriele A, Bellodi L: Age of onset of panic disorder: influence of familial liability to the disease and of childhood separation anxiety disorder. Am J Psychiatry 1995; 152:1362 1364[Abstract/Free Full Text] 31. Toren P, Eldar S, Cendor D, Wolmer L, Weizmean R, Zubadi R, Koren S: The prevalence of mitral valve prolapse in children with anxiety disorders. J Psychiatr Res 1999; 33:357361[Medline] 32. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry 2007; 46:267 283[Medline] 33. Neurotic, stress-related and somatoform disorders http://www.who.int/classifications/apps/ICD/icd10online/ (F40F48).

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36. Beck Anxiety Inventory. www.carrettin.com/forms/Beck_Anxiety_Inventory.pdf 37. Shear MK, Brown TA, Barlow DH, Money R, Sholomskas DE, Woods SW, Gorman JM, Papp LA: Multicenter collaborative panic disorder severity scale. Am J Psychiatry 1997; 154:15711575[Abstract/Free Full Text] 38. Bandelow B: Panic and Agoraphobia Scale (P&A/PAS). http://wwwuser.gwdg.de/ ukyp/pas.htm 39. Houck PR, Spiegel DA, Shear MK, Rucci P: Reliability of the self-report version of the panic disorder severity scale. Depress Anxiety 2002; 15:183185[Medline] 40. Newman MG, Holmes M, Zuellig AR, Kachin KE, Behar E: The reliability and validity of the panic disorder self-report: a new diagnostic screening measure of panic disorder. Psychol Assess 2006; 18:4961[Medline]

41. Structured Clinical Interview for DSM Disorders (SCID-IV).http://www.scid4.org/ 42. American Psychiatric Association: Practice Guideline for the Treatment of Patients with Panic Disorder. Am J Psychiatry 1998; 155, (May suppl):160[Medline] 43. Sadock BJ, Sadock VA, Editors: Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2007, p. 593 44. Simon NM, Fischmann D: The implications of medical and psychiatric comorbidity with panic disorder. J Clin Psychiatry 2005; 4:815 45. McNally RJ: Panic and posttraumatic stress disorder: implications for culture, risk, and treatment. Cogn Behav Ther 2008; 37:131134[Medline] 46. Zimmermann P, Wittchen HU, Hfler M, Pfister H, Kessler RC, Lieb R: Primary anxiety disorders and the development of subsequent alcohol use disorder: a 4-year community study of adolescents and young adults. Psychol Med 2003; 33:1211 1222[Medline] 47. Flint AJ, Cook JM, Rabins PV: Why is panic disorder less frequent in late-life? Am J Geriatr Psychiatry 1996; 4:96109 48. Flint AJ, Gagnon N: Diagnosis and management of panic disorder in older patients. Drugs Aging 2003; 20:881891[Medline] 49. Ballenger JC: Unrecognized prevalence of panic disorder in primary care, internal medicine and cardiology. Am J Cardiol 1987; 60:39J47J[Medline] 50. Sheikh JI, King RJ, Taylor CB; Comparative phenomenology of early-onset versus late-onset panic attacks: a pilot survey. Am J Psychiatry 1991; 148:1231 1233[Abstract/Free Full Text] 51. Pachana NA, Byrne GJ, Siddle H, Koloski N, Harley E, Arnold E: Development and validation of the Geriatric Anxiety Inventory. Int Psychogeriatr 2007; 1:103 114 52. Khan A, Leventhal RM, Khan S, Brown WA: Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database. J Affect Disord 2002; 68:183 190[Medline] 53. Sinoff G, Werner P: Anxiety disorder and accompanying subjective memory loss in the elderly as a predictor of future cognitive decline. Int J Geriatr Psychiatry 2003; 18:951959[Medline]
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Anxiety Disorders and Comorbid Medical Illness

Peter P. Roy-Byrne, M.D., Karina W. Davidson, Ph.D., Ronald C. Kessler, Ph.D., Gordon J.G. Asmundson, Ph.D., R.D., Psych., Renee D. Goodwin, Ph.D., M.P.H., Laura Kubzansky, Ph.D., R. Bruce Lydiard, Ph.D., M.D., Mary Jane Massie, M.D., Wayne Katon, M.D., Sally K. Laden, M.S., and Murray B. Stein, M.D., M.P.H., F.R.C.P.C.

Articles by Roy-Byrne, P. P. Articles by Stein, M. B.

TOP ABSTRACT INTRODUCTION ANXIETY DISORDERS AND COMORBID... RESEARCH PRIORITIES CONCLUSIONS REFERENCES

ABSTRACT
Objective: To provide an overview of the role of anxiety disorders in medical illness. Method: The Anxiety Disorders Association of America held a multidisciplinary conference from which conference leaders and speakers reviewed presentations and discussions, considered literature on prevalence, comorbidity, etiology and treatment, and made recommendations for research. Irritable bowel syndrome (IBS), asthma, cardiovascular disease (CVD), cancer and chronic pain were reviewed. Results: A substantial literature supports clinically important associations between psychiatric illness and chronic medical conditions. Most research focuses on depression, finding that depression can adversely affect self-care and increase the risk of incident medical illness, complications and mortality. Anxiety disorders are less well studied, but robust epidemiological and clinical evidence shows that anxiety disorders play an equally important role. Biological theories of the interactions between anxiety and IBS, CVD and chronic pain are presented. Available data suggest that anxiety disorders in medically ill patients should not be ignored and could be considered conjointly with depression when developing strategies for screening and intervention, particularly in primary care. Conclusions: Emerging data offer a strong argument for the role of anxiety in medical

illness and suggest that anxiety disorders rival depression in terms of risk, comorbidity and outcome. Research programs designed to advance our understanding of the impact of anxiety disorders on medical illness are needed to develop evidence-based approaches to improving patient care. (Reprinted with permission from General Hospital Psychiatry 2008; 30:208225)

TOP ABSTRACT INTRODUCTION ANXIETY DISORDERS AND COMORBID... RESEARCH PRIORITIES CONCLUSIONS REFERENCES

INTRODUCTION
Mental disorders occur with chronic medical conditions in many patients, causing significant role impairment, work loss and work cut-back (1, 2). Depression increases symptom burden and functional impairment and worsens prognosis for heart disease, stroke, diabetes mellitus, HIV/AIDS, cancer and other chronic illnesses (35). One nationally representative survey of over 130,000 Canadian adults demonstrated that depression independently increased role impairment by 21% compared to healthy controls. However, when depression occurred along with chronic lung disease, diabetes mellitus or heart disease, the rate of disability increased by over 50% (5). A more complete understanding of the adverse effect of depression on biological and self-care (e.g., adherence to diet, smoking cessation, exercise, medications) mechanisms and findings from treatment studies is emerging to guide patient care (614). These data paint a compelling picture of the importance of depression in medical illness. Much less is known about the impact of anxiety disorders on function and outcome in persons with chronic medical illness. There is convincing evidence that anxiety is associated with high rates of medically unexplained symptoms and increased utilization of healthcare resources (4, 1519). Moreover, anxiety disorders are strongly and independently associated with chronic medical illness (20, 21), low levels of physical health-related quality of life, and physical disability (2124). Indeed, the disability and related poor physical and economic outcomes associated with anxiety disorders may be as

great as with depression. In a sample of 480 primary care patients, the probability of missing time from work in the prior month for persons with an anxiety disorder (OR: 2.22) was as great as for persons with major depression (OR: 2.15) (25). In patients with diabetes, comorbid panic disorder had a significant adverse effect on symptom burden, functional impairment and HbA1c levels after controlling for depression (23). In the National Comorbidity Survey-Replication (NCS-R), Kessler et al. (1) reported that various anxiety disorders had equal or greater association than depression with four chronic physical disorders (i.e., hypertension, arthritis, asthma, ulcers) (Fig. 1).Similarly, the number of 30day role impairment days associated with anxiety disorders among respondents with these four chronic medical disorders was similar or greater to that seen in association with depression and dysthymia (Fig. 2) (1).

Figure 1. Associations (Odds Ratios) of DSM-III-R Mental Disorders Among NCS-R Respondents With Chronic Physical Disorders View larger version (18K): [in this window] [in a new window] * indicates not statistically significant at P .05) [1].

Figure 2. Number of 30-Day Role Impairment Days Associated With Comorbid DSM-III-R Mental Disorders Among NCS-R Respondents With Chronic Physical Disorders View larger version (15K): [in this window] [in a new window] *indicates not statistically significant at P .05. [1]

In recognition of the need to better understand and illustrate the effect of anxiety disorders on persons with chronic medical illnesses and with the hope of developing treatment strategies, the Anxiety Disorders Association of America (ADDA) convened a multidisciplinary conference on January 30 31, 2006, to review current data on the relationship between anxiety disorders and specific medical illnesses. Presenters and discussants included clinicians and researchers in psychiatry, psychology, primary care, healthcare systems, epidemiology, public health, healthcare policy and advocacy. The proceedings of the conference are summarized in this paper, which reviews anxiety disorders in the context of functional gastrointestinal disorders, asthma, heart disease, cancer and chronic pain. These selective reviews mainly focused on anxiety disorders per se and did not investigate numerous studies focused on "stress". In addition, specific recommendations are made for furthering the basic science and clinical research agenda to better understand the impact of anxiety disorders on medical illness and improve clinical outcomes and patient care.

TOP ABSTRACT INTRODUCTION ANXIETY DISORDERS AND COMORBID... RESEARCH PRIORITIES CONCLUSIONS REFERENCES

ANXIETY DISORDERS AND COMORBID MEDICAL ILLNESS FUNCTIONAL GASTROINTESTINAL DISEASES

Epidemiology. Irritable bowel syndrome (IBS) is characterized by chronic, unexplained abdominal pain or discomfort associated with diarrhea, constipation, or both (26). It is one of the most common and well studied of the 28 functional gastrointestinal disorders (FGIDs) (27), affecting an estimated 10% to 25% of the population and occurring in women twice as frequently as in men. A key feature of IBS is visceral hyperalgesia, defined as abnormally exaggerated visceral pain responses from gut events (e.g., experimental colonic distension, meals, infection/inflammation) (2729). Stress reactivity is considered an extremely important nondiagnostic feature of IBS (27, 29) and is characteristic of other disorders with which IBS most frequently overlaps, such as anxiety disorders, mood disorders and other functional somatic disorders.

There is a strong association between IBS and psychiatric diagnoses, particularly anxiety disorders (30). Rates of psychiatric diagnoses range from 54% to 94% in treatment-seeking patients with IBS (31, 32). Rates of anxiety and mood disorders in patients with IBS are significantly higher than in patients with inflammatory bowel disease (33). When psychiatric disorders co-exist with IBS, gastrointestinal symptoms are typically more severe and disabling. In a survey of university students. IBS was associated with high rates of generalized anxiety disorder (GAD) and higher levels of neuroticism, visceral anxiety, anxiety sensitivity and worry than in those without (34). A community-based survey of 3911 adults in the USA found that rates of panic disorder, generalized social anxiety disorder, posttraumatic stress disorder (PTSD) and major depression were significantly higher in respondents with IBS than in those without IBS, but that rates of psychiatric diagnoses in treatment-seekers were remarkably similar to non-treatment-seeking persons with IBS. Both treatment-seeking and non-treatment-seeking groups with IBS reported greater levels of functional impairment than non-IBS groups (35, 36). In a re-analysis of the Epidemiologic Catchment Area study (N = 13,537), respondents with panic disorder were nearly five times as likely to have IBS-like symptoms than those with no psychiatric diagnosis (37). The rate of IBS among persons with panic disorder appears to be over twice that of those without panic disorder (37). The temporal relationship between onset of anxiety disorders and IBS is not well studied, although one study found that IBS subjects with anxiety disorders were significantly more likely to report that the anxiety disorder preceded the onset of IBS (39). Up to one-third of IBS patients have PTSD (40), and prior physical/sexual abuse and PTSD are more frequent in women with IBS than in those with equally severe organic gastrointestinal disorders and are predictive of increased vulnerability for the onset or worsening of IBS (41, 42). Pathophysiology. There are multiple, nonexclusive potential etiologies for IBS, including inherited risk, infection/inflammation, severe traumatic events and psychiatric disorders, all of which may play a role in the onset or exacerbation of existing IBS symptoms (27, 43). Psychosocial stress is increasingly recognized as playing an important role in the onset, persistence and severity of IBS, regardless of presumed etiology (i.e., infections, stress-related, inherited risk) (44, 45). Sensitized central stress circuits may be important mediators of the distorted visceral perception/hyperalgesia and stress reactivity observed in IBS (45, 46), consistent with preclinical and clinical evidence that anxiety and stress can induce or worsen existing visceral hyperalgesia (47, 48). The neural pathways that process visceral pain signals also regulate the stress response, anxiety, mood and gastrointestinal function (28). A key mediator of these pathways is the neuropeptide corticotropin-releasing factor (CRF). Exposure to prolonged or severe stress, especially in vulnerable individuals, can result in persistent changes in CRF activity with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, extra-hypothalamic and peripheral CRF neural systems that mediate responses to stress, visceral hypersensitivity, colonic motility, immune response and fear conditioning (28, 38). If stress is sufficiently severe or persistent, the stress response may not be completely terminated, leading to continued CRF hyperactivity and release of stress mediators, including pro-inflammatory cytokines and catecholamines, resulting in sustained excessive inflammatory activity. There is some evidence, although not entirely consistent in direction, for HPA abnormalities and

altered pro-inflammatory cytokine activity in IBS (45, 49) and several disorders commonly overlapping with IBS (e.g., fibromyalgia, chronic fatigue, anxiety disorders, including PTSD, and mood disorders) (50). Thus, CRF dysregulation may be one potential neurobiological link among these seemingly unrelated, stress-reactive conditions (45, 46, 50). Antidepressants (51) and cognitive behavioral therapy (CBT) (52), both of which are effective in IBS and in reducing stress reactivity, may reduce circulating pro-inflammatory cytokines or improve immune function in individuals with stress-related disorders. An emerging neuroimaging literature suggests that, compared to healthy controls, experimental rectal distension is associated with altered reactivity of the anterior cingulate cortex, a brain region implicated in pain perception, anxiety, stress and prior trauma in persons with IBS (53). Recognition of the shared neurobiological underpinnings theoretically linking anxiety and stress may eventually provide the basis for mechanismbased psychotherapeutic and psychopharmacologic treatments for IBS (35). Treatment. Patients with mild IBS symptoms are generally seen in primary care settings and do not have significant functional impairment or psychological symptoms. Treatment for mild IBS focuses on education about the causes and course of IBS, reassurance of patients' concerns, and restrictions of foods and medications that exacerbate symptoms. Psychological treatments are usually reserved for patients with moderate or severe IBS symptoms and for patients with pain (Fig. 3)(27, 54). A meta-analysis of 32 psychotherapy trials in patients with IBS concluded that, despite the small sample sizes and nonstandardized methods, evidence exists to support the efficacy of psychological treatments in reducing IBS symptom severity compared to control conditions. Cognitive-behavioral therapy, which is the best studied intervention, teaches patients to regulate symptoms of IBS and alter behavior that reinforces or exacerbates symptoms (55, 56). Different psychotherapeutic techniques, including CBT, relaxation training, interpersonal psychotherapy and hypnotherapy, can be used in combination (54).

Figure 3. Rome III Guidelines for the Medical and Psychological Treatment of IBS. Reprinted with permission from Ref. [54].)

View larger version (59K): [in this window] [in a new window]

Antidepressants and anxiolytics are prescribed for patients with IBS for their effects on anxiety and mood as well as for direct analgesic effects. In their summary of the psychopharmacologic treatment literature, Levy et al. (54) suggested that the tricyclic antidepressants (TCAs) are more beneficial than the selective serotonin reuptake inhibitors (SSRIs), possibly due to the central analgesic actions associated with the noradrenergic properties of the TCAs. Nonetheless, the SSRIs are effective for underlying anxiety and depression, and there is emerging evidence that these newer agents are effective for IBS sufferers without psychiatric disorders (57). The benzodiazepines have had a limited place in the treatment of IBS because of concern over potential abuse and withdrawal. However, the limited available literature suggests that benzodiazepine treatment of anxiety is associated with improvement in anxiety and IBS (58, 59). The nonbenzodiazepine anxiolytic agent, buspirone, may have a role in the treatment of IBS, but studies are needed to support its use in this population. As in the treatment of anxiety disorders and depression, psycho-pharmacologic treatment should not be abandoned until the dose and duration of therapy are optimized (54).

ASTHMA
Epidemiology. Asthma is a chronic lung condition characterized by episodic inflammation and small airway constriction that can occur in response to environmental and other triggers. More than 30 million Americans have asthma, of whom 30% are children under the age of 18. Asthma ranges in severity from mild to life-threatening with an intermittent or persistent course. Age-adjusted mortality in 2003 was 1.4/100,000 population, with higher rates in African-Americans, women and the elderly. The prevalence of asthma has increased substantially over the past several decades, making it the most common chronic disease among youth worldwide, though the causes of this increase are unknown. Although death rates are stabilizing or decreasing, possibly due to improvements in medical care, asthma continues to pose a substantial economic burden. The total cost of asthma in 2004 was US$16 billion, US$11.5 billion due to direct healthcare costs (including US$5 billion in prescription drug costs) and US$4.6 billion in indirect costs associated with lost productivity at work and school and mortality (60). While there is no cure for asthma, the vast majority of persons with asthma can live symptom-free and without functional impairment with adequate routine medical care and adherence to asthma treatment. Yet, poor asthma control remains a problem among a substantial proportion of the population. As such, ongoing research aims to identify factors associated with poor asthma control. Recent evidence suggests that mental disorders may play a role in various aspects of onset

and course of asthma and are the subject of studies designed to better understand this relationship. Findings from community-based epidemiologic studies in youth and adults demonstrate a strong and consistent association between asthma and anxiety disorders (6166). In contrast, available evidence on the link between asthma and depression is somewhat mixed (63, 6769). The majority of studies to date on the link between mental disorders and asthma have relied on patient self-reports or parental reports of asthma. However, one study that examined the relationship between physician-diagnosed asthma and mental disorders found that anxiety disorders were significantly associated with both nonsevere [OR: 1.51 (1.002.32); P<.05) and severe asthma [OR: 2.09 (1.303.36); P<.05] (64), in contrast to the weaker and nonsignificant associations for mood disorders with lifetime nonsevere [OR: 1.44 (0.942.19)] or severe asthma [OR: 1.21 (0.751.98)]. Of note, nonsevere asthma (past 4 weeks) was significantly associated with increased likelihood of any affective disorder [OR: 2.42 (1.035.72); P<.05], while bipolar disorder was very strongly associated with lifetime severe asthma [OR: 5.64 (1.9516.35); P<.05]. Panic disorder, panic attacks, GAD and phobias appear to be the anxiety disorders most strongly associated with asthma (64). Another study compared 769 youth with physician-diagnosed asthma to 582 age-matched controls and found an approximately twofold increase in the prevalence of one or more anxiety or depressive disorders, with greater rates of anxiety compared to mood disorders, and a significant correlation between anxiety sensitivity and asthma severity (70). Clinical studies assessing the rates of mental disorders in patients with asthma, although largely limited to relatively small sample sizes and self-reported asthma status, have consistently found high rates of anxiety disorders in children, adolescents and adults (Table 1). Few studies have been able to control for potentially confounding or mediating factors in the links between asthma and mental disorders, such as smoking or use of asthma medications (78). One study found that adolescents with a history of life-threatening asthma attacks are more likely to have symptoms of PTSD, which was directly related to the lifethreatening experiences associated with asthma, compared to less severely ill patients or healthy controls (73). Another study examined the relationship between PTSD symptoms and asthma among male twins and found the association was not explained by common genetic factors (79).

View this table: [in this window] [in a new window]

Table 1. Anxiety Disorders in Clinical Samples of Patients With Asthma

One study of adolescents with asthma found that, after controlling for severity of asthma, the presence of an anxiety or depressive disorder was associated with an increased number of days with asthma symptoms in the past 2 weeks (mean: 5.4 days) compared to adolescents without these psychiatric diagnoses (mean: 3.5 days; P<.001), and that the number of anxiety-depressive symptoms was strongly associated with higher levels of asthma symptoms (P <.001) (80). The presence of anxiety disorders or other psychiatric diagnoses did not correlate with asthma severity in two studies of adult patients in asthma clinics (76, 81) or one large, primary care-based study (70). Findings for depression are somewhat equivocal, with some studies suggesting that depression is prevalent (7477). Nonetheless, poor asthma control, increased functional impairment, decreased quality of life, and utilization and cost of healthcare resources have been shown to be strongly associated with anxiety and mood disorders among persons with asthma (80, 82). Patients with comorbid asthma plus anxiety or mood disorders are more likely to use bronchodilators in the previous week (P<.02), have lower scores on asthma-control rating scales (P<.001) (e.g., nocturnal waking, activity limitation, wheezing, increased use of asthma medications, pulmonary function tests) (81) and lower quality of life as measured by activity limitation, asthma symptoms, environmental stimuli and emotional distress (P<.001) (81). Patients with asthma and a comorbid psychiatric diagnosis, including an anxiety disorder, are 4.9 times more likely to use an emergency room and 3.8 times more likely to be hospitalized (76), but few patients are treated for their mental disorder (81). Despite these robust data, comorbid anxiety and depressive disorders are only accurately diagnosed in approximately 40% of asthmatic patients in primary care (83). There are also a number of clinical and community-based studies that have found links between asthma and suicidal ideation (63, 84), suicide attempts and completed suicide (84). As suicide behavior has also been linked with anxiety disorders (85), further investigation into the risk of suicide behavior among individuals with asthma and anxiety disorders is needed. Smoking is a particularly problematic health behavior in youth with asthma, leading to higher symptom burden and treatment resistance. DSM-IV anxiety/depressive disorders in a sample of adolescent patients with asthma in one healthcare system have been found to be present in 14.5% of nonsmokers, 19.8% of susceptible nonsmokers and 37.8% of smokers. After controlling for several covariates, youth with comorbid anxiety and depressive disorders and asthma had a two-fold increased likelihood of smoking compared to those without. Youth with asthma who smoked reported significantly more asthma symptoms, reduced functioning due to asthma, less use of controller medication and more use of rescue medications compared to those who did not smoke (86). Pathophysiology. The mechanisms underlying the association between asthma and anxiety disorders are not

known. It may be that there is a causal link between asthma and anxiety disorders; yet, increasingly, evidence supports the possibility that one or more outside factors, either environmental or genetic, may influence the risk of both (87). One longitudinal study that tracked children from ages 3 through 18 and assessed temperamental and illness factors found that a history of self-reported poor respiratory health at age 15 predicted panic disorder/agoraphobia at ages 18 to 21 compared to participants without a history of respiratory problems (88). Another longitudinal, community-based study followed 591 young adults for 20 years, beginning at age 19, and examined the relationship between asthma and panic disorder (65). A bidirectional relationship was observed in which asthma predicted onset of later panic disorder, and panic disorder was antecedent to active asthma. Childhood anxiety, parental smoking and a family history of allergy have been suggested as possible shared etiologic factors in both asthma (65) and panic disorder (89). Environmental factors including low socioeconomic status, exposure to pollutants, environmental stressors and childhood adversity may predispose youth to both asthma and anxiety and depressive disorders (78). Potential factors that could play a role in causal mechanisms for the relationship between asthma and panic disorder include increased levels of anxiety associated with fear of the next asthma attack, the anxiogenic properties of asthma medications, hyperventilation associated with panic attacks, and poor adherence to asthma treatment in patients with psychiatric diagnoses (65, 78). Treatment. Data demonstrating the relationship between asthma and anxiety disorders suggest that psychopharmacological and/or psychosocial interventions might improve asthma control. Yet, there is a remarkable paucity of studies that address this issue. One recently published report from the Cochrane Collaboration reviewed the effectiveness of psychological treatment for adults with asthma (90). A total of 14 randomized, controlled studies of 617 subjects were reviewed. Most studies were small, and methodologies varied widely. However, data pooling suggests future avenues of research. Relaxation therapy reduced the need for rescue bronchodilators in two studies, and CBT improved quality of life in two other studies. Spirometry measures improved following bio-feedback in two studies, but not with relaxation therapy in four studies. Overall, the authors concluded that it is not possible to assess the role of psychotherapeutic interventions in patients with asthma because of the lack of an adequate database (90). Larger, more rigorously controlled trials in patients with comorbid asthma and anxiety, including trials of pharmacotherapy, are needed before the role of mental health interventions in the treatment of asthma can be determined.

CARDIOVASCULAR

DISEASE

Epidemiology. Cardiovascular disease (CVD) has been the leading cause of mortality in the USA for over 100 years, with one in three American adults now dying from one or more types of CVD, accounting for one out of every 2.8 deaths in 2004 and more deaths each year than cancer, chronic lung disease, accidents and diabetes mellitus combined. The estimated total cost of CVD in the USA for the year 2007 was US$431.8 billion (91). Hypertension, diabetes mellitus, hypercholesterolemia, elevated body mass index, unhealthy diet, sedentary lifestyle and smoking are key modifiable risk factors for CVD (91). Chronic stress, depression and anxiety also increase the risk of developing CVD and complicate recovery

following acute cardiac events (92). Much attention has been paid to depression as both a risk factor for incident CVD and a predictor of poor outcome in cardiac patients. Depression is strongly associated with increased rates of serious cardiac events, all-cause mortality and cardiac mortality following myocardial infarction (MI), unstable angina and coronary artery bypass surgery (7, 93). Although it is less well studied than depression, emerging data suggest that anxiety is also an important risk factor for both incidence and progression of CVD. Indeed, one comprehensive literature review concluded that there is considerable covariation between depression, anxiety and anger/hostility as risk factors for CVD (94). Denollet et al. (95) found that anxiety symptoms are core features of post-MI depression and concluded that screening for anxiety may be useful in identifying patients at risk for depression following MI. Studies in several cohorts suggest that the general distress shared across depression, anxiety and anger/hostility is a significant risk factor for incident CVD (9698). However, additional analyses in one study also showed that anxiety symptoms were associated with increased cardiac risk beyond effects of general distress, suggesting the utility of considering anxiety separately from depression and other psychosocial risk factors (96). Depression and anxiety are also as strongly associated with cardiac symptoms and functional impairment in patients with CVD as are physiological measures of cardiac impairment (i.e., number of vessels with 50% occlusion or decreased ejection fraction) (4, 99). The findings of community-based population studies demonstrate that anxiety symptoms (e.g., worry, tension, feeling restless, difficulty making decisions) and anxiety disorders are associated with increased risk for incident CVD, such as MI, sudden cardiac death, angina pectoris, and hypertension (100105). A recent overview of the literature summarizing findings from 11 prospective studies examining the association between chronic anxiety and incident CVD reported consistently elevated risk associated with anxiety with relative risks ranging from 1.5 to 8 (106). Especially strong data exist for phobic anxiety (100, 107). One study also recently reported increased risk of developing CVD associated with higher levels of PTSD symptoms (108). Anxiety disorders are also associated with adverse cardiac outcomes. In a recent study of 3369 generally healthy community-dwelling postmenopausal women, a history of recent panic attacks was associated with both coronary heart disease [HR: 4.20 (1.769.99)] and the combined end point of coronary heart disease or stroke [HR: 3.08 (1.605.94)] after controlling for multiple potential confounders (109). General measures of anxiety and psychological distress were associated with increased rates of 5-year cardiac-related mortality in patients with MI (110). Anxiety in post-MI patients was associated with adverse cardiac events, cardiovascular death (111113) and increased rates of cardiac rehospitalization and outpatient visits to cardiologists (113). Interestingly, one study of 318 male survivors of a first MI showed that anxiety (HR: 3.01; P = .019) was more strongly associated with subsequent cardiac events than depression (HR: 2.32; P = .039) or hostility (HR: 1.03; P = .950) (113). Studies on cardiac outcomes in patient populations find a particularly strong effect associated with panic disorder (114, 115). Other work has suggested that the trauma of having an MI may cause PTSD, which then adversely impacts survival (116). For example, PTSD was considered in a small study of post-MI patients and

found to be associated with cardiac rehospitalization and poor adherence to aspirin prophylaxis regimens (117). Pathophysiology. Rozanski and Kubzansky (118) proposed a number of pathways by which anxiety may influence CVD. Effects of anxiety may accumulate over time leading to cardiovascular damage, setting the stage for atherosclerosis and coronary artery disease (93, 119). Thus, similar to chronic stress and other negative emotions, anxiety may lead to excess activation of the HPA axis and sympathetic nervous system. Increases in sympathetic nervous system activity and release of plasma catecholamines may damage the vascular endothelium and also lead to the release of fatty acids above levels needed for metabolic requirements. Excess HPA activation may lead to increased inflammation (120). Anxiety is also hypothesized to increase cardiovascular reactivity to stress leading to greater strain on the heart as a result of increased resting heart rate, baroreflex dysfunction and variability in ventricular repolarization (111, 114, 118, 121). Moreover, anxiety has been linked to altered cardiovascular autonomic control with studies demonstrating reduced heart rate variability among individuals with high levels of anxiety (122). Taken together, the effects of sympathetic nervous system and HPA axis hyperactivity along with altered sympathovagal control of the heart increase the risk of incident CVD and lower the threshold for cardiac ischemia, arrhythmias and sudden cardiac death (93). Anxiety may also influence CVD indirectly, as anxiety is associated with poor health-related behaviors including smoking and excess alcohol consumption, which in turn increase the risk of CVD (122). Acute effects of anxiety are also possible. There is some evidence to suggest that extreme emotional states, like an acute anxiety episode, may actually trigger an MI (123, 124). Treatment. Despite the strong association between depression and CVD, many studies designed to assess the effect of psychosocial interventions or antidepressant medications on depression and CVD outcomes failed to show a significant difference between active treatment and placebo on CVD outcomes (7, 92, 125). Given that many patients have had long-term exposure to depressive symptoms and most interventions occur after disease processes are initiated (126), it may be that these interventions have not been administered during the appropriate etiologic window (107). There are very few studies of anxiety treatment in cardiac patients, although issues of exposure duration and appropriate timeframes for interventions are also likely to be relevant for treating anxiety. In a cohort of patients with PTSD who were recovering from an MI, the combination of trauma-focused CBT and education about treatment adherence resulted in improved PTSD symptoms and adherence to aspirin therapy (127). Fluoxetine treatment in patients with mild depression following their first MI resulted in significant improvements in measures of hostility (128). Casecontrol studies also suggest that the use of SSRIs may be associated with decreased rates of mortality in patients with depression and CVD (129). Clearly, knowledge about the effects of anxiety treatment on CVD risk and outcome is in its infancy and further studies are needed.

CANCER
Epidemiology.

Cancer is a common and frequently deadly diagnosis despite remarkable advances in the past 40 years. During 2006, 1.4 million new cases were diagnosed in the USA, and more than 560,000 Americans died from cancer. However, continued improvements in the prevention, diagnosis and treatment of cancer are at work to improve survival. The 5-year survival rates for all cancers increased from 50% in the 1970s to 65% between 1995 and 2001, and deaths from colon, rectum, stomach, prostate, breast and lung (men only) cancers are declining. As of 2002, there were 10.1 million Americans who had survived cancer or who were undergoing treatment (130). Conventional wisdom and clinical experience dictate that cancer is a source of situational anxiety, causing psychological distress, fear, dread and sadness. However, apart from these normative emotional responses, cancer is associated with high rates of anxiety and depressive disorders (Table 2), though the latter have been much more extensively studied. Prevalence rates for anxiety and depressive disorders are generally in the range of 10% to 30%, with rates of various anxiety disorders equivalent to or greater than those of depression in many cases. However, rates vary depending on the type and stage of cancer, treatment regimens, time since diagnosis, gender and methods used to diagnose psychiatric illness. Specific phobias, panic disorder with or without agoraphobia, and GAD are commonly reported anxiety disorders in this population, as are adjustment disorder with anxious mood or depressed/anxious mood and PTSD.

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Table 2. Anxiety Disorders Diagnosed Using Structured or Semistructured Interviews or Standardized Self-Report Instruments in Patients With Cancer

Pathophysiology. Factors that influence distress include endocrine or metabolic changes associated with cancer or its treatment, cancer prognosis, individual coping style and social support systems. Some medications commonly used in the treatment of cancer are associated with symptoms of anxiety (e.g., glucocorticoids) or depression (e.g., interferon, glucocorticoids) (140). Variables independently associated with anxiety disorders in one set of patients with advanced cancer who were receiving palliative care were global health status, emotional/cognitive/social functioning, fatigue, nausea and vomiting (136). In another study of patients with mixed types of cancer, anxiety disorders correlated with female sex

and poor social support systems (131). Dahl et al. (137) studied 1408 long-term survivors of testicular cancer and found that anxiety disorders correlated with young age at follow-up, relapse anxiety, psychiatric treatment, peripheral neuropathy, alcohol abuse, economic problems and sexual dysfunction. Anxiety and depression among women with a first recurrence of breast cancer correlated with current toxic chemotherapy treatment (i.e., doxorubicin/cyclophosphamide), history of major depression, and feelings of helplessness or hopelessness (133). Treatment. Even though psychiatric illness in the context of cancer can increase somatic symptom burden and impair functioning and quality of life, negatively affect adherence to cancer treatment regimens and result in poor outcomes (131, 137, 139, 141), they should not be considered untreatable. Attention to patients' mental health status is an essential part of cancer treatment. However, anxiety and mood disorders in patients with cancer are often untreated or inadequately treated because of time or training constraints or because oncologists do not ask about psychological distress or endorse its importance. Patients contribute to under-treatment by trivializing symptoms of fear, anxious preoccupation, or helplessness/hopelessness, or because they feel that these symptoms are an expected part of their diagnosis and treatment (142, 143). Many physicians prescribe short-term benzodiazepines to help patients cope with the situational anxiety associated with surgery, chemotherapy or radiation (144). There are relatively few placebo-controlled drug trials in patients with depression and cancer (12, 145151) and virtually none focusing on anxiety disorders. Nonetheless, the traditional antidepressants [e.g., TCAs, SSRIs, serotoninnorepinephrine reuptake inhibitors (SNRIs)] possess anxiolytic properties, and some studies demonstrated improvement in anxiety symptoms in patients with a primary diagnosis of depression (144, 148). This provides some degree of support for their use in patients with cancer and comorbid anxiety disorders (144, 152). In contrast, a large body of literature, as summarized in several reviews (153156), evaluates the use of psychological interventions in patients with cancer. Cognitively based psychotherapy alone or in conjunction with skills training and relaxation therapy has been shown in some controlled trials to improve quality of life, coping skills, symptoms of anxiety, and general distress (141, 156, 157). One rigorously conducted systematic review of 329 intervention trials concluded that extant data are insufficient to support strong recommendations for the use of psychological interventions for anxiety in patients with cancer. Few of these trials examined patients with specific anxiety disorders, such as panic disorder or GAD. The overwhelming number of trials examined patients with adjustment disorders, where placebo response rates are likely very high. However, CBT, therapistdelivered interventions, self-practice techniques, communication/expression training and guided imagery/visualization strategies warrant further study (154). Psychosocial interventions lasting 3 months or longer may be more effective than short-term treatment strategies (156, 157), and the combination of different behavioral treatments may be useful in relieving symptoms of anxiety (155). However, findings of recent studies show that psychological treatments do not actually affect survival time in cancer patients (158, 159).

CHRONIC

PAIN

Epidemiology. Contemporary models describe pain as a complex perceptual experience that is determined by sensory as well as psychological (i.e., cognition, emotion, behavior) and social influences. Pain is an essential adaptive process that enables one to curtail further physical harm and permit recuperation. However, for some persons pain becomes chronic, losing its adaptive qualities. The National Comorbidity Survey Part II estimates that approximately 7% of the general population in the USA has experienced chronic pain in the past 12 months (160), at an annual cost of about US $100 billion (161). However, because rates of chronic pain vary depending on the population, definition of chronicity (e.g., pain lasting 3 months vs. 6 months) and type of pain studied, rates upwards of 20% to 30% have been reported in recently published community-based population studies (162165). Chronic pain is associated with disability, physical deconditioning, excessive utilization of healthcare resources and emotional distress (163166). The spectrum of distress seen in chronic pain includes depression, anger, guilt, social withdrawal, fear and anxiety (160, 167, 168). Depression is strongly and consistently associated with chronic pain in both clinical and community-based samples (160, 162, 169). Fear and anxiety are also significant contributors to the experience of chronic pain, but until relatively recently the anxiety component of psychiatric morbidity in chronic pain received little attention. MeansChristensen et al. (170) found that primary care patients with somatic pain-related complaints (e.g., headache, stomach pain, muscle pain) had high rates not only of depressive symptoms, but also of anxiety symptoms (notably, panic and GAD symptoms). High rates of anxiety disorders have been observed in patients with different pain syndromes, including chronic spinal pain (11% to 27%) (165, 167), rheumatoid arthritis (25% to 35%) (160, 171), fibromyalgia (60%) (171) and migraine (172). In patients seeking treatment for chronic pain (Table 3), the most prevalent past 12-month anxiety disorders are phobic disorders (9% to 13%), GAD (0% to 13.4%) and panic disorder (2.1% to 7.2%). Particularly high rates of panic disorder and phobias are found in patients with chest pain and negative cardiac workups (178, 179). The most prevalent past 12-month anxiety disorders reported in community samples with chronic pain (Table 3) are specific phobia (12.5% to 15.7%), social anxiety disorder (8.3 to 11.8%) and PTSD (7.3 to 10.7%). These rates are higher than 12-month prevalence rates in the general US population (180). Pooled data from a recent survey of 85,088 community-dwelling adults from 17 countries indicate that persons with back or neck pain are two to three times more likely to have had past 12month panic disorder/agoraphobia, social anxiety disorder, GAD or PTSD compared to those without (181).

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Table 3. Twelve-Month Prevalence of Anxiety Disorders in Persons

[in this window] [in a new window]

With Pain in Community and Treatment-Seeking Samplesa

Data from the NCS (160) and the Midlife Development in the United States (MIDUS) survey (173) demonstrated that compared with the general population, rates of depression and anxiety disorders were significantly higher in persons with chronic pain. Somewhat surprisingly, they also found that the association with chronic pain was stronger for anxiety disorders than for depression. For example, among persons with chronic pain in the NCS, the 12-month prevalence of any anxiety disorder was 35.1% compared to 21.7% for any mood disorder (160). When chronic pain in persons with rheumatoid arthritis, migraine or back pain was assessed in MIDUS, the strength of association was consistently larger for panic attacks (OR: 2.093.58) and GAD (OR: 2.173.86) than for depression (OR: 1.48 2.84) (173). There is some evidence to suggest that anxiety disorders precede the onset of pain. In a sample of 146 injured workers with chronic musculoskeletal pain, Asmundson et al. (174) found that, in all but one case, the anxiety disorder preceded the pain complaint. Likewise, Kinney et al. (176) found that among 90 patients with chronic low back pain, 23% had a preexisting anxiety disorder. Additional research on temporal sequence and course of anxiety disorders in chronic pain is needed. Pathophysiology. Pain and anxiety are both associated with physiological arousal. Bodily changes stemming from arousal (see Sections on IBS and CVD) serve a protective function by promoting escape and withdrawal. However, if prolonged, arousal can have detrimental physical effects. Physical injury and stressful or uncontrollable experiences also initiate other complex neural and hormonal processes (e.g., release of cytokines, -endorphin, 5-HTmoduline) that, while designed to promote tissue healing and reinstate homeostasis, can be destructive to various body systems (e.g., muscle, bone, neural tissue) when prolonged (182, 183). Illustrating these effects, Sareen et al. (24) found strong associations between anxiety disorders, particularly PTSD, and medical illnesses characterized by pain (e.g., multiple sclerosis, ulcer, hernia, arthritis, rheumatism). Persons with anxiety sensitivity (i.e., fear of anxiety symptoms based on the belief they may have harmful consequences) or injury/illness sensitivity or who have preexisting anxiety disorders may respond to chronic pain with catastrophic misinterpretation of the meaning of the pain, physiologic arousal, fear of recurrent pain, fear of movement or reinjury, avoidance of pain, and hyper-vigilance (184). Such maladaptive responses may lead

to a self-perpetuating cycle that promotes and maintains activity limitations, disability, pain, and additional fear and anxiety (168, 185187). Treatment. There is a relatively large literature suggesting that CBT in patients with chronic pain may improve pain levels, coping skills and functional abilities (188190). Consideration of chronic pain and anxiety in the context of a cognitive-behavioral fear-avoidance phenomenon has implications for the design of therapeutic interventions. Graded exposure in vivo is one cognitive-behavioral technique that has been shown in single case-controlled (191, 192) and randomized controlled (193) studies to reduce fear and pain intensity and improve physical activity in patients with chronic pain. These treatments are promising for those with co-occurring chronic pain and anxiety disorders, although it remains to be determined what specific effect they will have on the anxiety disorder symptoms. There is also a large literature suggesting that antidepressants have beneficial effects in treating chronic pain, even in patients without comorbid depression. The TCAs and SNRIs appear to be more effective than the SSRIs in treating neuropathic pain (194).

CRITICAL

SUMMARY

The studies reviewed here have numerous methodologic limitations. Some epidemiological studies failed to use structured interviews or standardized rating scales, others did not account for medication effects and some used too narrow a sampling frame. Despite these limitations, each of which would presumably weaken any anxiety-medical condition association, the wealth of evidence clearly shows that anxiety is associated with an increased prevalence of these five broad categories of medical conditions. The extant data cannot tell us at this point the magnitude of these associations, nor how this association compares with depression, though the NCS-R data suggest that the association of anxiety with a number of medical illnesses is likely to be comparable to that of depression. Our understanding of pathophysiological substrates accounting for associations with these five medical conditions is largely inferential and mostly based on preclinical data or knowledge of human pathophysiology. Although more specific understanding is limited by the small number of available human studies, neuroimaging studies are providing a useful window into CNS substrates that may mediate links between anxiety and medical illness. Understanding of pathophysiology is much more advanced for the association between anxiety and some medical conditions (e.g., IBS, CVD) and poorly developed for others (e.g., cancer). Treatment studies with either an anxiety or depressive intervention have focused much more on some medical conditions (e.g., CVD, IBS) than on others (e.g., asthma, cancer), and the majority of treatment studies have targeted depression, with few if any treating anxiety. However, for some conditions (e.g., CVD), treatment may have an impact on behavioral and pathophysiological processes, as well as on some clinically important outcomes of the medical condition such as quality of life. Thus, it is not clear whether anxiety treatments can have an impact on the underlying medical condition, and if so, to what degree.

TOP ABSTRACT INTRODUCTION ANXIETY DISORDERS AND COMORBID... RESEARCH PRIORITIES CONCLUSIONS REFERENCES

RESEARCH PRIORITIES
Conference participants outlined research needs to advance understanding of anxiety disorders and comorbid medical illness and improve patient care. No attempt was made at the conference to rank order these priorities, but all were felt to be of substantial importance to the field.

EPIDEMIOLOGY

Include anxiety indicators, especially those fulfilling DSM-IV diagnostic criteria, in large population-based health surveys. Collect data on the economic impact of anxiety disorders in medically ill patients that are important to both the medical/scientific community and policy makers. Evaluate temporal onset in the relationship between anxiety disorders and medical illness by longitudinally following a cohort of children at risk of developing a chronic medical condition, such as asthma, and documenting which comes first. Conduct observational studies to identify the medical or psychiatric comorbidities that are most strongly associated with quality of life (critical new work in this area has recently been published (195)) and medical prognosis. The findings would aid primary care physicians to focus on baseline symptoms that most urgently require attention.

PATHOPHYSIOLOGY

Conduct studies that further examine the vicious cycle of central activationsomatization by identifying brain regions, neural circuits and neurotransmitter systems involved in the visceral hyperalgesia, hypervigilance and increased smooth muscle tone associated with anxiety disorders. Examine potential biological mechanisms of the association between anxiety disorders and medical conditions, while also adjusting for and examining the role of potential confounding/mediating factors.

TREATMENT

Develop generalized CBT interventions for primary care patients and measure the effect of improving fear, avoidance, somatization and other elements of negative affect on function, clinical outcomes of medical illness, and utilization patterns. Assess the utility of novel delivery methods for broad-based (i.e., targeting anxiety, depressive and related somatic symptoms) CBT, such as telephone- and web-based CBT or stepped collaborative-care approaches to treatment delivery. Study the effectiveness of CBT approaches in the top 10% of healthcare utilizers in a given healthcare system using a collaborative care model. Identify medically ill patients needing treatment by stratifying patients with DSM-IV anxiety disorders according to severity of emotional distress and randomizing each group to evidence-based treatment vs. usual care. Integrate successful components of collaborative care treatment models, such as brief evidence-based CBT combined with pharmacologic interventions in patients with panic disorder (196, 197), to address symptoms of anxiety and depression and improve functional and medical outcomes in primary care patients. Create a demonstration project that measures the clinical and economic outcomes when financial incentives are provided to primary care physicians for screening high utilizers of healthcare resources and using best-practices treatment guidelines.

TOP ABSTRACT INTRODUCTION ANXIETY DISORDERS AND COMORBID... RESEARCH PRIORITIES CONCLUSIONS REFERENCES

CONCLUSIONS
The clinical importance of the bidirectional relationship between psychiatric and physical illness is beginning to be appreciated by the medical, clinical and research communities. Extant studies primarily focus on comorbid depression. However, emerging evidence suggests that anxiety and the anxiety disorders, which have received relatively less attention, may be as important as depression. In addition, many patients have comorbid anxiety and depressive symptoms, which are associated with increased severity of psychiatric illness, additive functional impairment and medical costs. Much like depression, anxiety disorders and subsyndromal anxiety amplify symptoms of some medical illnesses and appear to worsen clinical outcomes. The considerable overlap of anxiety, depression and chronic stress states suggests that clinicians should broaden their search for mental health problems beyond depressive symptoms in their patients with chronic medical illnesses to include symptoms of anxiety.

Increased funding for research programs that address basic science issues, epidemiology, treatment and healthcare delivery systems is needed. Development of effective messages about the role of anxiety and anxiety disorders in common medical illnesses will facilitate educational approaches designed to increase awareness among patients, physicians, healthcare systems and policy makers. Inclusion of data about the role of mental disorders in comorbid medical illnesses into medical school, residency and continuing medical education curricula will improve awareness in the medical community. Primary care physicians who frequently see patients with chronic medical illness are in an excellent position to assess patients' mental state and begin appropriate interventions. However, there is a remarkable lack of data from rigorously designed clinical trials to guide treatment decisions in this population. In addition, stigma about mental health issues can color patients' acceptance of a psychiatric diagnosis. Patients who understand that a medical illness may be the result of a variety of risk factors that include mental health issues and brain function and who are engaged participants in their care are likely to have better clinical outcomes. Although much work remains to be done, the stage has been set to explore the relationship between anxiety disorders and medical illness with the aim of developing and subsequently promoting evidence-based treatment strategies to improve prognosis and quality of life in patients with chronic medical illnesses.

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TOP ABSTRACT METHOD RESULTS PSYCHOTHERAPY PLUS... SUBGROUP AND SENSITIVITY... DISCUSSION CLINICAL IMPLICATIONS AND FUTURE... REFERENCES

ABSTRACT
204. Background: Panic disorder can be treated with psychotherapy, pharmacotherapy or a combination of both. Aims: To summarise the evidence concerning the short- and long-term benefits and adverse effects of a combination of psychotherapy and antidepressant treatment. Method: Meta-analyses and meta-regressions were undertaken using data from all relevant randomised controlled trials identified by a comprehensive literature search. The primary outcome was relative risk (RR) of response. Results: We identified 23 randomised comparisons (21 trials involving a total of 1709 patients). In the acute-phase treatment, the combined therapy was superior to antidepressant pharmacotherapy (RR = 1.24, 95% CI 1.021.52) or psychotherapy (RR = 1.16, 95% CI 1.031.30). After termination of the acute-phase treatment, the combined therapy was more effective than pharmacotherapy alone (RR = 1.61, 95% CI 1.232.11) and was as effective as psychotherapy (RR = 0.96, 95% CI 0.791.16). Conclusions: Either combined therapy or psychotherapy alone may be chosen as first-line treatment for panic disorder with or without agoraphobia, depending on the patient's preferences. 205. (Reprinted with permission from British Journal of Psychiatry 2006; 188:305312) 206. 207. 208. Two categories of treatment have been shown to be effective in treating panic disorder with or without agoraphobia. One is psychotherapy and the other is pharmacotherapy using antidepressants and benzodiazepines (American Psychiatric Association, 1998; Nathan & Gorman, 2002). However, it is uncertain whether combining these two forms of treatment confers any additional benefit over and above either treatment alone, both in the short term and in the long term. The primary objective of this systematic review was therefore to review and synthesise evidence from randomised controlled trials that examined the short- and long-term benefits and adverse effects of a combination of psychotherapy and antidepressants compared with either therapy alone for the treatment of panic disorder. A separate

review that focuses on the use of psychotherapy in combination with benzodiazepines is in preparation. 209.

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METHOD
211.

