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Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment

OfficialreprintfromUpToDate
www.uptodate.com2014UpToDate

Pharmacotherapyforschizophrenia:Acuteandmaintenancephasetreatment
Authors
T.ScottStroup,MD,MPH
StephenMarder,MD

SectionEditor
MurrayBStein,MD,MPH

DeputyEditor
RichardHermann,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2014.|Thistopiclastupdated:Dec20,2013.
INTRODUCTIONSchizophreniaisapsychiatricdisorderinvolvingchronicorrecurrentpsychosis.Itiscommonlyassociatedwithimpairmentsinsocialandoccupational
functioning[1].Itisamongthemostdisablingandeconomicallycatastrophicmedicaldisorders,rankedbytheWorldHealthOrganizationasoneofthetoptenillnesses
contributingtotheglobalburdenofdisease[2].
Antipsychoticmedicationsarefirstlinemedicationtreatmentforschizophrenia.Theyhavebeenshowninclinicaltrialstobeeffectiveintreatingsymptomsandbehaviors
associatedwiththedisorder.Antipsychoticmedicationshavesignificantsideeffectsassessmentandmanagementoftheseadverseeffectsareanimportantpartof
treatment.Evidencebasedpsychosocialinterventionsinconjunctionwithpharmacotherapycanhelppatientsachieverecovery.
Thistopicaddressesthepharmacotherapyofschizophreniainacuteandmaintenancephasetreatment.Discussedseparatelyaretheuseoflongactingantipsychoticsand
managementofsideeffectsduringpharmacotherapyforschizophreniatheepidemiology,pathogenesis,clinicalpresentation,epidemiology,clinicalmanifestations,and
diagnosisofschizophreniapsychosocialinterventionsforschizophreniaandcommoncomorbidpresentationsofschizophrenia.(See"Pharmacotherapyforschizophrenia:
Longactinginjectableantipsychoticdrugs"and"Pharmacotherapyforschizophrenia:Sideeffectmanagement"and"Schizophrenia:Epidemiologyandpathogenesis"and
"Schizophrenia:Clinicalmanifestations,course,assessment,anddiagnosis"and"Psychosocialinterventionsforschizophrenia"and"Anxietyinschizophrenia"and
"Depressioninschizophrenia"and"Cooccurringschizophreniaandsubstanceusedisorder:Epidemiology,pathogenesis,clinicalmanifestations,anddiagnosis"and
"Guidelinesforprescribingclozapineinschizophrenia".)
ACUTEPHASEThefocusoftreatmentinschizophreniachangesasindividualsenterdifferentphasesoftheillness.Anacutephaseoccurswhenpatientswithaprior
historyofschizophreniahaveapsychoticrelapse,orduringthefirstepisodeofpsychosis.Atthistime,thefocusisonreducingtheseverityofpsychoticthoughtsand
behaviors.(See"Schizophrenia:Clinicalmanifestations,course,assessment,anddiagnosis",sectionon'Clinicalmanifestations'.)
PretreatmentassessmentWhenfeasible,patientswhoarestartedonanantipsychoticmedicationshouldreceiveabaselinephysicalexaminationwithaneurological
exam.Particularattentionshouldbefocusedonfactorsthatmaybeaffectedadverselybyantipsychoticmedication:(See"Pharmacotherapyforschizophrenia:Sideeffect
management".)
Bodymassindex(BMI)
Waistcircumference
Heartrate
Bloodpressure
Signsofamovementdisorder:
Extrapyramidalsymptoms(EPS):akathisia,parkinsonism,dystonias
Tardivedyskinesia:abnormalmovementsoftheface,perioralareas,tongue,extremities
Whenfeasible,laboratoryevaluationsshouldbeinitiatedbeforestartinganantipsychotic.Withtheexceptionofpatientstreatedwithclozapine,theantipsychoticcanusually
bestartedbeforetheresultsoflaboratorytestsareavailable.
CBC,electrolytes,fastingglucose,lipidprofile,liver,renalandthyroidfunctiontests
Whitebloodcell(WBC)countwithdifferentialforpatientstreatedwithclozapine
ECGforpatientswithacardiachistoryorthosebeingtreatedwithantipsychoticsthatmayprolongtheQTintervalsuchasclozapine,thioridazine,iloperidone,
ziprasidone.
AntipsychoticdrugefficacyandselectionAntipsychoticdrugsarefirstlinetreatmentforschizophrenia.Randomizedtrialshaveshownthatantipsychoticsreduce
positivesymptomsofschizophrenia,suchashallucinations,delusions,andsuspiciousness,comparedtoplacebo[3].Antipsychoticseliminateorreducethesesymptomsto
atolerablelevelinabout70percentofpatientswithschizophrenia[4].
Withtheexceptionofclozapine,carefulsystematicreviewsandmetaanalyseshavenotfoundconvincingevidencethatanyoftheantipsychoticsaremoreeffectivethan
anyotherforacuteschizophrenia[5].Clozapineismoreeffectiveforpatientswhodonotrespondfullytootherantipsychotics,butduetoincreasedriskofagranulocytosisis
reservedforthosewhodonotrespondwelltoorcannottolerateotherantipsychotics.(See'Treatmentresistantschizophrenia'below.)
Thereareimportantdifferencesamongtheantipsychoticsinareasotherthanefficacy,includingsideeffectsandavailableformulations(table1andtable2).Asaresult,the
selectionofanantipsychoticisoftenbasedontheseconsiderations.Theselectionmayvaryforselectpopulationsincludingindividualsinafirstpsychoticepisode,
individualswhoareonlypartialresponderstoantipsychotics,patientswhoareagitated,andindividualswhoaresensitivetoparticularsideeffectssuchasweightgain,EPS,
orsedation.(See'Initialmanagementofrefractorysymptoms'belowand'Managingfirstepisodes'belowand'Managementofagitation'belowand"Pharmacotherapyfor
schizophrenia:Sideeffectmanagement".)
AntipsychoticdrugcategoriesAntipsychoticmedicationsarecommonlygroupedintotwocategories,withsecondgeneration(oratypical)appliedtoclozapineand
allantipsychoticsfirstmarketedafterclozapinewasapprovedin1989,andfirstgenerationappliedtoantipsychoticsmarketedpreviously.Recentclinicalresearch,however,
hasstronglysuggestedthatthedistinctionbetweenfirstandsecondgenerationantipsychoticshasquestionablevalidityandisconfusing[5].Thepharmacologicproperties,
therapeuticeffects,andadverseeffectsarenotdistinctbetweenandareheterogeneouswithinthegroups.Nevertheless,thetermsfirstandsecondgenerationantipsychotic
arestillinwidespreaduse.Avaliddistinctionisthatthenewer(secondgeneration)antipsychoticstendtocausefewerextrapyramidalsideeffectsthantheolderones,
particularlyatthehighendofapproveddosageranges.
AdministrationThedoseofmostantipsychoticdrugsshouldbetitratedfromaninitialdosetothetherapeuticrangeasquicklyastolerated.Quetiapine,clozapine,and
iloperidoneneedtobeincreasedgraduallybeforereachingatherapeuticdose.Thetimeframefortitrationdiffersforeachdrugandalsodependsontheindividualpatients
toleranceofthedrugstendencytocausesedationandhypotension.Inmostcases,patientscanreachatherapeuticlevelinfiveorsixdayswithquetiapineandiloperidone,
andtwotothreeweekswithclozapine.Suggesteddosingandsideeffectprofilesforeachantipsychoticdrugareshownintables(table1andtable2).

