International Journal of Neuropsychopharmacology (2007), 10, S1S207. Copyright f 2007 CINP doi:10.

1017/S1461145707008255

S U P PL E M E N T

Antidepressant medications and other treatments of depressive disorders: a CINP Task Force report based on a review of evidence
Members of the Task Force : Norman Sartorius1 (Chairperson), Thomas C. Baghai2, David S. Baldwin4, Barbara Barrett5, Ursula Brand6, Wolfgang Fleischhacker7, Guy Goodwin8, Heinz Grunze2,3, Martin Knapp5, Brian E. Leonard9, Jerey Lieberman10, Yoshibumi Nakane11, Roger M. Pinder12, Alan F. Schatzberg13, Jaromr Svestka14 This text was written by : Thomas C. Baghai2, David S. Baldwin4, Barbara Barrett5, Pierre Baumann15, Kareem Ghalib16, Guy Goodwin8, Heinz Grunze2,3, Martin Knapp5, Brian E. Leonard9, John C. Markowitz17, Frank Padberg2, Roger Pinder12 and Norman Sartorius1. Substantial contributions to some of the chapters were made by Ursula Brand6, Max Fink18, Toshiaki Furukawa19, Konstantinos N. Fountoulakis20, Peter Jensen16, Shigenobu Kanba21, Anita Riecher-Rossler22. The text was edited by : Thomas C. Baghai2, Heinz Grunze2,3 and Norman Sartorius1 The names of the persons who produced the rst draft of the chapters are given in the table of contents. Website : www.cinp-antidpressant-task-force.de Address for correspondence : Thomas C. Baghai, M.D., Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstr. 7, D-80336 Munich, Germany. Tel. : +49-89-5160-5711 Fax : +49-89-5160-5718 E-mail : Baghai@med.uni-muenchen.de With copy to : Norman Sartorius, M.D., Ph.D., Chairperson of CINP Task Force, 14 chemin Colladon, 1209 Geneva, Switzerland. Tel. : +41-22-788 23 31 Fax : +41-22-788 23 34 E-mail : sartorius@normansartorius.com Heinz Grunze, M.D., School of Neurology, Neurobiology and Psychiatry, Newcastle University, UK. Tel. : +44-191-28-25765 Fax : +44-191-222-6162 E-mail : Heinz.Grunze@newcastle.ac.uk Aliations :
1 2

CINP

14 chemin Colladon, 1209 Geneva, Switzerland Dept. of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstr. 7, D-80336 Munich 3 School of Neurology, Neurobiology and Psychiatry, Newcastle University, Leazes Wing, Royal, Victoria Inrmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom

S2
4

CINP Antidepressant Task Force 2007

University Dept. of Psychiatry, Royal South Hants Hospital, Graham Road, Hampshire SO14 0YG, UK. 5 London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK. 6 EUFAMI (European Federation of Associations of Families of Mentally Ill People), Tagermoosstrasse 22, D-78462 Konstanz, Germany. 7 Dept. of Psychiatry, Innsbruck University Clinics, Anichstrasse 35, A-6020 Innsbruck, Austria 8 Dept. of Psychiatry, University of Oxford, Warneford Hospital, Oxford OC3 7JX, UK. 9 National University of Ireland, Galway, University Road, Galway, Ireland. 10 Dept. of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, 1051 Riverside Drive Unit #4, New York, N.Y. 10032, USA 11 Dept. of Neuropsychiatry, Nagasaki, University School of Medicine, Japan 12 Pharma Consultant, Vughterstraat 123D, 5211GA s-Hertogenbosch, The Netherlands. 13 Dept. of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Third Floor, Stanford, CA 94305-5717, USA. 14 Psychiatric Clinic, Medical Faculty of MU, Jihlavska 20, 639 00 Brno-Bohunice, Slovenia. 15 University Department of Psychiatry, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland 16 Child and Adolescent Psychiatry, Columbia and Cornell Universities, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021, USA. 17 Columbia and Cornell Universities, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021, USA. 18 St. James, New York, NY 11780-0457, Department of Psychiatry, School of Medicine, Stony Brook University, Long Island, New York, NY, USA 19 Dept. of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 Japan. 20 3rd Department of Psychiatry, Arisotle University of Thessaloniki, 55132 Aretsou Thessaloniki, Greece. 21 Yamanashi-ken Nakakomagun, Tomahocho Shimogatou 1110, 409-3898 Japan. 22 Psychiatrische Poliklinik, Universitatsspital Basel, 4031 Basel, Switzerland. Received 21 February 2007 ; Reviewed 31 March 2007 ; Revised 8 August 2007 ; Re-revised 5 November 2007 ; Accepted 5 November 2007 Contents Antidepressant medications and other treatments of depressive disorders: a CINP Task Force report based on a review of evidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1 1 Foreword (Brian E. Leonard). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S4 2 Note from the Editors (Thomas C. Baghai, Heinz Grunze, Norman Sartorius) . . . . . . . . . . . . . . . . . . . . . . . S4 3 Introduction (Norman Sartorius) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5 4 Method used to produce the review (Barbara Barrett, Ursula Brand, Heinz Grunze, Martin Knapp) . . . . . S9 4.1 Consensus process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9 4.2 Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S11 4.3 Additional sources of information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S12 4.4 Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S12 5 Diagnosis and epidemiology (Thomas C. Baghai, Heinz Grunze, Norman Sartorius) . . . . . . . . . . . . . . . . . .S14 5.1 Diagnosis of depressive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S14 5.2 Features of particular relevance to the treatment of depressive disorders . . . . . . . . . . . . . . . . . . . . . . .S16 5.3 Epidemiology of depressive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S26 6 Standards of care (Heinz Grunze). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S27 6.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S28 6.2 Access to mental health services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S30 6.3 Enhanced care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S30

CINP Antidepressant Task Force 2007

S3

7 Goals of treatment : response, remission, recovery (Heinz Grunze). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S31 7.1 Acute treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S32 7.2 Continuation and maintenance treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S35 7.3 Managing side eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S37 8 Mechanisms of action and future directions in the development of antidepressants (Thomas C. Baghai, Pierre Baumann, Brian E. Leonard, Roger Pinder) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S38 8.1 The development of antidepressants based on the monoamine hypothesis of depression. . . . . . . . . .S38 8.2 Developments leading to new understanding of the mechanism of action of antidepressants . . . . . .S39 8.3 The role of pharmacogenetics in understanding how antidepressants work. . . . . . . . . . . . . . . . . . . . .S44 9 Pharmacological treatment options (Thomas C. Baghai, Pierre Baumann, Konstantinos N. Fountoulakis, Toshiaki Furukawa, Guy Goodwin, Heinz Grunze, Peter Jensen, Shigenobu Kanba, Brian E. Leonard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S45 9.1 The use of medication in the acute treatment of depressive disorders. . . . . . . . . . . . . . . . . . . . . . . . . .S45 9.2 Continuation and maintenance therapy with antidepressants, mood stabilizers and other medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S81 10 Specic age- and gender-related conditions (Thomas C. Baghai, Kareem Ghalib, Heinz Grunze, Frank Padberg, Anita Riecher-Rossler). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S85 10.1 Gender-related dierences (Heinz Grunze, Anita Riecher-Rossler) . . . . . . . . . . . . . . . . . . . . . . . . . . . .S85 10.2 Age-related dierences (Thomas C. Baghai, Kareem Ghalib, Frank Padberg). . . . . . . . . . . . . . . . . . . .S87 11 Suicidality and antidepressants : depression and suicide (Heinz Grunze) . . . . . . . . . . . . . . . . . . . . . . . . . . .S98 12 Other treatments for depression (Thomas C. Baghai, Max Fink, John C. Markowitz, Frank Padberg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S103 12.1 Psychotherapy (John C. Markowitz) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S103 12.2 Electroconvulsive therapy (Thomas C. Baghai, Max Fink) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S104 12.3 Other non-pharmacological treatments (Thomas C. Baghai, Frank Padberg) . . . . . . . . . . . . . . . . . . .S106 13 Antidepressant drugs in the treatment of anxiety disorders (David Baldwin) . . . . . . . . . . . . . . . . . . . . . . .S110 14 Health economics : the cost of illness (Barbara Barrett, Martin Knapp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S110 14.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S110 14.2 The broad costs of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S111 14.3 Methodology : economic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S112 14.4 Economic evidence for pharmacological treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S113 14.5 Evidence on the cost-eectiveness of antidepressants and care management . . . . . . . . . . . . . . . . . . .S117 14.6 Economic evidence for pharmacological treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S117 14.7 Implications : economic evidence for pharmacological treatment options . . . . . . . . . . . . . . . . . . . . . .S118 14.8 Economic evidence for psychological treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S119 15 Conclusions and implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S121 16 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S122 17 Statement of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S122 18 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S123 19 Annexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S179 19.1 Annex 1 : Opinions and suggestions that could not be fully accommodated in the review (Thomas C. Baghai, Max Fink, Heinz Grunze, David Healy, Ulrich Hegerl, Florence Thibaut, Florence Thibaut, Markus Kosel, Min-Soo Lee, Shigenobu Kanba, Norman Sartorius) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S179 19.2 Annex 2 : Additional information on the types of economic evaluation (Barbara Barrett, Martin Knapp). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S181 19.3 Annex 3 : Additional information on electroconvulsive therapy (Thomas C. Baghai, Max Fink). . . .S184 19.4 Annex 4 : Additional information on transcranial magnetic stimulation (Frank Padberg) . . . . . . . . .S189 19.5 Annex 5 : Additional information on vagus nerve stimulation (Frank Padberg) . . . . . . . . . . . . . . . . .S190 19.6 Annex 6 : Additional information on acupuncture (Thomas C. Baghai). . . . . . . . . . . . . . . . . . . . . . . .S191 19.7 Annex 7 : Additional information on chronotherapeutics : light and wake therapy (Klaus Martiny) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S192 19.8 Annex 8 : Additional information on psychotherapy (John C. Markowitz) . . . . . . . . . . . . . . . . . . . . .S193

S4

CINP Antidepressant Task Force 2007

19.9 Annex 9 : Additional information on antidepressant drugs in the treatment of anxiety disorders (David Baldwin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S196 19.10 Annex 10 : List of regional meetings and countries represented . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S197 19.11 Annex 11 : Suggestions concerning the organization of national review meetings . . . . . . . . . . . . . . .S198 19.12 Annex 12 : Additional information on the European Federation of Associations of Families of People with Mental Illness (EUFAMI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S198 19.13 Annex 13 : List of Advisors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S199 20 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S205

1 Foreword According to the World Health Organization, depression is one of the most debilitating disorders affecting humankind. The social and economic costs of chronic ill health resulting from untreated or inadequately treated depression are considerable and frequently underestimated. The CINP established the Task Force on Antidepressant Medications in 2004 to examine all aspects of therapy with antidepressant drugs. This was considered necessary as, despite the availability of eective antidepressants for the past 50 years, a substantial minority of depressed patients either remains untreated or under treated. As the only international organization devoted to the promotion of research, education and the applications of neuropsychopharmacology to the clinic, the main task of the CINP is to extend the knowledge of the drugs that are available with the aim of improving the management of mental disorders. The purpose of this Task Force document was not to produce an academic monograph nor a set of guidelines, but to provide mental health and other professionals with comprehensive and objective information about the dierent aspects of the use of antidepressants important in clinical practice. The Task Force consisted of 15 experts in psychiatry, psychopharmacology, public health, economics and family care. The majority of its members are senior members of the CINP. The Task Force was also advised to rely in the course of its work on advisors in dierent countries selected because of their outstanding expertise in the matters covered by the review. The report presented here was approved by the Executive Committee and the Council of the CINP at its meeting in Chicago in July 2006. As a service to those engaged in mental health care and to ensure maximum impact, the Task Force review is being published as a supplement to the CINPs journal, the International Journal of Neuropsychopharmacology. In addition, the information will later

be made available on the CINP website. To facilitate access to the review for non-English-speakers, we also intend for it to be published in Chinese, French, Russian and Spanish. It is the intention of the CINP to provide, in the future, other task force publications dealing with other major groups of medications used for the treatment of mental disorders. We hope in this way to enhance the eectiveness of the CINP as a major international organization committed to improving knowledge worldwide of the appropriate use of psychotropic drugs for the optimal treatment of psychiatric disorders.
BRIAN E. LEONARD

President, CINP January 2007

2 Note from the Editors This review is the result of the work of many. The names of those who contributed the rst drafts of the text are given in the table of contents : in their present form, however, the chapters often dier signicantly from their original version. This is because they have been revised often more than once to do justice to the numerous comments and suggestions concerning additional evidence received from the Advisory Group and the members of the CINP Task Force. In selecting the members of the Advisory Group the Task Force made every eort to include experts from different countries and with outstanding expertise in a manner that was to make it possible to obtain advice and guidance in the relevant areas of knowledge and disciplines. Their contribution is acknowledged in the acknowledgements chapter 16. In addition, we would like to express our thanks for the particularly useful comments and suggestions, as well as additional materials, contributed by Profs. Baumann, Blier, Burrows, Dunn, Furukawa, Halaris, Kutcher, Remschmidt and Moller.

CINP Antidepressant Task Force 2007 The method used to produce the rst draft of the chapters of this review and the sources of data used are described in chapter 4.1. What makes this eort dierent from similar documents are the steps that were taken after the review of the literature was completed. First, as soon as the Task Force approved the text, the review was submitted for comments and review to an advisory group composed of experts from the countries the world over. At the same time the review was translated into Chinese, French, Russian and Spanish, and these versions of the text were then presented to experts in regional meetings held in Caracas, Munich, Paris, Shanghai and St. Petersburg. Present at each of these meetings were experts from the host country and from other countries that use the same language or share scientic traditions. The participants in these meetings undertook to organize national meetings in their countries to review the materials presented and to examine the facts in the light of the experience, special circumstances and evidence that may not have been available in international databases. The national meetings have been taking place during the year 2007 and will continue in 2008. The results of these meetings will be examined by the CINP and may be published, possibly together with results of new studies that become available or of studies that have been missed by those who drafted the chapters, by the members of the Advisory Group and the CINP Task Force. It would have been desirable to make the regional meetings coincide with CINP regional meetings : this however was not possible because of the need to complete the production of the review within a year which imposed serious time constraints on the work plan. However, the regional and national meetings included a number of members of the CINP. After lengthy discussions and some hesitation the Task Force decided to supplement the description of antidepressant medications with chapters that provide information about the diagnosis of depression (chapter 5.1) and its epidemiology (chapter 5.3), as well as about principles of caring for people with depression (chapter 6) and treatment that can be used in combination with antidepressants or alone (chapters 9.1 and 12). In view of the many discussions and dierences of opinion over whether to include description of other treatment methods, the Task Force nally decided to provide a brief description of these methods in the text of the review and to place more detailed information in the annexes (19.319.8). An important argument in this respect was that the main task of the Task Force was to produce a review of evidence (and experience) and not guidelines for

S5

treatment that should be produced at the national or even subnational level, taking evidence as well as local circumstances into account. In reviewing the evidence, we paid particular attention to results obtained in randomized control trials of antidepressant medications. The results of these trials are important, and their statistical signicance is often put forward as being sucient for recommendations about clinical practice. A statistically signicant dierence, however, is not always equal to a clinically meaningful dierence ; nor is the evidence obtained in research the only evidence to consider in making treatment decisions. For that reason, this review was developed in consultation with leading mental health experts, representatives of family organizations and specialists in medical disciplines other than psychiatry. These consultants generously provided advice, spoke from experience and contributed information published in non-English languages. We hope that this intensive process of consultation has helped the review to reect evidence from research as well as from experience and clinical wisdom.
T. C. BAGHAI, H. GRUNZE AND N. SARTORIUS

on behalf of the CINP Task Force Munich, Geneva, January 2007 3 Introduction The criteria used to assess whether a problem is of public health importance (and therefore should be a priority for health services) include the prevalence of the problem, the severity of its consequences, the likelihood that it will remain stable or grow if unattended and the availability of eective means of intervention to resolve or signicantly reduce the problem. Depressive disorders satised the rst three criteria long ago. These disorders are among the most frequent mental illnesses, and their prevalence matches that of many serious physical illnesses given priority in public health action. The consequences of depression, if left untreated, are grave and include increased morbidity and mortality from various physical illnesses as well as signicant impairment that produces more disability than many common chronic disorders such as diabetes and chronic collagenoses. Reports of the World Health Organization (WHO) show that depressive disorders rank very high in number of life years lost due to illness, premature death and disability. Depressive disorders also signicantly increase the risk of suicide and of suicidal attempts.

S6

CINP Antidepressant Task Force 2007 The introduction of antidepressant medications changed the public health importance of depressive disorders and their priority in health care services. In addition, recognizing that depressive disorders are frequent and severe, that they are likely to multiply in the years to come and that they complicate treatment of many physical disorders, it gradually became evident that antidepressant medications could help a signicant proportion of people with depressive disorders even when applied by general medical sta in primary care and non-psychiatric health services. It also became possible to speak publicly about depression because society accepted that depression was a disease that could be eectively treated by medical means medicinal drugs like many other diseases. Since the introduction of imipramine we know that antidepressant medications are not a miracle cure. They do help approximately two thirds of the people with depression if appropriately used (Klerman and Cole, 1965) : although this is considerably better than the response to placebo, which helped approximately one third of the people to whom it had been given in clinical trials, it still leaves one third of the patients with depression in whom the prescription of an antidepressant medication will not improve the condition. The addition of psychotherapy, better social support and the use of other, additional medications will help some of those who did not respond to the treatment with the rst prescribed antidepressant, but some others will still remain unwell. There is thus considerable room for further improvement of the eectiveness and safety of antidepressants and it is to be hoped that future research will result in still better medications and other methods of treatment of depressive disorders. Meanwhile, imperfect as they may be, the currently available antidepressant medications are a powerful tool that can be used in general and specialized mental health services. The lessened stigma of depression and the growing conviction that antidepressant medications are eective emboldened patients to seek help from health workers and motivated non-psychiatrists to deal with depression, to prescribe antidepressants and in general to see patients with depression as having a manageable health problem. The number of patients and doctors with this mindset grew over time, supported by an increase in the array of available medications, and the encouraging results of studies showing their usefulness and ever milder side eects. The general public and the media supported this notion as well. In several countries, direct advertisements to consumers

Depressive illness is likely to become even more prevalent in the decades to come for a variety of reasons. These include increased life expectancy both among the general population in many countries (with a concomitant increase in groups that are at particularly high risk for depressive disorders1) and among people with chronic physical illness often accompanied by depressive disorders (e.g. chronic gastrointestinal disorders, cardiovascular disorders and stroke) ; greater numbers of iatrogenic mental disorders, including depression ; and, in both developed and developing countries, continuously increasing levels of stress that parallel the weakening of social support. WHO has predicted that unipolar depression alone will be the second most important contributor to disability by the year 2020, not only in Europe and northern America, but worldwide (World Health Organization, 2001). The fourth criterion for public health importance, and for consequent action, is the availability of an eective intervention that can reduce or eliminate the problem and is suitable for widespread application. Until recently that criterion had not been satised for the majority of mental disorders. Although public health authorities succeeded in preventing some mental disorders (e.g. cretinism in areas where iodine deciency was eliminated, and of progressive paralysis in areas where infection with syphilis was brought under control), treatment of mental disorders was, by and large, not very eective. Electroconvulsive therapy (ECT) helped in treating people with certain forms of depressive disorders and schizophrenia, but the number of those who could not benet from ECT vastly surpassed the numbers of those who could. Thus this intervention did not t the criterion of wide applicability. Psychotherapy helped many, but the number of experts qualied to apply it were and still are small in most parts of the world. Psychotherapeutic strategies and techniques have become suciently well dened to be candidates for study in undergraduate medical education and in-service training of non-psychiatrists. Moreover, psychotherapies may have widespread utility, even in countries in which the purchase and regular distribution of medications are dierent (Bolton et al., 2003).

Despite a greater number of depressive symptoms requiring treatment in old age, the prevalence of major depressive disorder has not been reported to correlate with age (Patten et al., 2001 ; Steens et al., 2000). One explanation may be the inappropriateness of the diagnostic criteria for depression which are valid for depressive disorders in adults but not for those in the elderly.

CINP Antidepressant Task Force 2007 may have played a role (Berndt, 2005). The Prime Minister of Norway took a few weeks o to treat his depression and came back in good health. Famous artists and other stars described their depression and how they got better. Although this change of public opinion from seeing depressive disorders as an intractable form of madness to being a physical illness that could be treated by pills prescribed by the general practitioner was positive because it changed the way patients and medical sta thought about depression, it was also a step towards a dierent interpretation of depression. Increasingly, reports appeared claiming that depressive disorders are no more than variations of mood that do not warrant medical attention. Psychiatric epidemiologists published studies showing that the lifetime prevalence of depressive disorders was nearly 80 %, a gure that can easily be interpreted by the lay public as evidence that depressive disorders are part of normal life. This banalization of depressive disorders came about partly spontaneously and partly owing to promotion by various sects and anti-psychiatry movements. Depressive disorders, it was proclaimed, were most often not really diseases : rather, they were conditions that everyone had. Medications that had previously been hailed as miraculous cures were declared by some as an expensive and unnecessary form of placebo. Worse, they were reported as dangerous because they aected peoples personality and made them dependent on drugs. According to these arguments, it was only the coalition between doctors and drug manufacturers that kept alive the myth of depressive illness and its medical solution. Studies showing that successful treatment of depressive disorders not only helps people who suer from them but also benets society and patients families were neither widely known nor suciently publicized. What received much greater airing and prominence was the high cost of many medications and the large amounts of money made by producers and distributors of medications. To some extent, the idea that drugs used to treat mental disorders are expensive stems from the stigma that accompanies mental illness and the disregard for people who have these disorders. Even when psychiatric medications are inexpensive a months supply of a drug such as chlorpromazine costs no more than US$1 governments do not buy them, and the general public accepts that even a dollar a month is too much to spend for a person whom most of the population considers not worth it. Developments in research and technology have increased the number of active substances that could

S7

be used to treat depression, and the knowledge about their mechanisms of action continued to advance, which has enhanced possibilities of adjusting the treatment with psychopharmacological medications to the clinical needs of individual patients (see Table 1). The results of studies carried out to assess the effectiveness of the new substances showed that newly discovered medications are at least as good as their predecessors and that they have some advantages over other drugs. Studies comparing medications have increased, but they are frequently sponsored by drug companies, and their results are not always in harmony. Government-sponsored studies, which might help to resolve some of the contradictory results, are still far too few in numbers. There are also still far too few investigations of the eects of new drugs for patients in populations outside the major industrialized countries2. Some studies did show dierences in dosage and eects of medications given to patients living in countries with varying climate, nutrition and general morbidity patterns, but denitive studies of the eect of drugs on patients from dierent populations are still lacking. The scarcity of studies on psychotropic drugs in the third world is part of the larger problem of the predominance of research in a few highly developed countries. One recent study showed that only 6 % of the articles on mental health in the scientic literature come from other than high-income countries. The US and UK alone contribute 50 % of the accessible scientic literature on mental health matters (Saxena et al., 2006). In the light of these considerations, it is not surprising that the CINP, aware of its obligation to facilitate clinical interpretation of neuropsychopharmacological ndings (Ban, 2006a), felt that it would be useful to carry out a detailed technical review of antidepressant medications. Antidepressants are now used to treat many conditions, even if the justication for their use reects more of clinical experience and consensus instead of evidence (see Table 3) but it was decided that this review would concentrate on the use of antidepressants for the treatment of depression as dened in ICD-10 (World Health Organization, 1992)

More recently, studies sponsored by international pharmaceutical companies have included patients from India and other countries in the third world ; the results of these investigations usually do not report results obtained in such countries separately and mix the data from those countries with data obtained in other countries.

S8

CINP Antidepressant Task Force 2007

Table 1. Commonly used antidepressants3, including their primary mode of action and inuence on other receptor systems Primary pharmacodynamic mode of action SRI (+ +) SRI SRI (+ +) SRI (+ +) SRI (+ +) + SRI (+ +) + SRI/NRI (+/ +) SRI/NRI SRI/NRI NRI (NRI) a2 MT1/MT2 MAI MBI MAI MAI/MBI MAI/MBI MAI/MBI SMA (+) SMA DNRI (+) DA GM SRI SRI/NRI (+/ +) + SRI/NRI SRI/NRI SRI/NRI (+/ +) SRI/NRI SRI/NRI SRI/NRI SRI/NRI NRI (+ +) + NRI (+ +) NRI a2 NRI NRI Secondary pharmacodynamic actions

Pharmacological group SSRI SSRI SSRI SSRI SSRI SSRI SNRI SNRI SNRI NARI (NARI) NaSSA MT RIMA MAOI MAOI MAOI MAOI MAOI SMA SMA DNRI DA GM S-TCA S/N-TCA S/N-TCA S/N-TCA S/N-TCA S/N-TCA S/N-TCA S/N-TCA S/N-TCA N-TCA N-TCA N-TCA S-TetraCA N-TetraCA N-TetraCA

Generic name Citalopram Escitalopram4 Fluoxetine Fluvoxamine Paroxetine Sertraline Venlafaxine Duloxetine Milnacipran Reboxetine Viloxazine Mirtazapine Agomelatine5 Moclobemide Selegiline6 Phenelzine Isocarboxacid Tranylcypromine7 Pirasidol8 Nefazodone9 Trazodone Bupropion Trimipramine Tianeptine Clomipramine Amitriptyline Amitriptylinoxide Dibenzepine Dosulepine/Dothiepin Doxepin Imipramine Melitracen10 Protriptyline Desipramine Lofepramine Nortriptyline Mianserin Amoxapine Maprotiline

Additional eects

5-HT2C (M1) DRI

(M1) 5-HT2,3 ; +5-HT1 5-HT2C MAI, APD H1, a1, a2 (M1)

APD 5-HT2A, SRI 5-HT2, SRI NRI 5-HT2 NRI, D2 5-HT2

a1 H1, M1, a1, a2 M1, a1 H1, M1, a1, a2 H1, (M1), a1, a2

5-HT2 H1, M1, a1 M1, a1 M1 (M1) M1, a1 M1, a1 H1, a1 H1, (M1), a1

SRI, 5-HT2 NAR

For abbreviations see p. 9.

St. Johns wort is not included in the list of antidepressants because of it has no proven ecacy in severe depression. 4 In addition to its serotonin reuptake-inhibiting properties, escitalopram also binds to the allosteric site on the serotonin transporter. A new class of SSRIs has been proposed (allosteric serotonin reuptake inhibitors, ASRIs). 5 Not yet available ; currently under review by European authorities (EMEA). 6 In some countries selegiline has only been approved as a drug against Parkinsons disease, not as an antidepressant.

7 In some countries irreversible MAOIs are not longer available (e.g. Czech republic, Spain and others). 8 The use of pirasidol is limited to Russia and other eastern countries of the same geographical region. In the Russian literature it can also be found also under other names, such as pirlindol, pyrazidol, pirazidol and pirazidolum (for review see Mosolov, 1998). 9 Nefazodone has been withdrawn from the market in some countries. 10 Melitracen has activating properties in low dosages and is predominantly used in Asian countries in a combined formulation (Deanxit) with the antipsychotic drug upentixol.

CINP Antidepressant Task Force 2007 and DSM-IV (American Psychiatric Association, 1994). Later, it became obvious that it would be necessary to add chapters on the use of antidepressants for anxiety and chronic pain because these conditions are frequently associated with depression and possibly rely on the same pathophysiological mechanisms and pathways. The review is based on published evidence ; however, it also incorporates advice and comments of leading experts in the elds of psychiatry, pharmacology and public health. Additional sources of expertise consulted include regulatory agencies, patient and family organizations, representatives of the pharmaceutical industry and public health authorities. Our hope was that combining a review of the literature with the outcome of a wide-ranging discussion involving people whose experience usually is not published (or is published in places that are dicult to access) might produce a solid body of facts on which the CINP could reach consensus and make its opinion widely known. The particular aim of the consensus was to provide evidence and other information that would help to answer to at least the following questions :
$ $

S9

What areas of scientic investigation related to antidepressant medications and their use deserve priority ? (chapter 8) Are there depressive disorders that do not require treatment with antidepressant drugs ?11 (chapter 12)

This review presents evidence and experience that should help to answer these questions and facilitate the process of reaching a consensus that will guide public health action and the education of health workers, of the general public and of those who suer from depressive illnesses. 4. 4.1 Method used to produce the review Consensus process

Are antidepressant medications eective in alleviating symptoms of depression and in preventing relapses of depressive illness ? (predominantly chapters 9 and 7) Are the side eects of antidepressant drugs currently in use so severe that they outweigh the benets of these drugs ? (chapters 7.3 and 9.1.1.3) Is the treatment of depressive disorders with antidepressant drugs cost-eective for individuals and societies ? (chapter 14)

The challenge for the CINP Task Force created in May 2005 was to review the evidence on the use, eectiveness and safety of antidepressant medications and to assemble experience that clinicians using them and carers (e.g. family members) have accumulated. This challenge was to be met by preparing a review of published evidence and exposing it to a process of consultation with experts in dierent parts of the world. Thus, after an initial meeting with some members of the Task Force, Dr T. C. Baghai and Dr H. Grunze, with the assistance of Dr F. Padberg, prepared a review of pharmacological and therapeutic evidence on
11

For example, the NICE (National Institute for Clinical Excellence, UK) recommendations acknowledge a role for antidepressants in primary care in moderate and severe, but not mild depression. For these patients, NICE recommends observation or psychological intervention as rst-line treatment, and antidepressants only in the case of refractoriness (National Institute for Health and Clinical Excellence, 2004).

Table 1 abbreviations : (primary modes of action are explained in the text) : (+)=modest receptor binding anity ; (+ +)= appreciable receptor binding anity ; (+ +)=strong receptor binding anity ; +5-HT1=serotonin 1 receptor stimulation ; + 5-HT2=serotonin 2 receptor antagonism ; 5-HT2C= 5-HT2C receptor antagonist ; 5-HT3=serotonin 3 receptor antagonism ; a1=a1-receptor antagonism ; a2=a2-receptor antagonism ; all. 5-HTT=binding to the allosteric site of the serotonin transporter ; APD=amphetamine prodrug ; DA=dopamine (D2) receptor antagonist ; DNRI=dopamine and noradrenaline reuptake inhibitor ; DRI=dopamine reuptake inhibition ; GM=glutamatergic modulator ; H1=blockade of histamine 1 receptors ; M1=blockade of cholinergic muscarinic receptors ; MAI=monoamine oxidase A inhibition ; MBI=monoamine oxidase B inhibition ; MAOI=irreversible inhibitor of monoamine oxidase A and B ; MAOBI=irreversible inhibitor of monoamine oxidase B ; MT=melatonergic antidepressant ; MT1/MT2=melatonin 1 and melatonin 2 receptor agonist ; NAR=noradrenalinereleasing properties ; NARI=selective noradrenaline (norepinephrine) reuptake inhibitor ; NaSSA=noradrenergic and selective serotonergic antidepressant ; NRI=noradrenaline (norepinephrine) reuptake inhibition ; N-TCA=tricyclic antidepressant with primary noradrenergic eects ; N-TetraCA=tetracyclic antidepressant with primary noradrenergic eects ; RIMA=reversible inhibitor of monoamine oxidase A ; SMA=serotonin-modulating antidepressant ; SNRI=selective serotonin and noradrenaline reuptake inhibitor ; S/N-TCA=tricyclic antidepressant with similar serotonergic and noradrenergic eects ; SRI=serotonin reuptake inhibition ; SRS=serotonin reuptake stimulation ; SSRI=selective serotonin reuptake inhibitor ; S-TCA=tricyclic antidepressant with primary serotonergic eects ; S-TetraCA=tetracyclic antidepressant with primary serotonergic eects.