INCLUSION

CRITERIA

Randomised controlled trials that compared a combination of psychotherapy and antidepressant pharmacotherapy with either treatment alone for adult patients with panic disorder, with or without agoraphobia, were eligible for inclusion. 212. We included both individual and group formats of behaviour therapy involving some kind of exposure, cognitive therapy involving some kind of cognitive restructuring, cognitive-behavioural therapy involving elements of both cognitive and behavioural therapy, and other psychological approaches. All commonly prescribed antidepressants were eligible, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). 213. Studies in which there was irregular use of benzodiazepines or in which benzodiazepines were regularly administered at a constant dosage for long-term users were included, because it was considered that these did not undermine the comparability of the combined therapy with either monotherapy, and because such practices would reflect clinical reality more closely. The effect of this decision was examined in a sensitivity analysis. Studies in which benzodiazepines were combined with antidepressants as part of the study medication were excluded. 214. IDENTIFICATION OF TRIALS We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) with the keywords ANTIDEPRESSANT and PANIC up to April 2003. The CCDANCTR is a study-based register of randomised trials that incorporates the results of group searches of Medline (from 1966), EMBASE (from 1980), CINAHL (from 1982), PsycINFO (from 1974), PSYNDEX (from 1977) and LILACS (from 1982 to 1999), and hand searches of major psychiatric and medical journals, conference proceedings and trial registers. Two additional searches of the Cochrane Central Register of Controlled Trials

(CENTRAL) and Medline were also undertaken. No language restrictions were imposed on the search. 215. Two reviewers examined the titles and abstracts of studies identified by the electronic search, and then checked the full articles for eligibility. To identify further trials, the references cited in these studies and in other review papers were also checked, relevant studies were subjected to SciSearch, and experts in the field were contacted. 216. QUALITY ASSESSMENT AND DATA EXTRACTION Two independent reviewers assessed the methodological quality of the selected studies according to the recommendations of the Cochrane Reviewers' Handbook 4.2, 2 (Alderson et al., 2004), which emphasises allocation concealment (A, low risk of bias; B, moderate risk of bias; C, high risk of bias). We also rated the study as blinded when at least one outcome measure was assessed by an independent assessor who was masked to treatment allocation, and unblinded when the outcomes were assessed by someone who was aware of the allocated treatment. 217. In addition, we rated the adequacy of the psychotherapy as good when the way in which psychotherapy was actually conducted was examined by a third reviewer by means of audiotapes, etc., and as poor when the authors only provided a description of the therapy procedure. 218. Two reviewers independently extracted data from the original reports using standardised data-extraction forms. Our primary outcome was responsethat is, substantial improvement from baseline, such as very much or much improved according to the Clinical Global Impression scale (CGI; Guy, 1976), a decrease of more than 40% in the Panic Disorder Severity Scale score (Shear et al., 1997), and a reduction of more than 50% in panic frequency or the Fear Questionnaire Agoraphobia sub-scale (Marks & Mathews, 1979). Our secondary outcomes included global severity, frequency of panic attacks, phobic avoidance, general anxiety, depression, social dysfunction, patient satisfaction and cost-effectiveness. The total number of drop-outs for any reason was regarded as a proxy measure of the acceptability of treatment. Adverse effects were evaluated by examining the number of drop-outs due to adverse effects. 219. Any discrepancies were resolved by consensus between two or, where necessary, between all three reviewers. The decision to include in the meta-analysis studies that did not appropriately conceal allocation, that were unblinded or that scored poor with regard to adequacy of psychotherapy was examined in sensitivity analyses. 220. DATA SYNTHESIS Data were entered into Review Manager 4.2 (Windows software provided by the Cochrane Collaboration and available at http://www.cc-ims.net/RevMan) and double-checked for accuracy. For dichotomous outcomes, relative risk (RR) and 95% confidence intervals were calculated using a random-effects model, which yields superior results in terms of clinical interpretability and external generalisability compared with fixed-effects models and odds ratios or risk differences (Furukawa et al., 2002). For continuous outcomes, the standardised weighted mean difference (SMD) and 95% confidence intervals were calculated using a random-effects model.

221. For dichotomous outcomes, we used intention-to-treat analyses according to the following principle. When data on drop-outs were carried forward and included in the efficacy evaluation using the last-observation-carried-forward method, they were included as such. When drop-outs were excluded from any assessment in the primary studies (e.g. those who never returned for assessment after randomisation), they were considered to be non-responders in both active and comparison groups. The same principles were applied to outcomes after the end of continuation treatment. 222. SUBGROUP AND SENSITIVITY ANALYSES To investigate clinical heterogeneity, we planned three a priori subgroup analyses: for types of psychotherapies; for classes of antidepressants; and for patients with or without agoraphobia. Statistical heterogeneity between studies was assessed with the I-squared statistic and the Q statistic. If significant heterogeneity was noted (I2 > 30% or P < 0.10) (Higgins et al., 2003), sources were investigated. 223. In addition, sensitivity analyses were performed, restricting the data syntheses to studies of higher quality in terms of allocation concealment, blinding, operational diagnosis, adequacy of psychotherapy and control of benzodiazepine cointervention. Meta-regressions (Thompson & Sharp, 1999) were also performed to determine whether these variables had a significant effect on the pooled effect sizes. 224.

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RESULTS
226.

DESCRIPTION

OF

STUDIES

The electronic search identified 139 studies from CCDANCTR, an additional 164 studies from CENTRAL and 35 studies from Medline. By browsing their titles and abstracts, the two independent reviewers identified 135 articles as possible candidates, and full copies of these articles were obtained. Two independent reviewers then examined the strict eligibility of these papers. As a result of a further reference search, SciSearch and personal contacts, we identified 21 studies which satisfied the strict eligibility criteria. The interrater reliability of the eligibility criteria was found to be 94%. Because two trials provided two comparisons each (Sheehan et al., 1980; Mavissakalian & Michelson, 1986), there were 23 randomised

comparisons involving a total of 1709 participants (Table 1) (a more detailed version of Table 1 is presented as a data supplement to the online version of this paper). 227.

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Table 1. Characteristics of the Studies Included in the Review

228. The majority of the participants were women, and their average age was between 30 and 40 years. They had suffered from panic disorder for 5 to 10 years. Only one comparison focused on patients with panic disorder without agoraphobia, whereas 13 comparisons focused on patients with panic disorder with agoraphobia. The other studies were of mixed populations. 229. The typical length of the acute-phase active treatment was between 8 and 12 weeks. In total, 12 studies administered behaviour therapy that consisted of exposure and/or breathing retraining and/or relaxation exercises. None of the studies used narrowly defined cognitive therapy that relied only on cognitive restructuring. Nine studies administered cognitivebehavioural therapy that consisted of both behaviour and cognitive therapy elements. Two studies were categorised as Other psychotherapies. One of these used a mixture of cognitivebehavioural therapy and interpersonal psychotherapy (Berger et al., 2004) and the other used brief psychodynamic psychotherapy (Wiborg & Dahl, 1996). With regard to medications that were administered, 14 studies used TCAs (with an average dose of 146 mg/day of imipramine equivalents), 7 studies used SSRIs (average dose 32 mg/day fluoxetine equivalents) and 2 studies used monoamine oxidase inhibitors. 230. Response was defined in terms of the CGI scale in eight studies, in terms of the Fear Questionnaire Agoraphobia sub-scale in three studies, in terms of panic frequency in two studies, and in terms of other measures in 10 studies. In total, 13 studies reported continuous outcomes of global severity, 15 reported on panic frequency, 20 reported on agoraphobia, 18 reported on general anxiety, 18 reported on depression and 13 reported on social dysfunction. None of the studies reported on patient satisfaction or cost issues. 231. Six studies reported the results at the end of continuation treatment which lasted for between 3 and 9 months. Nine studies followed up the patients 624 months after termination of acute-phase and continuation treatments.

232. With regard to validity, all but four comparisons from three trials (Mavissakalian & Michelson, 1986; Wiborg & Dahl, 1996; Berger et al., 2004) scored B for allocation concealment. In total, 19 studies conducted blinded outcome assessments and four studies were unblinded (Mavissakalian et al., 1983; Spinhoven et al., 1996; Azhar, 2000; Berger et al., 2004). The interrater reliability of these two validity criteria was 94% for allocation concealment and 83% for outcome assessment. 233. Six studies reported that quality control of the psychotherapy was adequate (Zitrin et al., 1983; de Beurs et al., 1995; Fava et al., 1997; Loerch et al., 1999; Barlow et al., 2000; Kampman et al., 2002). Four studies acknowledged financial support from pharmaceutical companies (Fahy et al., 1992; de Beurs et al., 1995; Sharp et al., 1996; Loerch et al., 1999), and these companies marketed the drugs involved in the trials. Oehrberg et al. (1995) did not acknowledge financial support from a drug company, but three of the co-authors of that study were company employees. 234.

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PSYCHOTHERAPY PLUS ANTIDEPRESSANT TREATMENT

236.

ANTIDEPRESSANT

V.

ACUTE-PHASE

TREATMENT

Combining data from 11 studies involving 322 patients in the psychotherapy plus antidepressant arm and 347 patients in the antidepressant arm showed that the combination was 1.24 times (95% CI 1.021.52) more likely to produce a response at the end of 24 months of acute-phase treatment compared with the antidepressant alone (Fig. 1).There was moderate but statistically significant heterogeneity (P = 0.05, I2 = 44.9%). Furthermore, the funnel plot indicated that there was some publication bias, with one small study reporting an extreme result (Telch et al., 1985). Subgroup analyses suggested that there was greater heterogeneity in the other psychotherapies category (Wiborg & Dahl, 1996; Berge et al., 2004). When we omitted these studies, limiting the included studies to those that employed behavioural or cognitive-behavioural therapies, the RR remained the same (RR =

1.28, 95% CI 1.081.52) and there was no longer statistical heterogeneity (P = 0.18, I2 = 30.5%) or funnel-plot asymmetry. 237.

Figure 1. Psychotherapy Plus Antidepressant v. Antidepressant Alone: Response at the End of Acutephase Treatment. PT, Psychotherapy; AD, Antidepressant; RR, Relative Risk

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238. The superiority of the combination therapy was corroborated by secondary analyses using continuous data. The combination treatment decreased the global severity of the disorder (SMD = 0.36, 95% CI 0.60 to 0.11), depression (SMD = 0.52, 95% CI 0.76 to 0.28) and social dysfunction (SMD = 0.47, 95% CI 0.89 to 0.05). 239. There were no differences in overall drop-outs or in drop-outs due to sideeffects. 240. CONTINUATION TREATMENT There was considerable statistical heterogeneity (P = 0.005, I2 = 76.8%). Limiting the studies to behaviour and cognitive-behavioural therapies removed this heterogeneity (P = 0.55, I2 = 0%) and suggested that the combination therapy was 1.63 (95% CI 1.212.19) times more likely to produce a response than antidepressant treatment alone. 241. AFTER TERMINATION OF TREATMENT Figure 2 shows the findings of five studies that reported outcomes after 624 months of naturalistic follow-up. Combining outcomes based on 376 participants, the combination therapy was still superior to antidepressant treatment alone (RR = 1.61, 95% CI 1.232.11). No heterogeneity was noted (P = 0.50, I2 = 0%). 242.

Figure 2. Psychotherapy Plus Antidepressant v. Antidepressant Alone: Response After Termination of Treatment. PT, Psychotherapy; AD, Antidepressant; RR, Relative Risk

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243.

PSYCHOTHERAPY PSYCHOTHERAPY

PLUS

ANTIDEPRESSANT

V.

Although the comparison of psychotherapy plus antidepressant with psychotherapy alone is theoretically different from the comparison of psychotherapy plus antidepressant with psychotherapy plus placebo (Hollon & DeRubeis, 1981), our meta-analytical summaries were remarkably similar for the acute phase and followup evaluations. We therefore report here the aggregated results of trials comparing psychotherapy plus antidepressant with psychotherapy alone and psychotherapy plus placebo. 244. ACUTE-PHASE TREATMENT Combining data from 19 comparisons involving 592 patients in the psychotherapy plus antidepressant arm and 665 patients in the psychotherapy arm demonstrated that the combination was 1.16 times (95% CI 1.031.30) more likely to produce a response at the end of acute-phase treatment than psychotherapy alone (Fig. 3).The test for heterogeneity was not significant. 245.

Figure 3. Psychotherapy Plus Antidepressant v. Psychotherapy Alone: Response at the End of Acutephase Treatment. PT, Psychotherapy; AD, Antidepressant; RR, Relative Risk, I. Comparison A of Two From this Study;2. Comparison B of Two From This Study

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246. The same superiority of the combined therapy was noted with regard to the global severity (SMD = 0.43, 95% CI 0.60 to 0.26). When different aspects of panic disorder were examined, the combination therapy was found to be significantly superior with regard to reduction in phobic avoidance (SMD = 0.31, 95% CI 0.49 to 0.12), general anxiety (SMD = 0.41, 95% CI 0.59 to 0.23), depression (SMD = 0.39, 95% CI 0.59 to 0.20) and social dysfunction (SMD = 0.36, 95% CI 0.61 to 0.11). 247. Although the two arms did not differ in terms of overall drop-out rates, dropouts due to side-effects were much more frequent in the combined therapy arm (RR = 3.01, 95% CI 1.615.63). 248. CONTINUATION TREATMENT For as long as the treatments were continued, the advantage of the combination therapy appeared to persist, as the response rate at the end of continuation treatment still favoured the combination therapy (RR = 1.23, 95% CI 1.001.51), and the global severity was significantly lower in the combination arm (SMD = 0.65, 95% CI 0.97 to 0.33). 249. AFTER TERMINATION OF TREATMENT In total, 658 patients from nine studies were assessed 6 to 24 months after discontinuing treatment (Fig. 4).Neither the response rate nor the global severity measure differed significantly between the two arms, which suggests that any advantage of the combination therapy disappeared over time. 250.

Figure 4. Psychotherapy Plus Antidepressant v. Psychotherapy Alone: Response After Termination of Treatment. PT, Psychotherapy; AD, Antidepressant; RR, Relative Risk. I, Comparison A of Two From This Study; 2. Comparison B of Two From This Study View larger version (31K): [in this window] [in a new window]

251.

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SUBGROUP AND SENSITIVITY ANALYSES

253.

TYPES

OF

PSYCHOTHERAPY

For all the outcomes during the acute-phase or continuation treatments or after termination of treatment, the confidence intervals of the pooled estimates of the effectiveness of behaviour therapy and cognitive-behavioural therapy overlapped to a significant degree (Figs 1 4). Pooling these two types of psychotherapy together seldom resulted in significant heterogeneity. The only exception was the other psychotherapies category for the comparison of psychotherapy plus antidepressant with antidepressant treatment alone. The results of these studies were sometimes directionally different from those of the other studies in which behavioural or cognitive-behavioural therapies were administered, and combining them often resulted in significant heterogeneity.

254. CLASSES OF ANTIDEPRESSANTS We performed a meta-analysis of 14 studies in which TCAs were used and 7 studies in which SSRIs were used. The pooled estimates of the effect size of these two meta-analyses were very similar both to each other and to the overall results in terms of response or global severity (Table 2). 255.

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Table 2. Subgroup Analyses for Different Classes of Antidepressants and for Patients with and without Agoraphobia

256.

PATIENTS

WITH

AND

WITHOUT

AGORAPHOBIA

We performed a meta-analysis of 13 studies that focused on patients with agoraphobia only. The results were very similar to the overall results, and overlapped substantially with the results of the only study that focused on patients without agoraphobia (Barlow et al., 2000) (Table 2). 257. When only those studies that were of higher quality in terms of allocation concealment, blinding, diagnostic accuracy, adequacy of psychotherapy or control of benzodiazepine co-intervention were included, the pooled estimates that were obtained were virtually identical to the overall results. Meta-regression analysis did not reveal any significant contribution of these quality variables, either individually or in combination, which suggests that the overall findings are robust. 258.

DISCUSSION

260.

IMPORTANCE OF THE CLINICAL PROBLEM IN THE CONTEXT OF PREVIOUS REVIEWS

There are a number of reasons why the clinical question concerning combined psychotherapy and antidepressant treatment is important. First, combination therapy is frequently provided in clinical practice, possibly because 3050% of patients remain unimproved at the end of acute-phase treatment by either monotherapy. Second, it is now increasingly recognised that pharmacotherapy alone tends to result in substantial relapse rates not only when discontinued (Mavissakalian & Perel, 2002), but even when maintained at adequate dosage (Simon et al., 2002), whereas psychotherapy is associated with fewer relapses in the short term, but may not always be able to prevent them in the long term (Fava et al., 2001). 261. Several reviews of combination therapy can be found in the literature, but their conclusions have been variable, with some favouring the combination (Mattick et al., 1990; van Balkom et al., 1997), some favouring monotherapy (Gould et al., 1995; Taylor, 2000) and others drawing mixed or cautious conclusions (American Psychiatric Association, 1998; Schmidt et al., 2001). Most of these reviews have been either unsystematic or narrative only (American Psychiatric Association, 1998; Taylor, 2000; Schmidt et al., 2001) and, where meta-analytical summary was undertaken, this did not focus on head-to-head comparisons (Mattick et al., 1990; Gould et al., 1995; van Balkom et al., 1997), a practice that is known to be misleading (Song et al., 2003). 262. CURRENT FINDINGS This systematic review demonstrated that combining psychotherapy and antidepressant treatment produced outcomes that were consistently superior to either treatment alone for the acute-phase treatment, in terms of both the response rates and the continuous outcomes measuring various aspects of the disorder. Taking the average response rates of 5070% for single-modality treatments, the pooled RR of 1.2 for the combination therapy is equivalent to a value for the number needed to treat of between 7 and 10. During the acute-phase treatment, combination therapy resulted in more drop-outs due to side-effects than psychotherapy alone, and the number needed to harm was around 26. 263. The naturalistic follow-up of the randomised controlled trials that were included suggested that the combination therapy had a sustained advantage over antidepressant therapy. At 624 months after termination of treatment, the combined therapy still showed a number needed to treat of around 6 compared with antidepressant treatment alone. With regard to the comparison between the combination therapy and psychotherapy, there was no evidence of long-term benefit of the former compared with the latter. In this respect, it is interesting to note that,

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despite recent admonitions from several experts (Taylor, 2000; Schmidt et al., 2001; Foa et al., 2002), the combination therapy was found to have no disadvantage in the long term. 264. STRENGTHS AND LIMITATIONS This systematic review has several major strengths. First, we performed systematic and comprehensive searches for relevant trials. We identified 23 randomised comparisons from 21 studies, whereas previous reviews included a maximum of 13 studies. Second, we applied the intention-to-treat principle when performing metaanalysis of dichotomous outcomes by counting all of the drop-outs as nonresponders. This policy is especially pertinent in the context of the relative merits of the combination therapy over monotherapy in the long term, because we are interested in the number of patients doing well as a proportion of all those who started the acute-phase therapy, not just those who successfully completed it. Finally, the a priori planned heterogeneity and sensitivity analyses indicated that the results of the analyses were quite robust. 265. However, several potential limitations of this study must be acknowledged. First, the comparability of the treatment arms after termination of acute-phase and continuation treatments may be compromised by the naturalistic nature of the follow-up. Participants were usually free to seek further treatment between the termination of treatment and the follow-up assessments, and 3077% of them received additional therapies. Unfortunately, inadequate reporting of additional therapies precluded further examination of this issue across studies. If the published studies had reported the number of patients who did well without further treatment, the interpretation of the relative merits of the combination therapy v. monotherapies would have been more straightforward. Second, funnel-plot analyses suggested the possibility of publication bias. However, the exclusion of outliers did not affect the pooled estimates. Third, we must point out that until recently there have been no widely accepted and validated rating scales for panic disorder, and that some of the studies that were included used the authors' original scales. One study indicated that rating scales which have not been validated or standardised are more likely to report statistically significant findings (Marshall et al., 2000). Fourth, owing to this lack of accepted assessment methods for panic disorder, the definition of response (our primary outcome) had to be operationalised by a variety of measures. However, these overall results were corroborated by analyses that focused on specific aspects of the symptoms of panic disorder. 266. It must be noted that our review does not address the relative merits of combination therapy compared with sequential treatments. Given the present findings, some might argue for psychotherapy alone as first-line treatment, only considering combination therapy if psychotherapy fails. Although this appears to be a viable option, such a practice cannot be informed by the data available from these trials. 267.

268.

CLINICAL IMPLICATIONS AND FUTURE RESEARCH

270. The current findings from the TOP best available evidence ABSTRACT suggest that either combined METHOD therapy or psychotherapy RESULTS alone may be chosen as firstPSYCHOTHERAPY PLUS... line treatment for panic SUBGROUP AND SENSITIVITY... DISCUSSION disorder with or without CLINICAL IMPLICATIONS AND FUTURE... agoraphobia. Treatment REFERENCES decisions may depend on the patient's preferences and values. Antidepressant pharmacotherapy alone is not to be recommended as first-line treatment where appropriate resources are available. Although none of the studies included in this review examined cost issues, economic consideration of the costs of years of medication compared with one-off psychological treatment would also favour the use of psychotherapy (Otto et al., 2000). 271. Several issues warrant further investigation. First, in the acute-phase treatment, if we adhere to the strict intention-to-treat principle, the response rates are only slightly above 50% for combination therapy and slightly below 50% for psychotherapy alone. Therefore additional strategies may be required to deal with partial and non-responders to these therapies. Second, there are currently only limited data available on the effects of combining antidepressants with noncognitive-behavioural therapies, such as psychodynamic and interpersonal therapies. In this review, the only available trial that involved psychodynamic therapy showed increased benefit when combined with antidepressants. This suggests the potential value of future trials designed to investigate this type of combination in the treatment of panic disorder. 272.

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REFERENCES
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paroxetine in panic disorder patients unsuccessfully treated with cognitive behavioral therapy alone. Journal of Clinical Psychiatry, 63,772777. 292. Loerch, B. Graf-Morgenstern, M. Hautzinger, M. et al ( 1999) Randomised placebo-controlled trial of moclobernide, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia. British Journal of Psychiatry 174,205212.[Abstract/Free Full Text] 293. Marks, I. M. & Mathews, A. M. ( 1979) Brief standard self-rating for phobic patients. Behavior Research and Therapy. 17,263267.[Medline] 294. Marks, I. M. Gray, S. Cohen, D. et al ( 1983) Imipramine and brief therapists-aided exposure in agoraphobics having self-exposure homework. Archives of General Psychiatry, 40,153162.[Abstract/Free Full Text] 295. Marshall, M. Lockwood, A. Bradley, C. et al ( 2000) Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. British Journal of Psychiatry, 176,249252.[Abstract/Free Full Text] 296. Mattick, R. P. Andrews, G. Hadzl-Pavlovlc, D. et al ( 1990) Treatment of panic and agoraphobia. An integrative review. Journal of Nervous and Mental Disease. 178,567576.[Medline] 297. Mavissakalian, M. & Michelson, L. ( 1986) Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. Journal of Clinical Psychiatry, 47,117122. 298. Mavissakalian, M. R. & Perel, J. M. ( 2002) Duration of imipramine therapy and relapse in panic disorder with agoraphobia. Journal of Clinical Psychopharmacology, 22,294299.[Medline] 299. Mavissakalian, M. Michelson, L. & Dealy, R. S. ( 1983) Pharmacological treatment of agoraphobia: imipramine versus imipramine with programmed practice. British Journal of Psychiatry. 143,348355.[Abstract/Free Full Text] 300. Nathan, P. E. & Gorman, J. M. ( 2002) A Guide to Treatments That Work (2nd edn). New York: Oxford University Press. 301. Oehrberg, S. Christlansen, P. E. Behnke, K. et al ( 1995) Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study. British Journal of Psychiatry, 167,374379.[Abstract/Free Full Text] 302. Otto, M. W. Pollack, M. H. & Makl, K. M. ( 2000) Empirically supported treatments for panic disorder: costs, benefits and stepped care. Journal of Consulting and Clinical Psychology, 68,556563.[Medline] 303. Schmidt, N. B. Koselka, M. & Woolaway-Bickel, K. ( 2001) Combined treatments for phobic anxiety disorders. In Combined Treatments for Mental Disorders (eds M. T. Sammons & N. B. Schmidt). pp.81110. Washington, DC: American Psychological Association. 304. Sharp, D. M. Power, K. G. Simpson, R. J. et al ( 1996) Fluvoxamine, placebo, and cognitivebehaviour therapy used alone and in combination in the treatment of panic disorder and agoraphobia. Journal of Anxiety Disorders, 10,219 242. 305. Shear, M. K. Brown, T. A. Barlow, D. H. et al ( 1997) Multicenter collaborative panic disorder severity scale. American Journal of Psychiatry, 154,15711575.[Abstract/Free Full Text]

306. Sheehan, D. V. Ballenger, J. & Jacobsen, G. ( 1980) Treatment of endogenous anxiety with phobic, hysterical and hypochondriacal symptoms. Archives of General Psychiatry, 37,5159.[Abstract/Free Full Text] 307. Simon, N. M. Safren, S. A. Otto, M. W. et al ( 2002) Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder. Journal of Affective Disorders, 69,201208.[Medline] 308. Song, F. Altman, D. G. Glenny, A. M. et al ( 2003) Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ, 326,472476.[Abstract/Free Full Text] 309. Spinhoven, P. Onstein, E. J. Klinkhamer, R. A. et al ( 1996) Panic management, trazodone and a combination of both in the treatment of panic disorder: Clinical Psychology and Psychotherapy, 3,8692. 310. Stein, M. B. Ron Norton, G. Walker, J. R. et al ( 2000) Do selective serotonin re-uptake inhibitors enhance the efficacy of very brief cognitivebehavioral therapy for panic disorder? A pilot study. Psychiatry Research, 94,191 200.[Medline] 311. Taylor, S. ( 2000) Understanding and Treating Panic Disorder. Chichester: John Wiley & Sons. 312. Telch, M. J. Agras, W. S. Taylor, C. B. et al ( 1985) Combined pharmacological and behavioral treatment for agoraphobia. Behavior Research and Therapy, 23,325335.[Medline] 313. Thompson, S. G. & Sharp, S. J. ( 1999) Explaining heterogeneity in metaanalysis: a comparison of methods. Statistics in Medicine, 18,26932708.[Medline] 314. van Balkom, A. J. Bakker, A. Spinhoven, P. et al ( 1997) A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitivebehavioral and combination treatments. Journal of Nervous and Mental Disease, 185,510516.[Medline] 315. Wiberg, I. M. & Dahl A. A. ( 1996) Does brief dynamic psychotherapy reduce the relapse rate of panic disorder? Archives of General Psychiatry, 53,689 694.[Abstract/Free Full Text] 316. Zitrin, C. M. Klein, D. F. & Woerner, M. G. ( 1980) Treatment of agoraphobia with group exposure in vivo and imipramine. Archives of General Psychiatry, 37,6372.[Abstract/Free Full Text] 317. Zitrin, C. M. Klein, D. F. Woerner, M. G. et al ( 1983) Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Archives of General Psychiatry, 40,125138.[Abstract/Free Full Text]

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Influence of Psychiatric Comorbidity on Recovery and Recurrence in Generalized Anxiety Disorder, Social Phobia, and Panic Disorder: A 12-Year Prospective Study
Steven E. Bruce, Ph.D., Kimberly A. Yonkers, M.D., Michael W. Otto, Ph.D., Jane L. Eisen, M.D., Risa B. Weisberg, Ph.D., Maria Pagano, Ph.D., M. Tracie Shea, Ph.D., and Martin B. Keller, M.D.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

ABSTRACT
Objective: The authors sought to observe the long-term clinical course of anxiety disorders over 12 years and to examine the influence of comorbid psychiatric disorders on recovery from or recurrence of panic disorder, generalized anxiety disorder, and social phobia. Method: Data were drawn from the Harvard/Brown Anxiety Disorders Research Program, a prospective, naturalistic, longitudinal, multicenter study of adults with a current or past history of anxiety disorders. Probabilities of recovery and recurrence were calculated by using standard survival analysis methods. Proportional hazards regression analyses with timevarying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence. Results: Survival analyses revealed an overall chronic course for the majority of the anxiety disorders. Social phobia had the smallest probability of recovery after 12 years of follow-up. Moreover, patients who had prospectively observed recovery from their intake anxiety disorder had a high probability of recurrence over the follow-up period. The overall clinical course was worsened by several comorbid psychiatric conditions, including major depression and alcohol and other substance use disorders, and by comorbidity of generalized anxiety disorder and panic disorder with agoraphobia. Conclusions: These data depict the anxiety disorders as

insidious, with a chronic clinical course, low rates of recovery, and relatively high probabilities of recurrence. The presence of particular comorbid psychiatric disorders significantly lowered the likelihood of recovery from anxiety disorders and increased the likelihood of their recurrence. The findings add to the understanding of the nosology and treatment of these disorders. (Reprinted with permission from American Journal of Psychiatry 2005; 162:1179 1187)

Anxiety disorders are more common than any other major group of diagnoses, with the exception of substance use disorders. According to the National Comorbidity Survey, the overall lifetime prevalence of anxiety disorders is 24.9%, including rates of 3.5%, 13.3%, 5.1%, for panic disorder with or without agoraphobia, social phobia, and generalized anxiety disorder, respectively (1). The effects of these disorders on both physical health and occupational functioning have been well documented (26). In the WHO Collaborative Study on Psychological Problems in General Health Care, more than one-half of the patients with panic disorder without or with agoraphobia reported moderate to severe occupational dysfunction and physical disability (3). The severity of disability reported was similar to that reported for depressive episodes and higher than that for alcohol dependence. Despite the high prevalence of anxiety disorders and the morbidity associated with these disorders, much is yet to be learned about their clinical course. Information regarding the course of panic disorder is available from retrospective studies, but the results are inconsistent (79). Studies from the 1950s and 1960s found that 40%60% of patients with panic disorder were either unchanged or slightly improved (10). The findings of retrospective studies conducted since the availability of approved treatments for anxiety disorders are also variable, although some of these reports also found a lack of substantial improvement in subjects after a variable number of years (1113). Only a few prospective studies of panic disorder are available (1417). Most of these studies (1416) were limited by short follow-up periods, small sample sizes, and a lack of systematic remission definitions. Short-interval prospective data regarding the course of social phobia or generalized anxiety disorder are limited to the Harvard/ Brown Anxiety Disorders Research Program, a longitudinal, observational study of multiple anxiety disorders. The study reported here, from the Harvard/Brown Anxiety Disorders Research Program, had two objectives: 1) to examine the 12-year clinical course of anxiety disorders by determining rates of recovery and recurrence and 2) to explore the effect of psychiatric comorbidity on the clinical course of panic disorder without agoraphobia, panic disorder with agoraphobia, social phobia, and generalized anxiety disorder.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

METHOD
The Harvard/Brown Anxiety Disorders Research Program is a longitudinal, prospective, short-interval follow-up study of adults with a current or past history of anxiety disorders. In 1989-1991, 711 participants entered this study from more than 30 clinicians' practices at 11 clinical treatment facilities in the New England area. These methods are described in detail elsewhere (17). The primary inclusion criterion was a past or current diagnosis of any of the following disorders at intake: panic disorder without agoraphobia, panic disorder with agoraphobia, social phobia, and generalized anxiety disorder. Insufficient for inclusion, but frequently seen as comorbid conditions, were diagnoses of simple phobia, posttraumatic stress disorder, obsessive-compulsive disorder, and anxiety disorder not otherwise specified. Participants were required to be at least age 18 years at intake, willing to voluntarily participate in the study, and willing to sign a written consent form. Exclusion criteria consisted of the presence of an organic brain syndrome, a history of schizophrenia, and current psychosis at intake; otherwise, any comorbidity was allowed.

PROCEDURES
The data for the study reported here were derived from the structured diagnostic interview administered at intake and from subsequent follow-up interviews over 12 years. In the initial comprehensive evaluation, lifetime history was assessed with the Structured Clinical Interview for DSM-III-R Non-Affective Disorders, Patient Version, and the Research Diagnostic Criteria (RDC) Schedule for Affective Disorders and SchizophreniaLifetime Version (SADS-L) (18). Items on the Structured Clinical Interview for DSM-III-R NonAffective Disorders, Patient Version, and SADS-L were combined to create the SCALUP, a structured interview used to assess diagnoses at intake (available on request from Dr. Keller, Department of Psychiatry and Human Behavior, Brown University). The instrument yielded both present and past RDC diagnoses for affective disorders and DSM-III-R diagnoses for nonaffective (including anxiety) disorders. Interviews were conducted by trained, experienced bachelor's- and master's-level clinical interviewers and usually took place in single sessions lasting 24 hours. Follow-up interviews were conducted at 6-month intervals for the first 2 years, annually for years 36, and every 6 months in years 712. These interviews utilized the Longitudinal Interval Follow-Up Evaluation (19), which is used to assess the weekly course of disorders with psychiatric status ratings (Table 1). For a rating of the greatest severity of illness

(psychiatric status rating of 6), the respondent was required to meet the full DSM-III-R criteria for the disorder in addition to having severely disrupted functioning. A psychiatric status rating of 1 indicates an absence of symptoms. In addition, the Longitudinal Interval Follow-Up Evaluation was used to collect information on pharmacological treatment for each week during the interval, including information on the type of medication and average daily dose.

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Table 1. Psychiatric Status Ratings in the Harvard/Brown Anxiety Disorders Research Program's Longitudinal, Prospective Follow-Up Study of Adults With a Current or Past History of Anxiety Disordersa

Reliability and validity studies of the Longitudinal Interval Follow-Up Evaluation found good to excellent agreement on psychiatric status rating scores. Interrater reliability was measured with intraclass correlation coefficients (ICCs); ICCs for each of the disorders were as follows: 0.670.88 for panic disorder, 0.780.86 for generalized anxiety disorder, 0.750.86 for social phobia, and 0.730.74 for major depressive disorder (20). Long-term test-retest reliability over 1 year was also found to be very good to excellent for the anxiety disorders and for major depressive disorder. A separate external validity assessment comparing psychiatric status ratings with other psychosocial measures found good concurrent and discriminant validity (20).

DEFINITIONS

OF

RECOVERY

AND

RECURRENCE

Recovery and recurrence in this study were defined prospectively. A participant was considered to have recovered from anxiety disorder if he/she experienced 8 consecutive weeks at psychiatric status ratings of 2 or less (Table 1). Subjects who met this condition were virtually asymptomatic for 2 consecutive months. This definition of recovery has been widely used in studies of affective disorders and other disorders. For each disorder besides generalized anxiety disorder, recurrence was defined as the onset of symptoms at a psychiatric status rating level of 5 or greater for 2 consecutive weeks following a recovery (Table 1). For generalized anxiety disorder, recurrence was defined as the onset of symptoms at a psychiatric status rating of 5 or greater for 6 months following a recovery.

STATISTICAL

ANALYSES

Statistical analyses were conducted with SAS Version 6.07 (SAS Institute, Cary, N.C.).

Probabilities of recovery and recurrence were calculated by using standard survival analysis methods. Kaplan-Meier life tables were constructed for time to recovery and time to recurrence. Data for patients who were lost to follow-up were censored at the time of dropping out of the study. Proportional hazards regression analyses with time-varying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

RESULTS
The demographic and clinical characteristics of the patients assessed at intake between 1989 and 1991 (N=711) and of those who remained in the study at the 12-year follow-up (June 2003) (N=473) are summarized in Table 2. At intake, the subjects ranged in age from 18 to 86 years (mean=40.5 years). The ratio of female subjects to male subjects was 2:1. Minority group members represented only 3% of the study subjects, reflecting the patient populations of the recruiting sites. The majority (52%) were married, 39% had completed college or graduate school, and 42% were working full time. At intake, 357 subjects (50%) were experiencing an episode of panic disorder with agoraphobia, 82 (12%) panic disorder without agoraphobia, 179 (25%) generalized anxiety disorder, and 176 (24%) social phobia. Some subjects had more than one disorder. A total of 473 subjects remained enrolled in the study at the 12-year follow-up in June 2003. The distribution of anxiety disorder diagnoses, illness severity scores, demographic characteristics including gender, age of episode onset, and clinical correlates among the subjects who remained in the study were nearly identical to the distribution among the subjects at intake (Table 2). No significant demographic or diagnostic differences were found between the subjects included in the 12-year follow-up and those who dropped out of the study, nor were there significant differences in treatment received between those two groups.

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table: [in this window] [in a new window]

Table 2. Demographic and Clinical Characteristics of Patients at Intake and 12-Year Follow-Up in a Longitudinal, Prospective Follow-Up Study of Adults With a Current or Past History of Anxiety Disordersa

12-YEAR

LONGITUDINAL

COURSE

Recovery. With the exception of patients with panic disorder without agoraphobia, a majority of subjects were still in their intake episodes 12 years after study entry (Figure 1).KaplanMeier survival estimates showed that subjects with panic disorder without agoraphobia were more likely to have a recovery at all time points and had a 0.82 probability of achieving recovery of their intake episode of panic disorder without agoraphobia by year 12. In comparison, patients with generalized anxiety disorder, panic disorder with agoraphobia, and social phobia had much lower probabilities of achieving recovery over 12 years of follow-up (probabilities of 0.58, 0.48, and 0.37, respectively). Survival estimates were also calculated for patients with comorbid major depressive disorder (Figure 1). Examination of the survival curves showed a higher probability of recovery from the major depressive disorder than from the anxiety disorders, with the exception of panic disorder without agoraphobia. By year 12, the probability of recovering from major depressive disorder was 0.73.

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Figure 1. 12-Year Cumulative Probability of Recovery in Patients With Anxiety Disorders and Patients With Comorbid Major Depressive Disorder at Intake

Recurrence. Subjects who had a prospectively observed recovery from their intake anxiety disorder had a high probability of subsequently having a recurrence over the follow-up period (Figure 2).Although subjects with panic disorder without agoraphobia were found to have a higher likelihood of recovery, compared to those with panic disorder with agoraphobia, the probability of recurrence of the two disorders was quite similar (0.56 and 0.58, respectively). Individuals with generalized anxiety disorder or social phobia who recovered were somewhat less likely to have a recurrence over the 12-year follow-up period. The probability of having a recurrence of social phobia was 0.39 over 12 years, and the probability of recurrence in patients who had recovered from generalized anxiety disorder was 0.45 at the end of the 12 years. For comorbid major depressive disorder, there was a high likelihood of subsequent recurrence at some point during follow-up (probability of 0.75).

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Figure 2. 12-Year Cumulative Probability of Recurrence in Anxiety Disorder Patients and Patients With Comorbid Major Depressive Disorder Who Recovered From Their Intake Episode

In addition to examining overall clinical course, we also looked at the average amount of time patients with each disorder remained ill during the follow-up period. The average time spent in an illness episode during the study period was 80% for social phobia, 78% for panic disorder with agoraphobia, and 74% for generalized anxiety disorder. Patients with panic disorder without agoraphobia spent the least time in episode on average during the study period (41%).

PSYCHIATRIC

PREDICTORS

OF

ANXIETY

COURSE

When baseline diagnoses were used as predictors, we found no association of time to recovery with any of the index anxiety disorders or with the total number of comorbid baseline diagnoses. We examined co-occurring disorders as time-varying covariates (to explore whether changes in the course of one disorder over time influenced the subsequent course of other anxiety disorders) and found that several comorbid psychiatric disorders had a significant effect on course of the index anxiety disorders. We used Cox's proportional

hazards regression analyses with the comorbid disorders as time-varying covariates to estimate the effect that being in an episode of the "predicting" disorder had on the probability of recovery or recurrence in the subsequent week for each of the index anxiety disorders (expressed in risk ratios). Several significant relationships were found when we examined whether the presence of major depressive disorder influenced the subsequent clinical course of panic disorder without or with agoraphobia, generalized anxiety disorder, or social phobia (Table 3). For example, patients with comorbid major depressive disorder were one-half as likely to subsequently recover from panic disorder with agoraphobia or generalized anxiety disorder (risk ratio= 0.54, p 0.01; risk ratio=0.57, p 0.01, respectively), compared with patients without comorbid major depressive disorder. Likewise, relative to the absence of comorbid major depressive disorder, the presence of comorbid major depressive disorder increased by nearly twofold the likelihood that patients would have a recurrence of panic disorder with agoraphobia (risk ratio=1.85, p 0.05).

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Table 3. Risk of Recovery or Recurrence of Anxiety Disorders in Anxiety Disorder Patients With Comorbid Psychiatric Disorders

The presence of additional comorbid anxiety disorders was also found to be predictive of anxiety course. For instance, comorbid generalized anxiety disorder was found to decrease the probability of recovering from social phobia and increase the likelihood of its recurrence, relative to the absence of comorbid generalized anxiety disorder (risk ratio=0.56, p<0.05; risk ratio=4.15, p<0.01, respectively) (Table 3). Among patients with generalized anxiety disorder, those with comorbid panic disorder with agoraphobia had a significantly lower likelihood of recovering from generalized anxiety disorder, compared to those without comorbid panic disorder with agoraphobia (risk ratio=0.67, p<0.05). In contrast, none of the comorbid disorders significantly predicted recurrence of generalized anxiety disorder. The absence of associations of recurrence may be related to the smaller number of recurrences of generalized anxiety disorder (i.e., 31 recurrences, compared to 119 recoveries, for generalized anxiety disorder).

Analyses were also conducted to examine the relationship between alcohol and other substance use disorders and the clinical course of the anxiety disorders. The results indicated that the presence of a comorbid alcohol or other substance use disorder, compared to the absence of a disorder in this category, significantly decreased the likelihood of generalized anxiety disorder recovery by nearly fivefold (risk ratio=0.20, p<0.01) and significantly increased the likelihood of generalized anxiety disorder recurrence by more than threefold (risk ratio=3.09, p<0.05) (Table 3). Finally, proportional hazards regression analyses were conducted to determine if types of psychotropic treatment increased the likelihood of recovery. Overall, patients who recovered from panic disorder without agoraphobia, panic disorder with agoraphobia, generalized anxiety disorder, or social phobia were no more likely to be taking a selective serotonin reuptake inhibitor (SSRI) or a benzodiazepine the week before recovery than were those who did not recover. Further analyses of data for patients who recovered indicated that they were no more likely to be receiving a combined treatment approach of SSRIs and benzodiazepines the week prior to recovery than were those who did not recover. No other class of medication (e.g., tricyclics) was found to significantly increase the likelihood of recovery.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

DISCUSSION
To our knowledge, this study is the first to present data from more than a decade of prospective follow-up of the clinical course of anxiety disorders. The data suggest that, with the exception of panic disorder without agoraphobia, the anxiety disorders examined in this study are insidious and are characterized by a chronic clinical course with low rates of recovery and relatively high probabilities of recurrence. Clinical course data on panic disorder without agoraphobia and panic disorder with agoraphobia indicated that although panic disorder without agoraphobia remits at a much faster rate than panic disorder with agoraphobia, the rates of recurrence for the two disorders over 12 years are nearly identical (0.56 and 0.58, respectively). Patients with panic disorder with agoraphobia had, on average, an earlier age at onset and a longer duration of their intake episode, compared with patients who had panic disorder without agoraphobia. This difference in recovery rates is consistent with findings of prior studies examining clinical course (2124) and supports the hypothesis that the presence of agoraphobic avoidance unfavorably affects long-term

outcome. Differences in clinical course also lend support to the premise that the presence of agoraphobia may be a severity factor for panic disorder. For example, Starcevic and colleagues (25) found that patients with panic disorder with agoraphobia reported a greater number of panic symptoms and a more frequent occurrence of panic attacks than did patients with panic disorder without agoraphobia. They suggested that the severity of panic attacks, along with a variety of anticipatory fears about the consequences of the attacks, may contribute to the development of agoraphobia. In other studies, subjects with panic disorder with agoraphobia scored significantly higher on measures of perfectionism and anxious thoughts, compared with subjects with panic disorder without agoraphobia (26, 27). In our study, the patients with panic disorder without agoraphobia had higher recovery rates, spent considerably less time in illness episodes, and were less affected by comorbid conditions, compared with patients with any of the other anxiety disorders we considered. These findings lend support to the view that panic disorder without agoraphobia may be a distinct disorder that deserves more careful research scrutiny apart from panic disorder with agoraphobia. Social phobia, the most common of the anxiety disorders, was found to be the most chronic; patients with social phobia had a 0.63 probability of remaining in the original intake episode even after 12 years of follow-up. However, patients who did recover from social phobia had a lower rate of recurrence (probability=0.39) over 12 years, compared with patients with panic disorder (with or without agoraphobia), generalized anxiety disorder, or major depressive disorder. These findings suggest that although social phobia is typically a chronic, unremitting disorder, patients with social phobia whose symptoms improve to the point of recovery tend to stay well, relative to patients with other anxiety disorders. Other than the Harvard/Brown Anxiety Disorders Research Program, there exist very few studies examining the long-term clinical course of generalized anxiety disorder (2830). A dozen years of follow-up in the project indicate that generalized anxiety disorder is a chronic anxiety disorder, with 42% of patients remaining in their intake episode after 12 years. Of those who did recover, nearly one-half subsequently had a recurrence. These results are clearly inconsistent with earlier assumptions, reflected in the DSM-III criteria, that generalized anxiety disorder is a residual and innocuous condition that usually does not lead to significant impairment. Rather, the long-term course appears to be chronic in nature, with more recent studies showing significant impairment across multiple domains (3135). Examination of the clinical course of comorbid depression in Harvard/Brown Anxiety Disorders Research Program patients indicates a relatively high recovery rate and substantial likelihood of recurrence. The recovery rate over 12 years was found to be substantially higher for major depressive disorder than for the anxiety disorders, except for panic disorder without agoraphobia. However, compared with the 0.93 rate of recovery from major depressive disorder for patients in the Collaborative Depression Study, a similar prospective study examining the course of mood disorders (36), the 0.73 rate of recovery over 12 years in the Harvard/Brown Anxiety Disorders Research Program was much lower, suggesting that the presence of comorbid anxiety disorders reduces the overall likelihood of recovering from depression. Compared with survival estimates of recurrence of major depressive disorder from the Collaborative Depression Study (estimate of recurrence=0.80),

the pattern of recurrence over 12 years for major depressive disorder patients in the Harvard/Brown Anxiety Disorders Research Program (who had major depressive disorder comorbid with anxiety disorders) appears to be very similar (rate of recurrence=0.75) (Figure 2). One of the strengths of this study is its examination of the differential effects of the various comorbid conditions on anxiety disorder course. Although previous studies indicated that comorbid axis I and II diagnoses complicate the course of generalized anxiety disorder, only a few have identified specific predictors of recovery and recurrence (11, 37). Consistent with an earlier study in the Harvard/ Brown Anxiety Disorders Research Program (38), the current study found a lower likelihood of recovery from generalized anxiety disorder in patients with comorbid major depressive disorder and in patients with comorbid panic disorder with agoraphobia. In addition, the presence of a comorbid alcohol or other substance use disorder significantly decreased the likelihood of recovery from generalized anxiety disorder and significantly increased the risk of recurrence of this disorder. These findings, combined with the findings of Compton and colleagues (39), who reported that generalized anxiety disorder predicted the presence of additional substance dependence diagnoses, highlight the insidious reinforcing influence that generalized anxiety disorder and the alcohol and other substance use disorders have on each other. One noteworthy predictor of clinical course was the influence of comorbid generalized anxiety disorder, which was associated with a significantly lower likelihood of recovery from social phobia and a higher likelihood of its subsequent recurrence. This finding is consistent with the finding of Mennin and colleagues (40) that patients with social anxiety with comorbid generalized anxiety disorder demonstrated greater severity on measures of social anxiety, avoidance, functional impairment, and overall psychopathology, compared with patients without comorbid generalized anxiety disorder. Taken together, these previous findings and our current findings suggest that comorbid generalized anxiety disorder exacerbates the chronic course of social phobia, further impairing individuals with this disorder. Patients with panic disorder with agoraphobia and comorbid depression were less likely to recover from their panic disorder and more likely to have a subsequent recurrence. This finding is consistent with findings of prior studies in which comorbid major depressive disorder negatively affected the outcome of panic disorder with agoraphobia (22, 41, 42). Although comorbid major depressive disorder was not found to significantly affect the recurrence rates of generalized anxiety disorder, social phobia, and panic disorder without agoraphobia, the risk ratios indicated that the presence of comorbid depression increased by 62%90% the odds of the recurrence of generalized anxiety disorder, social phobia, and panic disorder without agoraphobia. Thus, our lack of significant findings could have been due to the low number of recoveries observed for many of the anxiety disorders, thus reducing power to detect additional relationships. The naturalistic design of this study can be viewed as both a strength and a limitation. Although it did not allow us to manipulate variables that might affect the course of anxiety disorders, it did provide a view of what is occurring in the real world in terms of the course of illness in clinical populations. This study is limited in its inclusion of clinical subjects

only. Thus, results may not be generalizable to nonclinical populations. The subjects in our study may have been more severely impaired by their disorders than persons with disorders who do not seek treatment. In addition, because the subjects were recruited in the late 1980s and early 1990s, the results may not be indicative of patients who received a diagnosis more recently. Although the treatment received by patients in the study was not found to be predictive of anxiety disorder course, the lack of a relationship was not unexpected and should be interpreted with caution. The Harvard/Brown Anxiety Disorders Research Program is an observational study of anxiety disorders, and, by design, the project observes but does not manipulate the treatment received by subjects. In naturalistic studies, adjustment for treatment effects is complex because of the well-known bias for patients with the most severe problems to receive the most treatment. Future studies in this project will employ newer statistical techniques (treatment propensity score analyses) that will help to minimize biases by matching treated and untreated subjects with regard to their estimated need for treatment. A final limitation may exist in our definitions of recovery and recurrence. One of the major difficulties in comparing the course of anxiety disorders across studies is the lack of consensus definitions of recovery and recurrence. For example, recurrence of panic disorder is defined differently in almost all of the small number of studies of panic disorder course, which makes comparison of findings difficult. Shear and others (43) noted that the characteristics of the clinical course of panic disorder are the primary reason for the difficulty of defining recurrence and stated that the mere presence or absence of panic attacks should not be the only factor in determining whether an individual has had a recurrence of panic disorder. Other factors such as level of phobic avoidance and persistence of the fear of future panic attacks should be carefully considered. During the consensus development conference on the treatment of panic disorder, a committee also noted the lack of consistency across researchers in defining how "responders" are characterized, as well as how recovery and recurrence are defined (44). They recommended the establishment of procedures to ensure comparability of studies, stating that because the frequency of panic attacks is so variable, longer time frames for observation are preferable, with 1 month the optimal time to assess whether a patient with panic disorder is recovering or having a recurrence. Our findings highlight the importance and need for longitudinal research to map the longterm clinical course of anxiety disorders. Moreover, examination of the potential negative influences of comorbid psychiatric diagnoses on overall clinical course can add a wealth of information to our understanding of the diagnosis and treatment of these disorders. These comorbid conditions should not be considered exclusion criteria for potential participants in future anxiety disorders research. On the contrary, inclusion of patients with comorbid conditions can provide clinicians and public policy makers with rich and much needed information about the effects of psychiatric comorbidity on the long-term outcome of anxiety disorders. Delineating the role that psychiatric comorbidity has on the course of anxiety disorders will help to facilitate the refinement of existing treatments, which should improve outcomes.

