Vol. 8 No.

4 2008

ROMANIAN JOURNAL OF PSYCHOPHARMACOLOGY

Editura Medical Universitar Craiova 2008

CONTENTS
The Role of Migration on Mental Health and Mental Illness Pedro Ruiz ..................................................................................................................................................... 207 Mechanism of Action and Clinical Features of Two SNRIs: Venlafaxine and Minalcipran Michel Bourin ................................................................................................................................................ 216 Low-Dose of ASA in the Prophylaxis of Migraine with Aura. A Retrospective Study Lidia Savi, Mihaela-Bianca Anoaica, Florica Popescu, Lorenzo Pinessi ...................................................... 237 Drug Development in Schizophrenia Michael Davidson, Delia Podea .................................................................................................................... 240 Quetiapine Fumarate in Practice Evaluation Programme Cristinel Stefanescu, Beatrice Costea ............................................................................................................ 254 Recent Drugs Developed in Unipolar Depression Michel Bourin, Corina Prica .......................................................................................................................... 265

A R P F

Romanian Journal of Psychopharmacology

FOUNDING EDITOR: EDITOR-IN-CHIEF: DEPUTY EDITOR:

Tudor UDRISTOIU Mihai Dumitru GHEORGHE Dragos MARINESCU

EDITORIAL BOARD
Michel BOURIN (France) Vasile CHIRITA (Romania) Michael DAVIDSON (Israel) Virgil ENATESCU (Romania) Carol FRIEDMANN (Romania) Ion FULGA (Romania) Iosif GABOS-GRECU (Romania)

Mihai Dumitru GHEORGHE (Romania) Alexandru GRIGORIU (Romania) Siegfried KASPER (Austria) Dragos MARINESCU (Romania) Ioana MICLUTIA (Romania) Radu MIHAILESCU (Romania) Hans-Jrgen MLLER (Germany) Dan PRELIPCEANU (Romania) Pedro RUIZ (United States) Ghiorghe TALAU (Romania) Tudor UDRISTOIU (Romania) Victor VOICU (Romania) Joseph ZOHAR (Israel)

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Romanian Journal of Psychopharmacology (2008) 8, 207-215

THE ROLE OF MIGRATION ON MENTAL HEALTH AND MENTAL ILLNESS

Pedro Ruiz1, M.D. Department of Psychiatry and Behavioral Sciences University of Texas Medical School at Houston

Abstract Since World War II the United States has experience a very large influx of migrants from all regions of the world. This migration process has been so intense that, at the present time, the United States society has become a pluralistic one. This multicultural and multiethnic influx has impacted in all levels of society, including health and mental health. These migrant groups brought with them, not only their ideals and aspirations to improve their socioeconomic status and/or their political stability but their norms, traditions, and cultural heritage as well. Undoubtedly, the extensive interchanges of cultures and traditions brought about some positive experiences but some negatives experiences as well. The health and mental health care systems are, perhaps, a good reflection of the outcomes of these interchanges. Thus, in this article, an examination of the Hispanic migration to the USA will be made as an example of this migratory experience. In so doing, the extend of the Hispanic migration will be described, the acculturation process will be examined and discussed, some positive and negatives mental health experiences will be addressed, and some conclusions and recommendations will be drawn from the overall discussion. Hopefully, the issues addressed in this article could be used as a guide in the study of other migration processes in different parts of the world. Additionally, this article could also serve as stimulus for further study and investigational efforts in this very timely topic. Key words: Migration, acculturation, mental health, and mental illness.

Introduction
Since the origin of civilization, migratory processes have been observed in all regions of the world. As a positive outcome of this process, humankind has spread to all continents on earth over several millenniums. As a result of this worldwide migratory process, five human races have evolved over these millenniums (1). The Caucasoid, Mongoloid, and Negroid races represent the largest groups of this migratory process and, thus, of the worlds population. The San (Bushmen) and Australian aborigines represent the rest of the worlds population subgroups.
1

Correspondence: Pedro Ruiz, 1300 Moursund Avenue, Houston, Texas 77030, USA. Phone: 713-500-2799; Fax: 713-500-2757; E-mail: pedro.ruiz@uth.tmc.edu

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Since World War II, however, these migratory processes have intensified from the developing countries toward the developed and industrialized nations. The migration towards the United States has been one of the most intense ones. However, during the last two decades, the migration to the countries of the European Union has also experienced major proporsions (2). Besides this migratory influx towards developed countries, a second migratory wave has also been recently observed from rural areas towards urban ones. This migratory process has been taking place not only in developed nations but in developing ones as well. For instance, in Latin America, this situation has occurred in Mexico City, Caracas, Lima, Rio de Janeiro, Buenos Aires, and many other major cities. Similarly, identical situations have happened in other continents and regions too. Obviously, these migratory processes have led to beneficial outcomes in most host countries but, unfortunately, to negative outcomes as well. In this article, the case of the Hispanic migration towards the United States will be examined. Specific attention will also be given to its impact in the health and mental health care systems. Additionally, focus will be made with respect to the acculturation process and its outcomes. Finally, conclusions and recommendations will be drawn, and hopefully applied not only in the United States but in other countries were similar situations have been identified.

The USA hispanic population

As it could be expected, the Hispanic migration towards the United States, as well as other migrations, is based on a hope, on the part of the migrants, to improve their socioeconomic status and/or their political stability (3). This migratory process has progressively increased in the last 4-5 decades in such a manner that, at the present time, Hispanics have become the largest ethnic minority group in the United States. As seen in table #1, Hispanics in year 2000 reached a level of 35.3 million or 12.5% of the total USA population (4). This number does not include the Puerto Ricans living in the Island of Puerto Rico who are estimated at 3.8 million, or the Hispanics who are illegal aliens in the United States who are estimated at 5 million (4). Table # 1. USA Population (in million)
TOTAL WHITE HISPANIC AFRICAN AMERICAN ASIAN AMERICAN NATIVE AMERICAN OTHER
Source: U.S. Census Bureau, 2000 (4)

2000 281.4 194.6 35.3 33.9 10.5 2.1 5.1

100 % 69.2 % 12.5 % 12.1 % 3.7 % 2.1 % 5.1 %

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What is also very significant is that currently the Hispanic growth rate in the USA is 58%; that is the fastest growth rate of any ethnic group in the United States, including the Caucasian (white) one (4). The current median age of the Hispanic population in the USA is 26.6 years; that is, the youngest one in the USA. Hispanics, on the other hand, however, currently has a median family income of $30,735 per year; that is, the lowest in the USA except the one for African Americans which is $27,910 (4). Likewise, 21.7% of Hispanic families currently live below the poverty level; that is, the lowest level in the USA except for African Americans, which have a poverty level of 22.7% (4). With respect to family integrity, 24.4% of the Hispanic families are currently headed by females; for Puerto Rican families this percentage is 39.4%. This percentage is the highest in the USA except the one for African Americans, which is 46.7% (4). Given their rapid population growth, the high poverty and low-income levels, and the fact that they tend to be employed in jobs that do not offer good fringe benefit packages, Hispanics tend to have low Medicaid and Medicare insurance coverage and high levels of medical uninsurance coverage (5)(6). Currently, Hispanics have a 33.4% rate of medical uninsurance coverage, compared to 21.2% for African Americans, 20.8% for Asian Americans and only 11% for Caucasians (whites) (4)(6). In this respect, it is interesting to note that in 1997, 43.6% of the illegal aliens living in the USA did not have medical insurance coverage (4); in comparison, however, to 34.2% of the foreign born aliens, 18.2% of the naturalized USA citizens, and 14.2% of the native (U.S. born) citizens (4). Finally, it should be noted that Hispanics are not a monolithic or homogeneous group in the United States. While the majority of Hispanics are Mexican Americans (46.8%), 16.3% are Puerto Ricans from either the U.S. mainland or the Island of Puerto Rico, 2.7% are Cuban Americans, 1.8% are from the Caribbean basin countries, 3.2% are from South American countries, 13.9% are from Spain or other Hispanic countries, and 11.4% are illegal Hispanic aliens (4).

The acculturation process

All migrant groups during their process of coping adjusting and adapting to the host country and, thus, to the host countrys majority culture, must face the process called acculturation. The acculturation process starts while the migrant still is in his/her native country, while he/she considers leaving the home country, and ends with the outcome of the adaptation phase to the host country (7). The outcome of this acculturation process could be one of the following four: 1) marginalization, 2) assimilation, 3) rejection, and 4) integration (8)(9). As seen in table #2, each of these four potential outcomes are the result of the judgmental decision on the part the migrants vis--vis the host majority culture. If the migrants decide to retain 209

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their native culture and also decide to foster relations with members of the host majority culture, integration will be the most probably outcome. On the other hand, if the migrants decide to retain their culture but reject the idea of fostering relations with the host majority culture, rejection will take place; still, however, if the migrants decide not to retain their native culture and also decide to foster relations with the members of the host majority culture, assimilation will result. Finally, if the migrants decide not to retain their native culture and also decide not to foster relations with the host majority culture, marginalization will take place; of course, the level of the outcomes will depend on the migrants variables such as: age, sex, marital status, education level, race, ethnicity, religion, socioeconomic status, etc. Also, on the host majority cultures variables such as: pluralistic, tolerant or racist attitudes. The negative or untoward behavioral outcomes of the acculturation process could be self-destructive actions such as: alcoholism/drug addiction, accidents, crime, homicide and/or suicide. Table # 2. Outcome of the Acculturation Process
A. Retention of ones culture B. Fostering contacts with the majority culture A B A B YES YES YES NO INTEGRATION REJECTION A B A B NO YES NO NO ASSIMILATION MARGINALIZATION
Adapted from: Dean P, Berry JW, Sartorius N, editors. Health and Cross-Cultural Psychology: Towards Applications. London: Sage Publication, 1988 (8).

An integral component of the acculturation process and its potential outcome have to do with the attitude, judgment and perception of the migrant groups by the members of the host majority society or culture. In this respect, it is interesting to note and assess a recent report that recently appeared in the press with respect to six major developed and industrialized nations vis-vis the ethnic/racial groups who have either migrated or settle in these countries. As seen in table #3, all of these countries majority culture members do not perceive well or disagree with the ethnic/racial or migrant groups who reside in these countries (10). Table # 3. How majority populations judge ethnic/racial groups
UNITED STATES GREAT BRITAIN FRANCE GERMANY RUSSIA TURKEY Agree 22 % 33 % 32 % 31 % 26 % 34 % Disagree 74 % 69 % 66 % 65 % 72 % 61 %

Adapted from: USA Today. June 13, 2003 (10).

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Outcomes of the acculturation process

Investigational efforts over the years concerning the potential outcomes resulting from acculturative stress have yielded some interesting findings. Among them, one focusing on suicide among migrant groups deserves attention and discussion. This study, which focuses on several ethnic minority groups who reside in the United States, offers very good perspectives of the result of acculturative stress among USA Hispanic migrants (7). It is a well-established fact that the rates of suicide in Hispanic countries such as Spain, Mexico, Argentina, etc., are rather low (7). Nevertheless, as Hispanic migrants leave their countries of origin to migrate to the United States, as in the case of Hispanics from Mexican extraction, their rates of suicide increase (10)(11). In this case, the suicide rate for 100,000 persons in Mexico in 1973 was 0.7; while in El Paso, Texas for Mexican Americans during the same period (1970-1972) was 7.0, and in Denver, Colorado (19701975) was 12.9 (11). In other words, as the acculturative stress intensifies, as it was the case in Denver, which is farther away from Mexico, the suicide rate increases. A similar situation has been observed with respect to illegal drug use among Hispanics from Mexican and Puerto Rican extraction who have migrated to the United States (12(13). In the case of Hispanics from Mexico, the substance abuse rate for adolescents in the study was of 1.79% in Mexico and 11.69% for Mexicans (Mexican American) in the United States (12). With respect to Puerto Ricans, the illegal drug use in the Puerto Rican population in the Island of Puerto Rico was 25%, while in the USA mainland was 53% (13). Likewise, the same situation was true with respect to alcoholism (14)(15)(16). In this case, among Mexican males, the frequent heavy drinking levels were 6% in Mexico (Michoacan), 27% during the first five years of migration to the United States, and 14% among Mexicans born in the United States (Mexican Americans) (14). Undoubtedly, the highest level of acculturative stress took place during the first five years of living in the United States. Additionally, for the Mexican American group, the acculturation process still have a significant impact in comparison with the United States born Mexican American group or the Mexicans who live in Mexico (15)(16). Finally, in the case of HIV infection and/or AIDS, USA Hispanics have faced a more serious impact than the Caucasian (white) population; that is, than the majority population. In many ways, this situation has to do with the outcome of the acculturation process, as well as the degree of marginalization that still occurs among the USA Hispanic population (17)(18)(19). Between USA adult and adolescent Hispanics, the AIDS cases-level is 18.1%, and among the USA pediatric/children Hispanics, the AIDS cases level is 22.7% (19). The USA total Hispanic population level currently being 12.5% (4). In contrast, however, the adult and adolescent AIDS cases level for the Caucasian (white) population in the USA is 46.9%, and among the 211

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pediatric/children Caucasian (white) population the AIDS cases level is 17.4% (19). The total Caucasian (white) population level in the USA currently being 69.2% (4). These disparities are certainly associated, among others, with cultural factors (20). It should also be noted that the high number of HIV infections and AIDS cases resulting from certain degree of marginalization among USA Hispanics is not a unique situation of the United States. Something similar is being observed across Latin America as well (21).

USA hispanic health and mental health care manpower

One of the major dilemmas currently facing the United States is the fact that the health and mental health care manpower does not reflect the ethnic and cultural representation of the USA current population. Despite the significant growth of the ethnic and cultural groups who reside in the United States during the last several decades, the ethnic and cultural mix of the health and mental health care manpower has not grown at the same rate (4)(5)(22). As it can be noted in table #4, the current levels of health and mental health care manpower insofar as medical students, physicians, psychiatrists, nurses, and pharmacists are insufficient to appropriately provide health and mental health care to the USA Hispanic population based on a culturally-sensitive approach. Thus, it is imperative that the existing majority populations health and mental health care manpower be trained as to how best treat not only the USA Hispanic population but other USA ethnic minority populations as well (23)(24)(25)(26). Table # 4. USA Hispanic health and mental health care manpower
MEDICAL STUDENTS PHYSICIANS PSYCHIATRISTS NURSES PHARMACISTS 2.0 % 5.4 % 4.6 % 2.2 % 2.2 %

Adapted from: Ruiz P. Access to health care for uninsured Hispanics: policy recommendations. Hospital and Community Psychiatry 1993; 44:958-962 (5).

Conclusions and recommendations

As it can be derived from the previous issues addressed and discussed, some conclusions can be drawn. Hopefully, these conclusions can be utilized to appropriate deal with the challenges faced in attempting to improve the health and mental health care of the ethnic minority groups who nowadays tend to migrate to developed and industrialized nations. These conclusions are as follows: It is essential to recognize the problem as a major impediment in the access and provision of high quality of health/mental health services for these ethnic and cultural minority groups. 212

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It is crucial to accept the need to provide culturally-sensitive health/mental health care to these ethnic and cultural minority groups. It is imperative to learn about the perception and understanding of the etiology and manifestations of medical and psychiatric illnesses and conditions among these ethnic and cultural minority groups.

It is very relevant to address all socioeconomic and cultural factors that might impinge in the health and mental health delivery system of these ethnic and cultural minority groups. It is very important to integrate ethnic, racial and cultural variables in the health and mental health research efforts directed to these ethnic and cultural minority groups.