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Becauseidentifyingtheappropriatedoserangecanbedifficultinthepremarketingphasesofdrugdevelopment,theantipsychoticdoseslisted(table2)deviatesomewhat
fromthoseapprovedbytheUSFoodandDrugAdministration,reflectingmorerecentresearchfindingsorclinicalexperience.Examplesinclude:
HaloperidoliseffectiveandmostusefulatdosesdrasticallybelowtheFDAspecifiedmaximumof100mg/day.Optimalhaloperidoldosagesareusuallybelow10
mg/dayandalmostalwaysbelow20mg/day.
Optimaldosagesofrisperidonearelowerthantheapproved16mg/daytypically,amaximumdoseforrisperidoneis6to8mg/day.
Resolutionofpsychoticsymptomsgenerallyoccursoverseveraldaysandmaytakeasmuchasfourtosixweeks.Cliniciansshouldavoidtheimpulsetochangethe
medicationordoseprematurely.Oncethedosereachesthetherapeuticrange,thedecisiontoincreasethedoseshouldfollowatleastseveraldaysoftreatmentduringwhich
theindividualshowslittleornoimprovement.Higherdosingshouldbeaccompaniedbycarefulobservationofthepatientforsideeffects.Ifpatientsfailtoshowimprovement
ondosesabovetheusualtherapeuticrange,thedoseshouldbereduced.
Asanexample,apatienttreatedwithrisperidonecanbestartedon2mgadministeredasasingledailydoseor1mgtwiceaday.Ifthisdoseiswelltolerated(ie,minimal
sedation,hypotension,orakathisia)thedosecanbeincreasedto3mgontheseconddayand4mgonthethirdday.Since4mgisinthetherapeuticrangeformostpatients,
theclinicianmaythenchoosetocontinuethisdoseforanadditionaltwoweeksbeforeconsideringanincrease.Ifthepatientshowsonlyminimalornoimprovement,thedose
canbeincreasedupto8mgdailywithcarefulmonitoringforclinicalresponseandsideeffects.Dosesofrisperidoneabove8mgdailyareassociatedwithsubstantialriskof
EPS.
Becauseofdoserelatedtoxicities,antipsychoticsshouldbeusedatthelowestdosethatiseffectiveforanindividual.Thetoxicitiesofantipsychoticdrugstypicallyincrease
withhigherdoseswhiletherapeuticeffectscanreachamaximum.Athighdoses,theadverseeffectsofanantipsychoticmaysurpassthemarginalbenefitofdosage
increases.Asaresult,increasingthedoseofantipsychoticforapatientwhoisalreadyexperiencingsignificantEPSisunlikelytoresultinadditionalsymptomreduction[6
8].
CourseofresponseWhenapatientwithschizophreniaisadministeredanantipsychoticmedication,theinitialresponseisoftenasideeffectsuchassedation,
restlessness,orposturalhypotension.Itisimportanttoexplainthistopatients,ortheymayconcludethatthemedicationisineffectiveorworseningtheircondition.Most
patientswhowillimproveonanantipsychoticshowthemostrapidimprovementinthefirsttwoweeks[9].Althoughtherateofimprovementmayslowaftertwoweeks,
patientswilloftencontinuetoimproveduringsubsequentweeksandmonths.
Duringthefirstweeksoftreatment,patientsmayfirstexperienceadecreaseintheseverityofsymptoms.Asaresult,theimpactofsymptomsonpatientbehaviormaybe
reduced[10].Hallucinationsordelusionsmaybelessfrighteningorthepatientmayfindthattheycandistractthemselvesbyfocusingtheirattentionelsewhere[11].
Delusionsthatarebasedonmisinterpretationsfromanearliertimemaylinger,whereasthetendencytomisinterpretnewinformationmaybereduced.
INITIALMANAGEMENTOFREFRACTORYSYMPTOMSPatientsshouldbeobservedonastabledoseofanantipsychoticfortwotosixweeksbeforeconcludingthe
drugisineffective.Thedurationofthetrialwillvarydependingonanumberoffactors:
Althoughpatientsimprovemostrapidlyduringthefirsttwoweeks,theymaycontinuetoimproveforseveralweeksorevenmonthsonastabledose[9].
However,recentevidencesuggeststhatifpatientsshowonlyaminimalresponsetoanantipsychoticdrugduringthefirsttwoweeks,itisunlikelythattheindividualwill
havearobustresponse[12].The2009SchizophreniaPORTrecommendsthattrialslastfortwotosixweeks.Thistimeframewillbeslightlylongerforantipsychotics
suchasiloperidoneandquetiapine,whichrequireslowtitration.