TOP ABSTRACT METHOD RESULTS DISCUSSION REFERENCES

REFERENCES
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21. Katschnig H, Amering M: The long-term course of panic disorder and its predictors. J Clin Psychopharmacol 1998; 18(6,suppl 2):6S11S[Medline] 22. Cowley DS, Flick SN, Roy Byrne PP: Long-term course and outcome in panic disorder: a naturalistic follow-up study. Anxiety 1996; 2:1321[Medline] 23. Carpiniello B, Baita A, Carta MG, Sitzia R, Macciardi AM, Murgia S, Altamura AC: Clinical and psychosocial outcome of patients affected by panic disorder with or without agoraphobia: results from a naturalistic follow-up study. Eur Psychiatry 2002; 17:394398[Medline] 24. Katschnig H, Amering M, Stolk JM, Klerman GL, Ballenger JC, Briggs A, Buller R, Cassano G, Garvey M, Roth M, Solyom C: Long-term follow-up after a drug trial for panic disorder. Br J Psychiatry 1995; 167:487494[Abstract/Free Full Text] 25. Starcevic V, Kellner R, Uhlenhuth EH, Pathak D: The phenomenology of panic attacks in panic disorder with and without agoraphobia. Compr Psychiatry 1993; 34:3641[Medline] 26. Uhlenhuth EH, Starcevic V, Warner TD, Matuzas W, McCarty T, Roberts B, Jenkusky S: A general anxiety-prone cognitive style in anxiety disorders. J Affect Disorders 2002; 70:241249[Medline] 27. Iketani T, Kiriike N, Stein MB, Nagao K, Nagata T, Minamikawa N, Shidao A, Fukuhara H: Relationship between perfectionism and agoraphobia in patients with panic disorder. Cogn Behav Ther 2002; 31:119128 28. Woodman CL, Noyes R Jr, Black DW, Schlosser S, Yagla SI: A 5-year follow-up study of generalized anxiety disorder and panic disorder. J Nerv Ment Dis 1999; 187:39[Medline] 29. Barbee JG, Billings CK, Bologna NB, Townsend MH: A follow-up study of DSMIII-R generalized anxiety disorder with syndromal and subsyndromal major depression. J Affect Disord 2003; 73:229236[Medline] 30. Durham RC, Chambers JA, MacDonald RR, Power KG, Major K: Does cognitivebehavioural therapy influence the long-term outcome of generalized anxiety disorder? an 814 year follow-up of two clinical trials. Psychol Med 2003; 33:499 509[Medline] 31. Wittchen HU: Generalized anxiety disorder: prevalence, burden, and cost to society. Depress Anxiety 2002; 16:162171[Medline] 32. Kessler RC, Wittchen HU: Patterns and correlates of generalized anxiety disorder in community samples. J Clin Psychiatry 2002; 63:(suppl 8)410

33. Brawman Mintzer O, Lydiard RB: Generalized anxiety disorder: issues in epidemiology. J Clin Psychiatry 1996; 57:(suppl 7)38 34. Kessler RC, DuPont RL, Berglund P, Wittchen H-U: Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. Am J Psychiatry 1999; 156:19151923[Abstract/Free Full Text] 35. Schweizer E, Rickels K: The long-term management of generalized anxiety disorder: issues and dilemmas. J Clin Psychiatry 1996; 57:(suppl 7)912 36. Mueller TI. Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, Warshaw M, Maser JD: Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry 1999; 156:1000 1006[Abstract/Free Full Text] 37. Angst J, Vollrath M: The natural history of anxiety disorders. Acta Psychiatr Scand 1991; 84:446452[Medline] 38. Bruce SE, Machan JT, Dyck I, Keller MB: Infrequency of "pure" GAD: impact of psychiatric comorbidity on clinical course. De press Anxiety 2001; 14:219225 39. Compton WM III, Cottler LB, Jacobs JL, Ben-Abdallah A, Spitznagel EL: The role of psychiatric disorders in predicting drug dependence treatment outcomes. Am J Psychiatry 2003; 160:890895[Abstract/Free Full Text] 40. Mennin DS, Heimberg RG, Jack MS: Comorbid generalized anxiety disorder in primary social phobia: symptom severity, functional impairment, and treatment response. J Anxiety Disord 2000; 14:325343[Medline] 41. Martinsen EW, Olsen T, Tonset E, Nyland KE, Aarre TF: Cognitive-behavioral group therapy for panic disorder in the general clinical setting: a naturalistic study with 1-year follow-up J Clin Psychiatry 1998; 59:437442[Medline] 42. Johnson MR, Lydiard RB: Comorbidity of major depression and panic disorder. J Clin Psychol 1998; 54:201210[Medline] 43. Shear MK, Clark D, Feske U: The road to recovery in panic disorder: response, remission, and relapse. J Clin Psychiatry 1998; 59:48 44. Shear MK, Maser JD: Standardized assessment for panic disorder research. Arch Gen Psychiatry 1994; 51:346354[Abstract/Free Full Text]
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INFLUENTIAL PUBLICATIONS

Novel Treatment Approaches for Refractory Anxiety Disorders

Articles by Pollack, M. H. Articles by Gorman, J. M.

Mark H. Pollack, M.D., Michael W. Otto, Ph.D., Peter P. Roy-Byrne, M.D., Jeremy D. Coplan, M.D., Barbara O. Rothbaum, Ph.D., Naomi M. Simon, M.D. M.Sc., and Jack M. Gorman, M.D.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

ABSTRACT
The Anxiety Disorders Association of America convened a conference of experts to address treatment-resistant anxiety disorders and review promising novel approaches to the treatment of refractory anxiety disorders. Workgroup leaders and other participants reviewed the literature and considered the presentations and discussions from the conference. Authors placed the emerging literature on new therapeutic approaches into clinical perspective and identified unmet needs and priority areas for future research. There is a relative paucity of efforts addressing inadequate response to anxiety disorder treatment. Systematic efforts to exhaust all therapeutic options and overcome barriers to effective treatment delivery are needed before patients can be considered treatment refractory. Cognitive behavioral therapy, especially in combination with pharmacotherapy, must be tailored to accommodate the effects of clinical context on treatment response. The literature on pharmacologic treatment of refractory anxiety disorders is small but growing and includes studies of augmentation strategies and non-traditional anxiolytics. Research efforts

to discover new pharmacologic targets are focusing on neuronal systems that mediate responses to stress and fear. A number of clinical and basic science studies were proposed that would advance the research agenda and improve treatment of patients with anxiety disorders. Significant advances have been made in the development of psychotherapeutic and pharmacologic treatments for anxiety disorders. Unfortunately, many patients remain symptomatic and functionally impaired. Progress in the development of new treatments has great promise, but will only succeed through a concerted research effort that systematically evaluates potential areas of importance and properly uses scarce resources. (Reprinted with permission from Depression and Anxiety 2008; 25:467476)

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

INTRODUCTION
Remarkable progress has been made in the development of medication and psychosocial treatment strategies for anxiety disorders (Ballenger, 2001). However, many patients remain symptomatic despite improvements in therapy. Randomized, controlled trials (RCTs) of pharmacotherapy for anxiety disorders report response rates of 4070% and remission rates of 2047% (Ballenger, 1999). In addition, these reported improvement rates may be overestimates because of selection bias, failure to publish negative trials, and exclusion from RCTs of clinically relevant patients with comorbid psychiatric or medical disorders (Roy-Byrne and Cowley, 1998). Anxiety disorders are considered treatment resistant when there are residual symptoms or when symptoms do not improve at all after some form of therapeutic intervention. However, research on treatment-resistant anxiety disorders has lagged behind similar studies of schizophrenia and major depressive disorder (Roy-Byrne and Cowley, 1998). Clearly, much work is needed to advance therapeutic strategies and

improve rates of clinically meaningful benefit for patients with treatment-resistant anxiety disorders. The Anxiety Disorders Association of America convened a 2-day conference in Chantilly, Virginia on June 1617, 2003 to address the issue of treatment-resistant anxiety disorders and review promising, novel therapeutic approaches. The conference consisted of presentations, open discussions, and workgroup sessions by clinicians and researchers in the fields of psychosocial therapies, psychopharmacology, and neurobiology (Appendix). The panel did not consider obsessive-compulsive disorder (OCD) because some believe that it may be better conceptualized as part of the obsessive-compulsive spectrum disorders and may be moved to a separate diagnostic category in the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-V) (Hollander and Zohar, 2004). In this article, we consider issues associated with treatment resistance, cognitive behavioral therapy (CBT), pharmacologic approaches, and new drug discovery. The review of CBT approaches discusses factors associated with poor response to psychotherapy and focuses on extinction-based learning, which is a concept that can be applied to all anxiety disorders. The pharmacotherapy sections review reported novel pharmacological strategies for refractory anxiety and potential new targets for drug development. Finally, we outline research priorities for studies of treatment-resistant anxiety disorders.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

THERAPEUTIC GOALS AND TREATMENT RESISTANCE

Many factors contribute to poor therapeutic response, including treatment-related factors (e.g., incorrect or incomplete diagnosis, inappropriate intervention, inadequate dosing, insufficient treatment duration), patient-related factors (e.g., comorbidity, poor adherence), and logistical factors (e.g., scarcity of trained treatment providers, inadequate insurance coverage). The dissemination of strategies to enhance appropriate diagnosis of anxiety disorders and relevant comorbidities, as well as the optimal use of pharmacologic and psychosocial strategies for their treatment is critical to improve therapeutic outcomes for

affected individuals. Patient engagement, influenced by patients' beliefs about anxiety, treatment preferences, experience of stigma, and readiness to change, is also critical. Systematic efforts at optimizing treatment engagement must be addressed before patients truly can be considered to be treatment refractory. Such efforts include patient education about the natural course of the illness, the benefits of effective treatment, and expected time frame for symptom resolution. Guidance about the importance of exposure to feared situations and the use of effective coping strategies and skills development is needed to achieve maximum clinical gains. Finally, the contribution of life stressors, comorbidity, and other factors should be assessed and addressed with appropriate targeted interventions (e.g., individual, couples, or family psychotherapy for intrapsychic or interpersonal difficulties) in a patient with a suboptimal clinical outcome (Roy-Byrne and Cowley, 1998). There is neither a universally accepted definition of treatment resistance nor consensus on the definitive number and characteristics of interventions needed to constitute an adequate treatment trial for persistently symptomatic anxiety disorders. Nonetheless, it appears intuitive that treatment goals should be to achieve well-defined therapeutic endpoints with sustained resolution of core anxiety symptoms, functional disability, and psychiatric comorbidities. Each anxiety disorder is unique in its natural course, presentation, and associated morbidity, and the metrics of response and remission must consider all affected domains, including vocational and social dysfunction and overall quality of life. Consensus standards have been proposed for response and remission based on improvement in multiple dimensions of individual anxiety disorders (Ballenger, 2001), though there is little empiric validation for these criteria and a lack of universal adoption by leading professional societies. Nonetheless, it is encouraging that these guidelines focus on the resolution or significant improvement in core anxiety symptoms, functional impairment, and comorbid depression. Proposed general endpoints for remission across anxiety disorders include reduction in Hamilton Rating Scale for Anxiety scores to 7, Sheehan Disability Scale scores to 1 (i.e., mildly disabled), and Hamilton Rating Scale for Depression scores to 7. In addition, disorder-specific remission criteria include reduction in the Panic Disorder Severity Scale to <7 for panic disorder, Liebowitz Social Anxiety Scale score to 30 for social anxiety disorder, and the Treatment Outcome for Posttraumatic Stress Disorder (PTSD) Scale score to 5 or 6 for PTSD (Ballenger, 2001).

COGNITIVE-BEHAVIORAL APPROACHES

It is difficult to identify a standard trial of CBT because of the remarkable heterogeneity of interventions for anxiety disorders. For example, exposure interventions may include imaginal, in vivo or interoceptive exposure, or the use of virtual reality technology for hard-toarrange exposures.

Attempts at defining treatment resistance in this context are fraught with difficulty given the wide range of CBT and the diversity of anxiety disorders. Nonetheless, certain key items should be addressed. An adequate course of CBT should include a full protocol of treatment, ideally defined by interventions found to be effective in at least two controlled trials. Treatment protocols often include 1216 sessions of a combination of information, cognitive restructuring, and exposure interventions, with skill rehearsal and exposure in home-practice assignments (Barlow, 2001). The use of protocoldriven CBT for anxiety disorders is well tolerated, cost-effective, and efficacious acutely and in the long term (Foa et al., 2002; McHugh et al., in press; Otto et al., 2004), with evidence for further gains following acute CBT as patients consolidate and extend learningbased approaches (Liebowitz et al., 1999). Supportive interventions, such as brief relaxation treatment or breathing retraining do not constitute an adequate CBT trial as these symptom management procedures alone do not, for example, add to the efficacy of CBT protocols for panic disorder (Schmidt et al., 2002). Failure to respond to an initial CBT protocol suggests the need for alternative interventions (e.g., greater attention to changing cognitions, refinement of the target or intensity of exposure interventions), other empirically supported treatments, or combined treatment modalities. Relevant recent findings on extinction learning and context that can be applied across the anxiety disorders are reviewed, and next-step strategies for non-response are considered.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

EXTINCTION

LEARNING

AND

LIMITING

FACTORS

Anxiety disorders are characterized by exaggerated distress and disability in response to phobic cues. As long as an individual can learn and integrate new experiences with phobic stimuli, exaggerated responses to phobic cues should respond to extinction learning, and anxiety, thus diminish. However, this assumes that the correct fears are being targeted and appropriate learning conditions are identified and established by the therapist. Informational and cognitive interventions often are used to facilitate and enhance initial exposure to fears, which are designed to become increasingly relevant to core fears as therapy progresses. Balance must be maintained between conditions that facilitate exposure to avoided phobic cues and conditions where exposure provides useful learning. Strategies that avert or attenuate anxiety in phobic situations (i.e., "safety behaviors") may temporarily

alleviate anxiety, but reduce long-term efficacy (Powers et al., 2004; Salkovskis et al., 1999). What is learned during extinction in one context (e.g., when safety behaviors or medications are available) may not generalize to a different context (e.g., when no safety behavior or medications are available) (Bouton, 2002). Stronger findings have been reported for shifts in internal context, such as medication effects (Mystkowski et al., 2003). Therapeutic approaches for treatment-resistant anxiety disorders should include strategies that maximize fear extinction during exposure and generalize this learning across contexts, seeking to reverse the effects of distraction, safety cues, and context shifts on the longerterm acquisition of a sense of safety when confronted by phobic cues (Powers et al., 2006). Attention to shifts in context, specifically internal context provided by pharmacotherapy, is relevant to combining medications with CBT. Context effects may explain the loss of efficacy seen in combination treatment trials when medications are later discontinued (e.g., Barlow et al., 2000). However, maintenance and extension of treatment gains are common when CBT is provided during and after medication taper (Otto et al., 2002). Context effects introduce additional complexity into the selection of the next-step strategy following partial response to CBT. Should patients be switched to pharmacotherapy, risking the introduction of context effects that may require additional CBT to prevent relapse in the future? If there was no response to CBT, then there is little reason to be concerned about context effects introduced by medications. However, if patients achieved a partial response to CBT, further honing of the targets of CBT interventions and identification of context effects that may be preventing generalization of exposure-based learning should be considered before addition of pharmacologic alternatives. There is a dearth of evidence addressing whether troubleshooting and persisting with CBT is better than switching treatment modalities (Kampman et al., 2002). In one small randomized trial, continuation of exposure-based treatment alone was at least as effective as its combination with imipramine or cognitive therapy (Fava et al., 1997). Further, dropout data from controlled trials of CBT and pharmacotherapy indicate that CBT tends to be more tolerable and acceptable than medication alternatives (Otto et al., 2005). Nonetheless, nonresponse to initial CBT does provide a call to therapists to re-evaluate whether core fears are being adequately targeted by cognitive and exposure interventions, with consideration of altering the timing, modality, and context (including the presence of safety cues that may undermine the efficacy of exposure treatments), to try to enhance response to additional CBT (e.g., Powers et al., 2004, 2006; Smits et al., 2006). In addition, recent research has introduced a new approach to combined treatment, in which pharmacotherapy is used to enhance therapeutic learning rather than attenuate symptoms (Ressler et al., 2004). The N-methyl-D-aspartate (NMDA) agonist, D-cycloserine (DCS) augments extinction learning in animal models after a single dose administered immediately before extinction trials (Walker et al., 2002). In a proof of concept translational RCT, 28 patients with acrophobia were randomized to virtual-reality exposure (VRE) therapy plus one of two doses of DCS or placebo, administered before each of 2 weekly VRE sessions (Ressler et al., 2004). DCS resulted in significantly less fear of heights compared with

placebo during the trial as well as following treatment. In an independent replication of the DCS enhancement effect, Hofmann et al. (2006) demonstrated better outcome in a sample of 27 outpatients with primarily generalized social anxiety disorder when treated with DCS versus placebo in the context of a five-session CBT protocol combining study pills with the latter four sessions of increasingly challenging public speech exposures. Furthermore, recent evidence also supports the efficacy of combined treatment with DCS for OCD, although there are indications that with ongoing exposure therapy CBT alone can catch up to the boost in efficacy provided by DCS (Kushner et al., in press). If these promising findings are further replicated, this strategy for combined treatment suggests a potentially expeditious way to improve the speed of onset and, perhaps, overall efficacy of CBT for anxiety.

CBT

FOR

PHARMACOTHERAPY

NON-RESPONDERS

CBT has been successfully used to facilitate discontinuation of benzodiazepines and antidepressants (Otto et al., 2002; Schmidt et al., 2002) as well as to boost response in patients who have failed previous medication trials for panic disorder and PTSD (Otto et al., 2003, 1999; Heldt et al., 2006). Accordingly, CBT remains a central strategy for patients who do not respond fully to pharmacotherapy.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

PHARMACOLOGIC APPROACHES
Though not intended as a study of treatment resistance, the results of a study in PTSD have relevance for the management of treatment-resistant anxiety disorders in general. Of 128 patients with PTSD who did not respond to an acute 12-week trial of sertraline, 54% converted to responders during a subsequent 24-week continuation phase (Londborg et al., 2001), suggesting that treatment may need to be continued for months beyond the typical acute 612-week course to consider a patient truly treatment refractory. However, as it is frequently difficult for patients to adhere to treatment for months with an inadequate

response, initiation of alternative or additional treatment strategies is often necessary to maintain a sense of therapeutic optimism. As is true for CBT, there is a relative dearth of data about pharmacotherapy for treatmentresistant anxiety disorders. Most available information comes from small, open-label, or retrospective reports. Nonetheless, the need for more effective and better-tolerated treatments has prompted exploration of pharmacological augmentation, novel uses of nontraditional anxiolytic drugs, and new drug development. No drug has yet received FDA approval for refractory anxiety so, as is typical in the management of refractory states, use of pharmacologic strategies in this context is off-label. In this section, we note evidence from randomized controlled trials (and in their absence, case series or reports) on pharmacotherapy for refractory anxiety disorders and novel uses of non-traditional antianxiety agents.

ATYPICAL

ANTIPSYCHOTICS

Augmentation of existing antianxiety treatments with atypical antipsychotics having mixed effects at dopaminergic and serotonin receptors appears to be an effective strategy for refractory anxiety disorders as evidenced by double-blind randomized controlled trials with risperidone and olanzapine for generalized anxiety disorder (GAD) (Brawman-Mintzer et al., 2005; Pollack et al., 2006) and PTSD (Bartzokis et al., 2005; Hamner et al., 2003; Monnelly et al., 2003; Stein et al., 2002). Further there are case studies reporting the efficacy of olanzapine for refractory panic disorder (Etxebeste et al., 2000; Khaldi et al., 2003) and one small randomized controlled trial with olanzapine monotherapy suggesting its efficacy in social anxiety disorder (though not specifically refractory patients) (Barnett et al., 2002).

ANTICONVULSANTS
Open-label case reports and case series suggest the adjunctive efficacy of anticonvulsants for refractory GAD, including gabapentin, which acts as an 2 delta voltage-gated, calcium ion channel antagonist and may enhance -aminobutyric acid (GABA) synthesis (Pollack et al., 1998), the voltage-gated calcium channel modulator levetiracetam (Pollack, 2002) and the selective GABA reuptake inhibitor tiagabine (Crane, 2003). In addition, reports suggest efficacy for gabapentin (Pollack et al., 1998), tiagabine (Zwanzger et al., 2001), and valproic acid (Ontiveros and Fontaine, 1992) for refractory panic. Further, case and chart reviews describe the potential efficacy of the addition of gabapentin (Brannon et al., 2000), topiramate (Berlant and van Kammen, 2002), tiagabine (Berigan, 2002), phenytoin (Bremner et al., 2004), valproate (Szymanski and Olympia, 1991), and levetiracetam (Kinrys et al., 2006), in individuals with civilian or combat-related PTSD, providing signals for efficacy in the domains of sleep duration, nightmare frequency and severity, and intrusive recollections. Likewise, efficacy was suggested for topiramate, an anticonvulsant that blocks sodium channels, increases GABA levels, and potentiates GABA activity at non-benzodiazepine receptors (Shaywitz and Liebowitz, 2003; Van Ameringen et al., 2004), valproic acid (Kinrys et al., 2003), and levetiracetam (Simon et al., 2004) in openlabel trials in social anxiety disorder.

Though not specifically tested in refractory patients, pregabalin, an 2 delta voltage-gated, calcium ion channel antagonist that has anticonvulsant and analgesic effects has been demonstrated to be effective for GAD and social anxiety disorder in controlled trials (Feltner et al., 2000; Rickels et al., 2005), with suggestions of an onset of anxiolytic response similar to the benzodiazepine comparator. Similarly, lamotrigine, an antagonist at sodium and calcium channels as well as a modulator of GABA and glutamatergic activity, was demonstrated effective in a small, randomized placebo-controlled study of individuals with PTSD (Hertzberg et al., 1999), as was gabapentin in an RCT for social anxiety disorder (Pande et al., 1999a).

NOVEL USES OF NON-TRADITIONAL ANXIOLYTICS AND OTHER PHARMACOLOGIC STRATEGIES

Pindolol, a -blocker with antagonist effects on the 5HT1A autoreceptor (thus potentially facilitating serotonergic activity) was demonstrated effective in a double-blind randomized, placebo-controlled trial of selective serotonin reuptake inhibitor (SSRI)-resistant panic disorder (Hirschmann et al., 2000), though not social anxiety disorder (Stein et al., 2001), with significant improvement observed at 2 weeks. Prazosin, a centrally active 1adrenergic antagonist, showed evidence of efficacy for the treatment of nightmares, sleep disturbance, and overall PTSD symptoms in a 20 week, double-blind, placebo-controlled crossover study of 10 combat veterans with chronic PTSD (Raskind et al., 2003). Similarly small case series suggest the potential efficacy of combined treatment with a tricyclic antidepressant and SSRI for panic disorder refractory to antidepressant monotherapy (Tiffon et al., 1994), buspirone augmentation of SSRI non-responders with social anxiety disorder (Van Ameringen et al., 1996) and the addition of triiodothyronine for PTSD (Agid et al., 2001).

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

NEW TARGETS FOR DRUG DEVELOPMENT

A tremendous research effort is underway to discover drugs that target specific neuronal

systems involved in mediating the stress response. By focusing on discrete neurobiological pathways, it is hoped that anxiolytic drugs will be discovered that normalize pathological activity in brain circuits and produce fewer adverse effects, including tolerance, dependence, and withdrawal effects (Nemeroff, 2003). Identification of multiple serotonin receptors has allowed investigation of compounds that act selectively at individual receptors and may be better tolerated than currently available SSRIs. Drugs with GABA-potentiating properties that are distinct from those of the benzodiazepines also are being studied as anxiolytics, as in the studies of the anticonvulsants described earlier. The GABA-A 2 subtype has been identified as a potential target for anxiolytic effects without sedation or dependence (Mohler et al., 2001). Some of the most promising avenues of new drug development involve non-monoamine, non-GABA neurotransmitters. For example, substance P (tachykinin NK1), corticotropinreleasing factor (CRF), L-glutamate, and other neurotransmitters that are pivotal to the regulation of anxiety and stress responses may be ideal targets for new drug development. Reports from preclinical studies have shown that manipulation of these neuronal systems produces evidence of anxiolytic and antidepressant effects.

NEXT-GENERATION

SSRIS

The SSRIs increase available serotonin in the synapse and lead to indiscriminate activity at multiple different serotonin receptors, some of which are believed to be associated with SSRI-related side effects. The observations that mice lacking 5-HT1A receptors exhibit pronounced anxious and fearful behaviors and do not respond to SSRIs (Gross et al., 2002) has led to studies of specific postsynaptic 5-HT1A receptor agonists as possible treatments for anxiety disorders (Gorman, 2003). A recent neurobiological substrate has been identified for treatment resistance in anxiety disorders to SSRIs. Subjects with generalized social anxiety disorder possessing the "short" arm of the serotonin transporter gene were significantly less likely to respond (40% non-responder rate) to maximally titrated SSRIs in comparison to subjects with the "long" arm of the serotonin transporter gene (Stein et al., 2006). Similar results for SSRI treatment resistance have been noted in panic disorder (Perna et al., 2005). It is not clear what the functional consequences of possession of the short versus long arm of the serotonin transporter imply, but these important observations may provide clues to the pharmacogenomic underpinnings of SSRI treatment resistance.

NEUROPEPTIDES
Neuropeptides are short-chain amino acids that act as neurotransmitters in regions of the brain involved with regulation of mood and stress responses. Recognition of a large number of neuropeptide targets for anxiety disorders has provided the rationale for studies of smallmolecule neuropeptide receptor ligands. Some of the most promising neuropeptide targets for anxiolytic drug discovery are substance P, CRF-1, CRF-2, neuropeptide Y, CCK-2, and galanin (Herranz, 2003; Holmes et al., 2003). A cholecystokinin (CCK) antagonist has been studied in patients with panic disorder (Pande et al., 1999b) and GAD (Adams et al., 1995), but was not more effective than a placebo. A possible explanation for the failure of the CCK antagonist to demonstrate its efficacy may be related to its relatively poor penetration.

The substance P antagonists are being investigated as treatments for depression and anxiety disorders. In late 2003, further development of MK-869, a substance P (NK1) antagonist that was studied through phase III clinical trials of depression (Kramer et al., 1998), was halted because of a failure to demonstrate efficacy. A second NK1 antagonist, L759274, is being studied in depression (Kramer et al., 2004). Efficacy of the CRF-1 receptor antagonist, R121919, was suggested by the findings of a small, open-label study of patients with major depression (Zobel et al., 2000). However, development of R121919 is no longer being pursued because of concerns about hepatotoxicity. Clinical trials of other CRF-1 receptor antagonists are currently underway (Gorman, 2003).

OTHER

MOLECULAR

TARGETS

Other molecular targets are being investigated as avenues toward anxiolytic drug development. The excitatory neurotransmitter, L-glutamate, and its NMDA and metabotropic glutamate (mGlu) receptors are potential drug development targets. The noncompetitive NMDA receptor antagonists (MK-801) and mGlu receptor agonists (LY354740) possess antidepressant and anxiolytic properties preclinically (Papp and Moryl, 1994; Schoepp et al., 2003), and the NMDA receptor antagonist, riluzole (Mathew et al., 2005) has been observed to exert anxiolytic effects in patients with anxiety disorders. In contrast, the NMDA partial agonist, DCS, failed to show efficacy in a small pilot study in patients with PTSD (Heresco-Levy et al., 2002), although, as noted, appeared to enhance the effect of CBT in the treatment of acrophobia and social anxiety disorder (Hofmann et al., 2006; Ressler et al., 2004). Brain-derived neurotrophic factor (BDNF), which is critical to neuronal plasticity, is inhibited by stress and has therefore been recognized as a potential target for drug development in mood and anxiety disorders (Hall et al., 2003; Rasmusson et al., 2002). Neurosteroid modulators of the GABA system, such as allopregnanolone, are being studied for anxiolytic effects (Lydiard, 2003). Other molecular targets of interest are the opioid receptor partial agonists (Dautzenberg et al., 2001) and cytokine modulators (Koh and Lee, 2004).

FUTURE DIRECTIONS

The most pressing research priorities TOP for advancing the treatment of ABSTRACT refractory anxiety disorders were INTRODUCTION identified. There is a remarkable lack THERAPEUTIC GOALS AND TREATMENT... of empirical data in this area. When COGNITIVE-BEHAVIORAL APPROACHES data are available, it is often obtained PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... from small controlled trials, openFUTURE DIRECTIONS label pilot studies, case reports, or CONCLUSIONS chart reviews. Therefore, the APPENDIX following list of research priorities are REFERENCES evidence-based when possible, but also include suggestions that are based on the opinions and clinical experiences of the experts who participated in this conference.

RESEARCH PRIORITIES FOR PHARMACOTHERAPY TRIALS

PSYCHOTHERAPY

AND

Conduct RCTs focused on strategies for achieving remission rather than partial response: aggressive psychotherapy regimens (i.e., intensive treatment, prolonged session times) and/or aggressive pharmacotherapy regimens (i.e., adequate dosing and duration [e.g., 6 months versus 6 weeks]), and outcome assessments that are more sensitive than measures of global improvement. Conduct prospective studies and post hoc analyses of existing psychotherapy and pharmacotherapy databases to define early predictors of response/ non-response that would identify modifiers of outcome and patients who would benefit from additional interventions, more prolonged treatment, or an alternative therapeutic approach. Include functional outcome assessments (e.g., measures of avoidance) in all studies and differentiate these measures from quality of life assessments. Conduct additional studies of the factors (e.g., context effects, safety behaviors, attentional factors) that may diminish the benefits of exposure treatments. Conduct randomized, controlled psychotherapy augmentation trials, particularly the role of memory enhancers, to examine whether pharmacotherapy can have a significant role in improving extinction learning and the salience of adaptive behaviors learned in therapy Conduct RCTs of pharmacologic augmentation therapy to validate the clinical signals suggested by open-label studies and case reports. Conduct effectiveness studies in patients with common comorbidities (e.g., depression, alcohol/substance abuse), women (including issues surrounding pregnancy/postpartum, menstrual cycle, menopause), underserved ethnic minorities, medically ill patients, and the elderly. Examine the impact of treatment on extant symptomatology and course of illness in at-risk and manifestly anxious children and adolescents.

Design and evaluate treatment algorithms for patients failing initial interventions, including testing approaches for combining different treatments (e.g., medication and CBT) with particular attention to context effects. Conduct investigations of strategies to better disseminate efficacious psychosocial and pharmacologic treatments.

RESEARCH PRIORITIES FOR NEW DRUG DEVELOPMENT

Conduct gene expression studies in animal models to identify possible targets for drug development ("bottom-up" approach). Identify neurodevelopment of anxiety-relevant circuits and evaluate the effect of drugs at different stages of development. Combine neuroimaging with other modes of inquiry (e.g., genotyping, neuroendocrinology, psychophysiology, psychotherapy, pharmacotherapy). Conduct neuroimaging studies of treatment response and non-response, including studies of placebo response. Conduct genotyping studies to identify treatment responders and risk factors for adverse effects. Conduct RCTs of new classes of medications to treat anxiety disorders. Conduct translational research to build on promising animal models for the reduction of fear and test these models in humans.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

CONCLUSIONS
Anxiety disorders are common and are associated with significant distress and dysfunction. Currently available interventions have demonstrable efficacy for reducing anxiety-related symptomatology. However, many patients remain symptomatic despite treatment, and a significant proportion remain impaired. Despite this, few controlled studies address inadequate treatment response in anxiety disorders. The need for refined CBT strategies

pales in comparison to the importance of disseminating CBT for anxiety disorders more generally, as these interventions are rarely received by patients in clinical practice (Goisman et al., 1999). These data join a larger literature indicating that in clinical care across the United States, few patients receive an adequate "dose" of psychotherapy (Hansen et al., 2002), a finding that is in concordance with the high rates of inadequate pharmacotherapy observed in primary care and specialty care settings (Roy-Byrne et al., 1999; Wang et al., 2000; Weilburg et al., 2003). Optimal use of available medications and the development of novel pharmacological strategies and agents along with the further application of empirically derived psychosocial therapies offer promise in improving this current situation, but a concerted research effort is warranted to systematically evaluate potential areas of importance and prudently use scarce resources. This article summarizes the current state of knowledge and serves as a call to action to mobilize efforts aimed at improving the lives of the many individuals who are adversely impacted by anxiety disorders.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

APPENDIX
The Anxiety Disorders Association of America Novel Approaches to Treatment of Refractory Anxiety Disorders conference Chair: Mark H. Pollack, MD.

WORKGROUP

1PSYCHOTHERAPY

Michael W. Otto, PhD, Massachusetts General Hospital (currently at Boston University); Barbara O. Rothbaum, PhD, Emory University (Workgroup Leaders); Bruce Cuthbert, PhD, National Institutes of Mental Health; Edna Foa, PhD, University of Pennsylvania; Richard Heimberg, PhD, Temple University; Stefan Hoffman, PhD, Boston University; Terry Keane, PhD, National Center for PTSD; Jerilyn Ross, MA, LICSW, Ross Center for Anxiety and Related Disorders; Kerry Ressler, MD, PhD, Emory University; Sabine Wilhelm, MD Massachusetts General Hospital; Doug Mennin, PhD, Yale University

WORKGROUP

PSYCHOPHARMACOLOGY

Mark H. Pollack MD, Massachusetts General Hospital (Workgroup Leader); David Katzelnick, MD, Healthcare Technology Systems, Inc.; Barry Leibowitz, PhD, National Institutes of Mental Health; Bruce Lydiard, MD, Southeast Health Consultants; Phil Ninan, MD, Emory University; Michael Van Ameringen, MD, McMaster University; Peter RoyByrne, MD, University of Washington; Beth Salcedo, MD, Ross Center; Kathy Shear, MD, University of Pittsburgh; Michael Johnson, MD, University of Florida; Naomi Simon, MD, Massachusetts General Hospital; Amy Wagner, MD, University of Washington.

WORKGROUP

NOVEL

BIOLOGICAL

APPROACHES

Jack Gorman, MD, Mount Sinai School of Medicine; Jeremy Coplan, MD, Downstate Medical Center (Workgroup Leaders); Dennis Charney, MD, Mount Sinai School of Medicine; Joe LeDoux, PhD, New York University; Israel Liberzon, MD, University of Michigan; Paul Plotsky, PhD, Emory. Scott Rauch, MD, Massachusetts General Hospital; David Silbersweig, MD, Weill Cornell Medical College; Rachel Yehuda, PhD, Mt. Sinai School of Medicine; Michael Owens, PhD, Emory University; Justine Kent, MD, Columbia University; Elizabeth Hoge, MD, Massachusetts General Hospital; Sanjay Mathew, MD, Columbia University; Ruth Lanius, MD, PhD, Western Ontario.

TOP ABSTRACT INTRODUCTION THERAPEUTIC GOALS AND TREATMENT... COGNITIVE-BEHAVIORAL APPROACHES PHARMACOLOGIC APPROACHES NEW TARGETS FOR DRUG... FUTURE DIRECTIONS CONCLUSIONS APPENDIX REFERENCES

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ABSTRACT

This section contains a compilation of recent publications that have TOP shaped the thinking in the field as well as classic works that remain ABSTRACT important to the subject reviewed in this issue. This bibliography has REFERENCES been compiled by experts in the field and members of the editorial and advisory boards. Entries are listed chronologically and within years by first author. Articles from the bibliography that are reprinted in this issue are in bold type.

TOP ABSTRACT REFERENCES

REFERENCES
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Craske MG, Farchione TJ, Allen LB, Barrios V, Stoyanova M, Rose R: Cognitive behavioral therapy for panic disorder and comorbidity: more of the same or less of more? Behav Res Ther 2007; 45:10951109[Medline] Etkin A, Wager TD: Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007; 164:14761488[Abstract/Free Full Text] Furukawa TA, Watanabe N, Churchill R: Combined psychotherapy plus antidepressants for panic disorder with or without agoraphobia. Cochrane Database Syst Rev 2007:CD004364 Milrod B, Leon AC, Busch F, Rudden M, Schwalberg M, Clarkin J, Aronson A, Singer M, Turchin W, Klass ET, Graf E, Teres JJ, Shear MK: A randomized controlled clinical trial of psychoanalytic psychotherapy for panic disorder. Am J Psychiatry 2007; 164:265272[Abstract/Free Full Text] Pollack MH, Lepola U, Koponen H, Simon NM, Worthington JJ, Emilien G, Tzanis E, Salinas E, Whitaker T, Gao B: A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder. Depress Anxiety 2007; 24:114[Medline] Siev J, Chambless DL: Specificity of treatment effects: cognitive therapy and relaxation for generalized anxiety and panic disorders. J Consult Clin Psychol 2007; 75:513522[Medline] Watanabe N, Churchill R, Furukawa TA: Combination of psychotherapy and benzodiazepines versus either therapy alone for panic disorder: a systematic review. BMC Psychiatry 2007; 7:18[Medline] Bystritsky A: Treatment-resistant anxiety disorders. Mol Psychiatry 2006; 11:805 814[Medline] Carlbring P, Bohman S, Brunt S, Buhrman M, Westling BE, Ekselius L, Andersson G: Remote treatment of panic disorder: a randomized trial of internet-based cognitive behavior therapy supplemented with telephone calls. Am J Psychiatry 2006; 163:21192125[Abstract/Free Full Text] Conway KP, Compton W, Stinson FS, Grant BF: Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2006; 67:247257[Medline] Furukawa TA, Watanabe N, Churchill R: Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. Br J Psychiatry 2006; 188:305312[Abstract/Free Full Text]

Goodwin RD, Roy-Byrne P: Panic and suicidal ideation and suicide attempts: results from the National Comorbidity Survey. Depress Anxiety 2006; 23:124 132[Medline] Heldt E, Gus Manfro G, Kipper L, Blaya C, Isolan L, Otto MW: One-year followup of pharmacotherapy-resistant patients with panic disorder treated with cognitivebehavior therapy: outcome and predictors of remission. Behav Res Ther 2006; 44:657665[Medline] Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters E: The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2006; 63:415424[Abstract/Free Full Text] Katon WJ: Clinical practice: panic disorder. N Engl J Med 2006; 354:2360 2367[Medline] Paulus MP, Stein, MB: An insular view of anxiety. Biol Psychiatry 2006; 60:383 387[Medline] Ross, LE, McLean LM: Anxiety disorders during pregnancy and the postpartum period: a systematic review. J Clin Psychiatry 2006; 67:12851298[Medline] Roy-Byrne P, Craske M, Stein M: Panic disorder. Lancet 2006; 368:1023 1032[Medline] Sareen J, Chartier M, Paulus MP, Stein MB: Illicit drug use and anxiety disorders: findings from two community surveys. Psychiatry Res 2006; 142:1117[Medline] Schraufnagel TJ, Wagner AW, Miranda J, Roy-Byrne PP: Treating minority patients with depression and anxiety: what does the evidence tell us. Gen Hosp Psychiatry 2006; 28:2736[Medline] Westra H, Dozois D: Preparing clients for cognitive behavior therapy: a randomized pilot study of motivational interviewing for anxiety. Cogn Ther Res 2006; 30:481 498 Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB, Pagano M, Shea MT, Keller MB: Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. Am J Psychiatry 2005; 162:1179 1187[Abstract/Free Full Text] Carlbring P, Nilsson-Ihrfelt E, Waara J, Kollenstam C, Buhrman M, Kaldo V, Sderberg M, Ekselius L, Andersson G: Treatment of panic disorder: live therapy vs. self-help via the Internet. Behav Res Ther 2005; 43:13211333[Medline]

Flint A: Anxiety and its disorders in late life: moving the field forward. Am J Geriatric Psychiatry 2005; 13:36[Medline] Hettema JM, Prescott CA, Meyers JM, Neale MC, Kendler KS: The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 2005; 62:182189[Abstract/Free Full Text] Mitte K: A meta-analysis of the efficacy of psycho- and pharmacotherapy in panic disorder with and without agoraphobia. J Affect Disord 2005; 88:2745[Medline] Roy-Byrne PP, Craske MG, Stein MB, Sullivan G, Bystritsky A, Katon W, Golinelli D, Sherbourne CD: A randomized effectiveness trial of cognitivebehavioral therapy and medication for primary care panic disorder. Arch Gen Psychiatry 2005; 62:290298[Abstract/Free Full Text] Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM, Kagan J, Snidman N, Faraone SV, Hirshfeld-Becker D, Tsuang MT, Slaugenhaupt SA, Rosenbaum JF, Sklar PB: The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol Psychiatry 2005; 57:1485 1492[Medline] Biederman J, Petty C, Faraone SV, Hirshfeld-Becker D, Pollack MH, Henin A, Gilbert J, Rosenbaum JF: Moderating effects of major depression on patterns of comorbidity in patients with panic disorder. Psychiatry Res 2004; 14:126,143149 Deacon BJ, Abramowitz JS: Cognitive and behavioral treatments for anxiety disorders: a review of meta-analytic findings. J Clin Psychol 2004; 160:429441 National Institute for Clinical Excellence: Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care.2004.http://www.nice.org.uk/CG022quickrefguide Sheikh JI, Swales PJ, Carlson EB, Lindley SE: Aging and panic disorder: phenomenology, comorbidity, and risk factors. Am J Geriatr Psychiatry 2004; 12:102109[Medline] Fleet RP, Lavoie KL, Martel JP, Dupuis G, Marchand A, Beitman BD: Two-year follow-up status of emergency department patients with chest pain: was it panic disorder? CJEM 2003; 5:247254[Medline] Lewis-Fernandez R, Guarnaccia PJ, Martinez IE, Salman E, Schmidt A, Liebowitz M: Comparative phenomenology of ataques de nervios, panic attacks, and panic disorder. Cult Med Psychiatry 2002; 26:199223[Medline]

Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D: Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry 2001; 58:681686[Abstract/Free Full Text] Katzelnick DJ, Kobak KA, DeLeire T, Henk HJ, Greist JH, Davidson JR, Schneier FR, Stein MB, Helstad CP: Impact of generalized social anxiety disorder in managed care. Am J Psychiatry 2001; 158:19992007[Abstract/Free Full Text] Fleet RP, Marchand A, Dupuis G, Kaczorowski J, Beitman BD: Comparing emergency department and psychiatric setting patients with panic disorder. Psychosomatics 1998; 39:512518[Abstract/Free Full Text] Shear MK, Brown TA, Barlow DH, Money R, Sholomskas DE, Woods SW, Gorman JM, Papp LA: Multicenter collaborative Panic Disorder Severity Scale. Am J Psychiatry 1997; 154:15711575[Abstract/Free Full Text] Nagy LM, Krystal JH, Woods SW, Charney DS: Clinical and medication outcome after short-term alprazolam and behavioral group treatment in panic disorder. 2.5 year naturalistic follow-up study. Arch Gen Psychiatry 1989; 46:993 999[Abstract/Free Full Text] Klein DF: Delineation of two drug-responsive Psychopharmacologia 1964; 5:397408[Medline] anxiety syndromes.

Klein DF, Fink M: Psychiatric reaction patterns to imipramine. Am J Psychiatry 1962; 119:432438[Abstract/Free Full Text] Mrtberg E, Clark DM, Sundin O, Aberg Wistedt A. Intensive group cognitive treatment and individual cognitive therapy vs. treatment as usual in social phobia: a randomized controlled trial. Acta Psychiatr Scand 2007; 115:142154[Medline] Sareen J, Campbell DW, Leslie WD, Malisza KL, Stein MB, Paulus MP, Kravetsky LB, Kjernisted KD, Walker JR, Reiss JP: Striatal function in generalized social phobia: a functional magnetic resonance imaging study. Biol Psychiatry 2007; 61:396404[Medline] Foa EB: Social anxiety disorder treatments: psychosocial therapies. J Clin Psychiatry 2006; 67(suppl 12):2730 Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW: Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry 2006; 63:298 304[Abstract/Free Full Text] Matthew SJ, Ho S: Etiology and neurobiology of social anxiety disorder. J Clin Psychiatry 2006; 67(suppl 12):913

Phan KL, Fitzgerald DA, Nathan PJ, Tancer ME: Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia. Biol Psychiatry 2006; 59:424429[Medline] Stein MB: An epidemiologic perspective on social anxiety disorder. J Clin Psychiatry 2006; 67(suppl 12):38 Liebowitz MR, Mangano RM, Bradwejn J, Asnis G, SAD Study Group: A randomized controlled trial of venlafaxine extended release in generalized social anxiety disorder. J Clin Psychiatry 2005; 66:238247[Medline] Mancini C, Van Ameringen M, Bennett M, Patterson B, Watson C: Emerging treatments for child and adolescent social phobia: a review. J Child Adolesc Psychopharmacol 2005; 15:589607[Medline] Bgels SM, Mansell W: Attention processes in the maintenance and treatment of social phobia: hypervigilance, avoidance and self-focused attention. Clin Psychol Rev. 2004; 24:827856[Medline] Van Ameringen M, Mancini C, Pipe B, Oakman J, Bennett M: An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004; 65:16741678[Medline] Heimberg RG: Cognitive-behavioral therapy for social anxiety disorder: current status and future directions. Biol Psychiatry 2002; 51:101108[Medline] Stein MB, Kean YM: Disability and quality of life in social phobia: epidemiologic findings. Am J Psychiatry 2000; 157:16061613[Abstract/Free Full Text] Liebowitz MR, Heimberg RG, Schneier FR, Hope DA, Davies S, Holt CS, Goetz D, Juster HR, Lin SH, Bruch MA, Marshall RD, Klein DF: Cognitive-behavioral group therapy versus phenelzine in social phobia: long-term outcome. Depress Anxiety 1999; 10:8998[Medline] Kessler RC, Berglund P: Social phobia subtypes in the National Comorbidity Survey. Am J Psychiatry 1998; 155:613619[Abstract/Free Full Text] Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, Juster HR, Campeas R, Bruch MA, Cloitre M, Fallon B, Klein DF: Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry 1998; 55:11331141[Abstract/Free Full Text] Liebowitz MR, Schneier F, Campeas R, Hollander E, Hatterer J, Fyer A, Gorman J, Papp L, Davies S, Gully R: Phenelzine vs atenolol in social phobia; a placebocontrolled comparison. Arch Gen Psychiatry 1992; 49:290300[Medline]

Cuadro clnico caracterizado por ataques de pnico frecuentes y a menudo paralizante o invalidantes, fue introducido por DSM III para designar estados de ansiedad patolgica aguda descritas bajo los conceptos equivalentes de crisis de pnico o crisis de angustia. Descritos en el siglo XIX por Westphal con el nombre de agarofobia, son reconceptualizados por Freud como neurosis de angustia o por Roth como sndrome de ansiedad fbica y despersonalizacin. Nuevamente reconsiderado como parte de los trastornos ansiosos tomando el nombre de TP en lel DSM III y posteriores en funcin de nuevos antecedentes biolgicos y farmacolgicos. En 1981 Klein, apoyndose en el efecto positivo de la imipramina sobre los ataques de pnico, propone su separacin del TAG y sugiere el modelo de trabajo, vigente hasta el presente, que da cuenta de una repeticin de crisis generadora de una ansiedad crnica invalidante donde se mezclan angustias anticipatorias y elementos fbicos variados reunidos bajo el concepto de agarofobia. El cuadro clnico se presenta con una frecuencia alta en la poblacin, ya que diferentes estudios indican una prevalencia de 1 a 3% y en una relacin de predominancia femenina de 3:2. De consulta frecuente en medicina familiar, los pacientes refieren una triada sintomtica de crisis aguda de pnico repetidas, ansiedad secundaria de tipo anticipatorio con o sin agarofobia. La psicopatologa es intensa: se trata de crisis o episodios agudos de ansiedad que comienza a menudo de forma brutal e inesperada que en escazos minutos aumenta hasta alcanzar un grado superior de desesperacin que los pacientes expresan como perdida de control o de catstrofe inminente, para descender progresiva y de manera variable en el curso de minutos u horas. Las primeras crisis suelen ser inesperadas, para dar paso a crisis posteriores, por aprendizaje o repeticin, gatilladas por factores ansiogenos o por el desarrollo de la agarofobia, dando la impresin de que el mismo sujeto puede desencadenar las crisis. En el conexto de crisis inesperadas, donde el paciente experimenta sensaciones intoreceptivas intensas de aumento de frecuencia cardiaca, dolores precordiales o sensaciones nauseosas asociadas a miedos catastroficos, de morir o perder la razon o el control de sus comportamientos, se construye un circulo vicioso de alerta aprendida que se transforma en una vulnerabilidad psicologica focalizada en los sntomas fisicos sentidos. Por lo tanto, las sensaciones fisicas, de naturaleza variable, son la primera expresin clinica que aparece y gatilla un pedido de ayuda o de intervencin inmediata en la medida que son anunciadoras de un mal mayor: infarto, perdida de control, locura. Ademas, toda la respuesta simpatica o parasimpatica implica reacciones fisiologicas que contribuyen a aumentar la angustia y la deseperacion: la hiperventilacion consiguiente que produce hipocapnia provoca a su vez sintomatologa aguda (parestesis, vertigo, contracturas), agudizando aun mas la experiencia del limite, que en las crisis mayores explican la desrealizacion, despersonalizacion, perdida de orientacin espacio-temporal u otras manifestaciones similares. Para el caso del trastorno de panico con agarofobia, la dinamica psicopatologica se construye a partir de la vulnerabilidad psicologica centrada en los sntomas somaticos y el temor de experimentar nuevas crisis bajo la forma de una ansiedad anticipatoria. Tambien, esta ansiedad anticipatorio se puede producir en relacion a ciertas circunstancias temidas por el sujeto en las cuales se puede

desencadenar una crisis o donde siente no tener un lugar seguro: lugares de encierro, como el metro o un automvil, tuneles o puentes; o donde se encuentra solo o desprotegido. El conjunto descrito sumariamente, determinado por variables culturales, sociales o medioambientales, es moderado por la presencia de seales segurizantes, genera la conducta de evitacion agarofobica, termino que describe el temor al espacio publico o a los espacios abiertos. Dependiendo de su intensidad, el paciente puede restringirse en su autonomia personal con consecuencias practicas evidentes: reduccion de su vida social, afectiva, laboral. Otros medios de luchar contra los trastornos de panico consiste en el uso, a veces consumo abusiso, de alcohol y medicamentos, estupefacientes u otros, pero tambien en un enfrentamiento cotidiano con el sufrimiento en el caso de aquellos que insisten en sobreponerse al miedo o a la angustia viajndo en metro o exponiendose a las situacin laborales o sociales que lo desencadenan. La evolucion del TP con o sin agarofobia es generalmente cronica y de aos, pero su pronostico varia en funcion del numero de crisis, el compromiso social o laboral, la amplitud de la evitacion y el o las modalidades terapeuticas. Un porcentaje importante de pacientes se mantiene en tratamiento despus de 5 aos y en un 20% subsiste el riesgo de depresiones y en un porcentaje menor, de suicidio. El diagnostico diferencial de un cuadro clinico de aparicion brusca como el TP obliga a descartar distintas patologas agudas cuya etiologia sea medica o neurologica, tales como hipoglicemias, trastornos del ritmo cardiaco, infarto, crisis hipertiroideas, accidentes vasculares transitorios, patologa vestibular, etc, como tambien ingestion toxica de sustancias tales como cafeina, cocaina, etc., o estados de abstinencia de drogas o alcohol. Con otras patologas del ambito de los trastornos ansiosos, como la fobia socila o la hipocondra suelen plantearse a veces dudas diagnosticas, pero es necesario recordar que en el caso de las fobias sociales la fuente ansiogenica es externa al sujeto y en el TP la ansiedad es originada por malestares corporales internos. La hipocondra, fenomenologicamente aparece en el contexto de conviccin de ser afectado por una enfermedad, en tanto el TP aparece vinculado a consultas reiteradas por una necesidad de seguridad de saber que no se tiene nada organico. Causas: el TP es una condicion que ha sido ampliamente consideredada en varios modelos etiologicos, cuyo potencial explicativo puede ser complementario Modelos neurobiologicos1: Varias observacioners neurofuncionales sugieren que el TP puede ser caracterizado como una enfermedad biologica y psicologica a la vez que tiene su sustrato anatomico en el tronco cerebral, la amigdala y la corteza prefrontal respectivamente. (Gormann, JM. Y al. A neuroanatomical hiptesis for panic disorder. Am. J. Psychiatry 1989; 146:148-161), y por una hiperactivacion frontal derecha en un temprano estudio de Katkin y al (1991) y confirmados por estudios posteriores que sustentan la hiptesis que los pacientes con esta patologa tiene una activacion incrementada de la region frontal derecha en situaciones valoradas
1

Katkin, ES and al. Individual differences in cortical evoked potentials as a function of heartbeat detection ability. Int J. Neurosci. 1991 Dec. 61 (3-4) 269-76

negativamente (Wiedermann, G. y al. Frontal brain asymmetry as a biological sustrate of emotions in patients with Panic Disorders. Arch. Gen Psychiatry. 1999; 56:78-84). En una reciente revision de la literatura sobre la neurobiologa, fenomenologia y tratamiento del TP, nuevamente se reafirma la hiptesis original confirmando la participacin de las mismas estructuras, pero ademas entrega elementos para apreciar los cambios positivos logrados tanto por la farmacoterpai como la psicoterapia en los distintos lugares del cerebro afectados como por ejemplo la accion de los medicamentos inhibidores de la recapatacion de serotonina que producen una disminucin de crisis de panico reduciendo la actividad de la amigdala e interfiriendo con su capacidad de estimular los sitios de proyeccion en el talamo y en el tallo cerebral (Gorman, JM., y al. Neuroanatomical Hypthesis of Panic Disorder, Revisited. Focus 2: 426-439, 2004) Los modelos biologicos y bioquimicos: los estudios geneticos realizados revelan la contribucin de muchos genes en la pstofisiologia del trastorno. Estudios de asociacin sugieren ligamiento de locus diferentes tales como el 7p15 y el q32-33 en el cromosoma 13. Hiptesis bioqumica. Desde el punto de vista biologico-bioquimico la etiologia del TP no es conocida, pero se reconocen al menos 5 teorias que pueden sostener la hiptesis de que juegan un rol etiologico: hiperactividad noradrenergica, alteracin de receptores Gaba porque los pacientes responden bien a las benzodiazepinas y porque la crisis de panico puede ser inducida por agonistas del Gaba en pacientes con trastornos de ansiedad, regulacin a la baja de receptores serotoninergicos post-sinapticos, y su realcion con el sistema noradrenergico, metabolismo del lactato, e influencia de sustancias ansiogenas. Hiptesis cognitivas Hiptesis psicoanaliticas

Causas

Los tastornos ansiosos tienen tendencia a encontrarse en las mismas familias, lo que obedece en parte a factores de indole genetica. Existen numerosos estudios en este sentido que comparan gemelos y padres de nios ansiosos. Por lo tanto, pareciera que existe una vulnerabilidad biologica general, como en la mayoria de los trastornos psiquiatricos que nos ayudara a comprender la etiopatogenia de este trastorno.