In this context, it is also very important to consider the implementation and assessment of a series of recommendations directed to improve the current health and mental health delivery system of these ethnic and cultural minority groups. These recommendations are as follows: Collect as much as possible nonclinical data (socioeconomic, ethnic, racial and cultural) while delivering health and mental health care to these ethnic and cultural minority groups. Performance and outcome measures should also be stratified along these lines. Advocate for full parity and access to health and mental health care in all population groups and subgroups. Design training programs that are ethnic and culturally sensitive to all population groups and subgroups. Additionally, strive to develop an ethnically and culturally sensitive health and mental health care manpower. Advocate and initiate programs directed to the elimination of stigma, prejudice and discrimination from the health and mental health care systems. Strive and advocate for a fair distribution of health and mental health care resources, and for community empowerment of these resources and programs. Strive for professional competence, preservation of the professional-patient confidentiality, high quality of services, and elimination of professionals conflicts of interest. Finally, it is also imperative that the health and mental health care systems in all countries and regions of the world operate under the chapters of medical professionalism. This chapter is based on three inalienable professional principles (27). They are as follows: Primacy of patient welfare Primacy of patient autonomy Primacy of social justice

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References
1. Kalow W, editor. Pharmacogenetics of Drug Metabolism. New York: Pergamon, 1992. 2. Ruiz P. New clinical perspectives in cultural psychiatry. Journal of Practical Psychiatry and Behavioral Health 1998; 4:150-156. 3. Ruiz P. Cultural barriers to effective medical care among Hispanic-Americans patients. Annual Review of Medicine 1985; 36:63-71. 4. U.S. Census Bureau, 2000. 5. Ruiz P. Access to health care for uninsured Hispanics: policy recommendations. Hospital and Community Psychiatry 1993; 44:958-962. 6. Ruiz P. Hispanic access to health/mental health services. Psychiatric Quarterly 2002;73:85-91. 7. Berry JW, Kim U, Minde T, Mok D. Comparative studies of acculturative stress. International Migration Review 1987; 21:491-511. 8. Dean P, Berry JW, Sartorius N, editors. Health and Cross-Cultural Psychology: Towards Applications. London: Sage Publication, 1988. 9. Group for the Advancement of Psychiatry. Suicide and Ethnicity. Report No. 128. New York: Brunner/Mazel Publications, 1989. 10. Hatcher C, Hatcher D. Ethnic group suicide: an analysis of Mexican-Americans and Anglo rates for El Paso, Texas. Crisis Intervention 1975; 6:2-9. 11. Ruiz P. Impacto cultural y migratorio en el fenomeno del suicido. In Sevilla 95. La Psiquiatria en la Decada del Cerebro. Madrid: ELA Editorial; 1995. p. 329-334. 12. Pumariega AJ, Swanson JW, Holzer CE, Linskey AO, Quintero-Salinas R. Cultural context and substance abuse in Hispanic adolescents. Journal of Child and Family Studies 1992;1:75-92. 13. Ruiz P, Langrod JG. Hispanic Americans. In Lowinson JH, Ruiz P, Millman RB, Langrod JG, editors. Substance Abuse: a Comprehensive Textbook. Baltimore: Williams & Wilkins; 1997. p. 705-711. 14. Caetano R, Medina Mora ME. Acculturation and drinking among people of Mexican descent in Mexico and the United States. Journal of Studies of Alcoholism 1988; 49:462-471. 15. Ruiz P. Alcoholismo en los Estados Unidos de Norteamerica: perspectiva MexicoAmeriana. Anales de Salud Mental 1995; XI:33-40. 16. Group for the Advancement of Psychiatry (GAP). Alcoholism in the United States: Racial and Ethnic Considerations. Report No. 141. Washington, D.C.: American Psychiatric Press, Inc., 1996. 214

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17. Fernandez F, Ruiz P, Bing EG. The mental health impact of AIDS on ethnic minorities. In Gaw AC, editor. Culture, Ethnicity, and Mental Illness. Washington, D.C.: American Psychiatric Press, Inc; 1993. p. 573-586. 18. Ruiz P, Fernandez F. Human immunodeficiency virus and the substance abuser: public policy considerations. Texas Medicine 1994; 90:64-67. 19. Centers for Disease Control and Prevention (CDC). HIV/AIDS surveillance report no. 1. Washington, D.C.: CDC; 1999. 20. Ruiz P, Guynn RW, Matorin AA. Psychiatric considerations in the diagnosis, treatment, and prevention of HIV/AIDS. Journal of Psychiatric Practice 2000; 6:129-139. 21. Ruiz P. El SIDA en las Americas. In Perales A, Saavedra A, Acha VJ, Bustamante R, Chue H, Alva J, et al., editors. Salud Mental y Psiquiatria en el Umbral del Nuevo Milenio. Lima, Peru: Centro de Produccion Editorial de la U.N.M.S.M.; 1998; 159-164. 22. Ruiz P, Venegas-Samuels K, Alarcon RD. The economics of pain: mental health care costs among minorities. Psychiatric Clinics of North America 1995; 18:659-670. 23. Ruiz P. Assessing, diagnosing and treating culturally diverse individuals: a Hispanic perspective. Psychiatric Quarterly 1995; 66:329-341. 24. Ruiz P, Alarcon RD. How culture and poverty exclude people from care. American Journal of Forensic Psychiatry 1996; 17:61-73. 25. Garza Trevio ES, Ruiz P, Venegas-Samuels K. A psychiatric curriculum directed to the care of the Hispanic patient. Academic Psychiatry 1997; 21:1-7. 26. Mezzich JE, Ruiz P, Muoz RA. Mental health care for Hispanic Americans: a current perspective. Cultural Diversity and Ethnic Minority Psychology 1999; 5:91-102. 27. Sox HC. Medical professionalism in the new millennium: a physician charter. Annals of Internal Medicine 2002; 136:243-246.

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MECHANISM OF ACTION AND CLINICAL FEATURES OF TWO SNRIs: VENLAFAXINE AND MILNACIPRAN
Michel Bourin1 Neurobiology of Anxiety and Depression, Faculty of Medicine Nantes, France Neurochemical Research Unit, University of Alberta, Edmonton, Alberta, Canada

Summary Specific serotonin and noradrenalin reuptake inhibitors (SNRIs) are a relatively recent class of antidepressants which have specificities making them a therapeutic choice. They are characterized by a mixed action on both major neuroamines of the depression, noradrenalin (NA) and serotonin (5HT). The double polarity of the reuptake inhibition of serotonin and noradrenalin ensures a profile of effectiveness comparable to tricyclic antidepressants (TCAs) and higher than selective serotonin reuptake inhibitors (SSRIs) in particular in severe depressions. The absence of affinity for muscarinic, histaminic, alpha 1-adrenergic receptors, and the absence of action on monoamine oxidase, limit its adverse effects and allow a greater tolerance than TCAs and equal to SSRIs. Currently two drugs of this class are available, milnacipran and venlafaxine, but several are in development. They are active on depressive symptoms as well as on certain co morbid symptoms (anxiety, sleep disorders) frequently associated with depression. SNRIs at the same time make it possible to obtain a raised rate of response, and also a significant rate of remission which decreases the risk of relapse and recurrence in medium and long term. From their good tolerance, they can also be prescribed in a long term treatment and with high dosages in refractory depression or with strong potential of relapse. From all these reasons, one can reasonably conclude that SNRIs represent therapeutic of choice in depression and that their prescription is likely to strongly increase in the years to come. Key words: Milnacipran, SNRIs, Antidepressant, Cost of treatment, Pharmacokinetics, Pharmacodynamics, Onset of action.

Introduction
Depression represents a major public health problem. It occupies the fourth highest rank of most frequent diseases occurring in the world and the second highest position in the economically developed countries. Since the discovery of the antidepressants and the use of imipramine, many antidepressant molecules are available for the clinician. The choice of the most adapted molecule remains however a major stake for the prognosis. Indeed the molecule must have an optimal
1

Correspondence: Michel Bourin, Neurobiology of Anxiety and Depression, Faculty of Medicine, BP 53508, 44035 Nantes Cedex 1, France. Tel: +33 240412853; Fax: + 33 240412856; E-mail: michel.bourin@ univ-nantes.fr

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effectiveness in order to obtain the remission in the short run as well as in the medium and long term in order to obtain recovery and to prevent possible recurrence. In parallel it must be the least dangerous and have less possible adverse effects to ensure the safety of the prescription and the observance of the patient. Other parameters must also be appreciated like the treatment of possible co morbidities associated factors associated such as anxiety for example, or specific indications which can be necessary according to the ground. All these criteria represent as many elements of orientation in the choice of antidepressant chemotherapy. Specific serotonin and noradrenalin reuptake inhibitors (SNRIs) are a relatively recent class of antidepressants which have specificities making them one of the best therapeutic choices. They are characterized by a mixed action on both major neuroamines of depression, noradrenalin (NA) and serotonin (5HT). Many authors evoked the interest of a no univocal target on the level of the cerebral monoamines in order to improve the effectiveness of ant depressive chemotherapy. These same authors explain the slightly higher effectiveness that such molecules could have compared to those having only one monoamine specificity, like specific inhibitors of serotonin reuptake (SSRIs). Tricyclic antidepressants (TCAs) also have a double pharmacodynamic profile. The major difference between SNRIs and TCAs lies in their specificity for these two amines and in their absence of affinity for other receptors, thus minimizing adverse side effects.

Mechanism of action
SNRIs are characterized by a mixed presynaptic inhibition of serotonin and noradrenalin reuptake. Venlafaxine also presents a weak inhibition of dopamine (DA) reuptake, which is not the case for milnacipran. This action is however modest compared to the inhibition of 5HT and NA reuptake. On the other hand, they do not act on the adrenergic, muscarinic, histaminic H1 receptors, responsible for the major part of adverse side effects of tricyclic antidepressants. They also lack affinity for opiod and gabaergic receptors and do not inhibit monoamine oxidase.

Pharmacodynamics
Venlafaxine Venlafaxine exists as a mixture of R and S-enantiomers. The R-enantiomer inhibits 5HT and NA reuptake simultaneously while the S-enantiomer inhibits mainly 5HT reuptake. In vitro, venlafaxine inhibits 3 to 5 times more 5HT reuptake that NA reuptake. DA reuptake inhibition is weak. The NA reuptake inhibition is dose dependent; thus at low doses venlafaxine 217

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acts like a SSRI, whereas at higher doses it acts like a SNRI. The dose where NA reuptake inhibition appears is uncertain and seems to be between 75 to 225mg/day. The principal metabolite of venlafaxine is the O-desmethylvenlafaxine (ODV). ODV has the same potential of 5HT and NA reuptake inhibition than parent molecule, but inhibits 4 times less DA reuptake. Milnacipran Milnacipran simultaneously inhibits 5-HT and NA reuptake. In contrast to venlafaxine, reuptake inhibition of both monoamines is more homogeneous. The reuptake inhibition varies slightly according to the dosage, but remains however rather homogeneous.
Inhibition of monoamine reuptake (In vitro measures in rat brain tissue)
IC50 nM Milnacipran Imipramine Citalopram Desipramine Venlafaxine Noradrenalin (NA) 100 40 2000 20 640 serotonin (5-HT) 203 14 1.3 4780 210 180 selectivity 5-HT 0.5 3 1540 0.004 3 65

ODM-venlafaxine 1160

Pharmacokinetic
Venlafaxine After oral administration, maximum concentration is obtained into 2 hours. Plasma protein binding is 27% for the parent molecule and 30% for the active metabolic. The metabolism is mainly hepatic, interesting cytochrome P450 enzymes. The principal metabolite is O-desmethylvenlafaxine (ODV) resulting from oxidation by CYP2D6. ODV is an active metabolite, unlike Ndesmethylvenlafaxine and NO-desmethylvenlafaxine metabolized respectively by CYPA3/4 and CYP2C19. At the major part of individuals, ODV concentration is between 2 and 3 times the parent molecule concentration. Because of a possible genetic polymorphism, the parent molecule concentration can be higher than ODV one among slow metabolism patients. Elimination is renal, in less than 48 hours, 87% of the dose is eliminated in not combined or combined form (ODV or minor metabolite) and 5 to 7% in unchanged form. The half life elimination is 5 hours for venlafaxine and 11 hours for ODV. Hepatic metabolism and renal elimination require posological adaptations in case of renal or hepatic insufficiency. 218

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Venlafaxine is also marketed in extended release form. In this galenic composition, the molecule is included in encapsulated micro spheres allowing the progressive release of the active substance. The bioavailability was measured to 45% at healthy volunteers (Patat et al., 1998) [1]. The maximum concentration is obtained after 5.5 hours for the mother molecule and after 9 hours for ODV. Milnacipran After oral administration, absorption is fast and nearly complete (higher than 90%). Feeding does not modify pharmacokinetic parameters. The maximum plasmatic concentrations are obtained between 0.5 and 4 hours. Biodisponibility of milnacipran is high, about 85%. Proteinic binding is weak of 13%, and the distribution volume is 5.3+/-0.41 l/kg. Interindividual variability is low. There is a linear concentration-dose relation. The metabolism is weak and the major part of the absorbed dose is eliminated in unchanged form. The principal metabolite is glucoroconjugated. The metabolism of milnacipran does not interest cytochrome P450 enzymes, which limits the risk of drug interactions particularly with the old subjects polymedicamented. Biotransformation of milnacipran led to inactive compounds. Elimination is both renal and hepatic, with renal and extra renal clearances respectively of 23.8 +/- 7.3 and 16.4 +/- 3.1 l/h. The half life of elimination is 8 hours. It is necessary to adapt doses in the event of renal insufficiency. The dose adaptation is facilitated by the linear concentration-dose relation.

Effectiveness in depression
1) Venlafaxine a) Global efficacy in depression from meta-analysis Many controlled trials have proved the efficacy of venlafaxine (IR or XR) in the treatment of depression. Those studies demonstrate the efficacy of this drug in comparison to placebo, and tend to show that venlafaxine have an efficacy overall equal to TCAs [2, 3] and slightly greater than SSRIs [4, 5, 6]. With the view to confirm those results, some meta-analysis has been recently led. A first meta-analysis, conducted by Einarson and colleagues (1999) in patients suffering from major depressive disorder (MDD), was aimed to compare venlafaxine XR, SSRIs (citalopram, fluoxetine, fluvoxamine, sertraline and paroxetine) and TCAs (amitriptyline, imipramine, desipramine, nortriptyline) [7]. This analysis includes the results from 44 randomized controlled trials on 4033 patients. The data compares the mean success rates in each group, defined as a 50% decrease of HAM-D or MADRS score. In the statistical analysis, venlafaxine success (73.7%) were significantly greater than SSRIs (61.1%) and TCAs (57.9%) (p 0.01). A second meta-analysis by Entsuah and colleagues (2001) compares venlafaxine (IR or ER) and SSRIs [8]. This study, pooled 8 comparable double-blind, active-controlled, randomized trials (4 219

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were either placebo-controlled), in a total of 2045 patients suffering from MDD. The efficacy was appreciated by response rates (decrease 50% from baseline of HAM-D 21 score), remission rates (HAM-D 17 7), and absence of depressed mood (score of 0 on the depressed mood items of the HAM-D 21) at the end point of studies (8 weeks). The result of the statistical analysis was in favor of venlafaxine in regard of response and remission rates but no significant difference was observed in absence of depressed mood criterion. More interesting, no gender or age-influence were measured in venlafaxine efficacy. It means that venlafaxine is both effective for men or women suffering from MDD, and that venlafaxine can be use at any age of life with an equal remission or response rate. The meta-analysis by Smith and colleagues (2001) is particularly interesting because venlafaxine IR or ER is compared with SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline), TCAs (clomipramine, imipramine, and dothiepin), amitriptyline or other drugs (trazadone and mirtazapine) [9]. This meta-analysis included 32 controlled trials and 5562 patients with MDD diagnosis. The primary outcome was the overall effect size assessed by the final HDRS score, the MADRS score, and the CGI score. In regard of the primary outcome there was a significant improvement in favor of venlafaxine comparing to SSRIs but not to TCAs (excepted imipramine) or other drugs. The second variable was response rates and remission rates who where in favor of venlafaxine. The results of these three meta-analysis are particularly interesting because they confirm the results expected on controlled studies in higher samples. According to the meta-analysis, it appears that venlafaxine (IR or XR) is clearly as efficacious as TCAs and slightly greater than SSRIs in the treatment of MDD. Furthermore, venlafaxine appears to be as efficacious for men as women and acts plenty on younger and older patients. b) Efficacy in severe forms of depression, in particular melancholic form To appreciate the interest of an antidepressant it is important to know his potential efficacy on most severe forms of the disease in particular on resistant depression or melancholia. Some controlled trials have been led in this goal and confirm the ability of venlafaxine to treat the most severe form of depressions. Clerc et al. (1994) [6], compared venlafaxine (200 mg/d) and fluoxetine (40 mg/d) among 68 patients suffering from MDD or melancholia in a 6-week double-blind trial. From the 4th week, a significant difference in favour of venlafaxine was observed on MADRS and HAM-D scales. At the 6th week (endpoint), venlafaxine showed a difference significantly greater at MADRS (p=0.028) and HAM-D (p=0.027). In treatment-resistant depression, Poirier et al. (1999) [10] compared venlafaxine (progressive increase in the doses up to 200 or 300 mg/d) with paroxetine (progressive increase in the doses up to 30 or 40 mg/d) among 122 in or out-patients. The diagnosis was sustained by DSM-III R, with a score of at least 18 on HAM-D for inclusion, and patients were 220

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required to have a history of two previous successive inefficacy antidepressant treatments prescribed at effective dose and for 4 weeks at least. At the end point, the primary outcome was the score on HAM-D scale. The percentage of responding patients (reduction of 50% or more of HAMD score) was 52% for venlafaxine and 33% for paroxetine, with a significant difference (p=0.044). The percentage of remission (HAM-D<10) was 42% with venlafaxine and 20% with paroxetine, with a significant difference (p=0.01). The efficacy on severe form of depression represents a real clinical interest and reinforces the ability for prescribing venlafaxine in depressed patients. c) High rate of remission and efficacy in relapse prevention. The ability to obtain a remission with an antidepressant treatment is a main important objective. A rate of response from 50 to 60% is usually obtained with the majority of antidepressants (Ferrier et al., 1999) [11]. Response is currently defined for the improvement of MADRS or HAM-D scores of 50% or more. According to Thase et al. (1995) [12], 30 to 50% of the patients will relapse in the 4 to 6 months following the treatment of the depressive episode. Incomplete remission represents a risk factor of recurrence. The rate of remission obtained with antidepressants thus represents a significant factor for the appreciation of the real effectiveness of a molecule and the benefit both human and socio-economic with its use. The increase of remission rates with venlafaxine XR or IR have been demonstrated in several controlled trials [13, 14] and also confirmed by meta-analysis [15]. A higher remission rate for venlafaxine in comparison to SSRIs was demonstrated in the meta-analysis of Poirier et al (1997) with a significantly higher absolute rate of patients obtaining a final HAM-D score lower or equal to 10 on HAM-D 17 in venlafaxine sample vs. protein sample (p=0.02) [16], and in the meta-analysis of Entsuah et al (2001) where significantly more patients achieved remission in the venlafaxine group (p0.05) [8]. These results have been confirmed by Smith et al meta-analysis (2001) [9]. In this study the remission rates obtained with venlafaxine were compared with those obtained with other antidepressants (TCAs, SSRIs, other molecules) in 18 controlled trials, but 16 using a SSRI as reference. The overall odds ratio for remission rate was 1.36 with a difference risk of 0.07 in favour of venlafaxine and a Number needed to treat of 14. It means that one extra patient reaches remission when venlafaxine instead another antidepressant (in fact instead a SSRI in this meta-analysis real conditions). It can appear slight in current practice, but in a socioeconomic approach it represents an important health benefit. The high remission rates obtained with venlafaxine are in favour of a good efficacy in longterm use, particularly in relapse and recurrence preventions. A maintenance treatment using imipramine can decrease recurrence risks, depending on the prescribed dose (Frank et al, 1993) 221