DoseadjustmentsIncasesofnonresponseorpartialresponse,theantipsychoticdosecanbegraduallyincreasedtowardthehighendoftherecommendedrange(table
2).
Mostcarefulstudiesofdosesabovetherecommendedrangehavenotfoundhigherdosestobemoreeffectivethanthemaximalrecommendeddose[13,14].Ifused,trialsof
higherdosesshouldbetimelimited,withreassessmentplannedwithinthreemonths.Unlessclearevidenceofimprovementisseen,highdosesshouldnotbecontinued[15].
Adosereductioncanbehelpfulincaseswheresideeffects,suchasakathisia,parkinsonism,sedation,orinsomniahaveobscuredthebenefitofahigherantipsychoticdose,
orhavebeenmistakenforsignsofineffectivetreatment,suchasagitationornegativesymptoms.
ChangingtoanotherantipsychoticSwitchingantipsychoticscanbehelpfulwhenapoorresponseisrelatedtosideeffects.Asanexample,inthelargeUS
effectivenessstudyofantipsychotictreatmentforschizophrenia,theClinicalAntipsychoticTrialsinInterventionEffectiveness(CATIE),patientswhogainedweightduringthe
firstphaseofantipsychotictreatmentfrequentlylostweightwhentheywerechangedtoziprasidone,anantipsychoticthatisnotassociatedwithweightgain[16].
Switchingantipsychoticsislessclearlybeneficialwhentheinitialmedicationlackedeffectiveness.Moststudieshaveshownthatpoorresponderstooneantipsychoticare
likelytobepoorresponderstoanotherantipsychoticexceptwhenthesecondagentisclozapine.(See'Treatmentresistantschizophrenia'below.)
Asanexample,ananalysisofpatientswhowereonolanzapine,quetiapine,orrisperidonepriortotheCATIEtrialshowedthatthepatientsonolanzapineorrisperidonewho
wererandomlyassignedtocontinuethesameantipsychotichadbetteroutcomesthanpatientswhowererandomlyassignedtochangeantipsychotics[17].(See
'Administration'below.)
AdministrationTwobasicstrategiesforchangingantipsychoticsare[18,19]:
Astandardcrosstitrationforastablepatient:Simultaneoustaperofthecurrentmedicationwithtitrationofthereplacementdruginthreetofourstepsoverseveraldays
toseveralweeks.
Forpatientsathigherriskofrelapse,thecurrentmedicationismaintainedatitsfulldoseasthenewmedicationisincreased.Oncetheseconddrughasreachedits
targetdose,thefirstmedicationmaybegraduallydecreasedanddiscontinued.Inmostcasesthischangecanbemanagedinonetotwoweeks.
Discontinuationofantipsychoticmedicationsisgenerallywelltolerated,exceptforclozapine,forwhichbothcholinergicreboundandwithdrawalemergentmovementdisorders
havebeenreported[2022].Aslowtaperofclozapineoveronetotwoweeksisrecommended.Chlorpromazineandthioridazinecanalsocausecholinergicreboundand
shouldbereducedoveraweekormore.
AddingasecondantipsychoticCliniciansoftenaddasecondantipsychoticwhenpatientshaveasuboptimalresponsetoasingledrug.Littleempiricalevidence
supportsthispractice[23].Althoughsomerandomizedtrialsindicatedthataugmentationofclozapinewithanotherantipsychoticmayhavesomebenefit,ametaanalysisof
thispracticefoundthesupportingevidencetobeweak[24].
TREATMENTRESISTANTSCHIZOPHRENIAPatientswithschizophreniawhorespondinadequatelytoaninitialantipsychotic,doseadjustments,orachangein
antipsychoticsareclassifiedashavingtreatmentresistantschizophrenia.Theefficacyofinterventionsfortreatmentresistantschizophrenia,includingclozapine,is
discussedseparately.Guidelinesforclozapineprescribing,dosing,monitoring,andsideeffectmanagementaredescribedseparately.(See"Treatmentresistant
schizophrenia"and"Guidelinesforprescribingclozapineinschizophrenia".)
CLOZAPINEFORSUICIDALITYINSCHIZOPHRENIAClozapinehasbeenshowninrandomizedtrialstoreducesuicideattemptsinpatientswithschizophreniaand
schizoaffectivedisorderathighriskforsuicide[25].Apatientwithschizophreniawhohaspersistentsuicidalideationwarrantingclinicianconcernmaybenefitfromatrialof
clozapine.Guidelinesforclozapineprescribing,dosing,monitoring,andsideeffectmanagementaredescribedseparately.Managementofsuicidalpatientsisdescribed