El espectro de patologas del TOC (Bruno Aouizerate, Jean Ives Rotg)

El concepto de un espectro de patologas con caractersticas de repeticin de conductas vinculadas al TOC como la tricotilomania y la dismorfobia, proviene del psicoanlisis, encontrando en la actualidad un nuevo impulso en base a que todas ellas responden a los inhibidores selectivos de la serotonina. Todavia no existe consenso en torno a cuales de los cuadros descritos corresponden a este espectro que comparte aspectos fisiopatolgicos y de tratamiento. Uno de los mas cercanos cuadros clnicos, por su fenomenologa es el sndrome de Tourette, y mas lejos la dismorfobia y la hipocrondria, aunque algunos autores consideran que otros fenmenos clnicos caractertizados por conductas repetitivas como la tricotilomania puede incluirse en este grupo. Calamari y col (1999), usaron tecnicas de analisis para agrupar subtipos de pacientes con TOC en base a los sntomas obsesivos y compulsivos mas prominentes, identificando 5 clusters: de dao, de acumulacin, de contaminacin, de certeza, de obsesiones, a los cuales en el ao 2004 agrego los de simetra y un subtipo mixto de contaminacin/acumulacin. La utilidad clinica de agrupar estos subtipos de pacientes con TOC persigue obviamente fines terapeuticos y de investigacin, en que por ejemplo aquellos pacientes agrupados en le cluster de dao, tiene una respuesta terapeutica menor a los medicamntos serotoninergicos y a la terapia cognitiva-conductual (Abramowitz, 2003) El sndrome de Tourette

Tratamiento

Por mucho tiempo, los TOC se han asociado a incurabilidad y rareza. Pero, la importancia y significacin de los hallazgos en la ultima decad del siglo XX y la primera del siglo XXI en el campo de la genetica, el metabolismo de los neurotrasmisores y especficamente de la serotonina, las interacciones familiares, la imagenologia, la neurofisiologa, los modelos de aprendizaje, han cambiado esta imagen negativa y desesperanzadfora. La revision de la literatura especializada da cuenta de un interes crciente por esta patologa, como tambien de la investigacin farmacologica y psicologica-terapeutica.

Los TOC se definen por la presencia de sntomas especificos de obsesiones y/o compulsiones, con compromiso, a veces bastante grave, de las relaciones laborales o sociales de la persona afectada. A menudo, los sntomas aparecen progresivamente en la infancia y adolescencia, aunque en algunas oportunidades aparecen agudamente,

despus de una depresion, un traumatismo o acontecimiento vital importante, y persisten con una cronicidad cercana al 80% de los pacientes, durante toda la vida del sujeto. La prevalencia se encuentra alrededor del 1.9 al 3.3% en el curso de la vida y es junto a las depresiones mayores, las fobias y los abusos de subtancias, una de las patologas mas frecuentes de la practica clnica. Se encuentra generalmente asociada a otros cuadros clnicos, en comorbilidad con las depresiones mayores, en mas del 60%, con los TB, y tambin con los trastornos ansiosos en cualquiera de sus modalidades clnicas. Una relacin de comorbilidad importante se encuentra tambin con los T. alimentarios y los Abusos de substancias como el alcohol. Con el Sindrome de G de la Tourette tiene una relacin especial compartiendo caractersticas fenomenolgicas y bases fisiopatolgicas. Desde el punto de vista psicopatolgico, el TOC es un cuadro heterogneo sintomticamente, aunque es posible separar varios grupos de pensamientos obsesivos: de contaminacin, de obsesiones vinculadas al cuerpo o somaticas, de orden y simetra y obsesiones con temas agresivos y sexuales. Las compulsiones son mayoritariamente de verificacin, seguidas de aquellas conductas de limpieza o lavados, de ordenar o clasificar y de acumulacin y coleccin de cosas u objetos. El cuadro clnico aparace precozmente en la vida del sujeto, alrededor de la adolescencia. Su comienzo es generalemnte insidioso, con intermitencias con periodos intercriticos de normalidad, para hacerse crnico con los aos. El impacto sobre la calidad de vida del sujeto, su trabajo o estudios es importante. El DSM IV-TR exige para su diagnostico los siguientes criterios:

Esta concepcin descriptiva del cuadro clinico esconde implcitamente una concepcin psicologica, cuyos antecedentes son antiguos y se remontan al modelo de la psicastenia de Janet en que el estado emocional encuentra un antecedente en un trastorno eidetico, que se puede comprender como una perturbacin del proceso de tratamiento de la informacin que dependen de creencias y esquemas cognitivos precozmente inscritos en la memoria del sujeto, lo que constituye el ncleo de la sicopatologa obsesiva. La psicastenia de Janet se define por un dficit de energia psiquica innata o adquirida, de donde los pensamientos obsesivos surgen como contenidos de estructuras mentales inferiores que perturban el pensamiento o actividad del intelecto superior y las compulsiones expresan la perdida de control del pensamiento conciente o voluntario incapaz de contener la emergencia de los contenidos inconcientes o inferiores. Estos deficits de pensamiento logico permite ademas la emergencia de otros procesos mentales como los sueos, los pensamientos magicos y las emociones inadaptadas, propios de la incompletad o imperfeccin del funcionamiento mental, propia de una concepcin fisicalista de la actividad mental. El modelo psicoanalitico, otras variante de una conceocion ebnergetica de la mente humana, considera que la angustia es primaria y este estado difuso se expresa en la sintomatologa mas especifica de obsesiones y compulsiones. La sintomatologa obsesiva representa la forma de neutralizar el afecto angustioso por la mediacin de mecanismos de defensa especificos. De esta manera se explica la tendencia compulsiva agresiva y violenta

hacia el objeto cuyo sentido invisible de prohibicin y culpabilidad se situa en el inconciente del sujeto.

En las dos dcadas pasadas se ha hecho un notable esfuerzo en comprender su fisiopatologa en bsqueda de hiptesis que permitan comprender mejor la etipopatogenia del cuadro y prononer alternativas de tratamientos. La investigacin clnica y experimental con la ayuda de las imgenes cerebrales apunta a conocer las relaciones funcionales y estructurales y los aspectos neuroqumicos a la base del cuadro clnico, su ubicacin neuroanatomica, y definir con mas claridad los procesos cognitivos y emocionales que ocupan un lugar central en su patogenia en relacin con la fenomenologa clnica.

Las obsesiones son definidas por los pacientes por la irrupcin intrusiva e persistente de una idea, un impulso o una representacin que se vive como un fenmeno patolgico, que surge de su propia activida psquica imponindose en ella de tal forma que se matienen pese al esfuerzo por desembarazarse de ellas. El carcter egodistonico del fenmeno, es traducido por el paciente a una imposicin externa de ideas obsesivas, vividas con angustia y realatadas con un lenguaje claramente notificativo en el sentido de Roa. Las compulsiones son comportamientos repetitivos imposibles de resistir por le paciente, quien se ve obligado a su realizacin. Esto implica que el paciente siente que los pensamientos obsesivos son en efecto una sobreestimacion de consecuencias negativas a las cuales puede exponerlos un acto o conducta suya errada, de la cual surge la duda persistente y angustiosa del error cometido que lo hace sobredimensionar los riesgos de acontecimientos lamentables y perjudiciales para si mismo o su entorno inmediato, en la medida que la duda se alimenta de la ansiedad de no tener una respuesta certera de que es lo que habra hecho, dicho o actuado. La compulsin aparece en este contexto de duda persistente como la repuesta que contribuye a calmar la ansiedad a las consecuencias del error supuestos del sujeto obsesivo, ya sea en un sentido preventivo o anticpatorio, o a reducir mediante diferentes rituales de limpieza o lavado, las consecuencias perjudiciales predefinidas en su mente del error incurrido. Los actos de verificacin consisten en en la necesidad de asegurar que la consecuencia negativa, producto de su error, ha sido sobreestimada, poniendo en el acto compulsivo una atencin absoluta para que se realicen todas las etapas que aseguren el adecuado ritual que le permita expurgar su duda culpable. Si se salta un paso, vuelve a repetir, a veces hasta el cansancio el ritual compulsivo, que le asegure un alivio durable. La reiteracin fenomenolgica descrita supone en el sujeto la puesta en marcha de procesos cognitivos, emocionales, motivacionales que tiene un asiento en la funcin de diversas estructuras cerebrales o de circuitos cerebrales vinculados con ellos. Una de las reas estudiadas es la corteza orbito-frontal implicada en funciones cognitivas, especialmente al deteccin de los errores. (p.5)

Los TOC se diagnostican frecuentemente en comorbilidad con otras patologas psiquiatritas. Entre las frecuentes, en un porcentaje de 30%, lo encontramos en relacion con un Episodio depresivo mayor, y en porcentajes menores los Trastornos Ansiosos en cualquiera de sus variedades clinicas, TAG, trastornos de panico, fobias sociles o especificas. Las patologas alimentarias tienen una representacin variable de comorbilidad con los TOC, siendo mas frecuente la bulimia que la anorexia en una relacion de 3:1. Patologas psicoticas como la esquizofrenia y adiccion a drogas o alcohol y trastornos de personalidad se encuentran en porcentajes variables y constituyen signos de pronstico negativo. Etiologia de los TOC Las hiptesis son variadas: Desde las primeras teorias basadas en las posesiones demoniacas hasta las psicoanaliticas y conductuales, los mecanismos neuroquimicosa alterados, las anormalidades neuroanatomicas y funcionales, las que implican los genes y el medio ambiente, ha pasado bastante tiempo y todava se continua investigando para esclarecer las bases etiologicas de esta compleja enfermedad. Neuroanatomicas

En el TOC se han encontrado regiones particulares del cerebro implicadas: la corteza orbito-frontal, la corteza singular y los ncleos de la base, especialmente el caudado. Estas estructuras, artificialmente separadas pues constituyen circuitos neuronales altamente complejo sin limites nitidos, serian responsables de las distintas variedades clinicas en las que se expresa el TOC, forman parte de un conjunto de interacciones entre los lbulos frontales, los ganglios de la base y las estructuras limbicas y paralimbicas, interrumpidas en los casos severisimos e invalidantes del trastorno por intervenciones quirurgicas como la capsulotomia o la cingulotomia, con resultados positivos. La neurofisiologa experimental ha agregado conocimiento reciente sobre las diversas funciones que cumple cada una de las zonas y circuitos neuronales citados: la corteza orbito frontal se divide en dos regiones diferenciadas, la primera ventrolateral se especializa en funciones cognitivas como la deteccion de errores y la seleccin de estimulos ambientales basados en la evsaluacion sensorial, procesos esenciales en la toma de decisiones y, la segunda, ventromedial tiene un rol significativo en la gestion de procesos emocionales y motivacionales, complementando los datos para la toma de decisin apropiada al estimulo, en el contexto apropiado. La region de la corteza cingular anterior es, por su parte, un centro de integracin de cogniciones y emociones localizado en el ncleo del sistema asociativo y limbico y consta de dos regiones, la dorsal vinculada a la funcion cognitiva y, ventral, especficamente implicada en las dimensiones motivacional y emocional del comportamiento del sujeto. Las tecnicas de neuroimagenes funcionales han permitido estudiar las correclaciones del TOC con sus correlatos neurales. Entre la gran cantidad de estudios referidos a

pacientes con sntomas indiferenciados, algunos se han focalizado en subtipos de pacientes con sntomas comunes. Neuropsicologicas ComportAMENTALES Genetica Los estudios en gemelos monocigotos han entregado evidencia de participacin genetica en el cuadro clinico. El 60% de los sujetos que comparten el 100% de su material genetico desarrollan un TOc, en relacion a solo el 2% de la poblacin general. Estudios que tienen como objetivo la familia del apciente, refieren un 10% de afectados (parientes de primer grado) por el trastorno; con lo que se concluye que la posibilidad de sufrir un cuadro de tal naturaleza es dependiente de la carga genetica del individuo, con solo 2% de individuos que lo desarrollan sin antecedentes genticos. Como en las otras patologas psiquicas, la enfermdad depende de un conjunto de factores de riesgo, donde la interaccion gene-ambiente se revela por el hecho de que no todos aquellos que comparten el patrimonio genetico desarrollan el trastorno. En la ultima decada se han reportado mas de 80 estudios de genes candidato, seleccionados por su cercania anatomica (candidatos posicionales) o por su rol etiologico putativo en algunas vias de neurotrasmision relacionadas con el TOC. Especificamwente, los genes implicados en las vis serotoninergicas, dopaminergicas y glutaminergicas y aquellos que intervienen en la formacin de la sustancia blanca se encuentra en el foco de atencin de los investigadores. Un ejemplo es el gene transportador de glutamato SLC1A1, consistemente asociado en todas las muestras de TOC. (Stewart, E., Pauls, D. The genetics of Obssessive-Compulsive Disorder, Focus 8:350-357, Summer, 2010) Neurobiologicas

Los antecedentes neurobiologicos del TOC se remontan a los aos 60 en que se observo que la Cloripramina, un medicamento antidepresivo, tenia la particularidad de ser selectivamente activo sobre un neurotrasmisor, la serotonina, imponiendose como el tratamiento elegido para el trastorno, actuando sobre el proceso de recaptura de la serotonina en el espacio sinaptico, aumentando por ende su accion postsinaptica. La asociacion preferencial del TOc con otras enfermedades como la depresion, los Tb, los trastornos ansiosos y los trastornos alimentarios, todos ellas vinculadas a la vulnerabilidad serotoninergica permite conceptualizar el conjunto como espectro serotoninergico, cuyo tratamiento seria transnosografico. Sin embargo surgen dudas acerca de la relacion exclusiva del Toc con el sistema serotoninergico en la medida que la accion de otros neurotrasmisores empieza a ser conocida

Waterwort DM, Bassett AS, Brzustowicz LM (2002) Recent advances in the genetics of schizophrenia. Cell Mol Life Sci 59:331348. [PubMed]

The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.

The Dopamine Hypothesis of Schizophrenia: Version IIIThe Final Common Pathway

1. Oliver D. Howes2,3 and 2. Shitij Kapur1,2 + Author Affiliations 1. 2Positron Emission Tomography (PET) Psychiatry Group, Medical Research Council (MRC) Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK 2. 3Institute of Psychiatry, King's College London, London SE5 8AF, UK 1. 1To whom correspondence should be addressed; PO Box 053, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK; tel: +44-20-7848-0593, fax: +44-20-78480287, e-mail: shitij.kapur@iop.kcl.ac.uk.

Abstract
CLASE 1 1.- Definicion de la psicopatologa Profesionales Estudio de los cuadros psicopatolgicos: cuadros clnicos, etiologa y tratamiento Definicin de los trastornos psicolgicos: disfuncionamiento psicolgico en las reas cognitiva, emocional y comportamental; malestar personal (alteracin del comportamiento global del individuo; carcter atpico e inesperado del comportamiento Normalidad/anormalidad: criterios Una definicin aceptada de anormalidad: disfuncionamientos comportamentales, emocionales o cognitivos inhabituales en el contexto cultural ej), asociado a malestar personal o a un disfuncionamiento considerablemente alterado Prototipos diagnosticos del DSM IV TR 2.- Concepciones histricas en psicopatologa: Tradicin sobre natural La tradicin biolgica

1920 Von Meduna schock insulinico para pacientes psicticos Cerlini terapia elctroconvulsiva 1950 primeros antipsicticos: la reserpina 1960 desarrollo de los ansioliticos El desarrollo de los tratamientos biolgicos La tradicin psicolgica PLaton, y la importancia del medio en el aprendizaje y la reeducacin El tratamiento moral de los pacientes mentales: Pinel y Tuke El psicoanlisis La terapia humanista La teora conductual y sus derivaciones El presente: ciencia e integracin conceptual Basado en la sofisticacin creciente de las herramientas conceptuales y metodologis cientficas y de la constatacin de que ninguna influencia biolgica, social o psicolgica actau sola e independientemente de los otros factores hace necesario un nuevo modelo que tiene en cuenta e integra todos los elementos en la comprensin de un cuadro clinico 3.- Modelo integrado en psicopatologa Modelo uni-multidimensional: Como se puede explicar la aparicion de la enfermedad? El enfoque multifactorial de la sicopatologa y las neurociencias actuales es el reconocer que la enfermedad es el producto de la interaccion compleja de muchos factores entre los cuales cabe distinguir una diatesis o vulnerabilidad biologica o genetica que interactua con factores de riesgo propios del medioambiente, de tipo psico-sociales en una configuracion sistemica, donde cada uno de los factores no tiene fuerza etiologica considerado aisladamente, es decir, fuera del contexto sistemico de influencias reciprocas. Sin embargo queda pendiente la pregunta de cmo podria ocurrir que este conjunto de elementos da origen en un determinado momento historico del individuoa una constelacin de signos y sntomas cualitativamente distintos que llamamos enfermedad, es decir, cuando se produce el cambio de cantidad de elementos o factores de riesgo de enfermar en la via final que llamamos esquizofrenia o depresion mayor, Trastorno Bipolar, etc. Sabemos que la explicacin causalista naturalista que explica la etiologia de un cuadro clinico por la mera asociacin de un elemento antecedente con una consecuencia o efecto no tiene fundamento epistemologico en la psiquiatria actual, ya que una fobia especifica si bien puede tener un antecedente muy importante en una experiencia muy desagradable en un momento anterior del sujeto, sta no basta para engendrar por si solo medio la fobia consecuente si no existe otros factores de vulnerabilidad que interactuen y que, juntos, hagan posible la aparicionde la enfermedad. La respuesta este cuestionamiento no es simple. En la compleja interaccion cuerpo-mente, desde Descartes a la actualidad, ha habido distintos enfoques epistemologicos para tratar de entender los cambios planteados. En este sentido, el pensamiento moderno ha fundado el conocimiento de los fenmenos en operaciones de desagregacion de los objetos en unidades mas simples, como lo demuestra ampliamente el estudio de las enfermedades mentales, como se grafica a proposito de la esquizofrenia por ejemplo, que desde el reconocimiento de anomalias estructurales del cerebro se avanza progresivamente

hasta el conocimiento de la estructura gentica y molecular de los cambios producidos en esas estructuras. Esta manera de mirar corresponde a la lgica cartesiana que inaugura la cientificidad moderna y el mtodo cientfico y alude al metodo de division de cada una de las dificultades en tantas partes como sea posible, con lo que en un proceso sumatorio se lograba finalmente el conocimiento del objeto de estudio. El estudio del mundo fisico demostraba el xito de este paradigma en la meduida que respondia a relaciones causales direcxtas entre elementos simples y en numero reducido. La reduccion analitica exhibia asi su potencialidad de conocer y analizar los fenmenos de la naturaleza. Este enfoque, con el tiempo ha sido cuestionado como paradigma del conocimiento por su dificultad para explicar la causalidad de fenmenos complejosentre los cuales se encuentran las conductas humanas, sanas o enfermas--, diciendo que la vision reductora de la realidad que opera el metodo analitico a traves de la desagregacion de los elemntos del todo, temina por sacrificar el objeto de estudio. Es la crtica de las perspectivas dialecticas de la filosofia del conocimiento, que en su interes por comprender los fenmenos historicos, habia cuestionado el enfoque cientifico. Para ello, sostiene, es necesaria no la reduccion del objeto en sus partes componentes, sino por el contrario, establecer una relacion con los demas objetos, en una referencia a la totalidad, en proceso creciente de sntesis parciales hasta lograr la totalidad. Pero, de acuerdo a Echeverria, R. El buho de Minerva: introduccin a la filosofia moderna, 1998), cuando esta perspectiva del conocimiento se esfuerza por mostrar que el todo no es la mera suma de las partes, acude a la explicacin de un supuesto transito de cantidad en calidad, que mediante un misteriosos salto logico trastocaba en una situacin diferente. Para el autor (p.276 ) Ejemplo de la fobia a la sangre: una joven ve una pelcula donde se asesina a una mujer. Esta joven transformada en estudiante de medicina se desmaya en el pabelln de anatoma patologica a la vista de la sangre en la autopsia de un cadver. Causas: a) Influencias del comportamiento: reaccin incondicionada asociada a las escenas de la pelcula condiconamiento clasico? Porque los dems alumnos no hacen un fobia? b) Influencias biolgicas: la alumna tiene o experimenta una reaccin vasovagal. Normalmente frente a un estimulo existe una repuesta del sistema nervioso que tiene como consecuencias aumento de los latidos cardiacos, aumento de su presin sangunea, mayor rubor, etc. En esta ocasin la misma reaccin pone en marcha mecanismos compensatorios: disminucin de la resistencia vascular, cada de la presin arterial, desmayo ya que la cantidad de sangre que afluye al cerebro disminuye notablemente. Esta reaccin se produce porque se sobreactiva el arco reflejo baroreceptor del cayado artico y del seno carotideo para bajar la presin arterial. Este mecanismo de reaccin sobre compensadora es hereditario y 61% de la familias que sufren este tipo de fobias responden con sobrecompensaciones de esste tipo en distintos grados. Pero este tipo de mecanismos compensadores no explica la totalidad del cuadro clnico c) Influencias emocionales : las reacciones desencadenadas tiene un punto de partida y estos son los estados emocionales que gatillan los cambios

fisiopatolgicos descritos, de tal forma que en todo cuadro clnico tenemos que considerar la influencia de las emociones d) Las influencias sociales: los refuerzos positivos y negativos tiene gran importancia en la progresin de comportamientos adaptativos o maladaptativos. Pataletas e) Influencias del desarrollo: los periodos crticos del desarrollo van a influir en la forma e intensidad en que se de una patologia Contribucin gentica Los genes: largas molculas de ADN que se pueden aislar en distintos lugares de los cromosomas que estn tambin en el nucleo de la celula. Herencia mendeliana versus herencia no mendeliana. Las enfermedades pueden deberse a alteraciones de uno o mas genes. Existen algunas enfermedades como la Fenilketinuria o la Enf. De Huntington que se vincula a la alteracin de un gen causando ya sea el retarfdo mental por la imposibilidad de metabolizar la fenilalanina de los alimentos o la enfermedad de Huntington vinculada a la deterioracin de un rea especifica ddel cerebro, los ganglios basales con consecuencias de alteraciones multiples de la personalidad, alteraciones cognitivas y motoras bajo la forma de temblores, sobresaltos involuntarios de todo el cuerpo La naturaleza de los genes: 23 pares de cromosomas; los 22 primeros son la base de los programas de desarrollo corporal y cerebral y el par 23 los cromosomas sexuales. Las molculas de ADN tiene una cierta estructura, de doble hlice. Una hlice esta constituida por dos espirales orientadas en direcciones opuestas con n orden molecular, cuya alteracin hace de esta molecular un gen defectuoso. Existen genes dominantes y recesivos que pueden determinar algunas caractersticas personales segn las leyes mendelianas (color ojos, pelo) pero la mayora de las carcteristicas humnas son poligenicas, como es el caso de las enfermedades mentales en que gracias a tcnicas de gentica cuantitativa se han podido determinar la influencia realtivamente mayor de algn gene en su determinacin. Segn estudiso recientes con tcnicas de gentica cuantitativa se ha podido determianr que la influencia gentica en los individuos oscila entre entre 32 y 64% en relacin ala heredibilidad de aptitudes cognitivas especificas como la memoria o la percepcin de relaciones espaciales y entre el 30 al 50% para ciertos rasgos de personalidad como la timidez o el grado de actividad. Para la determinacin de enfermedades mentales, su distribucin tambin ha sido claculada dependiendo si los individuos comparten 100 o 50% de material gentico por ejemplo y que esta contruibucion tiene que ser comprendida en su relacin con otras influencias medioambientales.
Focus 4:391-400, 2006 American Psychiatric Association
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Articles by Kendler, K. S.

"A Gene for. . .":The Nature of Gene Action in Psychiatric Disorders

Kenneth S. Kendler, M.D.

ABSTRACT
A central phrase in the new "GeneTalk" is "X is a gene for Y," in which X is a particular gene on the human genome and Y is a complex human disorder or trait. This article begins by sketching the historical origins of this phrase and the concept of the gene-phenotype relationship that underlies it. Five criteria are then proposed to evaluate the appropriateness of the "X is a gene for Y" concept: 1) strength of association, 2) specificity of relationship, 3) noncontingency of effect, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. Evidence from psychiatric genetics is then reviewed that address each of these criteria. The concept of "a gene for" is best understood as deriving from preformationist developmental theory in which geneslike preformationist anlagen"code for" traits in a simple, direct, and powerful way. However, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the concept of "X is a gene for Y." The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in complex causal pathways. The phrase "a gene for" and the preformationist concept of gene action that underlies it are inappropriate for psychiatric disorders. (Reprinted with permission from the American Journal of Psychiatry 2005; 162:1243 1252[Abstract/Free Full Text] )

The last 20 years has seen the rise of "GeneTalk" (1). A central phrase in GeneTalk, and one that has been heard widely in both lay (2) and professional arenas, is "X is a gene for Y," in which X is a particular gene on the human genome and Y is one of a wide variety of complex human disorders or traits such as depression, aggression, sexual orientation, obesity, infidelity, alcoholism, or schizophrenia. This essay begins with a brief review of the historical origins of the concept of "a gene for". I then propose criteria to assess the validity of this model of gene-phenotype relations and go on to evaluate these criteria as applied to genetic effects on psychiatric disorders. The essay concludes with general observations about our preconceptions and the reality of gene

action in psychiatric disorders. Although many of the issues raised in this essay are equally applicable to etiologically complex medical disorders, the focus here will be on psychiatric illness.

HISTORICAL ORIGINS OF THE CONCEPT OF "A GENE FOR"

Since humans started speculating about the nature of development and inheritance, a number of different conceptualizations have emerged about the nature of the guiding forces in these processes (3). In the 20th century, this discourse has come to focus largely on the nature of what Mendel originally termed "anlagen" or "elements," which in 1909 became "genes" (4). Of the multiple different views of the nature of the "gene," the one in which we are interesteda gene defined by the phenotype that it causesoriginated in the developmental theory of preformationism (5). One of the earliest articulated theories of development, preformationism was first proposed by Aristotle but became particularly influential in the 17th century (3, 5, 6). The essentials of the theory are eloquently described by Jacob: At a time when living beings are known by their visible structure alone, what has to be explained about generation [i.e., development] is the maintenance of this primary structure through succeeding generations. The structure cannot itself disappear; it has to persist in the seed from one generation to another. To maintain the continuity of shape, the "germ" of the little being to come has to be contained in the seed; it has to be "preformed." The germ already represents the visible structure of the future child.. . .It is the plan for the future living body. . .already materialized, like a miniature of the organism to come. It is like a scale model with all the parts, pieces and details already in position.. . .Fertilization only activates it and starts it growing. Only then can the germ develop, expand in all directions and acquire its final size, like those Japanese paper flowers which, when placed in water, unwind, unfold and assume their final shape. (7, p. 57) In preformationism, the egg or sperm was understood to contain all the final traits of the mature organism. Development consisted of the expansion of these preformed characteristics (or anlagen) into the individual traits of the adult organism. That is, these anlagen were truly for the adult traits with which they had a simple and direct causal relationship. In the 19th century, as the young field of biology struggled to fathom the mechanism of transmission of traits across generations, a number of the proposed theories of inheritance (where the "units" of inheritance had names such as pangenes, stirps, and gemmules) had important preformationist themes (3, 4). When Mendels groundbreaking work on genetics (originally published in 1866) was rediscovered in 1900, one common interpretation was that his "elements of inheritance" were the discrete anlagen predicted by preformationist theories (5). This interpretation was favored by two of the most influential geneticists of the day, the Dutchman de Vries (the most famous of the three "co-rediscovers" of Mendel [4]) and the Englishman Bateson (8).

In summarizing this exciting period in the history of biology, Allen (9) writes The implications that the discreteness of the gene implied the organism was constructed as a "mosaic" of adult traits was given explicit voice by Bateson with the first years of his encounter with Mendelism. Allen goes on to quote two passages from Bateson written, respectively, in 1901 and 1902 (9): In so far as Mendels law applies, the conclusion is forced upon us that the living organism is a complex of characteristics of which some, at least, are dissociable and are capable of being replicated by others. We thus reach the conception of unit characters which may be rearranged in the formation of reproductive cells. The organism is a collection of traits. We can pull out the yellowness and plug in greenness, pull out tallness and plug in dwarfness. Bateson was recasting, in a new language, preformationist concepts. The Mendelian anlagen (later genes) could be defined by their relationship to the particular phenotype (or "unit character") with which it had a privileged causal link. That is, such genes caused phenotypes in the same way that the preformationist anlagen prefigured adult traits. From this perspective, it made sense to speak of "a gene for greenness," "a gene for tallness," or a gene for any of the other innumerable unit characteristics of the adult organism. It is in this context that a rarely discussed early chapter of psychiatric genetics in the United States must be viewed, when reports appeared claiming to find, in series of large pedigrees, evidence for Mendelian genes "for" "Nomadism or the wandering impulse" (10) and "the neuropathic constitution" (11). This preformationist concept of the gene proved attractive to medical geneticists who, over the course of the 20th century, showed that most classical genetic disorders in humans (termed "Mendelian" diseases in honor of the Austrian monk) were due to hereditary units that behaved just like those first examined by Mendel (12). While medical geneticists came to understand that in biological systems, genes actually code for proteins, it became convenient and seemingly natural to think about preformationist-like genes for these classical genetic diseases in humans. The last 30 years have seen three interrelated further themes in the "a gene for" story. First, in the mid-1970s two influential books appeared that heightened the profile of genes and their potential impact on human behavior. "Sociobiology: The New Synthesis" by Wilson (13) launched the field of sociobiology (and later evolutionary psychology), discourse in which commonly included the concept of "genes for" a wide range of traits, including altruism, territoriality, jealousy, and ethics. "The Selfish Gene" by Dawkins (14) proposed a gene-centered view of evolution in which an organism, with its wide array of phenotypes, was viewed as a vehicle through which genes replicate themselves over evolutionary time. Second, with the developmental of an ever increasing set of powerful molecular tools, the specific genes and then the specific mutations in those genes were discovered that were responsible for all major classic human genetic disorders. So, when speaking about "a gene

for Y" in which Y was sickle-cell anemia, cystic fibrosis, or Huntingtons chorea it became possible to conceive of the gene not only as an abstract transmitted "unit" but also as a discrete piece of DNA at a specific location on a chromosome. Third, prompted by the sequencing of the human genome, the concept that DNA represented the "blueprint" of life (or in related versions the "code" or "recipe" for life) was widely promulgated in both the scientific and lay literature (2). The preformationist themes in this metaphor are evident: genes are to phenotypes as blueprints of a building are to the building themselves. So, this historical sketch suggests that our current concept of "X is a gene for Y" in humans has four major interrelated historical roots. First, the concept that development anlagen could be "for" adult traits arose in preformationist developmental theories. Second, the discovery of Mendels "elements" was interpreted by some as verifying this concept. Third, the idea that genes could be "for" human traits was supported by the discovery that genes for classical Mendelian medical disorders often acted just like the hereditary elements found in Mendels pea plants. Finally, these concepts became linked to DNA by a series of stunning discoveries in the last 20 years, so that strength of the "icon" of the double helix provided particular luster to potential discoveries in psychiatry of "a gene for".

CRITERIA FOR THE CONCEPT OF "A GENE FOR"

The remainder of this essay addresses the question of whether this preformationist model of gene actionin which genes are "for" phenotypesis appropriate for psychiatry. Based in part on prior efforts to develop guidelines for causal inference in epidemiology (e.g., reference 15), I suggest five criteria by which to judge the validity of the claim "X is a gene for Y": 1) strength of association of X with Y, 2) specificity of relationship of X with Y, 3) non-contingency of the effect of X on Y, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. In sum, I argue that If gene X has a strong, specific association with disease Y in all known environments and the physiological pathway from X to Y is short or well-understood, then it may be appropriate to speak of X as a gene for Y. But first, a few details are needed. The scientific basis of most claims that "X is a gene for Y" results from a statistical test called association analysis. In its simplest form, this test compares the frequency of specific DNA variants in or around gene X in a set of cases with disorder Y and a set of matched control subjects. An association is claimed if the frequency of these variants differ significantly in cases and control subjects. In both a conceptual and statistical sense, this approach is no different from the methods commonly used in the biomedical and social sciences to assess the relationship between putative risk factors and outcome variables such as smoking and lung cancer or childhood sexual abuse and depression. Therefore, standard "a gene for" claims are based on statistical and not biological grounds. Biological studies that trace etiologic pathways from X to Y should follow claims for association and would certainly provide confirmatory data. However, they have been very rare to date in psychiatric genetics. On its own, a significant p value in an association study

tells you nothing about the nature of the causal relationship between the gene and the disease.

STRENGTH OF ASSOCIATION
As with any risk factor for any outcome, the strength of association between a specific gene and a particular disease can vary in magnitude. In considering the criteria for "a gene for. . .," an historical standard of comparison is what has come to be called a Mendelian gene. The action of Mendelian genes is deterministic and not probabilistic. If a plant inherits a particular copy of the gene for wrinkled peas, it would not matter how much sunshine the plant received or the quality of its fertilizer. The plant will have wrinkled peas no matter what the environment does. In humans, we have many diseases that are due to Mendelian genes that behave exactly like the genes Mendel studied in his pea plants (12). If you have one copy of the pathogenic gene for Huntingtons disease, it does not matter what your diet is, whether your parents were loving or harsh, or if your peer group in adolescence were boy scouts or petty criminals. If you have the mutated gene and you live long enough, you will develop the disease. Furthermore, for most Mendelian genes in man, the only way to get the disorder is to have the disease gene. There is no way to "acquire" cystic fibrosis or Huntingtons disease through environmental exposure. So if having the disease gene always produces the disorder and the disorder never occurs without the disease gene, this produces a perfect association between the disease gene (X) and the disorder (Y). (Reality is somewhat more complex. Most Mendelian genes in man contain several different mutations, each of which can cause diseases that are sometimes of quite variable severity. But this claim still holds for all mutations of the gene considered together.) The strength of an association between a risk factor and a disease is most frequently quantified by a statistic called the odds ratio. Formally, the odds ratio is defined as the ratio of the odds of developing the disease among those exposed to the risk factor and the odds of disease among those not exposed to the risk factor. For Mendelian disorders in man, since the first of these figures is one and the second is zero, the odds ratio for the disorder given the pathogenic gene is infinite. Since this is a rather stringent criteria, for the sake of argument, let us say the association with Mendelian-like genes (an historical model for the concept of "a gene for") has an odds ratio of approximately 100 (Figure 1 ).

Figure 1. A Comparison of Estimated Odds Ratios for the Strength of Association Between Risk Factors and Key Outcomesa a Although the odds ratio for a classic Mendelian gene is actually , we estimate it here at approximately 100. Strong association (here odds ratio=15) approximates that seen between heavy smoking and lung cancer, industrial exposure to asbestos and mesothelioma, and severe stressful life events and the onset of major depression. Moderate association (odds ratio=5.0) approximates that seen for apolipoprotein E-4 and Alzheimers disease as well as the protective effect in Asian populations of the ALDH2*2 copy of the aldehyde dehydrogenase gene on risk for alcoholism. The associations seen between individual genes (or high-risk haplotypes) and psychiatric disorders (odds ratio=1.5) is an approximation obtained from a review of the current literature.

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Are there any genes whose strength of association with a psychiatric disorder is Mendelianlike? Two related sources of information, both gathered in the last two decades, indicate that the answer to this question is almost certainly "No." First, a gene that has a deterministic or nearly deterministic relationship with a phenotype produces an unmistakable signature in the pattern of illness in large pedigrees. Numerous investigators have now searched many parts of the globe (including nearly all psychiatric facilities in a modest-sized country [16]) seeking pedigrees in which major forms of psychiatric illness especially schizophrenia and bipolar illnessare distributed in the pattern expected from a Mendelian-like gene. Such pedigrees have not been found. Second, Mendelian-like genes also produce a distinctive result in genome-wide linkage studies, which effectively sweep the human genome looking for regions that contain genes that have an impact on risk of illness. While the technical details need not concern us, experts agree that for those disorders studied in genome-wide linkage scans of reasonable size and qualityespecially schizophrenia, bipolar illness, panic disorder, and eating disordersconclusive evidence has accumulated that even moderately rare genes of Mendelian-like effect do not exist. (The available evidence does not permit us to rule out, however, very rare Mendelian-like genes.) So, if we lack Mendelian genes for psychiatric disorders, with their very high odds ratios, what sort of magnitude of associations might we expect? One set of benchmarks might be provided by three examples of what would be considered very strong associations in epidemiology. The estimated odds ratio between heavy smoking and small cell carcinoma

of the lung is approximately 20 (17), between industrial exposure to asbestos and mesothelioma is approximately 15 (18), and between severe stressful life events and the onset of major depression is approximately 12 (19). Another more modest benchmark is provided by the two outstanding genetic association results in neuropsychiatry of the last decades. The association between the pathogenic "4 allele" of the apolipoprotein E gene and Alzheimers disease produces, in Caucasian populations, an odds ratio of approximately 3.0 (20). In Asian populations, the possession of the slow-metabolizing (ALDH2*2) copy of the aldehyde dehydrogenase gene conveys up to a 10-fold reduction in risk for the development of alcoholism (21). So, as depicted in Figure 1 , we have three possible benchmarks for the strength of the gene-phenotype association for psychiatric disorders: Mendelian-like (odds ratio of approximately 100), strong (odds ratio=1220), or moderate (odds ratio=310). Trying to summarize the magnitude of association found between functional candidate genes and psychiatric disorders is problematic because of the multiple methodologic difficulties in the interpretation of such studies (2224). Greatest reliability should be placed on the results of meta-analyses, which are now beginning to appear in the literature. A PubMed search from 2000 on (using publication type of "metaanalysis" and search words "gene" and "association") followed by a hand search and elimination of duplication yielded 10 significant meta-analytic estimates of odds ratios between individual genes and psychiatric disorders (Table 1 ) (excluding results from those meta-analyses that did not support the original positive reports). The odds ratios ranged from 1.07 to 1.57 with a median of approximately 1.30.

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Table 1. Meta-Analysis Results Published Since 2000 for Studies of Association Between Individual Genes and Psychiatric Disorders

Another strategy to localize candidate genes is to look for them under linkage peaks (socalled positional candidate genes). In schizophrenia, replicated evidence is now emerging for several such genes (28). For these genes, disease-associated haplotypessmall sections of DNA that have traveled together over evolutionary timecan often be found. The two

best replicated positional candidate genes for schizophrenia are dysbindin 1 and neuregulin 1. Not counting the original reports (where the effect size might be biased upward), estimates are available for the association between high-risk haplotypes and schizophrenia for both of these genes. For dysbindin, odds ratios of 1.24 (29), 1.23 (30), 1.40 (31), 1.70 (32), and 1.58 (33) have been reported or calculated from replication reports. For neuregulin 1, two replications were noted in a recent review, with odds ratios estimated to be 1.25 and 1.80 (28). Taken together, the meta-analyses of functional candidate gene association studies and early results from positional candidate genes suggest that the magnitude of the associations between individual genes and psychiatric illnesses have small odds ratios, largely from 1.1 to 1.6. Compared to our benchmarks, this effect size is very modest (Figure 1 ). Perhaps genes (or particular mutations or haplotypes) of larger effect size will be found. While results from linkage studies suggest that this is unlikely, it cannot be ruled out. Also to be considered is the statistical dictum that the first set of effects detected in any research area tend to be the most robust. If this is correct, further genes discovered for psychiatric disorders are likely to have smaller average effects than the genes found to date. The preformationist concept of "a gene for" implied a predetermined and largely irrevocable link between gene and phenotype. This is the pattern of association observed between gene and phenotype from Mendels original traits and for Mendelian genetic disorders in humans. By contrast, for psychiatric disorders, individual genes appear to have a quite modest association with psychiatric illness. While they may have an impact on risk, individual genes hardly predetermine illness, as would be expected if we had discovered "genes for" mental disorders.

SPECIFICITY OF ASSOCIATION
The second criterion to evaluate the appropriateness of the concept of "X is a gene for Y" is the degree of specificity in the relationship between X and Y. As illustrated in Figure 2 , does X influence risk for any other disorders in addition to Y? Or are there other genes that contribute to Y in addition to X?

Figure 2. Possible Gene-to-Phenotype Relationshipsa a Possible relationships between genes on the lefthand side of thefigure and phenotypes on the righthand side are shown. In a one-to-one relationship, gene X causes only phenotype Y, and phenotype Y is caused only by gene X. In a one-to-many relationship, gene X causes several phenotypes each in turn being only caused by X. In a many-to-one relationship, phenotype Y is caused by several genes each in turn only causing Y. In a many-to-many relationship, each gene causes several phenotypes and each phenotype is caused by several genes.

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In preformationist theory, anlagen had highly specific associations with the adult traits into which they developed. The hereditary elements of the pea that Mendel studied also had quite specific phenotypic effects. That is, one gene influenced pea color but not shape or height while another influenced shape but not height or color. However, as genetics developed, many genes were found that impacted on a variety of phenotypic characteristicsa phenomenon called pleiotropy. In man, many Mendelian genes produce one and only one disease syndrome (although sometimes of varying severity depending on the specific mutation). But there are exceptions where different abnormalities in a single gene can produce distinct genetic diseases. How specific are individual genes in their impact on risk for psychiatric disorders? Do most genes influence risk for one and only one psychiatric disorder? Twin studies, which study "genes" in the aggregate, suggest that genetic risk factors for psychiatric disorders are often nonspecific in their effect. A large-scale twin study of seven psychiatric and substance use disorders found one common genetic risk factor predisposing to drug abuse, alcohol dependence, antisocial personality disorder, and conduct disorder and a second common genetic factor influencing risk for major depression, generalized anxiety disorder, and phobia (34). Overlap of genetic risk factors for multiple disorders have been demonstrated in other twin studies (e.g., references 3537). We know much less about the specificity of the spectrum of effects on psychiatric disorders of individual genes. Meta-analyses reviewed in Table 1 show that variants at one gene (the 5-HT2A receptor) may predispose to risk for three different disorders (schizophrenia, bulimia, and anorexia nervosa). A pair of overlapping genes on chromosome 13q (termed G30 and G72) may be associated both with schizophrenia and bipolar illness (28). A

number of overlapping positive regions in linkage genome scans for bipolar illness and schizophrenia have led some to argue that this reflects shared genes between these two disorders (38). While difficult to evaluate critically, claims have been made that several popular candidate genes (e.g., serotonin transporter, dopamine transporter, dopamine 2 receptor) are significantly associated with a wide variety of psychiatric disorders or psychiatrically relevant traits (39, 40). While much remains unknown, current evidence suggests that many genes that influence risk for psychiatric disorders will not be diagnostically specific in their effect, thereby resembling the one-to-many relationship in Figure 2 rather than the one-to-one relationship. We are on firmer ground in evaluating whether genetic risk for psychiatric disorders results from the action of a single gene (the one-to-one relationship in Figure 2 ) or multiple genes (the many-to-one relationship in Figure 2 ). Some evidence bears on this question indirectly, as follows. Twin and adoption studies provide convincing evidence for significant genetic effects on virtually all major psychiatric disorders (41). Therefore, genes that affect risk for these disorders must exist somewhere on the human genome. Linkage studies examine how these aggregate genetic risk factors are distributed across the genome. If genetic risk resulted from a single gene, then all the linkage "signal" would be concentrated in a single location, with a resulting clear and robust statistical linkage peak. But, as noted earlier, this is a pattern that has not been observed in published genome scans for psychiatric disorders. Instead, a number of modest linkage peaks are usually seen, suggesting that the "packets" of genetic risk for these disorders are widely dispersed across the genome. (To complicate matters, genome scans will underestimate the number of genomic regions involved because of low power to detect genes of small effect size, but will overestimate the number because some of the observed "peaks" will be false positives.) Recently, data have emerged that addresses this question directly. A careful meta-analysis of 20 genome scans for schizophrenia has suggested 10 genomic regions likely to contain susceptibility genes (42). In addition, current evidence of bipolar disorder, the second-beststudied psychiatric disorder by linkage scans, also suggests multiple loci (43). The specificity of association implied in the "a gene for" concept has another implication worth exploring. Consistent with preformationist theory, specificity of gene action implies that the gene contains all information needed for the development of the trait. The environment might impact on the final phenotype, but its effect is nonspecific. That is, the gene "codes for" the trait, while the environment reflects background factors that support development but is not in and of itself "information-carrying." To illustrate how commonly we see genes and environment in this light, it is worth pondering a curious and asymmetrical feature of GeneTalk. While we find it easy to use the phrase "X is a gene for Y," it feels quite odd to say "A is an environment for B." For example, a large body of empirical work supports the hypothesis that severe life events are important environmental risk factors for major depression (44). The magnitude of the association between such events and the subsequent depressive episode is far greater than that observed for any of the genes that we have reviewed here. Yet, who has heard the phrase "a romantic breakup is an environment for depression"? I suggest that we feel comfortable with "X is a gene for Y" and not "A is an environment for B" because we

implicitly assume that genes have a privileged causal relationship with the phenotype not shared by environmental factors. However, empirical evidence does not support the position that genes code specifically for psychiatric illness while the environment reflects nonspecific "background effects." By definition, environmental factors are central to the etiology of posttraumatic stress disorder. In the aforementioned multivariate twin model, what distinguished major depression, generalized anxiety disorder, and phobia from one another were environmental and not genetic risk factors (34). In a detailed study of the impact of childhood parental loss on risk for common psychiatric and substance use disorders, death of a parent was specific in increasing risk for major depression and no other disorder (Kendler et al., unpublished results). Consistent with studies of stressful life events that have shown moderate separation of depressogenic and anxiogenic events (45, 46), a multivariate genetic study of symptoms of anxiety and depression showed that genetic factors influence nonspecific risk for all symptoms, whereas two environmental factors were identified that predisposed, with moderate specificity, for symptoms of depression and anxiety, respectively (47). The preformationist concept of "a gene for" implies high levels of specificity between gene and phenotype. While much remains to be learned in this area, current evidence suggests that instead of the "one-to-one" relationship implied by the concept of "a gene for. . .," genes and disorders in psychiatry are likely to have the "many-to-many" relationship depicted in Figure 2 . (The evidence that the association between individual genes and psychiatric disorders are typically weak and may often be nonspecific does not mean that the identification of such genes is unimportant. For example, such discoveries can identify pathophysiologic pathways, begin the lengthy process of clarifying how individual genes interact with each other and with environmental exposures to produce illness, and provide new targets for treatment.)