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[17]. The principal obstacle of a maintenance treatment prescription, in particular with TCAs, remains tolerance. Venlafaxine is a well tolerated molecule with which a maintenance treatment can reasonably be envisaged. Entsuah et al., (1996) [18], showed that long course venlafaxine treatments significantly decreases the risk of relapse compared to placebo. After 6 months among 304 patients treated over a long period, the cumulative rates of relapse were 11% with venlafaxine versus 23% with placebo (p=0.019) and 20% versus 34% at 1 year (p=0.022). d) Efficacy on associated anxious symptoms Patients suffering from MDD frequently exhibit anxious symptoms, and anxiety is sometimes the initial and principal complaint. The ability for an antidepressant to improve anxious associated symptoms thus represents a great interest and minimizes the anxiolytics prescription. Feighner et al. (1998) [19] demonstrated the effectiveness of venlafaxine for anxious symptoms in two controlled studies versus placebo. In the first study (Cunningham et al., 1997) [20], the use of venlafaxine XR or venlafaxine IR (75 to 150 mg/d), reduces the HAM-D psychic anxiety score significantly higher than in the placebo group. In a second study (Thase et al., 1997) [21], venlafaxine XR (75 to 225 mg/d) also showed a significantly greater reduction on HAM-D psychic score than placebo. In addition to the proven efficacy comparing to placebo, it appears that venlafaxine may have a greater improvement of anxious disorder associated with MDD in comparison than SSRIs. Silverstone et al. (1999) [22] studied venlafaxine XR and fluoxetine among 359 out-patients suffering from MDD. The duration of the study was 12 weeks and the judgement criteria were HAM-D, HAM-A and CGI. At 12 weeks, the response rates were 43% in the placebo group, 62% in the fluoxetine group and 67% in the venlafaxine XR group. A significant difference in remission rates with the two molecules compared to placebo was both observed, but the improvement on HAM-A was significantly higher with venlafaxine XR compared to fluoxetine (p=0.037). e) Improvement in life functioning Venlafaxine appears to be efficient in the treatment of MDD, but also improve the quality of life of patients suffering from severe or melancholic depression. In a-6 week, double-blind, placebocontrolled study in 285 patients with major depression or melancholia [23], venlafaxine (75 to 375mg/d) was significantly superior to placebo on the General Life Functioning (GLF), social activity, cognitive functioning, general health perceptions, and vitality scores. Compared to fluoxetine (20 to 80mg/d), venlafaxine shows a significant greater improvement of those criteria (excepted general health perception). Likewise, in a 6-week, double-blind, placebo-controlled study in 297 out-patients with MDD [24], venlafaxine (37.5 to 225mg/day) was significantly superior to 222

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placebo on the GLF total score with a non significant improvement on social activity, cognitive functioning, general health perceptions and vitality. Compared to fluoxetine (20 to 80mg/d), venlafaxine revealed a significant improvement on GLF total score. The improvement of life functioning with venlafaxine is linked with the good efficacy of this molecule which reduces the depressive symptoms and consequently improves the life functioning. It does not seems abnormal that global life functioning can be significantly greater with venlafaxine than with SSRI compounds in view of the slightly greater global efficacy demonstrated for SNRIs vs. SSRIs. 2) Milnacipran Milnacipran is a more recent molecule which also proved its antidepressive effectiveness compared to reference molecules and placebo. a) Efficacy in hospitalized or out-patients. Puech et al. (1997) [25] compared the efficacy of milnacipran (50 mg twice daily) with TCAs and SSRIs among hospitalised and external patients in a meta-analysis study of 1032 patients. In this study, milnacipram showed an efficacy significantly greater to placebo in term of response and remission on HDRS (Hamilton Depression Rating Scale) and MADRS. Symptomatology analysis described by each patient showed the efficacy of minacipran on the different symptoms of depression (anxiety, mnesic disorder, sleep disorder and retardation). b) Comparable efficacy by TCAs In the meta-analysis of Puech et al (1997)[25], no significant difference was measured in terms of effectiveness between milnacipran and imipramine (726 patients, incorporating 6 control studies) on MADRS and HDRS. Same results were demonstrated by Montgomery et al. (1996) [27] in a meta-analysis study of 2462 patients suffering from MDD comparing the effectiveness of milnacipran with TCAs and SSRIs. TCAs used were imipramine, amitriptyline, clomipramine and maprotiline. No significant difference can be highlighted in terms of responses between milnacipran and TCAs group using HDRS or MADRS. The mean deadline was 15.6 days under milnacipran and 15.9 days under TCAs (no significant difference). The remission rate was 39% with milnacipran (no significant difference). c) Efficacy greater than SSRIs in moderate and severe depressions The greater efficacy in comparison of SSRIs in MDD have been demonstrated in controlled trials [27, 28] and confirmed in meta-analysis [25, 26, and 29]. In their meta analysis of 1996, Montgomery et al. [26] also compared milnacipran (50 mg twice daily) with SSRIs (fluoxetine and 223

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fluvoxamine). At the end of the treatment, a significant difference was found in favour of milnacipran in terms of response judged by HDRS (p<0.05) and MADRS (p<0.01) the remission rate is 39% with milnacipran, significantly higher than with SSRIs (p<0.05). In the meta analysis of Puech et al. (1997) [25], 2 studies compared milnacipran with SSRIs (fluvoxamine and fluoxetine). The effectiveness of the two classes of antidepressants was measured with MADRS and HDRS. A difference in favour of milnacipran was observed, however not statistically significant. e) Efficacy in recurrence prevention To estimate the interest of milnacipran in recurrence prevention in case of recurrent MDD, Rouillon and colleagues (2000) have led a 12-month placebo-controlled trial [30]. Patients should have a history of recurrent MDD, and present MDD episodes according to DSM-III R with a HDRS score 18. Milnacipran was prescribed in a 6-week open phase, and responding patients were included on a 4-month open continuation phase to difference relapse that occurred in this continuation phase and recurrence that occurred in the maintenance phase. The final inclusion in the double-blind maintenance treatment occurred at month 6 with patients having a HDRS score 8, an improvement on CGI scale and an improvement on the A criterion of DSM-III R. The analysis criterion was the comparison in recurrence rates during the maintenance phase. Finally, 214 patients were randomized in the double-blind placebo-controlled phase of maintenance therapy comparing milnacipran and placebo from month 6 to 12. Absolute recurrence rates were 16.3% in the milnacipran group vs. 23.6% in the placebo group with a significant reduction of recurrence in favour of milnacipran (p <0.05 in the Kaplan Meier Survival Analysis). No significant differences with placebo in term of tolerability (adverse side effect or dropout for intolerance) were observed in the maintenance phase. According to this controlled study, milnacipran appears effective and safe in recurrence prevention. Furthermore, Rouillon and colleagues (2000) appreciate in this same group the consequences of milnacipran maintenance treatment in recurrence prevention on quality of life [31]. The analysis of this secondary criterion shows an important improvement of quality of life in the milnacipran maintenance treatment group particularly on the mobility, communication, psychosocial and total score.

Anxiety disorder treatment

Venlafaxine obtained the authorization use for the treatment of GAD (general anxiety disorder) in several countries now. Venlafaxine efficacy in this disorder is proved in multiple controlled-trials using BZD, buspirone or placebo [32, 33, 34, 35]. Meoni and colleagues (2001) led a pooled-analysis of five placebo-controlled trials including 2021 patients with DSM-IV GAD diagnosis for a 8-week analysis and 767 patients for a 6-month analysis comparing venlafaxine XR 224

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and placebo [36]. After 8 weeks of treatment, the effect size on 11 of the 14 HAM-A items was greater with venlafaxine XR than with placebo. After 6 months the effect size in the venlafaxine XR-treated patients increased compared with the 8-week value for 11 of the 14 items. Similar results were observed in the BSA (Brief Scale for Anxiety) item score. These results indicate that the specific symptoms of GAD can be treated with venlafaxine XR, both in the short and longer term. More recently, Katz and colleagues (2002) showed in a pooled-analysis of five placebocontrolled trials including 1839 patients with DSM IV diagnosis of GAD the efficacy of Venlafaxine XR in young and older patients [37]. According to the recent controlled trials comparing treatments of anxious disorder, it appears that antidepressants represent the treatment of first line of these diseases. Venlafaxine is effective in the treatment of GAD, and represents an alternative for SSRIs. The global effect seems however lower than with SSRIs. Venlafaxine acts on several symptoms of GAD and improve most of them, but have lower effects on somatic symptoms. The onset of action is between 1 to 3 weeks [33]. Compared to benzodiazepines, venlafaxine has no dependence potential and is not associated with withdrawal syndrome in case of brutal disruption. Pollack and colleagues (1996) demonstrated the benefits of venlafaxine in panic disorder in a 8-week placebo-controlled trial of 25 patients [38]. Nevertheless, venlafaxine is not use in usual practice for panic disorder.

Rapid onset of action

A time difference between the beginning of treatment and the beginning of antidepressant action exists. This onset of action usually lies between 2 and 4 weeks with the majority of antidepressants. If we compare the efficacy of an antidepressant molecule with a placebo, a significant difference is observed classically only after 4 to 6 weeks. This deadline is a limiting factor taking into account the significant risk of morbid-mortality which exists during this period. During this period of insufficient efficacy the occurring of first side effects of drug is accompanied by a significant risk of treatment interruption by the patient. Several studies have been carried out concerning the onset of antidepressant action of venlafaxine. Shweizer et al. (1991) [39], in a double-blind study versus placebo, highlighted a significant response from the second week in the venlafaxine group receiving 125 mg/d. In 1995, Guelfi et al [40] also showed a significant difference for the venlafaxine with the average dose of 350 mg/d compared to placebo at 4th day on MADRS and 1 week on HAM-D among melancholic patients. These results have been confirmed by several other studies. Entsuah et al. (1998) [41], for example compared the onset of antidepressant action of fast increase of venlafaxine doses up to 200 mg /d in one week, in two controlled-studies versus placebo. A significant difference on CGI is 225

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observable before two weeks. In 1996, Benkert et al [42] compared among 167 patients suffering from MDD or melancholia the effectiveness of the fast increase in venlafaxine (increase up to 375 mg/d in 5 days, then a maintenance of this dose during 10 days, followed by a reduction at 150 mg/d until the end of the study) with imipramine (increase up to 200 mg/d in 5 days, maintained until the end of the study). No difference was measured in term of effectiveness at the 42 th day, term of the study (MADRS and HAM-D). A significant difference in onset of antidepressant action exists at HAM-D (median time of response 14 days with venlafaxine and 21 days with imipramine), but any with the MADRS. The mechanism at the origin of this greater speed of antidepressant effectiveness of venlafaxine seems to be several origins. Blier (2001) [43], evokes the importance for this type of molecule of the mixed action on NA and 5HT. For him, the inter-relationship between these two systems brings feed-back negative mechanisms at presynaptic receptor levels and is responsible of a faster combined action. Muth et al. (1991) [44] showed the rapid desensitizing of beta-adrenergic receptors with venlafaxine and explaining the faster antidepressant kinetics obtained with this molecule. This desensitizing does not exist with the milnacipran (Neliat et al., 1996) [45]. For Derivan et al. (1995) [46], the rapid onset of antidepressant action would be explained at the same time by this rapid desensitizing and by the pharmacokinetic properties of venlafaxine. A short halflife combined with a good tolerance make it possible to obtain effective posologies quickly and to reach steady-state.

Tolerance
The tolerance of SNRIs is linked to their pharmacodynamic characteristics. For these molecules, the strong specificity which exists for 5HT and NA is associated with good effectiveness coupled to a good tolerance. Indeed, by the absence of action on the alpha 1-adrenergic, muscarinic, histaminic H1 receptors, and the absence of inhibition of the monoamine oxidase, the side effects are thus decreased compared to other molecules. 1) Venlafaxine To appreciate the frequency of adverse side effects with drugs, meta-analysis are particularly interesting because they pool a higher number of patients and are also more available to detect and evaluate the occurrence of adverse events. In a meta analysis of 1996, Rudolph et al [47] appreciated the frequency of adverse side effects with venlafaxine by 3082 patients. In this study, the total number of treatment interruptions for adverse effects was 18% in the venlafaxine group versus 6% in the placebo group. The principal time of drop-out during venlafaxine treatment occurred at the beginning of the treatment and beyond the 6th week dropouts are limited at 5%. Principal side effects met with a higher incidence 226

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than 10% for nauseas, insomnia, giddinesss, somnolence, constipation, sweats, headache, dry mouth, asthenia and nervousness. Among the observed side effects some are dose-dependant. They are disorders of ejaculation, giddinesss, increase in blood pressure, sweats, somnolence, tremors, agitation, anorexia, yawns and frilosity. Nauseas represent the principal significant side effect with venlafaxine. The uses of extended release form reduce their frequency (Cunningham et al., 1997) [20]. Their occurrence during treatment can be explained by the serotoninergic tone of the molecule. Indeed, venlafaxine inhibits 3 to 5 times more 5HT than NA reuptake. These nauseas are not dose-dependent and occur principally at the beginning of the treatment. In the majority of the cases as they will regress after the first weeks, posologies can be preserved and even increased. However, it remains an embarrassing adverse effect and can constitute a reason for premature treatment interruption. The rarer but potentially serious adverse side effects can be evaluated through the metaanalysis led by Rudolph in 1996 [47]. Manic switch seems to occur in 0.5%, cutaneous rash in 4% (3% in the placebo group), epilepsy in 0.26% (vs. 0.38% for the reference antidepressant, TCAs or not), withdrawal syndrome in 5% and gamma-GT increase to more than three times in 0.4% (0.2% for placebo and 0.9% for reference antidepressant). Cardiovascular effects are moderate. ECG does not show modification of PR, QRS or QT segments, but a slight acceleration of average heart rate can occurred. There is a dose-dependent rise of the blood pressure. Rudolph et al. (1996)[47] demonstrated that the frequency of blood pressure increases (PAD 90 mm Hg and/or increase PAD 10 mm Hg) respectively in 2% for placebo, 2% with venlafaxine lower than 100 mg/d, 13% with venlafaxine higher than 300 mg/d. This increase of the blood pressure is however generally transitory and maximum in the first weeks of treatment (Rudolph et al., 1998) [48]. Some cases of serotoninergic syndromes were described. They are however rare and supported by other molecules with cumulated 5HT potentiality. Because of cardiac toxicity absence, venlafaxine is well tolerated in case of overdose. Studies comparing the effectiveness and the tolerance of venlafaxine versus other antidepressants show for the majority of them, a significantly lower frequency of adverse effects and dropouts for side effects (in particular cholinergic) compared to TCAs, but also compared to SSRIs. Few studies on the safety of venlafaxine during pregnancy are available because of the recent use of venlafaxine in clinical practice. A retrospective study led by Einarson and colleagues in 2001[49] suggests an absence of major malformation rate increase in a sample of 150 women exposed to venlafaxine during pregnancy, compared to an equivalent sample of women exposed to SSRIs and a equivalent sample of women exposed to non teratogenic drugs. However, these results must be confirmed by others studies and venlafaxine is not indicated in case of pregnancy. 227

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2) Milnacipran The effectiveness and tolerance of milnacipran were analyzed in many controlled-studies versus TCAs or SSRIs. As concerning venlafaxine, meta-analysis interesting milnacipran are more potent to detect and evaluate the occurrence of adverse side effects because of the higher number of patients exposed. A meta analysis of Montgomery et al. (1996) [26] involving 2462 patients suffering from MDD compared milnacipran (50 mg twice daily) with other antidepressants. The analysis of the adverse effects takes also into account data of pharmacovigilance involving 5732 patients receiving milnacipran in various clinical tests. Compared to TCAs, there is no significant difference in terms of response or remission between the two groups. On the other hand, significantly more patients stopped their treatment for adverse effects in the TCAs group (14.8%) than milnacipran group (7.6%). The only undesirable event occurring twice more frequently with milnacipran is dysuria (2.1% vs. 0.6%). Dysuria observed with milnacipran can be explained by the noradrenergic tone of the molecule. On the other hand, anticholinergic symptoms (dry mouth, constipation) and histaminergic symptoms (sedation) are significantly less frequent. There is no increase of suicide ideation. At the cardiovascular level, there is not any modification of the ECG (in particular PR, QT, and QRS segment) with milnacipran contrary to TCAs. An orthostatic hypotension occurs in 21% of patients treated with milnacipran against 34% with TCAs. No hematological modification is detectable. There is no increase in hepatic enzymes. Compared with SSRIs (fluoxetine and fluvoxamine), a significant difference of effectiveness exists in favor of milnacipran. Interruptions for adverse effects are identical in the two groups (7.6% for milnacipran and 7.8% for SSRIs). Significantly more cephalalgias, mouth drynesss, dysuria, but less nauseas, diarrheas and hypotensions are observable with milnacipran. Puech et al. (1997) [25] also carried out a meta-analysis of 1032 patients comparing milnacipran, imipramine and SSRIs. The analysis of tolerance also took into account the data of pharmacovigilance concerning more than 3300 patients having taken milnacipran during comparative studies. The drops out of data for adverse effects were respectively 6.1% in the placebo group, 7.6% with milnacipran, and 7.8% with SSRIs and14.8% with TCAs. In the milnacipran group, 5 side effects were significantly more frequent than in the placebo group: dysuria (2.1%), giddiness (5%), anxiety (4.1%), flush (3%), and sweatiness (4.3%). Only dysuria was significantly more frequent compared to TCAs or SSRIs. Nausea were significantly less frequent than in the SSRIs group. Compared to TCAs, dry mouth, constipation, tremors, sweats, somnolence, tiredness and giddinesss were significantly less frequent. In long-term analysis milnacipran does not highlight emergence of adverse side effects with time (Puech et al., 1997) [25]. Milnacipran is not accompanied by degradation of cognitive 228

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functions and improves cognitive capacities by treating the depression. Hindmarch et al. (2000)[50] showed that milnacipran from 12.5 to 100 mg in single dose did not deteriorate cognitive functions analyzed by a psychomotor series of tests measuring response time, short-term memory, sedation and attention, in young healthy adult volonteers. With regard to the suicidal risk, milnacipran seems to be safe with decreasing suicidal risk without inducing suicidal ideation if they were not present initially. Montgomery et al. (1996) [26], have assessed the suicidal risks with milnacipran in comparison to TCAs and SSRIs in 5290 patients. They quantify the suicides or suicide attempts respectively to 6.46 (milnacipran), 8.99 (TCAs) and 22.9 (SSRIs) events by 100 patients per year. Finally, because of cardiac toxicity absence and lack of the parameters of conduction and repolarisation modification, milnacipran is a molecule relatively well tolerated in case of overdose. Several cases of massive absorptions were observed with a favorable evolution.