S10

CINP Antidepressant Task Force 2007

Table 2. Classication and criteria of major depressive disorder (DSM-IV ; American Psychiatric Association, 1994) and depressive episode (ICD-10 ; World Health Organization, 1992) (adapted from Bauer et al., 2002c) DSM-IV Major depressive disorder A. Single episode (296.2x) B. Recurrent (296.3x) ICD-10 A. Depressive episode (F32) B. Recurrent depressive disorder (F33) Severity :12
$

Mild (F.0) : at least 2 main symptoms, plus at least 2 accessory symptoms ; none of the symptoms intense Moderate (F.1) : at least 2 main symptoms, plus at least 3 accessory symptoms ; some symptoms marked Severe (F.2) : all 3 main symptoms, plus at least 4 accessory symptoms ; some symptoms severe with intensity

Criteria major depressive episode (abridged) : A. Over the last 2 weeks, 5 of the following features should be present most of the day, or nearly every day (must include 1 or 2) : 1. Depressed mood 2. Loss of interest or pleasure in almost all activities 3. Signicant weight loss or gain (more than 5 % change in 1 month) or an increase or decrease in appetite nearly every day 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation (observable by others) 6. Fatigue or loss of energy 7. Feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach about being sick) 8. Diminished ability to think or concentrate, or indecisiveness (either by subjective account or as observed by others) 9. Recurrent thoughts of death (not just fear of dying), or recurrent suicidal ideation, or a suicide attempt or a specic plan for committing suicide B. The symptoms cause clinically signicant distress or impairment in social, occupational or other important areas of functioning. C. The symptoms are not due to a physical/organic factor or illness D. The symptoms are not better explained by bereavement (although this can be complicated by major depression)

Criteria of depressive episode (abridged) : Minimum duration of episode : about 2 weeks Main symptoms : 1. Depressed mood 2. Loss of interest and enjoyment 3. Reduced energy, increased fatigability Accessory symptoms : 1. 2. 3. 4. 5. 6. 7. Reduced concentration and attention Reduced self-esteem and self-condence Ideas of guilt and unworthiness Agitation or retardation Ideas or acts of self-harm or suicide Sleep disturbances Loss of appetite

antidepressants. This initial review was supplemented with a review of evidence on the economic aspects of the treatment of depression prepared by Prof. Dr M. Knapp and Dr B. Barrett. That version of the review was presented to the CINP Task Force in January 2006 and revised in the light of comments received during the meeting. Several chapters were added with the involvement of experts in the relevant elds, such as the chapter on psychopharmacotherapy of children (rst draft contributed by Dr K. D. Ghalib) and the

chapter on psychotherapy (drafted by Dr J. C. Markowitz). The main purpose of the technical review is to reect the actual scientic evidence on the use and usefulness of antidepressants in the treatment of depression. But it also deals with other major indications for antidepressant medications (Table 3).
12 Severity of disease according ICD-10 does not necessarily include ratings of disability and impairment.

CINP Antidepressant Task Force 2007

Table 3. Indications other than depressive disorders for antidepressant medication (based on clinical experience, consensus and evidence) Main categories of diseases Anxiety disorders (see chapter 19.9)

S11

Specic condition
$ $ $ $ $

review at national level will be published locally and may subsequently be brought together in a summary paper. In July 2006 the review was examined by the Executive Committee and Council of the CINP, which recommended its publication and adopted the Consensus Statement presented in chapter 15. 4.2 Data sources

Pain conditions (see chapter 5.2.1.3.5) Schizophrenic spectrum disorders Other indications

$ $ $ $ $ $ $ $ $ $ $

Generalized anxiety disorder Panic disorder Social phobia Post-traumatic stress disorder Obsessive-compulsive disorder Chronic pain Somatoform disorders Schizophrenia Schizoaective disorders Postschizophrenic depression Adjustment disorders Personality disorders Akathisia Eating disorders Impulse control disturbances Insomnia

The revised draft was sent to the group of advisors listed on p. 199 (Annex 13 : List of Advisors) and further revised based on comments received. In April 2006, translation of the text into Chinese, French, Russian and Spanish began so translations would be ready for the next phase of the project. That phase commenced with a series of regional meetings that brought together 812 experts from the country in which the meeting was held and 810 representatives of other countries of the region who agreed to critically review the document and to organize a national meeting similar to the one they attended13. By the time that this review went to press national meetings were held in the following countries : Argentina, Australia, Austria, Brazil, Chile, China, Croatia, Czech Republic, Denmark, Dominican Republic, Ecuador, France, Hong Kong, Japan, Kazakhstan, Korea, Philippines, Serbia, Singapore, Slovakia, Taiwan, Ukraine. A list of countries represented at the regional meetings held in St. Petersburg, Munich, Shanghai, Caracas and Paris is given in Annex 10. Comments and suggestions as well as references to local studies published in English and other languages received from the participants at these meetings served to redraft the review. The results of the examination of the
13

The data considered in the development of this technical review have been extracted from dierent sources : the Medline database (up to October 2007), the Cochrane Library, review articles from Medlineindexed journals, meta-analyses14 (see Box 1), textbook chapters known to the authors of the draft or brought to their attention by members of the Task Force or the Advisory group and material supplied by pharmaceutical companies. Several national and international treatment guidelines were also examined, including the American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder (American Psychiatric Association, 2000), the Canadian Psychiatric Association and Canadian Network for Mood and Anxiety Treatments (CANMAT). Clinical guidelines for the treatment of depressive disorders (Canadian Psychiatric Association and Canadian Network for Mood and Anxiety Treatments (CANMAT), 2001), the guidelines by the German Psychiatric Society (Deutsche Gesellschaft fur Psychiatrie, Psychotherapie und Nervenheilkunde, DGPPN), Praxisleitlinien in Psychiatrie und Psychotherapie, Behandlungsleitlinie aektive Erkrankung edited by van Calker and Berger (2000), and the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, parts 1 and 2 (Bauer et al., 2002c ; Bauer et al., 2002b) as well as the Textbook of Mood Disorders (Stein et al., 2006). The review is mostly, but not exclusively, based on papers published between 1990 and 2007 not least also because of time constraints because over the past two decades the methodology of studies became more uniform and comparable, and consistent and full information became easier to retrieve since papers from this period are usually available electronically.

Suggestions concerning the organization of national meetings are given in Annex 10.

14 When using meta-analyses as the primary source of evidence, the authors were aware of the methodological limitations of the approach (Anderson, 2000b). Only when properly conducted can meta-analyses bring out possible subgroup dierences (heterogeneity) and publication biases (funnel plot analysis and others) (Sterne et al., 2000 ; Thompson, 1994). Meta-analyses performed according to the Cochrane method usually have the largest acceptance and best scientic ranking (see Box 1).

S12

CINP Antidepressant Task Force 2007

Box 1. Overview of the Cochrane method (example from Cipriani et al., 2005b) Search strategy :
$

Relevant studies were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (19662004) and Embase (19742004). Non-English-language articles were included.

Selection criteria :
$ $

Only randomized controlled trials were included. For trials with a cross-over design, only results from the rst randomization period were considered.

Data collection and analysis :

$ $ $

Data were independently extracted by two reviewers using a standard form. Responders to treatment were calculated on an intention-to-treat basis : dropouts were always included in this analysis. When data on dropouts were carried forward and included in the ecacy evaluation, they were analyzed according to the primary studies ; when dropouts were excluded from any assessment in the primary studies, they were considered as treatment failures. Scores from continuous outcomes were analyzed, including patients with a nal assessment or with the last observation carried forward. Tolerability data were analyzed by calculating the proportion of patients who failed to complete the study and who experienced adverse reactions out of the total number of randomized patients. The primary analyses used a xed-eects approach, and presented Peto odds ratio (PetoOR) and standardized mean dierence (SMD).

4.3

Additional sources of information

In addition to scientic experts, families and carers are represented on the Task Force group by EUFAMI the European Federation of Association of Families of People with Mental Illness15 (for more information on EUFAMI, see chapter 19.12, Annex 12 : Additional information on the European Federation of Associations of Families of People with Mental Illness (EUFAMI)). 4.4 Limitations

As the previous section makes clear, this technical review is based on publicly available materials obtained via a Medline database search and other evidence that was brought to the attention of the authors. For that reason, the review may be subject to several biases. For example, modern medicine requires decision making on the basis of hard data, i.e. data that come mainly from randomized controlled trials (RCTs). But even these data are not awless, and translating RCT results to everyday clinical practice is sometimes problematic. One major cause may be that the
15

population of patients included in RCTs diers signicantly from the natural population of the real world . To avoid this bias, in recent years the US National Institute of Mental Health (NIMH) designed and independently sponsored a clinical trial known as Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (Menza, 2006). Results from the initial phase of this trial are touched on in this review. Owing to the current technical and legislative climate16, patients who are included in randomized trials (RCT), tend to be chronic, refractory and closely afliated with doctors or with institutions and associations. This situation has a number of consequences, including lower response to active drugs and higher response to placebo. Moreover, a continuous increase in placebo response and simultaneous drop in the active compound response rate has been observed in RCTs over the past few decades. For this reason, it is now essentially impossible to interpret results of studies that do not include a placebo group.

EUFAMI is a not-for-prot organization registered in Belgium that currently represents 48 member associations from 1 non-European and 26 European countries. It was founded in 1992 by members of a several family and carer organizations. Family organization activities include advocating for better services, equal and housing rights, raising awareness at the national and local level, and countering stigma.

16 A variety of attributes of clinically routine patients, such as psychiatric comorbidity, concomitant somatic disease, concomitant use of most psychopharmacologic and other medications, suicidality, pregnancy and others represent exclusion criteria in RCTs and induce the selection of a subgroup of patients. Also, in some countries the fact that treatment in RCTs is sponsored causes the predominant inclusion of specic social subgroups of patients without health insurance.

CINP Antidepressant Task Force 2007 Statistical signicance and clinical eectiveness are not synonymous (for a denition, see Box 6) and not always closely correlated. The so-called ecacy gap between outcomes in clinical trials and in primary care may be inuenced by patient compliance, family and social supports, and negative media reporting on antidepressants (Wade, 2006). Another source of confusion is the use of rened statistical methods to demonstrate the therapeutic ecacy and eectiveness of antidepressants without a re-evaluation of the psychiatric nosology employed and without additional research in psychopathology. In addition it may be relevant to the interpretation of study results that by the 1990s single-center clinical investigations were replaced by multi-center centrally coordinated clinical investigations in which individual contributions are restricted to a small proportion of the total sample. Moreover, education and research in pharmacotherapy are controlled predominantly by the pharmaceutical industry (Ban, 2006b). In fact, most studies utilized for this report are from recent years and may shift the overall impression on the ecacy of antidepressants into the direction of limited ecacy, and thus may impact treatment related considerations, potentially underestimating the ecacy of antidepressants in a clinical cohort. It is therefore also important to keep in mind that the outcome of industry-sponsored phase III studies often cannot be taken at face value. The overt and covert inuence of the vested interests of study sponsors on results (sponsorship bias) has recently received a fair amount of attention (Healy, 2006 ; Heres et al., 2006 ; Lexchin et al., 2003 ; Lexchin and Light, 2006 ; Montgomery et al., 2004a ; Perlis et al., 2005 ; Procyshyn et al., 2004). On the other hand, failed trials are usually not published or are published only with low priority and after an extensive delay, as publication is usually not in the interest of the sponsor and may interfere with marketing strategies. For a complete assessment of the utility of antidepressants it would be helpful to take all those studies into account. But because it is not possible to report in full about unpublished studies, the Task Force decided to base its work only on peerreviewed, published papers and information from book chapters. Unpublished studies have not been considered in the main review, except within the chapter on treatment of children and adolescents (chapter 10.2.1), which includes some unpublished data available on Internet sites of pharmaceutical companies. Some, but not all companies have now committed themselves to an open database policy of supplying information regarding all controlled, companysponsored trials on their Internet site. However, using

S13

this information from some companies but not from others would also unfairly bias the results and views expressed here. Hence, the Task Forces decided to base its report only on peer-reviewed, published papers and information described in chapter 4.2 above. Unpublished materials, papers not available using a Medline database search and abstracts (posters and lectures) were considered only if they were presented at major conferences or explicitly supplied as additional information by a company (e.g. on the companys freely accessible Web page). Overall, those materials had no major impact on the technical review. The CINP Task Force is also well aware that most evidence quoted in this technical review originated from clinical studies carried out in Europe and North America. Results may therefore not be representative of populations living elsewhere and under dierent cultural and climatic conditions. Biological dierences, e.g. in metabolism, dierences in food intake, dierent patterns of physical morbidity as well as cross-cultural dierences in concepts of health and in the expression of depressive episodes all lead to differences in treatment outcome. The use of medication may dier from culture to culture with consequences for both compliance and treatment outcome. For example, Sugahara reports an adherence rate of 66.8 % over 13 weeks of antidepressant treatment in a nonpsychiatric outpatient clinical setting in Japan (Sugahara et al., 2005), whereas in Western European countries and North America compliance is usually worse (Brown et al., 2005 ; Demyttenaere, 1998). Most RCTs include patients who have been diagnosed as suering from major depression or depressive disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th revision (DSM-IV), or the International Statistical Classication of Diseases and Related Health Problems, 10th revision (ICD-10). By dening specic subgroups of patients suering from depressive disorders, both operationalized diagnostic systems may inuence treatment outcome. In addition, as mentioned above, a relatively high placebo response rate in patients suering from depressive disorders has an impact on ecacy studies of substances with possible antidepressant eects by reducing the likelihood of separating them from placebo. Finally, because the vast majority of RCTs deal with major depressive disorder, it remains unclear whether one can extrapolate from these studies to other (minor) forms of depression or depression comorbid with other mental or somatic illnesses. Another important, yet often forgotten, methodological issue is that the fact that just because two

S14

CINP Antidepressant Task Force 2007 dedicates several chapters on specic recommendations for safety and the use of an antidepressant in geriatric patients, adolescents and special groups, e.g. treatment-refractory patients. Table 4 supplies a comparative overview about the regulatory requirements in three selected regions. The limitations noted in this chapter have to some extent been corrected by the process of collaboration described in chapter 4.1. No review can in itself be an unbiased and conclusive piece of evidence, but can only direct readers to the original publications. Clearly, responsible treatment decisions should never be based on reviews, no matter how comprehensive, but on ones own critical reading of the sources. The Review should help readers in this respect and serve as support to the development of treatment guidelines at national level in which the knowledge of local conditions and experience can help to produce useful instructions for the practicing health professionals.

studies are signicantly positive in favor of a specic medication does not mean that both drugs are equal in ecacy. Variations in sample sizes make it hard to compare trials due to the related statistical power of the study. When including a large number of subjects, a drug-placebo dierence in the Hamilton Rating Scale for Depression (HAMD) of 2 may still be signicant, but not clinically meaningful. On the other hand, if the power calculation was too optimistic and only a small number of patients have been included, even a HAMD dierence of 6 may lack statistical signicance. In the case of superiority in comparison with placebo treatment, both statistical signicance and eect size are very important factors inuencing clinical eectiveness. However, it would clearly be beyond the scope of a review to detail the methodology of each trial mentioned and the Task Force decided that it would refer the reader to the original publications. Also, placebo response rates may dier substantially from study to study due to dierent allowances of rescue medication, settings, severity of illness and so on. Thus, relevant ndings may be obscured by high placebo responses and may also lead to the perception that placebo could be an adequate antidepressant. Again, it would be dicult within the scope of a review to give more detailed information for every single trial concerning all these potentially confounding factors. Nevertheless, the introduction of RCTs was a great step forward in clincal psychopharmacology, simply by the fact that they replaced testimonials (consensus of experts), contaminated by many other factors, in the demonstration of ecacy of antidepressants. Therefore, proving ecacy in RCTs remains the key issue for regulatory approval ; for instance, the European Medicines Agency (EMEA) recommends for the approval of an antidepressant medication both multiple arm short-term studies, including at least three dosages of the agent to be tested, an active comparator and placebo, and a randomized withdrawal study, proving maintenance of eect, with an observational period of at least six months (Dokument cpmp/ewp/ 518/97, Committee for Proprietary Medicinal Products, 2002.). However, even these sophisticated designs have their inherited short comings, and some experts would give preference to non-placebo controlled comparator trials proving superiority of the new compound (Barbui et al, 2001). Also between regulatory agencies there is no clear consensus what kind of evidence has to be considered sucient to support an antidepressant claim, or, to express it in the words of a title of this review, what makes an antidepressant useful . EMEA, for example,

5. 5.1

Diagnosis and epidemiology Diagnosis of depressive disorders

Despite decades of intensive biologically oriented psychiatric research, the etiology of depressive disorders is not yet fully understood. A multifactorial genesis is supposed. Besides psychological and social factors, biological variables, too, apparently play a major role, and lead in aggregate to disturbed central nervous system homeostasis. The so-called catecholamine- and serotonin-deciency hypothesis (Burke and Preskorn, 1995), which postulates a dearth of monoamines (noradrenaline and serotonin) within the synaptic cleft, is essential in understanding the pathophysiology of depression. Depressive syndromes responsible to specic antidepressant therapies are classied within diagnostic entities using operationalized diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders, 4th revision (DSM-IV) (American Psychiatric Association, 1994) and the International Classication of Diseases, 10th revision (ICD-10) (World Health Organization, 1992). Table 5 lists the variety of symptoms that characterize depressive disorders. To diagnose a major depressive disorder (MDD), according to the DSM-IV ve main criteria of depression must be met, and according to ICD-10 a minimum of two main symptoms and two accessory symptoms must be present (see Table 2 adopted from Bauer et al., 2002c). Sometimes, owing to standardized diagnostic procedures, subsyndromal depression in elderly patients

CINP Antidepressant Task Force 2007

Table 4. Requirements for licensure of a medication as an antidepressant in three exemplary regions EU (EMEA) (The European Agency for the Evaluation of Medicinal Products, 2002) A : Acute treatment EMEA gives specic recommendations for an antidepressant claim : Superiority vs. placebo in a three arm trial including both placebo and an active control to check internal validity, recommended duration 6 weeks. At least three dierent xed doses of the test substance should be used to determine the lower end of the eective dose range as well as the optimal dose. Randomized withdrawal study after acute response on test substance with re-randomization either to test substance or placebo, recommended duration up to 6 months. Note : For a claim for acute treatment, it is mandatory to fulll both A and B

S15

US (FDA) (U.S. Food and Drug Administration, 2006)

South Africa (MCC) (Medicines Control Council, 2007)

B : Maintenance of eect (Relapse prevention)

C : Prevention of recurrence (Prophylaxis)

Double-blind comparison against placebo, minimum duration 1 year.

MCC gives no specic Reports of adequate and recommendations for an well-controlled investigations antidepressant claim, but provide the primary basis for the following general determining whether there is recommendations : substantial evidence to support the claims of eectiveness for new Data presented in support of the safety and ecacy of the drugs medicine should be derived from FDA demands no specic design for clinical trials conducted in antidepressants, but recent compliance with internationally licensures had the following accepted GCP guidelines. The characteristics : studies should be properly Superiority vs. placebo in two designed and conducted, and pivotal studies (randomized, should be of acceptable statistical double-blind, adequate number power. of patients and statistical power). The trial design of the relevant Studies may include an active clinical studies should be such treatment control or a that the safety and ecacy of the dose-comparison control medicine can be established in No specic recommendations comparison to either placebo are supplied for a separate and/or a registered medicine in prophylactic claim the UK, USA, Sweden, Canada, Australia and EU. Registration of an antidepressant in selected other countries appears to be highly supportive for licensure : The Council aligns itself with the following regulatory authorities : USA (FDA), UK (MHRA), Sweden (MPA,) Australia (TGA), Canada (Health Canada), European Union (EMEA) and Japan (MWH). No specic recommendations are supplied for a separate prophylactic claim

EMEA=European Medicines Agency ; FDA=US Food and Drug Administration ; MCC=Medical Control Council of South Africa.

does not fulll the complete diagnostic criteria according to DSM-IV or ICD-10 even when antidepressant therapies are clearly needed (see chapter 10.2.2). In addition, dierences in the clinical picture of depressive disorders inuence both the choice and outcome of specic antidepressant treatment. The tendency of patients to stop eating and lose weight may also alter the clinical presentation of depressive disorders. These patients are more often referred to

general practitioners or specialists in internal medicine than to psychiatrists. The PRIME-MD Patient Health Questionnaire (PHQ-9) (Nease and Maloin, 2003) and even simpler screening questions (Arroll et al., 2005) have been suggested as appropriate instruments for accurately identifying depressed patients in primary care settings because there is good evidence that screening helps to identify persons in need of treatment (Berg, 2002).

S16

CINP Antidepressant Task Force 2007 5.2 Features of particular relevance to the treatment of depressive disorders The basis of the following chapter 5.2 are rarely RCTs but predominantly a clinical consensus of the CINP antidepressant task force predominantly based on clinical experience, open studies, case series and case reports. The information provided in this chapter should serve as a contribution to the actual knowledge base, not as a guideline for treatment. Table 6 summarizes diagnostic indications including diagnostic subgroups and psychiatric comorbidities for specic classes of antidepressants. 5.2.1 Unipolar depression

Table 5. Symptomatology of depressive disorders (American Psychiatric Association, 1994 ; World Health Organization, 1992 ; World Health Organization, 2005b) Category of depressive symptoms Aective symptoms

Symptom list
$ $ $

Psychomotor disturbances Disturbances of cognition and memory

$ $ $ $ $ $

$ $

Psychovegetative disturbances and somatic complaints

$ $ $ $ $ $ $

Depressed mood* Anhedonia* Anxiety17 Retardation Agitation Loss of energy and activity* Feelings of guilt Feelings of worthlessness Mood-congruent and -incongruent delusions Concentration decits Memory decits Sleep disturbances (insomnia, early morning awakening) Diurnal changes Loss of appetite and weight Sexual dysfunction Constipation Pain syndromes Hypertonia Tachycardia

* Core symptoms of depression.

The use of operationalized diagnostic systems such as ICD-10 and DSM-IV may cause an inclusion of larger populations in diagnostic categories in comparison to the former used categories based on psychopathology and psychiatric nosology e.g. introduced by Kurt Schneider or Emil Kraepelin. Distinguishing vital depression, depressive psychopathy18 and reactive depression according Schneider may inuence also therapeutic outcome during antidepressant therapies. Nevertheless the diagnostic systems help to compare similar populations suering from depressive disorders and to evaluate treatment eects worldwide. In this chapter the eects of diagnostic categories and subgroups on treatment outcome are described not only on basis of scientic evidence, but also based on a broad clinical consensus within the CINP antidepressant task force. The review of the subgroups of depression is selective, based on the relevance of clinical features to treatment choices.
17

A signicant proportion of depressive disorders show an episodic course. With the exception of the recurrent brief depressive episodes singled out in the ICD, the threshold for reaching a diagnosis is that symptoms be present for at least 2 weeks. Shorter duration places the episodes into a subthreshold group. The dierences between threshold and subthreshold depression are discernible but not very helpful in clinical work since it has been shown that subthreshold depression (for which treatment may not be reimbursable in some countries) causes disability and often requires treatment. Especially in children and adolescents, as well as in the elderly, depressive disorders comprise a variety of inherently dicult diagnostic problems. These diculties may be further aggravated by the presence of other conditions such as anxiety or personality disorders. The following sections describe specic subtypes of depressive symptoms that may inuence antidepressant therapy. For other subtypes of depression that respond similarly to treatment, no dierentiation appears to be warranted. 5.2.1.1 Severity of the disease Depressive episodes can be classied as mild, moderate or severe (ICD-10). Subsyndromal depression may enhance the risk of developing a syndromal depressive disorder according to ICD-10 and DSM-IV, and treatment may be necessary. In addition to clinical judgment, e.g. using ICD-10 diagnostic criteria or the Clinical Global Impressions scale (CGI-S, Item I, severity of disease) (National Institute of Mental Health, 1976), severity groups can be distinguished using instruments such as the Hamilton (Hamilton, 1960) or MontgomeryAsberg rating scales for de pression (Montgomery and Asberg, 1979). This subdivision is of clinical importance because there is some consensus in the literature that mild depressive syndromes should be treated by

Anxiety is not included in the diagnostic systems of ICD-10 and DSM-IV, but there is a broad clinical consensus that anxiety symptoms are accompanying depression frequently. 18 Psychopathy here is used as a historical term, not as a diagnostic category.

CINP Antidepressant Task Force 2007

S17

Table 6. Diagnostic indications for specic classes of antidepressants according clinical experience, open studies, case series, case reports and the consensus of the CINP Antidepressant Task Force Diagnostic subgroups or comorbidities Mild to moderate unipolar depression Severe unipolar depression, depression with melancholic features Depression with psychotic symptoms

Specic indications
$

Specic features
$ $

Usually treatment with established antidepressants, but treatment with St. Johns wort possible Dually acting antidepressants (TCAs, SNRIs, NaSSA) ECT Usually combination therapy using antidepressants and antipsychotics Lithium augmentation Highest eectiveness of ECT Some reports support the eectiveness of a SSRI monotherapy Combination of antidepressants with benzodiazepines or sedating antidepressants in case of agitation Nonsedating and activating antidepressants such as SSRIs or NARIs in case of psychomotor inhibition Good eectiveness of ECT MAOIs and SSRIs as rst line treatments Bright light therapy as an early augmentation strategy in case of at least moderate depression Bright light therapy as a monotherapy in case of mild depression possible Antidepressants with mixed serotonergic and noradrenergic or selective noradrenergic mode of action ecacious (TCAs, SNRIs, NARI, NaSSA) Earlier use of psychosocial therapies in combination with antidepressants

Good tolerability of phytotherapeutics Only St. Johns wort showed sucient ecacy Better ecacy in comparison to SSRIs Better ecacy in comparison to antidepressants High rate of treatment refractoriness Augmentation strategies should be considered at early stages to enhance ecacy

$ $

$ $ $

Psychomotor agitation and retardation/katatonic features

Acute sedating eects relieving rapidly the patients restlessness are useful in clinical routine Avoiding sedation in case of psychomotor retardation is useful Katatonic features may predict rapid ECT eects Better clinical eectiveness in comparison to other antidepressants Suicidality may be enhanced during bright light therapy

Atypical features Seasonal features

Depression with chronic pain

$ $

Possibly higher remission rates Better relieve of pain syndromes

Adjustment disorders

Bipolar depression

SSRIs or MAOIs as a rst line treatment recommended

Combination with mood stabilizers recommended Monotherapy with mood stabilizers possible Early combination of antidepressants with psychotherapy recommended No established treatment regimes supported by RCTs

RCTs are rare, but clinical experience suggests eectiveness of antidepressants TCAs and other dually acting antidepressants such as SNRIs may increase the switch risk

Dysthymia and double depression Recurrent brief depression

Combination may enhance eectiveness especially in chronic depression Higher risk for suicidal ideation

psychotherapy without additional biological therapies such as pharmacotherapy or electroconvulsive therapy (ECT). In moderate depression non-biological

treatments are also the rst choice in some guidelines, although, moderately depressed patients respond equally well to antidepressant medication. Moreover,

S18

CINP Antidepressant Task Force 2007 features by some authors) are also seen in depressed patients (Fink, 1992 ; Starkstein et al., 1996 ; Taylor and Fink, 2003). ECT has been reported to have an excellent eect in these cases (Fink, 1990 ; Rohland et al., 1993). Administration of benzodiazepines (lorazepam) during acute-phase treatment can lead to immediate relief of catatonic symptoms. For routine clinical cases, sedating antidepressants or combinations of nonsedating antidepressants with sedating benzodiazepines are used in agitated patients, whereas activating substances such as SSRIs or noradrenalin reuptake inhibitors (NARIs) are used in patients with predominantly psychomotor inhibition. 5.2.1.3.2 Melancholic features

there is a distinct probability that patients with mild to moderate depression may respond to phytotherapeutics such as St. Johns wort (Kasper, 2001 ; Laakmann et al., 1998) or benzodiazepines without antidepressants (though this option is not recommended) (Laakmann et al., 1996). There is also some evidence that very severe depressive syndromes show a better response to ECT, tricyclic antidepressants (TCAs) and dual-action substances such as venlafaxine, duloxetine and mirtazapine. 5.2.1.2 Depression with psychotic symptoms Psychotic features of depression such as hallucinations and delusions, e.g. delusional hypochondria, feelings of guilt or nihilistic thoughts, are predominantly mood congruent, but may also be non-congruent with depressed mood. Depressive episodes with psychotic symptoms are in most cases an indicator of the particular severity of the disease, including high risk of suicide. This additional risk factor must be taken into account in planning treatment. In patients suering from psychotic symptoms, a combination of antidepressant therapy with antipsychotic medication is usually recommended (Coryell, 1996). It has, however, been reported that this combination confers no benet for some patient subgroups, e.g. elderly patients (Mulsant et al., 2001). TCAs and selective serotonin reuptake inhibitors (SSRIs) in combination with antipsychotics are recommended, and amoxapine has been shown to exert somewhat lower but likewise signicant ecacy (Anton and Burch, 1990 ; Rothschild et al., 1993). SSRI monotherapy reportedly is ecacious during acute and maintenance treatment (Zanardi et al., 1996 ; Zanardi et al., 1997). ECT has been recommended as a possible rst-line treatment because of its high eectiveness during acute episodes (Coryell, 1998) and more favorable long-term outcome (Birkenhager et al., 2004) in this subgroup of patients, especially in comparison with pharmacotherapy (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). Finally, early consideration of lithium augmentation is recommended in this patient group especially in the case of antidepressant treatment failure (Bauer et al., 2003 ; Price et al., 1983). 5.2.1.3 Other clinical features with a possible impact on antidepressant therapies 5.2.1.3.1 Severe psychomotor agitation and retardation Severe psychomotor retardation, stupor, immobility or, in contrast, severe agitation (called catatonic