NONCONTINGENCY OF ASSOCIATION
Noncontingent association means that the relationship between gene X and disorder Y is not dependent on other factors, particularly exposure to a specific environment or on the presence of other genes. As mentioned earlier, this is a typical (albeit not uniform) feature of genes that cause classical Mendelian disorders in humans. If the association between gene and disease were contingent on particular environmental exposures, then we would have to amend our statement to read "X is a gene for Y given exposure to environment Z." Environmental contingencies for genetic effects on psychiatric disorders have been little investigated. Twin and adoption studies suggest that the impact of aggregate "genes" for major depression are altered by exposure to stressful life events (19, 48) and for schizophrenia and conduct disorder by exposure to a dysfunctional rearing environment (49, 50). A range of twin studies suggest that environmental experiences have an impact on genetic risk for several psychiatrically relevant traits, including aggression, disinhibition, and smoking (51). Recently, Caspi and colleagues have found evidence for interactions

between environmental risk factors and particular genes in the production of antisocial behavior (52) and depression (53), with the former finding having been replicated (54). We know almost nothing about gene-by-gene interactions in the etiology of psychiatric disorders. Although a number of association studies have reported interactions, I am unaware of any that have been widely replicated or supported by meta-analyses. Using statistical models applied to risk of illness in various classes of relatives, Risch has claimed that gene-by-gene interactions are important in the etiology of schizophrenia (55). Overall, we know little about the contingent nature of genetic effects for psychiatric disorders. The available information suggests that gene action contingent upon certain environmental exposures is probably not rare and may be relatively common for psychiatric disorders. This is also inconsistent with the preformationist concept of "a gene for. . .".

CAUSAL PROXIMITY
Preformationist developmental models assumed that anlagen developed directly into adult traits. The "blueprint for life" metaphor similarly assumes a direct correspondence between individual parts of the blueprint (windows, doors, fixtures) and the corresponding units of the completed building. Conceptualizing genes in this preformationist framework therefore carries the implicit assumption of a direct causal link between gene and phenotype. It is only with this assumption that usage of the "a gene for. . ." is congruent with the common meaning of the phrase "X is for Y" in English. To clarify this point, lets examine a typical list of such statements: I use a knife for buttering my toast. I have a backpack for carrying my computer to work each day. I was upset at my son for not doing his chores. In each case, there is an implied direct and immediate relationship between X and Y. To put it more formally, X and Y are directly linked in a formal logical train of action (first two examples) or thought (third example). Now, how does this common sense meaning of the word "for" apply to the phrase "X is a gene for Y"? Let me illustrate the problem with a vignette A jumbo jet contains about as many parts as there are genes in the human genome. If someone went into the fuselage and removed a 2-foot length of hydraulic cable connecting the cockpit to the wing flaps, the plane could not take off. Is this piece of equipment then a cable for flying? Most of us would be uneasy answering yes to this question. Why? Because this example violates our conception of causal proximity. When we say X is for Y, we expect X to be, to a first approximation, directly and immediately related to Y. That is not the case for the cable and flying. There are many, many mechanical steps required to get from the function of that cable to a jumbo jet rising off the runway.

Another vignette: Assume a Mendelian genetic disease due to a mutation in gene K. Gene Ks normal function is to produce an enzyme L that breaks down metabolite M in cells allowing M to be harmlessly secreted from the body. When K has a pathogenic mutation, the enzyme L that is produced no longer works. Therefore, levels of M rise, producing a well understood series of toxic effects, thereby producing the genetic disorder N. This scenario suggests the following potentially simple causal chain: mutated gene K dysfunctional enzyme L excess metabolite M disorder N. In this admittedly oversimplified story, a case could be made that gene K had sufficient causal proximity to disorder N to make plausible the claim that "K is a gene for N." However, it might be argued that even here, the complexity of the paths from levels of M to disorder N may be far from "simple." Contrast this situation to the causal chain from a gene mutation to a complex psychiatric disorder such as schizophrenia. Although early efforts have been made to begin to trace such pathways (e.g., reference 56), we probably do not know enough to articulate all the specific causal steps that would be needed to go from DNA basepair variation to, for example, the cognitive processes that predispose to delusion formation. What we can conclude with some confidence is that it will be very complex. Indeed, the causal link between that hydraulic cable and the jumbo jet flying will probably look very simple and short compared to the causal relationship between individual genes and the manifestations of schizophrenia. While the nature of the evidence reviewed here is largely inferential, it suggests that the pathways from most genes for psychiatric illness to their phenotypes would fail the causal proximity criterion implicit in the concept of "X is a gene for Y."

APPROPRIATE LEVEL OF EXPLANATION

Scientific theories typically strive to explain phenomenon at the most informative level. To provide an absurd example, no one would seek to understand the origin of hypertension at the level of quarks. In some ultimate way, quarks may be involved. But quarks are just the wrong level of inquiry for the problem. To illustrate how this issuethe appropriateness of level of explanationmay apply to our evaluation of the concept of "a gene for. . ." consider these two "thought experiments": Defects in gene X produce such profound mental retardation that affected individuals never develop speech. Is X is a gene for language? A research group has localized a gene that controls development of perfect pitch (57). Assuming that individuals with perfect pitch tend to particularly appreciate the music of Mozart, should they declare that they have found a gene for liking Mozart? For the first scenario, the answer to the query is clearly "No." Although gene X is associated with an absence of language development, its phenotypic effects are best

understood at the level of mental retardation, with muteness as a nonspecific consequence. X might be a "gene for" mental retardation but not language. Although the second scenario is subtler, if the causal pathway is truly gene variant pitch perception liking Mozart, then it is better science to conclude that this is a gene that influences pitch perception, one of the many effects of which might be to alter the pleasure of listening to Mozart. It is better science because it is more parsimonious (this gene is likely to have other effects such as influencing the pleasure of listening to Haydn, Beethoven, and Brahms) and because it has greater explanatory power. A final scenario: Scientist A studied the behavioral correlates of a particular variant at gene X and concluded "This is a very interesting gene that increases the rates of sky diving, speeding, mountain climbing, bungee jumping, and unprotected casual sex." Scientist B studied the same variant and concluded "This is a very interesting gene and effects levels of sensation-seeking." Who has done the better science? Since sensation seeking (and its close cousin noveltyseeking) are well studied traits (41), scientist B has provided results that are more parsimonious and potentially provide greater explanatory power. For example, only scientist B could predict that this gene ought to be related to other behaviors, like drug taking, that are known to be correlated with sensation-seeking. As reviewed here, genes have been and will continue to be found that have statistical relationships with risk for psychiatric disorders. However, will the action of these genes be best explained at the level of the disorders themselves? While we cannot answer this question definitively, I would judge this to be unlikely. Far more plausible is that we will find genes whose mode of action can be best understood at the level of more basic biological processes (e.g., neuronal cell migrations during development) and/or mental functions (e.g., processing of threat stimuli).

OVERVIEW AND CONCLUSION

The goal of this essay is to understand the historical origins of the key phrase "X is a gene for Y" and then to evaluate its appropriateness for psychiatric disorders. Our interest, of course, is not merely the phrase itself, but the conceptual framework that underlies this form of Gene-Talk. The use of the phrase "a gene for" implies (and in fact only makes sense in the context of) genes whichlike preformationist anlagen"code for" psychiatric illness in a simple, direct, and powerful way. I argue that the concept of "a gene for. . ." can best be understood as deriving from preformationist developmental theory which, in turn, influenced the interpretation of the concept of a gene in the work of Mendel, in medical genetics, and most recently in human molecular genetics. Five criteria were proposed for evaluating whether the preformationist

concept of "X is a gene for Y" is appropriate for psychiatric disorders. I then reviewed the available evidence, which was of variable quality, that addressed each of these criteria. The strength of association between individual genes and psychiatric disorders is weak and often nonspecific. Genes do not appear to contain all the information needed for the development of psychiatric illness, since environmental factors have, for several disorders, been shown to have causal specificity. The action of genes on psychiatric disorders may frequently be contingent on environmental exposures, although much needs to be learned in this area. The causal chain from genes to psychiatric disorders is probably long and complex. The appropriate level of explanation for gene action is much more likely to be basic biological or mental processes that contribute to psychiatric disorders rather than the disorders themselves. Thus, with varying degrees of confidence, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the preformationist concept of "a gene for. . .". The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in causal pathways of stunning complexity. On this basis, I suggest that we conclude that the phrase "X is a gene for Y," and the preformationist concept of gene action that underlies it, are inappropriate for psychiatric disorders. The strong, clear, and direct causal relationship implied by the concept of "a gene for. . ." does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely to ever discover "genes for" psychiatric illness.

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Las interacciones genesmedioambiente: Kandel, premio nbel de medicina, piensa que la influencia del medio es tan importante que puede despertar ciertos genes dormidos, lo que puede influir en la variacin del numero de receptores en la neurona, lo que terminara por influir en el funcionamiento quimico del cerebro. Estas influencias pueden ser decisivas en el curso del desarrollo del individuo y afectar la amnera como este reacciona frente a los mismos estimulos. Los tipos de enfermedades pueden ser distintos en su fenotipo segn el grado de desarrollo que afecten. El cerebro tambin es plstico y asi como enferma, los mecanismos compensatorios pueden influenciar el destino final del problema Para estudiar la relacin genes-medioambiente se han desarrollado dos modelos: a) Modelo ditesis-estrs b) Modelo reciprocidad genesmedioambiente a) Modelo ditesis-estrs: los genetistas dicen que ciertas caractersticas son heredadas y y que esas caractersticas se expresan ante el estrs, por ejemplo, la tendencia a desmayarse frente a la sangre. Cada disposicin heredada es una ditesis que es una condicin susceptible de desarrollar un trastorno. Si se hereda una tendencia o una predisposicin gentica se habla de ditesis o vulnerabilidad, y si es a una cosa determinada, una vulnerabilidad especifica, la que es gatillada por una experiencia de tal forma que entre mayor vulnerabilidad a algo, menor estimulo estresante y al revs, ante menor vulenerabilidad, mayor grado de estrs es necesario para desarrollar el trastorno. Una investigacin de Caspi, en el 2003 pone de manifiestao esta interaccion: de una poblacin de individuos seguidos desde los 3 aos hasta los 26, un 17% hizo deprrsiones y un 3% pens en el suicidio. La investigacin gentica revelo que los individuos que tenan mayor predisposicin depresiva tenan dos pares de alelos cortos, y entre este grupo, los que adems haban experimentado abusos durante la infancia presentaban dos veces mas riesgos de caer en depresin que los anteriores. En relacin a la expriencias negativas de la infancia, los que tenan alelos largos no eran afectados de la misma manera que los que tenan alelos cortos. Esta investigacin demuestar la

interaccion genes-medio y ha sido confirmada por otras posteriores con ayuda de imgenes cerebrales en que a individuos con alelos cortos las imgenes terrificantes producan mayor activacin cerebral en la regin de la amigadala que a los de alelos largos, mas resistentes al estrs. En otra investigacin, la poblacin que tenia genes asociados a la depresin, tenan tendencia a actitudes y comportamientos violentos cuando adems haban sido sometidos a maltratos infantiles, comportamientos que no se manifestaban si no ahbian estado sometido a los mismos maltratos. b) Modelo de interaccion reciproca genes-ambiente:la complejidad de la interaaciion es tal que ahora existen prubas que la dotacin gentica puede aumentar la posibilidad de encontrar elementos estresantes en la vida, es decir crear las condiciones para encontrarse com mas posibilidades de experimentar las circunstancias dificles o estresantes, como ejemplo, los fbicos a la sangre, tender a provocar pequeos accidentes para provocar la vista de la sangre. se parece esto a la compulsin a la repeticin de que habla Freud cuando describe conductas autodestructivas para el sujeto? En fecto Kendal dice que las personas con tendencias ala depresin tienden a buscar circunstancias difciles o relaciones dificles que las llevan a la depresin. Otra invesytigacion da cuenta de un geen de divorcio al decir que entre los gemelos di-cigotos exite el doble de probabilidades de divorciarse si el gemelo es divorciado y 6 veces mas si el verdadero gemeelo es divorciado. Indudablemente la gentica no lo explica todo, pero si determian ciertos rasgos de personalidad influye en que por ejemplo un individuo dependiente busque una pareja con autoridad para compensarse lo que puede llevar a divorcio por colusiones caracterolgicas inconcientes. c) El patrimonio no genmico del comportamiento: las experiencias en ratas criadas en las mismas condiciones en tres lugares distintos probo la diferencia en la expresin gentica entre ellas, lo mismo que las expreiencias de crianza en lugares cruzados de ratas recin nacidas de madres estresadas llevada a crirse con ratas calmadas pudo demostrar la influencia dela mbiente en su crianza y resistencia al estrs. Es decir, la influencia precoz de l medioambiente es tambin determinante en la expresin gentica, incluso invirtiendo su expresin como en el caso del estudio de Tienari y col, 1994 que descubrieron que los hijos de padres esquizofrnicos adptados muy precozmente presentaban una tendencia a desarrollar la enfermedad, sobre todo en aquellos adptados por familaias disfuncionales, en relacin a otros adptados por familaias sanas, lo que habla de las influencias ambientales, quese distribuyen sin embargo en relacin a la mayor o menor predisposicin gentica en porcentajes variables. d) Esta influencia reciproca tiene importancia desde el punto de vista de la prevencin de rasgos de personalidad o temperamentos inadecuados o de enfermedades mentales. Neurociencias: una visin de conjunto del SNC es fundamental para la comprensin del funcionamiento del individuo en realacion a sus comportamientos, emocioens y mecanismos cognitivos.

SNC, esta constituido por la espina dorsal y la estructura del cerebro, los sistemas nerviosos perisfricos subdividido en sistema nervioso autnomo (simptico y parasimptico) y el sistema nervioso somatico (control muscular); sistema endocrino; neurotrasmisores (serotonina, dopamina, GABA, noradrenalina) a) SNC trata toda la informacin recibida por los sentidos y reacciona cuando es necesario. El cerebro, rgano mas complejo del cuerpo humano, tiene 140.000 millones de neuronas. Las neuronas tiene dos prolongaciones: dendritas y axones que reciben y trasmiten la informacin nerviosa bajo la forma de impulsos qumicos. Entre una neurona y otra esta el espacio intersinaptico donde se desarrollan eventos importantes para la psicopatologa. La informacin qumica que se trasmite constituyen los neurotrasmisores, cuyos excesos o dficits estan asociados a grupos de patologas.

Dinamica neuronal: la fisiopatologa de cualquiera de las enfermedades mentales dice relacion con eventos producidos en cualquier nivel de la cascada de acontecimientos producidos en la trasmisin de la informacin Primer mensajero: nuerotrasmisor, neuromodulador u hormona acta sobrer un receptor que desencadenan a traves de una molcula transductora (proteina G) la activacion o inhibicin de algunas enzimas que incrementan o disminuye la concentracin de un segundo mensajero. Los segundos mensajeros actuan sobre enzimas protein-kinasas que tiene capacidad de producir cambios en proteinasespecificas mediante fosforilacion. Los terceros mensajeros (factores de transcripcion) inducen laactivacion de determinados genes que actuan como cuartos mensajeros y son a la vez factores de transcripcion que sintetizan proteinas, que constituidas en quintos mensajeros implica ya un cambio en la realidad de la neurona. El detalle del proceso es complejo b) La estructura del cerebro: constituida de dos partes, el tronco cerebral encargada de la mayora de las funciones automticas del cuerpo, y el cerebro anterior, la parte mas reciente evolutivamente. c) Hemisferios cerebrales y ncleos basales: dos hemisferios y ncleos basales situados en la sustancia blanca. (ncleo caudado y ncleo lenticular, que a su vez esta formado por el putamen y el globus pallidum con importantes funciones motoras). La corteza cerebral esta constituida por laminas conformando circunvalaciones con dos surcos principales: de Rolando y de Silvio. En el lbulo frontal existen varios surcos que separan las circunvalaciones frontal superior, media e inferior. Las funciones de la cortza frontal son mediados por distintos neurotrasmisores y se correlacionan con distintas patologas psiquiatritas: los mas cercanos son la dopamina y la serotonina

d) Diencefalo: formado por las estructuras entre los hemisferios, constituido por tlamo, epitlamo, subtlamo e hipotlamo. El talamo sirve como centro coordinador de la informacin que va a la corteza cerebral y se constituye de un complejo de ncleos funcionales que regulan distintas actividades corporales como el sueo, apetito, etc. e) Medula espinal f) El sistema nerviosos perisferico: sistema nerviosos somtico y sistema nerviosos autnomo dividido en sistema nervioso simptico y parasimptico g) El sistema endocrino y ejes HHS y HHT Los neurotrasmisores: La informacin que emite una neurona esta codificada en la forma de seales electricas que viajan por el axn a las terminales nerviosas a traves del especio sinaptico por los neurotrasmisores que actuan a nivel de diferentes tipos de receptores provocando diversos cambios a nivel de la celula post-sinaptica. Los receptores son de diversos tipos; ionotropicos que abren directamente un canal ionico que media movimientos motores y procesamiento de percepciones; metabotropicos, unidos a proteina G y tirosina cinasa que activa a los segundos mensajeros ya que estan implicados en elaboracin de emociones, aprendizaje y memoria; recptores sinapticos, que producen cambios en la transcripcion genetica e implicados en procesos mas complejos de adquisicin de memoria a largo plazo. La Dopamina, es uno de los neurotrasmisores importantes, tiene importancia en psicopatologa por su relacin con la esquizofrenia, aunque en la actualidad la accin de la clozapina que no bloquea la dopamina le otorga un rol menor. La dopamina presente en el cerebro en 4 grupos de proyecciones: nigroestratial, mesolimbica importante en la expresin de la emocion y la memoria y asocida a la produccin de sntomas positivos de la EQZ, mesocortical importante en la organizacin del comportamiento, motivacin, planificacin y comportamiento social vinculado a los sntomas negativos de la EQZ; y la proyeccion tuberoinfundibular implicado en la liberacin talamica de ciertas hormonas. La dopamina, tiene 5 tipos de receptores: excitatorios (D1 y D5) e inhibitorios (D2, D3 y D4) seria una especie de interruptor cerebral en su relacin con otros neurotrasmisores que al encontrar la via libre puede actuar, desregulando el sistema y permitiendo que aparezca el trastorno. El dficits de dopamina se asocia al mal de Parkinson. El sistema de la serotonina, nace en los ncleos del rafe, proyectandose a la corteza y la medula espeina. Tiene receptores en la cortexa frontal y en otras refiones cerebrales (5HT1a inhibitorio y 5TH2a excitatorio). Este sistema regula el humor, comportamientos y nuestros mecanismos de pensamiento. El sistema animico se correlaciona con dos compartimentos: cortical-dorsal en relacion con aspectos cognoscitivos negativos de la depresion, apatia y reatrdo psicomotor, alteraciones de la atencin y la funcion ejecutiva y el compartimento limbico-ventral que influiria en los comportamientos circadianos, somaticos y neurovegetativos de la depresion (Mayberg). Se encuentra en 6 circuitos neuronales mayores a partir del mesencfalo que algunos terminan en la corteza. Niveles bajos se asocia a comportamientos

agresivos y suicidio, a impulsividad o reacciones desproporcionadas, por lo que regulara nuestros comportamientos sexuales, agresivos y alimentarios. Se han descrito al menos 15 tipos y subtipos diferentes de receptores, que son sensibles a la serotonina. El GABA es otro neurotrasmisor que actua reduciendo la actividad post-sinaptica implicada en la reduccin de la ansiedad. Tambien recorre circuitos neuronales amplios en el cerebro, encontrndose que esta implicado en otras funciones mas alla del control de la ansiedad. La noradrenalina, estimula los receptores a y b adrenrgicos y se encuentra en el cerebro posterior regulando funciones corporales como la respiracin pero tambin en las reacciones de alarma. Puede que este realcionado con el pnico. La Dopamina, catecolamina, es uno de los neurotrasmisores importantes, tiene importancia en psicopatologa por su relacin con la esquizofrenia, aunque en la actualidad la accin de la clozapina que no bloquea la dopamina le otorga un rol menos importante. La dopamina seria una especie de interruptor cerebral en su relacin con otros neurotrasmisores que al encontrar la via libre puede actuar, desregulando el sistema y permitiendo que aparezca el trastorno. El dficits de dopamina se asocia al mal de Parkinson. El Glutamato es un neurotrasmisor vinculado a trastornos psiquiatricos desde hace 50 aos, aunque su investigacin se ha desarrollo mas en el area de los daos cerebrales isquemicos. Sin embargo, una mejor comprensin de la biologa molecular y y la fisiologia celelular de los receptores de glutamato ha potenciado la busqueda de nuevas alternativas etiopatogenicas y terapeuticas en diversos trastornos tales como la depresion, (donde los inhibidores de la recapatacion de la serotonina o norepinefrina estan lejos del ideal), en que los antagonistas del NMDA han inducido cambios importantes en la sintomatologa previamente resistente a los medicamentos convencionales, o en la Esquizofrenia, donde los efectos de los receptores antagonistas de la NMDA (Feenciclidina o Ketamina) sugieren fuertemente que la neurotrasmision y los receptores del NMDA estan comprometidos en la patognesis de la enfermedad (Moghaddam, 2003). Lo mismo ocurre con evidencias actuales de otras lineas de trabajo que implican a la mayoria de los genes asociados con altos riesgos de EQZ que pueden influenciar la funcion moduladora del receptor de NMDA o la interaccion entre los receptores intracelulares y las proteinas que vinculan al glutamato a las vias de transduccion de la seal. Implicaciones para la psicopatologa: Ejemplo TOC Influencias psico-sociales sobre la estructura del cerebro: la accin de los placebos en el control del dolor Interacciones de los factores psico-sociales e estructuras y funciones cerebrales Los antecedentes psicolgicos inducen reacciones diferentes en cada gruo cuando sonexpuestos a las mismas substancias. Por ejemplo monos que controlan su situacin son inyectados con substancias anti GABA y no se ponen ansiosos sino agresivos, mientras que los monos que tiene experiencias de no control de situaciones anteriores se transforman en mas ansiosos y con pnico. Por lo tanto una misma dosis y

sustancia tiene efectos distintos segn la experiencia psicolgica previa de los eindividuos. Otras investigaciones demuestran que las experiencia spsicologicas influyen en la estructura cerebral, en el nivel de actividad de los circuitos neuronales y en el numero de receptores en un celula. Lo mismo que la influencia del eestres sobre los ejes HHS, lo que demuestra la plasticidad del cerebro frente a los cambios inducidos. Las ciencias del comportamiento y cognitivas: condicionamientos y mecanismos cognitivos; sentimientos adquiridos de impotencia, aprendizaje social Las ciencias cognitivas y el inconciente Emociones Influencias culturales, sociales e interpersonales

Clase 2: Evaluacion y diagnstico de los trastornos psicolgicos a) Evaluacion Conceptos claves: fiabilidad, validez y estandarizacin La entrevista clnica: antedentes prximos y remotos Examen del estado mental: lucidez, apariencia y comportamiento, procesos de pensamiento, humor y afecto, funcionamiento intelectual Examen medico Evaluacin psicolgica: test y otros instrumentos Imgenes cerebrales: de la estructura y de la funcin cerebral b) Diagnostico Clasificacin Criterios o dimensiones Fiabilidad y validez diagnostica El DSM IV TR: forma multiaxial, criticas Conclusiones

Clase 3

La esquizofrenia

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Evolucion histrica del concepto Los grandes sndromes clnicos Sntomas positivos y negativos Criterios diagnosticos de la esquizofrenia segn DSM IV-TR Sub-tipos Criterios evolutivos (episdicos sin sntomas residuales entre los episodiso; o con sntomas residuales, especificando si aparecen sntomas negativos en primer lugar); episodios con remisin parcial, episodio nico con remisin completa

Otros trastornos psicticos Trastorno esquizofreniforme Trastorno esquizoafectivo Trastorno delirante Trastorno psictico breve Trastorno psictico compartido Prevalencia y causas de la esquizofrenia Epidemiologia Desarrollo: neurodesarrollo, recaidas Factores culturales

Gentica: estudios en poblaciones, gemelos, adoptados, descendeintes de gemelos, vinculaciones y asociaciones genticas, marcadores, observaciones multigeneticas Neurobiologa: neurotrasmisores, estructura cerbral, infecciones virales Influencias psicolgicas y sociales: estrs, familias y recaidas,

Tratmiento: Biolgicos Psicolgicos prevencion

PSICOPATOLOGA PARA CLNICOS

III.- TRASTORNOS Ansiosos y OBSESIVOS COMPULSIVOS Vision de conjunto

La ansiedad, fenmeno central en la historia humana, se extiende en el tiempo y la cultura de manera universal. Sin embargo, su estudio sistematico en psiquiatria clinica es reciente. Su prevalencia en la comunidad es alta y los costos asociados a su tratamiento ocupa el tercio del gasto total en servicios de salud mentals. Pese a ello, los cuadros ansiosos son a menudo mal diagnosticados y tratados en la practica medica psiquiatrita y psicologica general. En la actualidad, el campo de la investigacin clinica y neurobiologica de la ansiedad es uno de los mas interesantes y abarca aspectos dispares, desde la genetica hasta las disfunciones cognitivas, pasando por la neuroquimica, la anatomia y las contribuciuones del medio ambiente en cada uno de los trastornos ansiosos que se encuentran en el DSM IV-TR, marco de referencia para su anlisis psicopatologico en este texto. Por otro lado, el desarrollo de las tecnicas de imagen cerebral ha permitido conocer el funcionamiento cerebral y la accion de la farmacoterapia y psicoterapia en la normalizacion de la neuroanatoma funcional de los sujetos, ofreciendo un campo de reflexion y analisis muy interesante de los vinculos mente-cuerpo, tradicionalmente separados en la practica psiquiatrita de orientacin meramente biologica.

Breve historia de la neurosis Ansiedad y angustia Modificaciones del DSM

Los trastornos de ansiedad conocidos en el DSM IV estaban integrados dentro del concepto de neurosis en las anteriores versiones del DSM: la neurosis de ansiedad abarcaba el TAG y el TP y la neurosis fobica incluia la agarofobia, la fobia social, fobia especifica y el trastorno por separacion; solo la neurosis obsesiva compulsiva llevaba el mismo nombre, ahora convertido en TOC. El DSM IV-TR divide los trastornos de ansiedad en doce subtipos que incluyen el TP con y sin agarofobia, Fobia especifica o simple, agarofobia, Trastorno de Ansiedad Generalizado, TOC, Trastorno de Ansiedad debido a una condicion medica general o a abuso de sustancias, ademas del Trastorno de Stress Post-Traumatico y El Trastorno por estrs agudo, para integrar la respuesta a un estrs vivido dentro de 1 mes. Cuadros clinicos segn DSM IV TR: TAG, Trastorno panico, etc Fenomenologia del TAG Patognesis Farmacoterapia

Psicoterapia

Causas

The Structure of Genetic and Environmental Risk Factors for Anxiety Disorders in Men and Women John M. Hettema, MD, PhD; Carol A. Prescott, PhD; John M. Myers, MS; Michael C. Neale, PhD; Kenneth S. Kendler, MD Arch Gen Psychiatry. 2005;62:182-189. ABSTRACT

Background The anxiety disorders exhibit high levels of lifetime comorbidity with one another. Understanding the underlying causes of this comorbidity can provide insight into the etiology of the disorders and inform classification and treatment. Objective To explain anxiety disorder comorbidity by examining the structure of the underlying genetic and environmental risk factors. Design Lifetime diagnoses for 6 anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, and situational phobia) were obtained during personal interviews from a population-based twin registry. Multivariate structural equation modeling that allowed for sex differences was performed. Setting General community sample. Participants More than 5000 members of male-male and female-female twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measures Parameter estimates for best-fitting model. Results The full model, which contained 2 common genetic, shared environmental, and unique environmental factors plus disorder-specific factors, could be constrained to equality across male and female study participants. In the best-fitting model, the genetic influences on anxiety were best explained by 2 additive genetic factors common across the disorders. The first loaded most strongly in generalized anxiety disorder, panic disorder, and agoraphobia, whereas the second loaded primarily in the 2 specific phobias. Social phobia was intermediate in that it was influenced by both genetic factors. A small role for shared environmental influences was observed owing to a single common factor that accounted for less than 12% of the total variance for any disorder. Unique environmental influences could be explained by a single common factor plus disorder-specific effects. Conclusions The underlying structure of the genetic and environmental risk factors for the anxiety disorders is similar between men and women. Genes predispose to 2 broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety vs the specific phobias. The remaining associations between the disorders are largely explained by a unique environmental factor shared across the disorders and, to a lesser extent, a common shared environmental factor.

Circuitos neurales de la ansiedad

Disrupted Amygdalar Subregion Functional Connectivity and Evidence of a Compensatory Network in Generalized Anxiety Disorder
Amit Etkin, MD, PhD; Katherine E. Prater, BA; Alan F. Schatzberg, MD; Vinod Menon, PhD; Michael D. Greicius, MD Arch Gen Psychiatry. 2009;66(12):1361-1372. ABSTRACT

Context Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD. Objectives To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD. Design Cross-sectional study. Setting Academic medical center. Participants Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD. Main Outcome Measures Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry. Results Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased

connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network. Conclusions Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

Abnormal Attention Modulation of Fear Circuit Function in Pediatric Generalized Anxiety Disorder
Erin B. McClure, PhD; Christopher S. Monk, PhD; Eric E. Nelson, PhD; Jessica M. Parrish, BA; Abby Adler, BA; R. James R. Blair, PhD; Stephen Fromm, PhD; Dennis S. Charney, MD; Ellen Leibenluft, MD; Monique Ernst, MD, PhD; Daniel S. Pine, MD Arch Gen Psychiatry. 2007;64(1):97-106. Context Considerable work implicates abnormal neural activation and disrupted attention to facial-threat cues in adult anxiety disorders. However, in pediatric anxiety, no research has examined attention modulation of neural response to threat cues. Objective To determine whether attention modulates amygdala and cortical responses to facial-threat cues differentially in adolescents with generalized anxiety disorder and in healthy adolescents. Design Case-control study. Setting Government clinical research institute. Participants Fifteen adolescents with generalized anxiety disorder and 20 controls. Main Outcome Measures Blood oxygenation leveldependent signal as measured via functional magnetic resonance imaging. During imaging, participants completed a faceemotion rating task that systematically manipulated attention. Results While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful faces than to happy faces in a distributed network including the amygdala, ventral prefrontal cortex, and anterior cingulate cortex (P<.05, small-volume corrected, for all). Right amygdala findings appeared particularly strong. Functional connectivity analyses demonstrated positive correlations among the amygdala, ventral prefrontal cortex, and anterior cingulate cortex. Conclusions This is the first evidence in juveniles that generalized anxiety disorder associated patterns of pathologic fear circuit activation are particularly evident during certain attention states. Specifically, fear circuit hyperactivation occurred in an attention state involving focus on subjectively experienced fear. These findings underscore the importance of attention and its interaction with emotion in shaping the function of the adolescent human fear circuit.

Neural Bases of Social Anxiety Disorder

Emotional Reactivity and Cognitive Regulation During Social and Physical Threat Philippe R. Goldin, PhD; Tali Manber, MA; Shabnam Hakimi, BA; Turhan Canli, PhD; James J. Gross, PhD Arch Gen Psychiatry. 2009;66(2):170-180. ABSTRACT

Context Social anxiety disorder is thought to involve emotional hyperreactivity, cognitive distortions, and ineffective emotion regulation. While the neural bases of emotional reactivity to social stimuli have been described, the neural bases of emotional reactivity and cognitive regulation during social and physical threat, and their relationship to social anxiety symptom severity, have yet to be investigated. Objective To investigate behavioral and neural correlates of emotional reactivity and cognitive regulation in patients and controls during processing of social and physical threat stimuli. Design Participants were trained to implement cognitive-linguistic regulation of emotional reactivity induced by social (harsh facial expressions) and physical (violent scenes) threat while undergoing functional magnetic resonance imaging and providing behavioral ratings of negative emotion experience. Setting Academic psychology department. Participants Fifteen adults with social anxiety disorder and 17 demographically matched healthy controls. Main Outcome Measures emotion ratings. Blood oxygen leveldependent signal and negative

Results Behaviorally, patients reported greater negative emotion than controls during social and physical threat but showed equivalent reduction in negative emotion following cognitive regulation. Neurally, viewing social threat resulted in greater emotion-related neural responses in patients than controls, with social anxiety symptom severity related to activity in a network of emotion- and attention-processing regions in patients only. Viewing physical threat produced no between-group differences. Regulation during social threat resulted in greater cognitive and attention regulationrelated brain activation in controls compared with patients. Regulation

during physical threat produced greater cognitive controlrelated response (ie, right dorsolateral prefrontal cortex) in patients compared with controls. Conclusions Compared with controls, patients demonstrated exaggerated negative emotion reactivity and reduced cognitive regulationrelated neural activation, specifically for social threat stimuli. These findings help to elucidate potential neural mechanisms of emotion regulation that might serve as biomarkers for interventions for social anxiety disorder.

Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication
Ronald C. Kessler, PhD; Patricia Berglund, MBA; Olga Demler, MA, MS; Robert Jin, MA; Kathleen R. Merikangas, PhD; Ellen E. Walters, MS Arch Gen Psychiatry. 2005;62:593-602. Context Little is known about lifetime prevalence or age of onset of DSM-IV disorders. Objective To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older. Main Outcome Measures substance use disorders. Lifetime DSM-IV anxiety, mood, impulse-control, and

Results Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups.

Conclusions About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.

Rasgos ansiosos y del temperamento Neuripsicologia de los trastornos ansiosos Los tastornos ansiosos tienen tendencia a encontrarse en las mismas familias, lo que obedece en parte a factores de indole genetica. Existen numerosos estudios en este sentido que comparan gemelos y padres de nios ansiosos. Por lo tanto, pareciera que existe una vulnerabilidad biologica general, como en la mayoria de los trastornos psiquiatricos que nos ayudara a comprender la etiopatogenia de este trastorno. El decenio 2000-2010 ha sido promisorio en la entrega de informacin acerca de la interrelacion genetica y ambiental en la expresin fenotipica de los cuadros ansiosos, la aparicion de nuevos genes vinculados con la vulnerabilidad de los individuos a desarrollar clinica de ansiedad (Crowe) (Weissmann) (Flugge and Fuchs) (McEwen) y a comprender los mecanismos fisiopatologicos subyacentes como tambien las bases moleculares que permitira un mejor tratamiento de estos cuadrso clinicos.

El espectro de patologas del TOC (Bruno Aouizerate, Jean Ives Rotg)

El concepto de un espectro de patologas con caractersticas de repeticin de conductas vinculadas al TOC como la tricotilomania y la dismorfobia, proviene del psicoanlisis, encontrando en la actualidad un nuevo impulso en base a que todas ellas responden a los inhibidores selectivos de la serotonina. Todavia no existe consenso en torno a cuales de los cuadros descritos corresponden a este espectro que comparte aspectos fisiopatolgicos y de tratamiento. Uno de los mas cercanos cuadros clnicos, por su fenomenologa es el sndrome de Tourette, y mas lejos la dismorfobia y la hipocrondria, aunque algunos autores consideran que otros fenmenos clnicos caractertizados por conductas repetitivas como la tricotilomania puede incluirse en este grupo. Fenomenologia Patofisiologia TOC Farmacoteria Psicoterapiua

El sndrome de Tourette

Tratamiento

Los TOC se definen por la presencia de sntomas especificos de obsesiones y/o compulsiones, con compromiso, a veces bastante grave, de las relaciones laborales o sociales de la persona afectada. A menudo, los sntomas aparecen progresivamente en la infancia y adolescencia, aunque en algunas oportunidades aparecen agudamente, despus de una depresion, un traumatismo o acontecimiento vital importante, y persisten con una cronicidad cercana al 80% de los pacientes, durante toda la vida del sujeto. La prevalencia se encuentra alrededor del 1.9 al 3.3% en el curso de la vida y es junto a las depresiones mayores, las fobias y los abusos de subtancias, una de las patologas mas frecuentes de la practica clnica. Se encuentra generalmente asociada a otros cuadros clnicos, en comorbilidad con las depresiones mayores, en mas del 60%, con los TB, y tambin con los trastornos ansiosos en cualquiera de sus modalidades clnicas. Una relacin de comorbilidad importante se encuentra tambin con los T. alimentarios y los Abusos de substancias como el alcohol. Con el Sindrome de G de la Tourette tiene una relacin especial compartiendo caractersticas fenomenolgicas y bases fisiopatolgicas. Desde el punto de vista psicopatolgico, el TOC es un cuadro heterogneo sintomticamente, aunque es posible separar varios grupos de pensamientos obsesivos: de contaminacin, de obsesiones vinculadas al cuerpo o somaticas, de orden y simetra y obsesiones con temas agresivos y sexuales. Las compulsiones son mayoritariamente de verificacin, seguidas de aquellas conductas de limpieza o lavados, de ordenar o clasificar y de acumulacin y coleccin de cosas u objetos. El cuadro clnico parace con precocidad en la vida del sujeto, alrededor de la adolescencia. Su comienzo es generalemnte insidioso, con intermitencias con periodos intercriticos de normalidad, para hacerse crnico con los aos. El impacto sobre la calidad de vida del sujeto, su trabajo o estudios es importante. El DSM IV-TR exige para su diagnostico los siguientes criterios:

En las dos dcadas pasadas se ha hecho un notable esfuerzo en comprender su fisiopatologa en bsqueda de hiptesis que permitan comprender mejor la etipopatogenia del cuadro y prononer alternativas de tratamientos. La investigacin clnica y experimental con la ayuda de las imgenes cerebrales apunta a conocer las

relaciones funcionales y estructurales y los aspectos neuroqumicos a la base del cuadro clnico, su ubicacin neuroanatomica, y definir con mas claridad los procesos cognitivos y emocionales que ocupan un lugar central en su patogenia en relacin con la fenomenologa clnica. Las obsesiones son definifdas por los pacientes por la irrpcin intrusiva e persistente de una idea, un impulso o una representacin que se vive como un fenmeno patolgico, que surge de su propia activida psquica imponindose en ella de tal forma que se matienen pese al esfuerzo por desembarazarse de ellas. El carcter egodistonico del fenmeno, es traducido por el paciente a una imposicin externa de ideas obsesivas, vividas con angustia y realatadas con un lenguaje claramente notificativo en el sentido de Roa. Las compulsiones son comportamientos repetitivos imposibles de resistir por le paciente, quien se ve obligado a su realizacin. Esto implica que el paciente siente que los pensamientos obsesivos son en efecto una sobreestimacion de consecuencias negativas a las cuales puede exponerlos un acto o conducta suya errada, de la cual surge la duda persistente y angustiosa del error cometido que lo hace sobredimensionar los riesgos de acontecimientos lamentables y perjudiciales para si mismo o su entorno inmediato, en la medida que la duda se alimenta de la ansiedad de no tener una respuesta certera de que es lo que habra hecho, dicho o actuado. La compulsin aparece en este contexto de duda persistente como la repuesta que contribuye a calmar la ansiedad a las consecuencias del error supuestos del sujeto obsesivo, ya sea en un sentido preventivo o anticpatorio, o a reducir mediante diferentes rituales de limpieza o lavado, las consecuencias perjudiciales predefinidas en su mente del error incurrido. Los actos de verificacin consisten en en la necesidad de asegurar que la consecuencia negativa, producto de su error, ha sido sobreestimada, poniendo en el acto compulsivo una atencin absoluta para que se realicen todas las etapas que aseguren el adecuado ritual que le permita expurgar su duda culpable. Si se salta un paso, vuelve a repetir, a veces hasta el cansancio el ritual compulsivo, que le asegure un alivio durable. La reiteracin fenomenolgica descrita supone en el sujeto la puesta en marcha de procesos cognitivos, emocionales, motivacionales que tiene un asiento en la funcin de diversas estructuras cerebrales o de circuitos cerebrales vinculados con ellos. Una de las reas estudiadas es la corteza orbito-frontal implicada en funciones cognitivas, especialmente al deteccin de los errores. (p.5)

EXAMEN CLINICO Examen clinico de la expresin del paciente nos entrega elementos basicos de orientacin para el diagnostico clinico. En este sentido: La mimica del paciente, la expresin de su mirada, la actitud, sus estados afectivos acompaan generalmente el decurso de pensamiento y discurso. Si esta es generalizada, invadiendo la expresin corporal del individuo en relacin con sus

estados afectivos de euforia y exaltacin, toma el nombre de hipermimia maniaca o con movimientos hiperexpresivos en el caso de la histeria, de terror en los cuadros oniroides, de extasis en el delirante mstico, o por el contrario la hipomimia de la inhibicin y el dolor psiquico en el paciente depresivo con caracteristicas melancolicas. La disrelacion entre expresin y contenido, que caracteriza la paramimias o mimicas discordantes en la esquizofrenia, acompaada de risas inmotivadas deben diferenciarse de las ficticias, propias de los pacientes disociados histricos

La sicopatologa data desde el siglo XVIII de la mano de Pinel y de Janet y se ha enriquecido con el tiempo por otros cultores transformandose en una reflexion teorica sobre la clinica psiquiatrita, como una abstraccin del hecho clinico en si. (Pelegrino) La sicopatologa clinica que proponemos se caracteriza por un enfoque global e integrado de los fenmenos patologicos, acompaada de de una descripcin rigurosa de ellos, siempre contextual y vinculante con la experiencia vital del sujeto, con los objetivos de extraer lo esencial e invariante de sta de clasificacion de las patolog, correlacionandola con la evidencia aportada de la neurociencia actual y los otros instrumentos de conocimientos aportados por la investigacin epidemiologica, usando como guia integradora de la informacin la adherencia a un sistema de clasificacion de las patologas mentales como el DSM IV-TR o el ICD 10, de tal forma de entregar al estudiante un conjunto coherente de herramientas de analisis para el estudio de un caso particular. Obviamente, un modelo integrado como el que se ofrece difiere de los enfoques ateoricos explcitamente aceptados en los sistemas clasificatorios de las enfermedades mentales al uso, cuyo objetivo declarado es dejar de lado la discusin sobre el origen de los trastornos mentales poniendo de relieve la necesidad practica de comunicacin expedita con fines clinicos y de investigacin epidemiologica de autores de diversa raigambre teorica y cultural, favoreciendo el registro de los sntomas aparentes y el desarrollo de tecnicas de evaluacion sintomatica o de sndromes patologicos en la forma de escalas auto o heteroevaluativas, cuyos objetivos manifiestos son el screenings de poblaciones mas que el caso particular.

Los trastornos cognitivos: delirium, demencia y trastornos amnsicos 1.-Los trastornos incluidos en este apartado se recogian clsicamente entre los trastornos organicos del cerebro, es decir, eran fundamentados en un deterioro de la estructura cerebral que producia a su vez el compromiso de las funciones cognitivas de aprendizaje, memoria y conciencia. En el DSM IV-TR aparecen bajo la rbrica de

trastornos cognitivos. La razon mayor del cambio de denominacin se debe a la evidencia actual de que en toda patologa psiquiatrica-psicologica se encuentran tambin elementos de organicidad, como por ejemplo en la psicosis esquizofrenica donde la abundante bibliografa existente revelan cambios neuroquimicos y estructurales de la arquitectura cerebral en concomitancia con factores medioambientales, haciendo del concepto de organicidad inoperante para una distincin clinica entre ellos. Por ello, el rasgo del deterioro cognitivo, comn a los tres trastornos, ha sido considerado como el que mejor refleja la sicopatologa encontrada en los pacientes afectados, aunque sea criticable la difcil distincin de otros trastornos en el curso del desarrollo del individuo como los del aprendizaje o el retardo mental que aparecen precozmente y se manifiestan paradigmaticamente como trastornos de la cognicin. 2.- Cuadros clnicos 2.1 Delirium Definicin: El delirium es un cuadro clinico complejo que se define por a) la presencia de una perturbacin del estado de la conciencia del individuo y de la incapacidad de mantener la atencin acompaadas de b) trastornos cognitivos y de la percepcin, traducidos en trastornos de la memoria y desorientacin espacio-temporal, e ilusiones o alucinaciones respectivamente. Los otros criterios de definicin son, c) instalacion rpida de horas o dias, con fluctuaciones a lo largo del dia; y d) la evidencia de una o mas causas de produccin del cuadro clinico, en base a la evaluacion fisica y de laboratorio, imagineria cerebral u otros instrumentos diagnosticos.