Cost/efficacy ratio
Treatment of depression currently represents a true socio-economic stake. Greenberg et al. (1993) [51], for example quantified the cost of depression to $US 44 billions per year. Jonsson et al. (1994) [52] estimated a cost of 222 million per year in the United Kingdom. According to the high frequency of depression disease in the economically developed countries, and the total cost associated with his treatment, it is important to analyze the real benefice in term of economic gain that an antidepressant drug can procure. These concepts explain why economic studies of the cost and efficacy of antidepressant have recently increased recently. Financial concerns are especially important as Saris generally have a purchase cost higher than other antidepressant molecules. Studies were undertaken to appreciate the total cost of a depressive episode (including price of purchase, consultations, and cost in days of hospitalization, tests of laboratory, and possible lacks of work...) and cost/efficacy ratio for Saris compared to other molecules. Freeman et al. (2000) [53] analyzed the cost/efficacy ratio in United Kingdom in 4033 patients suffering from MDD treated by venlafaxine (324 patients), SSRIs (2657 patients) or TCAs (1052 patients). The results of this meta analysis show that the total effectiveness for ambulatory patients is 73.7% in the venlafaxine group, 61.4% in the SSRIs group and 59.3% in the TCAs group. The dropouts for adverse effects were respectively 10.9% for venlafaxine, 17.4% for SSRIs and 23.1% for TCAs. The cost of each treatment expressed in day without symptom were of 10.53 for venlafaxine, 13.23 for SSRIs and 15.525 for TCAs largely in favor of venlafaxine. Likewise, Griffiths et al. (1999) [54] compared the cost of the treatment of depressant patients treated by venlafaxine (188 patients) or TCAs (172 patients) after failure of a first SSRIs prescription. The average medical care total cost by patient over 12 months is $US 6543 in the venlafaxine group and 229

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$US 8073 in the TCAs group, with a no significant difference (p=0.18). In the venlafaxine group, there were significantly more consultations to a psychiatrist, a psychologist or a social worker, but less hospitalizations, hospital consultations or non psychiatric doctor consultations. Same studies were led for milnacipran to prove the economical interest to prescribe this molecule in MDD. Dardennes et al. (1998) [55] compared the health care cost in France of patients suffering from MDD and treated by milnacipran, SSRIs (fluoxetine or fluvoxamine) or TCAs (imipramine). This study involved 1470 patients resulting from three meta analysis. The average cost of the care by patients during 6 months including psychiatric consultations, drugs, laboratory tests and hospitalizations is respectively 8123 FF for milnacipran, 9084 FF for SSRIs and 8411 FF for TCAs. The socio-economic impact is henceforth a significant component in the choice of an antidepressant. Indeed, these studies showed that even if SNRIs are more expensive, the total cost of the medical care of a MDD episode is identical or slightly inferior than with SSRIs or TCAs. This slight difference in total cost can be explained partly by the good effectiveness of SNRIs coupled to a relatively good tolerance. From an economic point of view, SNRIs are thus a class of antidepressant presenting a very good cost/efficacy ratio.

Five years view

The profile of action and the advantages of SNRIs in terms of efficacy and tolerance make it possible to think that their prescription will increase in the next years. New molecules of this class are currently being studied and should reinforce the range of antidepressants offered. One can reasonably think that the pharmacological search of the next antidepressant molecules will be directed towards obtaining monoaminergic drugs having a strong specificity on the level of receptors as it is currently the case for SNRIs.

Conclusion
SRNIs are a relatively recent class of antidepressants. The double polarity of the reuptake inhibition of serotonin and noradrenalin ensures a profile of effectiveness comparable to TCAs and greater than SSRIs in particular in severe depressions. The absence of affinity for muscarinic, histaminic, 1-adrenergic receptors and the absence of action on monoamine oxidase limits the adverse effects and allows a higher tolerance than TCAs and at least equal to SSRIs. They are well tolerated by older subjects, and relatively not dangerous in case of overdose particularly in comparison to TCAs. They are active on depressive symptoms as well as on certain co morbid symptoms (anxiety, sleep disorder) frequently associated with depression. At the same time SNRIs make it possible to obtain a raised rate of response, but also a significant rate of remission decreasing the risk of relapse 230

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and recurrence in the medium and long term. Due to good tolerance, they can also be prescribed in a prolonged manner and with effective amounts in refractory forms of depression or patients with strong relapse potential. Currently two drugs of this class are available milnacipran and venlafaxine. These two molecules have certain specificities from their pharmacokinetic or pharmacodynamic profile. Nausea is the principal side effect of venlafaxine corresponding to a serotoninergic dominating profile. Conversely, milnacipran can be associated with urinary disorders because of its noradrenergic dominant profile. These side effects can be upsetting and embarrassing leading to premature interruption of treatment. However the particular profile of certain SNRIs could be used in clinic, and of the molecules such as duloxetine seems to be able to be indicated in certain forms of urinary incontinence. Even if these molecules have a higher selling price than other antidepressants, the socioeconomic surveys show a cost/efficacy ratio higher than TCAs and SSRIs. This favourable ratio is related to a good efficacy, coupled to a good tolerance, making it possible to limit the indirect costs of the total medical care during a depressive episode. For these reasons, one can reasonably conclude that SNRIs represent a therapy of choice in depression and that their prescription is likely to strongly increase in the years to come.

Key issues box

SNRIs are a recent class of antidepressants with a dual inhibiting activity on serotonin and noradrenalin reuptake. SNRIs show a good efficacy in the treatment of MDD, slightly higher than SSRIs and overall equal to TCAs. In the MDD treatment, SNRIs demonstrate a high rate of response but also a high rate of remission. Venlafaxine has a rapid onset of action in comparison to other antidepressants which can limit the dropout during the initiating phase of treatment for lake of efficacy. Venlafaxine may be indicated for anxious treatment (associated symptoms or GAD). Because of a high specificity on serotonin and noradrenalin reuptake inhibition, SNRIs are well tolerated and a long-term treatment in case of severe form of depression can be considered to decrease the risk of relapse or recurrence. The cost/effectiveness studies reveal that treating a MDD episode with a SNRI can led to a final socio-economic gain in comparison with other antidepressants. Studies concerning venlafaxine are largely more numerous than milnacipran ones. It appears important that new trials interesting milnacipran complete those now available. 231

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References
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14. Entsuah AR, Huang H, Thase ME. Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective reuptake inhibitors, or placebo. J. Clin. Psy. 62 (11), 869-77 (2001). 15. Thase ME, Entsuah AR, Rudolph RL. Remissions rates during treatment with venlafaxine or selective reuptake inhibitors. Br. J. Psy. 178, 234-41 (2001). 16. Poirier MF. Venlafaxine versus paroxetine in the treatment of resistant depression. Biol. Psy. 42, 243S (1997). 17. Frank E, Kupfer DJ, Perel JM et al. Comparison of full-dose versus half-dose pharmacotherapy in the maintenance of recurrent depression. J. Affect. Disord. 27, 139145 (1993). 18. Entsuah AR, Rudolph RL, Hackett D et al. Efficacy of venlafaxine and placebo during long-term treatment of depression: A pooled analysis of relapse rates. Int. Clin. Psy. 11, 137-145 (1996). 19. Feighner JP, Entsuah AR, Mc Pherson MK. Efficacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed outpatients. J. Affect. Disord. 47, 55-62 (1998) 20. Cunningham LA, for the Venlafaxine XR 208 Study Group. Once-daily venlafaxine extended-release (XR) and venlafaxine immediate-release (IR) in outpatients with major depression. Ann. Clin. Psy. 9, 157-164 (1997). ** A meta-analysis of milnacipran efficacy in MDD treatment with a large evaluation of adverse side effects who have been detected during the different trials, reinforced by pharmacovigilance observations. 21. Thase ME. Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. J. Clin. Psy. 58, 393-398 (1997). 22. Silverstone PH, Ravindran A, for the Venlafaxine XR 360 Study Group. Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. J. Clin. Psy. 60, 22-28 (1999). 23. Evans D, Nemeroff C, Thase M et al. Improvement in social activity level, general life and cognitive functionning with venlafaxine versus fluoxetine in inpatients with melancholic depression. Eur. Psy. 17 (supp 1), 194 (2002). 24. Kalin N, Nemeroff C, Wan G et al. Improvement in general life functionning with venlafaxine versus fluoxetine in outpatients with major (supp1), 194 (2002). 25. Puech A, Montgomery SA, Prost JF et al. Milnacipran, a new serotonin and noradrenalin reuptake inhibitor: An overview of its antidepressant activity and clinical tolerability. Int. Clin. Psychopharmacol. 12, 99-108 (1997). 233 depression. Eur. Psy. 17

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26. Montgomery SA, Prost JF, Solles A et al. Efficacy and tolerability of milnacipran: An overview. Int. Clin. Psychopharmacol. 11(supp4), 47-51 (1996). 27. Guelfi JD, Ansseau M, Corruble E et al. A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed in patients. Int. Clin. Psychopharmacol. 13 , 211-28 (1998). 28. Clerc G and the milnacipran/fluvoxamine group. Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenalin reuptake inhibitor: A comparison with fluvoxamine. Int. Clin. Psychopharmacol. 16, 145-151 (2001). 29. Lopez-Ibor J, Guelfi JD, Pletan Y et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int. Clin. Psychopharmacol 11 (supp4), 41-46 (1996). 30. Rouillon F, Warner B, Pezous N et al. Milnacipran efficacy in the prevention of recurrent depression: A 12-month placebo-controlled study. Int. Clin. Psychopharmacol 15, 133-140 (2000). 31. Rouillon F, Berdeaux G, Bisserbe JC et al. Prevention of recurrent depressive episodes with milnacipran: Consequences on quality of life. J. Affect. Disord. 58, 171-180 (2000). 32. Davidson JRT, Dupont RL, Hedges D et al. Efficacy, safety, and tolerability of Venlafaxine ER and buspirone in outpatients with generalized anxiety disorder. J. Clin. Psy. 60, 528-535 (1999). 33. Gelenberg AJ, Lydiard RB, Rudolph RL. Efficacy of Venlafaxine ER capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial. JAMA 283: 3082-3088 (2000). 34. Rickels K, Pollack MH, Sheehan DV et al. Efficacy of extended-release Venlafaxine in non nondepressed outpatients with generalized anxiety disorder. Am J Psy 157, 968-974 (2000). 35. Silverstone PH, Salinas E. Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder. J. Clin. Psy. 62, 523-529 (2001). 36. Meoni P, Salinas E, Brault Y et al. Pattern of symptom improvement following treatment with venlafaxine XR in patients with generalized anxiety disorder. J Clin Psy 62, 888-893 (2001). 37. Katz IR, Reynolds CF, Alexopoulos GS et al. Venlafaxine ER as a treatment for generalized anxiety disorder in older adults: Polled analysis of five randomized placebocontrolled clinical trials. J. Am. Geriat Soc. 50, 18-25 (2002). 38. Pollack MH, Worthingtor JJ, Otto MW et al. Venlafaxine for panic disorder: Result from a double blind, placebo-controlled study. Psychopharmacol. Bull. 32, 667-670 (1996). 234

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39. Shweizer E, Weise L, Clary C et al. Placebo-controlled trial of venlafaxine for the treatment of major depression. J. Clin. Psychopharmacol. 11, 233-236 (1991). 40. Guelfi JD, White C, Hackett D et al. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J. Clin. Psy. 56, 450-458 (1995). 41. Entsuah R, Derivan A, Kikta D. Early onset of antidepressant action of venlafaxine: Pattern analysis in intent-to-treat patients. Clin. Ther 20, 517-526 (1998). 42. Benkert O, Grunder G, Wetzel H et al. A randomized double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. J.Psy. Res. 30(6), 441-451 (1996). 43. Blier P. Pharmacology of rapid-onset antidepressant treatment strategies. J. Clin. Psy. 62 (supp15), 12-17 (2001). 44. Muth EA, Moyer JA, Haskins JT et al. Biochemical, neurophisiological, and behavioral effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine. Drug Dev. Res. 23, 191-199 (1991). 45. Neliat G, Bodinier MC, Panconi E et al. Lack of effect of repeated administration of milnacipran, a double noradrenalin and serotonin reuptake inhibitor, on the betaadrenoreceptor-linked adenylate cyclase system in the rat cerebral cortex. Neuropsychopharmacol 35, 589-593 (1996). 46. Derivan A, Entsuah AR, Kikta D. Venlafaxine: Measuring the onset of antidepressant action. Psychopharmacol. Bull. 31,439-447 (1995). 47. Rudolph RL, Derivan AT. The safety and tolerability of venlafaxine hydrochloride: Analysis of the clinical trials database. J Clin Psychopharmacol 16 (supp2), 54-59S (1996). ** An interesting study of adverse side effects of venlafaxine on a large sample of patients from controlled and open trials who evaluates the rate of occurring of frequent and rarer events during the treatment. 48. Rudolph RL, Fabre LF, Feighner JP et al. A randomized, placebo-controlled, doseresponse trial of venlafaxine hydrochloride in the treatment of major depression. J. Clin Psy. 59, 116-122 (1998). 49. Einarson A, Fatoye B, Sarkar M et al. Pregnancy outcome following gestional exposure to venlafaxine: A multicenter prospective controlled study. Am. J. Psy. 158 (10), 172838 (2001). 50. Hindmarch I, Rigney U, Stanley N et al. Pharmacodynamics of milnacipran in young and elderly volunteers. Br. J. Pharmacol 49 , 118-125 (2000). 51. Greenberg PE, Stiglin LE, Finkelstein SM et al. The economic burden of depression in 1990. J. Clin. Psy. 54, 405-418 (1993). 235

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52. Jonsson B, Bebbington PE. What price depression? The cost of depression and the costeffectiveness of pharmalogical treatment. Br. J. Psy. 164, 665-673 (1994). 53. Freeman H, Arikian S, Lenox-Smith A. Pharmacoeconomic analysis of antidepressants for major depressive disorder in the United Kindom. Pharmacoeconomics. 18, 143-148 (2000). 54. Griffiths RI, Sullivan EM, Frank RG et al. Medical resource use and cost of venlafaxine or tricyclic antidepressant therapy. Following selective serotonin reuptake inhibitor therapy for depression. Pharmacoeconomics. 15 , 495-505 (1999). 55. Dardennes R, Berdeaux G, Lafuma A et al. Comparison of the cost-effectiveness of milnacipran (a SNRI) with TCAs and SSRIs: A modeling approach. Eur. Psy. 14, 152162 (1999).

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LOW-DOSE OF ASA IN THE PROPHYLAXIS OF MIGRAINE WITH AURA. A RETROSPECTIVE STUDY

Lidia Savi1, Mihaela-Bianca Anoaica1, Florica Popescu2, Lorenzo Pinessi1 1 Headache Centre, Neurology II, Department of Neurosciences, University of Turin, Molinette Hospital, Turin, Italy 2 University of Medicine and Pharmacy of Craiova, Department of Pharmacology

Abstract Migraine, the most common disabling kind of headache, may impair the quality of life, limit daily activities and represent sometimes a significant financial burden to the patient and society. Migraine with aura, a form affecting a significant minority of migraine patients, may often cause severe anxiety and distress. Aim of this study was to evaluate the efficacy and tolerability of Acetylsalicylic Acid for migraine with aura prophylaxis. Key words: Migraine with aura, Acetylsalicylic Acid, prophylaxis.

Aim of the study

Migraine, the most common disabling kind of headache, may impair the quality of life, limit daily activities and represent sometimes a significant financial burden to the patient and society. Migraine with aura (MA), a form affecting a significant minority (~30%) of migraine patients, even if less frequent than migraine without aura, may often cause severe anxiety and distress. This happens because usually in the attacks severe headache coexists with the distinctive features of the disorder, which are the unilateral or bilateral transient neurological symptoms (visual, sensory or motor). Pathophysiology underlying migraine and in particular MA is not yet clear. Changes in serotonin concentrations have been implicated, as well as platelets activation. MA in the majority of cases is a relatively easy-to-diagnose form of headache, but when confronted with it, the real challenge is to select the most effective treatment. The therapeutic prophylaxis options for this form of migraine are very few and not always tailored to prevent the neurological symptoms. Pathophysiology underlying migraine and in particular MA is not yet clear. Changes in serotonin concentrations have been implicated, as well as platelets activation. Acetylsalicylic acid (ASA) is commonly used worldwide for many different conditions. It acts as an analgesic inhibiting COX-2 formation peripherally and centrally within the CNS; it also
1

Correspondemce: Mihaela-Bianca Anoaica, E-mail: dott.bianca@libero.it.

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reduces platelet activation and aggregation and studies report that it diminishes serotonin mediated firing of neurons in brain stem and hypothalamus. Platelet activation has frequently been found in migraine patients, particularly with aura, and symptomatic MA attacks have been reported in platelet diseases. In the past some studies used ASA at low dose in the prophylaxis of MA with controversial results. On the basis of these observations, aim of this study was to evaluate the efficacy and tolerability of ASA for MA prophylaxis.