Melancholic forms of depression are characterized by a higher age of occurrence, a loss of the ability to feel pleasure, depressive delusions and a variety of often severe somatic symptoms (Table 2 and Table 5), as well as major psychomotor symptoms. The treatment of depression with melancholic features is similar to that recommended for severe depression. Patients frequently respond to augmentative strategies, such as addition of lithium and sleep deprivation. 5.2.1.3.3 Atypical features

There is no clear agreement about the features that characterize atypical depression (Fountoulakis et al., 1999). In French-speaking countries the term atypical is used for depressed patients with psychotic features. According to DSM-IV, a diagnosis of atypical depression requires meeting two of the following criteria : increase in appetite and weight gain, hypersomnia, leaden paralysis and a long-standing pattern of interpersonal rejection sensitivity. The Inventory of Depressive Symptomatology Clinician Rating (IDS-C30) is also suitable for diagnosing atypical depression, and includes earlier age at onset, greater comorbidity with anxiety symptoms and greater symptom severity compared with non-atypical depression (Novick et al., 2005). Empirical data support the hypothesis that monoamine oxidase inhibitors (MAOIs) and SSRIs represent a rst-line treatment option that is superior to other pharmacological treatment (Andrews and Nemero, 1994 ; Henkel et al., 2006 ; Sogaard et al., 1999). Owing to the special precautions they require, in some countries irreversible MAOIs are not recommended as a rst-line treatment. 5.2.1.3.4 Seasonal features

Patients suering from depression that recurs on a regular, annual basis during fall or early winter

CINP Antidepressant Task Force 2007 and spring often show subsequent symptoms of bipolar disorder (chapter 5.2.2.1). In addition, depressive syndromes are frequently characterized by features listed as atypical in DSM-IV (see chapter 5.2.1.3.3). If depressive symptoms are of moderate severity, seasonal forms of depression are treated like other recurrent episodes. Bright light therapy (phototherapy ; see also chapter 19.7) can be used as an early augmentation strategy (chapter 12.3.8). Because of its proven ecacy (Kasper et al., 1990 ; Rosenthal et al., 1985), bright light therapy can even be used as monotherapy in the case of mild depression19 during a limited treatment trial. But the possibility of occurrence or enhancement of suicidal ideation during phototherapy must be taken into account (Praschak-Rieder et al., 1997). 5.2.1.3.5 Depressive syndromes in pain conditions

S19

been discussed (Fava, 2003c). Antidepressants are now seen by many as an essential supplement in a variety of therapeutic regimes for pain control. 5.2.1.3.6 Depressive syndromes in adjustment disorders Because symptoms of adjustment disorders and depressive disorders may be identical, and also because depressive episodes often occur after exposure to severe stress, there is no reason to oer patients suering from adjustment disorder therapeutic regimes other than those that oered to patients with depressive disorders. This is especially true during the period of acute treatment. Although controlled ecacy trials in adjustment disorders are rare, both clinical experience and retrospective studies (Hameed et al., 2005) suggest no dierence between depression and adjustment disorder in response rates to treatment. The use of psychosocial therapies in adjustment disorders may begin earlier and be more intense. 5.2.2 Other forms of depressive disorders 5.2.2.1 Bipolar depression Diagnostic criteria for a depressive episode due to bipolar I disorder are the same as already described for cases of unipolar depression (see chapter 5.1). In addition, a diagnosis of bipolar disorder must be based on at least one previous manic or mixed episode, including a period of abnormally and persistently elevated, expansive or irritable mood lasting at least 1 week (even shorter, if hospitalization is necessary). During this time, grandiosity or inated self-esteem are normally present together with decreased need for sleep, hyperactivity, psychomotor agitation, racing thoughts with ight of ideas, distractibility and a drive to keep talking that causes marked impairment in social functioning. In the case of a mixed episode, these symptoms occur simultaneously with depressive symptoms for at least 1 week. In the case of bipolar II disorder, the patients history must include at least one episode of hypomania (a period of manic symptoms of lesser severity that lasts at least 24 days). However, shorter hypomanic bleeps may also justify treating a patient according to criteria for bipolar depression, not unipolar depression (Akiskal et al., 2000 ; Cassano et al., 1988). Finally, continuity between bipolar II disorder and unipolar severe (major) depression has been suggested (Akiskal and Benazzi, 2006). Because the symptoms of bipolar depression are identical to those of unipolar depression, and because at the time of the initial depressive episode it is not

Depressive disorders and predominantly chronic pain are frequent comorbid conditions. Approximately 70 % of patients with major depression present with physical complaints (Fava, 2002 ; Simon et al., 1999b). Severe pain caused by somatic diseases comorbid with depression makes the treatment of depression dicult. Somatoform disorders, bromyalgia and similar conditions characterized by pain are often accompanied by depressed mood. Eective treatment of neuropathic pain requires the application of antidepressants with a mixed serotonergic and noradrenergic mode of action, such as the TCA amitriptyline (Saarto and Wien, 2005, 2007). Newer antidepressants have been shown to be useful in the treatment of pain conditions with and without comorbid depression. Various pharmacodynamic classes, such as SSRIs, NARIs, noradrenergic and selective serotonergic antidepressants (NaSSAs) (Mattia et al., 2002) and selective serotonin and noradrenalin reuptake inhibitors (SNRIs) (Barkin and Barkin, 2005 ; Gendreau et al., 2005) have shown ecacy in anecdotal reports, only SNRI and TCA have proven ecacy according a recent Cochrane review (Saarto and Wien, 2007). It seems plausible that antidepressants with both serotonergic and noradrenergic properties could be particularly eective in treating pain and painful physical symptoms. Higher remission rates in these subgroups of depressed patients have recently
19 There exists no clear cut denition for mild depression in the literature. In addition to the severity of disease mentioned in the ICD-10 (World Health Organization, 1992) the subdivision of depressive syndromes can be done with rating scale cut o values using the CGI or HAMD scale (e.g. as done in Laakmann et al., 1996 and 1998).

S20

CINP Antidepressant Task Force 2007 depression, although it produces very similar levels of disabilities. Also, an additional and superimposing major depressive episode can occur in patients already suering from dysthymia, diagnosed then as a double depression or double major depressive disorder . When a dysthymic episode follows a depressive episode, the dierential diagnosis of both disorders is dicult because the symptoms of dysthymia are then indistinguishable from the (reduced) symptoms of depressive disorder with only partial remission, which should be diagnosed in this case. Only after full remission lasting at least 6 months can the subsequent dysthymic symptoms are diagnosed as dysthymia. Because both diagnostic entities respond to the same antidepressant, identical acute treatment plans can be prescribed for depressive disorders, dysthymia and double depression. In addition, antipsychotic treatment such as amisulpride22 (Rocca et al., 2002 ; Zanardi and Smeraldi, 2005) may be of use. Due to the chronic nature of dysthymic disorders, earlier implementation of psychotherapy can help. Treatment goals should be formulated somewhat more cautiously because dysthymia appears to have less likelihood of complete recovery (Judd et al., 1998a). The combination of pharmacotherapy and an empirically supported psychotherapy may be optimal for chronically depressed patients (Keller et al., 2000 ; Rush and Thase, 1999 ; Markowitz, 1993). 5.2.2.3 Recurrent brief depression23 Recurrent brief depression (RBD) is characterized by depressive episodes that occur at least once a month and last only a few days (Pezawas et al., 2001). The combination of depressive disorders and RBD exhibits a relatively high prevalence. The substantially higher risk for suicidal ideation in such cases presents a special concern. Most trials investigating antidepressant therapies were designed to judge therapeutic ecacy in major depressive disorders. Dierent study designs are needed to properly investigate the combination of depressive disorders and RBD. The literature contains a variety of negative results concerning RCTs of SSRIs in the treatment and prophylaxis of RBD (e.g. Angst and Dobler-Mikola, 1985 ; Montgomery et al., 1994),

possible to make a diagnosis of bipolar disorder, up to 50 % of younger patients suering from depression at the rst index episode later receive a diagnosis of a bipolar disorder (Angst, 2006 ; Goldberg, 2003). These rates are, however, controversial (Patten, 2006). Although the evidence for the ecacy and eectiveness of antidepressant treatment of bipolar depression is less compelling than that for treatment of unipolar depression, the same substances that lead to clinical improvement in unipolar depression can be used in bipolar depression. Because of a lower switch risk from depression to hypomania or mania and given their good ecacy, predominantly SSRIs or MAOIs (Gijsman et al., 2004) and bupropion (Sachs et al., 1994) in combination with mood stabilizers are considered to be the treatment of choice (Grunze et al., 2002). In addition monotherapies using mood stabilizers such as lithium or lamotrigine or atypical antipsychotics (e.g. quetiapine) are possible. Because there is no uniform denition of switch , the switch rates in scientic publications vary widely. Nevertheless, a threefold higher switch rate during TCA therapy in comparison with SSRI treatment has been reported (Peet, 1994). It has thus been suggested that all antidepressants, but especially TCAs and dual-action antidepressants such as SNRIs, be recommended20 in combination with mood stabilizers to prevent an enhanced switch risk. It should be mentioned that for bipolar depression there is also reasonably good evidence for monotherapy with the mood stabilizers lithium and lamotrigine as well as with the atypical antipsychotics olanzapine and quetiapine (Yatham, 2005). Moreover the use of adjunctive antidepressant medication in was not associated in with increased ecacy in comparison to treatment with mood stabilizers alone (Sachs et al., 2007). However, to date there is no proof that these treatment regimens work any better than antidepressants (Moller et al., 2006). 5.2.2.2 Dysthymia and depressive disorder in combination with dysthymia21 Diagnostic criteria for dysthymia and depressive disorders dier in the severity and duration of symptoms. Dysthymia constitutes a chronic depressive syndrome of lower intensity of symptoms than severe
20

In clinical practice this recommendation is followed more frequently in the US than in European countries. The scientic basis for this suggestion is still a matter of debate. 21 From a scientic perspective, there is presently insucient reason to dene double depression as a specic subgroup of depressive disorders.

22 Amisulpride is not available in the US, and for the time being, the use of other antipsychotics for dysthymia is not recommended. 23 According to DSM-IV, recurrent brief depression can only be diagnosed as subthreshold major depressive disorder (MDD). According to ICD-10, it is a diagnostic category of recurrent depressive disorder (RBD). The combination of severe depressive disorders and RBD is sometimes called combined depression (CD) (Pezawas et al., 2001).

CINP Antidepressant Task Force 2007 but methodological problems and highly selective patient samples may account for the results (Pezawas et al., 2001). There are as yet no ecacious treatment algorithms for RBD (Pezawas et al., 2005). 5.2.3 Depressive disorders with comorbid psychiatric disorders Comorbidity of depressive disorders with other psychiatric disorders is common (Pincus et al., 1999) and signicantly aects treatment outcomes. The greater the number of concurrent comorbid conditions, the greater the severity, morbidity and chronicity of depressive disorders (Rush et al., 2005c). Treatment of depression that occurs with other conditions thus calls for special attention and reection in treatment plans. 5.2.3.1 Other psychiatric disorders24 5.2.3.1.1 Anxiety disorders

S21

to have an earlier age of onset of depression, greater depressive symptomatology, greater functional impairment and more previous suicide attempts than patients with depression alone (Davis et al., 2006). Because pharmacokinetic and -dynamic drug interactions, as well as psychosocial consequences of drug abuse, all inuence response and recovery rates from depressive disorders, a combined therapeutic approach should address both the depressive disorder and the comorbid condition. This is especially true for psychotherapeutic and psychosocial approaches, but it holds as well for pharmacological treatment plans, e.g. in choosing antidepressants of lower pharmacological interaction potential, as is the case for some SSRIs, NARIs and dual-action antidepressants. 5.2.3.2 Personality disorders25 About one-third of depressed patients also have a personality disorder. The most common forms are obsessive-compulsive (16 %), paranoid (10 %) and schizoid (7 %) personality disorder (Hasin et al., 2005). In such instances, the eects of biological antidepressant therapies are less impressive, and treatment takes longer. Depression may be a positive predictive factor in the treatment of persons who have personality disorders (Shea et al., 1992). Early implementation of psychotherapeutic approaches in treatment may be helpful. 5.2.4 Depressive disorders with comorbid somatic disorders26 5.2.4.1 Physical disorders27 Depressive syndromes are frequently present in people with severe and chronic physical disorders. Somatic disorders or their treatment may be directly responsible for depressive symptoms (Patten and Barbui, 2004). The choice of treatment will depend on the severity of depression, comorbid somatic risks and somatic treatment. If an organic factor is the source of the depressive syndromes ( organic depression ), treating the organic disease rst must be considered when it can be done directly (e.g. substitution of thyroid hormones in case
25

A lifetime prevalence of more than 40 % for the comorbid depression and anxiety disorders, such as panic disorder, phobias and generalized anxiety disorder, has been reported in patients suering from depressive disorders (Hasin et al., 2005). Up to now, however, it has not been suciently clear whether the two diagnostic conditions are distinct or represent a single mixed anxiety-depression syndrome (or a spectrum disorder ). Patients with depressive disorders and comorbid panic disorder show dierences in the clinical course and severity of disease compared with patients suering from depressive disorders alone (Grunhaus et al., 1994). Because comorbid conditions can diminish the clinical eectiveness of antidepressant pharmacotherapy (Grunhaus et al., 1986), they should be considered in treatment plans. Administering antidepressants with demonstrated ecacy for both diagnostic entities (e.g. in the case of depressive and anxiety disorders, SSRIs such as paroxetine (Montgomery, 1992)), together with implementing specic psychotherapeutic options for depression and anxiety, seems to be a useful strategy (see also chapters 13 and 19.9). 5.2.3.1.2 Substance abuse

Disorders related to the use of alcohol, nicotine and other drugs often occur together with depression, and in the US have a lifetime comorbidity of 40, 30 and 17 %, respectively (Hasin et al., 2005). Depressed patients with comorbid substance abuse are more likely
24

Axis I disorders according to DSM-IV.

Axis II disorders according to DSM-IV. The concept of comorbidity does not necessarily include known causal interdependencies between somatic diseases and depression. Nevertheless, in some cases of comorbidity these may be known, and in others they may exist without precise knowledge. In addition, dierent somatic and psychiatric phenotypes of the same disease may exist. 27 The treatment of depression during chronic pain conditions is described in chapter 5.2.1.3.5.
26

S22

CINP Antidepressant Task Force 2007

Table 7. Examples of organic factors that may cause depressive disorders (see also Evans et al., 2005 ; Katona, 1997 ; World Psychiatric Association, 2006) Category of organic disease Neurological disorders Organic illness
$ $ $ $ $ $ $ $ $ $ $ $

Endocrine disorders

$ $ $ $ $

Other medical disorders

$ $ $ $ $ $

Pharmacogenic depression

28

$ $ $ $ $ $

Stroke Dementia Epilepsy Huntingtons chorea Hydrocephalus Central nervous system (CNS) infectious diseases CNS neoplasias Parkinsons disease Narcolepsy Sleep apnea Trauma Wilsons disease Adrenal disorders (Cushings disease, Addisons disease) Hyperaldosteronism Hyper- or hypoparathyroidism Hyper- or hypothyroidism Postpartum hormonal changes Neoplasias and paraneoplastic syndromes Cardiopulmonary diseases Autoimmune disorders (e.g. lupus erythematodes) Porphyria Uremia Avitaminoses (vitamins B12, C, folate, niacin or thiamine) Analgesics (ibuprofen, indometacin, opiates, phenacetin) Antibiotics (streptomycin, sulfonamides, tetracyclines) Antihypertensives (reserpin, clonidine, digitalis) Chemotherapeutics (asparaginase, azathioprine, bleomycine, trimethoprim, vincristine) Hormones (high-estrogen oral contraceptives) Immune system therapy/suppression (corticosteroids, interferons, mycophenolate mofetile, tacrolismus)

of hypothyroidism) and when depression is of mild to medium severity. When depression is severe or there is risk of suicide, an additional symptomatic antidepressant treatment is obligatory. The same is true if the organic factor cannot be treated owing to other conditions (e.g. immune system suppressors in the case of transplantation) or if recovery is unlikely (e.g. stroke). Table 7 lists possible organic causes for depressive syndromes. 5.2.4.1.1 Cardiovascular disorders

A variety of studies conrm the interdependency of medical disorders and the risk for developing depressive symptoms caused by comorbid depressive
28

It is presently not clear whether depressive syndromes following treatment with classical antipsychotics represent symptoms of the disease or a side eect of treatment.

disorders or adjustment disorder (Glassman et al., 2003 ; Glassman, 2005 ; Glassman et al., 2006). An exceptionally high comorbidity of depressive symptoms and cardiovascular disorders (CVDs) has been described (Purebl et al., 2006), but the detection of depression in patients suering from CVD is relatively low. Moreover, the comorbidity of depressive disorders and CVD signicantly inuences the medical outcome of coronary artery disease and myocardial infarction (Frasure-Smith et al., 1993 ; Musselman et al., 1998), especially when depressive symptoms are refractory (Carney et al., 2004). Knowledge about differential risk factors or predictors of adverse events in patients suering from myocardial infarction and depression is still limited (Jae et al., 2006). Depression enhances cardiovascular mortality independent of other cardiovascular risk factors (Penninx et al., 2001) and appears also to be an independent additional risk

CINP Antidepressant Task Force 2007 factor for cardiovascular disease (Wulsin and Singal, 2003). The most important inuencing factor may be the severity of the depressive syndrome (Penninx et al., 2001) or the presence of a major depressive disorder (Schulz et al., 2000). Less severe forms of depression seem to be less deleterious. Another apparently important inuencing factor is activation of central stress regulation systems, predominantly hypothalamic-pituitary adrenal (HPA)-axis activation present in the majority of depressed patients (Lederbogen et al., 1999). There is consensus that it is important to treat depression in this patient subgroup suciently, although, both a signicantly lowered risk of death or recurrent myocardial infarction in patients taking selective SSRIs (Taylor et al., 2005) and a failure to prove lowered cardiac risk due to antidepressant treatment (Berkman et al., 2003 ; Shimbo et al., 2005) have been reported. Antidepressant pharmacotherapy stipulates using drugs that have as low a drug-drug interaction risk as possible and exert no negative inuence on cardiac conductance, rhythm or output. Most modern antidepressants t this prole, including SSRIs, NARIs and dual-action substances. In addition, because depression may worsen coronary blood ow (Lederbogen et al., 2001), it seems plausible to make use of the diminishing eects of SSRIs on platelet aggregation (Maurer-Spurej et al., 2004) to achieve further benet for patients suering from depression and cardiovascular disease. 5.2.4.1.2 Endocrinological disorders and diabetes mellitus Depression has been shown to be a risk factor for type II diabetes mellitus (Eaton et al., 1996) ; a bidirectional positive association has been assumed (Eaton, 2002 ; Evans et al., 2005). Endocrinological disturbances known to be present during depressive states, such as hypercortisolism, may facilitate the development of diabetes. A negative inuence of depression on therapeutic adherence and the risk of vascular complications and disability have been described. The eectiveness of antidepressant treatments in diabetic patients has been shown, but the potential benet for blood glucose and HbA1c levels remains unclear (Evans et al., 2005). Antidepressants and antipsychotics with sedating properties due to antihistaminergic eects also facilitate weight gain and the development of metabolic syndromes, worsen diabetes mellitus or abett a switch from prediabetic syndrome to frank diabetes (American Diabetes Association, 2005). 5.2.4.1.3 Renal disorders

S23

Severe acute and chronic renal diseases can cause depressive syndromes (Kimmel and Peterson, 2005) within adjustment disorders. They also represent a psychosocial burden capable of initiating episodes of depressive disorders. Both cases call for an antidepressant treatment plan. In addition to psychotherapeutic counseling, antidepressant pharmacotherapy may be necessary. Renal failure can complicate antidepressant pharmacotherapy because diminished renal clearance can provoke increased side eects and toxic eects of antidepressants. Increased responsiveness to antidepressant drugs (Finkelstein et al., 2002) along with greater unpredictability and interpatient variability (Dawling et al., 1982) have been reported. Dose adjustment is often necessary, e.g. half the standard does at the outset of treatment. Antidepressants with a lower likelihood of interacting with other drugs via the cytochrome P-450 system (see chapter 9.1.1.1), such as the SSRIs sertraline or citalopram, are suggested. Frequent evaluation of side eects and blood level monitoring are useful tools to prevent overdoses. If renal failure progresses to end-stage renal disease and hemodialysis, hemoperfusion or hemoltration are necessary, lower antidepressant plasma levels are possible, and dose adjustment may be required considering blood levels, ecacy and side eects. 5.2.4.1.4 Hepatic disorders

Patients suering from chronic hepatitis may develop enhanced risk for depression, especially in the case of treatment with interferon (Asnis and De La Garza, II, 2006), and some may even require prophylactic antidepressant treatment (Schaefer et al., 2002 ; Schaefer et al., 2003). Comorbidity of depression and hepatic diseases demands specic precautions. Antidepressant drugs are metabolized in the liver, and only a small proportion of some substances (e.g. 2 % of paroxetine) can be secreted unchanged in the urine (Tossani et al., 2005). Antidepressants rank 5th on the list of drugs that cause liver injury (Andrade et al., 2005). The hepatotoxic properties of antidepressants can lead to transient increases in liver enzymes, but also to fulminant liver failure. For that reason, in depression accompanied by liver disease it is necessary to start treatment using substances that have a lower probability of causing additional liver damage. TCAs, MAOIs and nefazodone appear to have higher hepatotoxicity compared with newer agents such as SSRIs (Lucena et al., 2003). But SSRIs and other modern

S24

CINP Antidepressant Task Force 2007 drugs are to be expected, especially with carbamazepine. 5.2.4.2.2 Stroke and dementia

substances also require dose adaptation in patients suering from liver disease to prevent side eects and intolerable toxicity which may occur because of a lower clearance of antidepressants and metabolites, and consequently prolonged elimination times (Demolis et al., 1996 ; Joe et al., 1998 ; Suri et al., 2005). Milnacipran may be an exception : because it is metabolized outside the liver, it appears possible to use milnacipran in the case of liver impairment without having to adapt the dose (Montgomery et al., 1996 ; Puozzo et al., 1998). 5.2.4.2 Neurological disorders Depression is a relatively common psychiatric comorbidity of most neurological disorders, with prevalence rates ranging between 20 and 50 % among patients with epilepsy, stroke, dementia, Parkinsons disease and multiple sclerosis (Kanner, 2005b). In addition, a side eect of treatment of neurological disorders (e.g. with corticosteroids) enhances risks for depression. Antidepressant pharmacotherapy is therefore mandatory in most cases of medium to severe depression. Antidepressant pharmacotherapy may however worsen the neurological condition of patients. For example, in patients taking high doses of antidepressants, the incidence of seizures rises markedly. This is particularly important if TCAs, especially maprotiline, are used. 5.2.4.2.1 Epilepsy

A bidirectional relationship between the incidence of epilepsy and depression has been described (Kanner, 2005a). In addition, patients with treatment-resistant epilepsy who have undergone temporal lobectomy often experience post-surgical depression following temporal lobectomies (Kanner, 2003), and antidepressant pharmacotherapy may be necessary. Lifting of depression after resective surgical treatment for epilepsy has also been reported (Spencer et al., 2003). Because lower therapeutic doses of antidepressants may also trigger seizures in patients suering from epilepsy, cautious treatment using the lowest ecacious doses is mandatory, especially with TCA treatment, because TCAs may diminish the threshold for seizures. But SSRIs, too, have the potential to prolong epileptic seizures, e.g. during ECT treatment) (Curran, 1995), or to cause lower sodium levels, which lower the seizure threshold. Fluoxetine and uvoxamine seem to exhibit the lowest risk for seizures (Pisani et al., 1999). In addition, pharmacokinetic interactions between antidepressants and antiepileptic

Patients suering from severe depression who need hospitalization are at an increased risk of developing cerebrovascular disorders (Nilsson and Kessing, 2004). Patients hospitalized after stroke very often not only suer from neurological disturbances but also show depressed mood, requiring treatment. A concept of a vascular or arteriosclerotic depression has been proposed (Krishnan and McDonald, 1995). Symptoms of depression in Alzheimers disease (AD) (Derouesne and Lacomblez, 2004) and other forms of dementia are often seen but are rarely distinguishable from apathy, loss of drive and aective disturbances that are among the symptoms of Alzheimers disease. Moreover, depressive symptoms seem to be an independent risk factor for later development of AD (Green et al., 2003 ; Ownby et al., 2006). A history of depression is associated with a more rapid cognitive decline in patients with AD and pronounced neuropathological changes in the hippocampus (Rapp et al., 2006). It has been suggested that AD and depression are associated with shared risk factors such as sex, age, vascular function and apolipoprotein E4 (APOE4) (Gallarda, 1999). This connection notwithstanding, meta-analyses show no improvement in cognitive function or disability following treatment for post-stroke depression (Anderson et al., 2004), although relief of depression in itself may justify pharmacologic treatment (Hackett et al., 2004). Moreover, good ecacy of the NaSSA mirtazapine in preventing post-stroke depression has been reported (Niedermaier et al., 2004 ; Ween, 2005). Also SSRI or NARI in the treatment of poststroke depression have shown to be superior to placebo (Rickards, 2005), moreover SSRI or TCA treatment during the rst 6 months poststroke signicantly increased the survival of both depressed and nondepressed patients (Jorge et al., 2003). The recovery after stroke appeared to be enhanced by the use of antidepressant medication if treatment was started within the rst month after stroke (Narushima et al., 2003b). In addition, on the long term, an improved cognitive function after remission of poststroke depression is likely to remain stable if no additional cerebrovascular events occur (Narushima et al., 2003a) and also an improvement of executive functioning following stroke seems to be enhanced due to antidepressant treatment (Narushima et al., 2007).

CINP Antidepressant Task Force 2007 Treatment of depression must not be allowed to contribute to a worsening of dementia, e.g. due to anticholinergic side eects. For this reason SSRIs, NARIs, SNRIs and NaSSAs would appear to compare favorably with TCAs. 5.2.4.2.3 Parkinsons disease

S25

The risk for depressive disorders in patients suering from Parkinsons disease (PD) (Hantz et al., 1994) is controversial. A high prevalence of depression in PD (2040 %) has been reported (Lieberman, 2006), and even up to 50 % (McDonald et al., 2003). In addition, depression may precede the diagnosis of PD (Schuurman et al., 2002). Although published controlled studies are lacking it seems that antidepressant treatment is benecial for patients and improves the overall quality of life (Anon., 2002 ; Weintraub et al., 2005). Both SSRIs and SNRIs are generally well tolerated and ecacious (Lemke, 2002 ; Menza et al., 2004). Selegiline can be integrated into MAO-B inhibitor treatment plans for PD (Bodkin and Amsterdam, 2002), even though its therapeutic eect on depression may in some cases be only modest (Amsterdam, 2003). The potential benet of the anticholinergic properties of TCAs in PD should be considered. Given that concomitant heart disease, prostatic enlargement and acute angle-closure glaucoma are frequent comorbid conditions in elderly patients suering from PD, TCAs should be used with caution in this patient group (Cummings and Masterman, 1999). A moderate association of SSRI use and extrapyramidal motor side eects has been reported in susceptible patients (Schillevoort et al., 2002). These eects include acute dystonia, akathisia and aggravation of parkinsonism (Anon., 2001). They may be caused by an interaction between serotonergic and dopaminergic pathways (Lambert et al., 1998). 5.2.4.2.4 Encephalitis disseminata/multiple sclerosis Even though patients suering from multiple sclerosis often show aective disturbance without depression, such as pathological laughing and crying (Feinstein et al., 1999), anxiety and euphoria (Diaz-Olavarrieta et al., 1999), an association between multiple sclerosis and depression has also been reported (Patten and Metz, 1997). In these cases, antidepressant pharmacotherapy should be considered. 5.2.4.2.5 Migraine

Comorbid migraine signicantly inuences the quality of life of depressed patients (Hung et al., 2006). When migraine accompanies depressive disorder, antidepressant pharmacotherapy not only ameliorates depressive symptoms but can also prevent migraine attacks. Both TCAs (amitriptyline) and SSRIs (uoxetine) have shown eectiveness in this indication, in the usual antidepressant doses (Campo-Arias, 2004), but exacerbation of migraine attacks during SSRI treatment has also been described (Bickel et al., 2005). Patients prescribed triptans for migraine who are also taking SSRIs, MAOIs or lithium may be at enhanced risk of developing serotinin syndrome. Because the number of serotonin syndromes reported is low, and their severity mild to moderate, combined use of triptans and SSRIs or lithium appears to be only a relative contraindication. But owing to the limited results published to date, MAOIs should be strictly avoided (Gardner and Lynd, 1998). 5.2.4.3 Infectious disorders Infectious diseases are often accompanied by psychiatric syndromes such as depression. This may be true not only during the acute state of the disease but also after adequate treatment of the medical condition. For example, mixed anxiety-depression syndrome has been reported to follow medical recovery from falciparum malaria (Dugbartey et al., 1998). Also, patients infected with hepatitis C are more likely to suer psychiatric comorbidities such as depressive disorders (Butt et al., 2006). In addition, specic somatic therapies such as interferones or antibiotics may increase the risk of developing severe depressive symptoms. Infectious diseases aecting the nervous system, such as Lyme disease (Fallon and Nields, 1994) or neurosyphilis (neuro-lues) (Pavlovic and Milovic, 1999), have been associated with psychiatric disorders, including major depression. A particular interdependency has been described between infection with the human immunodeciency virus (HIV), acquired immunodeciency syndrome (AIDS) and depressive disorders : depression is believed to be associated with HIV risk behaviors (Hutton et al., 2004), and HIV infection is associated with depression and suicidal behavior (Jin et al., 2006 ; Porche and Willis, 2006). For further details see (Maj et al., 1993). Both the infection and the depressive syndrome should be adequately treated, considing all options, including antidepressant pharmacotherapy. Possible interactions between antidepressants and medical treatments such as antibiotics must also be taken into account.

Depression is one of the most frequent comorbid disorders in chronic migraine (Mercante et al., 2005).