Psicopatologa: El cuadro clinico se manifiesta por la aparicion mas o mas o menos brusca de de horas a das respecto a un estado de normalidad previa, de trastornos en la orientacin espacio-temporal, oscilando desde una hipervigilancia traducida en una sensibilidad muy aguda en relacion al medio ambiente, sobresaltandose frente a cualquier ruido por ejemplo, o por un estado de somnolencia, de retraccion u apatia, condiciones que fluctuan a lo largo de las horas o dias. Si se le solicita mantener la atencin sobre un objeto o una tarea, es incapaz de mantenerla distrayendose en funcion de cualquier otro estmulo, asi como es incapaz de repetir series numericas sin cometer errores o de repetir a la inversa los 12 meses del ao. Sigue difcilmente las indicaciones entregadas a diferencia de los dementes que a pesar de su deterioro cognitivo son capaces de seguir ordenes simples como las referidas a vestirse primero con el pantaln y despus con su camisa. El paciente con delirium ES INCAPAZ DE constestar preguntas simples tales como que ha desayunado en la maana o quien lo ha visitado revelando un deterioro de su memoria de hechos recientes, y tambien puede manifestarse desorientado con respecto a lugares y objetos. El pensamiento desorganizado se expresa en un discurso incoherente, enlentecido (bradepsiquia) o excitado y taquipsiquico. La perdida de control mental en los cuadros de inicio mas gradual es

fuente de intensa angustia, como tambien el recuerdo de alucinaciones que han sido muy vvidas y terrorficas. Lipowski, Z.J. (1990) Acute confusional status. N.Y: Oxford University Press, afirma que se conocen casos escritos hace 2500 aos, lo que historicamente implica que es uno de los trastornos mentales mas precozmente conocidos. La sicopatologa alemana clasica conoci este cuadro

V Trastornos alimentarios Los trastornos alimentarios, frecuentes en nuestra realidad clnica, se han conocido mejor en estos ltimos aos. En efecto, su clnica, tratamiento y evolucin en el corto tiempo es mejor conocida como tambin sus relaciones con distintas otras patologas psiquitricas, como los trastornos del humor o trastornos ansiosos, sobre todo trastornos obsesivo compulsivos. Se encuentra en mas o menos 5% de la poblacin adolescente y de mujeres jvenes y pueden configurar cuadrso clnicos bien diferenciados como la anorexia nervosa o la bulimia, o constituir cuadros menos caracteristicos cuya evolucin y pronostico difieren para cada individuo. Principales tipos de trastornos alimentarios La anorexia nerviosa tiene como caracterstica central una conducta patolgica que constituye una verdadera estrategia de restriccin alimentaria, actitud generada ante la presencia de los otros, frente a los cuales el o la paciente disimula sus preocupaciones alimentarias ya sea por la via de minimizarla, justificarla o esconderla frente a los ojos de sus cercanos. Sus trastornos de comportamiento en relacin a la comida pueden, an algunos casos, pasar desapercibidos para esos cercanos en la medida que el trastorno ocurre a menudo en gente activa con buen rendimiento laboral o acadmico, que al mismo tiempo utiliza como pretexto la falta de tiempo, el estrs o las altas exigencias personales para justificar las irregularidades en la comida. Solo cuando el cuadro clnico se hace evidente aparecen conductas de enmascaramiento o negacin de la naturaleza de sus problemas, sin expresar por otro lado, quejas emocionales o sntomas de tipo psicolgico o psiquitricos. Las anorxicas o (os) se sienten orgullosos del control que ejercen sobre su rgimen y sobre su alimentacin, teniendo xito en el propsito de perder peso. Pero su comportamiento frente a las comidas asume actitudes caractersticas: escamotean el alimento frente a sus familiares con argumentos o pretextos de todo tipo, o comen con extrema lentitud con la finalidad de lograr una restriccin calrica o alimentaria global, sobre todo de alimentos ricos en azucares o grasas. Si bien el logro de adelgazar traducido en una perdida de peso mayor al 15% de su peso corporal, el rasgo principal o el corazn del problema reside en la obsesion por adelgazar, lo que el Prof. Roa destacaba como delirio de belleza, basado en la grave perturbacin de la imagen corporal de las anorxicas que en tanto lograban un vientre excavado, ignoraban las formas esquelticas que dejan asombrado al observador de la grave negacin de los pacientes que exhiben un temor intenso a subir de peso y recobrar sus formas, aunque se manifieste un cuadro de desnutricin severa. Regularmente los pacientes acuden a otras formas asociadas a la estrategia de adelgazamiento, para suprimir o eludir sensaciones de hambre o resistir y controlar sus necesidades: anorexigenos, laxantes,

ejercicio fsico extenuante son comnmente utilizados. El recurso a los vomitos aparece como una conducta corriente que permite un control mayor de la ingesta y del entorno, posibilitando comidas normales para disimular antes sus parientes sus preocupaciones ponderales. El DSM IV-TR describe dos tipos de anorexia nerviosa

1. La bulimia: concepto, cuadro clnico, consecuencias medicas y aspectos psicolgicos asociados (la boulimie: Francois Nef) Es el trastorno clnico alimentario mas frecuente en el sexo femenino y se define por la presencia de episodios de ingestin masiva de alimentos vivida como incontrolable, compensadas con tcnicas de purgacin como vomitos o ingesta de diurticos o laxantes, generalmente. Los episodios se desencadena impulsivamente, en momentos de soledad o estrs o a veces espontneamente. No es infrecuente que se produzcan despus de dificultades afectivas o relacionales. Para poder realizar sus conductas bulmicas, los pacientes cuidan de estar abastececidos, generalemnte de alimenbtos rpidamente consumibles, que en presencia de familares y amigos ingieren a escondidas, hasta que ven interrumpida su ingesta por sensaciones de plenitud y malestar gasticos, traducidos en dolores abdominales, nauseas y vomitos. Para cumplir con los crierios diagnosticos exigidos por el DSM IV-TR para bulimia, los episodios bulmicos deben ser repetidos al menos 2 veces a la semana durante un periodo de 3 meses (criterio C), revelando una impulsividad que se evidencia por el uso de alimentos generalmente a la mano en la casa o el trabajo, generalemnte azucarados o calricos, que se consumen apuradamente, en secreto o a hurtadillas, en un contexto adems, de ansiedad o irracionalidad que hace imposible una eleccin libre, acompaada a veces de otras ingestiones propias de una verdadera anarqua en el control de impulsos del sujeto. A diferencia de las (o) anorxicas, el peso del paciente bulmico es mas o menos normal, aunque persiste el deseo de adelgazar, no existiendo en forma organizada la estrategia de reduccin de peso como en las anorxicas. Entre los episodios agudos, aparecen conductas restrictivas acompaadas de culpabilidad o remordimientos en una bsqueda de equilibrio calrico, conductas que se hacen mas extremas cuando reaparecen las crisis, a la forma de vomitos provocados o practicas deportivas exageradas y uso de diurticos o laxantes, que continan en el tiempo sin lograr sino compensaciones aparentes, ya que su lgica se reduce a una desorganizacin alimentaria tal que determina o favorece respuestas fisiolgicas como la hipoglicemia o el hambre que condiciona vientos deseos de comida. 2. Las crisis bulmica Desde el punto de vista psicopatologico, las crisis bulimicas aparecen en las tardes, o en la noche, en soledad, desarrollandose en un esquema secuencial con varios factores que las gatillarian: ganas irresistibles de comer, sensaciones de hambre o desnutricin, estrs o afectos negativos imprecisos previos como sentimientos de soledad, rabia, ansiedad;

disputas o perdidas afectivas o situaciones frustrantes, etc., favorecidos por la disponibilidad de alimentos, ingesta de alcohol o soledad. Las crisis se detienen regularmente por la aparicion de dolores estomacales, sensaciones de plenitud gastrica o nauseosa, miedo o culpabilidad, necesidad de purgar o la llegada de terceros, para repetirse nuevamente cuando el sentimiento de malestar ha desaparecido y se han dispado los sentimientos negativos vinculados a la crisis, para continuar con posterioridad convertidas en verdaderos circulos viciosos que persisten en el tiempo. Las pacientes bulimicas experimentan una sobrerrepresentacion calorica de su alimentacin, a menudo por el tipo de alimentos ingeridos y por su forma de ingestin, a hurtadillas y fuera de horario, confundiendo ingesta subjetiva con ingesta objetiva. En los periodos intercriticos consumen una alimentacin proporcionada al igual que la poblacin normal, la que en la crisis se rompe favoreciendo la ingesta de glucidos y lipidos, para quemarlas despus con las purgas o la actividad fisica excesiva. Fisiopatologicamente, no se conoce bien los mecanismos de la saciedad en las pacientes bulimicas, pero su percepcin interna (Nef y Simon, 2004) de saciedad esta alterada, lo que perdura despus de la normalizacion del cuadro clinico. Los alimentos compuestos de glucidos y lipidos son los que se perciben menos saciedores del apetito y mas gatilladores de crisis, y paradjicamente son los mas temidos porque se asocian a la gordura. Estas observaciones dicen relacion con un desequilibrio del sistema del apetito-saciedad que tarda en recuperarse si no existe una regularizacion del comportamiento alimentario posterior. Cooper, 2003 ha indagado en la tesis de aue la bulimia tendria una funcion de regulacin emocional. La bulimia comparte algunos rasgos con los otros trastornos alimentarios, pero se diferencia de la anorexia en que los sujetos bulimicos conservan su peso normal, la ingesta alimentara es objetivamente mayor, la busqueda de ladelgadez es por motivaciones de bienestar y salud y no meramente por la pura belleza (delirio de belleza de Roa), sintiendose menos amenazadas en su identidad, conservando una conciencia nde enfermedad, reflejando vergenza de sus crisis, purgas y de la inmundicia de su cuerpo, deseando desprenderse de su patologa, por contraste con las anorexicas, que se sienten orgullosas de su delgadez extrema. La hiperfagia bulimica es otro trastorno alimentario que se caracteriza por episodios repetidos de sobreingesta pero sin el desenlace regular de la compensacin (purga o exceso de activ.), en un patron desordenado y variable entre las comidas, sin una finalidad claramente perceptible

3. Epidemiologia La bulimia tal como es descrita es un fenmeno reciente, prcticamente desconocida antes de los aos 50 del siglo XX. Con posterioridad a los aos 90 se asiste a una progresiva busqueda de ayuda especializada para su tratamiento y esto no es debido a una mejor deteccion del cuadro clinico sino mas bien a factores culturales que

disociando el cuerpo de sujeto en nuestras sociedades post-industriales, hacen del cuerpo su especio de representacin: cuerpos delgados se asocian a los habitos y valores de vida propios de una economia de mercado que valoriza la competitividad, el individualismo, la abundancia de bienes y servicios y el culto del cuerpo. La prevalencia de la bulimia se estima en 3% de la poblacin general, especialmente ne mujeres adolescentes y jvenes al comienzo de la edad adulta. Las formas incompletas pueden alcanzar un porcentaje mayor. Segn algunos autores, la sobrerepresentacion femenina se explicaRIA por la autoestima debil en las mujeres por relacion a los hombres , fuertemente influenciada por la apariencia fisica y la necesidad de aprobacin social, donde la belleza corporal y el xito social son signos de autocontrol y delgadez corporal. Por otro lado, en las mujeres adolescentes se producen fenmenos de engrosamiento corporal a diferencia de los hombres que se acercan al estereotipo de una figura masculina musculosa y deportiva, lo que hace mas estresante la vida para las adolescentes mujeres que hombres, constituyendose en otro factor de riesgo para el desarrollo del cuadro. Factores de riesgo en la bulimia (Nef) 4. 5. 6. 7. 8. Factores culturales Factores propios del desarrollo Causas: dimensiones sociales, familiares Causas: dimensiones biolgicas Causas: dimensiones psicolgicas

La bulimia se encuentra asociada frecuentemente a otras patologas psicologicas o psiquiatritas, entre las cuales se destaca los trastornos del humor y la ansiedad generalizada. De cada 2 personas bulimicas, 1 tiene un trastorno del humor. Cuando la depresion precede a la bulimia se la considera un factor de vulnerabiulidad psiquica o fisica. Para el caso de la ansiedad generalizada o social, los porcentajes de incidencia es el mismo, siendo normal la precedencia de la ansiedad acompaada de reacciones fisiologicas de estrs, donde las crisis de bulimia y las purgas pueden entenderse como mecanismos temporales de reduccin de la angustia. La asociacin con patologas adictivas es frecuente. A este abuso de drogas, alcohol, anfetaminas u otros se asocia la sobreutilizacion de mediacamentos para controlar el peso corporal, en la forma de diureticos, laxantes, quemadores de grasa, etc, que actuan como medios de gestion de sus emociones negativas. Los trastornos de personalidad, donde destaca la impulsividad y la sensibilidad en las relaciones interpersonales, son tambien frecuentes, acompaados habitualmente de descontrol e inestabilidad en sus relaciones sociales y afectivas. Prevencion y Tratamientos medicamentosos y psicoteraputicos 9. Excurso: la obesidad

VI TRSTORNOS DEL SUEO

1. Concepto y visin de conjunto Sueo normal Neurobiologa Funciones fisiologicas del sueo Exploracion del sueo, vigilancia y somnolencia 2. Los cuadros clnicos en el DSM IV-TR: las disommnias y las parasomnias 3. Tratamientos mdicos y psicolgicos VII LOS TRASTORNOS DE LA SEXUALIDAD Y DE LA IDENTIDAD SEXUAL 1. 2. 3. 4. 5. 6. Concepto y visin de conjunto Trastornos de la identidad sexual Las disfunciones sexuales Causas y tratamientos de las disfunciones sexuales Las parafilias Evaluacin y tratamiento de las parafilias

VIII TRASTORNOS VINCULADOS A ABUSO DE SUBSTANCIAS ADICTIVAS 1. 2. 3. 4. 5. 6. 7. 8. Concepto y visin de conjunto Trastornos por adiccin a tranquilizantes: alcohol, ansiolticos e hipnticos Trastornos por adiicion a estimulantes: anfetaminas, cocana, nicotina Trastornos por adiccin a la cafena Trastornos por adiccin a los opiceos Trastornos por adiccin a alucingenos: marihuana, LSD y otros Causas: biolgicas, psicolgicas y socioculturaless Tratamiento

IX TRASTORNOS DE PERSONALIDAD 1. 2. 3. 4. Concepto y visin de conjunto Trastornos del cluster A Trastornos del cluster B Trastornos del cluster C

IX TRASTORNOS DE PERSONALIDAD 5. Concepto y visin de conjunto:

De la propuesta de Hipcrates de organizar los patrones caracteristicos de la conducta de los hombres a la sitematizacion que encontramos en los actuales sistemas de clasificacion de los Trastornos mentales han pasdo 2500 aos. En el intertanto, los humores han dejado su lugar a los neurotrasmisores, segundos mensajeros, neuromoduladores, y a otros nombres acuados por la biologa molecular, pero la evidencia de que los factores biologicos se correlacionan con patrones mas o menos caracteristicos, persistentes y relativamente previsibles de la conducta de los individuos, permenacen en el tiempo y han recobrado renovado interes empirico y clinico en estas ultimas decadas, de la mano de la investigacin en neurociencias y las ciencias comportamentales que ha permitido el desplazamiento de una nueva mirada mdica, como lo sealara M Foucault a proposito del nacimiento de la clinica medica, para ahora desplazarse a lo que ocurre en el interior del cerebro. Hoy se sabe por ejemplo que los individuos son sujetos integrados, que heredan un determinado temperamento que los diferencia desde la cuna, y que afecta el desarrollo ulterior de la personalidad. La dialectica de la crianza con interacciones reciprocas de padres e hijos puede alterar un rumbo en la contruccion de la personalidad adulta dependiendo de la dinamica de cuidados o de abusos instaurada a esa temprana edad. La exposicin a situaciones traumaticas posteriores tambien pueden influir en el cambio de un patron de personalidad, y en definitiva originar un trastorno psiquiatrico de la personalidad, pero lo basico, en este nuevo tiempo, es que la fatalidad del destino de alguien que nacio asi, propio de aos incluso recientes, en base a los nuevos conocimientos se trastoca en algunas posibilidades de cambio. El nacimiento de la sicopatologa de la personalidad tiene claros exponentes en la Psiquiatria alemana de comienzos de siglo XX: conocidos son los aportes de Kraepelin, Kretchsmerk, Schneider, Tellenbach y otros en la descripcin de tipos o temperamentos y clasificaciones de trastornos de personalidad que influirn decisivamente en las actuales clasificaciones del DSM IV- TR y del CIE 10. No menos, sino mas imporportante fueron los desarrollos freudianos de una teoria del comportamiento y la personalidad,y de su patologa. (REYNALDO). Freud se centro en las neurosis sintomatica y el problema de al angustia, y asumio que las patologias del carcter de tipo pre-edipicas, hacian de los sujetos menos inclinados al cambio, acentuando la idea generalizada de que los trastornos de la personalidad, tenian un pobre pronostico. Desarrollos teoricos posteriores (M. Klein, Kernberg, Kohut, entre los autores mas importantes en la tradicin psicoanalitica) han hecho cambiar esta impresin, al menos para algunas categoras de trastornos de la personalidad. Desde el punto de vista de su categorizacin, los TP han sido incluidos en todos los DSM, experimentando cambios desde la primera version de este sistema clasificatorio en 1952 hasta el DSM IV-TR actual del ao 2000 (en proceso de cambio). En el DSM del ao 1952, los trastornos de personalidad reflejaban los conocimientos de la epoca y el prejuicio de una armadura caracterologica en el paciente que impedia todo posible cambio. Los cambios se sucedieron con lentitud y ya en el DSM IV se introduce una definicin de un trastorno de personalidad, subrayando aspectos relacionados con su inicio precoz, persistencia temporal, carcter de primario y malestar clinico significativo en las areas laboral y social, definicin que algunos critican por se r demasiado inespecifica y ambigua en la medida que tambien podria caracterizar trastornos del eje I como la distimia.

Definiciones Evolucion historica Modelos categoriales y modelos dimensionales: del DSM IV TR al DSM V

El DSM V, sistema de clasificacion ad-portas de su aparicion en el 2012, considera que los trastornos de personalidad representan variantes desadaptativas de rasgos de personalidad que se imbrican con los de una personalidad normal y entre ellos, por que habria que desarrollar una clasificacion de tipo dimensional con el objeto de comparar su utilidad con respecto a la actualmente existente y que es utilizada en este texto. El problema consiste en saber si el trastorno de personalidad es una variacin extrema de un comportamiento de una persona normal o un modo cualitativamente distinto de un comportamiento normal: la diferencia de grado o el tipo de una personalidad refleja bien el concepto de dimension o categora del trastorno. El punto de partida de ste cambio conceptual son las limitaciones del modelo categorial del DSM IV TR: primero, la concurrencia de criterios diagnosticos, que hace que en la practica clinica sea difcil establecer un diagnostrico especifico de trastorno de personalidad. En efecto, la revision de la literatura indica que la mayoria de los apcientes cumplen criterios para mas de una categora (Livesley, 2003) (Wideger y TRull, 1998), por lo que su trastorno no queda adecuadamente descrito en una categora diagnostica (tabla de Morey); segundo, la heterogeneidad de los pacientes que comparten un mismo diagnostico. Lynam (2002) por ejemplo seala lasa diferencias existentes entre dos sujetos diagnosticados como psicoptas en relacion a factores de disciplina, competencia o negligencia que los lleva diferencialmente al xito o al fracaso, las que se reproducen en otros trastornos de personalidad como los por dependencia; tercero, la arbitrariedad en el establecimiento de los limites entre lo normal y lo patologico, ya que el umbral entre lo uno y lo otro carece de una justificacin racional, con excepcion del limite entre el trasdtorno esquizotipico y el limite, con lo que se desdibujan otros propositos de las clasificaciones en relacion a decisiones en politicas de salud; cuarto, en sentido opuesto al primero, se encuentra la insuficiente cobertura de una categora diagnostica que lleva a los clinicos a establecer un diagnostico generico de trastorno de personalidad (Verheul y Widiger, 2004), lo que podria tener solucion jerarquizando la estructura de personalidad de un sujeto a lo largo de una unica dimension, o agregando mas categoras diagnosticas. Una propuesta en este sentido es la quintofactorial de la personalidad normal, segn la cual se puede evaluafr a una persona en funcion de una serie de 5 dimensiones de la personalidad, de cuya combinacin resultan las diferencias individuales (Costa y Widiger, 1994, 2002). Los individuos podrian ser evaluados y situados en los puntos, medios o bajos en una escala continua de cada una de las dimensiones de extraversin , atractivo social, conciencia de autocuidado, estabilidad emocional y apertura a la experiencia (Golberg, 1993). Otras propuestas recientes (Westen y Sheldler, 2000) desarrollan estrategias de descripcin de forma cuantitativa y asi conservar las categoras de trastornos de la personalidad. Los enfoques de Livesley (2003) se basa en un intento empirico de desarrollo de un modelo

dimensional basado en analisis factoriales que le permitan obtener las dimensiones fundamentales de los trastornos de personalidad que integraran totalidad de llas categoras actualmente existentes. Clark (1993) ha ensayado un ensamblaje de sntomas propios de los trastornos de personalidad, trastornos de ansiedad y estado animico, bajo la logica de la concurrencia de de diagnosticos con los del eje I, para reunir estos trastornos en cuatro espectros clinicos consistentes en dimensiones de organizacin cognitiva, impulsividad, instabilidad afectiva y ansiedad como pares opuestos a organizacin perceptiva, agresividad, e inhibicin, reduciendo asi solo a 4 trastornos de personalidad (histrionico, narcisista, por dependencia y pasivo-agresivo). Los modelos son abundantes en la investigacin actual. Pero no alcanzan consenso, como lo expone Otto Kenberg quien seala que la forma propuesta por el DSM V, implica un cambio significativo en el enfoque diagnstico de los trastornos de personalidad. El DSM III y DSM IV focalizaba sus criterios en la atencin propia de la prctica clnica, fomentando la investigacin en el diagnostico, epidemiologa, psico-biologa, curso clnico y tratamiento de stos trastornos. En cambio el DSM V propone un conglomerado complejo de modelos diferentes, con criterios que abarca 5 niveles de funcionamiento de personalidad, 5 tipos de personalidad, 6 escalas de calificacin de rasgos de personalidad, etc., modelos que el autor considera que no pueden coexistir felizmente y sera difcil de usarse en la prctica, adems de criticar mas de fondola utilidad clnica de ste enfoque que en vez de centrarse en los tipos de personas, considera tipos de calificaciones escalares en 5 desordenes de personalidad, dejando afuera otros importantes y validados clnicamente en la comunidad. Su critica adems, profundiza otros aspectos de la propuesta del DSM V, que utiliza un modelo de rasgos propios de la psicologa acadmica de lo normal, sin apoyo emprico de su utilidad para el diagnstico, versus la clnica real. Si bien se manifiesta de acuerdo con la investigacin de rasgos, los clnicos requieren un modelo diagnstico til, simple, y que permita la descripcin de las interrelaciones de los procesos psicolgicos de los individuos, y no uno que no funciona en el mundo real, y que lleve a que el eje II (dg. De la personalidad) no sea utilizado por los clnicos para una mejor comprensin integral de los pacientes psiquitricos.

Epidemiologia

El DSM IV-TR reune los trastornos de personalidad en 3 grupos basado en sus semejanzas: el cluster A calificado como el grupo de los bizarros o excentricos comprende los trastornos de la personalidad paranoico, esquizoide y esquizotipico; el cluster B comprende el grupo de los emotivos, erraticos o enfaticos, integrado por los trastornos de personalidad antisocial , limite, histrionico y narcisista; y el cluster C define a las personas ansiosas o temerosas, integrada por los trastornos de personalidad evitativa, dependiente y obsesiva-compulsiva; definiendolos como patron permanente e inflexible de experiencia interna y de comportamiento que se aparta notablemente de lo que es esperado por la

cultura del individuo y que tiene un origen en la adolescencia o comienzos de la edad adulta, estable en el tiempo y fuente de sufrimientos o de una alteracin de su funcionaMIENTO. Se trata por lo tanto de una manera caracteristica de comportarse y de pensar, la que es rigida e inadaptada y fuente de sufrimiento o disfuncionamiento personal. Esta definicin general permite esbozar 1.- los criterios diagnosticos generales que se manifiestan por, a) elementos cognitivos o formas de autopercepcion o interpretacin de si mismo, los otros o los acontecimientos vividos, b) elementos afectivos que los limitan o les permiten mayOr expresividad emocional, c) elementos interpersonales distribuidos a lo largo de dos polos, de dominancia ante la sumisin o afiliacin frente al desapego y d) elementos problematicos de control de impulsos, tambien distribuidos en un continuo de mayor o menor control. (estas descripciones sirven para caracterizar la sicopatologa de cada uno de los trastornos). 2.- Permanencia e inflexibilidad, que alude a la mantencion en el tiempo de un amplio rango de conductas, pensamientos o percepciones que se manifiestan en distintos contextos, que pasa a ser la referencia central que precede a los criterios especificos que debe considerar el cuadro clinico. Asi construidas las categoras diagnosticas, los estudios epidemiologicos El diagnostico de trastorno de personalidad Comorbilidad Tratamiento

6. Trastornos del cluster A 2.1.- Personalidad paranoica La definicin contenidA EN EL dsm iv tr de personalidad paranoica en el criterio A. desconfianza o sospecha invasora con respecto a los otros, cuyas intenciones son interpretadas como dainas y que aparece al comienzo de la edad adulta y se manifiesta en diversos contextos, como lo recoge el criterio B de la definicin (anotarlos y verficar definicin), requiere a nuestro juicio una precision mayor articulada por una sicopatologa que debe remontarse a los origenes del concepto. Kreapelin en 1985 uso el concepto de paranoia para describir los delirios sistematizados y sectoriales en funcion de la evolucion de este cuadro hacia la demencia precoz. Mas adelante, describio las caracteristicas de la personalidad paranoica, dandole el carcter de personalidad premorbida a los rasgos de un sujeto desconfiado, irritable, susceptible, sobrevalorado, caracteristicas que con variantes, otros autores utilizaron para describir otros tipos de personalidad: Kretschmer para describir la paranoia sensitiva por ejemplo. Freud, desde una perspectiva distinta, la concibe como una neurosis de defensa, que desarrolla en el caso S. como una negacion de las conductas homosexuales

a. Causas b. Tratamiento c. Comentarios 7. Trastornos del cluster B a. Causas b. Tratamiento c. Comentarios 8. Trastornos del cluster C

a. Causas b. Tratamiento c. Comentarios

Patologas adictivas La conducta adictiva no se concibe solamente como una conducta desviada, sino en el marco de un proceso regulatorio de regulacin del equilibrio de sujeto (sistema placer-displacer-goce) por intermediacin del comportamiento adictivo, ante el fracaso de otros mecanismos habituales regulatorios (internos) Estudios rcientes han puesto de rlevancia factores biologivos (temperamento), historia de eventos vitales y calidad de las interacciones tempranas con su medioambiente y la calidad de su aparato psiquico en la genesis de la sicopatologa adictiva. Las dimensiones psicopatologicas pueden distribuirse en gradientes y constituyen una constelacin sintomatica propia de una personalidad dependiente: impulsividadcompiulsividad, busqueda de sensaciones-anhedonia, depresion anaclitica-depresion de introyeccion, alexitimia-representacion de emociones. Estas 4 dimensiones se distribuyen de manera variable en los sujetos Se ha podido individualizar los grupos de riesgo adictivo con una o mas dimensiones dominantes en correlacion con perfiles de personalidad especificos Evolucion dde las conductas de adiccion Las conductas de adiccion tiene en comun un acto de destruccin corporal, de los vinculos y de la capacidad de pensar del sujeto para investir la realidad psiquica y las necesidades corporales

El trastorno contribuye a poner al sujetoi en un circulo vicioso, que termina por empobrecer las relaciones de las persdonas, en la medida que son conductas repetitivas La repeticin de esas conducta, necesarias ademas para mantener el equilibrio masoquista del sujeto, son las dificultan el proceso identitario y encierra al apciente en modo de expresin sintomatica maracda por la ruptura con la familia y su grupo social Interpretacin psicoanalitica de las adicciones (Reynaldo) Trastornos adictivos en el sentido del DSM IV TR Dependencia al OH: esta adccion la mas antigua ha pasado progresivamente de una consideracin socila y moral, el alcoholismo a una enfermedad que implica su medicalizacion y compromiso terapeutico. Posteriormente ha tomado la forma de conducta compleja de tipo patologica para ser actualemnet integrada a una categora de patologas Trastorno viculado aun asubstancia lo que traduce una voluntad de poner dentro de una categora comun sin referencia a un actaegoria psicopatologica comun, dada ala ateoricidad del DSM. El mismo argumento vale para la integracin de otras substancias adictivas en la misma nomenclatura, dando cuenta de una evolucion, sicopatologa, comorbilidad, clnica y biologa semejantes

Mecanismos neurofisiologicos de la ansiedad La estimulacion ansiogena del ambiente activa las estructuras gabaergicas que actuan sobre el ncleo del rafe y las estructuiras del tronco cerebral. Estas activan el sistema limdico cuyos contenidos recuerdan al sujeto los comportamientos de defensa y ansiedad. Estos estados son reforzados por la actividad neuroendocrina de (eje HHS, que libera cortisol e instala el cuadro ansioso El TOC puede entrar asi en la categoria de aberraciones sensoriales, incluso desde le punto de vista neurologico ya que esto se asemeja a las ateraciones del comportamiento de origen central. . En este tipo de alteraciones los elementos de control de las redes que aseguran los actos cotidianos son alterados. Los ToC empiezan a menudo durante la adolescencia , antes de los 25 aos, y la frecuencia de obnsesiones y compulsiones puede ser tan alta que comprometa la actividad profesional u otra del individuo. .La angustia y malestar es dificl de dominar pues los actos repetitivos incontrolables son inducidos por situaciones a veces anidinas que desencadena comportamientos esterotipados o la fases de la ansiedad. Los individuos conocen su problema, luchan contra ellas pero estas terminan por dominarlos (caso clinico)

Los Toc son extraoprdinariamente variados: tricotilomania, onicofagia, etc Pueden llegar a ser invalidantes y perturbar la vida social y preofesional por lo que el paciente no puede progresar en la estructuracionde unaaccion coordinada

Ansiedad y abuso de substancias Evolucion historica del concepto: Berrios Epidemiologia Modelo de trabajo para el estudio de la ansiedad y el miedo

Existe una larga historia en relacion a la neurobiologia de la ansiedad. Es clasico el experimento de remocion de las regionesw subcorticales incluyendo la amigdala, talamo, hipotalamo e hipocampo del gato y sus reacciones de intenso miedo frente a estimulos nuevos acompaados de signos de activacion simpatica difusa, con aumentode la presion arterial, piloereccion, excrecion de epinefrina de la medula adrenal, etc., que sugieren que son estas estructuras del cerebro medio las mediadoras de la respuesta humana a la ansiedad. LeDoux, autor clasico en el tema, agrega a las estructuras anteriores que forman el circuito de Papez, la amigdala, que en los modelos animales juega un rol imporante en los procesos de miedo y ansiedad, por su relacion con el aparato olfatorio. Estos trabajos pioneros, han dado lugar a la construccion de unmodelo de trabajo similar al del estudio de la esquizofrenia para los estudios actuales sobre la ansiedad y el miedo (Charney and Deutch, 1996). Este modelo puede explicar como un estimulo gatilla las primeras sensaciones de tocar o sentir las que son integradas en una imagen coherente que crece en el espacio tiempo activando los recuerdos previos de experiencias similares con la respectiva valencia emocional, que lleva a la correspondiente respuesta motora. Los circuitos cerebrales

especificos que median esta respuesta conforman el circuito cerebral del miedo y la ansiedad (TEXBOOCK of anxiety disorders, Stein, D y al).

Avances en investigacion: Gattaz y Bussato (2009) Incidencia y consecuencias de la EQZ a traves del globo: 10 aos atrs, se decia que el significado y las implicancias de la eqz eran universales y uniformes en diferentes culturas y lugares (jablensky, 1999, Eaton, 1999) por evidencias basadas en el estudio Ten Country Study, coordinado por la OMS, que se refera ademas, a las consecuencias en diferentes culturas. La incidencia de la enfermedad se interpret comom un fenomeno uniforme a traves del mundo, con independencia de las caracteristicas individules o grpales o de trayectorias de vida, teniendo un pronostico mas favorable en aquellos individuos que residian en pequeas o medianas comunidades en comparacion con aquellos que vivian en ciudades populosas. Esta representacion de la invariabilidad de la enfermedad la hacia una enfermedad especial, vision que ha ido cambiando en estos aos, en que investigaciones sitematicas han demostrado, por lo contrrario, amplias variaciones en relacion a las personas, grupos, poblaciones y regiones afectadas, que plantean nuevas aperturas y visiones del problema (p.4) McGrath y col., 2004, reviso sistematicamente las investigaciones realizadas entre 1965 y el ao 2001, buscando responder vaias dudas en torno a la incidencia de la esquizofrenia, su diferenciacion por sexo, tendencias y distribucion por zonas geograficas, distribucion en poblacions migrantes y nativas, llegando a la conclusion que existen variaciones en todos esos campos de analisis, no pudiendose sostener la hipotesis de la uniformidad y universalidad del trastorno en trminos estaticos (Kirbride et al. 2006; Menezes ert al. 2007). La tasa de incidencia de esquizofrenia y otras psicosis en poblaciones migrantes ha sido un tpico mayor de l investigacion epidemiologoica actual, que ha demostrado consistemente una tasa mayor de incidencia de esquizofrenia en los hijos de la poblacion nativa migrante originaria, sosteniendose la tesis que la larga experiencias de frustracion y discriminacion puede ser un posible mecanismo para el incremento del riesgo de enfermedad en ese grupo estudiado, conclusion que se puede extender a otras psicosis, por los resultados de estudios realizados en paises como Suecia e Israel (Coid et al, 2008; Weiser et al., 2008) que evidenciaron el incremento de la patologia entre las minorias etnicas, despues de ajustar los resultados por genero, edad y estatus socio-economico. Desde el punto de vista de distribucion espacial de la enfermedad, Krabbendam and Vas Os (2005) encontraron que el riesgo de la enfermedad era el doble en las areas urbanas de la grna ciudad que en las zonas rurales, e hipotetizaron la interaccion compleja de genes y medio-ambiente como explicacion del fenomeno. Como puede deducirse, falta todavia la comprension mas fina que permita responder a la pregunta mas especifica de cuales son los factores del medio que influyen en estas

heterogeneas cifras. Consecuente con los datos anteriores, se podria suponer que el pronostico de los pacientes que vivan en los medios vecinos o de menor complejidad para la vida, deberia ser mejor. Sin embargo, estudios y meta-analisis realizados e por distintos investigadores en diferentes poblaciones arrojan resultados conflictivos (Mnezes et al, 2006; Cohen et al, 2008), que deben ser sometidos a otras investigaciones respondiendo cuestiones especificas para una contibucion mas eficaz a la comprension de la etiologia de la esquizofrenia y otroas psicosis. Interacciones genes-medioambiente (p.19)

Origenes de la esquizifrenia en el curso del neurodesarrollo neuronal Desde el comienzo, Kraepelin y Bleuler consideraron que los pacientes con cuadros psicticos de tipo demencia precoz primero, esquizofrenia despus, tenan un sustrato neuropatolgico, pues en la historia clnica infantil haban elementos conductuales y signos neurolgicos blandos que se podan interpretar como parte de un desarrollo anormal del cerebro, hiptesis que perdura durante todo el siglo XX y es especialmente reconsiderada a partir de los aos 60-80 con las investigaciones alrededor de dopamina y la accin farmacolgica de los antipsicoticos. En las dos dcadas siguientes, los investigadores extienedn su campo de investigacin a hiptesis claramente centradas en el desarrollo del cerebro de futuros pacientes examienado la fisiopatologa cortical y los dficits cognitivos consustantivos de la enfermedad, por un lado, y a travs de los estudiso epidemiolgicos, por el otro, examinado las hiptesis concernientes a los factores de riesgo (obsttricos, neonatales, etc), inaugurando un programa de trabajo que tiene como objetivo comprender los diversos aspectos de la patognesis y evolucin de la enfermedad. Desde los trabajos de Murray y Lewis en 1987 y Feinberg en 1982, que postulaban los efectos de las complicaciones obstetricass y epidemis virales y los efectos de la mayor o menor poda neuronal en el curso de la adolescencia, hasta los mas actuales que enfatizan cambios en la gnesis de la citoarquitectura y funcin de las clulas nerviosas con consecuencias para el desarrollo de sistemas crticos a nivel del cerebro, no han pasdo mas de 20 aos, pero ya han avanzado en un desplazamiento de la mirada inicial, hasta profundidades que alcanzan las las regulaciones genticas y de eventos moleculares de cambios que se producen en la neurona para producir la sucesin de derivaciones que llevan finalmente a la emergencia de la enfermedad. Las evidencias principales de estas investigaciones las researemos brevemente: a) Complicaciones obsttricas y gestacionales Existen en la literatura medica varios artculos fundados en un metodologa clara que avalan la hiptesis de la influencia de las complicaciones obsttricas en la gnesis posterior de una esquizofrenia. Los mataanalisis de esos estudios revelan que el riesgo aumentado por tales eventos de provcar la enfermedad se situa en 1,5 a 2 veces mas en relacin a la poblacin normal (Cannon, 2002, 2008), lo que significa un pequeo riesgo considerando que el solo atribuible a

un locus gentico es similar. Ademas, la hiptesis ha sido cuestionada desde otros puntos de vista: la no especificidad como factor de riesgo en la medida que tambin se ha considerado como factor de riesgo de los TB (Bain, 2000), autismo y otras condiciones ligadas al desarrollo neurolgico (Eschenbach, 1997), lo que hace de ella una hiptesis genrica para un espectro de complicaciones psico-psiquiatricas. Ademas de lo anterior, se cuestiona el hecho de que las consecuencias patogeneticas de las complicaciones obsttricas se expresen a diferentes momentos del desarrollo cerebral, introduce la idea de que por si sola no sea suficiente para el desarrollo de la enfermedad, la que requerira de la interaccion de factores genticos, dado que las anormalidades genticas y las complicaciones obsttricas fueron halladas en poblaciones con antecdentes de esquizofrenia familiar (Cannon, 2008), estudios que han sido reafirmados por otros que han explorado el potencial dao de la interaccion hipoxia cerbarl en RN con Apgar bajos y genes especficos implicados en la biologa molecualr de la injuria neuronal por hipoxia en la produccin de ulteriores trastornos del desarrollo, hetrogeneos y con variable expresin clnica. Un poco diferente es el resultado cuando se examinan estudios recientes sobrer la interaccion viral en el curso del embarazo con riesgo potencial de esquizofrenia ulterior, donde se ha encontado una evidencia consistente (Brown and Derkits, 2010). Lo mismo ocurre con la interaccion gestacin y exposicin a hambrunas en periodos de guerra u otras ocasiones, donde se encuentra el doble de riesgo de desarrollar el cuadro clnico en etapas de adolescencia o mas tradiamente (susser and Lin, 1992), por razones problables de alteracin de la biologa molecualr del feto en desarrollo. Como se puede apreciar, si bien aparece una relacin consistente entre ambos eventos, los investigadores no pueden implicar un mecanismo especifico para explicar las consecuencias de la asociacin ni porque las alteraciones se expresan en distintas etapas del desarrollo neuronal, dando origen a distintos problemas de salud mental. Lo mas aceptable es decir que los diversos factores sealados interrumpen procesos biolgicos en el cerebro en crecimiento con efectos clnicos variados que se expresan en distintos momentos de la vida, siempre en relacin con otros factores protectores y modificadores de la estructura y funcin neuronal, incluyendo la base gentica y el desarrollo ambiental postnacimiento del sujeto. La disrupcin de los circuitos neuronales en los sujetos a riesgo puede ser sutiles o menores en la niez, previos a la aparicin de la enfermedad. Estos cambios perceptibles en baja edad pueden aparecer a los 6 meses de vida como trastornos motores, seales perceptibles en el lenguaje, dficits cognitivos en el curso de la niez y dificultades escolares y sociales. Los actuales estudios de la dcada 2000-2010 en genes con riesgo y potencialidad especifica para esquizofrenia, complementan lo expuesto hasta ahora: lo preponderante de la interrelacion genesmedioambiente en la etipopatogenia de la enfermedad, evidenciando el impacto sobre los procesos bsicos del temprano desarrollo cerebral, especialmente en el proceso de esculpido neuronal de los circuitos neuronles, como lo refieren Stefansson y colab en 2009, en relacin al efecto especifico de genes en etapas criticas de la formacin sinptica y la plasticidad, y mas aun, en fenmenos bsicos de

fisiologa y excitabilidad celular (Huffaker, 2009), procesos a su vez bsicos para el desarrollo temprano de los circuitos neuronales. Pero este proceso no es lineal (Lewis, Levitt, 2002), pues los procesos de dao pueden ser dimensiones no absolutas y tender a distintas vas de expresin entre la niez y la adultez, pudendo en muchos casos no llegar nunca a expresarse clnicamente como enfermedad, ya que el cerebro en desarrollo tiene una gran capacidad de compensacin funcional (Kolb, 1989) Una pregunta sugestiva surge cuando la esquizofrenia aparece en la terecra dcada de la vida sin haberse observado fenmenos previos de alteraciones blandas como las descritas como propias de una alteracin en el desarrollo neuronal. Una de las respuestas es que existe una interaccion entre factores tempranos y eventos que ocurren en la primera etapa de la vida adulta, focalizandose los estudios en los procesos de podamiento neuronal que ocurre en los procesos de reorganizacin sinptica cerebral en la adolescencia, es decir, daos producidos en los programas de organizacin de los circuitos cerebrales corticales que involucran tanto factores genticos como ambientales que podran iniciar un desarrollo alterado de los patrones de maduracin que lleva a una cascada de aberraciones en los procesos de maduracin que continan desarrollndose hasta comprometer una sub-poblacion de las llamadas sinapsis asimtricas, presumiblemente excitatorias y glutamatergicas en un momento en que tdavia no ha sido terminado el proceso de podamiento de las concexiones inhibitorias gaba-ergicas, alterando un eficiente trabajo funcional a nivel cortical, que se evidencia por los niveles elevados de enzimas importantes para el metabolismo de la dopamina. (Tunbridge, 2007). Una ultima etapa en este proceso de investigacin de los procesos de desarrollo cerebral tiene que ver con los procesos de maduracin a nivel molecular que pueden interactuar con las anormalidades del cerebro en desarrollo para llevar a un sujeto a desarrollar la enfermedad, como producto de la confluencia de esos factores de riesgo sobre la conectividad cortical en los primeros aos de la vida adulta (cf. Meyer-Linderberg, 2007)

TRASTORNOS BIPOLARES (Continuacin) El concepto de trastorno bipolar es reciente, no asi la patologia que se conoce desde los comienzos de la historia occidental. En el siglo XVIII, Philippe Pinel separa la mania de la idiocia y de la melancolia. Posteriormente Falret y Baillarger describieron la locura circular (folie circulaire) y la locura de doble forma (folie double forme), como dos entidades clinicas antecedentes de la psicosis maniaca depresiva descrita por Kreapelin, diferenciandolo asi de la demencia precoz. El cambio de nombre de la psicosis maniaca-depresiva se produce en la decada de los 50 del siglo XX con la demostracion que los estados maniacales respondian al Litio y las distinciones de

Leonard de los desordenes afectivos en la base de la polaridad, seprando las psicosis maniaco-depresivas como enfermedad de la melancolia pura y la depresion, es decir, enfatizando de algun modo los trastornos del animo, como sustrato de la patologia mas que el trastorno psicotico inherente al diagnostico de psicosis maniaco-depresiva, abriendo paso a los cambios sobrevinientes de una entidad clinica de trastorno bipolar dentro de los trastornos afectivos e incorporandose como tal en el DSM III en los aos 80.

En la actualidad, el diagnostico de enfermedad bipolar se hace considerando la presentacion de los sintomas y el curso natural de la enfermedad y se han hecho vances considerables en la comprension de la neurobiologia y genetica, pero todavia se esta lejos de una validacion diagnostica por referencia a una etiologia o anormalidad patofisiologica caracteristica. (Bipolar disorder: Lakshmi N. Yatham) Los trastornos bipolares son enefermedades cronicas con fuerte tendencia alas recaidas y recurrencia de episodios afectivos mayores o menores. Los episodios sindromaticos se intercalan con periodos eutimicos, durante los cuales niveles sub sindromaticos del cuadro clinico a menudo estan presentes a lo largo de un continuun de severidad de sintomas depresivos, maniacos o hipomaniacos, siempre dinamicos y cambiantes, en que los sintomas depresivos tienden a dominar el curso de la enfermedad en una proporcion de 3: 1 para el TB I y 37:1 para los TB II, que en terminos amplios podria concebirse como una enfermedad menos seria ya que sus periodos asintomaticos tiende a correlacionarse con periodos mas amplios sin recaidas o recurrencias. Estos aspectos tiene significacion para el manejo medico del trastornoa lo largo de la vida que implica para el clinico entregar informacion adecuada al paciente y sus familaires sobre las caracteristicas diferenciales de su trastorno y el tratamiento elegido, sobre la alerta temprana de sintomas que pudieran significar recaidas

Los estados mixtos de los trastornos bipolares El DSM IV-TR exige la presencia de todos los criterios de los episodios depresivos y maniacos para sustentar un Episodio Mixto de TB. Pese a su importancia clinica y relativa frecuencia (alrededor del 40 % de TB I son episodios mixtos), esta forma de presentacion se conoce mas limitadamente que otras manifestaciones de los TB debido a su frecuente exclusion de los protocolos de estudio, a juzgar por la revision de estudios de la ultima decada en las revistas especialidadas mas conocidas (A.J. of Psych y Arch. Gen. of Psych). Clinicamente, los episodios mixtos pueden ir desde una depresion a mania o pueden aparecer al mismo tiempo. Se correlacion frecuentemnente con virajes producidos por el uso de antidepresivos, abuso de sedantes y pobre respuesta clinica. Comparados con pacientes maniacos puros, los pacientes con episodios mixtos tenian antecedentes previos de episodios semejantes, periodos largos de hospitalizacion, altas tasas de comorbilidad con TOC, sexo generalmente femenino y alta suicidabilidad no asociados necesariamente a periodos

depresivos sino tambien a episodios mixtos con sentimientos de mayor energia, impulsividad e irritabilidad. La definicion del DSM IV TR de episodio mixto es muy restrictiva, en circunstancias que los sintomas de subsindromes depresivos pueden ser muy distintos a la mania pura, por lo que algunos autores abogan por un criterio mas amplio.

Comorbilidad de los TB: alcohol, nicotina

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Linking Molecules to Mood: New Insight Into the Biology of Depression

Vaishnav Krishnan, M.D., Ph.D., and Eric J. Nestler, M.D., Ph.D Biologia de la depresion El articulo revela que la enfermedad depresiva mayor es un condicion hereditaria que se asocia a nivel molecular con sutiles alteraciones celulares en una red neuronal compleja. Este es el reflejo de un nuevo desplazameinto de la mirada que deja de focalizar la fisiopatologia y el tratamiento de las enfermedades del animo en los neurotrasmisores y los recpetores localizados en las superficie de las menbranas celualres para incursionar en la cascada de eventos intracelulares y las vias que sigue la seal y sus anormalidades en diferentes patologia humanas. Los efectos bioquimicos de estas vias de seales alteradas pueden jugar un rol al mediatizar niveles hormonales que influyen en algunas manifestaciones clinicas de lo episodios bipolares como son la edad de comienzo en la adolescencia, o gatillando episodios del post-parto o asociando o potenciando la ciclacion rapida con hipotiroidismo o gatillando episodios animicos en reepuesta a a los glucocorticoides exogeno.

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Estudios en cerebros post-mortem de pacientes con trastorno bipolar han mostrado niveles aumentados de la proteina PubMed Citation G estimulante, lo que se ha relacionado con la accion terapeutica del Litio que actuaria Articles by Krishnan, V. a nivel intracelular interviniendo y Articles by Nestler, E. J. atenuando la excesiva sealizacion en diferentes vias, mas que por una accion como si fuera un sistema neurotrasmisor per se. Otros estudios se dedican a comprender los efectos de laprotein kinasa C (PKC), la que juega un rol enla plasticidad sinaptica y en funciones de aprendizaje y memoria celular, y recibe efectos

derivados de la accion terapeutica del Litio atenuando su actividad y regulando a la baja la expresion de la isoenzina v en la corteza frontal y el hipocampo

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Am J Psychiatry 161:1848-1855, October 2004 2004 American Psychiatric Association

Reduced Spinophilin But Not Microtubule-Associated Protein 2 Expression in the Hippocampal Formation in Schizophrenia and Mood Disorders: Molecular Evidence for a Pathology of Dendritic Spines (Fundamentalmente en EQZ)

Neurotransmitters Bipolar Disorder Depression Schizophrenia Spectrum Disorders Molecular Biology Other Neuroanatomy Related Article

Amanda J. Law, Ph.D., Cynthia Shannon Weickert, Ph.D., Thomas M. Hyde, M.D., Ph.D., Joel E. Kleinman, M.D., Ph.D., and Paul J. Harrison, D.M.(Oxon), F.R.C.Psych.
Raymond F. Deicken, Mary P. Pegues, Susan Anzalone, Robert Feiwell, and Brian Soher Lower Concentration of Hippocampal N-Acetylaspartate in Familial Bipolar I Disorder Am J Psychiatry, May 2003; 160: 873 882 Las investigaciones han sugerido la participacin de las proteinas que participan en el proceso de union-transduccion de la seal del nucletido guanina en el mecanismo de accion del Litio y en la fisiopatologa del trastorno bipolar, ya que altos niveles de Gs alfa, anticuerpos selectivos de la proteina G, se encuentran en pacientes eutimicos con TB. Junto a este tipo de evidencias bioqumicas que subyacen a la patognesis de la enfermedad, no totalmente claros hasta ahora, otros estudios han indicado alteraciones en los componentes del AMPc, entre los cuales se encuentra la proteina G, como parte del mismo proceso. Uno de esos componentes es el sistema de fosforilacion que se encuentra alterado en las plaquetas de pacientes maniacodepresivos, deprimidos y eutimicos en una proporcion importante en reloacion a sujetos sanos. Estas alteraciones pueden a su vez, estar a la base de otros procesos celulares tales como la movilizacin del Ca, la organizacin del citoesqueleto, como tambien en algunos procesos neutroficos de la celula, importantes en la genesis de los trastornos del animo. A pesar de aos de investigacin, los mecanismos moleculares asociados a los trastornos del animo permanecen en una relativa oscuridad, pero estudios posteriores al reseado implican a uno de los principales sustratos de la protein quinasa A, el Rap1, en la patognesis de la depresion. El estudio de

Differential and Brain RegionSpecific Regulation of Rap1 and Epac in Depressed Suicide Victims
Yogesh Dwivedi, PhD; Amal C. Mondal, PhD; Hooriyah S. Rizavi, MS; Gabor Faludi, MD; Miklos Palkovits, MD; Andrea Sarosi, MD; Robert R. Conley, MD; Ghanshyam N. Pandey, PhD Arch Gen Psychiatry. 2006;63:639-648.

Es un ejemplo de ello, donde se llega ala conclusion de que la expresion y la ACTIVACION de Rap1 se encuentra disminuido diferencialmente en el cerbro, sobre todo en el cerebro de individuos que llegaron al suicidio, lo que hace postularlo como un elemento que participa de la fisiopatologia de esta enfermedad a nivel molecular y celular, campo de investigacion que esta en pleno desarrllo
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Linking Molecules to Mood: New Insight Into the Biology of Depression

Vaishnav Krishnan, M.D., Ph.D., and Eric J. Nestler, M.D., Ph.D Como lo evidencia la investigacin de Vaishnav Krishnan sobrer la compleja interaccion de eventos en un tercer nivwel de complejidad, implicando mecanismos fisiopatologicos diferentes en individuos distintos con el mismo diagnostico, buscando comprender la etiologia de los trastornos del animo.

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Bases neuroanatomicas y neurofisiologicas de los trastornos mentales La tecnologa basada en neuroimagenes ha permitido un desplazamiento mayor de la mirada psiquiatrica al interior del cerebro humano, en un intento de caracterizar la patologa cerebral de trastornos cuya etiologia permanece en penumbras y su clinica no es uniforme, tales como la esquizofrenia o los trastornos del humor. La investigacin reciente ha evolucionado desde la exploracion de areas cerebrales especificas vinculadas con patologas determinadas a una mirada global de su funcionamiento, especialmente al rol de la sustancia blanca y las redes neuronales, basadas en la nueva tecnologa, buscando el donde se inician los mecanismos fisiopatologicos subyacentes a las patologas para comprender como la patologa produce las manifestaciones clinicas que el

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psicopatologo registra descriptivamente. El cambio producido ha ayudado a concebir modelos que no tan solo han permitido clarificar el mecanismo de redes neuronales implicadas en ciertos trastornos sino que tambien comprender mas sobre las interacciones entre variables genetica, ambientales, comportamentales, etc., y la estructura y funcion sistemica del cerebro que subyace a la clinica, para el logro de una recalibracion psicoptalogica de los trastornos psiquiatricos.

EQZ (Martha Shenton) Dos factores principales han motivado la investigacin sobre el conocimiento de las anormalidades de la materia gris en el cerebro de pacientes esquizofrenicos y si esto ya se encuentran en el primer episodio de la enfermedad. Primero, lograr mayor profundidad en la comprensin de los mecanismos fisopatologicos y de las causas del problema, y segundo, despejar la confusion de esas evidencias en relacion con el efecto de los medicamentos sobre la estructura cerebral. (Revisar Scherk and Falsai, 2006; Konopaske, 2008; Steen, 2006; Vita, 2006). Las evidencias de estos estudios son claras en afirmar que las anormalidades se encuentran ya en el primer episodio de Eqz, e incluso antes de la aparicion clinica del cuadro (Pantelis, 2003) en el complejo del hipocampo, girus temporal superior, corteza frontal inferior y gyrus singular, y que en pacientes cronicos tales anormalidades son mas extensas en la region de la corteza frontal, especialmente en corteza prefrontal dorsolateral y coteza temporal y singular. Interesante es contatar tambien que las anormalidades caracteristicas de la materia gris no se debe a muerte neuronal, ya que no se observa la gliosis propia de la respuesta inmune a la necrosis celular, lo que no ecluye la muerte celular por aptosis o muerte celular programada. La atrofia cerebral, iniciada antes de la enfermedad, parace vincularse mas con el periodo de desarrollo cerebral, siguiendo un patron curvilineo,ya que desacuerdo a Van Haren (2008) en pacientes jvenes se observa un deterioro mas pronunciado que en pacientes cronicos en comparacin con un poblacin normal, lo que es concordante con la edad de comienzo tipico de la enfemedad y la epoca de intensos cambios estructurales en los cerebros de individuos sanos, en lo que dice relacion con la agresiva maduracion en la epoca de podado sinaptico, objeto de atencin detallada en varios estudios. La esquizofrenia se ha revelado como un enfermedad derivada de una integracin neuronal defectuosa que interfiere seriamente con procesos de integracin cognitiva como la concibiera instintivamente Bleuler, que involucra fallas en la asociacin normativa entre las cogniciones originadas en la corteza prefrontal y las areas talamicas y cerebelosas (Andreassen, 1999) que se traducen en representaciones mentales defectuosas como un loosening (laxitud) de las asocianes normales en el sentido psicopatologico clasico. El sustrato de estas fallas se busca en distintos procesos de la maduracion neuronal, desde las anomalias de la mielinizacion que juega un rol significativo en el incremento de la velocidad de trasmisin de los potenciales de accion de la seal neuronal hasta anomalias de la sustancia blanca cerebral que constituye la infraestructura anatomica que permite la comunicacin entre regiones cerebarales a distancia (Park, 2004; Price, 2006) influyendo causalmente en la desorganizacin cognitiva y la sintomatologioa psicotica propia de la enfermedad.