Materials and methods

We reviewed the charts of 88 (59 females and 29 males, age range 18-65 yrs) patients suffering from MA according to the ICHD II criteria, attending to Turin University Headache Centre. 35 subjects (22 females, 13 males, age range 18-65 yrs,) were treated with ASA at low dose, 53 (37 females, 16 males, age range 18-65 yrs) with other prophylactic therapies normally used for migraine for a period of at least 4 months. Patients taking ASA began with a dosage of 300 mg/day for minimum 4 months, and then reduced the dosage to 200 and 100 mg/day before stopping. Headache frequency, duration, intensity, disability, accompanying symptoms, duration and intensity of the aura were evaluated before beginning the treatment and after the end of it.

Results
30 (85.7%) subjects treated with ASA referred positive results, while only 33(62.3%) of patients who undergone other prophylactic treatments did (p = 0.032). Very few adverse events (mainly gastric pain) were reported by very few patients.

Conclusions and discussion

On the basis of the data of this retrospective analysis ASA seems to be a very effective prophylactic treatment for MA. Its mechanism of action has not yet been clarified. ASA is widely used, safe and inexpensive; it is one of the best preventive treatments for vascular diseases and it has a very good tolerability profile in particular compared to the other pharmacological prophylaxis treatment actually used for this form of migraine. Its efficacy in the prophylaxis could also explain the positive results obtained in many MA patients who undergone closure of the Patent Foramen Ovale (PFO), since after surgery they are usually treated with ASA at low dose for at least 6 months and all the evaluations we have are at six months from the closure of it.

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References
1. Bensenor I.M., Cook N.R., Lee I.-M. , Chown M.J., Hennekens C.H., Buring J.E., 2001 Low-dose aspirin for migraine prophylaxis in women, Cephalalgia, 21, 175-183. 2. Musumba C.O., Walley T., 2006 Aspirin: old and new, J.R. Coll Physicians Edimb 36, 308-311. 3. Diener A.C., Kurth T., Dodick D., 2007 Patent Foramen Ovale and Migraine, Current Pain and Headache Reports, 11, 236-240. 4. Crassard I., Conard J., Bousser M.G., 2001 Migraine and hemostasis, Cephalalgia, 630-636. 5. Buring J.E., Peto R., Hennekens C.H., 2007 Low-dose aspirin for migraine prophylaxis, J.A.M.A., 264, 1711-1713.

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DRUG DEVELOPMENT IN SCHIZOPHRENIA

1

Michael Davidson1, Delia Podea2 Dept. of Psychiatry, Tel Aviv University, Chaim. Sheba Medical Center, Tel-Hashomer, Israel 2 University of Medicine and Pharmacy Arad, Romania

Abstract Schizophrenia is a devastating mental disease that affects about 1 % of the human population worldwide. Despite many promising developments, there is no ideal antipsychotic yet, but enormous opportunities currently exist to develop new drugs for schizophrenia. The atypical antipsychotics have profoundly impacted the treatment of schizophrenia, but challenges still remain in the psychopharmacological treatment of schizophrenia, in particular, treatment of the negative and cognitive symptoms. After a short review of currently available antipsychotics and of the lessons learnt from trials like CATIE and EUFEST, we present the pipeline for future drug development in schizophrenia, starting with drugs already in phase II or III of clinical development. Also, we review specific issues related to research being done on new drugs to treat cognitive impairment in patients with schizophrenia. The clinical implications of the introduction of these new drugs for schizophrenia are also discussed. Keywords: schizophrenia, antipsychotics, drug development.

Introduction
Schizophrenia is a phenomenological construct which overlaps with many other psychiatric diagnostic categories (i.e. bipolar disorder, schizotypal personality disorders, and mild to moderate mental retardation). The phenomena of schizophrenia are probably induced by different combinations of genes and environmental effects, which, depending on personality variables, manifest differently in different individuals. Schizophrenias diagnostic umbrella covers a wide range of manifestations, from somewhat-imperfect brain function, with moderately abnormal life course but reasonably good quality of life, to severe functional impairment, total dependence on others, and very poor quality of life. Manifestations such as a-volition and depression, abnormal thought processing, delusions and hallucinations, as well as cognitive impairment and misperception of other peoples feelings (poor social cognition) are responsible for the social and vocational functional impairment. Widely diverse combinations of these conditions manifest in different individuals, or at different times in the same individuals, all fitting under the umbrella of
1

Correspondence: Michael Davidson, Department of Psychiatry, Tel Aviv University. Tel.: +972 526666565; e-mail: mdavidson6@gmail.com.

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schizophrenia. Some, but not all of these conditions are, in a more attenuated form, a part of the normal human experience (a-volition, poor cognitive performance, paranoia, misperceptions, difficulty to interpret the feelings of others).

Why the penicillin/spirochete story is not going to repeat itself

Because of the multi-factorial etiology, the heterogeneous phenomenological construct, and the continuum with normal human condition, it is highly unlikely that a single pharmacological intervention targeted at a biological abnormality will have a significant impact on all or most of the conditions that add up to schizophrenia, and on the resulting functional impairment. Barring prevention, it is unlikely that an intervention will correct such diverse aspects of abnormal brain functioning, once it is manifested. It would be, in a way, similar to the expectation that the same pharmacological intervention will treat diabetes-related weight gain, retinopathy, and ketoacidosis coma. Hence, in the future, different patients will be treated differently, and different symptoms in the same patient will be treated with different drugs. It is therefore reasonable to expect that progress will be incremental, rather than breakthrough treatment developments.

How useful for drug development is the currently available knowledge on the biology of schizophrenia?
Understanding the pathophysiology of schizophrenia is obviously pertinent to identifying targets for drug development. Similarly, identifying trait and state biological markers associated with schizophrenia, or with sub-types of schizophrenia, is useful in reducing the biological heterogeneity resulting from classifications based only on observable phenomenology. However, despite intensive research, and occasional claims of success, there has been no major progress in understanding the pathophysiological mechanisms responsible for schizophrenia. Following the serendipitous observation that compounds that ameliorate psychotic symptoms of schizophrenia also block in-vitro dopamine receptors, the first rational line of research hypothesized that psychosis is the result of excess dopamine activity. Since the early seventies, when this hypothesis was first advanced, until the present time, different technologies have been used to assess dopamine activity in patients affected by schizophrenia and to compare it to healthy controls. Dopamine metabolites, dopamine receptors, hormones under dopaminergic controls, and other neurotransmitters interacting with dopamine have all been investigated. Repeatedly, studies have demonstrated mean differences between groups of patients and groups of controls but invariably, the findings in patients were not specific and sensitive enough to distinguish patients from controls, or to be useful for isolated biologically-homogenous groups of patients. More worrisome, even the mean group differences between patients and controls failed to replicate in 241

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most cases, or to provide a consistent, plausible, and relevant explanation for the alleged mean group differences. Attempts to reformulate the hyperdopaminergic hypothesis into a dopamine disregulation hypothesis have not yielded better results. The second major hypothesis, which dominated the research on the pathophysiology of schizophrenia since the mid-eighties, has been the PCP/NMDA model. This hypothesis claims that since the drug of abuse phencyclidine, which blocks NMDA receptors, produces manifestations similar to schizophrenia, manipulations of NMDA receptors might benefit schizophrenia. As with the dopamine hypothesis, no direct evidence of abnormalities in the NMDA neurotransmission could be demonstrated, and a plethora of studies and pharmacological attempts to manipulate NMDA receptors has not yet produced any benefits. This realization has let investigators to try to deconstruct the syndrome of schizophrenia into simpler components (called, at different times, symptoms or endophenotype or biological markers) in the hope that they might be easier to study. Aspects of cognitive impairment, presence of visual or auditory hallucinations, abnormal visual and auditory reactions (P50), have all been considered as possible biological markers. Unfortunately, none of them have been useful in predicting treatment response or in identifying and characterizing homogenous subgroups of schizophrenic patients. In the end, the only features useful in predicting the course of illness (poor), or treatment response (poor), were a few commonsense variables such as earlier, younger onset of illness, poor premorbid function, lack of rapid response to treatment, poor cognition, and chronicity. These phenomenological (non-biological), mostly retrospective characteristics were not be helpful in understanding the illness or tin decreasing the heterogeneity of the trial sample.

The first generation antipsychotic drugs (FGA)

First-generation antipsychotic/anti-schizophrenia drugs (also known as conventional or typical neuroleptics) were discovered serendipitously in the fifties, and became widely available by the late sixties. The introduction of FGAs revolutionized mental health care strategies and led to a period of deinstitutionalization, during which patients with schizophrenia were released from large state hospitals to be cared in the community. The drugs ameliorate or suppressed psychosis in half to 2/3 of the patients, but not negative, deficit symptoms (a-volition), or cognitive impairment. About15 antipsychotic drugs of different chemical structures and receptor profiles became available on the market. The main difference between the drugs consisted in potency per milligram and adverse-effect profile, rather than efficacy. These drugs differed mostly in dose-dependent Parkinsons-like rigidity and tremor (EPS), psychomotor restlessness (akathisia), and sedative effects. In the late seventies it also became known that most of these drugs produced involuntary movements (tardive dyskinesia, or TD) in 5-20% of the patients, depending on patients age and 242

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cumulative exposure in terms of dose and time. However, not all the drugs caused the same adverse effects. Some, like Perphenazine, caused less EPS and weight gain, while others caused more EPS (haloperidol), or weight gain (chlorpromazine).

Clozapine as the forerunner of second-generation antipsychotic drugs

Clinical observations made in the seventies and trials conducted by Sandoz in the eighties have indicated that, among the available drugs, clozapine was more effective than the rest in ameliorating psychosis, as well as free of EPS and TD adverse effects. It is generally accepted that clozapine, first synthesized in 1958, is the prototypical atypical antipsychotic. Later studies also attributed to clozapine the ability to ameliorate suicidal ideations. Deficit negative symptoms and cognitive impairment were also claimed for clozapine, but the effect size was very small and the trials have not always been replicated. Interestingly, the uncertain advantages in terms of negative symptoms and cognitive benefits were highlighted by the academic community, while the metabolic adverse effects, chiefly weight gain, were mostly disregarded. More importantly, it was noticed that clozapine occasionally produced fatal agranulocitosis. This in turn prompted the pharmaceutical industry to try to make clozapine-like drugs with no agranulocitosis, which came to be known as second-generation antipsychotics. In-vitro receptor-binding work and theoretical formulations have indicated that a unique ratio of dopaminergic/serotonergic receptor-binding properties distinguished second-generation from first-generation drugs and conferred their improved efficacy and tolerability profile. Competitive hypotheses suggested that fast dissociations from DA2 receptors and/or lower DA2 receptor occupancies were responsible for clozapine's unique proprieties. Unfortunately, neither of the hypothesis has strong experimental support and the reason for clozapines unique proprieties remained unknown.

The second-generation antipsychotic drugs

Manipulation of the dopaminergic/serotonergic receptor-binding profile and of the dopaminergic profile alone by medicinal chemistry have created the second-generation antipsychotics (also knows as atypical neuroleptics) such as Risperidone (JNJ), Olanzapine (Lilly), Quetiapine(Astra-Zeneca), Ziprasidone (Pfizer), Aripiprazole (Osu_BMS), Amisulpride (Sanofi), Sertindole (Abbot-Lundbeck). Second-generation drugs differ among themselves chemically and pharmacologically, not less than they differ from the first-generation antipsychotics. For example, risperidone is closer pharmacologically and clinically to the first-generation haloperidol than to the second-generation olanzapine or ziprasidone. Risperidone produces Parkinsonism like the firstgeneration drugs, and much more than second-generation (olanzapine, ziprasidone , aripiprazole). Some first-generation drugs (chlorpromazine) and second-generation drugs (olanzapine, quetiapine) 243

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produce more weight gain than other second-generation drugs (ziprasidone or aripiprazole). Hence, there is much overlap between first- and second-generation drugs in terms of adverse effects. In terms of efficacy, the prevailing idea among prescribers is that the second-generation drugs ziprasidone, aripiprazole, and quetiapine are less effective than second-generation drugs Clozapine and Olanzapine, but this is supported only partially by data. It is possible that some of the differences between second-generation drugs stem from the fact that the optimal dose is better known for one drug (e.g. olanzapine) than for the other (e.g. quetiapine), and not to the difference between compounds. All second-generation drugs probably cause less TD, although they are not totally free of TD adverse effects. All of them cause akathisia. It has been suggested that the distinction between the first-generation class of antipsychotics and the second-generation class is only partially based on pharmacological or clinical properties, and mostly on dose optimization. Meta-analyses based on sponsor-initiated trials attribute some advantages to the second-generation drugs in general, and characterize each of them in terms of tolerability and efficacy; however, the studies and analyses have been repeatedly challenged. CATIE, Cutlass, and the EUFEST trials This confusing situation has prompted the US government to sponsor an independent trial, CATIE, comparing 4 second-generation drugs with a representative first-generation drug. Results of the trials show no overwhelming advantage of second-generation over first-generation drugs or of one drug over another within the second generation. Olanzapine has an advantage over the rest of the drugs in efficacy, as measured by survival in the trial and very little EPS, but also a disadvantage in terms of weight gain. Risperidone and perphenazine (the representative of the first generation) follow in terms of efficacy and EPS, with a better metabolic profile than olanzapine. Quitiapine has slightly worst efficacy performance compared to the rest, with a good EPS profile and a metabolic profile which is better than olanzapine and worse than risperidone. Ziprasidone showed a good EPS profile and good metabolic profile (similar to Perphenazine), but unremarkable efficacy. In terms of cognitive performance and negative symptoms, no drug has clear advantages in the planned analysis. Interestingly, in an unplanned analysis perphenazine, the representative of the first-generation drugs has an advantage over the rest of the drugs. Because of design issues, it was not possible to confirm or disprove the advantage of the second-generation drugs in terms of Tardive Dyskinesia. Aripiprazole was not included since it was not available at the planning of the trial. A similar trial, funded by the UK government, CUtlas, showed no difference in terms of efficacy between the tested drugs. A third independently-funded trial, EUFEST, suggested that all second-generation drugs tested were more effective that haloperidol, with olanzapine leading the SGA, but this trial has been criticized for its non-blind design. None of the tested drugs in the publicly funded trials distinguished itself from the rest in terms of cognitive benefits. 244

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While the first generation antipsychotics have profoundly impacted the treatment of schizophrenia, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of schizophrenia. The significant gains in tolerability produced by the second generation antipsychotics have not generally been accompanied by major advances in clinical efficacy. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia, which greatly impact overall morbidity, is needed.

Second-generation antipsychotics as blockbusters

Interestingly, despite the fact that the advantages of SGA over FGA are not overwhelming, they replaced the FGA in most of the markets, achieving blockbuster status shortly after launch. This is probably the result of a combination of factors: the real, albeit small advantages of SGA, wishful thinking on the part of opinion leaders, prescribers, patients, and families, and sophisticated marketing tactics. Interestingly, the drug companies market projections for the second-generation drugs were in the hundreds of millions range, and not, as it turned out, in the billions of dollars range. Risperidone, which was the first to hit the market, and olanzapine, which followed shortly after, were initially perceived by prescribers and opinion leaders as a "clozapine without agranulocitosis (see above on clozapine). Scores of post-marketing trials initiated by the sponsors demonstrated minor but highly publicized advantages in improving cognitive performance and deficit symptoms. However, these advantages have been disproved in independent trials (e.g. Green et al 2003, CATIE, EUFEST) and the sponsors never tried to petition the FDA to add negative symptoms or cognition to the approval language. Most probably the very minor cognitive benefits in the sponsors' trials were due to dosing effects and other features in the trial design. Using excessively high doses of a comparator with sedative effects, taking advantage of the lack of Parkinsonism, and counting manual skills as cognitive functions are some examples explaining the apparent advantage of the SGA in terms of cognitive performance. Furthermore, since the sponsored phase IV trials were not intended for regulatory purposes, researchers allowed themselves to publish multiple post-hoc analyses of each separate cognitive subtest until a few of the tests tested positive. Paradoxically, despite lack of true positive results, cognitive impairment has become a major target for treatment.