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separately.(See"Guidelinesforprescribingclozapineinschizophrenia"and"Suicidalideationandbehaviorinadults".)
MANAGEMENTOFAGITATIONClinicalmanagementoftheacutelyagitatedpatientwithschizophreniaisacommonobjectiveoninpatientunitsandothersettings.
Agitationcanbedefinedasastatecharacterizedbymotorrestlessness,excitement,andmentaltension.
CausesTreatmentofagitationinpatientswithschizophreniashouldbeguidedbythecause,whichcanincludeextrapyramidalsymptoms(EPS),substanceuse,or
psychosis.
ExtrapyramidalsymptomsAkathisiacanbedifficulttodistinguishfrompsychoticagitationwhenpatientsareunabletodescribetheexperienceofrestlessness[26].
Akathisiacanbetreatedwithabenzodiazepineeg,lorazepamcanbestartedat0.5mgorallytwicedailyandincrementallyincreasedtoamaximumof6to10mg/day.
SubstanceuseUptohalfofindividualswithschizophreniahaveacomorbidsubstanceusedisorder[27].Useofstimulantssuchasphencyclidine(PCP),
methamphetamine,andcocainecancauseagitation,ascanwithdrawalfromalcoholorbenzodiazepines.Agitationfromsubstanceuseorwithdrawalcanbediagnosedbya
history,physicalexam,andtoxicology.(See'Pharmacotherapyforcomorbiddisorders'belowand"Cooccurringschizophreniaandsubstanceusedisorder:Epidemiology,
pathogenesis,clinicalmanifestations,anddiagnosis".)
PsychosisPsychoticsymptomsofschizophrenia,suchasfrighteningdelusions,suspiciousness,andcommandhallucinationscancausepatientstobecomeagitated.
Theagitationassociatedwithpsychosiscanbetreatedwithanantipsychoticoranantipsychoticcombinedwithabenzodiazepine.Theselectionofadrugandtherouteof
administrationdependonanumberofconsiderationsincludingtheurgencyofcalmingthepatientandthecooperativenessofthepatient[28].Asnotedbelow,thechoiceof
anantipsychoticdependsontheformulationselected.Itisimportanttonotethatthetreatmentgoalistoinduceacalmerstate,whichcanoftenbeaccomplishedwithout
inducingsedation.
TreatmentAlthoughantipsychoticmedicationscantakedaystoweeksbeforehavingarobustantipsychoticeffect,theygenerallyhaveacalmingeffectwithinminutesfor
agitatedpatients.Therouteofadministrationinfluencestimetoonset,asdescribedbelow(table3).(See"Firstgenerationantipsychoticmedications:Pharmacology,
administration,andcomparativesideeffects"and"Secondgenerationantipsychoticmedications:Pharmacology,administration,andcomparativesideeffects".)
Standardoralformulations:Althoughmanyclinicianstendtofavorsedatingantipsychoticsforagitatedpatients,nonsedatingagentscanalsobeeffectiveforreducing
agitation.Risperidone1to2mgorolanzapine5to10mgwillusuallybeeffectiveinthesecircumstances.
Oralrapidlydissolvingformulations:Oralrapidlydissolvingformulationsareavailableforrisperidone,olanzapine,andaripiprazole.Theseformulationsarehelpfulwhena
patientiswillingtotakeapillbymouth,buteithercannotordoesnotswallowit.Dosingfortheseformulationsisthesameasforstandardoralformulations,eg,
risperidone1to2mgorolanzapine5to10mg.
Shortactingintramuscular(IM)injectableformulations(eg,haloperidol,olanzapine,aripiprazole,andziprasidone):Olanzapine5or10mgadministeredintramuscularlyis
agoodchoiceundermostcircumstances.IMhaloperidoliseffectivebutshouldbegivenwithbenztropineordiphenhydraminetoreducetheriskofsevereEPSincluding
dystonias.
Acombinationofhaloperidol5mg,lorazepam2mg,andbenztropine1mggivenintramuscularlycanbeeffectivetotreatsevereagitationinschizophrenia.
WeadviseagainsttheuseofIMchlorpromazine,whichcaninducesevereposturalhypotension.
AkathisiafromanyIMantipsychoticcancontributetoagitation.
InjectableIMantipsychoticshavetwopotentialadvantagesoveroralantipsychotics.First,theycanbeadministeredsafelytouncooperativeindividuals.Second,
patientsreachaneffectiveplasmaconcentrationsoonerthanwithoralformulations.Forexample,patientsmayexperienceacalmingeffectwithin10to30