Trastornos cognitivos y Esquizofrenia (Imgenes funcionales)

Bases genticas de los T del Humor

Las bases genticas de los trastornos los TB permanecen desconocidas hasta ahora a pesar de los intentos de los ltimos aos por su delucidacion. Ultimamente se ha foclizado el estudio en los factores epigeneticos en su interrelacion con el medio, que actan sobre el ADN y la estructura de la cromatina, los que se piensa pueden influir en el desarrollo de los TB. El concepto de epigenetica en sentido amplio hace referencia al estudio de las modificaciones heredables en la expresin de los genes que no pertenecen a la secuencia del ADN. En su relacin con los TB, la epigenetica se sustenta en observaciones experimentales que demuestra que la regulacin epigenetica de la funcin de un gene es altamente dinmica, pueden producir efectos fenotpicos transgeneracionales y son factores crticos para el normal funcionamiento del genoma y por ende puede daar seriamente el genoma, la clelula o al individuo. Los estudios que traducen estas observaciones a la clnica de los TB hablan por ejemplo de las diferencias fenotpicas de los gemelos monocigoticos cuya discordancia para el cuadro clnico es de 62 y 79% para hombres y mujeres respectivamente, lo que se interpreta como evidencia de las interacciones ambientales que produce enfermedad en uno de los dos gemelos predispuestos genticamente. El mecanismo de accin de los cambios epigeneticos en el individuo que llega a enfermar parte por una pre epi-mutacion, que ocurre en el curso de la maduracin de la lnea celular germinal y puede estar influida por numerosas casusas entre las cuales se ha citado la diferenciacin tisular, influencias pre y post natles, medio ambiente, etc., afectando a un gemelo total o parcialemnte lo que se expresa clnicamente en discordancias en la manifestacin de la enfermedad en trminos de edad de comienzo, severidad o respuesta a los medicamentos. Otro grupo de estudios se refiere a los efectos sobre el sexo y la susceptibilidad de enfermar en hombre y mujeres. Kaminsky, 2006 ha abordado este complejo tema a travs del conocido efecto epigenetico de las hormonas sexuales, abandonando la tradicional explicacin sobre el vinculo de los riesgos genticos sobre estas hormonas. Los efectos epigeneticos relevantes para comprender las causas de las enfermedades mentales, y especificaemnte los TB, se han desarrollado en esta ultima dcada e incluyen evidencia de que factores dietticos, qumicos, fsicos y psico-sociales pueden modular el perfil gentico del genoma en locus especficos o no, anunciando una revolucin en la comprensin etiolgica de los problemas psiquitricos y del mecanismo de accin de algunos frmacos como el Litio y el Ac. Valproico cuya accin modificadora de las caractersticas epigeneticas es conocida (Cf. OBrien and Klein, 2009; Weaver, 2004; Kyle and Pichard, 2006)

Los TB son entidades clnicas complejas, cuya aparicin y desarrollo es continuo desde la niez-adolescencia a la adultez (Geller, 2008), lo que ha estimulado la indagacin retrospectiva y prospectiva para determinar antecdentes clnicos o anomalas biolgicas en el diagnostico precoz de tales trastornos (Duffy, 2009). La edad de comienzo de la enfermedad clnica se encuentra entre la adolescencia media y los 20 aos (Mittchell, 2009), aunque es mas precoz en aquellos con anteccdentes familiares de TB. Estudios de Bellivier (2003) y Hamshere, 2009) demuestran la determinacin gentica del trstorno, donde los pacientes con comienzo de la enfermedad anterior a los 13 aos y con fuerte historia familiar de bipolaridad tenan mas intentos suicidas, proporcin mayor de cicladores rapidos y mas episodiso maniacos y depresivos, mayor deterioro funcional. Por el contrario, aquellos pacientes que debutaban tardamente con un TB, se correlacionan con factores mdicos como enfermedades cerebrovasculares o de pequeos vasos y por dao traumatico cerebral, mas que con factores genticos, y si cursan con episodios maniacales, existe alta morbi-mortalidad asociada, pero en general el pronostico del Trastono es mejor en este grupo etario de pacientes que en que de comienzo precoz.

TRASTORNOS ANSIOSOS /Esq.gral 1. 2. 3. 4. 5. 6. aspectos evolutivos clasificacion Clinica de cada uno de los T de A. Epidemiologia Causas Tratamiento
Summer 2006

Focus 4:391-400, 2006 American Psychiatric Association

relevance

focus

INFLUENTIAL PUBLICATIONS

"A Gene for. . .":The Nature of Gene Action in Psychiatric Disorders

Kenneth S. Kendler, M.D.

Abstract Full Text (PDF) Citation Map

ABSTRACT
A central phrase in the new "GeneTalk" is "X is a gene for Y," in which X is a particular Email this article to a Colleague gene on the human genome and Y is a Similar articles in this journal complex human disorder or trait. This article Alert me to new issues of the journal begins by sketching the historical origins of Add to My Articles & Searches this phrase and the concept of the gene- Download to citation manager phenotype relationship that underlies it. Five criteria are then proposed to evaluate the appropriateness of the "X is a gene for Y" concept: 1) strength of association, 2) specificity of relationship, 3) noncontingency of effect, 4) causal proximity of X to Y, and 5) Citing Articles via Google Scholar the degree to which X is the appropriate level of explanation for Y. Evidence from psychiatric genetics is then reviewed that address each of these criteria. The concept of "a gene for" is best understood as deriving Articles by Kendler, K. S. from preformationist developmental theory in Search for Related Content which geneslike preformationist anlagen "code for" traits in a simple, direct, and powerful way. However, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the concept of "X is a gene for Y." The impact of individual Articles by Kendler, K. S. genes on risk for psychiatric illness is small, often nonspecific, and embedded in complex causal pathways. The phrase "a gene for" and the preformationist concept of gene action that underlies it are inappropriate for psychiatric disorders. (Reprinted with permission from the American Journal of Psychiatry 2005; 162:1243 1252[Abstract/Free Full Text] )

The last 20 years has seen the rise of "GeneTalk" (1). A central phrase in GeneTalk, and one that has been heard widely in both lay (2) and professional arenas, is "X is a gene for Y," in which X is a particular gene on the human genome and Y is one of a wide variety of complex human disorders or traits such as depression, aggression, sexual orientation, obesity, infidelity, alcoholism, or schizophrenia. This essay begins with a brief review of the historical origins of the concept of "a gene for". I then propose criteria to assess the validity of this model of gene-phenotype relations and go on to evaluate these criteria as applied to genetic effects on psychiatric disorders. The essay concludes with general observations about our preconceptions and the reality of gene action in psychiatric disorders. Although many of the issues raised in this essay are equally applicable to etiologically complex medical disorders, the focus here will be on psychiatric illness.

HISTORICAL ORIGINS OF THE CONCEPT OF "A GENE FOR"

Since humans started speculating about the nature of development and inheritance, a number of different conceptualizations have emerged about the nature of the guiding forces in these processes (3). In the 20th century, this discourse has come to focus largely on the nature of what Mendel originally termed "anlagen" or "elements," which in 1909 became "genes" (4). Of the multiple different views of the nature of the "gene," the one in which we are interesteda gene defined by the phenotype that it causesoriginated in the developmental theory of preformationism (5). One of the earliest articulated theories of development, preformationism was first proposed by Aristotle but became particularly influential in the 17th century (3, 5, 6). The essentials of the theory are eloquently described by Jacob: At a time when living beings are known by their visible structure alone, what has to be explained about generation [i.e., development] is the maintenance of this primary structure through succeeding generations. The structure cannot itself disappear; it has to persist in the seed from one generation to another. To maintain the continuity of shape, the "germ" of the little being to come has to be contained in the seed; it has to be "preformed." The germ already represents the visible structure of the future child.. . .It is the plan for the future living body. . .already materialized, like a miniature of the organism to come. It is like a scale model with all the parts, pieces and details already in position.. . .Fertilization only activates it and starts it growing. Only then can the germ develop, expand in all directions and acquire its final size, like those Japanese paper flowers which, when placed in water, unwind, unfold and assume their final shape. (7, p. 57) In preformationism, the egg or sperm was understood to contain all the final traits of the mature organism. Development consisted of the expansion of these preformed

characteristics (or anlagen) into the individual traits of the adult organism. That is, these anlagen were truly for the adult traits with which they had a simple and direct causal relationship. In the 19th century, as the young field of biology struggled to fathom the mechanism of transmission of traits across generations, a number of the proposed theories of inheritance (where the "units" of inheritance had names such as pangenes, stirps, and gemmules) had important preformationist themes (3, 4). When Mendels groundbreaking work on genetics (originally published in 1866) was rediscovered in 1900, one common interpretation was that his "elements of inheritance" were the discrete anlagen predicted by preformationist theories (5). This interpretation was favored by two of the most influential geneticists of the day, the Dutchman de Vries (the most famous of the three "co-rediscovers" of Mendel [4]) and the Englishman Bateson (8). In summarizing this exciting period in the history of biology, Allen (9) writes The implications that the discreteness of the gene implied the organism was constructed as a "mosaic" of adult traits was given explicit voice by Bateson with the first years of his encounter with Mendelism. Allen goes on to quote two passages from Bateson written, respectively, in 1901 and 1902 (9): In so far as Mendels law applies, the conclusion is forced upon us that the living organism is a complex of characteristics of which some, at least, are dissociable and are capable of being replicated by others. We thus reach the conception of unit characters which may be rearranged in the formation of reproductive cells. The organism is a collection of traits. We can pull out the yellowness and plug in greenness, pull out tallness and plug in dwarfness. Bateson was recasting, in a new language, preformationist concepts. The Mendelian anlagen (later genes) could be defined by their relationship to the particular phenotype (or "unit character") with which it had a privileged causal link. That is, such genes caused phenotypes in the same way that the preformationist anlagen prefigured adult traits. From this perspective, it made sense to speak of "a gene for greenness," "a gene for tallness," or a gene for any of the other innumerable unit characteristics of the adult organism. It is in this context that a rarely discussed early chapter of psychiatric genetics in the United States must be viewed, when reports appeared claiming to find, in series of large pedigrees, evidence for Mendelian genes "for" "Nomadism or the wandering impulse" (10) and "the neuropathic constitution" (11). This preformationist concept of the gene proved attractive to medical geneticists who, over the course of the 20th century, showed that most classical genetic disorders in humans (termed "Mendelian" diseases in honor of the Austrian monk) were due to hereditary units that behaved just like those first examined by Mendel (12).

While medical geneticists came to understand that in biological systems, genes actually code for proteins, it became convenient and seemingly natural to think about preformationist-like genes for these classical genetic diseases in humans. The last 30 years have seen three interrelated further themes in the "a gene for" story. First, in the mid-1970s two influential books appeared that heightened the profile of genes and their potential impact on human behavior. "Sociobiology: The New Synthesis" by Wilson (13) launched the field of sociobiology (and later evolutionary psychology), discourse in which commonly included the concept of "genes for" a wide range of traits, including altruism, territoriality, jealousy, and ethics. "The Selfish Gene" by Dawkins (14) proposed a gene-centered view of evolution in which an organism, with its wide array of phenotypes, was viewed as a vehicle through which genes replicate themselves over evolutionary time. Second, with the developmental of an ever increasing set of powerful molecular tools, the specific genes and then the specific mutations in those genes were discovered that were responsible for all major classic human genetic disorders. So, when speaking about "a gene for Y" in which Y was sickle-cell anemia, cystic fibrosis, or Huntingtons chorea it became possible to conceive of the gene not only as an abstract transmitted "unit" but also as a discrete piece of DNA at a specific location on a chromosome. Third, prompted by the sequencing of the human genome, the concept that DNA represented the "blueprint" of life (or in related versions the "code" or "recipe" for life) was widely promulgated in both the scientific and lay literature (2). The preformationist themes in this metaphor are evident: genes are to phenotypes as blueprints of a building are to the building themselves. So, this historical sketch suggests that our current concept of "X is a gene for Y" in humans has four major interrelated historical roots. First, the concept that development anlagen could be "for" adult traits arose in preformationist developmental theories. Second, the discovery of Mendels "elements" was interpreted by some as verifying this concept. Third, the idea that genes could be "for" human traits was supported by the discovery that genes for classical Mendelian medical disorders often acted just like the hereditary elements found in Mendels pea plants. Finally, these concepts became linked to DNA by a series of stunning discoveries in the last 20 years, so that strength of the "icon" of the double helix provided particular luster to potential discoveries in psychiatry of "a gene for".

CRITERIA FOR THE CONCEPT OF "A GENE FOR"

The remainder of this essay addresses the question of whether this preformationist model of gene actionin which genes are "for" phenotypesis appropriate for psychiatry. Based in part on prior efforts to develop guidelines for causal inference in epidemiology (e.g., reference 15), I suggest five criteria by which to judge the validity of the claim "X is a gene for Y": 1) strength of association of X with Y, 2) specificity of relationship of X with Y, 3) non-contingency of the effect of X on Y, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. In sum, I argue that If gene X has a strong, specific association with disease Y in all known environments and the physiological pathway from X to Y is short or well-understood, then it may be appropriate to speak of X as a gene for Y.

But first, a few details are needed. The scientific basis of most claims that "X is a gene for Y" results from a statistical test called association analysis. In its simplest form, this test compares the frequency of specific DNA variants in or around gene X in a set of cases with disorder Y and a set of matched control subjects. An association is claimed if the frequency of these variants differ significantly in cases and control subjects. In both a conceptual and statistical sense, this approach is no different from the methods commonly used in the biomedical and social sciences to assess the relationship between putative risk factors and outcome variables such as smoking and lung cancer or childhood sexual abuse and depression. Therefore, standard "a gene for" claims are based on statistical and not biological grounds. Biological studies that trace etiologic pathways from X to Y should follow claims for association and would certainly provide confirmatory data. However, they have been very rare to date in psychiatric genetics. On its own, a significant p value in an association study tells you nothing about the nature of the causal relationship between the gene and the disease.

STRENGTH OF ASSOCIATION
As with any risk factor for any outcome, the strength of association between a specific gene and a particular disease can vary in magnitude. In considering the criteria for "a gene for. . .," an historical standard of comparison is what has come to be called a Mendelian gene. The action of Mendelian genes is deterministic and not probabilistic. If a plant inherits a particular copy of the gene for wrinkled peas, it would not matter how much sunshine the plant received or the quality of its fertilizer. The plant will have wrinkled peas no matter what the environment does. In humans, we have many diseases that are due to Mendelian genes that behave exactly like the genes Mendel studied in his pea plants (12). If you have one copy of the pathogenic gene for Huntingtons disease, it does not matter what your diet is, whether your parents were loving or harsh, or if your peer group in adolescence were boy scouts or petty criminals. If you have the mutated gene and you live long enough, you will develop the disease. Furthermore, for most Mendelian genes in man, the only way to get the disorder is to have the disease gene. There is no way to "acquire" cystic fibrosis or Huntingtons disease through environmental exposure. So if having the disease gene always produces the disorder and the disorder never occurs without the disease gene, this produces a perfect association between the disease gene (X) and the disorder (Y). (Reality is somewhat more complex. Most Mendelian genes in man contain several different mutations, each of which can cause diseases that are sometimes of quite variable severity. But this claim still holds for all mutations of the gene considered together.) The strength of an association between a risk factor and a disease is most frequently quantified by a statistic called the odds ratio. Formally, the odds ratio is defined as the ratio of the odds of developing the disease among those exposed to the risk factor and the odds of disease among those not exposed to the risk factor. For Mendelian disorders in man, since the first of these figures is one and the second is zero, the odds ratio for the disorder given

the pathogenic gene is infinite. Since this is a rather stringent criteria, for the sake of argument, let us say the association with Mendelian-like genes (an historical model for the concept of "a gene for") has an odds ratio of approximately 100 (Figure 1 ).

Figure 1. A Comparison of Estimated Odds Ratios for the Strength of Association Between Risk Factors and Key Outcomesa a Although the odds ratio for a classic Mendelian gene is actually , we estimate it here at approximately 100. Strong association (here odds ratio=15) approximates that seen between heavy smoking and lung cancer, industrial exposure to asbestos and mesothelioma, and severe stressful life events and the onset of major depression. Moderate association (odds ratio=5.0) approximates that seen for apolipoprotein E-4 and Alzheimers disease as well as the protective effect in Asian populations of the ALDH2*2 copy of the aldehyde dehydrogenase gene on risk for alcoholism. The associations seen between individual genes (or high-risk haplotypes) and psychiatric disorders (odds ratio=1.5) is an approximation obtained from a review of the current literature.

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Are there any genes whose strength of association with a psychiatric disorder is Mendelianlike? Two related sources of information, both gathered in the last two decades, indicate that the answer to this question is almost certainly "No." First, a gene that has a deterministic or nearly deterministic relationship with a phenotype produces an unmistakable signature in the pattern of illness in large pedigrees. Numerous investigators have now searched many parts of the globe (including nearly all psychiatric facilities in a modest-sized country [16]) seeking pedigrees in which major forms of psychiatric illness especially schizophrenia and bipolar illnessare distributed in the pattern expected from a Mendelian-like gene. Such pedigrees have not been found. Second, Mendelian-like genes also produce a distinctive result in genome-wide linkage studies, which effectively sweep the human genome looking for regions that contain genes that have an impact on risk of illness. While the technical details need not concern us, experts agree that for those disorders studied in genome-wide linkage scans of reasonable size and qualityespecially schizophrenia, bipolar illness, panic disorder, and eating disordersconclusive evidence has accumulated that even moderately rare genes of

Mendelian-like effect do not exist. (The available evidence does not permit us to rule out, however, very rare Mendelian-like genes.) So, if we lack Mendelian genes for psychiatric disorders, with their very high odds ratios, what sort of magnitude of associations might we expect? One set of benchmarks might be provided by three examples of what would be considered very strong associations in epidemiology. The estimated odds ratio between heavy smoking and small cell carcinoma of the lung is approximately 20 (17), between industrial exposure to asbestos and mesothelioma is approximately 15 (18), and between severe stressful life events and the onset of major depression is approximately 12 (19). Another more modest benchmark is provided by the two outstanding genetic association results in neuropsychiatry of the last decades. The association between the pathogenic "4 allele" of the apolipoprotein E gene and Alzheimers disease produces, in Caucasian populations, an odds ratio of approximately 3.0 (20). In Asian populations, the possession of the slow-metabolizing (ALDH2*2) copy of the aldehyde dehydrogenase gene conveys up to a 10-fold reduction in risk for the development of alcoholism (21). So, as depicted in Figure 1 , we have three possible benchmarks for the strength of the gene-phenotype association for psychiatric disorders: Mendelian-like (odds ratio of approximately 100), strong (odds ratio=1220), or moderate (odds ratio=310). Trying to summarize the magnitude of association found between functional candidate genes and psychiatric disorders is problematic because of the multiple methodologic difficulties in the interpretation of such studies (2224). Greatest reliability should be placed on the results of meta-analyses, which are now beginning to appear in the literature. A PubMed search from 2000 on (using publication type of "metaanalysis" and search words "gene" and "association") followed by a hand search and elimination of duplication yielded 10 significant meta-analytic estimates of odds ratios between individual genes and psychiatric disorders (Table 1 ) (excluding results from those meta-analyses that did not support the original positive reports). The odds ratios ranged from 1.07 to 1.57 with a median of approximately 1.30.

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Table 1. Meta-Analysis Results Published Since 2000 for Studies of Association Between Individual Genes and Psychiatric Disorders

Another strategy to localize candidate genes is to look for them under linkage peaks (socalled positional candidate genes). In schizophrenia, replicated evidence is now emerging for several such genes (28). For these genes, disease-associated haplotypessmall sections of DNA that have traveled together over evolutionary timecan often be found. The two best replicated positional candidate genes for schizophrenia are dysbindin 1 and neuregulin 1. Not counting the original reports (where the effect size might be biased upward), estimates are available for the association between high-risk haplotypes and schizophrenia for both of these genes. For dysbindin, odds ratios of 1.24 (29), 1.23 (30), 1.40 (31), 1.70 (32), and 1.58 (33) have been reported or calculated from replication reports. For neuregulin 1, two replications were noted in a recent review, with odds ratios estimated to be 1.25 and 1.80 (28). Taken together, the meta-analyses of functional candidate gene association studies and early results from positional candidate genes suggest that the magnitude of the associations between individual genes and psychiatric illnesses have small odds ratios, largely from 1.1 to 1.6. Compared to our benchmarks, this effect size is very modest (Figure 1 ). Perhaps genes (or particular mutations or haplotypes) of larger effect size will be found. While results from linkage studies suggest that this is unlikely, it cannot be ruled out. Also to be considered is the statistical dictum that the first set of effects detected in any research area tend to be the most robust. If this is correct, further genes discovered for psychiatric disorders are likely to have smaller average effects than the genes found to date. The preformationist concept of "a gene for" implied a predetermined and largely irrevocable link between gene and phenotype. This is the pattern of association observed between gene and phenotype from Mendels original traits and for Mendelian genetic disorders in humans. By contrast, for psychiatric disorders, individual genes appear to have a quite modest association with psychiatric illness. While they may have an impact on risk, individual genes hardly predetermine illness, as would be expected if we had discovered "genes for" mental disorders.

SPECIFICITY OF ASSOCIATION
The second criterion to evaluate the appropriateness of the concept of "X is a gene for Y" is the degree of specificity in the relationship between X and Y. As illustrated in Figure 2 , does X influence risk for any other disorders in addition to Y? Or are there other genes that contribute to Y in addition to X?

Figure 2. Possible Gene-to-Phenotype Relationshipsa a Possible relationships between genes on the lefthand side of thefigure and phenotypes on the righthand side are shown. In a one-to-one relationship, gene X causes only phenotype Y, and phenotype Y is caused only by gene X. In a one-to-many relationship, gene X causes several phenotypes each in turn being only caused by X. In a many-to-one relationship, phenotype Y is caused by several genes each in turn only causing Y. In a many-to-many relationship, each gene causes several phenotypes and each phenotype is caused by several genes.

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In preformationist theory, anlagen had highly specific associations with the adult traits into which they developed. The hereditary elements of the pea that Mendel studied also had quite specific phenotypic effects. That is, one gene influenced pea color but not shape or height while another influenced shape but not height or color. However, as genetics developed, many genes were found that impacted on a variety of phenotypic characteristicsa phenomenon called pleiotropy. In man, many Mendelian genes produce one and only one disease syndrome (although sometimes of varying severity depending on the specific mutation). But there are exceptions where different abnormalities in a single gene can produce distinct genetic diseases. How specific are individual genes in their impact on risk for psychiatric disorders? Do most genes influence risk for one and only one psychiatric disorder? Twin studies, which study "genes" in the aggregate, suggest that genetic risk factors for psychiatric disorders are often nonspecific in their effect. A large-scale twin study of seven psychiatric and substance use disorders found one common genetic risk factor predisposing to drug abuse, alcohol dependence, antisocial personality disorder, and conduct disorder and a second common genetic factor influencing risk for major depression, generalized anxiety disorder, and phobia (34). Overlap of genetic risk factors for multiple disorders have been demonstrated in other twin studies (e.g., references 3537). We know much less about the specificity of the spectrum of effects on psychiatric disorders of individual genes. Meta-analyses reviewed in Table 1 show that variants at one gene (the 5-HT2A receptor) may predispose to risk for three different disorders (schizophrenia, bulimia, and anorexia nervosa). A pair of overlapping genes on chromosome 13q (termed G30 and G72) may be associated both with schizophrenia and bipolar illness (28). A

number of overlapping positive regions in linkage genome scans for bipolar illness and schizophrenia have led some to argue that this reflects shared genes between these two disorders (38). While difficult to evaluate critically, claims have been made that several popular candidate genes (e.g., serotonin transporter, dopamine transporter, dopamine 2 receptor) are significantly associated with a wide variety of psychiatric disorders or psychiatrically relevant traits (39, 40). While much remains unknown, current evidence suggests that many genes that influence risk for psychiatric disorders will not be diagnostically specific in their effect, thereby resembling the one-to-many relationship in Figure 2 rather than the one-to-one relationship. We are on firmer ground in evaluating whether genetic risk for psychiatric disorders results from the action of a single gene (the one-to-one relationship in Figure 2 ) or multiple genes (the many-to-one relationship in Figure 2 ). Some evidence bears on this question indirectly, as follows. Twin and adoption studies provide convincing evidence for significant genetic effects on virtually all major psychiatric disorders (41). Therefore, genes that affect risk for these disorders must exist somewhere on the human genome. Linkage studies examine how these aggregate genetic risk factors are distributed across the genome. If genetic risk resulted from a single gene, then all the linkage "signal" would be concentrated in a single location, with a resulting clear and robust statistical linkage peak. But, as noted earlier, this is a pattern that has not been observed in published genome scans for psychiatric disorders. Instead, a number of modest linkage peaks are usually seen, suggesting that the "packets" of genetic risk for these disorders are widely dispersed across the genome. (To complicate matters, genome scans will underestimate the number of genomic regions involved because of low power to detect genes of small effect size, but will overestimate the number because some of the observed "peaks" will be false positives.) Recently, data have emerged that addresses this question directly. A careful meta-analysis of 20 genome scans for schizophrenia has suggested 10 genomic regions likely to contain susceptibility genes (42). In addition, current evidence of bipolar disorder, the second-beststudied psychiatric disorder by linkage scans, also suggests multiple loci (43). The specificity of association implied in the "a gene for" concept has another implication worth exploring. Consistent with preformationist theory, specificity of gene action implies that the gene contains all information needed for the development of the trait. The environment might impact on the final phenotype, but its effect is nonspecific. That is, the gene "codes for" the trait, while the environment reflects background factors that support development but is not in and of itself "information-carrying." To illustrate how commonly we see genes and environment in this light, it is worth pondering a curious and asymmetrical feature of GeneTalk. While we find it easy to use the phrase "X is a gene for Y," it feels quite odd to say "A is an environment for B." For example, a large body of empirical work supports the hypothesis that severe life events are important environmental risk factors for major depression (44). The magnitude of the association between such events and the subsequent depressive episode is far greater than that observed for any of the genes that we have reviewed here. Yet, who has heard the phrase "a romantic breakup is an environment for depression"? I suggest that we feel comfortable with "X is a gene for Y" and not "A is an environment for B" because we

implicitly assume that genes have a privileged causal relationship with the phenotype not shared by environmental factors. However, empirical evidence does not support the position that genes code specifically for psychiatric illness while the environment reflects nonspecific "background effects." By definition, environmental factors are central to the etiology of posttraumatic stress disorder. In the aforementioned multivariate twin model, what distinguished major depression, generalized anxiety disorder, and phobia from one another were environmental and not genetic risk factors (34). In a detailed study of the impact of childhood parental loss on risk for common psychiatric and substance use disorders, death of a parent was specific in increasing risk for major depression and no other disorder (Kendler et al., unpublished results). Consistent with studies of stressful life events that have shown moderate separation of depressogenic and anxiogenic events (45, 46), a multivariate genetic study of symptoms of anxiety and depression showed that genetic factors influence nonspecific risk for all symptoms, whereas two environmental factors were identified that predisposed, with moderate specificity, for symptoms of depression and anxiety, respectively (47). The preformationist concept of "a gene for" implies high levels of specificity between gene and phenotype. While much remains to be learned in this area, current evidence suggests that instead of the "one-to-one" relationship implied by the concept of "a gene for. . .," genes and disorders in psychiatry are likely to have the "many-to-many" relationship depicted in Figure 2 . (The evidence that the association between individual genes and psychiatric disorders are typically weak and may often be nonspecific does not mean that the identification of such genes is unimportant. For example, such discoveries can identify pathophysiologic pathways, begin the lengthy process of clarifying how individual genes interact with each other and with environmental exposures to produce illness, and provide new targets for treatment.)

NONCONTINGENCY OF ASSOCIATION
Noncontingent association means that the relationship between gene X and disorder Y is not dependent on other factors, particularly exposure to a specific environment or on the presence of other genes. As mentioned earlier, this is a typical (albeit not uniform) feature of genes that cause classical Mendelian disorders in humans. If the association between gene and disease were contingent on particular environmental exposures, then we would have to amend our statement to read "X is a gene for Y given exposure to environment Z." Environmental contingencies for genetic effects on psychiatric disorders have been little investigated. Twin and adoption studies suggest that the impact of aggregate "genes" for major depression are altered by exposure to stressful life events (19, 48) and for schizophrenia and conduct disorder by exposure to a dysfunctional rearing environment (49, 50). A range of twin studies suggest that environmental experiences have an impact on genetic risk for several psychiatrically relevant traits, including aggression, disinhibition, and smoking (51). Recently, Caspi and colleagues have found evidence for interactions

between environmental risk factors and particular genes in the production of antisocial behavior (52) and depression (53), with the former finding having been replicated (54). We know almost nothing about gene-by-gene interactions in the etiology of psychiatric disorders. Although a number of association studies have reported interactions, I am unaware of any that have been widely replicated or supported by meta-analyses. Using statistical models applied to risk of illness in various classes of relatives, Risch has claimed that gene-by-gene interactions are important in the etiology of schizophrenia (55). Overall, we know little about the contingent nature of genetic effects for psychiatric disorders. The available information suggests that gene action contingent upon certain environmental exposures is probably not rare and may be relatively common for psychiatric disorders. This is also inconsistent with the preformationist concept of "a gene for. . .".

CAUSAL PROXIMITY
Preformationist developmental models assumed that anlagen developed directly into adult traits. The "blueprint for life" metaphor similarly assumes a direct correspondence between individual parts of the blueprint (windows, doors, fixtures) and the corresponding units of the completed building. Conceptualizing genes in this preformationist framework therefore carries the implicit assumption of a direct causal link between gene and phenotype. It is only with this assumption that usage of the "a gene for. . ." is congruent with the common meaning of the phrase "X is for Y" in English. To clarify this point, lets examine a typical list of such statements: I use a knife for buttering my toast. I have a backpack for carrying my computer to work each day. I was upset at my son for not doing his chores. In each case, there is an implied direct and immediate relationship between X and Y. To put it more formally, X and Y are directly linked in a formal logical train of action (first two examples) or thought (third example). Now, how does this common sense meaning of the word "for" apply to the phrase "X is a gene for Y"? Let me illustrate the problem with a vignette A jumbo jet contains about as many parts as there are genes in the human genome. If someone went into the fuselage and removed a 2-foot length of hydraulic cable connecting the cockpit to the wing flaps, the plane could not take off. Is this piece of equipment then a cable for flying? Most of us would be uneasy answering yes to this question. Why? Because this example violates our conception of causal proximity. When we say X is for Y, we expect X to be, to a first approximation, directly and immediately related to Y. That is not the case for the cable and flying. There are many, many mechanical steps required to get from the function of that cable to a jumbo jet rising off the runway.

Another vignette: Assume a Mendelian genetic disease due to a mutation in gene K. Gene Ks normal function is to produce an enzyme L that breaks down metabolite M in cells allowing M to be harmlessly secreted from the body. When K has a pathogenic mutation, the enzyme L that is produced no longer works. Therefore, levels of M rise, producing a well understood series of toxic effects, thereby producing the genetic disorder N. This scenario suggests the following potentially simple causal chain: mutated gene K dysfunctional enzyme L excess metabolite M disorder N. In this admittedly oversimplified story, a case could be made that gene K had sufficient causal proximity to disorder N to make plausible the claim that "K is a gene for N." However, it might be argued that even here, the complexity of the paths from levels of M to disorder N may be far from "simple." Contrast this situation to the causal chain from a gene mutation to a complex psychiatric disorder such as schizophrenia. Although early efforts have been made to begin to trace such pathways (e.g., reference 56), we probably do not know enough to articulate all the specific causal steps that would be needed to go from DNA basepair variation to, for example, the cognitive processes that predispose to delusion formation. What we can conclude with some confidence is that it will be very complex. Indeed, the causal link between that hydraulic cable and the jumbo jet flying will probably look very simple and short compared to the causal relationship between individual genes and the manifestations of schizophrenia. While the nature of the evidence reviewed here is largely inferential, it suggests that the pathways from most genes for psychiatric illness to their phenotypes would fail the causal proximity criterion implicit in the concept of "X is a gene for Y."

APPROPRIATE LEVEL OF EXPLANATION

Scientific theories typically strive to explain phenomenon at the most informative level. To provide an absurd example, no one would seek to understand the origin of hypertension at the level of quarks. In some ultimate way, quarks may be involved. But quarks are just the wrong level of inquiry for the problem. To illustrate how this issuethe appropriateness of level of explanationmay apply to our evaluation of the concept of "a gene for. . ." consider these two "thought experiments": Defects in gene X produce such profound mental retardation that affected individuals never develop speech. Is X is a gene for language? A research group has localized a gene that controls development of perfect pitch (57). Assuming that individuals with perfect pitch tend to particularly appreciate the music of Mozart, should they declare that they have found a gene for liking Mozart? For the first scenario, the answer to the query is clearly "No." Although gene X is associated with an absence of language development, its phenotypic effects are best

understood at the level of mental retardation, with muteness as a nonspecific consequence. X might be a "gene for" mental retardation but not language. Although the second scenario is subtler, if the causal pathway is truly gene variant pitch perception liking Mozart, then it is better science to conclude that this is a gene that influences pitch perception, one of the many effects of which might be to alter the pleasure of listening to Mozart. It is better science because it is more parsimonious (this gene is likely to have other effects such as influencing the pleasure of listening to Haydn, Beethoven, and Brahms) and because it has greater explanatory power. A final scenario: Scientist A studied the behavioral correlates of a particular variant at gene X and concluded "This is a very interesting gene that increases the rates of sky diving, speeding, mountain climbing, bungee jumping, and unprotected casual sex." Scientist B studied the same variant and concluded "This is a very interesting gene and effects levels of sensation-seeking." Who has done the better science? Since sensation seeking (and its close cousin noveltyseeking) are well studied traits (41), scientist B has provided results that are more parsimonious and potentially provide greater explanatory power. For example, only scientist B could predict that this gene ought to be related to other behaviors, like drug taking, that are known to be correlated with sensation-seeking. As reviewed here, genes have been and will continue to be found that have statistical relationships with risk for psychiatric disorders. However, will the action of these genes be best explained at the level of the disorders themselves? While we cannot answer this question definitively, I would judge this to be unlikely. Far more plausible is that we will find genes whose mode of action can be best understood at the level of more basic biological processes (e.g., neuronal cell migrations during development) and/or mental functions (e.g., processing of threat stimuli).

OVERVIEW AND CONCLUSION

The goal of this essay is to understand the historical origins of the key phrase "X is a gene for Y" and then to evaluate its appropriateness for psychiatric disorders. Our interest, of course, is not merely the phrase itself, but the conceptual framework that underlies this form of Gene-Talk. The use of the phrase "a gene for" implies (and in fact only makes sense in the context of) genes whichlike preformationist anlagen"code for" psychiatric illness in a simple, direct, and powerful way. I argue that the concept of "a gene for. . ." can best be understood as deriving from preformationist developmental theory which, in turn, influenced the interpretation of the concept of a gene in the work of Mendel, in medical genetics, and most recently in human molecular genetics. Five criteria were proposed for evaluating whether the preformationist

concept of "X is a gene for Y" is appropriate for psychiatric disorders. I then reviewed the available evidence, which was of variable quality, that addressed each of these criteria. The strength of association between individual genes and psychiatric disorders is weak and often nonspecific. Genes do not appear to contain all the information needed for the development of psychiatric illness, since environmental factors have, for several disorders, been shown to have causal specificity. The action of genes on psychiatric disorders may frequently be contingent on environmental exposures, although much needs to be learned in this area. The causal chain from genes to psychiatric disorders is probably long and complex. The appropriate level of explanation for gene action is much more likely to be basic biological or mental processes that contribute to psychiatric disorders rather than the disorders themselves. Thus, with varying degrees of confidence, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the preformationist concept of "a gene for. . .". The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in causal pathways of stunning complexity. On this basis, I suggest that we conclude that the phrase "X is a gene for Y," and the preformationist concept of gene action that underlies it, are inappropriate for psychiatric disorders. The strong, clear, and direct causal relationship implied by the concept of "a gene for. . ." does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely to ever discover "genes for" psychiatric illness.

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"A Gene for. . .":The Nature of Gene Action in Psychiatric Disorders

Kenneth S. Kendler, M.D.

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ABSTRACT
A central phrase in the new "GeneTalk" is "X Citing Articles via Google Scholar is a gene for Y," in which X is a particular gene on the human genome and Y is a complex human disorder or trait. This article begins by sketching the historical origins of this phrase and the concept of the gene- Articles by Kendler, K. S. phenotype relationship that underlies it. Five Search for Related Content criteria are then proposed to evaluate the appropriateness of the "X is a gene for Y" concept: 1) strength of association, 2) specificity of relationship, 3) noncontingency of effect, 4) causal proximity of X to Y, and 5) Articles by Kendler, K. S. the degree to which X is the appropriate level of explanation for Y. Evidence from psychiatric genetics is then reviewed that address each of these criteria. The concept of "a gene for" is best understood as deriving from preformationist developmental theory in which geneslike preformationist anlagen"code for" traits in a simple, direct, and powerful way. However, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the concept of "X is a gene for Y." The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in complex causal pathways. The phrase "a gene for" and the preformationist concept of gene action that underlies it are inappropriate for psychiatric disorders. (Reprinted with permission from the American Journal of Psychiatry 2005; 162:1243 1252[Abstract/Free Full Text] )

The last 20 years has seen the rise of "GeneTalk" (1). A central phrase in GeneTalk, and one that has been heard widely in both lay (2) and professional arenas, is "X is a gene for

Y," in which X is a particular gene on the human genome and Y is one of a wide variety of complex human disorders or traits such as depression, aggression, sexual orientation, obesity, infidelity, alcoholism, or schizophrenia. This essay begins with a brief review of the historical origins of the concept of "a gene for". I then propose criteria to assess the validity of this model of gene-phenotype relations and go on to evaluate these criteria as applied to genetic effects on psychiatric disorders. The essay concludes with general observations about our preconceptions and the reality of gene action in psychiatric disorders. Although many of the issues raised in this essay are equally applicable to etiologically complex medical disorders, the focus here will be on psychiatric illness.

HISTORICAL ORIGINS OF THE CONCEPT OF "A GENE FOR"

Since humans started speculating about the nature of development and inheritance, a number of different conceptualizations have emerged about the nature of the guiding forces in these processes (3). In the 20th century, this discourse has come to focus largely on the nature of what Mendel originally termed "anlagen" or "elements," which in 1909 became "genes" (4). Of the multiple different views of the nature of the "gene," the one in which we are interesteda gene defined by the phenotype that it causesoriginated in the developmental theory of preformationism (5). One of the earliest articulated theories of development, preformationism was first proposed by Aristotle but became particularly influential in the 17th century (3, 5, 6). The essentials of the theory are eloquently described by Jacob: At a time when living beings are known by their visible structure alone, what has to be explained about generation [i.e., development] is the maintenance of this primary structure through succeeding generations. The structure cannot itself disappear; it has to persist in the seed from one generation to another. To maintain the continuity of shape, the "germ" of the little being to come has to be contained in the seed; it has to be "preformed." The germ already represents the visible structure of the future child.. . .It is the plan for the future living body. . .already materialized, like a miniature of the organism to come. It is like a scale model with all the parts, pieces and details already in position.. . .Fertilization only activates it and starts it growing. Only then can the germ develop, expand in all directions and acquire its final size, like those Japanese paper flowers which, when placed in water, unwind, unfold and assume their final shape. (7, p. 57) In preformationism, the egg or sperm was understood to contain all the final traits of the mature organism. Development consisted of the expansion of these preformed characteristics (or anlagen) into the individual traits of the adult organism. That is, these anlagen were truly for the adult traits with which they had a simple and direct causal relationship.

In the 19th century, as the young field of biology struggled to fathom the mechanism of transmission of traits across generations, a number of the proposed theories of inheritance (where the "units" of inheritance had names such as pangenes, stirps, and gemmules) had important preformationist themes (3, 4). When Mendels groundbreaking work on genetics (originally published in 1866) was rediscovered in 1900, one common interpretation was that his "elements of inheritance" were the discrete anlagen predicted by preformationist theories (5). This interpretation was favored by two of the most influential geneticists of the day, the Dutchman de Vries (the most famous of the three "co-rediscovers" of Mendel [4]) and the Englishman Bateson (8). In summarizing this exciting period in the history of biology, Allen (9) writes The implications that the discreteness of the gene implied the organism was constructed as a "mosaic" of adult traits was given explicit voice by Bateson with the first years of his encounter with Mendelism. Allen goes on to quote two passages from Bateson written, respectively, in 1901 and 1902 (9): In so far as Mendels law applies, the conclusion is forced upon us that the living organism is a complex of characteristics of which some, at least, are dissociable and are capable of being replicated by others. We thus reach the conception of unit characters which may be rearranged in the formation of reproductive cells. The organism is a collection of traits. We can pull out the yellowness and plug in greenness, pull out tallness and plug in dwarfness. Bateson was recasting, in a new language, preformationist concepts. The Mendelian anlagen (later genes) could be defined by their relationship to the particular phenotype (or "unit character") with which it had a privileged causal link. That is, such genes caused phenotypes in the same way that the preformationist anlagen prefigured adult traits. From this perspective, it made sense to speak of "a gene for greenness," "a gene for tallness," or a gene for any of the other innumerable unit characteristics of the adult organism. It is in this context that a rarely discussed early chapter of psychiatric genetics in the United States must be viewed, when reports appeared claiming to find, in series of large pedigrees, evidence for Mendelian genes "for" "Nomadism or the wandering impulse" (10) and "the neuropathic constitution" (11). This preformationist concept of the gene proved attractive to medical geneticists who, over the course of the 20th century, showed that most classical genetic disorders in humans (termed "Mendelian" diseases in honor of the Austrian monk) were due to hereditary units that behaved just like those first examined by Mendel (12). While medical geneticists came to understand that in biological systems, genes actually code for proteins, it became convenient and seemingly natural to think about preformationist-like genes for these classical genetic diseases in humans.

The last 30 years have seen three interrelated further themes in the "a gene for" story. First, in the mid-1970s two influential books appeared that heightened the profile of genes and their potential impact on human behavior. "Sociobiology: The New Synthesis" by Wilson (13) launched the field of sociobiology (and later evolutionary psychology), discourse in which commonly included the concept of "genes for" a wide range of traits, including altruism, territoriality, jealousy, and ethics. "The Selfish Gene" by Dawkins (14) proposed a gene-centered view of evolution in which an organism, with its wide array of phenotypes, was viewed as a vehicle through which genes replicate themselves over evolutionary time. Second, with the developmental of an ever increasing set of powerful molecular tools, the specific genes and then the specific mutations in those genes were discovered that were responsible for all major classic human genetic disorders. So, when speaking about "a gene for Y" in which Y was sickle-cell anemia, cystic fibrosis, or Huntingtons chorea it became possible to conceive of the gene not only as an abstract transmitted "unit" but also as a discrete piece of DNA at a specific location on a chromosome. Third, prompted by the sequencing of the human genome, the concept that DNA represented the "blueprint" of life (or in related versions the "code" or "recipe" for life) was widely promulgated in both the scientific and lay literature (2). The preformationist themes in this metaphor are evident: genes are to phenotypes as blueprints of a building are to the building themselves. So, this historical sketch suggests that our current concept of "X is a gene for Y" in humans has four major interrelated historical roots. First, the concept that development anlagen could be "for" adult traits arose in preformationist developmental theories. Second, the discovery of Mendels "elements" was interpreted by some as verifying this concept. Third, the idea that genes could be "for" human traits was supported by the discovery that genes for classical Mendelian medical disorders often acted just like the hereditary elements found in Mendels pea plants. Finally, these concepts became linked to DNA by a series of stunning discoveries in the last 20 years, so that strength of the "icon" of the double helix provided particular luster to potential discoveries in psychiatry of "a gene for".

CRITERIA FOR THE CONCEPT OF "A GENE FOR"

The remainder of this essay addresses the question of whether this preformationist model of gene actionin which genes are "for" phenotypesis appropriate for psychiatry. Based in part on prior efforts to develop guidelines for causal inference in epidemiology (e.g., reference 15), I suggest five criteria by which to judge the validity of the claim "X is a gene for Y": 1) strength of association of X with Y, 2) specificity of relationship of X with Y, 3) non-contingency of the effect of X on Y, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. In sum, I argue that If gene X has a strong, specific association with disease Y in all known environments and the physiological pathway from X to Y is short or well-understood, then it may be appropriate to speak of X as a gene for Y. But first, a few details are needed. The scientific basis of most claims that "X is a gene for Y" results from a statistical test called association analysis. In its simplest form, this test compares the frequency of specific DNA variants in or around gene X in a set of cases with

disorder Y and a set of matched control subjects. An association is claimed if the frequency of these variants differ significantly in cases and control subjects. In both a conceptual and statistical sense, this approach is no different from the methods commonly used in the biomedical and social sciences to assess the relationship between putative risk factors and outcome variables such as smoking and lung cancer or childhood sexual abuse and depression. Therefore, standard "a gene for" claims are based on statistical and not biological grounds. Biological studies that trace etiologic pathways from X to Y should follow claims for association and would certainly provide confirmatory data. However, they have been very rare to date in psychiatric genetics. On its own, a significant p value in an association study tells you nothing about the nature of the causal relationship between the gene and the disease.

STRENGTH OF ASSOCIATION
As with any risk factor for any outcome, the strength of association between a specific gene and a particular disease can vary in magnitude. In considering the criteria for "a gene for. . .," an historical standard of comparison is what has come to be called a Mendelian gene. The action of Mendelian genes is deterministic and not probabilistic. If a plant inherits a particular copy of the gene for wrinkled peas, it would not matter how much sunshine the plant received or the quality of its fertilizer. The plant will have wrinkled peas no matter what the environment does. In humans, we have many diseases that are due to Mendelian genes that behave exactly like the genes Mendel studied in his pea plants (12). If you have one copy of the pathogenic gene for Huntingtons disease, it does not matter what your diet is, whether your parents were loving or harsh, or if your peer group in adolescence were boy scouts or petty criminals. If you have the mutated gene and you live long enough, you will develop the disease. Furthermore, for most Mendelian genes in man, the only way to get the disorder is to have the disease gene. There is no way to "acquire" cystic fibrosis or Huntingtons disease through environmental exposure. So if having the disease gene always produces the disorder and the disorder never occurs without the disease gene, this produces a perfect association between the disease gene (X) and the disorder (Y). (Reality is somewhat more complex. Most Mendelian genes in man contain several different mutations, each of which can cause diseases that are sometimes of quite variable severity. But this claim still holds for all mutations of the gene considered together.) The strength of an association between a risk factor and a disease is most frequently quantified by a statistic called the odds ratio. Formally, the odds ratio is defined as the ratio of the odds of developing the disease among those exposed to the risk factor and the odds of disease among those not exposed to the risk factor. For Mendelian disorders in man, since the first of these figures is one and the second is zero, the odds ratio for the disorder given the pathogenic gene is infinite. Since this is a rather stringent criteria, for the sake of argument, let us say the association with Mendelian-like genes (an historical model for the concept of "a gene for") has an odds ratio of approximately 100 (Figure 1 ).

Figure 1. A Comparison of Estimated Odds Ratios for the Strength of Association Between Risk Factors and Key Outcomesa a Although the odds ratio for a classic Mendelian gene is actually , we estimate it here at approximately 100. Strong association (here odds ratio=15) approximates that seen between heavy smoking and lung cancer, industrial exposure to asbestos and mesothelioma, and severe stressful life events and the onset of major depression. Moderate association (odds ratio=5.0) approximates that seen for apolipoprotein E-4 and Alzheimers disease as well as the protective effect in Asian populations of the ALDH2*2 copy of the aldehyde dehydrogenase gene on risk for alcoholism. The associations seen between individual genes (or high-risk haplotypes) and psychiatric disorders (odds ratio=1.5) is an approximation obtained from a review of the current literature.

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Are there any genes whose strength of association with a psychiatric disorder is Mendelianlike? Two related sources of information, both gathered in the last two decades, indicate that the answer to this question is almost certainly "No." First, a gene that has a deterministic or nearly deterministic relationship with a phenotype produces an unmistakable signature in the pattern of illness in large pedigrees. Numerous investigators have now searched many parts of the globe (including nearly all psychiatric facilities in a modest-sized country [16]) seeking pedigrees in which major forms of psychiatric illness especially schizophrenia and bipolar illnessare distributed in the pattern expected from a Mendelian-like gene. Such pedigrees have not been found. Second, Mendelian-like genes also produce a distinctive result in genome-wide linkage studies, which effectively sweep the human genome looking for regions that contain genes that have an impact on risk of illness. While the technical details need not concern us, experts agree that for those disorders studied in genome-wide linkage scans of reasonable size and qualityespecially schizophrenia, bipolar illness, panic disorder, and eating disordersconclusive evidence has accumulated that even moderately rare genes of Mendelian-like effect do not exist. (The available evidence does not permit us to rule out, however, very rare Mendelian-like genes.)

So, if we lack Mendelian genes for psychiatric disorders, with their very high odds ratios, what sort of magnitude of associations might we expect? One set of benchmarks might be provided by three examples of what would be considered very strong associations in epidemiology. The estimated odds ratio between heavy smoking and small cell carcinoma of the lung is approximately 20 (17), between industrial exposure to asbestos and mesothelioma is approximately 15 (18), and between severe stressful life events and the onset of major depression is approximately 12 (19). Another more modest benchmark is provided by the two outstanding genetic association results in neuropsychiatry of the last decades. The association between the pathogenic "4 allele" of the apolipoprotein E gene and Alzheimers disease produces, in Caucasian populations, an odds ratio of approximately 3.0 (20). In Asian populations, the possession of the slow-metabolizing (ALDH2*2) copy of the aldehyde dehydrogenase gene conveys up to a 10-fold reduction in risk for the development of alcoholism (21). So, as depicted in Figure 1 , we have three possible benchmarks for the strength of the gene-phenotype association for psychiatric disorders: Mendelian-like (odds ratio of approximately 100), strong (odds ratio=1220), or moderate (odds ratio=310). Trying to summarize the magnitude of association found between functional candidate genes and psychiatric disorders is problematic because of the multiple methodologic difficulties in the interpretation of such studies (2224). Greatest reliability should be placed on the results of meta-analyses, which are now beginning to appear in the literature. A PubMed search from 2000 on (using publication type of "metaanalysis" and search words "gene" and "association") followed by a hand search and elimination of duplication yielded 10 significant meta-analytic estimates of odds ratios between individual genes and psychiatric disorders (Table 1 ) (excluding results from those meta-analyses that did not support the original positive reports). The odds ratios ranged from 1.07 to 1.57 with a median of approximately 1.30.