Future targets in schizophrenia drug development

Despite continues government and industry commitment, no major breakthrough in the treatment of schizophrenia is expected in the coming decade. There are a number of factors supporting this forecast, ranging from the complexities of brain function and human behavior in general to the fact that no animal model or other experimental model for schizophrenia exists. 245

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Experimental models are either based on in-vitro and in-vivo manipulations of neurotransmitters believed but not proven to be involved in schizophrenia, or on animal behaviors related to adverse effects of antipsychotics rather than efficacy. Moreover, the heterogeneity of schizophrenia and the overlap with other conditions is supported by recent basic science findings. It appears that individuals affected by mental illness in general and by schizophrenia in particular carry multiple genes that confer illness vulnerability in various constellations. These genetic constellations interact with environmental factors, many of them yet unidentified. Even if the path from vulnerability gene to pathophysiology to treatment to drug were discovered (we are many years from it), it would still be necessary to deal with multiple genes and to determine which ones are on that causative path to the illness. Similarly, understanding of the more distal, common pathway of the pathophysiology of schizophrenia at the level of brain circuits and neurotransmission has not advanced to the point that rational drug design is feasible. This is not to say that incremental progress in the treatment of schizophrenia is unlikely or irrelevant. On the contrary, there are currently at least three lines of anti-schizophrenia drug development in different stages of progress. First and closest to market are selective Dopamine D1, D2, D3, and D4 blockers, or D2-HT2 blockers. These are basically attempts at improving the firstand second-generation drugs. These drugs have a good chance of reaching phase III and beyond, but will probably not constitute a major advance. Second is the more innovative direction which focuses on NMDA receptors, and separately on nicotinic receptors. The rational behind the NMDA approach is to treat deficit (negative symptoms) and cognitive impairment, and maybe psychosis, with an NMDA agonist. The approach has a very weak theoretical basis but is scientifically challenging. Third, several compounds, still in the laboratory or in very early clinical development, are being developed even though there's no theoretical basis as to why they should be effective in schizophrenia. The main impetus for developing these compounds is that they bind in vitro to some of the same receptors as some, but not most, antipsychotic drugs (, ). The NMDA hypothesis builds on the observation, made in the late seventies, that ingestion of the street drug phencyclidine (PCP) produced depersonalization and agitation in some individuals. This phenomenon, which mimics a few of the manifestations of schizophrenia, has allowed investigators during the 1980s and 1990s to use phencyclidine and its probe ketamine as a human model of schizophrenia. Also, since the late 1950s, the anesthetic ketamine has been known to induce "emergence reactions" in about half of individuals during the recovery from anesthesia, that resembles some features of schizophrenia. Since the hypothesis was that the psychotropic effects of both PCP and ketamine are exerted through NMDA receptors both are potent noncompetitive NMDA receptor antagonists, interfereing with the calcium flux through the channel - it was further hypothesized that abnormalities in NMDA neurotransmission might be responsible for schizophrenia and that pharmacological interference with NMDA receptors could benefit it. 246

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Albeit challenging, this hypothesis contains several serious weaknesses. First, PCP and its pharmacological probe Ketamine, which are NMDA antagonists, consistently cause anxiety, mild aggression, occasional delirium, and a few other non-specific symptoms in controls and in schizophrenia patients. The core manifestations of schizophrenia are much less consistently induced by PCP or by the probes. Furthermore, the same behavioral manifestations can be induced by PCP and Ketamine via mechanisms which have nothing to do with schizophrenia. Since there is no known biological abnormality in NMDA transmission in schizophrenia, this later possibility is a very viable one. Moreover, several trials attempting to pharmacologically manipulate NMDA neurotransmission, mostly with partial agonists of the glycine type or re-uptake inhibitors, have been disappointing. A possible albeit unlikely explanation for the disappointing results is that the glycine-type compound used in previous trials failed because of poor BBB (blood brain barrier) penetration and other shortcomings related to the drugs brain kinetics. Indeed, several of the big pharmaceutical companies are currently conducting phase I or POC phase II trials of glycine reuptake inhibitors which allegedly have more favorable brain kinetics. However, even if, despite the negative earlier trials, and the meager rationale that this line of research shows that glycine reuptake drugs do have a place in the treatment of schizophrenia, they will be expected to treat mostly negative symptoms since there is no theoretical basis at all to assume that they will benefit psychosis. Hence, they will be used as add-ons to antipsychotics. Over the last few years Ely Lilly has conducted trials with a new family of compounds of the m-Glu (metabotropic glutamate) receptor agonists class. Apparently these compounds also affect NMDA receptors but the mechanism of action is far from clear. Despite some initial positive results the development has been delayed, probably due to AE. Because the likelihood of understanding the pathophysiology of schizophrenia in the foreseeable future is very low, and the need for more effective and better tolerated drugs is so acute, and the market so large, it would apparently make sense to take quasi theoretical approach to drug development. This is exactly what researchers do when they test compounds which protect brain tissue or encourage regeneration. Similarly, compounds that bind to brain receptors like and are currently in preclinical or early clinical trials, but there is no much rationale for it. Because there are no animal models and no human biological markers for schizophrenia, it is essential to bring every such compound to the end of phase II in order to make a go/no go determination. Obviously this is not an efficient and feasible way to develop drugs, particularly when no rationale for it exists in the first place. Three to five new second-generation-like drugs with allegedly broader efficacy and better tolerability are currently in phase II and late phase III. These drugs perform in-vitro similarly to the 247

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second-generation drugs - they affect mainly DA2 and 5HT2 receptors. The best known representatives of this class are: paliperidonea primary active metabolite of risperidone 9 hydroxyrisperidone developed by Janssen Pharmaceutica asenapine, a new 5-HT2A- and D2-receptor antagonist developed by Pfizerand Organon) ; over 3000 patients have participated in clinical trials of asenapine, and the FDA accepted the manufacturer's NDA (new drug approval) on November 26, 2007 for standard review; bifeprunox, a partial agonists at D2 receptors and agonist of 5-HT1A receptors developed by Solveyand Lundbeck. In summary, a review of drugs in early development indicates that the competition for the next decade and beyond will not be among drugs based on an understanding of the disease or other revolutionary concepts, but rather between drugs which constitute an incremental progress over previous generations.

The future of cognitive impairment treatment in schizophrenia

The relationship between impaired cognitive functioning and poor functioning is a major factor behind recent efforts to stimulate the development of cognitive-enhancing agents. Though in the end second-generation antipsychotics turned out not to benefit cognition, the interest in cognition, raised by the sponsors' marketing efforts, has left the academic community and the sponsors committed to cognition as a target for treatment. In 2002, the NIH set up a partnership between industry and academia to study the possibility of treating cognitive impairment in schizophrenia. However, despite massive investments from the government and commitment from the academic community, this effort produced only an assessment scale for cognitive impairment, to be used in future trials, but no treatments. A number of investigators, with or without industry support, are currently engaged in trials targeting cognitive impairment. Based on preliminary electrophysiological data in schizophrenic patients, and on the fact that nicotine improves attention in general, current trials have focused on a nicotinic receptor subtype. Preliminary results are not encouraging. Another line of research is based on drugs known to improve cognition in Alzheimers patients, such as cholinergic drugs, or presumed to improve cognition in Alzheimers patients, such as ampakines, a new class of compounds known to enhance attention span and alertness, and to facilitate learning and memory. The ampakines take their name from the glutamatergic AMPA receptor with which they strongly interact. Although data clearly indicate that there is nothing in common between the cognitive impairment in Alzheimers and schizophrenia, this research is based on the hope that the drugs have a non-specific pro-cognitive effect. However, even if these attempts were successful, the drugs will not treat the psychotic symptoms. Moreover, cognitive impairment in schizophrenia might not be related to the psychotic illness at all, but is probably part of the basic constituency and genetic make-up of the 248

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affected individual. Data indicate that many years before these individuals manifest psychosis and are diagnosed with schizophrenia, they suffer from mild cognitive impairment. Hence, in a way the expectation to improve cognitive impairment in schizophrenia would be like attempting to raise intelligence in borderline mental retardation individuals. This might be possible in the future but cannot be viewed as part of antipsychotic treatment. A more realistic goal would be to devise antipsychotic drugs, free of adverse effects, which would not interfere with cognitive performance, as currently available drugs probably do. In summary, the uncertainty regarding the advantage of the second-generation antipsychotics over the first-generation ones is mounting. Because of the disappointment with this class of drugs and because most of them are becoming generic, their existence is not going to impact on the acceptance of future drugs, particularly if they offer a new mechanism of action. What might impact acceptance is the skepticism caused by that disappointment and the increasing sophistication in assessing the efficacy of new drugs, which has been lately achieved by prescribers. Hence it is unlikely that any future drug in schizophrenia would achieve overnight blockbuster status, as risperidone or olanzapine had done more than a decade ago. On the other hand, the minimal impact that recent trials had on prescribing practices indicates that in a devastating disease such as schizophrenia, with such a limited therapeutic arsenal, prescribers will hang on to any real or perceived advantage, regardless of cost, and that payers will acquiesce to it. This indicates that future drugs with real albeit small advantages have the potential to capture a considerable market share without being blockbusters. If cognition in schizophrenia can be improved, it will be with the help of an add-on drug and not necessarily as part of the antipsychotic drug treatment. New action mechanisms will be a major advantage for a new drug.

Overview of the clinical development plan

Usual Phase I programs with D2 blocking compounds tend to focus, in addition to the usual safety parameters, on movement abnormalities such as tremor, rigidity, akathesia, and involuntary movements. Cognitive functioning might already be assessed already in phase I. Simple cognitive tests measuring attention, memory, and markers such as auditory evoked potentials and continuous performance test are probably the best candidates. The design of the trials should probably be ascending, single dose, and double-blind placebo controlled, with pharmacokinetics. A number of considerations arise as to whether phase I trials should be conducted in patients with schizophrenia or in healthy controls. Patients with schizophrenia who have been exposed to antipsychotic drugs tend to tolerated higher doses of antipsychotics, both in terms of movement abnormalities (tremor, rigidity, akathisia, involuntary movements) and in terms of sedation, compared to controls. Theoretically, from the 249

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tolerability point of view, trials in patients are preferred. However, since patients will have to be washed-out of previous drugs without apparent benefit from the new drug (since they get a single dose), this might not be feasible for ethical reasons. Probably 2-4 cohorts each of 9-12 subjects should be included. Unfortunately, single dose trials in healthy controls provide only partial information about tolerability. First, there are differences in tolerability between patients and controls. Second, when multiple doses (e.g. six-week trials) are given, there is drug accumulation on the one hand and tolerability on the other hand. Therefore, it is probably necessary to first conduct a maximum tolerated dose (phase II-A) trial in chronic stable schizophrenic patients. It should consist of 2 or 3 sequentially dose-ascending cohorts, each comprised of about 20-25 patients treated for 4 weeks. Despite the obvious shortcomings, there are some advantages to conducting maximum tolerated dose trials in an open-label manner. When looking for obvious and objective signs of tolerability and safety, the open label shortcomings might be overcome. Furthermore, the open design may facilitate and expedite the trial and help clinically in observing AEs. To take full advantage of such a trial it might be advisable to conduct in some of the patients pre-pulse inhibition and evoked potential studies (at baseline off drug and again at the end of the trial) to asses the drug potential to benefit cognition. The phase II-B (Proof of Concept POC) trials should be conducted in acutely exacerbated schizophrenic patients (PANSS over 70 with a minimum score on psychosis items and limited chronicity). These are the only patients who have the potential to show symptoms improvement. It should consist of 2-3 doses of the experimental compound, placebo, and active control (e.g. risperidone 3-6 mg, olanzapine 15-20 mg) and last for 6 weeks. Each arm should include about 80 patients and the primary outcome measurements should be the score on total PANSS and CGI. To this secondary, exploratory measurements can be added. An optional open-label or blind cross-over continuation trial of several months is generally part of the design. It is not unusual for data obtained in phase II POC to be used as a pivotal trial, hence one, or at the most two trials might be sufficient. Regardless, the pivotal trials must show antipsychotic efficacy, compared to placebo in acutely exacerbated patients treated for 4-6 weeks, as well as longterm (6-12 months) maintenance of remission. Hence, a separate maintenance trial is necessary. In terms of design and N there is not much difference between phase II-B and Phase III trials. A large number of trials are currently underway mostly funded by the large pharmaceutical companies but some also by non-for profit and for profit foundations. Some are trying to develop drugs based on know mechanisms which are better tolerated than currently available drugs. Others are exploring new mechanism of actions such as neuroprotection (BDNF) neurosteroids and attempts to affect second messengers. However this later efforts are handicapped by the lack of progress in understanding the pathphysiology of psychosis and schizophrenia leading some to explore a-theoretical models for the treatment of this disease. 250

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Romanian Journal of Psychopharmacology (2008) 8, 254-264

QUETIAPINE FUMARATE IN PRACTICE EVALUATION PROGRAMME

Cristinel Stefanescu1, Beatrice Costea2 1 U.M.F. Gr. T. Popa Iasi 2 Medical Affairs Advisor CNS/GITA, AstraZeneca Romania

Abstract Aim of the study An observational non-interventional study evaluating the severity and evolution of symptoms in schizophrenia based on the BPRS (Brief Psychiatry Rating Scale) and CGI (Clinical Global Impression) during treatment with quetiapine fumarate in usual clinical practice. Objectives Primary objectives To assess at baseline and after treatment administration the severity of the illness in patients with schizophrenia, using the scores obtained after the application of the CGI scale To assess the changes in symptoms of patients treated with quetiapine for 24 weeks, using BPRS (Brief Psychiatry Rating Scale) as an assessment tool Secondary objectives To assess use of medication and patient compliance with treatment. Study design Observational non-interventional study involving 122 centers in Romania. The study enrolled 1387 patients (both men and women), over 18 years of age, newly diagnosed or with a recorded diagnosis of schizophrenia, irrespective of its clinical form, in accordance with the DSM VI criteria. Method The patients received quetiapine treatment in doses ranging between 400 and 750 mg/d, for 24 weeks, starting with a titration period; they were assessed on 6 visits, in accordance with usual clinical practice. Results The 1387 patients enrolled in the study had been diagnosed with different forms of schizophrenia, while the mean age of the patients was 39 years. At the end of the 24 weeks quetiapine treatment, the mean BPRS score reached 16.96 as compared to 45.02 at the beginning of the program. The severity of the illness assessed based on the CGI scale decreased considerably during the study in the majority of the assessed patients. At the beginning of the study, 92.4% of the antipsychotic-naive patients and approximately 95.7% of the patients previously treated with antipsychotics had moderate to very severe illness (CGI-S score>4). At the end of the study, 76.3% of the antipsychotic-naive patients and 78.4% of the patients who had previously received antipsychotics had a mild degree of illness, were
1

Correspondence: Cristinel Stefanescu. Tel.: +40 744 518195; e-mail: cristinel.stefanescu@gmail.com.

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minimally ill or were clinically normal (CGI score <3). The decrease in the disease severity was similar in the two patient groups whether previously treated or not. The Clinical Global Impression Improvement Score (CGI-I) progressed favourably in over 95% of the assessed patients. Quetiapine administration led to the obvious improvement of the clinical condition supported by the decrease of the BPRS and CGI score recorded on the 6 visits of the protocol. The comparative analysis of the BPRS scores in the two groups of naive and previously treated patients showed that patients who had not received prior treatment had significantly lower scores after 5 months (p=0.013) and 6 months respectively (p=0.002) of Quetiapine treatment. The data shows that although in the beginning symptoms were more severe at naive patients comparing to the previously treated patients (significantly higher BPRS score, p=0.002) the treatment benefit was significantly more important after 5 months of treatment. The improvement in symptoms recorded at the end of the study accompanied the adjustments of the daily dose performed every month. Conclusion This study shows Quetiapine efficacy in patients with schizophrenia-related disorders. At the same time, it is a well-tolerated antipsychotic medication. These factors predict a favourable prognosis and good evolution of the disorder, preventing the occurrence of subsequent relapse.

Introduction
The efficient control of schizophrenia symptoms is vital in the long-term treatment of schizophrenia patients. Quetiapine fumarate is an atypical antipsychotic drug featuring a clozapine-like activity profile and a low potential for extrapyramidal symptoms (EPS). Quetiapine is rapidly absorbed after oral administration and binds to serotonin and dopamine receptors at clinically efficient levels for at least 12 hours (Gefvert et al 1998). Clinical data indicate that a clinical dose between 300-450 mg is suitable for the majority of schizophrenia patients, although it may be adjusted between 150-175 mg/d based on clinical response and tolerability. In schizophrenia patients quetiapine proved to be efficient in treating positive symptoms (Small et al 1997), negative symptoms (Arvanitis et al 1997, Borison et al 1996, Small et al 1997), cognitive symptoms (Purdon et al 1999, Velligan et al 1999) and affective symptoms (Hellewell et al 1998). Clinical practice and subsequent studies showed that a dose of 600 mg/d helps control symptoms in the majority of adults (Emsley et al 2000, De Nayer et al 2003, Zhong et al 2003, Knegtering et al 2004, Riedel et al 2004, Sirota et al 2004, Keks et al 2004, Mavreas et al 2004, Kopala et al 2004). It was also shown that Quetiapine is at least as efficient as typical antipsychotics (Copolov et al 2000, Kasper and Muller-Spahn 2000, Emsley et al 2000) although Quetiapine is more efficient than haloperidol in the improvement of negative symptoms 255

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(ESTO trial, AstraZeneca data on file) and prompted a higher response rate as compared with chlorpromazine (Peuskens and Link 1997). Moreover, Quetiapine is at least as efficient as risperidone (Mullen et al 1999) and shows a clinical profile suggesting an antipsychotic efficiency at least similar to olanzapine. Quetiapine is also well tolerated. In clinical studies, the percentage of patients who discontinued treatment due to side effects amounted to 5.4%, significantly lower than with haloperidol (11.3%), clorpromazine (11,2%) and risperidone (11.5%) (AstraZeneca data on file). The appearance of EPS associated to Quetiapine treatment is not higher than with placebo (Arvanitis et al 1997) and is significantly lower than with haloperidol (Copolov et al 2000) and chlorpromazine treatment (Peuskens and Link 1997). Moreover, unlike risperidone and olanzapine, an increased dose of Quetiapine does not produce an increased rate of EPS (Arvanitis et al 1997), a characteristic only featured by clozapine. At the same time, an increased dose of Quetiapine is not accompanied by high levels of prolactin (Arvanitis et al 1997); instead, there were reductions of initially high plasma prolactin levels due to previous treatment with other antipsychotics (Peuskens and Link 1997, Emsley et al 2000, Copolov et al 2000). The potential risk of weight gain after the Quetiapine treatment (Jones et al 2000, Westhead et al 2000) is substantially reduced as compared to olanzapine or clozapine treatment. The minimal cardiovascular effects determined by Quetiapine prompted the conclusion that blood monitoring, blood pressure measurements and routine ECG are unnecessary. Currently, in Romania there are no data on the severity of the disease (assessed based on the CGI scale) in schizophrenia patients treated with antipsychotics and no analysis of the changes of CGI scores during Quetiapine treatment. Similarly, although the BPRS scale is used in daily practice, no data has been published regarding changes in BPRS scores during Quetiapine treatment.