S26

CINP Antidepressant Task Force 2007 out by the International Consortium of Psychiatric Epidemiology (ICPE), 37000 adults in 10 countries (in the Americas, Europe and Asia) were interviewed with the WMH-CIDI (World Health Organization Composite International Diagnostic Interview ; Kessler et al., 2003 ; Robins et al., 1988 ; Wittchen, 1994). The lifetime prevalence of depression varied widely from 3 % in Japan to 16.9 % in the US, with most countries in the range between 8 % and 12 % (Andrade et al., 2003). Across the Asia-Pacic region, lifetime rates ranged from 1.1 to 19.9 % (Chiu, 2004). In an extended WHO household survey with the WMH-CIDI of more than 60000 adults in 14 countries (Americas, Europe, Middle East, Africa and Asia), the 12-month prevalence of mood disorders ranged from 0.8 % (Nigeria) to 9.6 % (US) (Demyttenaere et al., 2004). A South American study that focused not on the diagnosis of depression but on depressive symptoms found prevalence rates up to 72.6 % (Rodriguez and Puerta, 1997). The prevalence of depression in Venezuela is reported to vary between dierent parts of the country. Only 1 out of 10 depressed patients receives care and treatment. Similar numbers hold true for Mexico. With a lifetime prevalence of 9.1 % for aective disorders, there is a wide variance between urban and rural areas. However, use of services for any psychiatric disorder is low : 11.7 % for those with one psychiatric diagnosis and 19.4 % for those with two diagnoses (Medina-Mora et al., 2003). These results and the ICPE study demonstrate the potential impact of psychosocial and cultural factors on the manifestation and diagnosis of depression as well as the methodological diculties of studies of depression. The European Study of the Epidemiology of Mental Disorders (ESEMeD), which used methods similar to those of the WHO study, found a 12-month prevalence rate of 4.2 % for mood disorders across six European nations, comparable to the results of the WHO study (Alonso et al., 2004) and to earlier WHO estimates of the prevalence of depression (Sartorius et al., 1993 ; Sartorius, 1993). Other publications describing the prevalence of depression in northern Africa are currently in preparation. The low rates in Nigeria, however, might be explained by the fact that most diagnostic criteria for depression and the scales used in developed countries may be not appropriate for assessing functional impairment in rural African communities, and that many features of depression, e.g. fatigue, could be misinterpreted as signs of HIV infection. Another possible explanation may be that depression occurs at a later age in Africa (Gureje et al., 2007). The Nigerian survey sample had a mean age of onset of about 30 years, but

5.2.4.4 Neoplasias and paraneoplastic syndromes Stressful life events including severe physical illness including neoplasias have been linked to depressive symptoms and to major depressive disorder (Monroe and Simons, 1991). Depression occurs at an increased rate in patients suering from cancer (Rodin et al., 2007). Recently in cancer patients rates of 19 % for depressive symptoms and 8 % for major depressive disorder have been reported (Wedding et al., 2007). Moreover most chemotherapeutics used in the pharmacological teatment of cancer (see Table 10) may cause a pharmacogenic depression. Oncologists play a key role in screening for psychiatric disorders including anxiety and depression in patients with cancer (Miovic and Block, 2007). The treatment should include the available pharmacoand psychotherapeutic approaches and improves quality of life substancially (Miovic and Block, 2007). Of course potential interactions of antidepressant medications with somatic disturbances due to cancer, e.g. renal (see chapter 5.2.4.1.3) or liver (see chapter 5.2.4.1.4) failure and pharmacological interactions with chemotherapeutics (see chapter 9.1.1.1) have to be taken into account and substances with low interaction potential e.g. citalopram, sertraline or venlafaxine may be advantageous. In addition mianserin has shown good ecacy in a RCT (van Heeringen and Zivkov, 1996). 5.3 Epidemiology of depressive disorders

Depressive disorders are very common. They are among the main causes of disability due to disease, and the World Health Organization (WHO) estimates that they will be the second most important cause of disability by the year 2020 (World Health Organization, 2002). Chronic depressive episodes are common and are associated with greater illness burden and socioeconomic disadvantage (Gilmer et al., 2005). Throughout Europe, 23 % of years of healthy life is lost due to brain disorders ; they cause approximately onethird of all burden of disease (Olesen and Leonardi, 2003). Among these disorders, depression plays a predominant role. In Europe depression is the major cause of disability, with a prevalence of around 5 % per year (Paykel et al., 2005), a still present widespread underrecognition and undertreatment of depressive disorders has been reported recently (Lecrubier, 2007). Epidemiological studies of depression show considerable variation across and within countries (see Figure 1), to a large extent on account of imperfect assessment instruments. One recent estimate put prevalence at 16 % (Ebmeier et al., 2006). In a study carried

CINP Antidepressant Task Force 2007

30 25 20 15 10 5 0 Prevalence (%)
Ankara, Turkey Athens, Greece Bangalore, India Berlin, Germany Groningen, Netherlands Ibadan, Nigeria Mainz, Germany Manchester, UK Nagasaki, Japan Paris, France Rio de Janeiro, Brazil Santiago, Chile Seattle, USA Shanghai, China Verona, Italy

S27

Figure 1. Dierential prevalence of depression in primary health care in dierent WHO centers (Goldberg and Lecrubier, 1995 ; Ustun and Sartorius, 1995).

the median age of onset of major depressive disorder in the sample was about 45 years. In other words, most of the respondents had lived through the mean age of onset. Another survey among the elderly in Nigeria conrms a much later age of onset (compared with what is commonly reported in the literature) and yields a much higher prevalence of depression. Correcting for these confounders by using appropriate scales and symptom criteria, Bolton et al. found the point prevalence as high as 21 % for depression in Uganda (Bolton et al., 2004). The fact that older prevalence studies reported lower prevalence rates in comparison to newer studies has been reported early : The lowest gures in studies performed between 1961 and 1978 are at least 9 times greater than the highest gures in surveys between 1931 and 1961 (Hoenig, 1980). Because the second period correspondents with the introduction of antidepressants, it could be argued that the presence of eective treatments may enhance the awareness for now better treatable diseases. But in addition the postulated increasing prevalence or changing diagnostic systems including a higher sensitivity for depressive disorders may serve as an explanation. The average age of onset is reported to be between 20 and 30 years (Ebmeier et al., 2006). Marked gender dierences have been reported ; women are aected twice as often as men (Kessler, 2003). In addition,

women are twice as likely as men to report a positive family history of mood disorder, which is associated with a younger age of onset of depression (Nierenberg et al., 2007). In addition not only the prevalence but also the consequences of depressive disorders, such as impairment and suicidality, are aected by age and gender of patients (see also chapter 10). The mean duration of depressive episodes was 16 weeks. About 90 % of patients are suering from at least moderate up to very severe forms of depression, causing severe impairment in their daily activities (Kessler et al., 2003). The particular health importance of depression is further heightened by the prediction that the prevalence of depressive disorder will increase in the years to come (Sartorius, 2001). The rationale for this prediction includes demographic factors (e.g. increased life expectancy at all ages), better chances of survival of people with chronic diseases often comorbid with depression, iatrogenic eects (e.g. because the widespread use of drugs is likely to increase rates of depression), passive risks inherent in social changes (such as diminishing family care and increased numbers of people living alone) and rising levels of stress observable in many countries. While depressive disorders in most, but not all studies appear to be within the same range worldwide (27 %), estimates of rates of suicide attempts and completed suicides vary greatly among countries. The recent increases in suicide rates in eastern European countries are a particularly good example of the impact of changes in society on rates of suicide (Sartorius, 1995). 6. Standards of care

According to WHO, fewer than 25 % (in some countries less than 10 %) of depressed patients receive adequate care :
Barriers to eective care include the lack of resources, lack of trained providers, and the social stigma associated with mental disorders, including depression. Primary care-based quality improvement programs for depression have been shown to improve the
$ $ $ $ $ $

quality of care satisfaction with care health outcomes functioning economic productivity and household wealth at a reasonable cost. (World Health Organization, 2005b).

To achieve these goals, as put forward by WHO, education of the population and those who deliver health care is crucial to increase the number of patients being diagnosed correctly and early. When a diagnosis

S28

CINP Antidepressant Task Force 2007 cost-eectiveness, the main argument is that the primary care physician is generally in a better position to diagnose and treat depression if he or she is responsible for the overall medical care of the patient, which may include other ongoing medical diseases and the potential for drug-drug interactions. In addition, patients tend to see the primary care physician rst because somatic complaints are part of the depressive syndrome. The important role of primary care physicians is also shown in a German survey (Wittchen and Pittrow, 2002), which found that 10.9 % of unselected patients visiting their primary care doctor suer from depression. However, only 55 % of them were recognized by their doctors as having depression, despite the fact that 72 % of the primary care physicians participating considered their competence in diagnosing depression to be good. To study the degree to which primary care physicians recognize depression as a mental health problem, Dutch researchers looked at accuracy of diagnosis and treatment in accordance with clinical guidelines for depression. The researchers found that nonrecognition, misdiagnosis and inadequate treatment were not limited to patients with relatively mild and brief depression but were also prominent in patients with persistent depression who consulted their general practitioner 8.2 times on average during the year their depression persisted (Van Os et al., 2006). Standardized training programs are obviously needed and can be helpful in improving management of depression by primary care physicians (Van Os et al., 1999). Thus, arguments in favor of early consultation with a psychiatrist include the complexity of a differentiated diagnosis and treatment of depressive disorders, including all the considerations mentioned above and of utmost importance expertise in assessing the risk of suicide and, in rare cases, homicide. If health resources are limited, e.g. in developing countries where both psychiatrists and clinical psychologists are often in very short supply, patients should have access to personnel with sucient knowledge and experience to diagnose depression, e.g. general practitioners or at least trained nurses. If resources allow, identication of the core symptoms of depression should be considered against a checklist, such as the Diagnostic and Statistical Manual of Mental Disorders, 4th revision (DSM-IV) (American Psychiatric Association, 1994), or the International Statistical Classication of Diseases and Related Health Problems, 10th revision (ICD-10) (World Health Organization, 1992), to improve condence in and reliability of diagnosis of depression. Structured interviews, such as the Structured Clinical Interview

of depression has been established, patients and caregivers should gain unrestricted access to mental health and complementary services. Even in highly industrialized countries, there is a large gap between the relatively high prevalence of depressive disorders and the less frequent use and late onset of the use of antidepressant treatments (Henkel and Moller, 2005). In the case of treatment-resistant depressive disorders, further enhancement of therapeutic approaches should be provided as well (see also chapter 9.1.12) to attain the ultimate treatment goal of full remission. Unfortunately, these standards are realized for only a minority of patients. On a global scale, the primary diagnosis is more often made and treatment supplied by other resources, e.g. traditional healers. 6.1 Diagnosis

In comparing recommendations and clinical practice in dierent countries, there seems to be no general consensus on who should establish the diagnosis of depression. Whereas most European guidelines, including the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines (Bauer et al., 2002c), explicitly or implicitly refer to a trained psychiatrist for establishing a diagnosis of depression, several review papers by US experts acknowledge a role for primary care physicians in establishing diagnosis and initiating initial treatment. In the US, a majority of patients suering from depressive disorders are diagnosed and treated by general practitioners or well-trained clinical psychologists. The screening instruments for GPs therefore should incluce a screening for the main core symptoms of depression (see chapter 5.1). Other countries take a dierent approach, e.g. China, where most depressed patients are treated by psychiatrists and in some extend by neurologists and internal specialists, or some South-East Asian, e.g. Philippines, and South American countries, e.g. Bolivia, where traditional healers play a prominent role (Seguin, 1986). Their contribution to the management of depression should not be underestimated, as non-specic aspects, including beliefs and trust, are important variables for any treatment success (Alarcon et al., 1999 ; Shepherd and Sartorius, 1989). Nevertheless, psychiatric consultation is recommended when a patient has not shown marked improvement within 8 weeks of initial treatment or when the primary care physician is concerned about the complexity of the case (Wittchen and Pittrow, 2002), and also when collaboration between psychiatrists and clinical psychologists is needed. In some countries guidelines recommend also shorter intervals, e.g. 6 weeks in China. Aside from considerations of

CINP Antidepressant Task Force 2007 for DSM-IV (SCID), may be helpful tools, especially if in doubt. Due to the time-consuming nature of the SCID in primary care settings, the shorter Mini International Neuropsychiatric Interview (MINI) can help to generate reliable DSM-IV and ICD-10 diagnoses. Note, however, that though such instruments may be very sensitive, their validity could be low. In non-specialist settings, the value of routine administration of simple questionnaires to detect and measure depression remains unclear. A review by Gilbody et al. found it unreliable in the majority of studies (Gilbody et al., 2003b). In contrast, the US Preventive Services Task Force (US Preventive Services Task Force, 2002) and the Canadian Task Force on Preventive Health Care (MacMillan et al., 2005) report on good evidence that screening instruments improve accurate identication of depression in adults in primary care settings, although evidence for children and adolescents is insucient. Of the multitude of screening instruments available, the PRIME-MD Patient Health Questionnaire (PHQ-9) is considered the best available screening tool for depression in primary care (Nease and Maloin, 2003). Comorbidity, especially with anxiety disorders or substance abuse, may often mask the underlying depressive illness. On the other hand, after establishing the diagnosis of depression, patients should routinely be interviewed for other major psychiatric disorders, as their presence will impact the choice of treatment. Organic conditions such as neurological illnesses, e.g. multiple sclerosis or any other lesions involving subcortical or cortical areas and other limbic circuits, should always be excluded. However, when discussing the potential underdiagnosis of depression, someone should also be aware of the caveat of overdiagnosing. As demonstrated by Beck (Beck, 1967) in a sample of 486 probands, ranging from non depressed controls to severely depressed patients, there is still a fair amount of clinical features of depression even in normal controls (see Table 8). With increasing public and specialist awareness of depression, strict diagnostic criteria should be followed, the diagnosis should not be based of one of few features, and the diagnosis should be regularly rechecked to avoid overdiagnosis and at least unnecessary, if not harmful, treatment. Once a diagnosis of major (unipolar) depression has been established, keeping all potential caveats in mind, the level of symptom severity, functional impairment and impact on quality of life should be determined. If possible, this should be done not only on the basis of patients reports but also on the basis of the history supplied by relatives and objective data, e.g.

S29

Table 8. Frequency of Clinical features of patients varying in depth of depression, based on a sample of n=486 probands (adapted from Beck, 1967) Depth of depression None Mild Moderate Severe ( %) ( %) ( %) ( %) 18 6 3 25 16 6 13 18 14 25 27 14 23 39 31 17 19 72 32 11 53 72 13 47 42 58 56 46 56 54 62 55 33 26 94 70 29 72 94 37 73 68 85 75 64 83 88 89 73 61 38 98 87 28 75 94 37 94 83 86 90 60 92 88 84 88 88 52

Clinical feature Sad facies Stooped posture Crying in interview Speech : slow, etc. Low mood Diurnal variation of mood Suicidal wishes Indecisiveness Hopelessness Feeling inadequate Conscious guilt Loss of interest Loss of motivation Fatigability Sleep disturbance Loss of appetite Constipation

recent periods on sick leave. To characterize the depressive syndrome as well as to choose the appropriate treatment and treatment setting, any psychotic symptoms and most important suicidal thoughts or plans must be assessed at the rst visit. Especially suicidality, the outstanding threat of depressive disorders, determines the further treatment plan, since in some instances it may be necessary to hospitalize a patient against his or her will. Given that more than 10 % of depressed patients commit suicide (Angst et al., 2005 ; for patients who received no inpatient psychiatric treatment, lower rates have been reported (Simon and Von Kor, 1998)), acute suicidality constitutes a medical emergency that calls for immediate and consequent action. In addition it is essential to optimize the awareness of suicidal ideations and attempts. Predictors of elevated suicide risk include greater severity of depression, suicidal ideation, hopelessness, unemployment, comorbid psychotic disorder, substance abuse, personality disorder, a family history of mental disorders, history of attempted suicide, male gender, or being widowed or divorced (Brown et al., 2000 ; Moscicki, 1999). Thus, it is crucial to be aware of the patients history and evaluate signs of suicidality, e.g. hopelessness (Goldston et al., 2006 ; Sinclair et al., 2005), on a regular basis.

S30

CINP Antidepressant Task Force 2007

Box 2. Principles of access to services (adapted from the BAP guidelines)

$

$ $

Assessment should be oered by a trained psychiatrist29 with an understanding of both the medical and psychological treatments available for management of depressive disorders. Patients should have access to early intervention, which must include the option of hospital admission. Appropriate use of legal powers of detention is mandatory for the successful management of risks in some patients with acute depression and suicidality. Consistent outpatient follow-up is necessary, and many individual patients may require more complex interventions in community settings.

To obtain a full clinical picture prior to treatment, patients and, if available, relatives should be interviewed about previous illness and treatment history, and other concurrent psychiatric and somatic disorders, including non-psychiatric medication. Because psychosocial stress factors may both contribute to the onset of a depressive episode and interfere with treatment success, recent life events should be documented and may lead to early psychotherapeutic intervention in addition to medication. Especially for patients who do not respond to treatment, diagnosis should be rechecked regularly for correctness. Treatment success could, for example, be confounded by ongoing substance abuse or underlying personality disorder. In addition, because in most cases bipolar disorder rst manifests with a depressive episode, patients and relatives should be questioned for emerging (hypo)manic symptoms both at the initial taking of the patients history and also during treatment. Emergence of (hypo)manic symptoms usually leads to changes in treatment plans, e.g. discontinuing antidepressants and switching to mood stabilizers. 6.2 Access to mental health services

possibility of direct hospital admission, health and insurance policies in dierent countries may not yet reect this standard ; elsewhere, a lack of resources makes it dicult. Nevertheless, considering the consequences of inadequate diagnosis and treatment (including treatment settings) for prolonged illness, chronicity and nally potential suicide, measures must be taken to ensure these standards worldwide. 6.3 Enhanced care

The following principles of access to services are adapted from the British Association for Psychopharmacology (BAP) guidelines for treating bipolar disorder (Goodwin, 2003) but also apply to unipolar depression (see Box 2). Whether diagnosis and treatment initiation should be done by a primary care physician, a health professional or a trained psychiatrist has been discussed above. While WHO has recommended general practitioners and World Psychiatric Association (WPA) psychiatrists as primary care suppliers, CINP currently has no position of its own. With respect to easy access to a trained psychiatrist, including the
29

Because there are too few trained psychiatrists worldwide, clinical psychologists and well-trained nurses may also help to provide sucient care for depressed patients.

Guidelines (e.g. APA (American Psychiatric Association, 2000), WFSBP (Bauer et al., 2002c ; Bauer et al., 2002b)) embody a uniform consensus that, independent of the choice of the specic medical treatment intervention, general components of psychiatric management and psychotherapeutic support should be initiated and continued throughout the entire treatment (Bauer et al., 2002c). As a rst step, a therapeutic alliance must be established. This includes the psychiatrist or physician taking full responsibility for diagnosis, physical examination, other investigations and explanation of the medical plan of management to the patient and his relatives. The therapist should take his time to listen to the patients complaints and always communicate clearly, understandably and honestly what he thinks. He should determine together with the patient a treatment plan and the appropriate treatment setting, and, for outpatients, ensure regular visits. During acute phase treatment, weekly or biweekly visits are recommended (Bauer et al., 2002c) ; during the continuation phase and after syndromal recovery, a frequency of one visit per month appears to be adequate (Bauer et al., 2002c). In the case of concurrent psychotherapy supplied by a psychotherapist, frequent communication between the physician and therapist about the patients status should be ensured. In addition, a good communication between the treating psychiatrist and the GP about the patients general health status and the recommended laboratory controls during antidepressant treatment is essential.

CINP Antidepressant Task Force 2007

Box 3. Principles of enhanced care (adapted and modied according to Goodwin, 2003)
$ $

S31

$ $

$ $

Educate yourself and then the patient and his relatives about the disorder. Ensure that you are always up to date regarding the latest developments in diagnosis and treatment through continuing medical education. Try to base the treatment decision on evidence and not on beliefs. Use the evidence also to address the acute treatment modalities of the illness, the risk of relapse and the benet of psychotherapeutic engagement to the patient. Educate the patient and his relatives about the treatment for the illness to enhance adherence. In addition, inform the patient and his relatives about possible side eects of medication and potential symptoms that may question the original diagnosis, e.g. emergence of (hypo)manic symptoms. Inform the patient and his relatives that enhanced drive before the onset of antidepressant action in the initial antidepressant treatment phase could lead to increased risk of suicide. Make the patient aware of stressors, the impact of sleep disturbance, the importance of regular patterns of activity and early signs of relapse. Educate the patient about the poor outcome associated with alcohol and substance abuse and, if required, give appropriate advice and oer treatment. Evaluate and manage functional impairment and supply the patient and his family with a realistic view about his capacity to work and function within the family. Identify potential sources of psychosocial support in the community and help the patient to contact them.

Box 3 presents an example for enhanced care adapted from Goodwin et al. (Goodwin, 2003). Other aspects of enhanced care, e.g. therapeutic drug monitoring, will be addressed more specically in the next chapter (see also chapter 9.1.1.1.3). In primary care settings, integrated quality improvement strategies involving combinations of clinician and patient education, nurse case management, enhanced support from specialist psychiatric services and monitoring of drug concordance have been shown to be clinically and cost-eective in the short term, but this eect disappears in longer-term follow-up. However, simple and relatively cheap telephone support, counselling and medication monitoring delivered by counsellors or nurse practitioners are clinically eective and likely to be cost eective (Gilbody et al., 2003a ; Gilbody et al., 2003b).

Response

Remission

Relapse

Free interval Recurrence

Healthy

Depressed Spontaneous course Acute treatment Continuation and maintenance treatment

Figure 2. Long-term treatment of depression (modied from Kupfer, 1991).

Clearly, clinical management of depression goes far beyond these criteria, which are meant to establish evidence for ecacy of treatment. Although remission is recognized as the optimal outcome of treatment for depression, remission lacks a universally accepted denition (Israel, 2006).
$

7. Goals of treatment : response, remission, recovery Traditionally, treatment is divided into acute, continuation and maintenance (prophylactic) phases (Kupfer, 2005) (see Figure 2). Clinical trials focus on symptomatic relief measured by specic scales, e.g. the HAMD score (Hamilton, 1967), and dene response and remission in relation to these scores (usually 50 % reduction of the baseline score as response and a specic cut-o as remission , see Box 4). It should be kept in mind that remission as dened in clinical trials does not necessarily correspond to remission in clinical terms.

Goals of clinical management can be divided into acute, intermediate and long-term goals. The ultimate goal of acute treatment is to achieve remission, in other words not only being asymptomatic (in the sense of not meeting the criteria for diagnosis of the disorder and having no or only minimal residual symptoms) but also showing improvement in psychosocial and occupational functioning. The intermediate goal is further stabilization and preventing relapse, eliminating subsyndromal symptoms and restoring the prior level of functioning. The long-term goal is full recovery (Rush et al., 2006a) to prevent further episodes, maintain functioning and ensure a satisfactory quality of life (AHCPR (Agency for Health Care Policy and Research), 1999 ;

S32

CINP Antidepressant Task Force 2007

Box 4. Denition of response and remission (Thase, 2003)

$ $

The traditional denition of response to antidepressant therapy includes a 50 % improvement in symptoms30. Remission is dened as the absence of depressive symptoms and a full return to premorbid levels of functioning. In most randomized controlled studies, an absolute rating scale threshold is dened as remission (e.g. HAMD score f7). Full Recovery is dened as the full regain of social and occupational functioning without residual symptoms of depression.

Box 5. Choice of a specic drug The availability of dierent antidepressants may vary from country to country (see chapter 14). Among the antidepressants available, proven ecacy must be the rst consideration. In the next step, the choice of a specic drug should take into account not only the subtype of depression but also previous experience with antidepressants, especially potential tolerability problems in conjunction with contraindications due to medical comorbidity, and nally the preference of the patient after explaining potential advantages and disadvantages of candidate medications.

American Psychiatric Association, 2000 ; Bauer et al., 2002c). From the patients perspective, the most important criteria for remission are the presence of features of positive mental health such as optimism and selfcondence, self-satisfaction and a return to ones usual, normal self and level of functioning (Zimmerman et al., 2006). Therefore, while the patient is still depressed, the therapist should facilitate the maintenance of social activities and prevent stigmatization. This includes the use of psychotherapeutic and sociotherapeutic approaches. Depressive disorders are frequently associated with signicant impairments in social functioning due to a long persistence of residual symptoms after remission of depressive symptoms (Fava et al., 2007 ; Hirschfeld et al., 2000). To regain social and occupational functioning therefore is one of the major treatment goals. Depression is associated with marked suering, morbidity, and a high risk of recurrence and/or chronicity. Treating patients with depression to a state of remission is associated with a signicantly improved long-term outcome, including reduced risk of relapse (Ramana et al., 1995 ; Rush et al., 2006b) and improved functioning. Thus, remission (which can be dened as the nearly complete absence of depressive symptoms) should be the goal of the acute phase of pharmacotherapy (Thase and Ninan, 2002). However, an important goal in all phases of the illness is to prevent suicide as the most deleterious, and unfortunately still frequent outcome of depression (Angst et al., 2005), as well as to prevent

death from somatic disorders associated with depression, e.g. cardiovascular disease (Angst et al., 2002a). Optimal clinical eectiveness of the treatment should also include optimized safety and tolerability. Assessing and documenting the achievement of these treatment goals on a regular basis is of utmost importance because it guides further treatment decisions. 7.1 Acute treatment

30

Response and remission are usually measured using instruments such as the MontgomeryAsberg Depression Rating Scale (MADRS) or the HAMD rating scale. In comparing RCTs, it is important to be aware of the time interval after which response or remission was achieved.

Initiation of antidepressant treatment should be a rst step of an overall treatment plan. If antidepressant treatment with medication is the choice, it may be combined with varying degrees of psychosocial intervention ranging from basic psychoeducation to formal augmentation with an empirically supported psychotherapy, if necessary in combination with psychosocial support. The decision which medication to choose depends on several factors (see Box 5). Depending on the setting (inpatient or outpatient), the medical constitution of the patient and previous experience, the rate of titration may vary considerably. The usual recommendation for outpatients is to start with the lowest eective dose to ensure good tolerability. If no side eects occur or if side eects fade within a few days, further stepwise dosage increases up to the usual standard dose (see Table 11) can be made until relief of symptoms is observed. Especially when specialist care is not available, e.g. in a general hospital, and ease of use, high tolerability and low drug-drug interaction potential are of importance, the recommended rst choice of antidepressant is a selective serotonin reuptake inhibitor (SSRI) or other, newer antidepressant with a favorable side eect prole (Voellinger et al., 2003). Regardless of the drug chosen, during antidepressant pharmacotherapy one must reckon with a delay of several weeks until sucient antidepressant eects can be seen. Up to now no denite response prediction using

CINP Antidepressant Task Force 2007 biological variables can be used during an antidepressant pharmacotherapy. Nevertheless behavioral changes such as an early improvement in motor retardation or a reduction of anxiety have been reported to be dependent of the clinical prole of the class of the prescribed antidepressant and may be clinically usefull to predict the later treatment response (Katz, 2004). This has also been true in the case of a comparison of the eects of TCA and psychotherapy whereas Amitriptyline had early eects on vegetative symptoms of depression psychotherapy showed more delayed eects on mood, suicidal ideation, work, and interests (DiMascio et al., 1979). In addition also an overall early onset of improvement has been shown to be highly predictive of later outcome (Stassen et al., 1996, 1997 ; Stassen and Angst, 1998). An absence of any change (improvement <20 %) during the rst two weeks of treatment is highly predictive of clinical non-response during the following weeks of treatment (Stassen et al., 1996 ; Stassen and Angst, 1998). Therefore the prior postulated lag of clinical response to antidepressants has been questioned during the last years due to the fact that an eective antidepressant treatment initiates clinical changes even during the rst week of antidepressant treatment (Stassen et al., 1999 ; Taylor et al., 2006). If a treatment is not the rst medication trial and a patient has previously been on uoxetine or irreversible monoamine oxidase inhibitors (MAOIs), a washout period of at least 2 weeks (up to 5 weeks in the case of a switch from uoxetine to irreversible MAOIs) must be observed, especially when treatment with a serotonergic acting drug is planned. Otherwise, serotonin syndrome a potential lethal complication may, rarely, occur (Boyer and Shannon, 2005 ; Haddad, 2001). Serotonin syndrome is not specic only to SSRIs but may also occur with other serotonergic acting substances, e.g. venlafaxine in combination with MAOIs (Phillips and Ringo, 1995). When switching to reversible MAOIs, e.g. moclobemide, a few (23) days of pausing medication is sucient (Dingemanse et al., 1995 ; Dingemanse et al., 1998). For details of MAOI tolerability, see also chapter 9.1.3.2. On the other hand, sudden discontinuation of antidepressant treatment usually cannot be advised, but the possibility of immediate switching has been proposed (Wohlreich et al., 2005b ; Wohlreich et al., 2005a). When switching from one medication to another, overlapping tapering is recommended unless a specic medication, e.g. an irreversible MAOI, requires a washout phase (Larsen, 1988). Sudden cessation of treatment can lead to discontinuation symptoms (see chapter 9.1.1.3.2), which have

S33

been described for numerous classes of antidepressant drugs (particularly common with MAOIs, venlafaxine and SSRIs, especially paroxetine, and less common with uoxetine and escitalopram) (Baboolal, 2004 ; Haddad, 1998 ; Rosenbaum et al., 1998 ; Schatzberg et al., 2006). The reported frequency of antidepressant discontinuation syndromes varies widely from 1060 % depending on the class of medication and study methodology, with an estimated average of 20 % (Warner et al, 2006). A survey of the French pharmacovigilance database revealed that SSRIs are clearly associated with a higher risk of discontinuation syndrome than other antidepressants (OR 5.05, 95 % CI 3.816.68) and in particular venlafaxine and paroxetine (OR 12.16, 95 % CI 6.1723.35 and OR 8.47, 95 % CI 5.6312.65, respectively) (Trenque et al., 2002). Discontinuation syndrome may also aect newborns of mothers who are taking SSRIs. A database analysis revealed a total of 93 suspected cases of SSRI-induced neonatal discontinuation syndrome. These were regarded as sucient to suggest a possible causal relation. Sixty-four of the cases were associated with paroxetine, 14 with uoxetine, 9 with sertraline and 7 with citalopram (Sanz et al., 2005a). It is also worth noting that the novel pharmacological compound agomelatine has not been on the market suciently long enough for a nal judgement regarding discontinuation symptoms, but the substance was not associated with discontinuation symptoms in one, specially designed, randomized, double blind, placebo-controlled, discontinuation study (Montgomery et al., 2004c). Antidepressant discontinuation syndrome presents as a u-like syndrome and is to some degree similar to the well-known activation syndrome that can occur when starting a serotonergic drug. Symptoms of discontinuation syndrome include agitation, sleep disturbances, sweating, gastrointestinal discomfort and headache, and may take up to 2 weeks to subside. Symptoms may put the patient at risk for an early relapse (Fava, 2003a ; Harvey et al., 2003) and may stress the therapeutic alliance (Garner et al., 1993). Abruptly stopping TCA treatment may put susceptible patients at risk for cholinergic syndrome, especially older patients or patients with pre-existing neurological conditions (Garner et al., 1993). Where there is doubt whether the symptomatology is related to drug discontinuation, reintroducing the previous medication with consequent cessation of symptoms may clarify the issue. Expectations regarding the potential ecacy of a given treatment dier according to expert reviews and guidelines. For acute treatment, recommendations vary regarding how long the drug of rst choice