minutesfollowingIMadministration.Calmingeffectsmaytake30to60minutesfollowingoraladministration.
Althoughrepeatadministrationofanoralorintramuscularantipsychoticiscommonwhenthepriordosedoesnotsufficientlyreduceagitation,theoverallantipsychoticdose
shouldbelimited,becausethesemedicationscancausesignificantsideeffectssuchashypotension,EPS,andsedation,particularlyathighdosesoverabriefperiodof
time[9].Maximumantipsychoticdosesareshowninatable(table3).
Tolimittheamountofantipsychoticused,mostphysicianseitherstartwithacombinationofanantipsychoticandbenzodiazepineoruseabenzodiazepinewhenpatientsfail
torespondtooneortwodosesofanantipsychoticforagitation.Lorazepamcanbeadministeredas1to2mgorallyor0.5to1mgintramuscularlyforcalming.
MANAGINGFIRSTEPISODESPatientsinafirstpsychoticepisodetendtohavehigherresponseratesthanpatientswhohaveexperiencedmultiplepsychoticepisodes.
Theseindividualsalsorespondtolowerantipsychoticdoses[29].Atthesametime,youngerpatientsandfirstepisodepatientshaveagreatervulnerabilitytosideeffects
suchasweightgainandextrapyramidalsideeffects(EPS)[30].Sincemanyfirstepisodepatientsarealsoreluctanttotakeanantipsychotic,itisimportanttominimize
adverseeffects.
TheSchizophreniaPatientOutcomesResearchTeam(PORT)recommendedtreatingfirstepisodeswithantipsychoticsotherthanclozapineorolanzapine.Bothofthese
medicationsareassociatedwithmoreweightgain,insulinresistanceanddyslipidemiathanotherantipsychotics[3].Inaddition,clozapinecancauseagranulocytosis.
TheSchizophreniaPORTrecommendedthatfirstepisodepatientsreceiveantipsychoticdosesinthelowerhalfoftherecommendeddoserange[3].Asexamples,afirst
episodepatientwouldbetreatedwith1to3mgofrisperidoneor10mgofaripiprazoledaily.Anexceptiontothisrecommendationshouldbemadeforquetiapine,whichmay
requiretitrationto500to600mgdaily.
MAINTENANCETREATMENTPatientswithschizophreniawhohaverecoveredfromanacutepsychoticepisodewillusuallyreachastableormaintenancephaseinwhich
psychoticsymptomsarereasonablywellcontrolled.Thegoalofmaintenanceantipsychotictreatmentofschizophreniaistominimizesymptomsandfunctionalimpairments,
avoidrelapses,andpromoterecoverythatallowsselfdetermination,fullintegrationintosociety,andpursuitofpersonalgoals.
EfficacyForpatientswithschizophreniawhohaverecoveredfromanacutepsychoticepisode,wesuggestthatantipsychoticmedicationshouldbecontinuedindefinitely,
evenforpatientswhohaveachievedremissionfromafirstpsychoticepisode.ThissuggestionisinaccordancewiththerecommendationoftheSchizophreniaPORT[3].The
lowesteffectivedosethatachievestherapeuticgoalsshouldbeused.Patientsshouldparticipateintheclinicaldecisionmakingregardingthedurationofantipsychoticdrug
treatment.
Multiplerandomizedtrialshavefoundthatmaintenanceantipsychoticmedicationreducestheriskofrelapseoveraperiodofuptotwoyears.Ametaanalysisof6493
patientswithschizophreniain65randomizedtrialsof7to12monthsdurationfoundthatpatientswhocontinuedonanantipsychoticexperiencedalowerrelapserate
comparedtopatientswithdrawnfromanantipsychoticandreceivingplacebo(27versus64percentnumberneededtotreattobenefit=3,95%CI23)[31].Otherstudiesof
uptotwoyearshavefoundsimilarresults[32].
Asevenyearfollowupassessmentofpatientsrandomlyassignedtoeitheradosereductionstrategyortomaintenanceantipsychotictreatmentfoundresultsthatconflict
withthestudiesofuptotwoyears.Tworeportsthatfollowdescribeaninterventionandfollowupassessmentofpatientswhoexperiencedafirstepisodeofpsychosisand
subsequentlymetcriteriaforremissionpriortoenrollmentinthetrial[33,34].
Theinitialtrialrandomlyassigned128patientstocontinuemaintenancetreatmentortoadosereductionstrategy[33].Aftertwoyears,patientsassignedtothedose
reductionstrategyhadahigherrateofrelapse,withoutoffsettingadvantages,comparedtopatientscontinuingonmaintenancetreatment.