Design and Method

This non-interventional study was conducted in 122 Romanian centers; the subjects enrolled were patients with a recorded diagnosis of schizophrenia in which the specialist decided either initiation of Quetiapine treatment (in newly diagnosed patients) or switching from previous treatment and Quetiapine administration. The study protocol and the informed consent form were sent for notification to the National Drugs Agency, according to current regulations. All visits in this observational, non-interventional study were conducted according to current practice. On the first visit, the patients were enrolled in the study after signing the informed consent providing access to their personal information; psychiatric examination, a brief physical examination were performed, while vitals, height and weight, previous antipsychotic medication, concomitant drug administration (anticholinergic included), adverse reactions to treatment and BPRS/CGI scores 256

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(severity) were recorded. Subsequent visits followed the changes of symptoms; BPRS/CGI scores (severity/improvement), weight and concomitant medication were recorded. The physicians recorded the adverse reactions spontaneously reported during the treatment according to current procedure in clinical practice. For newly diagnosed patients in which the physician decided the initiation of Quetiapine treatment, it underwent titration according to the approved SPC, while in patients previously treated with antipsychotics who were switched to the new therapy, Quetiapine titration was performed concomitantly with the withdrawal of the previously administered antipsychotic. This titration procedure was conducted during up to 7 days, followed by 5 weeks of Quetiapine flexible dosing based on the individual clinical response. Subsequently, the specialist was able to perform additional adjustments observing the approved maximum dose of 750 mg/d divided in 2 intakes.

Study population
Eligible patients were men and women over 18 years of age, with an established diagnosis of schizophrenia in which the specialist physician had decided to initiate Quetiapine treatment irrespective of this program. The patients who had previously signed the informed consent providing access to their information were enrolled.

Assessments
History and a physical examination were performed upon inclusion in the study. Previous antipsychotic medication and adverse reactions to treatment were particularly recorded. The physical examination included also recording of height, weight, blood pressure and pulse. Psychiatric evaluation included psychiatric interview and recording BPRS and CGI scores. On the other visits, the BPRS and CGI scores were recorded based on psychiatric examination.

Efficacy variables
The indicators of drug efficacy used in the study were improvement of the clinical global impression disease severity (CGI-S) and of the BPRS score as compared to baseline, as well as the favourable changes of the clinical global impression improvement (CGI-I). At the same time, patient compliance with Quetiapine treatment was also analysed.

Safety and tolerability

The study protocol provided that the physicians are responsible with recording adverse events reported spontaneously during the course of the treatment according to current procedures in routine clinical practice.

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Statistical analysis
In this observational study of usual clinical practice, on a drug whose efficacy and safety were shown in prospective, comparative studies performed on relevant groups of patients, only a descriptive statistical analysis was conducted (e.g. ANOVA test, Student T-test).

Results
Baseline characteristics of study population This study enrolled 1387 patients, with a mean age of 39 and a median of 38 years. The patients were uniformly distributed in the study groups based on sex and age. These patients were diagnosed with different forms of schizophrenia and schizophrenia-related disorders. Upon entry it was remarked that 335 patients had a medical history, 143 males (42.7%) and 192 females (57.3%). As far as psychiatric history is concerned, a slight predominance of the females was also noted. Out of the 516 patients with psychiatric history, 284 were females (55.0%) and 232 were males (45.9%). Due to lack of records, the percentage of patients using typical and atypical antipsychotics is not known in previously treated patients. The mean weight of patients enrolled in the study was 71.59 kg. Treatment regimens The mean doses of Quetiapine administered during the 6 study visits were: first dose 516.36 mg, dose 2 591.02 mg, dose 3 612.76 mg, dose 4 618.43 mg, dose 5 620.12 and dose 6 616.81 mg, therefore a mean dose increase was necessary between the first and the sixth visit (V 6). Since no data were recorded, an analysis of the secondary objective, adherence with treatment was not conducted. Minimal, medium and maximum dosage are shown in Fig. no. 1.
2000 1500 1000 500 0
min mean max

min mean max

doza 1 25 516,36 1200

doza 2 100 591,02 1200

doza 3 100 612,76 1200

doza 4 50 618,43 1600

doza 5 100 620,12 1600

doza 6 100 616,81 1600

Fig. no. 1. Used Quetiapine doses

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Efficacy During the study, the illness severity assessed on the basis of the CGI-S scale decreased considerably in the majority of the evaluated patients. At the beginning of the study, 92.4% of the antipsychotic-naive patients and 95.7% respectively of the patients previously treated with antipsychotics had moderate to severe illness (CGI-S score > 4). At the end of the study 76.3% of the antipsychotic-naive patients and 78.4% respectively of the patients previously treated with antipsychotics had only mild disease, were minimally ill or were clinically normal (CGI -S score <3) (Fig. no. 2 & 3).

100% 80% 60% 40% 20% 0% 1

normal, not ill (1) markedly ill (5)

2
minimally ill (2) severely ill (6)

4
mildly ill (3) very severely ill (7)

6
moderately ill (4)

Fig. no. 2. Clinical global impression CGI-severity in antipsychotic treatment-naive patients

100% 80% 60% 40% 20% 0% 1

normal,not ill (1) markedly ill (5)

2
minimally ill (2) severely ill (6)

4
mildly ill (3) very severely ill (7)

6
moderately ill (4)

Fig. no. 3. Clinical global impression CGI-severity in patients previously treated with antipsychotics

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The reduction in the disease severity was similar in the two groups of previously treated or nave patients. The Clinical Global Impression-Improvement score (CGI-I) had a favourable evolution in over 95% of the assessed patients. One month after the beginning of the study, 84.3% of the nave patients and 78.9% of the previously treated patients showed improvement of symptoms in the range of minimum up to a maximum (CGI I score <3), percentage which increased to 96.2% and 96.4% respectively after 24 weeks Quetiapine treatment (Fig. no. 4 & 5).

100% 80% 60% 40% 20% 0% 2

very much improved (1) minimally worse (5)

3
much improved (2) much worse (6)

4
very much worse (7)

6
no change (4)

minimally improved (3)

Fig. no 4. Clinical global impression improvement (CGI-I) in antipsychotic treatment-naive patients

100% 80% 60% 40% 20% 0% 2

very much improved (1) minimally worse (5)

3
much improved (2) much worse (6)

6
no change (4)

minimally improved (3) very much worse (7)

Fig. no. 5. Clinical global impression improvement (CGI-I) in patients previously treated with antipsychotics

The changes of BPRS over time, as tool for the assessment of the therapy efficacy, showed a clear improvement, demonstrated by the decrease of the score on the 6 visits. At V 1, the mean score was 45.02, at V2 36.02, at V3 29.02, at V4 23.67, at V5 19.87 and at V6 16.96. 260

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Treatment efficacy is also supported by the evolution of the maximum scores on the BPRS scale noted at each visit. At V1 the maximum score was 98 points, then at V2 96, at V3 90, at V4 86, at V5 80 and at V6 76 points (Fig. no. 6). A parallel analysis of the patients' scores was conducted, as they were divided in two groups based on whether they were previously treated with antipsychotics or not.
120 100 80 60 40 20 0
min mean max mom 1 3 45,02 98 mom 2 2 36,62 96 mom 3 1 29,02 90 mom 4 0 23,67 86 mom 5 0 19,87 80 mom 6 0 16,96 76

min mean max

Fig. no. 6. BPRS evolution at the 6 moments of the study

The favourable evolution was recorded both in antipsychotic treatment-naive patients and in previously treated patients. As seen in Fig. no. 7, at V1 the BPRS scores recorded in treatment-naive patients ranged between 7 and 84 (average 47.1), at V2 between 2 and 82 (average 37.84), at V3 between 2 and 70 ( average 28.81), at V4 between 0 and 52 ( average 22.71), at V5 between 0 and 55 ( average 18.54), and at V6 between 0 and 52 ( average 15.42).
90 80 70 60 50 40 30 20 10 0
min mean max

min mean max

mom 1 7 47,1 84

mom 2 2 37,84 82

mom 3 2 28,81 70

mom 4 0 22,71 52

mom 5 0 18,54 55

mom 6 0 15,42 52

Fig. no. 7. BPRS evolution at the 6 moments of the study antipsychotic treatment-naive patients

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In patients previously treated with antipsychotics the evolution of scores ranged as follows: at V1 the BPRS scores varied between 3 and 98 (average 44.19), at V2 between 3 and 96 (average 36.13), at V3 between 1 and 90 (average 29.1), at V4 between 0 and 86 (average 24.05), at V5 between 0 and 80 ( average 20.41), and at V6 between 0 and 76 ( average 17.58) (Fig. no. 8).
120 100 80 60 40 20 0
min mean max mom 1 3 44,19 98 mom 2 3 36,13 96 mom 3 1 29,1 90 mom 4 0 24,05 86 mom 5 0 20,41 80 mom 6 0 17,58 76

min mean max

Fig. no. 8. BPRS evolution at the 6 moments of the study patients previously treated with antipsychotics Following the statistical analysis of data, a significant difference in the decreasing of BPRS scores from one visit to another was noted in both groups of patients, treatment naive and previously treated (Student T-test, p=0.001). The comparative analysis of BPRS scores between the two groups showed that treatment-naive patients had significantly lower scores after 5 months (p= 0.013 ANOVA test) and previously treated patients after 6 months (p=0.002 test ANOVA) of Quetiapine treatment. This shows that although their symptoms were initially worse as compared to patients who already received medication (significantly higher BPRS score, p=0.002 ANOVA test) the therapeutic benefit was significantly more important after 5 months of treatment. No differences were noted in changes of BPRS score in men as compared to women except for the assessment conducted after 4 months of Quetiapine treatment when a statistically significant lower score was recorded in men than in women (p=0.05, ANOVA test). Scores changes on CGI-S and CGI-I scales emphasize the arguments supporting Quetiapine efficacy provided by the analysis of the BPRS scores. A clinical, gradual improvement, marked by significant differences between the consecutive visits was noted, which is a positive landmark and proof of Quetiapine efficacy in the treatment of schizophrenia-related psychiatric disorders. Safety and Tolerability No adverse events to impact upon the compliance or safety of patients were recorded during the study. No patient discontinued the study due to adverse events. A conclusion regarding weight variations during the treatment cannot be formulated due to lack of records. 262

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Discussions
This study shows that Quetiapine, administered in daily dosage of 400-750 mg, twice/day is efficient in the treatment of schizophrenia-related psychotic disorders. A gradual decrease in the BPRS score was noted as objective indicator of the clinical severity. In other words, the intensity of subjects' symptoms decreased or even went into remission. This positive development was recorded in all patients whether treated with antipsychotics before enrolment or not. The results obtained on the assessment of the clinical global impression are consistent with the evolutive trend of BPRS scores, while a big difference was noted between the severity of the disorder at baseline as compared to the end of the study (V6) and a constant favourable evolution of the improvement in the clinical global impression persisted over the entire duration of the study (CGI-I). There were no adverse events or other incidents to determine early discontinuation from the study, aspects which support good safety and tolerability, predictors of patient compliance. The data recorded is consistent with the literature data, which describe and show efficacy as well as good safety and tolerability of Quetiapine in these patients.

Conclusions
This study shows Quetiapine efficacy in patients with schizophrenia-related disorders. At the same time, it is a well-tolerated antipsychotic drug. These factors predict a favourable prognosis and good evolution of the disorder, preventing the occurrence of subsequent relapse.

References
1. Arvanitis LA, Miller BG and the Seroquel Trial 13 Study Group. Multiple fixed doses of Seroquel (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997;42:233-246. 2. Borison RL, Arvanitis LA, Miller BG. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. US Seroquel Study Group. J Clin Psychopharmacol 1996;16:158-169. 3. Copolov DL, Link CGG, Kowalcyk B. A multicentre, double-blind, randomized comparison of quetiapine (ICI 204,636, Seroquel) and haloperidol in schizophrenia. Psychol Med 2000;30:95-106. 4. Emsley RA, Raniwalla J, Bailey PJ et al. A comparison of the effects of quetiapine (Seroquel) and haloperidol in schizophrenic patients with a history and a demonstrated partial response to conventional antipsychotic therapy. Int Clin Psychopharmacol 2000;15(3):121-131. 263

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5. Gefvert O, Bergstrm M, Lngstrm B, et al. Time course of central nervous dopamineD2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology 1998; 135:119-126. 6. Hellewell JSE, Kalali AH, Langham SG et al. Patient satisfaction and acceptability of long-term treatment with quetiapine. In J Psych Clin Pract 1999;3:105-113. 7. Hellewell J, McKellar M, Raniwalla J. Seroquel: efficacy in aggression, hostility and low mood of schizophrenia. Abstract presented at the CINP Congress 1998, Glasgow, UK. 8. Jones AM, Rak IW, Raniwalla J et al. Weight changes in patients treated with Seroquel (quetiapine). Schizophrenia Res 2000;41:206 and poster presented at Winter Workshop 2000, Davos, Switzerland. 9. Kasper S, Muller-Spahn F. Review of quetiapine and its clinical applications in schizophrenia. Exp Opin Pharmacotherapy 2000;1:783-801. 10. Mullen J, Reinstein M, Bari M et al. Quetiapine and risperidone in outpatients with psychotic disorders: results of the QUEST trial. Presented at the12th ECNP Congress 1999, London, UK. 11. Peuskens J, Link CGG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997;96:265-273. 12. Purdon S, Malla A, Labelle A et al. Long-term treatment with quetiapine improves cognitive function in schizophrenia: a double-blind study. Presented at the ACNP Annual Meeting 1999, Acapulco, Mexico. 13. Small JG, Hirsch SR, Arvanitis LA et al. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry 1997; 54:549-557. 14. Velligan DI, Newcomer J, Pultz J et al. Changes in cognitive functioning with quetiapine fumarate versus haloperidol. Poster presented at the ACNP Annual Meeting 1999, Acapulco, Mexico. 15. Westhead EK et al. Long term effect of quetiapine on weight in patients with schizophrenia receiving no concomitant antipsychotic medication. Int J Neuropsychopharmacol 2000; 3(1): S147 and poster presentation P.01.206.

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RECENT DRUGS DEVELOPED IN UNIPOLAR DEPRESSION

Michel Bourin1, Corina Prica1,2 1 Neurobiology of Anxiety and Depression, Faculty of Medicine Nantes, France 2 Dept. of Animal Physiology and Biophysics, Faculty of Biology, Bucharest, Romania

Abstract There is a need for new antidepressants in the treatment of unipolar depression for several reasons: a third of the unipolar patients do not respond to the antidepressants, it takes 3 weeks to improve the patients and the treatment has some side effects depending of the patients. We provide a report on duloxetine and agomelatine, two new antidepressants, in the treatment of unipolar depression, one of them seems to have a new mechanism of action. Key words: agomelatine, duloxetine, unipolar depression.

Abbreviations: SSRIs, serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; SERT serotonin reuptake transporters; NET, norepinephrine reuptake transporters; 5-HT, 5-hydroxytryptamine; NE, norepinephrine; MDD, major depressive disorder; DA, dopamine; NA, noradrenalin; acid; HAMD, Hamilton Rating Scale for depression; MADRS, Montgomery-Asberg Depression Rating Scale; CGIS, Clinical Global Impression Scale for Severity; GBR, global benefit-risk; MAOs, monoamine oxidase.

Introduction
Given the enormous impact of depression upon both the individual patient and the healthcare system as a whole, the need for effective treatment is clear. There is still a need for new drugs in treatment for unipolar depression, so in the few last years there are two antidepressants developed in unipolar depression: duloxetine and agomelatine. The first one shows the same profile from the previous antidepressant venlafaxine as a reuptake inhibitor of both serotonin and norepinephrine. Agomelatine seams to have a new profile, it is an antagonist of the melatonin MT1 and MT2 receptors and is a partial agonist of 5-HT2C receptors. Our review of new antidepressants will be focused on both of these products.
1

Correspondence: Michel Bourin, Neurobiology of Anxiety and Depression, Faculty of Medicine, BP 53508, 44035 Nantes Cedex 1, France. Tel: +33 240412853; Fax: + 33 240412856; E-mail: michel.bourin@ univ-nantes.fr

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Duloxetine
Antidepressant medications, in particular the selective serotonin reuptake inhibitors (SSRIs), currently represent the first line of treatment for major depressive disorder (MDD). SSRIs attained clinical acceptance over tricyclic antidepressants (TCAs) in part due to their improved tolerability profile, including lower rates of anticholinergic events, orthostatic hypotension, sedation, and lower toxicity in overdose [1,2]. [4]. However, SSRIs have not demonstrated superior efficacy when The compared with TCAs [3], and up to half of all depressed patients fail to respond to SSRI therapy Thus, the need for alternative safe and effective treatments for MDD is clear. antidepressant duloxetine is a dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) [5], but lacks significant affinity for muscarinic, histaminergic, adrenergic, dopaminergic, serotonergic, and opioid receptors [6]. Previous double-blind, placebo-controlled studies have established the safety and efficacy of duloxetine in the treatment of MDD [7-12] The efficacy of duloxetine in the treatment of depression is thought to be mediated by inhibition of the neuronal reuptake of 5-HT and NE. Preclinical studies in animal models have established duloxetine's effects on monoamine concentrations, [13], and the results of in vitro studies using preparations of animal and human monoamine transporters showed duloxetine to have high affinity for both the 5-HT and NE reuptake transporters (SERT and NET, respectively). In vivo data in human subjects support duloxetine's dual-monoamine mechanism of action) [14, 15]. Using in vitro preparations of human monoamine transporters, Bymaster et al (2001) [16], is found that duloxetine displayed high-affinity, dose-dependent binding to the SERT and NET. Duloxetine is a balanced and potent reuptake inhibitor of both 5-HT and NE, and lacks significant affinity for other receptors [6]. The safety and efficacy of duloxetine in the acute treatment of MDD have been established in double-blind, placebo-controlled studies [7, 8, 9, 12]. It was proposed that the relatively high probabilities of remission observed in these studies (ranging from 43% to 57%) may result from duloxetines efficacy in both emotional and physical symptom domains. Moreover, results from a 52-week open-label study indicated that duloxetine was efficacious, safe, and well tolerated in the long-term treatment of MDD [17]. Selecting an appropriate dose of medication for a patient requires detailed knowledge of efficacy and safety data, which can usually be obtained from the prescribing information provided with the drug. However, data are frequently pooled across a wide dose range, including all doses studied during the course of regulatory registration trials. Such is the case for the antidepressant duloxetine, a dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) [5, 6]. The package insert summarizes data, much of it published, [7-12, 18] across the studied dose range from 20 mg twice daily (BID) to 60 mg BID, for total daily doses of 40120 mg/day. However, the United States Food and Drug Administration (FDA) approved dose range for duloxetine in the 266