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Table 1. Meta-Analysis Results Published Since 2000 for Studies of Association Between Individual Genes and Psychiatric Disorders

Another strategy to localize candidate genes is to look for them under linkage peaks (socalled positional candidate genes). In schizophrenia, replicated evidence is now emerging for several such genes (28). For these genes, disease-associated haplotypessmall sections of DNA that have traveled together over evolutionary timecan often be found. The two best replicated positional candidate genes for schizophrenia are dysbindin 1 and neuregulin 1. Not counting the original reports (where the effect size might be biased upward), estimates are available for the association between high-risk haplotypes and schizophrenia for both of these genes. For dysbindin, odds ratios of 1.24 (29), 1.23 (30), 1.40 (31), 1.70 (32), and 1.58 (33) have been reported or calculated from replication reports. For neuregulin 1, two replications were noted in a recent review, with odds ratios estimated to be 1.25 and 1.80 (28). Taken together, the meta-analyses of functional candidate gene association studies and early results from positional candidate genes suggest that the magnitude of the associations between individual genes and psychiatric illnesses have small odds ratios, largely from 1.1 to 1.6. Compared to our benchmarks, this effect size is very modest (Figure 1 ). Perhaps genes (or particular mutations or haplotypes) of larger effect size will be found. While results from linkage studies suggest that this is unlikely, it cannot be ruled out. Also to be considered is the statistical dictum that the first set of effects detected in any research area tend to be the most robust. If this is correct, further genes discovered for psychiatric disorders are likely to have smaller average effects than the genes found to date. The preformationist concept of "a gene for" implied a predetermined and largely irrevocable link between gene and phenotype. This is the pattern of association observed between gene and phenotype from Mendels original traits and for Mendelian genetic disorders in humans. By contrast, for psychiatric disorders, individual genes appear to have a quite modest association with psychiatric illness. While they may have an impact on risk, individual genes hardly predetermine illness, as would be expected if we had discovered "genes for" mental disorders.

SPECIFICITY OF ASSOCIATION
The second criterion to evaluate the appropriateness of the concept of "X is a gene for Y" is the degree of specificity in the relationship between X and Y. As illustrated in Figure 2 , does X influence risk for any other disorders in addition to Y? Or are there other genes that contribute to Y in addition to X?

Figure 2. Possible Gene-to-Phenotype Relationshipsa a Possible relationships between genes on the lefthand side of thefigure and phenotypes on the righthand side are shown. In a one-to-one relationship, gene X causes only phenotype Y, and phenotype Y is caused only by gene X. In a one-to-many relationship, gene X causes several phenotypes each in turn being only caused by X. In a many-to-one relationship, phenotype Y is caused by several genes each in turn only causing Y. In a many-to-many relationship, each gene causes several phenotypes and each phenotype is caused by several genes.

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In preformationist theory, anlagen had highly specific associations with the adult traits into which they developed. The hereditary elements of the pea that Mendel studied also had quite specific phenotypic effects. That is, one gene influenced pea color but not shape or height while another influenced shape but not height or color. However, as genetics developed, many genes were found that impacted on a variety of phenotypic characteristicsa phenomenon called pleiotropy. In man, many Mendelian genes produce one and only one disease syndrome (although sometimes of varying severity depending on the specific mutation). But there are exceptions where different abnormalities in a single gene can produce distinct genetic diseases. How specific are individual genes in their impact on risk for psychiatric disorders? Do most genes influence risk for one and only one psychiatric disorder? Twin studies, which study "genes" in the aggregate, suggest that genetic risk factors for psychiatric disorders are often nonspecific in their effect. A large-scale twin study of seven psychiatric and substance use disorders found one common genetic risk factor predisposing to drug abuse, alcohol dependence, antisocial personality disorder, and conduct disorder and a second common genetic factor influencing risk for major depression, generalized anxiety disorder, and phobia (34). Overlap of genetic risk factors for multiple disorders have been demonstrated in other twin studies (e.g., references 3537). We know much less about the specificity of the spectrum of effects on psychiatric disorders of individual genes. Meta-analyses reviewed in Table 1 show that variants at one gene (the 5-HT2A receptor) may predispose to risk for three different disorders (schizophrenia, bulimia, and anorexia nervosa). A pair of overlapping genes on chromosome 13q (termed G30 and G72) may be associated both with schizophrenia and bipolar illness (28). A

number of overlapping positive regions in linkage genome scans for bipolar illness and schizophrenia have led some to argue that this reflects shared genes between these two disorders (38). While difficult to evaluate critically, claims have been made that several popular candidate genes (e.g., serotonin transporter, dopamine transporter, dopamine 2 receptor) are significantly associated with a wide variety of psychiatric disorders or psychiatrically relevant traits (39, 40). While much remains unknown, current evidence suggests that many genes that influence risk for psychiatric disorders will not be diagnostically specific in their effect, thereby resembling the one-to-many relationship in Figure 2 rather than the one-to-one relationship. We are on firmer ground in evaluating whether genetic risk for psychiatric disorders results from the action of a single gene (the one-to-one relationship in Figure 2 ) or multiple genes (the many-to-one relationship in Figure 2 ). Some evidence bears on this question indirectly, as follows. Twin and adoption studies provide convincing evidence for significant genetic effects on virtually all major psychiatric disorders (41). Therefore, genes that affect risk for these disorders must exist somewhere on the human genome. Linkage studies examine how these aggregate genetic risk factors are distributed across the genome. If genetic risk resulted from a single gene, then all the linkage "signal" would be concentrated in a single location, with a resulting clear and robust statistical linkage peak. But, as noted earlier, this is a pattern that has not been observed in published genome scans for psychiatric disorders. Instead, a number of modest linkage peaks are usually seen, suggesting that the "packets" of genetic risk for these disorders are widely dispersed across the genome. (To complicate matters, genome scans will underestimate the number of genomic regions involved because of low power to detect genes of small effect size, but will overestimate the number because some of the observed "peaks" will be false positives.) Recently, data have emerged that addresses this question directly. A careful meta-analysis of 20 genome scans for schizophrenia has suggested 10 genomic regions likely to contain susceptibility genes (42). In addition, current evidence of bipolar disorder, the second-beststudied psychiatric disorder by linkage scans, also suggests multiple loci (43). The specificity of association implied in the "a gene for" concept has another implication worth exploring. Consistent with preformationist theory, specificity of gene action implies that the gene contains all information needed for the development of the trait. The environment might impact on the final phenotype, but its effect is nonspecific. That is, the gene "codes for" the trait, while the environment reflects background factors that support development but is not in and of itself "information-carrying." To illustrate how commonly we see genes and environment in this light, it is worth pondering a curious and asymmetrical feature of GeneTalk. While we find it easy to use the phrase "X is a gene for Y," it feels quite odd to say "A is an environment for B." For example, a large body of empirical work supports the hypothesis that severe life events are important environmental risk factors for major depression (44). The magnitude of the association between such events and the subsequent depressive episode is far greater than that observed for any of the genes that we have reviewed here. Yet, who has heard the phrase "a romantic breakup is an environment for depression"? I suggest that we feel comfortable with "X is a gene for Y" and not "A is an environment for B" because we

implicitly assume that genes have a privileged causal relationship with the phenotype not shared by environmental factors. However, empirical evidence does not support the position that genes code specifically for psychiatric illness while the environment reflects nonspecific "background effects." By definition, environmental factors are central to the etiology of posttraumatic stress disorder. In the aforementioned multivariate twin model, what distinguished major depression, generalized anxiety disorder, and phobia from one another were environmental and not genetic risk factors (34). In a detailed study of the impact of childhood parental loss on risk for common psychiatric and substance use disorders, death of a parent was specific in increasing risk for major depression and no other disorder (Kendler et al., unpublished results). Consistent with studies of stressful life events that have shown moderate separation of depressogenic and anxiogenic events (45, 46), a multivariate genetic study of symptoms of anxiety and depression showed that genetic factors influence nonspecific risk for all symptoms, whereas two environmental factors were identified that predisposed, with moderate specificity, for symptoms of depression and anxiety, respectively (47). The preformationist concept of "a gene for" implies high levels of specificity between gene and phenotype. While much remains to be learned in this area, current evidence suggests that instead of the "one-to-one" relationship implied by the concept of "a gene for. . .," genes and disorders in psychiatry are likely to have the "many-to-many" relationship depicted in Figure 2 . (The evidence that the association between individual genes and psychiatric disorders are typically weak and may often be nonspecific does not mean that the identification of such genes is unimportant. For example, such discoveries can identify pathophysiologic pathways, begin the lengthy process of clarifying how individual genes interact with each other and with environmental exposures to produce illness, and provide new targets for treatment.)

NONCONTINGENCY OF ASSOCIATION
Noncontingent association means that the relationship between gene X and disorder Y is not dependent on other factors, particularly exposure to a specific environment or on the presence of other genes. As mentioned earlier, this is a typical (albeit not uniform) feature of genes that cause classical Mendelian disorders in humans. If the association between gene and disease were contingent on particular environmental exposures, then we would have to amend our statement to read "X is a gene for Y given exposure to environment Z." Environmental contingencies for genetic effects on psychiatric disorders have been little investigated. Twin and adoption studies suggest that the impact of aggregate "genes" for major depression are altered by exposure to stressful life events (19, 48) and for schizophrenia and conduct disorder by exposure to a dysfunctional rearing environment (49, 50). A range of twin studies suggest that environmental experiences have an impact on genetic risk for several psychiatrically relevant traits, including aggression, disinhibition, and smoking (51). Recently, Caspi and colleagues have found evidence for interactions

between environmental risk factors and particular genes in the production of antisocial behavior (52) and depression (53), with the former finding having been replicated (54). We know almost nothing about gene-by-gene interactions in the etiology of psychiatric disorders. Although a number of association studies have reported interactions, I am unaware of any that have been widely replicated or supported by meta-analyses. Using statistical models applied to risk of illness in various classes of relatives, Risch has claimed that gene-by-gene interactions are important in the etiology of schizophrenia (55). Overall, we know little about the contingent nature of genetic effects for psychiatric disorders. The available information suggests that gene action contingent upon certain environmental exposures is probably not rare and may be relatively common for psychiatric disorders. This is also inconsistent with the preformationist concept of "a gene for. . .".

CAUSAL PROXIMITY
Preformationist developmental models assumed that anlagen developed directly into adult traits. The "blueprint for life" metaphor similarly assumes a direct correspondence between individual parts of the blueprint (windows, doors, fixtures) and the corresponding units of the completed building. Conceptualizing genes in this preformationist framework therefore carries the implicit assumption of a direct causal link between gene and phenotype. It is only with this assumption that usage of the "a gene for. . ." is congruent with the common meaning of the phrase "X is for Y" in English. To clarify this point, lets examine a typical list of such statements: I use a knife for buttering my toast. I have a backpack for carrying my computer to work each day. I was upset at my son for not doing his chores. In each case, there is an implied direct and immediate relationship between X and Y. To put it more formally, X and Y are directly linked in a formal logical train of action (first two examples) or thought (third example). Now, how does this common sense meaning of the word "for" apply to the phrase "X is a gene for Y"? Let me illustrate the problem with a vignette A jumbo jet contains about as many parts as there are genes in the human genome. If someone went into the fuselage and removed a 2-foot length of hydraulic cable connecting the cockpit to the wing flaps, the plane could not take off. Is this piece of equipment then a cable for flying? Most of us would be uneasy answering yes to this question. Why? Because this example violates our conception of causal proximity. When we say X is for Y, we expect X to be, to a first approximation, directly and immediately related to Y. That is not the case for the cable and flying. There are many, many mechanical steps required to get from the function of that cable to a jumbo jet rising off the runway.

Another vignette: Assume a Mendelian genetic disease due to a mutation in gene K. Gene Ks normal function is to produce an enzyme L that breaks down metabolite M in cells allowing M to be harmlessly secreted from the body. When K has a pathogenic mutation, the enzyme L that is produced no longer works. Therefore, levels of M rise, producing a well understood series of toxic effects, thereby producing the genetic disorder N. This scenario suggests the following potentially simple causal chain: mutated gene K dysfunctional enzyme L excess metabolite M disorder N. In this admittedly oversimplified story, a case could be made that gene K had sufficient causal proximity to disorder N to make plausible the claim that "K is a gene for N." However, it might be argued that even here, the complexity of the paths from levels of M to disorder N may be far from "simple." Contrast this situation to the causal chain from a gene mutation to a complex psychiatric disorder such as schizophrenia. Although early efforts have been made to begin to trace such pathways (e.g., reference 56), we probably do not know enough to articulate all the specific causal steps that would be needed to go from DNA basepair variation to, for example, the cognitive processes that predispose to delusion formation. What we can conclude with some confidence is that it will be very complex. Indeed, the causal link between that hydraulic cable and the jumbo jet flying will probably look very simple and short compared to the causal relationship between individual genes and the manifestations of schizophrenia. While the nature of the evidence reviewed here is largely inferential, it suggests that the pathways from most genes for psychiatric illness to their phenotypes would fail the causal proximity criterion implicit in the concept of "X is a gene for Y."

APPROPRIATE LEVEL OF EXPLANATION

Scientific theories typically strive to explain phenomenon at the most informative level. To provide an absurd example, no one would seek to understand the origin of hypertension at the level of quarks. In some ultimate way, quarks may be involved. But quarks are just the wrong level of inquiry for the problem. To illustrate how this issuethe appropriateness of level of explanationmay apply to our evaluation of the concept of "a gene for. . ." consider these two "thought experiments": Defects in gene X produce such profound mental retardation that affected individuals never develop speech. Is X is a gene for language? A research group has localized a gene that controls development of perfect pitch (57). Assuming that individuals with perfect pitch tend to particularly appreciate the music of Mozart, should they declare that they have found a gene for liking Mozart? For the first scenario, the answer to the query is clearly "No." Although gene X is associated with an absence of language development, its phenotypic effects are best

understood at the level of mental retardation, with muteness as a nonspecific consequence. X might be a "gene for" mental retardation but not language. Although the second scenario is subtler, if the causal pathway is truly gene variant pitch perception liking Mozart, then it is better science to conclude that this is a gene that influences pitch perception, one of the many effects of which might be to alter the pleasure of listening to Mozart. It is better science because it is more parsimonious (this gene is likely to have other effects such as influencing the pleasure of listening to Haydn, Beethoven, and Brahms) and because it has greater explanatory power. A final scenario: Scientist A studied the behavioral correlates of a particular variant at gene X and concluded "This is a very interesting gene that increases the rates of sky diving, speeding, mountain climbing, bungee jumping, and unprotected casual sex." Scientist B studied the same variant and concluded "This is a very interesting gene and effects levels of sensation-seeking." Who has done the better science? Since sensation seeking (and its close cousin noveltyseeking) are well studied traits (41), scientist B has provided results that are more parsimonious and potentially provide greater explanatory power. For example, only scientist B could predict that this gene ought to be related to other behaviors, like drug taking, that are known to be correlated with sensation-seeking. As reviewed here, genes have been and will continue to be found that have statistical relationships with risk for psychiatric disorders. However, will the action of these genes be best explained at the level of the disorders themselves? While we cannot answer this question definitively, I would judge this to be unlikely. Far more plausible is that we will find genes whose mode of action can be best understood at the level of more basic biological processes (e.g., neuronal cell migrations during development) and/or mental functions (e.g., processing of threat stimuli).

OVERVIEW AND CONCLUSION

The goal of this essay is to understand the historical origins of the key phrase "X is a gene for Y" and then to evaluate its appropriateness for psychiatric disorders. Our interest, of course, is not merely the phrase itself, but the conceptual framework that underlies this form of Gene-Talk. The use of the phrase "a gene for" implies (and in fact only makes sense in the context of) genes whichlike preformationist anlagen"code for" psychiatric illness in a simple, direct, and powerful way. I argue that the concept of "a gene for. . ." can best be understood as deriving from preformationist developmental theory which, in turn, influenced the interpretation of the concept of a gene in the work of Mendel, in medical genetics, and most recently in human molecular genetics. Five criteria were proposed for evaluating whether the preformationist

concept of "X is a gene for Y" is appropriate for psychiatric disorders. I then reviewed the available evidence, which was of variable quality, that addressed each of these criteria. The strength of association between individual genes and psychiatric disorders is weak and often nonspecific. Genes do not appear to contain all the information needed for the development of psychiatric illness, since environmental factors have, for several disorders, been shown to have causal specificity. The action of genes on psychiatric disorders may frequently be contingent on environmental exposures, although much needs to be learned in this area. The causal chain from genes to psychiatric disorders is probably long and complex. The appropriate level of explanation for gene action is much more likely to be basic biological or mental processes that contribute to psychiatric disorders rather than the disorders themselves. Thus, with varying degrees of confidence, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the preformationist concept of "a gene for. . .". The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in causal pathways of stunning complexity. On this basis, I suggest that we conclude that the phrase "X is a gene for Y," and the preformationist concept of gene action that underlies it, are inappropriate for psychiatric disorders. The strong, clear, and direct causal relationship implied by the concept of "a gene for. . ." does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely to ever discover "genes for" psychiatric illness.

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J, Peltonen L, ODonovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, Mc-Quillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T: Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 2003; 73:34 48[Medline] 43. Mathews CA, Reus VI: Genetic linkage in bipolar disorder. CNS Spect 2003; 8:891904 44. Tennant C: Life events, stress and depression: a review of recent findings. Aust NZ J Psychiatry 2002; 36:173182[Medline] 45. Finlay-Jones R, Brown GW: Types of stressful life events and the onset of anxiety and depressive disorders. Psychol Med 1981; 11:803815[Medline] 46. Kendler KS, Karkowski L, Prescott CA: Stressful life events and major depression: risk period, long-term contextual threat and diagnostic specificity. J Nerv Ment Dis 1998; 186:661669[Medline] 47. Kendler KS, Heath AC, Martin NG, Eaves LJ: Symptoms of anxiety and symptoms of depression: same genes, different environments? Arch Gen Psychiatry 1987; 44:451457[Abstract/Free Full Text] 48. Eaves L, Silberg J, Erkanli A: Resolving multiple epigenetic pathways to adolescent depression. J Child Psychol Psychiatry 2003; 44:10061014[Medline] 49. Tienari P, Wynne LC, Sorri A, Lahti I, Laksy K, Moring J, Naarala M, Nieminen P, Wahlberg KE: Genotype-environment interaction in schizophrenia-spectrum disorder: long-term follow-up study of Finnish adoptees. Br J Psychiatry 2004; 184:216222[Abstract/Free Full Text] 50. Cadoret RJ, Yates WR, Troughton E, Woodworth G, Stewart MA: Geneenvironment interaction in genesis of aggressivity and conduct disorders. Arch Gen Psychiatry 1995; 52:916924[Abstract/Free Full Text] 51. Kendler KS: Twin studies of psychiatric illness: an update. Arch Gen Psychiatry 2001; 58:10051014[Abstract/Free Full Text] 52. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R: Role of genotype in the cycle of violence in maltreated children. Science 2002; 297:851854[Abstract/Free Full Text] 53. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R: Influence of life stress on depression:

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"A Gene for. . .":The Nature of Gene Action in Psychiatric Disorders

Kenneth S. Kendler, M.D.

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ABSTRACT
A central phrase in the new "GeneTalk" is "X is a gene for Y," in which X is a particular gene on the human genome and Y is a Articles by Kendler, K. S. complex human disorder or trait. This article Search for Related Content begins by sketching the historical origins of this phrase and the concept of the genephenotype relationship that underlies it. Five criteria are then proposed to evaluate the appropriateness of the "X is a gene for Y" Articles by Kendler, K. S. concept: 1) strength of association, 2) specificity of relationship, 3) noncontingency of effect, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. Evidence from psychiatric genetics is then reviewed that address each of these criteria. The concept of "a gene for" is best understood as deriving from preformationist developmental theory in which geneslike preformationist anlagen"code for" traits in a simple, direct, and powerful way. However, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the concept of "X is a gene for Y." The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in complex causal pathways. The phrase "a gene for" and the preformationist concept of gene action that underlies it are inappropriate for psychiatric disorders. (Reprinted with permission from the American Journal of Psychiatry 2005; 162:1243 1252[Abstract/Free Full Text] )

The last 20 years has seen the rise of "GeneTalk" (1). A central phrase in GeneTalk, and one that has been heard widely in both lay (2) and professional arenas, is "X is a gene for Y," in which X is a particular gene on the human genome and Y is one of a wide variety of

complex human disorders or traits such as depression, aggression, sexual orientation, obesity, infidelity, alcoholism, or schizophrenia. This essay begins with a brief review of the historical origins of the concept of "a gene for". I then propose criteria to assess the validity of this model of gene-phenotype relations and go on to evaluate these criteria as applied to genetic effects on psychiatric disorders. The essay concludes with general observations about our preconceptions and the reality of gene action in psychiatric disorders. Although many of the issues raised in this essay are equally applicable to etiologically complex medical disorders, the focus here will be on psychiatric illness.

HISTORICAL ORIGINS OF THE CONCEPT OF "A GENE FOR"

Since humans started speculating about the nature of development and inheritance, a number of different conceptualizations have emerged about the nature of the guiding forces in these processes (3). In the 20th century, this discourse has come to focus largely on the nature of what Mendel originally termed "anlagen" or "elements," which in 1909 became "genes" (4). Of the multiple different views of the nature of the "gene," the one in which we are interesteda gene defined by the phenotype that it causesoriginated in the developmental theory of preformationism (5). One of the earliest articulated theories of development, preformationism was first proposed by Aristotle but became particularly influential in the 17th century (3, 5, 6). The essentials of the theory are eloquently described by Jacob: At a time when living beings are known by their visible structure alone, what has to be explained about generation [i.e., development] is the maintenance of this primary structure through succeeding generations. The structure cannot itself disappear; it has to persist in the seed from one generation to another. To maintain the continuity of shape, the "germ" of the little being to come has to be contained in the seed; it has to be "preformed." The germ already represents the visible structure of the future child.. . .It is the plan for the future living body. . .already materialized, like a miniature of the organism to come. It is like a scale model with all the parts, pieces and details already in position.. . .Fertilization only activates it and starts it growing. Only then can the germ develop, expand in all directions and acquire its final size, like those Japanese paper flowers which, when placed in water, unwind, unfold and assume their final shape. (7, p. 57) In preformationism, the egg or sperm was understood to contain all the final traits of the mature organism. Development consisted of the expansion of these preformed characteristics (or anlagen) into the individual traits of the adult organism. That is, these anlagen were truly for the adult traits with which they had a simple and direct causal relationship. In the 19th century, as the young field of biology struggled to fathom the mechanism of transmission of traits across generations, a number of the proposed theories of inheritance

(where the "units" of inheritance had names such as pangenes, stirps, and gemmules) had important preformationist themes (3, 4). When Mendels groundbreaking work on genetics (originally published in 1866) was rediscovered in 1900, one common interpretation was that his "elements of inheritance" were the discrete anlagen predicted by preformationist theories (5). This interpretation was favored by two of the most influential geneticists of the day, the Dutchman de Vries (the most famous of the three "co-rediscovers" of Mendel [4]) and the Englishman Bateson (8). In summarizing this exciting period in the history of biology, Allen (9) writes The implications that the discreteness of the gene implied the organism was constructed as a "mosaic" of adult traits was given explicit voice by Bateson with the first years of his encounter with Mendelism. Allen goes on to quote two passages from Bateson written, respectively, in 1901 and 1902 (9): In so far as Mendels law applies, the conclusion is forced upon us that the living organism is a complex of characteristics of which some, at least, are dissociable and are capable of being replicated by others. We thus reach the conception of unit characters which may be rearranged in the formation of reproductive cells. The organism is a collection of traits. We can pull out the yellowness and plug in greenness, pull out tallness and plug in dwarfness. Bateson was recasting, in a new language, preformationist concepts. The Mendelian anlagen (later genes) could be defined by their relationship to the particular phenotype (or "unit character") with which it had a privileged causal link. That is, such genes caused phenotypes in the same way that the preformationist anlagen prefigured adult traits. From this perspective, it made sense to speak of "a gene for greenness," "a gene for tallness," or a gene for any of the other innumerable unit characteristics of the adult organism. It is in this context that a rarely discussed early chapter of psychiatric genetics in the United States must be viewed, when reports appeared claiming to find, in series of large pedigrees, evidence for Mendelian genes "for" "Nomadism or the wandering impulse" (10) and "the neuropathic constitution" (11). This preformationist concept of the gene proved attractive to medical geneticists who, over the course of the 20th century, showed that most classical genetic disorders in humans (termed "Mendelian" diseases in honor of the Austrian monk) were due to hereditary units that behaved just like those first examined by Mendel (12). While medical geneticists came to understand that in biological systems, genes actually code for proteins, it became convenient and seemingly natural to think about preformationist-like genes for these classical genetic diseases in humans. The last 30 years have seen three interrelated further themes in the "a gene for" story. First, in the mid-1970s two influential books appeared that heightened the profile of genes and their potential impact on human behavior. "Sociobiology: The New Synthesis" by Wilson

(13) launched the field of sociobiology (and later evolutionary psychology), discourse in which commonly included the concept of "genes for" a wide range of traits, including altruism, territoriality, jealousy, and ethics. "The Selfish Gene" by Dawkins (14) proposed a gene-centered view of evolution in which an organism, with its wide array of phenotypes, was viewed as a vehicle through which genes replicate themselves over evolutionary time. Second, with the developmental of an ever increasing set of powerful molecular tools, the specific genes and then the specific mutations in those genes were discovered that were responsible for all major classic human genetic disorders. So, when speaking about "a gene for Y" in which Y was sickle-cell anemia, cystic fibrosis, or Huntingtons chorea it became possible to conceive of the gene not only as an abstract transmitted "unit" but also as a discrete piece of DNA at a specific location on a chromosome. Third, prompted by the sequencing of the human genome, the concept that DNA represented the "blueprint" of life (or in related versions the "code" or "recipe" for life) was widely promulgated in both the scientific and lay literature (2). The preformationist themes in this metaphor are evident: genes are to phenotypes as blueprints of a building are to the building themselves. So, this historical sketch suggests that our current concept of "X is a gene for Y" in humans has four major interrelated historical roots. First, the concept that development anlagen could be "for" adult traits arose in preformationist developmental theories. Second, the discovery of Mendels "elements" was interpreted by some as verifying this concept. Third, the idea that genes could be "for" human traits was supported by the discovery that genes for classical Mendelian medical disorders often acted just like the hereditary elements found in Mendels pea plants. Finally, these concepts became linked to DNA by a series of stunning discoveries in the last 20 years, so that strength of the "icon" of the double helix provided particular luster to potential discoveries in psychiatry of "a gene for".

CRITERIA FOR THE CONCEPT OF "A GENE FOR"

The remainder of this essay addresses the question of whether this preformationist model of gene actionin which genes are "for" phenotypesis appropriate for psychiatry. Based in part on prior efforts to develop guidelines for causal inference in epidemiology (e.g., reference 15), I suggest five criteria by which to judge the validity of the claim "X is a gene for Y": 1) strength of association of X with Y, 2) specificity of relationship of X with Y, 3) non-contingency of the effect of X on Y, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. In sum, I argue that If gene X has a strong, specific association with disease Y in all known environments and the physiological pathway from X to Y is short or well-understood, then it may be appropriate to speak of X as a gene for Y. But first, a few details are needed. The scientific basis of most claims that "X is a gene for Y" results from a statistical test called association analysis. In its simplest form, this test compares the frequency of specific DNA variants in or around gene X in a set of cases with disorder Y and a set of matched control subjects. An association is claimed if the frequency of these variants differ significantly in cases and control subjects. In both a conceptual and statistical sense, this approach is no different from the methods commonly used in the

biomedical and social sciences to assess the relationship between putative risk factors and outcome variables such as smoking and lung cancer or childhood sexual abuse and depression. Therefore, standard "a gene for" claims are based on statistical and not biological grounds. Biological studies that trace etiologic pathways from X to Y should follow claims for association and would certainly provide confirmatory data. However, they have been very rare to date in psychiatric genetics. On its own, a significant p value in an association study tells you nothing about the nature of the causal relationship between the gene and the disease.

STRENGTH OF ASSOCIATION
As with any risk factor for any outcome, the strength of association between a specific gene and a particular disease can vary in magnitude. In considering the criteria for "a gene for. . .," an historical standard of comparison is what has come to be called a Mendelian gene. The action of Mendelian genes is deterministic and not probabilistic. If a plant inherits a particular copy of the gene for wrinkled peas, it would not matter how much sunshine the plant received or the quality of its fertilizer. The plant will have wrinkled peas no matter what the environment does. In humans, we have many diseases that are due to Mendelian genes that behave exactly like the genes Mendel studied in his pea plants (12). If you have one copy of the pathogenic gene for Huntingtons disease, it does not matter what your diet is, whether your parents were loving or harsh, or if your peer group in adolescence were boy scouts or petty criminals. If you have the mutated gene and you live long enough, you will develop the disease. Furthermore, for most Mendelian genes in man, the only way to get the disorder is to have the disease gene. There is no way to "acquire" cystic fibrosis or Huntingtons disease through environmental exposure. So if having the disease gene always produces the disorder and the disorder never occurs without the disease gene, this produces a perfect association between the disease gene (X) and the disorder (Y). (Reality is somewhat more complex. Most Mendelian genes in man contain several different mutations, each of which can cause diseases that are sometimes of quite variable severity. But this claim still holds for all mutations of the gene considered together.) The strength of an association between a risk factor and a disease is most frequently quantified by a statistic called the odds ratio. Formally, the odds ratio is defined as the ratio of the odds of developing the disease among those exposed to the risk factor and the odds of disease among those not exposed to the risk factor. For Mendelian disorders in man, since the first of these figures is one and the second is zero, the odds ratio for the disorder given the pathogenic gene is infinite. Since this is a rather stringent criteria, for the sake of argument, let us say the association with Mendelian-like genes (an historical model for the concept of "a gene for") has an odds ratio of approximately 100 (Figure 1 ).

Figure 1. A Comparison of Estimated Odds Ratios for the Strength of Association Between Risk Factors and Key Outcomesa a Although the odds ratio for a classic Mendelian gene is actually , we estimate it here at approximately 100. Strong association (here odds ratio=15) approximates that seen between heavy smoking and lung cancer, industrial exposure to asbestos and mesothelioma, and severe stressful life events and the onset of major depression. Moderate association (odds ratio=5.0) approximates that seen for apolipoprotein E-4 and Alzheimers disease as well as the protective effect in Asian populations of the ALDH2*2 copy of the aldehyde dehydrogenase gene on risk for alcoholism. The associations seen between individual genes (or high-risk haplotypes) and psychiatric disorders (odds ratio=1.5) is an approximation obtained from a review of the current literature.

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Are there any genes whose strength of association with a psychiatric disorder is Mendelianlike? Two related sources of information, both gathered in the last two decades, indicate that the answer to this question is almost certainly "No." First, a gene that has a deterministic or nearly deterministic relationship with a phenotype produces an unmistakable signature in the pattern of illness in large pedigrees. Numerous investigators have now searched many parts of the globe (including nearly all psychiatric facilities in a modest-sized country [16]) seeking pedigrees in which major forms of psychiatric illness especially schizophrenia and bipolar illnessare distributed in the pattern expected from a Mendelian-like gene. Such pedigrees have not been found. Second, Mendelian-like genes also produce a distinctive result in genome-wide linkage studies, which effectively sweep the human genome looking for regions that contain genes that have an impact on risk of illness. While the technical details need not concern us, experts agree that for those disorders studied in genome-wide linkage scans of reasonable size and qualityespecially schizophrenia, bipolar illness, panic disorder, and eating disordersconclusive evidence has accumulated that even moderately rare genes of Mendelian-like effect do not exist. (The available evidence does not permit us to rule out, however, very rare Mendelian-like genes.) So, if we lack Mendelian genes for psychiatric disorders, with their very high odds ratios, what sort of magnitude of associations might we expect? One set of benchmarks might be provided by three examples of what would be considered very strong associations in epidemiology. The estimated odds ratio between heavy smoking and small cell carcinoma

of the lung is approximately 20 (17), between industrial exposure to asbestos and mesothelioma is approximately 15 (18), and between severe stressful life events and the onset of major depression is approximately 12 (19). Another more modest benchmark is provided by the two outstanding genetic association results in neuropsychiatry of the last decades. The association between the pathogenic "4 allele" of the apolipoprotein E gene and Alzheimers disease produces, in Caucasian populations, an odds ratio of approximately 3.0 (20). In Asian populations, the possession of the slow-metabolizing (ALDH2*2) copy of the aldehyde dehydrogenase gene conveys up to a 10-fold reduction in risk for the development of alcoholism (21). So, as depicted in Figure 1 , we have three possible benchmarks for the strength of the gene-phenotype association for psychiatric disorders: Mendelian-like (odds ratio of approximately 100), strong (odds ratio=1220), or moderate (odds ratio=310). Trying to summarize the magnitude of association found between functional candidate genes and psychiatric disorders is problematic because of the multiple methodologic difficulties in the interpretation of such studies (2224). Greatest reliability should be placed on the results of meta-analyses, which are now beginning to appear in the literature. A PubMed search from 2000 on (using publication type of "metaanalysis" and search words "gene" and "association") followed by a hand search and elimination of duplication yielded 10 significant meta-analytic estimates of odds ratios between individual genes and psychiatric disorders (Table 1 ) (excluding results from those meta-analyses that did not support the original positive reports). The odds ratios ranged from 1.07 to 1.57 with a median of approximately 1.30.

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Table 1. Meta-Analysis Results Published Since 2000 for Studies of Association Between Individual Genes and Psychiatric Disorders

Another strategy to localize candidate genes is to look for them under linkage peaks (socalled positional candidate genes). In schizophrenia, replicated evidence is now emerging for several such genes (28). For these genes, disease-associated haplotypessmall sections of DNA that have traveled together over evolutionary timecan often be found. The two

best replicated positional candidate genes for schizophrenia are dysbindin 1 and neuregulin 1. Not counting the original reports (where the effect size might be biased upward), estimates are available for the association between high-risk haplotypes and schizophrenia for both of these genes. For dysbindin, odds ratios of 1.24 (29), 1.23 (30), 1.40 (31), 1.70 (32), and 1.58 (33) have been reported or calculated from replication reports. For neuregulin 1, two replications were noted in a recent review, with odds ratios estimated to be 1.25 and 1.80 (28). Taken together, the meta-analyses of functional candidate gene association studies and early results from positional candidate genes suggest that the magnitude of the associations between individual genes and psychiatric illnesses have small odds ratios, largely from 1.1 to 1.6. Compared to our benchmarks, this effect size is very modest (Figure 1 ). Perhaps genes (or particular mutations or haplotypes) of larger effect size will be found. While results from linkage studies suggest that this is unlikely, it cannot be ruled out. Also to be considered is the statistical dictum that the first set of effects detected in any research area tend to be the most robust. If this is correct, further genes discovered for psychiatric disorders are likely to have smaller average effects than the genes found to date. The preformationist concept of "a gene for" implied a predetermined and largely irrevocable link between gene and phenotype. This is the pattern of association observed between gene and phenotype from Mendels original traits and for Mendelian genetic disorders in humans. By contrast, for psychiatric disorders, individual genes appear to have a quite modest association with psychiatric illness. While they may have an impact on risk, individual genes hardly predetermine illness, as would be expected if we had discovered "genes for" mental disorders.

SPECIFICITY OF ASSOCIATION
The second criterion to evaluate the appropriateness of the concept of "X is a gene for Y" is the degree of specificity in the relationship between X and Y. As illustrated in Figure 2 , does X influence risk for any other disorders in addition to Y? Or are there other genes that contribute to Y in addition to X?

Figure 2. Possible Gene-to-Phenotype Relationshipsa a Possible relationships between genes on the lefthand side of thefigure and phenotypes on the righthand side are shown. In a one-to-one relationship, gene X causes only phenotype Y, and phenotype Y is caused only by gene X. In a one-to-many relationship, gene X causes several phenotypes each in turn being only caused by X. In a many-to-one relationship, phenotype Y is caused by several genes each in turn only causing Y. In a many-to-many relationship, each gene causes several phenotypes and each phenotype is caused by several genes.

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In preformationist theory, anlagen had highly specific associations with the adult traits into which they developed. The hereditary elements of the pea that Mendel studied also had quite specific phenotypic effects. That is, one gene influenced pea color but not shape or height while another influenced shape but not height or color. However, as genetics developed, many genes were found that impacted on a variety of phenotypic characteristicsa phenomenon called pleiotropy. In man, many Mendelian genes produce one and only one disease syndrome (although sometimes of varying severity depending on the specific mutation). But there are exceptions where different abnormalities in a single gene can produce distinct genetic diseases. How specific are individual genes in their impact on risk for psychiatric disorders? Do most genes influence risk for one and only one psychiatric disorder? Twin studies, which study "genes" in the aggregate, suggest that genetic risk factors for psychiatric disorders are often nonspecific in their effect. A large-scale twin study of seven psychiatric and substance use disorders found one common genetic risk factor predisposing to drug abuse, alcohol dependence, antisocial personality disorder, and conduct disorder and a second common genetic factor influencing risk for major depression, generalized anxiety disorder, and phobia (34). Overlap of genetic risk factors for multiple disorders have been demonstrated in other twin studies (e.g., references 3537). We know much less about the specificity of the spectrum of effects on psychiatric disorders of individual genes. Meta-analyses reviewed in Table 1 show that variants at one gene (the 5-HT2A receptor) may predispose to risk for three different disorders (schizophrenia, bulimia, and anorexia nervosa). A pair of overlapping genes on chromosome 13q (termed G30 and G72) may be associated both with schizophrenia and bipolar illness (28). A

number of overlapping positive regions in linkage genome scans for bipolar illness and schizophrenia have led some to argue that this reflects shared genes between these two disorders (38). While difficult to evaluate critically, claims have been made that several popular candidate genes (e.g., serotonin transporter, dopamine transporter, dopamine 2 receptor) are significantly associated with a wide variety of psychiatric disorders or psychiatrically relevant traits (39, 40). While much remains unknown, current evidence suggests that many genes that influence risk for psychiatric disorders will not be diagnostically specific in their effect, thereby resembling the one-to-many relationship in Figure 2 rather than the one-to-one relationship. We are on firmer ground in evaluating whether genetic risk for psychiatric disorders results from the action of a single gene (the one-to-one relationship in Figure 2 ) or multiple genes (the many-to-one relationship in Figure 2 ). Some evidence bears on this question indirectly, as follows. Twin and adoption studies provide convincing evidence for significant genetic effects on virtually all major psychiatric disorders (41). Therefore, genes that affect risk for these disorders must exist somewhere on the human genome. Linkage studies examine how these aggregate genetic risk factors are distributed across the genome. If genetic risk resulted from a single gene, then all the linkage "signal" would be concentrated in a single location, with a resulting clear and robust statistical linkage peak. But, as noted earlier, this is a pattern that has not been observed in published genome scans for psychiatric disorders. Instead, a number of modest linkage peaks are usually seen, suggesting that the "packets" of genetic risk for these disorders are widely dispersed across the genome. (To complicate matters, genome scans will underestimate the number of genomic regions involved because of low power to detect genes of small effect size, but will overestimate the number because some of the observed "peaks" will be false positives.) Recently, data have emerged that addresses this question directly. A careful meta-analysis of 20 genome scans for schizophrenia has suggested 10 genomic regions likely to contain susceptibility genes (42). In addition, current evidence of bipolar disorder, the second-beststudied psychiatric disorder by linkage scans, also suggests multiple loci (43). The specificity of association implied in the "a gene for" concept has another implication worth exploring. Consistent with preformationist theory, specificity of gene action implies that the gene contains all information needed for the development of the trait. The environment might impact on the final phenotype, but its effect is nonspecific. That is, the gene "codes for" the trait, while the environment reflects background factors that support development but is not in and of itself "information-carrying." To illustrate how commonly we see genes and environment in this light, it is worth pondering a curious and asymmetrical feature of GeneTalk. While we find it easy to use the phrase "X is a gene for Y," it feels quite odd to say "A is an environment for B." For example, a large body of empirical work supports the hypothesis that severe life events are important environmental risk factors for major depression (44). The magnitude of the association between such events and the subsequent depressive episode is far greater than that observed for any of the genes that we have reviewed here. Yet, who has heard the phrase "a romantic breakup is an environment for depression"? I suggest that we feel comfortable with "X is a gene for Y" and not "A is an environment for B" because we

implicitly assume that genes have a privileged causal relationship with the phenotype not shared by environmental factors. However, empirical evidence does not support the position that genes code specifically for psychiatric illness while the environment reflects nonspecific "background effects." By definition, environmental factors are central to the etiology of posttraumatic stress disorder. In the aforementioned multivariate twin model, what distinguished major depression, generalized anxiety disorder, and phobia from one another were environmental and not genetic risk factors (34). In a detailed study of the impact of childhood parental loss on risk for common psychiatric and substance use disorders, death of a parent was specific in increasing risk for major depression and no other disorder (Kendler et al., unpublished results). Consistent with studies of stressful life events that have shown moderate separation of depressogenic and anxiogenic events (45, 46), a multivariate genetic study of symptoms of anxiety and depression showed that genetic factors influence nonspecific risk for all symptoms, whereas two environmental factors were identified that predisposed, with moderate specificity, for symptoms of depression and anxiety, respectively (47). The preformationist concept of "a gene for" implies high levels of specificity between gene and phenotype. While much remains to be learned in this area, current evidence suggests that instead of the "one-to-one" relationship implied by the concept of "a gene for. . .," genes and disorders in psychiatry are likely to have the "many-to-many" relationship depicted in Figure 2 . (The evidence that the association between individual genes and psychiatric disorders are typically weak and may often be nonspecific does not mean that the identification of such genes is unimportant. For example, such discoveries can identify pathophysiologic pathways, begin the lengthy process of clarifying how individual genes interact with each other and with environmental exposures to produce illness, and provide new targets for treatment.)

NONCONTINGENCY OF ASSOCIATION
Noncontingent association means that the relationship between gene X and disorder Y is not dependent on other factors, particularly exposure to a specific environment or on the presence of other genes. As mentioned earlier, this is a typical (albeit not uniform) feature of genes that cause classical Mendelian disorders in humans. If the association between gene and disease were contingent on particular environmental exposures, then we would have to amend our statement to read "X is a gene for Y given exposure to environment Z." Environmental contingencies for genetic effects on psychiatric disorders have been little investigated. Twin and adoption studies suggest that the impact of aggregate "genes" for major depression are altered by exposure to stressful life events (19, 48) and for schizophrenia and conduct disorder by exposure to a dysfunctional rearing environment (49, 50). A range of twin studies suggest that environmental experiences have an impact on genetic risk for several psychiatrically relevant traits, including aggression, disinhibition, and smoking (51). Recently, Caspi and colleagues have found evidence for interactions

between environmental risk factors and particular genes in the production of antisocial behavior (52) and depression (53), with the former finding having been replicated (54). We know almost nothing about gene-by-gene interactions in the etiology of psychiatric disorders. Although a number of association studies have reported interactions, I am unaware of any that have been widely replicated or supported by meta-analyses. Using statistical models applied to risk of illness in various classes of relatives, Risch has claimed that gene-by-gene interactions are important in the etiology of schizophrenia (55). Overall, we know little about the contingent nature of genetic effects for psychiatric disorders. The available information suggests that gene action contingent upon certain environmental exposures is probably not rare and may be relatively common for psychiatric disorders. This is also inconsistent with the preformationist concept of "a gene for. . .".

CAUSAL PROXIMITY
Preformationist developmental models assumed that anlagen developed directly into adult traits. The "blueprint for life" metaphor similarly assumes a direct correspondence between individual parts of the blueprint (windows, doors, fixtures) and the corresponding units of the completed building. Conceptualizing genes in this preformationist framework therefore carries the implicit assumption of a direct causal link between gene and phenotype. It is only with this assumption that usage of the "a gene for. . ." is congruent with the common meaning of the phrase "X is for Y" in English. To clarify this point, lets examine a typical list of such statements: I use a knife for buttering my toast. I have a backpack for carrying my computer to work each day. I was upset at my son for not doing his chores. In each case, there is an implied direct and immediate relationship between X and Y. To put it more formally, X and Y are directly linked in a formal logical train of action (first two examples) or thought (third example). Now, how does this common sense meaning of the word "for" apply to the phrase "X is a gene for Y"? Let me illustrate the problem with a vignette A jumbo jet contains about as many parts as there are genes in the human genome. If someone went into the fuselage and removed a 2-foot length of hydraulic cable connecting the cockpit to the wing flaps, the plane could not take off. Is this piece of equipment then a cable for flying? Most of us would be uneasy answering yes to this question. Why? Because this example violates our conception of causal proximity. When we say X is for Y, we expect X to be, to a first approximation, directly and immediately related to Y. That is not the case for the cable and flying. There are many, many mechanical steps required to get from the function of that cable to a jumbo jet rising off the runway.

Another vignette: Assume a Mendelian genetic disease due to a mutation in gene K. Gene Ks normal function is to produce an enzyme L that breaks down metabolite M in cells allowing M to be harmlessly secreted from the body. When K has a pathogenic mutation, the enzyme L that is produced no longer works. Therefore, levels of M rise, producing a well understood series of toxic effects, thereby producing the genetic disorder N. This scenario suggests the following potentially simple causal chain: mutated gene K dysfunctional enzyme L excess metabolite M disorder N. In this admittedly oversimplified story, a case could be made that gene K had sufficient causal proximity to disorder N to make plausible the claim that "K is a gene for N." However, it might be argued that even here, the complexity of the paths from levels of M to disorder N may be far from "simple." Contrast this situation to the causal chain from a gene mutation to a complex psychiatric disorder such as schizophrenia. Although early efforts have been made to begin to trace such pathways (e.g., reference 56), we probably do not know enough to articulate all the specific causal steps that would be needed to go from DNA basepair variation to, for example, the cognitive processes that predispose to delusion formation. What we can conclude with some confidence is that it will be very complex. Indeed, the causal link between that hydraulic cable and the jumbo jet flying will probably look very simple and short compared to the causal relationship between individual genes and the manifestations of schizophrenia. While the nature of the evidence reviewed here is largely inferential, it suggests that the pathways from most genes for psychiatric illness to their phenotypes would fail the causal proximity criterion implicit in the concept of "X is a gene for Y."

APPROPRIATE LEVEL OF EXPLANATION

Scientific theories typically strive to explain phenomenon at the most informative level. To provide an absurd example, no one would seek to understand the origin of hypertension at the level of quarks. In some ultimate way, quarks may be involved. But quarks are just the wrong level of inquiry for the problem. To illustrate how this issuethe appropriateness of level of explanationmay apply to our evaluation of the concept of "a gene for. . ." consider these two "thought experiments": Defects in gene X produce such profound mental retardation that affected individuals never develop speech. Is X is a gene for language? A research group has localized a gene that controls development of perfect pitch (57). Assuming that individuals with perfect pitch tend to particularly appreciate the music of Mozart, should they declare that they have found a gene for liking Mozart? For the first scenario, the answer to the query is clearly "No." Although gene X is associated with an absence of language development, its phenotypic effects are best

understood at the level of mental retardation, with muteness as a nonspecific consequence. X might be a "gene for" mental retardation but not language. Although the second scenario is subtler, if the causal pathway is truly gene variant pitch perception liking Mozart, then it is better science to conclude that this is a gene that influences pitch perception, one of the many effects of which might be to alter the pleasure of listening to Mozart. It is better science because it is more parsimonious (this gene is likely to have other effects such as influencing the pleasure of listening to Haydn, Beethoven, and Brahms) and because it has greater explanatory power. A final scenario: Scientist A studied the behavioral correlates of a particular variant at gene X and concluded "This is a very interesting gene that increases the rates of sky diving, speeding, mountain climbing, bungee jumping, and unprotected casual sex." Scientist B studied the same variant and concluded "This is a very interesting gene and effects levels of sensation-seeking." Who has done the better science? Since sensation seeking (and its close cousin noveltyseeking) are well studied traits (41), scientist B has provided results that are more parsimonious and potentially provide greater explanatory power. For example, only scientist B could predict that this gene ought to be related to other behaviors, like drug taking, that are known to be correlated with sensation-seeking. As reviewed here, genes have been and will continue to be found that have statistical relationships with risk for psychiatric disorders. However, will the action of these genes be best explained at the level of the disorders themselves? While we cannot answer this question definitively, I would judge this to be unlikely. Far more plausible is that we will find genes whose mode of action can be best understood at the level of more basic biological processes (e.g., neuronal cell migrations during development) and/or mental functions (e.g., processing of threat stimuli).

OVERVIEW AND CONCLUSION

The goal of this essay is to understand the historical origins of the key phrase "X is a gene for Y" and then to evaluate its appropriateness for psychiatric disorders. Our interest, of course, is not merely the phrase itself, but the conceptual framework that underlies this form of Gene-Talk. The use of the phrase "a gene for" implies (and in fact only makes sense in the context of) genes whichlike preformationist anlagen"code for" psychiatric illness in a simple, direct, and powerful way. I argue that the concept of "a gene for. . ." can best be understood as deriving from preformationist developmental theory which, in turn, influenced the interpretation of the concept of a gene in the work of Mendel, in medical genetics, and most recently in human molecular genetics. Five criteria were proposed for evaluating whether the preformationist

concept of "X is a gene for Y" is appropriate for psychiatric disorders. I then reviewed the available evidence, which was of variable quality, that addressed each of these criteria. The strength of association between individual genes and psychiatric disorders is weak and often nonspecific. Genes do not appear to contain all the information needed for the development of psychiatric illness, since environmental factors have, for several disorders, been shown to have causal specificity. The action of genes on psychiatric disorders may frequently be contingent on environmental exposures, although much needs to be learned in this area. The causal chain from genes to psychiatric disorders is probably long and complex. The appropriate level of explanation for gene action is much more likely to be basic biological or mental processes that contribute to psychiatric disorders rather than the disorders themselves. Thus, with varying degrees of confidence, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the preformationist concept of "a gene for. . .". The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in causal pathways of stunning complexity. On this basis, I suggest that we conclude that the phrase "X is a gene for Y," and the preformationist concept of gene action that underlies it, are inappropriate for psychiatric disorders. The strong, clear, and direct causal relationship implied by the concept of "a gene for. . ." does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely to ever discover "genes for" psychiatric illness.

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