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Asubsequentassessmentatsevenyearsfollowupincluded103ofthe128patients(81percent)whoparticipatedinthetrial[34].Patientswhohadoriginallybeen
assignedtothedosereductionstrategyexperiencedahigherrateofrecovery(ie,symptomaticandfunctionalremission)comparedtopatientsoriginallyassignedto
maintenancetreatment.
Morestudiesoflongertermoutcomesofmaintenancetreatmentversusdosereductionareneededbeforewewouldsuggestanapproachotherthanindefinitecontinuationof
maintenancetreatmentforpatientswithschizophreniafollowinganacuteepisodeofpsychosis.
Asthesetrialsdemonstrate,somepeoplewithschizophreniadowellwithoutcontinuousantipsychotictreatmenthowever,theyarenotidentifiableprospectively[35].
Otherconsiderationsregardingselectionofantipsychoticmedicationformaintenancetreatmentmirrorthoseforpharmacotherapyduringtheacutephase.(See'Antipsychotic
drugefficacyandselection'above.)
MedicationadherenceLongactinginjectableantipsychoticsmaybeusefulforpatientswithschizophreniawhoexperiencefrequentrelapsesduetononadherenceto
antipsychoticmedications.Theyalsomaybehelpfulforpatientswhowillnottakeoralantipsychoticsregularly.(See"Pharmacotherapyforschizophrenia:Longacting
injectableantipsychoticdrugs".)
Otherstrategiestopromotebetteradherencetoantipsychoticsincludesimplifyingmedicationregimens(eg,fewermedications,fewerpills,fewerdailydoses)andactive
engagementofpatientsintreatmentplanning(ie,shareddecisionmaking).
TreatmentofcognitiveimpairmentImprovingcognitiveimpairmenthasincreasinglybecomeanobjectiveoftreatmentforschizophrenia.Preliminarystudiessuggest
thatantipsychoticmedicationmayimprovecognitionwhenreceivedearlyinthecourseofschizophrenia[36,37].Studiesofpatientswithchronicschizophreniahavegenerally
foundlessimprovementincognitionduringantipsychotictreatment[3740].Trialsofothermedications(includingnmethyldaspartate(NMDA)glutamatergicreceptor
agonists,glycine,Dserine,ampakineCX516,Dcycloserine,donepezil,rivastigmine,andgalantamine)havefailedtoshowsignificantbenefit[4149].
PharmacotherapyforcomorbiddisordersDepressivedisordersandanxietydisorderscanbechallengingtodiagnoseinpatientswithschizophrenia.Aprimarycomorbid
disorderneedstobedistinguishedfromsymptomsofschizophrenia,antipsychoticdrugsideeffects,andotherclinicalpresentations.Properlydiagnosed,however,these
syndromescanrespondtoantidepressantandanxiolyticmedications[50].(See"Depressioninschizophrenia"and"Anxietyinschizophrenia".)
Substanceabuseanddependenceoccuratahighprevalenceinschizophrenia[51].Thecombinationofaseverementalillnessandasubstanceusedisorder(SUD),
commonlydescribedasdualdiagnosis,isassociatedwithincreasedmorbidity,poorerfunctioning,decreasedadherencetomedication,andhigherratesofrelapse
comparedtoeitherdisorderindividually[52].Integratedtreatmentstrategiesfordualdiagnosisthatincludepharmacotherapyhavebeendevelopedforindividualswith
schizophreniaandSUDs.(See"Cooccurringschizophreniaandsubstanceusedisorder:Epidemiology,pathogenesis,clinicalmanifestations,anddiagnosis".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasicspatienteducationpieces
arewritteninplainlanguage,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticles
arebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,
andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsome
medicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducation
articlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Schizophrenia(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Patientstreatedwithanantipsychoticforschizophreniashouldbeassessedpriortotreatmentifpossibleandatregularintervalsfor:(See'Pretreatmentassessment'
above.)
Signsofamovementdisorderincludingextrapyramidalsymptomsandtardivedyskinesia
Symptomsofmetabolicsyndromeincludingmeasurementsofbodymassindex,waistcircumference,hemoglobinA1c,serumlipids,andbloodpressure
ECGforpatientswithahistoryofcardiacdiseaseorwhenstartinganantipsychoticthatprolongstheQTinterval
Werecommendantipsychoticmedicationasfirstlinemedicationtreatmentforacuteandmaintenancephasetreatmentforschizophrenia(Grade1A).(See
'Antipsychoticdrugefficacyandselection'above.)
Forpatientswithschizophreniawhohaverecoveredfromanacutepsychoticepisode,wesuggestthatantipsychoticmedicationshouldbecontinuedindefinitelyatthe
lowesteffectivedosethatachievestherapeuticgoals(Grade2C).Thisapproachissuggestedevenforpatientswhohaveachievedremissionfromafirstpsychotic
episode.(See'Maintenancetreatment'above.)
Theselectionofwhichantipsychoticmedicationtouseforanindividualpatientwithschizophreniashouldbemadebasedonpatientclinicalfactorsandthesideeffect
profilesofantipsychoticdrugs.Withtheexceptionofclozapineforpatientswithrefractorysymptoms,thereisnotconvincingevidencetofavoroneantipsychoticover
theothersbasedonefficacy.(See'Antipsychoticdrugefficacyandselection'above.)
Becauseolanzapineisassociatedwithsignificantweightgainandmetabolicadverseeffects,leadingguidelinesstatethatitshouldnotbeusedasafirstline
agentforfirstepisodepatients,butshouldbeconsideredforpatientswhofailtreatmentwithafirstlineagent.
Otherstrategiesforthepatientwithschizophreniawhohasnotadequatelyrespondedtoanantipsychoticdruginclude:
Changingtoanotherantipsychotichasbeenshowntobeaneffectivestrategyforaddressingsideeffectproblemsbutisnotclearlyassociatedwithimproved
efficacy,withtheexceptionofclozapine.(See'Changingtoanotherantipsychotic'above.)
Clozapine.(See"Treatmentresistantschizophrenia",sectionon'Clozapine'and"Guidelinesforprescribingclozapineinschizophrenia".)
Addingasecondantipsychoticmedicationhasnotbeenprovenefficaciousinrandomizedtrials.Forpatientswithpsychoticsymptomsthatdonotrespondtotwo
trialsofantipsychoticmonotherapy,atrialofclozapineisstronglyrecommendedbeforecombiningtwoantipsychotics.(See'Addingasecondantipsychotic'
above.)
Hospitalizedpatientswithschizophreniamayrequiretreatmentforagitation.Ifagitationisassociatedwithpsychoticsymptomsofschizophrenia,itcanbetreatedwitha
standardoralformulation,rapiddissolving,orintramuscularlyinjectedantipsychotic,dependingonthelevelofpatientparticipation.Othercausesofagitationshouldbe
ruledout,includingakathisiaandsubstanceabuseorwithdrawal.(See'Managementofagitation'above.)
Longactinginjectable(LAI)antipsychoticmedicationmaybeusefulforpatientswithschizophreniawhennonadherencetooralantipsychoticsleadstofrequentrelapse.
LAIantipsychoticsareadministeredattwotofourweekintervals.Asanexample,fluphenazinedecanoatecanbeadministeredatadosebetween6.25to50mg
intramuscularlyeverytwoweeks.Extrapyramidalsymptomscanbeprominentathigherdoses.(See'Medicationadherence'aboveand"Pharmacotherapyfor