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treatment of major depressive disorder (MDD) is 4060 mg/day. Further, as is often the case in registration clinical trials, the primary outcome measure was the mean change in the 17-item Hamilton Rating Scale for Depression (HAMD17) total score. While this outcome is utilized by regulatory agencies to establish superiority of a drug over placebo, it does not always provide the physician with all of the clinically relevant information regarding treatment outcomes. Duloxetine is approved at two specific doses for the treatment of MDD (40 and 60 mg/day), in order to assist the physician in making an informed dosage choice. Duloxetine demonstrated significant superiority to placebo on the primary efficacy outcome, mean change in HAMD17 total score, in both studies of duloxetine 60 mg once daily and in one of the two studies of 20 mg BID dosing. Categorical changes in HAMD 17 scores can be used to classify patients into meaningful patterns of clinical change, including response and remission. The endpoint probabilities of response and remission among patients receiving duloxetine 60 mg QD (pooled data) were 62.8% and 42.9%, respectively, while the corresponding probabilities at the 40 mg daily dose were 37.3% and 31.2%. These differences may be dose-dependent or related to the differing treatment periods for the 40 and 60 mg studies (8 weeks vs. 9 weeks, respectively). The proportions of patients achieving response and remission at endpoint in the present analyses are similar to those reported in previous studies of pooled data across different classes of antidepressant medications [2, 19]. These results from four double-blind, placebo-controlled studies suggest that duloxetine provides safe and effective acute phase treatment of MDD at doses of 4060 mg/day. Compared with placebo, the 60 mg QD dose was more consistently effective than the 20 mg BID dose. However, the incidence of certain treatment-emergent adverse events may be lower at the 40 mg dose [20]. Another report compares duloxetine with venlafaxine in patients with MDD. In order to evaluate the two therapies from efficacy and safety perspectives in a consolidated manner, the global benefitrisk (GBR) assessment was chosen as the primary outcome measure. This methodology has been used previously for comparisons of venlafaxine with SSRIs and placebo [21, 22]. The primary objective of the studies was to compare the GBR profiles of duloxetine 60 mg/day and venlafaxine extended release (venlafaxine) 150 mg/day (75 mg for 2 weeks) after 6 weeks of treatment in patients with MDD. Data from these studies indicate that duloxetine 60 mg/ day and venlafaxine 150 mg/day have similar GBR profiles for the treatment of patients with MDD during 6 weeks of double-blind therapy. Treatment for six additional weeks including upward dose adjustment if clinically indicated resulted in a similar outcome. From an efficacy perspective, the 60 mg/day dose of duloxetine and the 150 mg/day dose of venlafaxine were similar, with no significant differences observed between duloxetine and venlafaxine at these doses as measured by improvement on the HAMD17 total score over 6 weeks 267

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of treatment, remission rates, response rates, and secondary efficacy measures. Again, extension of double-blind therapy and upward titration of study medications did not result in significant differences between treatments, and the onset of efficacy based on AMD-defined response and remission criteria was similar for both treatments over the 12 week treatment period. The GBR assessment suggests that duloxetine 60 mg/day and venlafaxine 150 mg/day have a similar benefitrisk profile when treating patients with MDD for up to 12 weeks. Secondary efficacy measures also demonstrated little difference between the two drugs including response and remission rates. Duloxetine 60 mg/day was associated with more nausea and dizziness than venlafaxine during the first 6 weeks of the study, and the rate of discontinuation due to an adverse event was significantly higher in the duloxetine group than the venlafaxine group during both 6 weeks and 12 weeks of treatment. On the other hand, venlafaxine-treated patients experienced significantly more symptoms on discontinuation of treatment during the taper period. Additional head to head studies, including trials of longer duration, are warranted to determine if patients with MDD might have a better benefitrisk profile with one drug compared to the other [23]. Another study was not, by itself, specifically designed or powered to facilitate head-to-head comparisons of efficacy between paroxetine (20 mg QD) and duloxetine (80 or 120 mg/day) [24]. Patients treated with duloxetine at doses of 80 or 120 mg/day had significantly greater improvement on the primary efficacy measure (HAMD17 total score) compared with placebo following acute (8 weeks) treatment. Significantly greater improvements, compared with placebo, were also observed for duloxetine-treated patients on MADRS, HAMA, CGI-S, and PGI-I scales, in addition to four of the HAMD17 subscales. Together with results from previous studies, these findings support the efficacy of duloxetine in the acute treatment of MDD at doses of 60120 mg/day [7-9]. Remission, as opposed to partial remission with residual symptomatology or response, is emerging as the new standard in the treatment of depression [25, 26]. Patients with partial remission not only suffer from residual depressive symptoms but may have an increased risk of relapse compared with those patients in full remission [27, 28]. In the present study, 8 weeks of treatment with duloxetine (80 or 120 mg/day) resulted in significantly higher probability of remission at endpoint compared with placebo. Estimated probabilities of remission for duloxetine 80 mg/day (51%) and 120 mg/day (58%) are similar to those reported previously for patients receiving these doses of duloxetine [9]. The estimated probability of remission for paroxetine (20 mg once daily ) in this study (47%) was higher than that observed in a previous acute trial, in which the estimated probability of remission for paroxetine 20 mg QD was 34% [9]. The probability of remission observed for paroxetine in the present study was slightly, although not significantly, lower than that observed with either duloxetine dose, consistent with a 268

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previous study in which the probability of remission was significantly greater for duloxetine (80 mg/day) compared with paroxetine (Goldstein et al., 2002) [9]. Although the present study was not specifically designed or powered for comparisons between duloxetine and paroxetine, the results support previous investigations suggesting the superiority of dual reuptake inhibitors over SSRIs in inducing remission in patients with MDD [2, 3, 19, 29-32]. In the present study, duloxetine, was shown to be effective in the acute and long-term (6 months) treatment of MDD at doses of 80 and 120 mg/day. The results are supportive of findings obtained in previous acute, double-blind, placebo-controlled trials, at doses from 60120 mg/day, and demonstrate that duloxetine induces remission in a substantial proportion of patients [7-9, 12]. Furthermore, the results support those obtained from a 52-week open-label study regarding longterm maintenance of efficacy. The safety and tolerability profile of duloxetine in this long-term study was similar to that observed in acute-phase studies, suggesting a role for duloxetine in the long-term therapeutic management of MDD.

Agomelatine
Most antidepressant drugs act not only on molecular targets directly responsible for their expected therapeutic action (monoamine transporters, monoamine oxidase A, presynaptic inhibitory auto- and hetero-receptors), but also on secondary targets at the origin of side effects. In particular, tricyclic antidepressants, which inhibit serotonin and/or noradrenaline reuptake, are most often endowed with antagonist properties at histamine H1, muscarinic and a1-adrenergic receptors, thereby causing sedation, body weight gain, constipation, memory disorders, orthostatic hypotension, etc. The selective monoamine reuptake inhibitors are better tolerated because they are generally devoid of such secondary effects. However, through the indirect promotion of serotonin action at specific receptors, they unavoidably produce some gastrointestinal, sleep and sexual disorders. Agomelatine markedly differs from other classes of antidepressant drugs: its primary molecular targets in vivo are the melatonin MT1 and MT2 receptors, where it acts as a potent agonist, and the 5-HT2C receptors, where it exerts clear-cut antagonist properties [33]. Several clinical trials confirmed the antidepressant efficacy of agomelatine in patients with major depressive disorders [34-36], including the most severe forms of depression [37]. Extensive investigations aimed at assessing the possible influence of agomelatine on central 5-HT neurotransmission demonstrated that, in contrast to other antidepressant classes, agomelatine, under acute as well as chronic treatment conditions, affected neither 5-HT release not the density and functional state of 5-HT receptors, which are known to play key roles in the mechanisms of action of tricyclics, SSRIs and MAO inhibitors [38, 39]. In particular, in double-blind, randomized, placebo controlled studies; agomelatine has not been shown to produce fatigue, headache, dry mouth or palpitations [34, 36, 40]. 269

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Indeed, the only brain receptor for which agomelatine was found to have some affinity is the 5-HT22 receptor, and previous studies had already shown that its blockade can contribute to promote the therapeutic action of antidepressant drugs and reduce some of their side effects. Actually, clear-cut antagonist effects of agomelatine at 5-HT2C receptors expressed in transfected cells on the one hand and responsible for specific in vivo effects on the other could be evidenced using appropriate paradigms [38, 41]. In particular, in contrast to melatonin, which is inactive on central DA and NA neurotransmission, agomelatine was found to enhance DA and NA release selectively in the rat frontal cortex, as expected from in vivo blockade of inhibitory 5-HT2C receptors [38]. In this respect, agomelatine resembles trazodone, an antidepressant that also possesses strong 5-HT2C antagonist properties [42]. However, the latter drug is also a potent H1 antagonist [43], which explains why it also produces side effects such as diurnal somnolence and body weight gain. The unique pharmacological profile of agomelatine, an agonist at MT1 and MT2 receptors and antagonist at 5-HT2C receptors, can explain its effective antidepressant action with relative lack of side effects but the actual neurobiological mechanisms triggered by this drug have still to be elucidated. Further ongoing investigations should contribute to explain the neurobiological basis of its antidepressant action. These investigations include notably studies on the possible synergy of both receptor families (MT and 5-HT2C) implicated in the pharmacological profile of agomelatine, and the molecular and cellular mechanisms underlying antidepressant-induced neuroplasticity (since recent data showed that agomelatine also exerts a stimulatory influence on cell proliferation within the subgranular layer on the hippocampal dentate gyrus in rodents [44,45]. Agomelatine should be particularly useful for more thorough understanding of antidepressant action because of its unique pharmacological profile accounting for its effective antidepressant action and relative lack of side effects Efficacy in general depressed populations The antidepressant efficacy of agomelatine was seen in a placebo-controlled dose-ranging study with paroxetine as an active control [34]. This 8-week study included 711 MDD patients (66.5% female, mean age 42.3 years) with a mean baseline Hamilton Rating Scale for Depression (HAMD) score of 27.4. The patients were randomly assigned to receive agomelatine (1, 5, or 25 mg/day), paroxetine (20 mg/day), or placebo. There was a significant difference in mean final HAMD score between agomelatine and placebo, which was most significant for 25 mg/day agomelatine (mean final HAMD score 12.778.23 versus placebo 15.348.87, P <0.05). The dosage of 25 mg/day agomelatine in the evening was thus confirmed as the effective dose. Agomelatine was further studied in a recent 6-week, double-blind, randomized, placebo-controlled 270

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study [36]. The 212 patients in the study were aged 18 to 65 years with MDD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) [46] and a HAMD score of at least 22. They were randomly allocated to receive 25 mg/day agomelatine or placebo, for 2 weeks, after which the agomelatine dose could be adjusted to 50 mg/day. Both patients and investigators were blinded to this dose adjustment, which was determined centrally according to the patients improvement on the 17-item HAM-D-17 and Clinical Global Impression (CGI) scores. A total of 211 patients made up the intention-to-treat population with 106 patients in the agomelatine group and 105 patients in the placebo group. There was a significantly lower mean HAM-D total score at end point in the agomelatine group (25 and 50 mg/day) compared with the placebo group (from 26.52.8 at baseline to 14.17.7 with agomelatine and from 26.73.0 to 16.57.4 with placebo, P = 0.026) [36]. The HAMD scale results were confirmed by the CGI Severity and Improvement (CGI-S and CGI-I) scores at end point. The agomelatine group had significantly lower CGI-S scores at end point than the placebo group (estimated between group difference, 0.44; P = 0.017) and there was a trend in favor of the agomelatine group for the CGI-I score. The responder rate, defined as a reduction in HAMD score, 50%, was better in the agomelatine group than the placebo group (49.1% versus 34.3%, P = 0.03). There was also a significant difference in time to first response in favor of agomelatine compared with placebo (P = 0.032). The dosage was increased under double-blind conditions in 34% of the agomelatine group and 37% of the placebo group. At 6 weeks, 27.8% of the patients in the 50 mg/day agomelatine group were responders compared with 13.2% in the raised placebo group. There was a significant difference in the HAMD total score at end point between these two groups (from 26.02.6 at baseline to 17.57.4 for 50 mg/day agomelatine group and from 26.72.8 to 20.46.0 for the double placebo group, P = 0.045) [36]. As no response to treatment in the first 24 weeks of treatment is an indicator of future treatment failure [47,48], the strategy of flexible agomelatine dosing in patients with an insufficient response after 2 weeks to obtain an improvement at 6 weeks. Efficacy in severe depression Demonstrating efficacy in severe depression is important because this patient group is often perceived as extremely difficult to treat [49]. The level of dysfunction increases with the severity of the depression, as does the risk of serious consequences like suicide [50]. Even though there is no single, generally accepted scale, the cut-offs used in the agomelatine studies to define more severe populations (HAMD score 25) [34,36] agree with those most often reported in studies of severe depression [50]. Treatment of more severely depressed patients with agomelatine results in significantly lower HAMD scores at end point than placebo (from 27.72.3 at baseline to 14.47.9 at end point 271

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for agomelatine and from 28.12.4 to 17.37.2 for placebo, P = 0.024) [36], in line with similar reductions observed in more severe subpopulations of other studies with agomelatine [34]. The response rates of severely depressed patients to agomelatine were significantly higher than placebo (48.7% versus 30.7%, P = 0.024) with a significantly faster time to first response (P = 0.006). A meta-analysis of the results observed in severely depressed subpopulations of three agomelatine studies [34,36]shows that there is a tendency for an increase in the magnitude of the treatment effect with increasing severity of depression at baseline. [37]. Antidepressant efficacy of agomelatine versus other antidepressants Selective serotonin reuptake inhibitor The SSRI paroxetine was used as an active control in a placebo-controlled study with agomelatine [34]. While the antidepressant efficacy of agomelatine has not been compared head-tohead with an SSRI, the results indicate that agomelatine has similar efficacy to paroxetine in patients with MDD. Moreover, there appears to be a significant advantage in severe depression in terms of reduction in HAMD score for 25 mg/day agomelatine compared with placebo (P <0.05), but not for 20 mg/day paroxetine compared with placebo (P <0.09) [34]. Finally, there was a significant difference between the placebo group and the agomelatine group in terms of HAMD mean total score at the first observation after 2 weeks (P <0.05). A difference for paroxetine was not recorded until the second observation at 4 weeks (P <0.05). Specific studies are necessary to assess this potential advantage of agomelatine. Serotonin and noradrenaline reuptake inhibitor The preliminary reports of two trials of agomelatine versus the SNRI venlafaxine indicate that the two antidepressants have comparable efficacy. Preliminary data for a study in a population of 332 patients with MDD (HAMD score 20) are available. In this 6-week study, patients received either 25 mg/day agomelatine (n = 165) or 75 mg/day venlafaxine (n = 167). The dose was adjusted after 2 weeks to 50 mg/day agomelatine or 150 mg/day venlafaxine according to the improvement in the depressive symptoms. In the full analysis set, the HAMD scores at week 6 were similar in the agomelatine and venlafaxine groups. Another trial was conducted versus venlafaxine including 277 patients with MDD with a baseline score of 20 on the Montgomery and Asberg Depression Rating Scale (MADRS). The patients were randomly allocated to receive either 50 mg/day agomelatine (n = 137) or 75 mg/day venlafaxine for 2 weeks followed by 150 mg/day venlafaxine for the rest of the 12-week study (n = 140). There was no dose augmentation step in the agomelatine group. The results of this trial show the similarity of the two treatments in terms of antidepressant efficacy. These preliminary results indicate that agomelatine has a comparable antidepressant efficacy to venlafaxine. 272

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Side effects Agomelatine does not produce any of the side effects that can be attributed to excessive stimulation of some peripheral and central 5-HT receptors by treatments with the latter antidepressant drugs. In particular, no nausea, diarrhea, or sexual dysfunction has been reported to occur in depressed patients treated with agomelatine [34, 36]. Furthermore, no discontinuation symptoms were noted after cessation of agomelatine treatment, in contrast to that found with paroxetine [51]. Also, unlike other antidepressants, notably SSRIs, agomelatine does not produce insomnia, fragmentation of slow-wave sleep, and nightmares, but rather improves the quality of sleep, with increases in both slow-wave sleep, and to a lower extent, REM sleep, in validated animal models of sleep alterations [52] as well as in depressed patients. Because, as mentioned above, at least part of the effects of agomelatine appeared to be induced through non-melatonin-mediated mechanisms, extensive in vitro binding studies were performed in order to detect possible interaction of agomelatine with melatonin-unrelated receptors, enzymes, transporters and ion channels. These studies clearly demonstrated that agomelatine has no affinity for H1, muscarinic and a1-adrenergic receptors, thereby explaining why this drug does not share the side effects of other antidepressants, especially tricyclics that are mediated through the blockade of these receptors.

Conclusion
Duloxetine is not a true new antidepressant, its properties are close to venlaflaxine or minalcipran, but agomelatine seems to have a complete different profile: MT1, MT2 and 5HT2C agonist. It will be of interest to see if agomelatine expand the spectrum of treatment for unipolar depression.

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