S34

CINP Antidepressant Task Force 2007 and uoxetine, onset of improvement occurred in more than 70 % of patients within the rst 3 weeks. There was no evidence for pronounced improvement rates thereafter. Also, during mirtazapine and paroxetine treatment early improvement was a highly sensitive predictor of later stable response or remission (Szegedi et al., 2003). By the same token, evidence suggests that older patients especially may take longer to show a full response to antidepressant medication (up to 12 weeks) (Furukawa et al., 2000). To bridge the time until onset of symptomatic improvement and for acute relief of symptoms, e.g. agitation and sleep disturbance, short-term addition of benzodiazepines may be considered, as they have been shown to accelerate response (Furukawa et al., 2000 ; Furukawa et al., 2001a ; Furukawa et al., 2001b ; Smith et al., 2002). Bear in mind, however, that depressed patients treated in mental health settings often receive long-term treatment with benzodiazepines, which is inconsistent with guideline recommendations (Clark et al., 2004 ; Valenstein et al., 2004). Additional augmentation therapies such as sleep deprivation and light therapy may also be considered. To establish true refractoriness in the case of nonresponse or suspected insucient dosage, if available, therapeutic drug monitoring (TDM) may be helpful (see also chapter 9.1.1.1.3). TDM is based on the hypothesis that a well-dened relationship exists between drug plasma concentration and its clinical eects (therapeutic eects, adverse eects and toxicity). This hypothesis is generally well accepted for lithium and for the TCAs nortriptyline, amitriptyline, desipramine and imipramine (Baumann et al., 2005). But results are inconsistent for other tricyclics, SSRIs and several more recently introduced antidepressants, with the exception of venlafaxine (Corruble and Guel, 2000). Due to the economic aspects of TDM (measuring plasma levels for a single psychoactive drug, including its metabolites, costs between E20 and E80) (Baumann et al., 2005), TDM should be reserved for cases where a relationship can be demonstrated between serum concentration eectiveness and side eects and in conjunction with a clinical question, e.g. insucient treatment response, side eects due to overdosing and so on. Moreover, serum level measurements should only be performed under steady-state conditions (at least ve half-lives, in most drugs 1 week after a dosage increase or decrease) and when the concentration of a drug is at a minimum (trough level). Several factors may interfere with antidepressant serum concentration, including absorption and excretion of the drug, bioavailability and binding to plasma proteins. These factors determine the plasma half-life of the

should be tested and when to alter treatment depending on time and degree of improvement. All available antidepressants are estimated to produce treatment responses of 5075 % in moderately to severely depressed patients, which means that despite sucient dosage, 2550 % of patients do not respond suciently to the initial treatment selection. However, of those responding, the estimated likelihood that they would have also responded to placebo is 25 % to 50 %. This has also been outlined by Davis et al.s meta-analysis, in which, response rates with active drugs, ranged from 45 % to 79 %, and, with placebo, from 23 % to 48 %. (Davis et al., 1993). Higher levels of pain and somatization predict a longer time to remission. Higher levels of pain correlates with severity of depression as shown in a Swedish population study (Andersson et al, 1993). Pain especially may be a marker for depression that is more dicult to treat as demonstrated by a secondary analysis of an imipramine/interpersonal psychotherapy combination study (Karp et al., 2005). The investigators of this study concluded that patients with recurrent depression should thus be screened for painful physical symptoms. They also suggest these symptoms may require a more aggressive treatment or the use of dual-mechanism antidepressants, although the usefulness of this approach still needs to be proven. The decision regarding whether a response is sufcient can be guided by administration of established rating scales. As outlined by Rush and Kupfer (Bauer et al., 2002c ; Kupfer and Rush, 1983), non-response would be dened as a f25 % decrease in baseline symptom severity, partial response as a 2649 % decrease and response as a o50 % decrease. According to World Federation of Societies of Biological Psychiatry (WFSBP) guidelines, an acute-phase medication trial should last at least 6 weeks, and 810 weeks to dene the full extent of symptom reduction (Bauer et al., 2002c). This contrasts with a recommendation from a round-table consensus published by Hirscheld et al. calling for a switch of antidepressant in the case of non-response after 4 weeks of treatment. Patients remaining as partial responders after 68 weeks should receive a dose escalation, followed by augmentation or switching strategies (Hirschfeld et al., 2002 ; Quitkin et al., 2005). These recommendations are based, among others, on the ndings of Nierenberg et al. (2000) showing that in patients who had not received at least 30 % reduction of symptom severity by 4 weeks on uoxetine, the likelihood of a response at 8 weeks was only about 1227 %. Similarly, Stassen and Angst (1998) reported that in a controlled study comparing moclobemide

CINP Antidepressant Task Force 2007 drug, e.g. a short (about 210 hours) plasma half-life for venlafaxine, trazodone, tranylcypromine and moclobemide, or a very extensive plasma half-life, e.g. 315 days, for uoxetine and its metabolite noruoxetine. Several potential pharmacokinetic interactions between antidepressants and other medications are due to common metabolism by cytochrome P-450 (CYP) enzyme isoforms and/or enzyme inhibition (see also chapter 9.1.1.1.2, Table 12). Genetically determined polymorphisms of CYP2D6 and CYP2D19 are of high clinical relevance for antidepressants that are substrates of these enzymes, including tricyclic antidepressants (TCAs), some SSRIs, venlafaxine and mirtazapine. Roughly 58 % of Caucasians are considered to be poor metabolizers (PM) and 17 % are ultrarapid metabolizers (UM) (Baumann et al., 2005) ; the rst leads to increased serum levels and the latter to insucient buildup of serum concentrations. In Asian populations, the PM type may be less prevalent (about 1 % among Thai, Chinese and Japanese populations, and up to 4.8 % among Indians (Kitada, 2003)). But other enzymes may show variabilities that require further investigation in populations other than Caucasians (Morrison and Levy, 2004). Concomitant medication processed by the same enzymes inuences the metabolic rate of other substances. For example, some SSRIs that inhibit CYP2D6, especially uoxetine and paroxetine, but also bupropion, may result in clinically signicant inhibition with a consequent increase in serum levels of other substrates, e.g. antiarrhythmics, b-receptor antagonists such as propanolol and metoprolol, and opioids, e.g. codeine. Other antidepressants, including imipramine, nefazodone, venlafaxine and reboxetine31, are metabolized by the CYP3A4 pathway ; some antidepressants, e.g. noruoxetine, the metabolite of uoxetine and uvoxamine, also show potent inhibition of this enzyme (Baumann et al., 2005). Thus, TDM may also be an important tool in monitoring interactions when augmentation or combination treatments are considered (Baumann et al., 2005). When the chosen antidepressant treatment is eective and symptomatic remission has been achieved, the usual recommendation is to continue the antidepressant in unchanged dose unless side eects require tapering down. It is also recommended to continue the full dose of acute treatment during the maintenance phase. Frank et al. and Franchini et al. demonstrated that patients on maintenance therapy
31 As of this writing, reboxetine is marketed in Europe but not in the US.

S35

who received only half the acute phase dose of imipramine or paroxetine, respectively, rather than the full dose showed a signicantly higher rate of recurrence (Franchini et al., 1998 ; Frank et al., 1990). Thus, the frequent clinical practice of reducing dosage for maintenance treatment lacks an evidential base and may increase the patients risk of relapse. The situation may be dierent when full response during acute treatment has already been achieved with lowdose antidepressants ; in this case, it may be reasonable to continue treatment in the lower-dose range (Furukawa et al., 2003). 7.2 Continuation and maintenance treatment

Following initial remission from acute depression, continuation treatment should ensure stabilization, prevent early relapses, improve further functionality and foster reintegration. It is generally recommended to continue with the eective antidepressant monotherapy or combination treatment for at least another 36 months (Hirschfeld, 2000, see also Table 9), but patients with a history of long previous episodes may be candidates for longer continuation phase treatments (Ramana et al., 1995). Although relapse or recurrence may be prevented with long-term pharmacotherapy, this approach is only suited to patients at high risk of relapse or recurrence (Nierenberg et al., 2003). In a prospective 15-month follow-up study in depressed patients strong predictors of subsequent early relapses were residual symptoms. Relapses occurred in 76 % (13/17) of patients with residual symptoms and 25 % (10/40) of patients without (Ramana et al., 1995). It is thus strongly recommended to continue treatment until all symptoms have totally subsided (Prien, 1990). However, for patients whose history includes a previous, untreated episode, the individual duration of continuation treatment can be determined by asking about the time elapsed until spontaneous recovery occurred. For example, if a previous untreated episode lasted 9 months, continuation treatment of this episode should now last at least for the same time period. In general, treatment durations of between 6 months and 2 years have been recommended (Burrows, 1992 ; Burrows et al., 1993). If a decision for long-term maintenance treatment (prophylaxis against new depressive episodes) has been made, the transition from continuation to prophylaxis is not clear-cut. However, if there is no indication for prophylaxis or if the patient refuses to continue on medication, slow tapering o at the end of continuation is strongly advised. It has been suggested that the tapering phase should last at least 46 months (Bauer et al., 2002c).

S36

CINP Antidepressant Task Force 2007

Table 9. Selected guidelines for duration of antidepressant treatment following acute treatment response (adapted from Geddes et al., 2003 and extended) Recommended duration of continuation after medical management of the acute episode (months) UK Defeat Depression Consensus Statement (Paykel and Priest, 1992) US Agency for Health Care Policy and Research (Agency for Health Care Policy and Research, 1993) British Association for Psychopharmacology (Anderson et al., 2000) American Psychiatric Association (American Psychiatric Association, 2000) Korean Guidelines (Lee et al., 2006) 46 49

Number of episodes that would indicate that longer maintenance treatment is appropriate o2 o2

6 45 612

o3 in the past 5 years (or o6 in total) not specied 2 years up to indenitely for patients with : o3 episodes 2 episodes + family + family history of mood disorder comorbid dysthymia a history of recurrence within 1 year after discontinuing medications a severe depressive episode a history of poor acute treatment response

Brazilian Guidelines (Fleck et al., 2003) Australian and New Zealand Guidelines (Ellis, 2004)

6 12

o3 in past 5 years (or o5 in total) in recurrent depression :up to 3 years

Maintenance treatment is most commonly appropriate for patients with recurring episodes, especially when more than one episode prior to the present one has occurred during the last 5 years or when remission has been dicult to achieve. Other factors that inuence the decision in favor of maintenance treatment include the number as well as the severity of previous episodes, the duration of previous symptom-free intervals, and comorbidity with other psychiatric or medical illnesses as well as the presence of suicidal ideation. Combining an antidepressant with lithium may not only improve relapse prevention (Sackeim et al., 2001a) but also be more protective against suicide (Muller-Oerlinghausen et al., 2006). Once a patient has stabilized on the combination, it is unwise to withdraw lithium for at least a year (Bauer et al., 2000 ; Bschor et al., 2002). However, there are no controlled studies for assessing the optimal length of maintenance treatment in general or how to identify clear predictors for choosing an individual time span. In patients with more than two or three relapses, yearlong or sometimes lifelong prophylactic treatment has

been recommended, e.g. the WFSBP Guidelines recommend maintenance treatment of 510 years in recurrent patients not at special risk. They consider lifelong maintenance in patients at greater risk, e.g. with more severe episodes, and especially when two or three attempts to withdraw medication have been followed by another episode within a year (Bauer et al., 2003). Risk factors for recurring depression have also been summarized by Nierenberg et al. (Nierenberg et al., 2003) based on evidence from several studies (Doogan and Caillard, 1992 ; Judd et al., 1998b ; Keller, 1999 ; Keller and Boland, 1998 ; Kupfer et al., 1992 ; Montgomery et al., 1988 ; Nelson, 2006 ; Ramana et al., 1995 ; Rush et al., 2006b) (Table 10). Analysing recent randomized, controlled maintenance studies, Fakra et al found that treatment prevents roughly 50 % of the recurrences that occur under placebo, regardless of the duration of the study or the pharmacological nature of the antidepressant drug (Fakra et al, 2006). Of special interest for daily practice, dealing with refractory patients, are the recent

CINP Antidepressant Task Force 2007

Table 10. Risk factors that inuence the probability of recurrence of a depressive episode (modied from Nierenberg et al., 2003) Risk factors for depressive recurrence Residual symptoms More than three prior depressive episodes Chronic depression (episode o2 years) Family history of mood disorders Comorbidities (e.g. anxiety disorder, substance abuse) Late onset (age >60 years) Two or more acute medication trials to achieve remission

S37

studies (e.g., Frank et al, 1990, Robinson et al, 1991, Terra and Montgomery, 1998), including a metaanalysis of long-term treatment (Geddes et al., 2003), clearly support the ecacy of antidepressant maintenance in clinical trial subjects, the role of long-term antidepressant continuation in less severely depressed patients still requires further clarication. 7.3 Managing side eects

ndings of the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study. With two or more acute treatment trials needed to achieve remission, the probability of a relapse increases : 33.5 % after the rst treatment step, 47.4 % after the second, 42.9 % after the third and 50 % after the fourth (Rush et al., 2006b). On the other hand, chances of relapse decrease and prognosis improves depending on the time elapsed since discontinuing medication. The risk of a depressive relapse is 60 % on placebo (compared with 29 % on antidepressants) after 1 year. For the second and third year, the risk to relapse on both antidepressants and placebo is reduced by 50 % compared with the rst year (29 % for placebo) and may continue to decline (Geddes et al., 2003). Thus, decisions regarding long-term treatment must be made on an individual basis, taking into account the patients past experience with longer medication-free intervals, if any. In selected patients, long-term treatment may be not favorable. A literature review by Fava (Fava, 2003a) raised the question whether at least a substantial subgroup of depressed patients may not benet from maintenance medication and may experience a worsening of the long-term course of the illness. According to Fava, the mechanism of this paradoxical eect may include growing tolerance to antidepressants, onset of resistance upon each challenge with the same antidepressant and withdrawal symptoms on sudden discontinuation of antidepressants, leading to destabilization. Fava speculates that continued drug treatment may initiate biological processes that counteract the initial acute eects of a drug and may result in loss of clinical eectiveness. When drugs are withdrawn abruptly, these processes may operate unopposed at least for some time and increase vulnerability to relapse. Whereas a multitude of clinical

This section focuses on general management of side eects. Medication-specic side eects are detailed in the specic sections on patients (see chapters 9.1.2 up to 9.1.11). Patients complaints about side eects of medications should always been taken seriously to forestall non-adherence and uncontrolled discontinuation. But patients do not always report side eects spontaneously, so active probing is recommended. Therapists must be familiar with drug side-eect proles. 7.3.1 Frequency of the occurrence of side eects Minor side eects are common and are associated with most medication trials. They dier depending on the class of drug, e.g., SSRIs may produce more agitation, anxiety, diarrhea, insomnia, nausea and vomiting, whereas TCAs produce more dry mouth, dizziness and constipation. A meta-analysis of Trindade reports on an equal number of side eects in controlled studies comparing SSRIs and TCAs, though dierent in their nature (Trindade et al., 1998). However, more recent metaanalyses express a tendency for a better overall tolerability of newer antidepressants when compared with older ones (Anderson, 2000 ; Anderson, 1998 ; Peretti et al., 2000 ; Wilson and Mottram, 2004), also reected by a slightly higher adherence to SSRIs in controlled studies (Anderson, 2000 ; Anderson, 1998 ; Peretti et al., 2000 ; Wilson and Mottram, 2004). The patient interview must clarify whether somatic symptoms are true side eects or part of the depressive syndrome. For patients taking SSRIs, symptoms may also be due to an activation syndrome including restlessness and agitation or to unreported discontinuation (Fava, 2006). 7.3.2 Consequences for treatment If side eects are tolerable and the patient is responding either completely or at least partially and is willing to continue with a drug despite side eects, careful tapering of the medication is a reasonable rst step. If side eects are already occurring at unusually low

S38

CINP Antidepressant Task Force 2007 slices in vitro, whereas iproniazid, the rst clinically eective MAOI, inhibited the intraneuronal metabolism of these biogenic amines, gave support to the emerging monoamine hypothesis of depression (Ban, 2001). However, despite the renement of the pharmacology of antidepressants, which led to the synthesis of drugs that were highly selective in blocking either the reuptake of noradrenaline (noradrenaline reuptake inhibitors, NRIs, as exemplied by maprotiline and reboxetine) or serotonin (selective serotonin reuptake inhibitors, SSRIs, as exemplied by uoxetine) (Brunello et al., 2002 ; Nutt, 2002), it soon became apparent that not all antidepressants blocked the monoamine transporters. Indeed, mianserin, a tetracyclic compound, was the rst eective antidepressant to act on neither monoamine transporters nor on monoamine oxidase (Tatsumi et al., 1997). Later it was found that mianserin had a unique mode of action in that it increased the release of noradrenaline by blocking the presynaptic, inhibitory, a2-adrenoceptors. As these receptors, on stimulation by intersynaptic noradrenaline, normally reduce the inux of calcium ions and thereby reduce the calcium-dependent release of noradrenaline, drugs that specically block the presynaptic a2-adrenoceptors would be expected to increase the intraneuronal concentration of calcium and thereby increase noradrenaline release. This is how mianserin was thought to act. More recently mirtazapine, a structural relative of mianserin, has been developed, which combines enhanced release of noradrenaline with increased release of serotonin, leading to enhanced activation of postsynaptic 5-HT1A receptors and an antagonism of 5-HT2 and 5-HT3 receptors (Haddjeri et al., 1998). Thus, a slight modication of the tetracyclic structure of mianserin has led to the development of a dual-action antidepressant that lacks the gastrointestinal and neurological side eects of the SSRIs, adverse eects that are the result of activation of serotonin receptors (5-HT2C, 5-HT3) in the gastrointestinal tract and on blood vessel walls. Also pharmacotherapies for depression with dopaminergic activity predominantly developed as antipsychotic agents have shown ecacy in the treatment of depression (Amore and Jori, 2001 ; Papakostas, 2006). Moreover the positive inuence of antidepressants on monoamine neurotransmitter systems is not limited to the treatment of depressive disorders. Therapeutic eects are also observed in the treatment of anxiety disorders such as panic disorder or generalized anxiety disorders (Kahn et al, 1979) leading to the hypothesis that inuence on specic neurotransmitters may inuence the regulation of behavior

doses, TDM and potential identication of a poor metabolizer status may be helpful (Baumann et al., 2005). If, after tapering medication, side eects do not subside or ecacy is lost, switching drugs with slow tapering o, stopping and then titration of a new antidepressant is advised. In general, SSRIs and mixed serotonergic/noradrenergic antidepressants have a more favorable side-eect prole than older TCAs or irreversible MAOIs (Preskorn, 1995, Kahn and Halbreich, 2005). But newer antidepressants may also not be as well tolerated as generally assumed, and an activation syndrome, observed especially with SSRIs, may have implications for their use, e.g. in adolescents (see chapter 10.2.1.5). The frequency of these side eects may be underestimated because clinical trials often only disclose spontaneously reported side eects, and in natural settings they may be much more common. In the context of managing side eects, psycho-education of the patient plays an essential role. Experience of side eects is less frightening if the patient is aware about their possibility, especially when they may subside after some days, e.g. increased sleepiness. Informed patients may be more likely to tolerate a drug and to stay on it. When side eects are severe, stopping an antidepressant and restarting with another is advised, provided the patient is willing.

8 Mechanisms of action and future directions in the development of antidepressants 8.1 The development of antidepressants based on the monoamine hypothesis of depression Following the accidental discovery of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) some 50 years ago (Slattery et al., 2004), the use of opium and some former alternatives (e.g. dinitrile succinate, hematoporphyrin, reserpine) in the treatment of depression was fortunately promptly abandoned (Ban, 2001). Further information on the development of psychopharmacology can be seen in a CINP monograph (Ban et al, 1998). The pharmaceutical industry has developed numerous antidepressants that had similar therapeutic and adverse side eects. In the process, the mechanisms underlying the actions of eective drugs have been dened. These relate to blocking the re-uptake of transmitters, reducing their enzymatic break down or acting pre-synaptically to prolong their release. The observation that imipramine reduced the transport of tritiated noradrenaline and serotonin into rat brain

CINP Antidepressant Task Force 2007 and moods such as impulsive aggression (Linnoila et al., 1983) independently of disease categories (for review see Morilak and Frazer, 2005). It is interesting to note that following 2 decades of emphasizing the specicity of action of antidepressants on noradrenaline, serotonin or even dopamine (e.g. bupropion), there is now a renewed interest in antidepressants with dual action, in other words, tricyclic-like antidepressants that lack cardiotoxicity and other adverse side eects. Venlafaxine and to a far lesser extent duloxetine are examples of monoamine reuptake inhibitors that, at normal therapeutic doses, show a greater potency in inhibiting serotonin rather than noradrenaline reuptake, whereas milnacipran is more selective in inhibiting noradrenaline reuptake at normal doses. These dual-action antidepressants (Briley, 1998) enhance both noradrenaline and serotonin. While venlafaxine exerts its dual action at higher therapeutic doses, both duloxetine and mirtazapine do so across the therapeutic dose range (Briley, 1998). Recent developments also show important dierences between dierent subtypes of SSRIs. For example, escitalopram, which binds to both the primary binding site and to the allosteric site on the serotonin transporter, seems to be dierent from other SSRIs (Chen et al., 2005 ; Sanchez et al., 2004 ; Thase, 2006). Despite the plethora of dierent types of antidepressants that have been marketed over the past 30 years (Table 11) (for review see Richelson, 2001), the main advance has been made not in terms of ecacy but safety. Modern antidepressants are no more eective than the rst tricyclics, such as imipramine or amitriptyline. While it is generally assumed that all eective antidepressants enhance monoaminergic function in some way, their common mode of action remains an enigma. It has long been realized that there is a disparity between the qualitative and quantitative eects of these drugs on monoamine transport and the onset of their therapeutic action (Nestler, 1998). In addition to the delay in onset of therapeutic action, acute depletion of tryptophan from the diet, an event that signicantly decreases the concentration of brain serotonin, results in either no eect or a mild dysphoria in healthy volunteers and does not aect the mood state of untreated depressed patients (Delgado, 2004 ; Nestler, 1998). Nevertheless, tryptophan depletion is able to acutely reverse therapeutic action in long-term SSRI treatment and to cause acute relapse in recovered unmedicated patients who have responded to SSRIs (Bell et al., 2001 ; Delgado et al., 1999 ; Smith et al., 1997). These eects show that in

S39

vulnerable individuals, acute lowering of 5HT function can contribute to depressive states. The discovery that chronic antidepressant treatment produces adaptive changes in postsynaptic badrenoceptors that approximately correlated with the onset of the antidepressant eect (Sulser et al., 1978) stimulated new ideas regarding the mode of action of antidepressants by directing research away from presynaptic to postsynaptic events. It soon became apparent that the changes in postsynaptic monoamine receptors were coupled to changes in intracellular signal transduction molecules. This stimulated research into the eects of chronic antidepressants on neuropeptides, neurotrophic factors and intracellular signaling molecules (Manji et al., 2001 ; Wong and Licinio, 2004). A variety of recent studies support the hypothesis that possibly a decreased expression of brain-derived neurotrophic factor (BDNF) contributes to the development of depressive disorders and that upregulation of BDNF plays a role in the action of antidepressant treatments (Duman and Monteggia, 2006). Thus, the monoamine hypothesis of depression, and the explanation of how antidepressants work, has gradually evolved into a molecular hypothesis. This hypothesis is based on the view that adverse environmental factors, such as stress, acting on a genetic vulnerability, cause maladaptive changes in a range of neurotransmitters among which the monoamines are presumed to play a signicant role. Eective antidepressant treatments normalize the disturbed neurotransmitter networks that are assumed to be responsible for the clinical features of depression (Castren, 2005). The monoamine hypothesis has stimulated the search for genes that are altered in depression or by chronic application of antidepressants in the hope that the molecules encoded by these genes could provide targets for novel types of antidepressants (Knuuttila et al., 2004 ; Wong and Licinio, 2004). In spite of the rapidly increasing knowledge about antidepressants up to now there is no established relationship between the pharmacological prole of antidepressants and their therapeutic effects. 8.2 Developments leading to new understanding of the mechanism of action of antidepressants Despite the advances that have been made in the treatment of depression over the past 50 years, a number of major problems remain. These include a lack of response or only a partial response to treatment by a substantial proportion of patients. In addition, the

S40

CINP Antidepressant Task Force 2007 endocrine, immune and neurotransmitter systems that are largely reversed by chronic, but not acute, antidepressant treatment, including electroconvulsive seizures (ECS) (Leonard and Song, 2002 ; Zhou et al., 1998). Dysfunction of the brain serotonergic system has been shown to relate to the mood changes in depression and bipolar disorder (Spoont, 1992) and there is evidence that the changes in serotonin are widespread and linked to the depression-like behaviour in the OBX model (Hasegawa et al., 2005 ; Watanabe et al., 2006). The OBX model has been shown to be particularly suitable for studying the complex relationships between the brain, behaviour, the neuroendocrine and immune systems, in addition to detecting poutative antidepressants that do not act primarily on brain monoamine systems (Breivik et al., 2006). The gestational stress (GS) model is based on the observation that pre-natal stress, in both animals and humans, as associated with an increased risk of depression in later life (Huizink et al., 2004). Such changes are associated with an increased incidence of depression and anxiety particularly in female ospring (Weinstock, 2007). When pregnant rats undergo daily restraint stress for one week during the mid-gestational period, the ospring show increased immobility in a stressful environment (such as the open eld apparatus) and in the forced swim test, a test that simulates learned helplessness and depressed mood. This suggests that rats stress in utero display depressive-like behaviours post partum, changes that are reduced by chronic antidepressant treatment. Despite the limitations of these rodent models of depression, they have been benecial in providing possible links between the main symptoms of depression and changes in monoamines, endocrine and immune systems (Leonard and Song, 1999). As these models, like depressed patients, only respond eectively to chronically administered antidepressants, they also give some insight into the possible mechanisms of action of these drugs. Recent reports describe alterations in the expression of numerous genes, notably those coding for neurotrophic factors such as BDNF and nerve growth factor (NGF) (Alfonso et al., 2006) as well as structural modications in the areas of the brain related to mood disorders in such animal models submitted to those paradigms. This has led to depression research being focused on the hippocampus, amygdala, cortex and related neuronal circuits (LeDoux, 2000). The importance of these regions in the pathophysiology of depression has gained support from brain-imaging

diagnosis of depression, and the dierent types of depression, is dependent on the symptoms ; these are frequently complicated by comorbidity with other psychiatric disorders. Clearly, the development of specic diagnostic tests for depression would be a major advantage, but to date, no such tests have been reliably devised. It would also be a help if there were reliable animal models of depression, but again, those that are available have been of limited value for detecting novel compounds or in elucidating the mechanisms whereby antidepressants work. Most animal models of depression rely on stress-induced abnormalities in behavior and in the subsequent changes in neuroendocrine and neurotransmitter (mainly monoamine) function. In the past, animal models of depression have largely been based on acute observations of the eects of drugs that either reduce the functional activity of brain monoamines that are assumed to be responsible for the symptoms of depression (for example, reserpine) or that reverse the behaviors that simulate some of the symptoms of depression (for example, learned helplessness induced by unavoidable foot-shock). While such models have been useful in the development of new antidepressants that largely resemble those already available, they have been less successful in identifying novel agents. This situation has stimulated research into models (in rats) that not only exhibit behavioural changes that may be relevant to depression (anhedonia, decreased libido, changes in locomotor activity and in the sleep prole, cognitive and memory decits) but also in neurotransmitter function (particularly in the monoamines), in the hypothalamic-pituitary-adrenal (HPA) axis and in the immune axis. A relevant animal model should full at least 3 criteria, namely predictive validity (an ability to detect all treatments that are therapeutically eective), face validity (an ability to produce behavioral changes that are similar to those seen in depressed patients) and construct validity (by exhibiting psychobiological changes that may underlie depression). While several rodent models of depression full the rst two criteria, it is more dicult to validate the third criterion until the precise causes of depression are known. Nevertheless, the olfactory bulbectomised rat model and the gestational stress models probably full these criteria better than others. The olfactory bulbectomised rat (OBX) model is now widely accepted as a model that bears similarities to the agitated form of depression (Harkin et al., 2006 ; Jesberger and Richardson, 1988 ; Leonard and Song, 2002 ; Willner, 1990). Thus surgical removal of the olfactory bulbs results in changes in the behavioural,

CINP Antidepressant Task Force 2007 studies, which have identied many cortical and subcortical structures that are altered in depressed patients. These observations are complemented by those from post-mortem studies : in the same regions, alterations of both neuron and glial cell density and size appear to be aected, suggesting functional impairment of these regions associated with depressive disorders (for review see Gould and Manji, 2004). Eective antidepressant treatments have also identied the importance of these brain regions (Tamminga et al., 2002). Clearly, the application of neuroscience to understanding brain function and psychopathology has resulted in novel insights into the psychobiology and biological subtypes of depression (Hasler et al., 2004), and possibly how antidepressants work. This raises the question, Is mood chemistry ? , the subject of an important review by Castren (Castren, 2005). This new concept suggests that depression results from a malfunction of neuronal networks and that antidepressants work by improving information processing in the aected networks. At the basis of such disordered networks lies a failure of neuroplasticity. Thus, some antidepressants seem to increase the development of new neurons in the hippocampus (Malberg et al., 2000). This increase in neurogenesis in the hippocampus associated with long-term antidepressant treatment correlates with behavioral changes caused by chronic antidepressant treatments in animal models of depression (Santarelli et al., 2003). Note that numerous alterations other than a decrease in the rate of neurogenesis or in neuronal turnover in the hippocampus have been reported in depression, such as modications in neuronal architecture. Very few publications have reported the eect of antidepressants on them. Such observations are particularly pertinent to the mode of action of antidepressants, as for the rst time, a cellular explanation has been proposed that identies a possible reason for the delay in onset of response to treatment independent of the nature of that treatment. This hypothesis has led to the further observation that elimination of neurons through apoptotic cell death increases simultaneously with increased neurogenesis, events that are linked to antidepressant-induced increases in neurotrophic factors such as BDNF. It may be hypothesized that, in the hippocampus, antidepressants increase neuronal turnover rather than neurogenesis per se (Sairanen et al., 2005). What are the implications of such ndings for the development of future antidepressants ? Clearly, the conventional approach whereby specic monoamine

S41

neurotransmitters are targeted must be reconsidered. It can be argued that such an approach has failed to bring about any major benets to the depressed patient in terms of therapeutic ecacy. Further targets, while they may include monoamine receptors such as the 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7 (Pauwels, 2000), have certainly produced some potentially interesting possibilities in rodent models of depression, but so far they have not yet been validated clinically. There is evidence that 5-HT1A and 5-HT1B/D antagonists augment the antidepressant response, but the clinical evidence that such drugs are eective antidepressants when administered alone is equivocal (Bosker et al., 2004). Similarly, the a2-adrenoceptor has been targeted following the discovery that the tetracyclic antidepressants mianserin and mirtazapine act as antagonists at the pre-synaptic a2-adrenoceptor (Blier, 2001) and block certain 5HT2 receptors. Therefore, both drugs inuence noradrenergic and serotonergic neurotransmission. Recently, it was shown that a peptide that is a member32 of the S100 protein family interacts with the 5-HT1B receptor ; there is experimental evidence that the function of this receptor depends on expression of the p11 peptide (Sanacora et al., 2000). The concentration of the p11 peptide was shown to be low in post-mortem brains from depressed patients. In knockout mice lacking the p11 peptide, depressivelike behavior was noted, whereas overexpression of p11 increases 5-HT1B receptor function in cells and recapitulates behaviors seen after antidepressant treatment. Chronic antidepressant treatments, including electroconvulsive therapy (ECT), increased p11 expression and counteracted the depression-like phenotype (Svenningsson et al., 2006). These results serve to emphasize the potential importance of the 5-HT1B receptor in animal models for depression and suggest that the 5-HT1D receptor, the analogous serotonin receptor in humans, may play a role in antidepressant therapies. Non-monoamine approaches have included antagonists of tachykinin receptors. The endogenous agonists include the peptide substance P, which is physiologically involved with pain perception, but experimental studies have demonstrated that NK1 receptors may function to modulate serotonergic transmission (Santarelli et al., 2001). Antagonists of these receptors would therefore be expected to exert the opposite eect upon serotonergic transmission and
32

S100 is a protein characterized by two calcium binding sites. There are at least 21 dierent types of S100 proteins in the so-called S100 protein family.