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schizophrenia:Longactinginjectableantipsychoticdrugs".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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48. KumariV,AasenI,ffytcheD,etal.Neuralcorrelatesofadjunctiverivastigminetreatmenttoantipsychoticsinschizophrenia:arandomized,placebocontrolled,double
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49. BuchananRW,ConleyRR,DickinsonD,etal.Galantamineforthetreatmentofcognitiveimpairmentsinpeoplewithschizophrenia.AmJPsychiatry2008165:82.
50. BuckleyPF,MillerBJ,LehrerDS,CastleDJ.Psychiatriccomorbiditiesandschizophrenia.SchizophrBull200935:383.
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Topic14805Version12.0

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GRAPHICS
Selectedadverseeffectsofantipsychoticmedicationsforschizophrenia
Weight

gain/diabetes
mellitus

Hyper
cholesterolemia

EPS/TD

Prolactin
elevation

Sedation

Anti
cholinergic

Orthostatic

QTc

side

hypotension

prolongation

effects

Firstgenerationagents
Chlorpromazine

+++

+++

++

+++

+++

+++

Fluphenazine

+++

Haloperidol

+++

+++

ND

+++

++

Loxapine

++

ND

++

++

++

Perphenazine

++
+

ND

++

++

++

ND

ND

+++

++

++

Thioridazine*

++

ND

+++

+++

++++

++++

+++

Thiothixene

++

ND

+++

++

Trifluoperazine

++

ND

+++

++

ND

Pimozide

Secondgenerationagents [1]
Aripiprazole

Asenapine

++

++

Clozapine

+++

+++

+++

+++

+++

Iloperidone

++

++

+++

++

Lurasidone

++

Olanzapine

+++

+++

++

++

Paliperidone

++

++

+++

++

Quetiapine

++

+++

++

++

++

Risperidone

++

++

+++

++

Ziprasidone

++

Adverseeffectsmaybedosedependent.
EPS:extrapyramidalsymptomsTD:tardivedyskinesiaND:nodata.
*Thioridazineisalsoassociatedwithdosedependentretinitispigmentosa.Refertotext.

Clozapinealsocausesgranulocytopeniaoragranulocytosisinapproximately1percentofpatientsrequiringregularbloodcellcountmonitoring.
Adaptedfrom:
1. TreatmentGuidelinesfromTheMedicalLetter,August2010Vol.8(96):61.www.medicalletter.org.
Graphic82533Version14.0

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Pharmacologyofantipsychotics:Dosing(adult),formulations,kineticsandpotentialfordruginteractions
Usualoral
Agent

dose
range
(mg/day)

Initialoral
dose
(mg/day)

Usual
maximum
oraldose

Halflifeafter
Formulations

oral

Primary

administration

metabolism

(mg/day)*

(hours)

Enzyme(s)
inhibited

(seenote)

Firstgenerationantipsychotics(FGAs)
Chlorpromazine

400to600

25to200

800

Tab,IM

30

CYP2D6,other

CYP2D6

CYPsandUGT
glucuronidation
toactiveand
inactive
metabolites
Fluphenazine

2to15

2to10

12

Tab,IM,LAI,oral

33

CYP2D6

CYP2D6

20

CYPs2D6,3A4

CYPs2D6,3A4

andUGT

(moderate)

solution
Haloperidol

2to20

2to10

30

Tab,IM,LAI,oral
solution

glucuronidation
some
metabolites
potentiallyactive
ortoxic
Loxapine

2080

20

100

Capsuleoral

12

CYPs1A2,2D6,

inhalationforuse

3A4andUGT

inhealthcare
settingsas

glucuronidation
toactiveand

alternativetoIM

inactive

injection

metabolites

None

Oralsolutionand
IMinjection
availablein
countriesother
thanUnitedStates
Perphenazine

12to24

8to16

24

Tab

912

CYPs2D6,3A4

CYP2D6

andotherCYPs
toactiveand
inactive
metabolites
Pimozide

8to10

1to2

10

Tab

55

CYPs1A2,2D6,

CYP2D6

3A4andothers

4(CYP2D6poor
metabolizer)
Thiothixene

10to20

5to10

30

Capsule

33

(tiotixene)
Thioridazine

CYP1A2and

None

otherCYPs
200to600

150

600

Tab

2125

CYP2D6and

CYP2D6

otherCYPsto
active
(mesoridazine)
andinactive
metabolites
Trifluoperazine

15to20

4to10

40

Tab

22

CYP1A2

None

30

Tab,ODT,IM,LAI,

7594

CYPs2D6and

None

Secondgenerationantipsychotics(SGAs)
Aripiprazole

10to15

10to15

oralsolution

3A4toactive
andinactive
metabolites

Asenapine

10to20

10

20

Sublingualtab

24

CYP1A2and

None

UGT
glucuronidation
Clozapine

150to600

2550

900

Tab,ODT,oral

12

suspension

Iloperidone

12to24

24
12(CYP2D6

Tab

1826

CYP1A2,other

CYP2D6

CYPs,andUGT
glucuronidation

(moderate)

CYP2D6and

CYP3A4

otherCYPsto

(moderate)

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poor

activeand

metabolizer

inactive

orreceiving2D6

metabolites

inhibitor
cotreatment)

Lurasidone

40to80

40

160

20(renalor

80(moderateor

hepatic
insufficiency)

severerenal
insufficiency,

Tab

2937(steadystate)