S42

CINP Antidepressant Task Force 2007 suggests that GABA receptor agonists, particularly those targeting the G protein-coupled GABA-B receptor that are prominently located in limbic regions of the brain, may be of interest. For a detailed review of new hypotheses on antidepressant modes of action, see (Slattery et al., 2004). A novel antidepressant, agomelatine, was recently developed. It acts as an agonist at melatonergic receptors MT1 and MT2 and as an antagonist at 5-HT2C receptors (Audinot et al., 2003 ; Descamps-Francois et al., 2003 ; Millan et al., 2003 ; Millan et al., 2005 ; Pevet, 2002 ; Yous et al., 1992). Melatonin is secreted by the pineal gland and, via the suprachiasmatic nucleus in the hypothalamus, acts as the endogenous circadian rhythm oscillator. Circadian rhythms are known to be altered in depression (Darcourt et al., 1992). Consequently, it has been hypothesized that a drug acting as an agonist at melatonin receptors and as an antagonist at 5-HT2C receptors (which have been implicated as being oversensitive in anxiety and depression) could facilitate resynchronization in circadian rhythms (Krauchi et al., 1997 ; Leproult et al., 2005) and have useful antidepressant properties (Kennedy and Emsley, 2006 ; Loo et al., 2002). The close interrelationship between the endocrine and immune systems has stimulated research into the role of pro-inammatory cytokines into the etiology of depression. Thus, the observation that inammatory mediators, such as the pro-inammatory cytokines interleukin (IL)-1 and IL-6, tumor necrosis factor-a, cinterferon and prostaglandin E2, are elevated in the blood of depressed patients has led to the macrophage hypothesis of depression (Smith, 1991). In addition, the treatment of non-depressed persons suering from hepatitis with a-interferon often results in severe depression (Wichers and Maes, 2002). Furthermore, many of the symptoms that occur in depression (e.g. altered sleep prole, mood, memory, appetite, libido, cognitive function, endocrine function) may also be caused by pro-inammatory cytokines that are increased in the blood and cerebrospinal uid (CSF) of depressed patients (Dantzer, 2004). Conversely, chronic treatment with antidepressants attenuates the release of pro-inammatory cytokines from activated macrophages both in the blood (Xia et al., 1996) and in the brain (Obuchowicz et al., 2006). These ndings suggest that antagonists of pro-inammatory cytokines, and possibly cyclo-oxygenase (COX)-2 inhibitors that reduce the synthesis of prostaglandin E2 in the brain, could act as novel antidepressants (Leonard, 2001). There is some clinical evidence that COX inhibitors have antidepressant-like activity (Collantes-Estevez and Fernandez-Perez, 2003).

enhance function (Culman et al., 1997). While considerable excitement was generated regarding the antidepressant potential of the rst NK1 antagonist to be developed some years ago (Schwarz and Ackenheil, 2002), further clinical studies have proved disappointing. Nevertheless, with three known types of NK receptors, the search continues for antagonists with potential therapeutic properties (Kramer et al., 1998). Among the amino acid neurotransmitters, attention has been directed to the N-methyl-D-aspartate (NMDA) receptor complex. Experimental ndings have shown that most classes of antidepressants decrease the anity of the glycine site on the NMDA receptor complex (Grundemar and Hakanson, 1994) following chronic antidepressant treatment. This modulation of the NMDA receptor complex may prove to be a novel approach to drug development, as the NMDA antagonist ketamine has been shown to cause a rapid but transient improvement in mood in depressed patients (Paul et al., 1994). At the cellular level, NMDA antagonists block the atrophy of hippocampal CA3 pyramidal neurons and the inhibition of neurogenesis caused by stress (Berman et al., 2000a). Another possible approach to modulating the glycine site on the NMDA receptor involves s(sigma)-receptor antagonists. Igmesine was the rst s1-receptor antagonist shown to have antidepressant activity (Manji and Lenox, 1999 ; Roman et al., 1990), but it could not subsequently be conrmed in randomized controlled trials (RCTs) (Volz and Stoll, 2004). Therefore, and due to marketing reasons, it has not been developed further (Volz and Stoll, 2004). An exploratory RCT using the antibiotic drug d-cycloserine (DCS), which acts as a partial agonist at the NMDARGLY site, showed a reduction in depressive symptoms but no statistically signicant advantage in comparison to placebo adjuvant treatment (Heresco-Levy et al., 2006). The antidepressant tianeptine has been demonstrated to counteract the stress-induced increase in the NMDA/AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) ratio (Kole et al., 2002). Recently the idea that inuence on the regulation of glutamatergic neurotransmission may contribute to the development of new substances with antidepressants (Krystal, 2007 ; Witkin et al., 2007) has been supported by the publication of case reports (Goforth and Holsinger, 2007 ; Liebrenz et al., 2007) and one RCT (Zarate et al., 2006) showing a rapid antidepressant ecacy of ketamine treatment. Of the other amino acid receptors that are possible targets, the observation that the concentration of c-amino butyric acid (GABA) is decreased in the brains of depressed patients (Sanacora et al., 2000)

CINP Antidepressant Task Force 2007 Epidemiological studies show that there is a correlation between chronic depression and the likelihood of dementia in later life (Geerlings et al., 2000 ; Visser et al., 2000). Inammatory changes in the brain are pathological features of both dementia and depression (Steens et al., 1997). It would appear that an increase in inammation-induced apoptosis, together with a reduction in the synthesis of neurotrophic factors caused by a chronic increase in brain glucocorticoid concentrations (Leonard and Myint, 2006b, Sapolsky, 2000), may play a major role in the pathology of these disorders. In addition, a reduction in the neuroprotective components of the tryptophan-kynurenine pathway in the brain (such as kynurenic acid) further contribute to the neurodegenerative changes seen in chronic depression (Leonard and Myint, 2006a). Such changes have been postulated to cause neuronal damage and thereby predispose the depressed patient to dementia (Leonard and Myint, 2006b). How do antidepressants counteract the neurodegenerative changes that underlie chronic depression ? There is now experimental evidence that antidepressants increase the development of new neurons in the hippocampus (Malberg et al., 2000), an eect that may account for delay in the therapeutic response. New neuronal networks are thus established in response to chronic antidepressant treatment (Sairanen et al., 2005). In support of this view, antidepressants are known to enhance axonal and dendritic sprouting (Vaidya et al., 1999). Thus, in chronic depression, glucocorticoids and inammatory mediators are responsible for increasing neuronal apoptosis and preventing repair of damaged neuronal networks. Eective antidepressant treatment appears, at least partly, to reverse such changes. Whereas neurotransmitter receptors would appear to be the most accessible targets for the development of new antidepressants, there is now considerable research interest in intracellular signal transduction mechanisms. These are targets for neurosteroids, neurotrophic factors and enzymes that are linked, directly and indirectly, to postsynaptic receptors that reect the action of both neurotransmitters and other physiologically active molecules such as the cytokines. To date, only one drug has been developed that appears to act by inhibiting a component of the postreceptor signaling system, rolipram, a phosphodiesterase inhibitor that is presumed to act by inhibiting breakdown of the second messengers cyclic adenosine and guanosine monophosphates. As a consequence, the postsynaptic response to receptor stimulation is increased. Nonetheless, compared with TCAs, rolipram has shown inferior therapeutic ecacy in

S43

RCTs (Hebenstreit et al., 1989 ; Scott et al., 1991). In the future, it seems likely that other postsynaptic targets will be investigated, including mitogen-activated protein (MAP) kinase agonists that indirectly increase the synthesis of BDNF, a key neurotrophic factor for repairing damaged neurons (Altar, 1999). Other possible targets include protein kinase C (PKC), an enzyme involved in regulating neuronal excitability, neurotransmitter release and long-term synaptic events (Manji and Lenox, 1999). Finally, in view of the importance of mechanisms that reduce apoptosis, and thereby assist in neurogenesis, antidepressants may be developed that act as promoters of anti-apoptotic proteins such as Bcl-2. This protein attenuates apoptosis by sequestering the pro-apoptotic caspase enzymes (Altar, 1999). Dysregulation of the hypothalamicpituitary adrenocortical (HPA) system is well known and one of the major neuroendocrine abnormalities in major depressive disorder. This dysregulation includes elevated levels of corticotropin-releasing hormone (CRH) (Nemero et al., 1984), corticotropin (ACTH) and cortisol (Linkowski et al., 1987) during depressive episodes, which normalize after clinical remission. Nevertheless, newer, more recent contributions to our knowledge about depression have also been made. Higher HPA activity during the rst weeks of antidepressant pharmacotherapy seems to be associated with lower rates of early treatment response (Hatzinger et al., 2002). Furthermore, and signicantly, persisting cortisol hypersecretion indicates lower remission rates (Ising et al., 2006) and a higher risk for recurrence of depression, even when a reduction of depressive symptoms or even clinical remission has been achieved (Zobel et al., 1999). Moreover, during the long-term course of depression, increasing HPA system deterioration is highly correlated not only with severity of disease, indicated by higher psychometric depression scores, but also with the number of previous episodes (Hatzinger et al., 2002). However, both molecular investigations and animal studies show that classical antidepressants, e.g. TCAs, modulate regulation of the HPA system by enhancing expression of glucocorticoid receptors, thereby improving the feedback mechanism of the HPA system (Barden et al., 1995 ; Holsboer and Barden, 1996). Thus, regulation of the HPA system appears to play a major role in the pathophysiology of depressive episodes. As such, it opens a variety of new pharmacotherapeutic approaches to depression that dier fundamentally from antidepressants available up to now. The HPA and immune axis has become an important target for antidepressant development due to

S44

CINP Antidepressant Task Force 2007 disease and hypertension, and psychiatric illness are polygenic and therefore inuenced by multiple factors linked to the genetic substrate and the environment. Recent research has tended to focus on genes that encode neurotransmitter receptors together with enzymes involved in monoaminergic transmission. So far, the results of studies have been equivocal in their ndings, with multiple claims for gene associations that could not be replicated. The limitations of the studies include small sample sizes coupled with the small magnitude of the genetic eect. Nevertheless, meta-analyses have identied several genetic variants of candidate genes. In bipolar disorder, for example, a variant of the MAO-A gene has been identied (Furlong et al., 1999), although other investigators have been unable to conrm this nding (Schulze et al., 2000). There have been several studies of the promoter polymorphism of the serotonin transporter gene. The type of polymorphism is functionally important, as there appears to be an association between depression and anxiety and the short allele (Lesch et al., 1996). In addition, the short allele of this functional polymorphism in the promoter region of the serotonin transporter gene was found to enhance the inuence of stressful life events on depression (Caspi et al., 2003). However, once again, not all investigators have been able to replicate this nding (Serretti et al., 1999). Polymorphisms of other receptors and enzymes of the biogenic amines have also been investigated. These include the tyrosine and tryptophan hydroxylase genes, the catechol-O-methyl transferase gene, as well as genes for the serotonin and dopamine receptors (Kato, 2001). To date these studies have yielded inconclusive or negative results. In addition, functional polymorphisms in the angiotensin converting enzyme (ACE) gene seem to inuence the risk for developing depressive disorders (Arinami et al., 1996 ; Baghai et al., 2006a), HPA axis activity (Baghai et al., 2002) and the clinical eectiveness of antidepressant therapies (Baghai et al., 2001 ; Bondy et al., 2005). Also, the glucocorticoid receptor-regulating co-chaperone FKBP5 has been shown to inuence both the susceptibility to depression and response to antidepressant treatment (Binder et al., 2004). The conventional view that unipolar depression is under the control of the same genes irrespective of the age of onset of the disorder has been challenged by studies of late-onset depression (Hickie et al., 2001) Thus, Hickie et al. (2001) have shown that late-onset depression is associated with a mutation in the methylene tetrahydrofolate reductase gene, which controls

the key role of stress in initiating depression. In the development of novel drugs that target the HPA axis, one approach involves antagonists of the CRF (=CRH)-1 receptors. Clinical studies have shown that the concentration of CRF is increased in the cerebrospinal uid (CSF) of both suicide victims and in depressed patients (Nemero, 1996). However, despite initial promising clinical experience, so far CRF antagonists have shown no ecacy in treating depression in RCTs. More success has been reported in developing glucocorticoid type-2 receptor antagonists. This approach was based on the observation that hypersecretion of cortisol is a frequent occurrence in patients with chronic depression in which melancholic features are prominent. Preliminary clinical evidence suggests that novel glucocorticoid receptor antagonists may be benecial in such subgroups of depressed patients (Gallagher and Young, In Press). In conclusion, there are many possibilities for the future development of antidepressants. Microarray technology should enable candidate genes to be identied and targeted, and undoubtedly such methods will play an increasingly important role in drug discovery in years to come. However, it seems that the more conventional approach involving the identication of malfunctioning neurotransmitters and their signaling systems, and correcting their defects with novel molecules, oers the greater chance of success in the near term. 8.3 The role of pharmacogenetics in understanding how antidepressants work Pharmacogenetics, a term proposed by Vogel in 1959, is the study of genetically based, inter-individual variability in response to drugs and their side eects. It is now realized that polymorphisms of the cytochrome P-450 microsomal oxidase system in the liver are responsible for many of the genetic dierences that aect drug responsiveness and metabolism. An important area that is related to pharmacogenetics is pharmacogenomics. Whereas pharmacogenetics is concerned with the individual patient and how dierences in metabolism and drug response are a reection of genetic makeup, pharmacogenomics involves the structure of the genome and how targeting compounds to it may lead to novel drugs that can be used to treat specic psychiatric disorders. Classical genetics of human disease concentrate on monogenic disorders in which a single mutation or gene is the cause of the disorder. However, complex medical disorders such as diabetes, coronary artery

CINP Antidepressant Task Force 2007 an important cofactor in monoamine biosynthesis ; this mutation was not found in patients whose depression occurred at an earlier stage. It appears that this same mutation predisposes patients to cerebrovascular disease and is associated with increased plasma homocysteine and folate deciencies, which frequently occur in late-onset depression. Such observations serve to emphasize the diculties that exist in attempting to identify specic genetic factors that may predispose to depression. Moreover, operationalized diagnostic systems such as ICD-10 and DSM-IV, actually in use, promote only relatively fuzzy distinctions between subgroups of depressed patients who suer from potentially biologically dierent diagnostic entities. This confusion may contribute to reported diculties in association studies. In future, better diagnostic systems or investigation of endophenotypes may help to dene genetically dierent subgroups of depressive disorders. Only a few small studies have been published in which pharmacogenetics has been used to predict therapeutic response in individual patients. These studies have investigated genetic variations in the serotonin receptors (Lesch and Gutknecht, 2004), serotonin transporter and their promoter regions, and their associations with poor response to treatment with SSRI antidepressants (Joyce et al., 2003 ; Zanardi et al., 2001). Again, other investigators have been unable to replicate the observations that these parameters are associated with poor antidepressant response (Kim et al., 2000). For a more extensive update on recent ndings, we refer to published reviews on pharmacogenetics and pharmacogenomics (Holsboer, 2001 ; Kirchheiner et al., 2004 ; Malhotra et al., 2004 ; Mancama and Kerwin, 2003 ; Serretti et al., 2005). The current lack of knowledge of susceptibility genes for depression seems unlikely to discourage further research aimed at identifying the genetic basis of mood disorders by the application of DNA genotyping and genome-wide case-control studies (Risch, 2000). 9 Pharmacological treatment options 9.1 The use of medication in the acute treatment of depressive disorders 9.1.1 Introduction This section provides general information regarding benets and risks during the pharmacotherapy of depression, followed by further discussion regarding mechanism of action and specic drugs. General

S45

considerations during antidepressant acute and maintenance therapies are described in chapter 7. The treatment of depressive disorders consists of complex multimodal therapy that is determined by the current state of the illness. The main modalities are pharmacotherapy, psychotherapy and sociotherapy33. Although they are often used in combination, here we will predominantly describe pharmacotherapeutic options. Pharmacotherapy is not always mandatory for less severe forms of depression, but severe depression usually requires medication or electroconvulsive therapy (ECT). In addition, a variety of other biological interventions, such as sleep deprivation and bright light therapy, may be helpful in certain patient subgroups. The discovery of tricyclic antidepressants (TCAs) was a milestone in the treatment of depression, and the TCA amitriptyline has consistently been included in the World Health Organizations (WHOs) list of essential drugs (World Health Organization, 2005a), updated biennially, although information about antidepressants has remained unchanged over the last few years. In developing countries or in other countries in which TCAs are preferred antidepressants it may also be reasonable to consider drugs with proven ecacy that are better tolerated than amitriptyline such as SSRIs but that are sometimes not prescribed because of their cost. However, despite the undoubted eectiveness of TCAs, it soon became apparent that the anticholinergic and antihistaminergic side eects of TCAs such as Imipramine or Amitriptyline can cause problems. New antidepressants, both TCAs such as desipramine and newer classes such as SSRIs, NARIs or SNRIs were developed with a more selective mode of action. The results were lower rates of of anticholinergic and antihistaminergic side eects in most of the published studies. But interestingly also antidepressant eects of selectively anticholinergic acting substances have been reported (Furey and Drevets, 2006). For historical reasons, currently available antidepressants are usually classied according to their chemical structure and mode of action. This classication seems sensible, e.g. to separate TCAs and tetracyclic antidepressants from modern substances to describe safety and tolerability properties and to follow widespread habits and to follow a scientic and historical classication. Nevertheless it may be useful to use a dierent ordering scheme in evolving treatment plans and algorithms. Classication according to
33 Sociotherapy designates non-medical, social and work-related components of the care process.

S46

CINP Antidepressant Task Force 2007

Box 6. Denitions ecacy/clinical eectiveness/eciency Ecacy is the power of a substance to produce the eects that it is supposed to produce (e.g. antidepressant eects). Clinical eectiveness is the ability to successfully achieve clinical remission. Eciency describes the relationship between eectiveness and the spent resources and costs.

the predominant mode of action, which is already applied to modern antidepressant substances, is more logical and practical. We thus suggest describing different classes of modern antidepressants according their main mode of action, and recommend subdividing the older tri- and tetracyclic substances according their predominant inuence on serotonergic and noradrenergic neurotransmission. In this review, we present the classes of antidepressants in their approximate chronological order. Currently, tri- and tetracyclic antidepressants with predominant serotonergic (S-TCA), noradrenergic (N-TCA) or mixed serotonergic/noradrenergic (S/NTCA) action are available. To simplify things for more practicable treatment plans, tri- and tetracyclic antidepressants are summarized within the TCA group34. Additional agents on the market include selective and reversible inhibitors of monoamine oxidase A (RIMA) ; an irreversible MAO-B inhibitor (MAOBI) ; non-selective and irreversible inhibitors of MAO-A and -B (MAOIs) ; selective serotonin reuptake inhibitors (SSRIs) ; selective noradrenaline reuptake inhibitors (NARIs) ; antidepressants with a dual mode of action, such as selective serotonin and noradrenaline reuptake inhibitors (SNRIs) ; and noradrenergic and specic serotonergic antidepressants (NaSSAs) acting via blockade of a2- and 5-HT2 receptors and enhanced release of noradrenaline and serotonin (Blakely, 2001 ; Frazer, 2001 ; Haddjeri et al., 1998 ; Kent, 2000 ; Pacher et al., 2001 ; Stahl, 1998b). In addition, a dopamine and noradrenaline reuptake inhibitor (DNRI) and serotonin modulating antidepressants (SMAs) are available. The most recently developed mechanism of action is agonism at melatonergic MT1 and MT2
For educational purposes it could be justied to use only a pharmacodynamic classication model of antidepressants. Due to historical reasons and after a consensus process in addition the classication according the chemical structure was retained. 35 Antidepressants such as uoxetine, trimipramine, mirtazapine, mianserin, venlafaxine and reboxetine are generally marketed as racemic compounds. Both the pharmacological and pharmacokinetic proles of these substances may dier between the enantiomers, e.g. of citalopram (Baumann et al., 2002 ; Baumann and Eap, 2001) or uoxetine. In the case of the latter, a dierent pharmacological prole of the two enantiomers may cause dierences in cardiac tolerability (Magyar et al., 2003).
34

receptors and selective antagonism at serotonergic 5-HT2C receptors, represented by the antidepressant agomelatine (Audinot et al., 2003), which is currently under review by authorities in Europe. Other developments include the use of single enantiomers instead of racemic compounds35. A consistent trend towards increased use of generic antidepressants over the last few years has been reported (Bruck et al., 1992)36. In addition, it remains unclear whether pharmacogenetic dierences in populations of dierent countries play a major role in clinical trials investigating ecacy and tolerability. Moreover, outsourcing of clinical trials may cause diculties in interpreting study results ; caution is recommended, especially in cases where study results from dierent countries are pooled. In particular, there is concern that the practice by pharmaceutical companies of comparing the results of multicenter studies carried out in many dierent countries could raise doubts about the ndings. A summary of commonly used antidepressants, including their primary mode of action and inuence on other receptor systems, is shown in Table 1. According the review from Sanchez et al. (1999) semiquantitative information about receptor anities concerning the main pharmacodynamic mode of action of the antidepressants and their major metabolites has been included (Sanchez and Hyttel, 1999). Similar information about receptor anities concerning secondary and additional pharmacodynamic proles may not be helpful in clinical routine due to a huge interindividual variation in the sensitivity of depressed patients. Therefore this detailed information has been omitted. Possible adverse events can be deduced from chapter 7.3 and Table 16, the magnitude of adverse events due to secondary pharmacodynamic actions has to be evaluated in each individual patient and may vary during the treatment course.

36

Original brand-name antidepressants and generic substances are assumed to exert similar ecacy and tolerability, but we do not know whether that is true for each country. Direct comparisons between brand-name formulations and generics and between dierent generic substances have not yet been published.

CINP Antidepressant Task Force 2007

Table 11. Commonly used antidepressants, including dosage recommendations37 Dose recommended by the producer Starting dose (mg) 25 2575 3060 50 100 20 2550 2575 120180 75 2575 40/6038 510 20 50100 2575 20 70 2575 20 30 50 15 150300 100 2550 20 15 10 4 oral : 30 transdermal : 6 50 37.5 10 50100 2550 75 100 Dosage range (mg/day) 2550 150300 180300 100400 200300 2060 100250 100300 240720 75150 150300 60120 1020 2080 100300 150300 2060 140210 150225 2030 60120 100200 3045 300600 300600 75300 2060 3090 2060 812 oral : 3060 transdermal : 612 50200 37.5 2040 200600 150400 75375 200500

S47

Generic name Agomelatine Amitriptyline Amitriptylinoxide Amoxapine Bupropion Citalopram Clomipramine Desipramine Dibenzepine Dosulepine/Dothiepin Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Isocarboxacid Lofepramine Maprotiline Melitracen Mianserin Milnacipran Mirtazapine Moclobemide Nefazodone Nortriptyline Paroxetine Phenelzine Protriptyline Reboxetine Selegiline Sertraline Tianeptine Tranylcypromine Trazodone Trimipramine Venlafaxine Viloxazine

37 Dierent dosages are used on dierent continents and in dierent countries (Patten et al., 2005 ; Sartorius, 1986). For some populations, e.g. Japanese patients, the dose recommendations presented above are usually too high. In addition, marketing aspects may inuence dosage recommendations owing to calculation of the lowest possible daily treatment costs. Indication-adjusted dose recommendations may also be important. Finally, indications for antidepressants vary from one country to another. 38 Recommended starting dose in the US is 40 mg ; in Europe it is 60 mg.

Despite the development of a variety of new antidepressants with dierent pharmacodynamic proles, to date the hope of better ecacy and clinical eectiveness (see Box 6) over older antidepressants has not been fullled. In contrast to eciency, the focus of eectiveness is achievement as such, not the resources spent, so anything that is eective is not necessarily ecient, but anything that is ecient also has to be eective. In psychiatry, the distinction between ecacy (ideal use) and clinical eectiveness (typical use) is often drawn. Whereas ecacy may be shown in clinical trials, clinical eectiveness has to be demonstrated in clinical practice. Some reports of better ecacy for some recently developed antidepressants require further conrmation. Up to now there is no consensus that any of the recently developed antidepressants showed superiority in head-to-head comparisons with older antidepressants such as TCA or irreversible MAOIs concerning their clinical eectiveness. But even in the case of a proven ecacy of antidepressants the clinical eectiveness may be diminished due high discontinuation rates. These seem to be inuenced by noncompliance due to side eect proles of antidepressants (Hotopf et al., 1997). In addition, it is necessary to evaluate the clinical relevance of small mean dierences in depression rating scales between active substances or antidepressant and placebo treatment, even in the case of statistical signicance. Moreover, the results of failed trials, e.g. due to high placebo response rates, and the probable huge amount of still unpublished data from clinical trials, should be evaluated before recommendations for specic substances can be made (see chapter 4.4). The usual recommended daily dosages for starting and maintaining antidepressant treatments are presented in Table 11. A further problem is the lack of information about both ecacy and tolerability of antidepressants for large portions of the world population. Predominantly genetic, but also cultural dierences, may contribute to a dierential responsiveness of ethnic groups during antidepressant treatment. In interpreting the existing literature it is particularly important to consider the lack of information about the treatment eects of most and especially newer antidepressants, e.g. in the black African population. Nevertheless, the main advantages of newer antidepressants are the overall better tolerability and safety in comparison with older substances. Although newer antidepressants are better tolerated and cause fewer and less serious side eects, their specic

S48

CINP Antidepressant Task Force 2007

Box 7. Denition of pharmacotherapy-resistant depression (modied according to Berlim and Turecki, 2007 ; Burrows et al., 1994 ; Fava, 2003b ; Fava and Davidson, 1996 ; Helmchen, 1974 ; Leonard, 1988 ; Nierenberg and Amsterdam, 1990 ; Rush et al., 2003b ; Sackeim, 2001 ; Souery et al., 1999 ; Thase et al., 1997) Therapy resistance or non-response to treatment in depression are terms used to describe the lack of reaction to appropriate treatment. The denition of appropriate treatment varies among experts. While some consider that appropriate treatment must include two courses of pharmacotherapy with antidepressants of dierent groups in sucient doses and duration (Burrows et al., 1994), others believe that, in addition, pharmacotherapeutic augmentation therapy and treatment with cognitive-behavioral therapy and interpersonal psychotherapy must precede the decision that the condition is therapy resistant (Thase et al., 1997).

side-eect prole still must be taken into account during treatment. In addition, the latency of several weeks until the onset of sucient therapeutic eects remains a serious and clinically relevant problem. This principle holds true for each antidepressant and each class of antidepressant mechanisms. There are some reports of a faster onset of response for newer dualacting compounds, e.g. mirtazapine (Benkert et al., 2000 ; Benkert et al., 2006 ; Leinonen et al., 1999 ; Montgomery, 1999) and venlafaxine (Benkert et al., 1996 ; Montgomery, 1999) in comparison to other antidepressants e.g. SSRIs or TCAs, but the clinical relevance of these ndings remains controversial (Blier, 2003 ; Nierenberg, 2001). In addition early drugspecic behavioral changes which may be predictive for the clinical response (Katz et al., 2004) are not recorded suciently in all RCTs. Moreover, demographic factors and treatment settings appear to inuence antidepressant choice more than clinical factors and evidence (Sim et al., 2006). The only methods of achieving more rapid acting, but unfortunately in most cases not sustained, antidepressant eects are wakefulness therapy (Wu and Bunney, 1990) (see chapter 12.3.6) and in some patients, in a more potent and enduring way, ECT (ECT review group, 2003 ; Gangadhar et al., 1982) (see chapter 12.3.1). A further general problem in the pharmacotherapy of depression is the possible non-response to initial antidepressant treatment (Charney et al., 2002 ; Nierenberg and Amsterdam, 1990 ; Sackeim, 2001). The problem of inconsistencies in dening treatment resistant/refractory depression (see the denition in Box 8) has been described in a recent review (Berlim and Turecki, 2007). About 50 % of depressed patients do not respond adequately to a rst course of an adequate antidepressant treatment (about 30 % do not show satisfactory improvement, and about 20 % drop out due to problems of tolerance). Adequacy of treatment includes treatment with proven ecacy during a time interval of at least 46 weeks in a sucient therapeutic dose range, including reliable patient adherence to

therapy (Fava, 2003a ; Kupfer and Charney, 2003 ; Sackeim, 2001). Half of these patients fail to respond to a second antidepressant treatment trial. If several antidepressant treatment trials have been inecacious, even lower response rates after switching to another drug may be observed (Fava et al., 2006). Some authors include the use of augmentation strategies in the denition of treatment resistance or nonresponse to antidepressant treatment. In addition to obvious biological hypotheses for therapy resistance, such as occult medical conditions causing depression, substance abuse interfering with antidepressant treatments or abnormal metabolism (Rush et al., 2003b), psychosocial factors, too, may be responsible for failed treatment trials (Grote and Frank, 2003). As described further below, even given the difculty in predicting the most eective solution for any one patient, the range of appropriate pharmacological treatment strategies includes adjustment of dosage, switch to an antidepressant of another class, switch to an antidepressant of the same class, combination therapies with more than one antidepressant, and pharmacological and non-pharmacological augmentation strategies. Strategies such as lithium augmentation (Bauer et al., 2003 ; Zullino and Baumann, 2001) or augmentation using thyroid hormones (Bauer et al., 1998) and other available methods are described in chapter 9.1.12. In addition, the concomitant use of benzodiazepines, e.g. lorazepam for the treatment of agitation in depressive disorder or alprazolam for the treatment of anxiety in depression (Moller, 2002), can be a clinically useful addendum. Prescription of anxiolytics as a monotherapy is barely eective in severe depression (Laakmann et al., 1996). Nevertheless, in the case of persistent non-responsiveness, the UK ECT review group and other authors consider the use of ECT in comparison with all of these strategies as clinically more eective and still the method of choice for treatment-resistant depression (Davidson et al., 1978 ; ECT review group, 2003 ; Folkerts et al., 1997 ; Kroessler, 1985) even if not all of these patients respond well to ECT.

CINP Antidepressant Task Force 2007 Non-response to pharmacotherapy (see Box 7) used as primary treatment implies that sucient treatment attempts have been made with ecacious psychotherapies such as cognitive-behavioral therapy (CBT) or interpersonal psychotherapy (IPT) (Thase et al., 1997). The following chapters introduce the intravenous use of antidepressants, pharmacogenetics and therapeutic drug monitoring, and general side eects, then describe all presently available antidepressants according their mode of action, clinical eectiveness and main side-eect and risk prole. 9.1.1.1 Metabolism, pharmacokinetics, pharmacogenetics, therapeutic drug monitoring and interactions of antidepressants 9.1.1.1.1 Introduction

S49

The pharmacological eect of an antidepressant depends on its presence in the target organ, i.e. the brain. Metabolites may contribute to its overall activity (Hendset et al., 2006 ; Rudorfer and Potter, 1997). Therefore, the consequences of its absorption, distribution, metabolism and elimination (ADME), which are the fundamental parameters dening its pharmacokinetics, must be considered at a level of importance similar to that of its pharmacodynamics at receptor and transporter sites. Cytochrome P-450 and conjugating enzymes are the main enzyme systems involved in the metabolism of antidepressants. The study of their individual roles helps to understand pharmacokinetic interactions and their clinical consequences, even though, especially in the case of TCAs, a clear correlation between clinical response and plasma levels of antidepressants cannot be drawn (Burrows et al., 1972 ; Burrows et al., 1977). Many isozymes of cytochrome P-450 and glucuronidating enzymes present a genetic polymorphism, which result in important interindividual dierences in drug metabolism in patients. Thus it may be assumed that drug plasma concentrations, rather than dose, reect concentration in the brain, and this assumption has prompted numerous studies on the relationship of drug plasma concentrations and clinical eects and the introduction of therapeutic drug monitoring (TDM). 9.1.1.1.2 Metabolism and pharmacogenetics of antidepressants Most antidepressants are metabolized by a phase I reaction implicating one or several isozymes of cytochrome P-450 to more polar metabolites. Then, via a

phase II reaction, they undergo conjugation (Table 12) (Liston et al., 2001). Drugs such as tertiary amine TCAs and SSRIs such as uoxetine, citalopram and escitalopram, but also venlafaxine are converted to active metabolites that may also be eliminated by phase I and phase II enzymes. As both environmental and genetic factors determine the fate of the drug in the organism, pharmacogenetic tests represent a useful tool for diagnosing the metabolic status of the patient. The rst case report on the clinical consequences of impaired hydroxylation of nortriptyline, due to a genetically determined poor metabolizer status (CYP2D6) and high plasma concentrations of this antidepressant in a depressed patient (Bertilsson et al., 1981), prompted rapid development of research in the eld of pharmacogenetics of psychotropic drugs. Most forms of cyctochrome P-450 implicated in the metabolism of antidepressants present a genetic polymorphism (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 and CYP2B6), or their activity varies highly among individuals (CYP3A4) for as yet unknown reasons. The genetic polymorphism of CYP2D6 is the most relevant for the metabolism of psychotropic drugs (Table 12). Generally, gene deletion or a defective gene leads to poor metabolizer (PM) status, and gene duplication or multiplication results in ultrarapid drug metabolism (ultrarapid metabolizer, UM). These patients dier from extensive (EM) or intermediate (IM) metabolizers, who are carriers of two or one active genes, respectively. The proportion of PMs, EMs, IMs and UMs diers among dierent ethnic groups. From a clinical point of view, PMs have a higher risk of experiencing adverse eects as a consequence of impaired drug metabolism, whereas UMs are at risk of non-response to a treatment due to the fact that even at high doses, steady-state drug concentrations may not reach therapeutic levels. This situation is illustrated by case studies of UMs who responded to tricyclic drugs only after very high drug doses (Bertilsson et al., 1985) or after comedication with a cytochrome P-450 inhibitor (Baumann et al., 1998 ; Conus et al., 1996). Genotyping and phenotyping represent certain trait markers and state markers , respectively (Steimer et al., 2001). Phenotyping is available for most of the above-mentioned CYP isozymes. It is generally carried out by administering one or several ( cocktail ) test probes to patients and subsequently collecting blood or urine, followed by analyzing the parent compound and the metabolite formed by the particular enzyme (Clement Jerdi et al., 2005). Clearly, the result of phenotyping is inuenced by comedication,

S50

CINP Antidepressant Task Force 2007

Table 12. Antidepressants as substrates of cytochrome P-450 (CYP) Drug (and/or metabolite) substrate of Class of antidepressants Active (and clinically non-relevant) metabolites Other forms of CYP

Drug

CYP2D6

CYP2C19

Tricyclic and structurally related antidepressants Amitriptyline nortriptyline (10-OH-amitriptyline) (10-OH-nortriptyline) Amitriptyline N-oxide amitriptyline and others (cf. amitriptyline) Clomipramine desmethylclomipramine (2- and 8-OH-clomipramine) Desipramine Dothiepine Doxepin (a) desmethyldoxepin (a) Imipramine desipramine (2-OH-imipramine) (2-OH-desipramine) Lofepramine desipramine (2-OH-desipramine) Maprotiline (N-desmethylmaprotiline) (3-OH and 2-OH-maprotiline) Mianserin (b) N-desmethylmianserin (mianserin N-oxide) (8-OH-mianserin) Milnacipran Mirtazapine (b) N-desmethlymirtazapine (8-OH-mirtazapine) (10-OH-nortriptyline) Nortriptyline Trimipramine (b) desmethyltrimipramine (OH-metabolite) (2-OH-desipramine)

+ (+) + + (+)

CYP3A4, CYP1A2, CYP2C9 (CYP3A4, CYP1A2, CYP2C9) CYP1A2, CYP3A4, CYP2C19

(+)

+ (+) + (+)

+ +

CYP2C9, CYP1A2 CYP1A2, CYP3A4

+ (+) +

(+) + + CYP1A2

CYP3A4, CYP2B6, CY1A2

+ + +

CYP1A2, CYP3A4

+ + (+) +

CYP3A4

CINP Antidepressant Task Force 2007

Table 12. (cont.) Drug (and/or metabolite) substrate of Class of antidepressants SSRIs Citalopram (b) desmethylcitalopram (didesmethylcitalopram) (citalopram propionic acid derivative) Escitalopram S-desmethylcitalopram (S-didesmethylcitalopram) (S-citalopram propionic acid derivative) Fluoxetine (b) noruoxetine Fluvoxamine Paroxetine Sertraline norsertraline Other antidepressants Bupropion Dibenzepine Duloxetine (desmethylduloxetine) Milnacipran Nefazodone 3-OH-nefazodone m-CPP Reboxetine (b) Trazodone m-CPP Venlafaxine (b) O-desmethylvenlafaxine (N-desmethylvenlafaxine) (N,O-didesmethylvenlafaxine) Viloxazine St. Johns wort MAOIs Moclobemide Tranylcypromine x + + + CYP2C9, CYP3A4 x x (+) + x + (+) x x CYP3A4 + (+) + + CYP3A4 Active (and clinically non-relevant) metabolites

S51

Drug

CYP2D6

CYP2C19

Other forms of CYP

+ (+) +

CYP3A4

+ (+) + + + x

CYP2C9, CYP3A4 CYP1A2 CYP3A4, x2C9, x2B6

x +

CYP2B6 CYP1A2

CYP3A4 CYP3A4, CYP1A2

* From Baumann (in preparation), (cf. also Wilkinson, 2005). No studies available. (a) A mixture of geometric isomers : the isomers dier in their pharmacological and pharmacokinetic prole. (b) Chiral drugs : the isomers (of the drug and of their chiral metabolites) may dier in their pharmacological and pharmacokinetic prole.

S52

CINP Antidepressant Task Force 2007

Table 13. Indications for TDM of antidepressants (according to Baumann et al., 2004) Suspected non-compliance Drugs for which TDM is mandatory for safety reasons (e.g. lithium) Lack of clinical response, or insucient response even if doses considered adequate Adverse eects despite the use of generally recommended doses Risk for drug interactions in comedicated patients Situations involving problems of pharmacovigilance Relapse prevention in long-term treatment, prophylactic treatment Recurrence despite good compliance and adequate doses Presence of a genetic particularity concerning drug metabolism (genetic deciency, gene multiplication) Special populations
$ $ $

Children and adolescents Elderly patients (o65 years) Patients with somatic comorbidities (hepatic or renal insuciency, cardiovascular disease)

Forensic psychiatry Problems occurring after switching from an original preparation to a generic form (and vice versa)

which inhibits the test enzyme. Guidelines are available for the optimal use of pharmacogenetic tests (De Leon et al., 2006). Because their clinical relevance has not yet been demonstrated in studies with psychiatric patients, we will mention only briey that transport proteins such as P-glycoprotein may regulate the transport of many drugs, including antidepressants, from the intestine into the blood and through the blood-brain barrier (Fromm, 2000 ; Kim, 2006 ; Lin, 2003 ; Marzolini et al., 2004). Some but not all antidepressants are substrates of this transport protein, which displays a genetic polymorphism (Uhr et al., 2000 ; Uhr and Grauer, 2003). 9.1.1.1.3 TDM of antidepressants

with regard to recommended plasma concentration ranges ( therapeutic windows ) for antidepressants. The concomitant analysis of the active metabolite is mandatory for some drugs, as indicated in Table 14. This consensus guideline includes a comprehensive list with drugs with a recommended TDM level for each one, as well as numerous recommendations for treating physicians and laboratories about how to use TDM optimally. It also contains tables summarizing the literature data on drug plasma concentrations measured at xed doses and they may inform about the reliability of the drug plasma concentration measured in a patient treated with a particular dose. 9.1.1.1.4 Pharmacogenetics and TDM

TDM of antidepressant drugs is widely practiced to optimize the pharmacotherapy of depression (Baumann et al., 2004 ; Brsen, 1996 ; Burke and Preskorn, 1999 ; Mitchell, 2000 ; Mitchell, 2004). Table 13 lists indications for TDM of antidepressants and other psychotropic drugs. Bear in mind that, unfortunately, poor compliance is observed not only in patients treated with antidepressants (Meijer et al., 2001). Treating physicians also induce underuse or inappropriate use of TDM for antidepressants (Mann et al., 2006b). Only for some antidepressant drugs, such as TCAs (and lithium), in contrast to former publications (Burrows et al., 1972 ; Burrows et al., 1977) now there is reasonably good evidence for a relationship between drug plasma concentration and clinical eectiveness (Baumann et al., 2004). Table 14 represents the result of a consensus among experts

It is now generally acknowledged that pharmacogenetic tests represent a useful tool in nding an optimal drug dose (Bertilsson et al., 2002 ; Ensom et al., 2001 ; Ingelman-Sundberg et al., 1999 ; Steimer et al., 2001), but clearly tests should be combined with TDM (Baumann et al., 2004 ; Kirchheiner et al., 2001 ; Kirchheiner et al., 2004). Pharmacogenetic tests are also recommended in elderly patients as part of an approach aimed at avoiding adverse eects (Egger et al., 2005). The main advantage of these tests is to explain unexpected plasma concentrations of drugs and their metabolites. A few pharmacoepidemiological studies conrm that, indeed, the CYP2D6 genotype determines the plasma concentration of some antidepressants (Grasmader et al., 2004 ; Mulder et al., 2006), and one

CINP Antidepressant Task Force 2007 may conclude that CYP2D6 genotyping before starting pharmacotherapy could help to prevent increased drug plasma concentrations and concentrationdependent adverse eects. There is some preliminary support for the hypothesis that pharmacogenetic tests may also be advantageous from an economic point of view, as they may help to avoid adverse eects and rehospitalization, and reduce the duration of hospitalization (Chen et al., 1996). A recent analysis of the literature demonstrates the advantage of including TDM and pharmacogenetic tests in pharmacovigilance programs (Jaquenoud Sirot et al., 2006) (cf. also Phillips et al., 2001). However, despite a 25-year history of pharmacogenetics in psychiatry, these tests are still rarely routinely used, as shown in a recent study carried out in New Zealand and Australia (Gardiner and Begg, 2005), in spite of some recommendations to introduce pharmacogenetic testing into clinical practice (De Leon, 2006 ; De Leon et al., 2006a ; De Leon et al., 2006b ; Gardiner and Begg, 2006 ; Zourkova and Hadasova, 2003). 9.1.1.1.5 Pharmakokinetic interactions

S53

Table 14. TDM of antidepressants : recommended plasma concentration ranges ( therapeutic windows) (Baumann et al., 2004) Recommended therapeutic range (consensus) 80200 ng/ml 30130 ng/ml 175450 ng/ml 100300 ng/ml 50150 ng/ml 1580 ng/ml 120300 ng/ml 150300 ng/ml 175300 ng/ml 125200 ng/ml 1570 ng/ml 4080 ng/ml 3001000 ng/ml 70170 ng/ml 70120 ng/ml 10100 ng/ml 1050 ng/ml f50 ng/ml 6501500 ng/ml 150350 ng/ml 195400 ng/ml 20500 ng/ml

Drug and active metabolite Antidepressants Amitriptyline plus nortriptyline Citalopram Clomipramine plus norclomipramine Desipramine Doxepin plus nordoxepin Escitalopram Fluoxetine plus noruoxetine Fluvoxamine Imipramine plus desipramine Maprotiline Mianserin Mirtazapine Moclobemide Nortriptyline Paroxetine Reboxetine Sertraline Tranylcypromine Trazodone Trimipramine Venlafaxine plus O-desmethylvenlafaxine Viloxazine

Many patients are comedicated with other psychotropic and/or somatic drugs as a consequence of comorbidities or non-response to monotherapy. Patients suering from recurrent depression are submitted to long-term treatment. This increases the lifetime risk of comorbidities, which necessitate simultaneous treatment with several drugs. Adverse eects are then to be expected as a consequence of pharmacodynamic interactions between drugs or when a pharmacokinetic interaction results in an increase in drug plasma concentrations, which may reach toxic levels. Several drugs (uoxetine, paroxetine, uvoxamine, trimipramine etc.) and metabolites (noruoxetine) are known to be clinically relevant inhibitors of some forms of cytochrome P-450 (Table 12). As a consequence, pharmacokinetic interactions between antidepressants and other drugs (including antidepressants) may have important clinical consequences, as they may act as substrates and/or inhibitors of cytochrome P-450 (Table 12). Classical examples are the interaction between uvoxamine (Bertschy et al., 1991) or uoxetine (Aranow et al., 1989) and tricyclic drugs. Table 15 lists some of the most potent inhibitors and inducers of the cytochrome P-450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 (Armstrong and Cozza, 2000 ; Baxter, 2006 ; Bonnabry et al., 2001 ; Cozza and Armstrong, 2005 ; Jaquenoud Sirot et al., 2006 ; Wilkinson, 2005) (cf. also http:/ /

medicine.iupui.edu/ockhart/table.htm (14-8-2006), www.pharmacoclin.ch (14-8-2006)). It is striking to observe that authors dier in their appreciation of the inhibiting and inducing properties of some compounds (cf. also Armstrong and Cozza, 2000). Regrettably, some therapists tend to avoid risky comedications, which per se could be extremely useful for the patient. TDM should be recommended to allow concomitant treatments that, a priori, seem to present a risk but that could be highly benecial for some patients. 9.1.1.2 Galenic forms of antidepressants 9.1.1.2.1 Oral antidepressants

Antidepressant medication used for oral application is delivered as immediate release (IR) and extended release (ER, XR) formulations. In addition quick dissolving tablets are available from some manufacturers possibly enhancing the convenience by the

S54

CINP Antidepressant Task Force 2007 (DeVane, 2003 ; Entsuah and Chitra, 1997 ; Norman and Olver, 2004 ; Olver et al., 2004). 9.1.1.2.2 Transdermal antidepressants

Table 15. Typical inhibitors and inducers of cytochrome P-450 Antidepressants and other CYP-450 substrates Broccoli (Brassica oleracea) Caeine Carbamazepine Cimetidine Ciprooxacin Clarithromycin Dexamethasone Dihydralazine Diltiazem Efavirenz Erythromycine Fluoxetine Fluvoxamine Grapefruit juice (Citrus paradisi) Haloperidol Indinavir Intraconazole Ketoconazole Levomepromazine MDMA (ecstasy) Mexiletine Mifepristone Nefazodone Nevirapine Noroxazine Omeprazole Paroxetine Phenobarbital Phenytoin Primidone Rifampicin Ritonavir Rofecoxib Saquinavir St. Johns wort (Hypericum perforatum) Tobacco smoking (Nicotiana) Valproic acid Verapamil CYP inducing (+) and inhibiting (x) properties CYP1A2+ CYP1A2x CYP2C9+, CYP3A+ CYP1A2x, CYP2D6x, CYP2D6x CYP1A2x CYP3Ax CYP2C9x CYP1A2x CYP3Ax CYP3A+ CYP3Ax CYP2C19x, CYP2D6x CYP1A2x, CYP2C9x, CYP2C19x CYP3Ax CYP2D6x CYP3Ax CYP3Ax CYP3Ax CYP2D6x CYP2D6x CYP3Ax CYP3Ax CYP3Ax CYP3A+ CYP1A2x CYP1A2+ CYP2D6x CYP2C9+, CYP3A+ CYP2C9+, CYP3A+ CYP2C9+ CYP1A2+, CYP2C9+, CYP3A+ CYP1A2+, CYP3Ax CYP1A2x CYP3Ax CYP2C9+, CYP3A+ CYP1A2+ CYP3Ax, CYP2C9x CYP3Ax

To date only one antidepressant, the MAOBI selegiline is available in some countries as a transdermal patch (see chapter 9.1.2). The patients acceptance seems to be good and it has been described that the transdermal system possibly may excert a better ecacy in comparison to orally administered selegiline (Morgan, 2007). 9.1.1.2.3 Intravenous antidepressants

patients (Behnke et al., 2003). While there is common consensus that no dierences concerning the clinical eectiveness can be observed, tolerability advantagtes of ER formulations in comparison to IR formulations have been reported e.g. in case of the SNRI venlafaxine

Parenteral administration of antidepressants during the rst 2 weeks of an acute depressive episode is common practice in several countries, particularly in continental Europe. However, the advantages of parenteral over oral administration of antidepressants, if any, have not been clearly demonstrated, neither from a pharmacological nor from a clinical viewpoint. It is reasonable to suggest that intravenous (i.v.) administration avoids intermediate stages and thus may result in higher plasma levels of TCAs. Unfortunately, most of the relevant literature is published in languages other than English, and access to it is limited. There has been, however, published, that intravenous administration of Clomipramine and Maprotiline may have a faster onset of action in comparison with oral therapy (Gastpar et al., 1986). The drugs that are currently available for i.v. administration are clomipramine, doxepine, maprotiline, citalopram and mirtazapine. Note that clomipramine is not approved by the FDA for treatment of depression but only for obsessive-compulsive disorder (OCD). In continental Europe, however, i.v. clomipramine infusions are common practice, although research that supports the treatment is lacking. Eight studies have been published on the treatment of refractory depression (Bogdanowicz et al., 1991 ; Ceskova et al., 1983 ; Fountoulakis et al., 2004 ; Laux and Reimer, 1979 ; Nahunek et al., 1983 ; Ravizza, 1979 ; Sallee et al., 1997 ; Zapletalek et al., 1982), only three on the treatment of OCD (Fallon et al., 1998 ; Koran et al., 1998 ; Mundo et al., 1999), whereas another three studies use i.v. clomipramine as a challenge test (Golden et al., 1990 ; Kupfer et al., 1991 ; Sallee et al., 1998). Open studies are conrming a fast onset of treatment response with parenteral clomipramine and desipramine in drug resistant depression within one week (Ceskova et al., 1983 ; Nahunek et al., 1983).

CINP Antidepressant Task Force 2007 The usual practice of infusions suggests starting with ampoule (amp) of clomipramine (1 ml, 12.5 mg) and adding 1 amp (2 ml, 25 mg) every day to reach a maximum of 56 amp (125150 mg). Anecdotal data report higher doses up to 89 amp per day (200225 mg), but this is considered to be a highly aggressive strategy not supported by the literature. Close monitoring of cardiac function and blood pressure is essential because of side eects. Maprotiline is also available in i.v. form (Drago et al., 1983 ; Kissling et al., 1985 ; Zapletalek et al., 1982), but data regarding its ecacy are few. Intravenous citalopram was recently introduced (Kasper and Muller-Spahn, 2002). In one double-blind study i.v. citalopram showed superior response rates over oral (p.o.) citalopram (79 vs. 63 %) in severely depressed patients at 8 weeks (Guel et al., 2000 ; review : Moukaddam and Hirschfeld, 2004). It has also been shown to be eective in the treatment of OCD in an open trial (Pallanti et al., 2002). Even more recently, i.v. mirtazapine was introduced and was reported to be eective in the treatment for depressed patients in open naturalistic studies (Konstantinidis et al., 2002 ; Muhlbacher et al., 2006). Overall, the practice of i.v. administration has not been adequately shown to be superior to oral administration in the majority of depressive patients, but it may be recommended for treatment of refractory cases. In these refractory cases, it seems that at least some of these patients benet from the bypassing of the gastrointestinal tract and achieve better and faster drug levels. 9.1.1.3 Summary of side eects39 Antidepressant drugs can produce common side eects according their receptor proles. In addition, possible discontinuation symptoms and the potential for allergic reactions and blood dyscrasias must be taken into consideration. The use of TCAs appeared to be problematic in some cases due to their inherent side-eect prole. Anticholinergic and antihistaminergic side eects are of particular concern, and possible cardiovascular complications, especially in case of overdose, have consequently limited their use (Burrows et al., 1976 ;

S55

Burrows et al., 1981 ; Vohra et al., 1975 ; Vohra and Burrows, 1974). New antidepressants have a more selective mode of action and are therefore more frequently used as a rst-line therapy due to their favorable tolerability prole (Burrows and Norman, 1997). Despite their fewer anticholinergic eects, however, it is important to pay attention to the specic sideeect proles of the newer substances. In particular, the activating properties of NARIs can cause tremor and restlessness together with sleep disturbances. SSRIs raise serotonin levels at multiple sites and at multiple receptors throughout the brain (Stahl, 1998a), and can lead to nausea, headache, agitation and a general activation syndrome , sexual dysfunction and sometimes sleeplessness. Substances with additional antihistaminergic properties, such as mianserin, mirtazapine and doxepin, may induce drowsiness, especially during the beginning of the treatment. Later, increased appetite and weight gain often emerges as a problem that markedly inuences compliance (Kent, 2000). Especially during the rst days of use of antihistaminergic antidepressants, patients must be informed about possible eects on their driving performance (see chapter 9.1.1.3.4). But untreated depression, too, usually worsens patients driving due to prolonged reaction times and concentration decits. After the rst week of treatment (Ramaekers, 2003) and during long-term treatment driving ability generally normalizes. This normalization may depend on the applied daily dosage. In addition, dierences in driving performance based on treatment with sedating or non-sedating antidepressants have been reported (Ridout et al., 2003 ; Wingen et al., 2005). Table 16 presents specic side-eect proles based on the eect of antidepressants on receptors and neurotransmitters. Using this table in combination with Table 1, one can deduce the specic side-eect prole to be expected for a specic antidepressant. 9.1.1.3.1 Blood dyscrasias and disturbance of erythro- and leucopoiesis during the use of antidepressants Neutropenia and thrombocytopenia40 have been observed during treatment with mood stabilizers like carbamazepine (Sheehan and Shelley, 1990), lamotrigine (LeDrew et al., 2005 ; Ural et al., 2005) and valproate (Vesta and Medina, 2003). During
40

39

The subdivision in dierent classes of antidepressants including additional eects on specic receptors can be seen in Table 1. Together with Table 16 an individual side eect prole of each single antidepressant can be deduced. In addition to that prole also the used dose and the individual sensitivity of a patient inuences the probability and magnitude of side eects.

Also, antipsychotics such as clozapine or olanzapine (Duggal et al., 2004), used in augmentation therapies (see chapter 9.1.12), may cause leukopenia culminating in agranulocytosis.

S56

CINP Antidepressant Task Force 2007

Table 16. Modes of action and receptor proles, and direct and indirect eects of antidepressants possibly associated with clinically relevant and compliance-inuencing side eects Inuenced receptors or neurotransmitters M1 receptor

Mode of action Antimuscarinic/anticholinergic

Typical side eects (receptor)41

$ $ $ $ $ $ $ $ $

H1 receptor

Antihistaminergic

$ $ $ $ $ $

a1/2-receptor NA transporter

Antiadrenergic Noradrenalin reuptake inhibition/ noradrenergic eects

$ $ $

Dry mouth Accommodation disturbances Constipation Miction disturbances Worsening of angle-closure glaucoma Hyperhidrosis Cognitive disturbances Delirium Cardiac arrhythmias Sedation Drowsiness Daytime tiredness Increased appetite Weight gain Metabolic syndrome Hypotension

5-HT transporter blockade/5-HT receptor agonism

Serotonin-reuptake inhibition/ serotonergic eects

Tremor Dry mouth $ Tachycardia $ Restlessness $ Sleep disturbances $ Hypertonia $ Headache (5-HT1D) Restlessness, agitation, akathisia (5-HT2) $ Anxiety, panic (5-HT2) $ Decreased appetite (5-HT2) $ Weight reduction (5-HT2) $ Sleep disturbances (5-HT2) $ Sexual dysfunction (5-HT2) $ Nausea (5HT3) $ Diarrhea (5-HT4) Serotonin syndrome (all 5-HT receptors ; predominantly in combination) $ Lack of emotion $ SIADH42 $ Enhanced bleeding risk43

antidepressant monotherapy using a variety of substances, including TCA (Gibson, 1974 ; Gravenor et al., 1986) and tetracyclic substances such as mianserin (Thomas and Read, 1990), neutropenia has been reported. Divergent reports about newer antidepres41 The sorting order represents grading from common and less serious to more serious but predominantly rare side eects. 42 Syndrome of inappropriate secretion of antidiuretic hormone, possibly resulting in hyponatremia and generalized epileptic convulsions 43 Due to decreased platelet concentration or diminished platelet aggregation.

sants such as SSRIs (Ozcanli et al., 2005 ; TrescoliSerrano and Smith, 1996), venlafaxine (Anghelescu et al., 2002 ; Lucht et al., 2000) and mirtazapine (Anon., 2004 ; Ozcanli et al., 2005) have been published. They have also been reported to have negative eects on leucopoiesis, but due to rare reports and frequent combination therapies the causal interdependencies are not clear. As a therapeutic or even prophylactic option additional lithium therapy should be owing to its potential not only to augment antidepressant therapies (Bauer et al., 2003) but also to stimulate leucopoiesis (Hager et al., 2002).

CINP Antidepressant Task Force 2007 9.1.1.3.2 Dependence potential of antidepressants44 and demarcation from a discontinuation syndrome Haddad identied 21 English-language case reports of antidepressant addiction (Diagnostic and Statistical Manual of Mental Disorders, 4th revision (DSM-IV) substance dependence criteria) published since 1963 (Haddad, 1999). Sixteen of these reports involved tranylcypromine or amineptine, which have atypical dopaminergic and stimulant properties, but have been withdrawn from the market in most countries. Subject characteristics included male sex (14/21), personality problems (10/21) and prior substance misuse (14/21). Signs of addiction such as increasing tolerance and compulsive use are not a feature of antidepressants45. Accordingly, addiction in the currently accepted sense of the term is not clinically associated with antidepressant drugs. Only bupropion, used as an antidepressant and for smoking cessation, has been controversial. But the compound has been shown not to be amphetamine-like, and its potential for human abuse is very unlikely (Grith et al., 1983 ; Miller and Grith, 1983). DSM-IV, whatever its limitations, does seem accurately to capture the real hazards of addiction, and on that basis, antidepressants are not, as a class, substances of misuse and hence should not be described as addictive. Still, the addictive potential of antidepressants is a popular, widely held belief. It is promoted by reports in which individuals claim to have had severe withdrawal symptoms and to have extreme diculties in stopping taking antidepressants. Moreover, authors such as Charles Medawar nourish the belief by painting it as part of a broader conspiracy (Medawar and Hardon, 2004) : Both literally and metaphorically, all the drugs in this story cause some degree of dependence. People get hooked not only on the drugs, but also on the idea of drugs as solutions for mental distress. Subtle interplays of power and dependence nurture this process of medicalisation, as if through a Conspiracy of Goodwill. On this basis, addiction becomes equated with the side eects of drugs, and even ideas about drugs. When it is reasonable to use the emotive term addictive and when it is not appears to be a matter of debate.

S57

The denition of dependence potential varies among dierent systems of classication. DSM-IV denes substance dependence in relation to a mixed picture of tolerance, withdrawal eects and compulsive drug-taking behavior, usually accompanied by a craving for the positive eects of the drug. 45 In addition, antidepressants have no market value for drug abusers, an authentic measure of abuse potential.