CYP3A4toactive

None

andinactive
metabolites

moderate
hepatic
insufficiency)
40(severe
hepatic
insufficiency)
Olanzapine

10to20

5to10

30

Tab,ODT,IM,LAI

3038

CYP1A2and

None

UGT
glucuronidation
Paliperidone

6to12

12

ERtab,LAI

23

Paliperidoneis

None

excretedmainly
unchangedin
urine
necessitating
dosereductionin
renal
insufficiency
Quetiapine

150to750

50

(immediate

750(immediate

Tab,ERtab

612

CYP3A4

None

Tab,ODT,LAI,oral

20

CYP2D6toactive

CYP2D6

(paliperidone)

(moderate)

release)

release)

800(extended
release)

400to800
(extended
release)
Risperidone

2to6

1to2

solution

andinactive
metabolitesPgp
substrate
Ziprasidone

40to160

40to80

200

Capsule,IM

7oral

CYP3A4

None

25IM

Dosesshownaretotaldailydose,oraladministration,formaintenancetreatmentofschizophreniainotherwisehealthyadults.Foradditional
information,refertoLexicompindividualdrugmonographsincludedwithUpToDate.
ODT:orallydissolvingtabletTab:tabletERtab:extendedreleasetabletIM:shortactingintramuscularinjectionLAI:longactinginjectable(eg,depot)CYP:
cytochromeP450Pgp:membranePglycoproteintransportersUGTglucuronidation:uridine5'diphosphateglucuronyltransferases
*Usualmaximumtotaloraldailydoseformaintenancetreatmentofschizophreniainadultpatientswithoutsignificantcomorbidity.Dosesshownmaynotbethe
maximumdoseusedinsomeclinicaltrialsorinexceptionalpatients.
Onlypotenttomoderateinhibitoreffectsarelistedinthistable.Foradditionalinformationincludingmoderatetoweakinhibitororinducereffects,andto
determinespecificdruginteractions,refertoindividualdrugmonographssectionondruginteractionsandtheLexiInteractprogramincludedwithUpToDate.
SmokingmaydecreasebloodconcentrationsofantipsychoticsprimarilymetabolizedbyCYP1A2.
Preparedwithdatafrom:
1. LexicompOnline.Copyright19782014Lexicomp,Inc.AllRightsReserved.
2. WynnGH,etal(eds)ClinicalManualofDrugInteractionPrinciplesforMedicalPracticeAPApublishing,WashingtonDC.Copyright2009.
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Antipsychoticsforinitialmanagementoftheacutelyagitatedadultpatientwithpsychosis
Maximum
Initial

Formulation

Route

dose

initial

Frequency
(hours)

(mg)

doseper
24hours

Timetopeak
plasma

Notes

concentration
(hours)

(mg)
Firstgenerationagents
Haloperidol

Shortacting

IM,IV

25

0.52*

30

0.51

lactateinjection

Droperidol

Sedation,hypotensionandprolongation
ofQTcintervalmorepronouncedwith

Oralsolution

PO

0.55

30

Injection(short

IM,IV

2.55

24*

40

0.5

acting)

injection.EPSrisk.
Rapidonsetof310minutes
advantageousinseverelyagitated
violentpatients.DoserelatedQTc
prolongationandriskofcardiac
arrhythmias.EPSrisk.

Fluphenazine

Shortacting

IM

1.25

10

ND

hydrochloride

1mgshortactingIMinjectionis
equivalentto~2.5mgoral.EPSrisk.

injection

Chlorpromazine

Oralsolution

PO

12.5

10

Injection(short

IM,IV

25

14

200

0.5

acting)

Hypotension,sedationandinjectionsite
painarelimitingsideeffects.Notafirst
lineagent.

Secondgenerationagents
Aripiprazole

Injection(short

IM

9.75

30

PO

1015

30

35

Injection(short
acting)

IM

510

24

30

0.250.75

Disintegrating

PO

510

0.52

20

PO

12

0.52

1.5

acting)
Disintegrating

Lesssedating.Minimalprolongationof
QTcintervalororthostatichypotension.

tablet,oral
solution
Olanzapine

Decreasedclearanceinfemaleand/or
nonsmokingpatients.

tablet
Risperidone

Disintegrating
tablet,oral

Decreasedclearanceinrenaland/or
hepaticimpairment.

solution
Ziprasidone

Shortacting

IM

mesylate
injection

1020

24

40

0.51

DoserelatedQTcprolongationandrisk
ofcardiacarrhythmias.

Dosereductionnecessaryforolderadults,debilitatedpatientsandifusedincombinationwithothersedation.Seeaccompanyingtextfor
discussionofelectrocardiographandothermonitoringforagentsknowntocauseprolongationoftheQTcinterval.
ND:nodataEPS:extrapyramidalsymptoms.
*Itmaybenecessarytorepeatinitialdoseorfractionthereofafter15to20minutesinpatientswithsevereagitationuntildesiredlevelofsedationattained.
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Disclosures
Disclosures:T.ScottStroup,MD,MPHOtherFinancialInterest:Genentech[Schizophrenia(drugtotreatnegative/cognitivesymptoms
inschizophrenianotonmarket)].StephenMarder,MDGrant/Research/ClinicalTrialSupport:Novartis[Antipsychoticmedications
(iloperidone)]Sunovion[Antipsychoticmedications(lurasidone)].Consultant/AdvisoryBoards:Pfizer[Antipsychoticmedications
(ziprasidone)]Otsuka[Antipsychoticmedications(aripiprazole)]Lundbeck[Antipsychoticmedications(aripiprazole)].MurrayBStein,
MD,MPHNothingtodisclose.RichardHermann,MDEmployeeofUpToDate,Inc.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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