44

It would, however, be surprising if, on discontinuation, psychotropic drugs did not produce some withdrawal eects. Clearly they are often taken for relatively long periods of time, and receptors adapt in signicant ways to their presence. Once the drug is removed, these changes will be expressed as imbalances in neurotransmitter function and subjective adverse eects. Typically, these eects may include agitation, sleep disturbances, sweating, gastrointestinal discomfort and headache, and may take up to 2 weeks to subside. In addition several reports about a u-like syndrome after sudden cessation of antidepressants such as SSRIs, MAOIs, or SMAs have been published (Belloeuf et al., 2000 ; Curtin et al., 2002 ; Lejoyeux et al., 1992 ; Rajagopalan and Little, 1999 ; Schatzberg et al., 1997). In a prospective survey of 97 patients stopping an SSRI treatment (Bogetto et al., 2002), the onset of symptoms occurred within 2 days on average. Discernible eects were more likely with high doses and prolonged treatment. With less than 5 weeks exposure, withdrawal eects are very unusual and would be unexpected. When a discontinuation syndrome occurs, it is particularly dramatic in newborns whose mothers were treated with serotonergic drugs until delivery (Isbister et al., 2001 ; Misri and Kostaras, 2002 ; Nijhuis et al., 2001 ; Wen et al., 2006). Dierences in the rates of discontinuation syndrome have been reported after patients stabilized on uoxetine, sertraline or paroxetine had their maintenance therapy interrupted with double-blind substitution for 58 days. The incidence of discontinuation syndrome was lower in uoxetine than in sertraline or paroxetine groups (14, 60 and 66 %, respectively) in accordance with the half-life of the substance (Rosenbaum et al., 1998). The symptom categories seen with SSRIs and venlafaxine are disequilibrium (giddiness or even vertigo), sensory abnormalities (e.g. headache, pins-and-needles sensation), gastrointestinal upset (e.g. nausea), general somatic distress (e.g. lethargy), sleep disturbance and aective symptoms (Fava et al., 1997 ; Haddad, 1998 ; Schatzberg et al., 2006). In a database analysis, a total of 93 suspected cases of SSRI-induced neonatal withdrawal syndrome were reported and were regarded as sucient information to conrm a possible causal relation. Sixty-four of the cases were associated with paroxetine, 14 with uoxetine, 9 with sertraline and 7 with citalopram (Sanz et al., 2005b). A survey of the French pharmacovigilance database revealed that SSRIs are clearly associated with a higher risk of withdrawal syndrome (OR 5.05, 95 % CI 3.816.68) and in particular with the SNRI venlafaxine and the SSRI paroxetine

S58

CINP Antidepressant Task Force 2007 discussed (Dean, 2002 ; Haddad, 1999). Withdrawal symptoms have even (though rarely) been described following discontinuation of herbal antidepressants such as St. Johns wort (Beckman et al., 2000). The apparent absence of appropriate notication that such eects can occur runs consistently through the messages. There is also a pervasive hostility to the doctors (usually general practitioners, it would appear) who prescribe the drug. It is a real challenge to know how to evaluate this evidence in a quantitative sense as well as qualitatively, in relation to the motivation and needs of people who use Internet discussion boards. There is clearly a remarkable opportunity to harness patient experience through the Internet, but a qualitative free-for-all could well be self-perpetuating and ultimately uninformative because it is very likely to suer from a variety of confounding biases. There is also the complication that there appears to be a prospect of secondary gain from suing multinational drug companies who own patents on individual drugs. This issue is related to a much broader challenge, which is to improve current methods of post-marketing surveillance. Finally, aside from the issues of addiction, but important from the point of view of management, it is certainly possible that on discontinuation patients may relapse with the original anxiety or depressive symptoms that promoted the use of antidepressants (Geddes et al., 2003). To prevent discontinuation symptoms a slow tapering of antidepressant medication in case of a planned discontinuation has been recommended (Rosenbaum and Zajecka, 1997 ; Shelton, 2001 ; Warner et al., 2006). Clearly, when this occurs, a clinical decision must be made whether to continue with the medication and accept the benet of symptom control or discontinue mediciation and see the return of symptoms. There is no convincing evidence that the use of antidepressants makes returning anxiety or low-grade depressive symptoms worse, but obviously the costs and benets of long-term use of any medication must be weighed on an individual basis. In conclusion, the consensus view among experts is that antidepressant drugs are not addictive (Nutt, 2003) in the normally understood sense of the word and as regularly applied, e.g. to opiates. However, as with all medicines, their benet comes at the potential cost of adverse eects. These adverse eects are somatic symptoms on withdrawal. Extending prescription for minor symptoms or syndromes runs the risk of the harm being perceived as greater than the benet. There are undoubtedly some problems with the use and, particularly, the discontinuation of

(OR 12.16, 95 % CI 6.1723.35 and OR 8.47, 95 % CI 5.6312.65, respectively) (Trenque et al., 2002). It should, of course, be a critical part of the information given to patients that such eects can arise. They can usually be abolished by restarting the withdrawn drug and avoided by substituting uoxetine to cover withdrawal, since it has a prolonged half-life. In the war of words and their meanings that dominate this debate, the potential of causing withdrawal seems to be used synonymously with dependence and addiction by some authors and the expression discontinuation symptoms sometimes appears to be preferred by those who feel the eects are too mild to be regarded as evidence of a serious problem. The frequency and severity of withdrawal symptoms is a key issue. Withdrawal symptoms following long-term use of antidepressants are related not to the disease but to drug tapering or stoppage. They must be distinguished from a recurrence of the actual depressive episode and from a rebound with symptoms of an even higher intensity (Bauer et al., 2002b). Unfortunately, measurement of withdrawal eects is imprecise and is confounded by expectations under ordinary clinical conditions. The more sensitive the measure, the more likely it is that withdrawal eects will be detected. It would, however, be extremely misleading to imply that these eects generally constitute a serious barrier to discontinuation in the majority of patients (Bogetto et al., 2002). When clinician and patient ratings are compared under double-blind conditions, there is also a high level of agreement (Rosenbaum et al., 1998). This nding is important because the claim is sometimes made that companies and clinicians are in a conspiracy to deny how severe these symptoms are. Just as it would be surprising not to have some withdrawal eects, odd physical eects as a result of individual dierences on discontinuing a drug are also to be expected. About 50 comments on paroxetine withdrawal, from discussion boards posted between January 1999 and May 2002, were provided to the Seroxat users website (http://www.seroxatusergroup.org.uk). There is in fact a reasonable concordance with the symptoms described in the literature, although the eects are often described as very severe and unexpected. Discontinuation symptoms and treatment interruption-emergent events were more frequent after paroxetine compared with uoxetine treatment due to the dierent half-lives of the compounds (Judge et al., 2002). In addition, similar to the misuse of nonpsychotropic medications, excessive use of antidepressants has also been reported, and the addiction potential of antidepressants has been

CINP Antidepressant Task Force 2007

Box 8. Discontinuation symptoms and relapse after stopping antidepressant treatments : conclusion

S59

Antidepressant medications do not produce dependence that corresponds to criteria of the ICD-10 and the DSM-IV classications. They have no dependence potential in laboratory animal trials, and their use does not satisfy other criteria for the diagnosis of substance dependence46, such as increasing tolerance and craving. If applied in therapeutic doses, sudden interruption of intake will cause discontinuation symptoms, as reported for several antidepressants, such as escitalopram (Baldwin et al., 2005), paroxetine and sertraline (Rosenbaum et al., 1998) or venlafaxine (Fava et al., 1997). This fact and several case reports of dependence on uoxetine (Menecier et al., 1997), tianeptine (Guillem and Lepine, 2003 ; Leterme et al., 2003 ; Saatcioglu et al., 2006 ; Vandel et al., 1999) and tranylcypromine47 (Ben-Arie and George, 1979 ; Briggs et al., 1990 ; Westermeyer, 1989) led to the erroneous belief that antidepressant medications produce dependence, which resulted in the reluctance of doctors and patients to use these medications where indicated.

antidepressants that merit clinical care, clear labeling and information for patients. But there seems little reason why, with that precaution, they should not be used safely. This is the usual experience of psychiatrists working in secondary care. 9.1.1.3.3 Use of antidepressants during pregnancy, post-partum depression and breast feeding The pregnancy and post-partum periods are considered to be relatively high risk times for developing depressive symptoms as well as depressive episodes in women (see also chapter 10.1) (for review see Cohen et al., 2004 ; Nonacs and Cohen, 2003). Both acute and prophylactic treatment of depressive disorders during pregnancy may pose a dicult-to-solve therapeutic problem and require individual risk-benet analysis. Untreated depression is associated with impaired feto-placental function, premature delivery, miscarriage, low fetal growth and perinatal unwanted eects, whereas use of antidepressant drugs during pregnancy might entail risk of teratogenesis, neonatal toxicity, discontinuation symptoms and neuropsychological-behavioral impairment (Bellantuono et al., 2006). In addition, during antidepressant pharmacotherapy after birth, each available antidepressant is excreted in the milk (approximately 1 % of plasma levels can be seen) and may inuence infants during breast feeding (for review see Burt et al., 2001 ; Dodd

Denitions of dependence and addiction are still controversial (OBrien et al., 2006). Physical dependence is characterized by symptoms of withdrawal after discontinuation of a substance ; addiction is most commonly is dened as the compulsive need and repeated use of a substance despite clear evidence of morbidity secondary to such use leading to tolerance and craving beyond voluntary control. 47 The dependence potential of tranylcypromine is related to the fact that one of its metabolites is an amphetamine (Briggs et al., 1990). Some countries in Europe have discontinued its use, partly because of that and partly because of other adverse eects.

46

et al., 2000 ; Suri et al., 1998). Therefore, the risk of untreated depressive disorders causing maternal stress that also inuences the fetus and birth outcomes, as well as enhanced risk for suicide, must be evaluated together with a possible increased risk for fetal malformation, growth impairment, fetal and neonatal toxicity, and behavioral teratogenicity caused by antidepressant treatment (Wisner et al., 2000). These benets and risks of antidepressant pharmacotherapy must also be assessed and compared with other non-pharmacologic treatment alternatives, e.g. ECT (chapter 12.2), which can safely be administered during pregnancy and breast feeding (Rabheru, 2001 ; Walker and Swartz, 1994). Sleep deprivation (chapter 12.3.7) (Parry et al., 2000) and bright light therapy (chapter 12.3.8) (Oren et al., 2002) should be considered. Because RCTs during pregnancy are not ethically acceptable and no controlled studies of the use of antidepressants during pregnancy have been published, all knowledge on the subject is anecdotal. Single case reports, case series and epidemiological data must be analyzed carefully, including patients individual histories. In addition to concerns about malformations and neonatal complications, the risk of inuence on behavioral development, e.g. abnormal emotional behavior in ospring, cannot to date be excluded. Accordingly, recent studies in new born mice have shown an eect of serotonin and SSRI (Fluoxetine) treatment on behavioral phenotypes, leading to the hypothesis that these eects may indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function (Ansorge et al., 2004). Enhanced risk of intrauterine death or congenital malformation has generally not been reported in conjunction with TCAs and uoxetine or other SSRIs (Wisner et al., 1999). Nevertheless, more neonatal complications were seen. Children of mothers treated with uoxetine during the rst trimester of pregnancy showed lower maternal weight gain during pregnancy

S60

CINP Antidepressant Task Force 2007 uation therapies during pregnancy and the postpartum period must also be considered (Ernst and Goldberg, 2002). 9.1.1.3.4 Antidepressants and tness to drive

(which is also associated with untreated depression) together with decreased birth weight of neonates and a higher rate of premature birth (Chambers et al., 1996). Moreover, infants of mothers treated with uoxetine during breast feeding showed reduced growth (Chambers et al., 1999). The overall development of children of mothers receiving TCAs or SSRIs during pregnancy did not dier from that of controls (Wisner et al., 1999). A meta-analysis reported that use of newer antidepressants such as SSRIs, SNRIs, NARIs, NaSSAs and DNRIs is not associated with an increased risk of major malformations above the baseline of 13 % in the population (Einarson and Einarson, 2005). Nevertheless, a recently published case-control study that has been somewhat contested by experts (Blier, 2006) reported an association between the maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension in newborns as a probable cause of substantially enhanced infant mortality (Chambers et al., 2006). In addition, a warning has been published not to use paroxetine within the rst trimester of pregnancy owing to a twofold increase in the rate of cardiovascular malformation (GSK Clinical Trial Register ; http://ctr.gsk.co.uk/ Summary/paroxetine/epip083.pdf). Recently published reports conrm the potentially increased risk of congenital malformation following paroxetine treatment (Cuzzell, 2006), therefore its use during pregnancy should be avoided. Also, the manufacturer of bupropion has established a Pregnancy Registry program primarily to collect safety data regarding the use of this substance during pregnancy (White and Andrews, 1999). Newer compounds whose teratogenic risks are unknown or incomplete should not be used as rst-line agents in the pharmacological treatment of depression during pregnancy and breastfeeding (Gentile, 2005). Even agents considered so far to be safe for mother and child during breast feeding, such as mirtazapine (Aichhorn et al., 2004) and escitalopram (Rampono et al., 2000), should be evaluated carefully as they have not been available for suciently long time for a nal risk evaluation. The Health Reserarch Group therefore even suggests to wait at least seven years from the start of the marketing of a new drug until reliable statements about the safety of this drug can be published, because the numbers of probands and patients receiving new drugs in RCTs may be to small to detect even life threatening rare adverse events (Wolfe et al., 2005). Although published studies show that plasma levels in babies are often below detectable levels (Blier, 2006), data from large prospective studies are lacking. Finally, the specic safety proles of maintenance and contin-

Most patients treated with antidepressants are not hospitalized, but continue to live in their community. It is therefore important to know whether antidepressants inuence activities such as car driving, which requires intact psychomotor functioning. Some antidepressants produce side eects that include dizziness, sedation, blurred vision, sleepiness, and diculty concentrating on tasks and making decisions. Some of these symptoms must be assumed to be similar to those observed in untreated depressed patients, and therefore the driving capacity of each patient must be examined individually, independently of his or her treatment (Laux, 2002). One of the main tests used in this context is the same as that introduced for testing driving behavior in subjects who have ingested alcohol : the standard deviation of lateral position (SDLP) is an index of road-tracking precision or weaving , as described in detail by Van Laar et al. (1992). This test is carried out in real conditions, where the subjects are driving a test car (on-the-road driving test), but other methods have also been used, where car driving is only simulated (Brunnauer et al., 2006 ; Laux, 2002). This means that comparisons between dierent studies are sometimes dicult. The literature is surprisingly thin with regard to studies regarding the inuence of antidepressants on driving behavior, and most of them were carried out with healthy volunteers treated with a single dose of an antidepressant drug (Table 17). In healthy subjects, tricyclic drugs such as imipramine (van Laar et al., 1995) or amitriptyline (Louwerens et al., 1984) and others generally impair driving behavior after acute medication, but some tolerance my develop after prolonged administration (Table 17). According to Laux et al., most tricyclic drugs (amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, opipramol and trimipramine) and the tetracyclic antidepressants maprotiline and mianserin clearly decrease driving capacity, especially during the rst 1014 days following initiation of treatment (Laux, 2001). A retrospective cohort study showed that elderly patients treated with TCAs represent a higher risk group for trac accidents in comparison to a group of control subjects (Ramaekers, 2003 ; Ray et al., 1992). Tricyclic drugs are increasingly used in low doses for the treatment of neuropathic pain (Sindrup et al., 2005). In a small group of patients

CINP Antidepressant Task Force 2007

Table 17. Fitness to drive during application of antidepressants in healthy volunteers Antidepressant Amitriptyline Dothiepin Doxepin Escitalopram Fluoxetine Imipramine Mianserin Mirtazapine Study details Healthy volunteers, 75 mg Healthy volunteers, 75150 mg Healthy volunteers, 75 mg Healthy volunteers, 1020 mg Healthy volunteers, 20 mg Healthy volunteers, 50 mg Healthy volunteers, 3060 mg Healthy volunteers, 1530 mg Outcome SDLP elevation, adaptation after 1 week SDLP not dierent from placebo SDLP elevation, adaptation after 1 week Driving and psychomotor performance not aected Reduced attention, driving performance not aected SDLP elevation, adaptation after 1 week Impaired driving performance, adaptation after 1 week SDLP elevation, impaired driving performance, adaptation after 1 week Driving performance not dierent from placebo Highway driving performance not impaired, slight impairment of lateral position control after 400 mg per day Impaired psychomotor performance, road tracking not aected Simulated car driving not aected No eect on SDLP or psychomotor performance Reference Louwerens et al., 1984 Ramaekers et al., 1995 Schoenmakers et al., 1989 Wingen et al., 2005 Ramaekers et al., 1995 van Laar et al., 1995 Louwerens et al., 1984 ; Ramaekers et al., 1998 Ramaekers et al., 1995 ; Ramaekers et al., 1998 ; Wingen et al., 2005 Ramaekers et al., 1992 van Laar et al., 1995

S61

Moclobemide Nefazodone

Healthy volunteers, 200 mg Healthy volunteers, 200 or 400 mg

Paroxetine Sertraline Venlafaxine

Healthy volunteers, 2040 mg Healthy volunteers, 100200 mg Healthy volunteers, 37.575 mg

Robbe and OHanlon, 1995 Warrington, 1991 OHanlon et al., 1998

SDLP, Standard deviation of lateral position.

suering from this disease, a rst dose of 25 mg amitriptyline signicantly impaired driving performance, in comparison to placebo. After a 2-week treatment with 25 mg/day amitriptyline, tolerance had developed as the dierences between placebo vs verum were not any more signicant (the drug was always administered in the evening, about 13h before the test). These eects of the TCA appear to be related to their pharmacological properties as a1-, muscarinic and/or H1 antagonists. As expected, due to their pharmacological prole, the H1 antagonists mianserin (15 mg/ day) and mirtazapine (30 mg/day) impaired slightly driving performance on day 2 in healthy volunteers (Ramaekers et al., 1998) (Table 17). However, tolerance apparently developed as on day 8, the eect was gone for mirtazapine, and strongly decreased for mianserin. Dose was then increased to 30 mg/day and 60 mg/ day, respectively : on day 16 of treatment, there was some impairment of the driving performance with both antidepressants. This indicates that tolerance was

not complete. In a similar study carried out by the same research group with healthy volunteers treated for one week with 30 mg/day mirtazapine conrmed that this drug impairs car driving performance on day 2, but not later on (Wingen et al., 2005). As concluded also from other studies, mirtazapine should be administered in the evening and the physician should inform the mirtazapine treated patient that car driving represents some risks, especially at the beginning of the treatment. A naturalistic clinical study with depressive patients treated chronically with mirtazapine nevertheless demonstrated that this drug did less impair driving performance than TCAs, SSRIs and venlafaxine (Brunnauer et al., 2006), but it also conrms that depressive illness per se represents a risk factor. In contrast, escitalopram (Wingen et al., 2005), uoxetine (Ramaekers et al., 1995), paroxetine (Robbe and OHanlon, 1995), sertraline (Warrington, 1991) and moclobemide (Ramaekers et al., 1992), which are mostly devoid of the properties mentioned above for TCA (a1-, muscarinic and/or H1 antagonists), do not

S62

CINP Antidepressant Task Force 2007 drugs may impair driving capability (Veldhuijzen et al., 2006). 9.1.2 Monoamine oxidase inhibitors48

signicantly inuence driving behavior (Table 17). However, the information that sertraline does not impair simulated car driving in healthy volunteers is only mentioned in an abstract of a review paper (Warrington, 1991), but no comprehensive experimental report is available (Table 17). With regard to escitalopram, an already mentioned study (Wingen et al., 2005) (Table 17) shows that a one week treatment with 20 mg/day escitalopram did not result in an impairment of the driving capability of the healthy subjects, whether after acute nor after a 1-week treatment. This is in line with the low anity of escitalopram for histamine receptors. Conicting results were obtained for venlafaxine. While it is considered relatively safe by some authors when tested in healthy volunteers (Ramaekers, 2003 ; OHanlon et al., 1998) (Table 17), others observed that depressive patients treated with venlafaxine performed less well than those treated with mirtazapine, but no data are available about the doses used (Brunnauer et al., 2006). It has to be considered that patients may have comedications such as benzodiazepines, either prescribed or as a self-medication. They certainly impair driving ability much more that antidepressants (Bramness et al., 2003 ; Van Laar and Volkerts, 1998, Van Laar et al., 1992). This eect can be even more pronounced in situations where such a drug is a substrate of CYP3A4 (e.g. alprazolam) or CYP2C19 (e.g. diazepam) and where it is administered to subjects comedicated with other drugs (see also chapter 9.1.1.1.5) which per se do not impair driving behavior but which are known inhibitors of one of these enzymes (e.g. uoxetine, moclobemide) (Ramaekers, 2003). The eect of an antidepressant can be be directly compared with that of alcohol, at a particular blood alcohol concentration (BAC : 0.5, 0.8, , mg/ml) (Ramaekers, 2003). It is clinically important that some tricyclic drugs (and benzodiazepines) enhance the impairing eect of alcohol on skills related to driving behavior (Landauer et al., 1969), while generally SSRIs do not modify these alcohol eects (Baxter, 2006). In conclusion, depressed patients must be informed that, owing to their illness, driving performance may denitely decrease, and that the risk of trac accidents is increased by alcohol or benzodiazepine consumption. Moreover, the decision to medicate with an antidepressant must be made based on the patients situation with regard to his daily occupations, including car driving. However, it must be considered that, as shown by a recent study, patients often ignore warning labels on packages indicating that these

9.1.2.1 Ecacy A comparable ecacy prole for all available irreversible MAOIs similar to that of TCAs has been reported, but this is true only for outpatients (Thase et al., 1995), even if they have been TCA treatment failures. For inpatients, TCAs have been reported to be more effective than phenelzine and isocarboxazid (for review see : Thase et al., 1995). In other studies a similar ecacy of phenelzine in comparison to the TCAs imipramine in inpatients (Davidson et al, 1981), nortriptyline (Georgotas et al., 1986) and amitriptyline in outpatients (Ravaris et al., 1980) has been reported. Responsivity to MAOI treatment is highest in patients suering from depression with anergic or atypical features49 (Henkel et al., 2006 ; Himmelhoch et al., 1991 ; Thase et al., 1992 ; Thase et al., 1995), but anergic features were predominantly investigated in bipolar depression. Despite this ecacy prole, there is a broad consensus that irreversible MAOIs are considered predominantly as a second-line treatment strategy because of their potential to cause serious adverse events (see below, chapter 9.1.2.2) (Bauer et al., 2002c). Especially with depression resistant to TCAs, MAOI monotherapy or the combination of MAOIs and TCAs or mood stabilizers has been suggested based on promising results of case reports and retrospective data analyses (Amsterdam and Shults, 2005 ; Feighner et al., 1985 ; Schmauss et al., 1988). Tranylcypromine treatment has shown no signicant advantage in terms of remission rates compared with venlafaxine and mirtazapine combination therapy in outpatients with treatment-resistant depression (McGrath et al., 2006). Due to the lower side-eect burden of the SNRI/NaSSA combination compared with irreversible MAOIs, combination therapy may also be suitable for patients suering from highly treatment resistant depression (McGrath et al., 2006), but comparative RCTs up to now are missing.

48

The following sections describe the ecacy and safety prole of all available antidepressants. Substances are classed in groups according to their main mode of action. Because frequency of prescription varies among dierent countries, the group order corresponds to a more neutral and approximately historical chronology. 49 See chapter 5.2.1.3.3 for a detailed description of the concept of atypical depression. In France the term atypical depression is synonymous to depression with psychotic symptoms (see chapter 5.2.1.2).

CINP Antidepressant Task Force 2007

Box 9. List of tyramine-rich foods and beverages (excerpt)

S63

High-protein food that has undergone protein breakdown by aging, air drying, fermentation, pickling, smoking or bacterial contamination. Patients should not eat dried meats, dry sausages, hard salamis, pickled herring, any spoiled or improperly stored meat, pods of broad beans (fava bean), liver, yeast extract, sauerkraut, pepperoni, soybean products (including soy sauce and tofu) or aged cheeses. In addition beverages, such as tap beers and beers that have not been pasteurized, (red) wine and excessive use of caeine or chocolate should be avoided. Patients must beware of all supplements containing tyramine.

Dose-escalating strategies with MAOI therapy have also been suggested, but very few clinical data indicate that ultra-high-dose treatment with tranylcypromine is eective in refractory depression (Adli et al., 2005). As described in chapter 5.2.4.2.3, the preferential MAO-B inhibitor selegiline, which is mainly used in combination therapy for Parkinsons disease, may also exert signicant antidepressant eects (Amsterdam, 2003 ; Bodkin and Amsterdam, 2002). This is especially true at higher doses (>10 mg/day), which possibly also inhibit MAO-A activity (Mann et al., 1989). Selegiline transdermal system has shown superiority in comparison to placebo in several short-term (Feiger et al., 2006) and long-term RCTs (Amsterdam and Bodkin, 2006). In addition it has been described that the transdermal system possibly may excert a better ecacy in comparison to orally administered selegiline (Morgan, 2007). To date only a selegiline transdermal system has been approved as an antidepressant by the US Food and Drug Administration (FDA). The approval process in Europe is still ongoing. Actual data have been summarized in a recently published review (Frampton and Plosker, 2007). The reversible inhibitors of monoamine oxidase A (RIMAs) are considered to be as eective as TCAs and SSRIs, but somewhat less eective than irreversible MAOIs (Lotufo-Neto et al., 1999 ; Sogaard et al., 1999). It has been reported that there is evidence from meta-analyses that higher doses of moclobemide may sometimes enhance ecacy in treating depressive disorders (Lotufo-Neto et al., 1999). 9.1.2.2 Safety and tolerability Interactions of predominantly irreversible MAOIs with sympathomimetic medication or tyraminecontaining food carry a risk of hypertensive crisis of potentially fatal outcome (Amsterdam and Shults, 2005 ; Brown and Bryant, 1988). For this reason, there is broad clinical consensus that MAOIs are considered only as second-line antidepressants. Moreover, they entail dietary restrictions that prevent ingestion of tyramine-rich food (see Box 9).

MAOI ultra-high-dose therapy can cause delirium. In addition, following discontinuation of irreversible MAOI therapy, withdrawal phenomena such as agitation, anxiety, sleeplessness or drowsiness and even hallucinations and delirium have been described (Dilsaver, 1988). For more information concerning a possible dependence potential of MAOIs, see chapter 9.1.1.3.2 and Box 8. The risk of serotonin syndrome due to the concomitant use or accidental combination of other serotonin-enhancing antidepressants, such as SSRIs, S-TCAs, SNRIs or SMAs, must be taken into account. Depending on the half-life of the substances used, a drug-free time interval of at least 2 weeks in the case of serotonergic medication before or after irreversible MAOIs is necessary to minimize the risk of severe adverse events. Prescribing MAOIs following uoxetine requires lengthening the time interval to 56 weeks. In the case of serotonergic substances following the RIMA moclobemide, the time interval can be shortened to 3 days. Restricted intake of tyraminerich foods is not necessary when using RIMAs ; however, in dose ranges above 900 mg/day, e.g. for moclobemide50, the risk of interactions with tyramine might again become clinically relevant (Bonnet, 2003). Moreover, RIMAs interact with concomitantly used serotonin-enhancing drugs (Livingston and Livingston, 1996), and have the potential to cause severe serotonin syndrome (Dardennes et al., 1998 ; Guma et al., 1999 ; Roxanas and Machado, 1998). Prescribing the selegiline transdermal patch in higher dose ranges (9 or 12 mg/day) requires dietary modications. Moclobemide may be suitable, particularly in the treatment of bipolar depression, due to a low switch risk (Silverstone, 2001).

50

During the licencing process, from a clinical point of view, overly low doses have been recommended possibly due to marketing or pricing strategies. In the UK, in comparison with other countries, a 200 % dose has been proposed. The same recommendation was made in Germany several months after introduction of the drug onto the market.

S64

CINP Antidepressant Task Force 2007 with lesser sedating eects, such as clomipramine or desipramine, appear superior in retarded and anergic depression. TCAs with inherently stronger antihistaminergic eects, such as doxepin, amitriptyline and dosulepine, have advantages in agitated patients with signicant sleep disturbances. 9.1.3.2 Safety and tolerability The main concerns in using TCAs as a rst-line treatment are anticholinergic and antihistaminergic side eects possibly inuencing substantially tolerability and therapy adherence. Sedating properties may help in the treatment of depression-related sleep disturbance, but daytime drowsiness and sedation often lead to discontinuation of treatment. In the long term, increased appetite, resulting weight gain and in some cases even risk of enhancing the high rate of metabolic syndromes in depression also play a crucial role. Treatment safety can be increased by using modern antidepressants with greater specicity and a tolerability prole that includes a lower risk of cardiovascular and neurological side eects. Suicidal behavior may be a further reason to be cautious in prescribing TCAs as rst-line treatment.52 Whereas SSRIs, NaSSAs and SNRIs are associated with fewer completed suicide attempts in cases of drug overdose, a positive association between TCAs and fatal suicide attempts has been reported (Frey et al., 2002 ; Gibbons et al., 2005 ; Jonsson et al., 2004). One reason may be that despite the ecacy of TCAs in treating depression, they have greater toxicity compared with the newer antidepressants. This is especially true in case of overdose due to the electrocardiographically measured QTc time prolongation and enhanced cardiotoxicity caused by some, but not all TCAs. 9.1.4 Other modes of action not directly involving monoamines : the modied TCA tianeptine Despite its modied tricyclic structure, initial studies showed that tianeptine did not share pharmacological properties with TCAs, MAOIs or SSRIs (Wilde and Beneld, 1995). Although acute in vitro and in vivo studies suggest that tianeptine enhances [3H]5-HT reuptake into rat cortical and hippocampal synaptosomes (Fattaccini et al., 1990 ; Mennini et al., 1987), more recent studies assessing the release of serotonin
52 In chapter 11 (Suicidality and antidepressants : depression and suicide) the discussion about the postulated potential of SSRIs to induce suicidal ideations or suicide attempts has been evaluated in detail.

9.1.3 Non-selective monoamine reuptake inhibitors/tricyclic antidepressants Ever since the introduction of the rst antidepressant, imipramine, and for a long time, tricyclics were the primary pharmacotherapeutic option in the treatment of depression. The TCA amitriptyline is even mentioned in the World Health Organizations (WHOs) list of essential drugs (World Health Organization, 2005a). Nevertheless, in recent years tri- and tetracyclic antidepressants have lost their status as rstline treatment for depression in several developed countries due in part to their particular side-eect prole and the introduction of newer antidepressants in these countries. Even absent sucient scientic justication for this approach, from a clinical point of view in preparing antidepressant treatment plans it may be useful to subdivide TCAs not only according their sedating and activating properties but also according to their inuence on serotonergic, noradrenergic and dopaminergic neurotransmission. In the event of treatment failure and pharmacotherapy resistance, switching from serotonergic to noradrenergic or mixed action TCAs seems to be plausible. But unfortunately, controlled studies supporting this method are still are lacking. 9.1.3.1 Ecacy51 As described previously, TCA treatment is eective in depressive disorders, independent of subtype or severity of depression. Controlled studies comparing TCAs with other classes of antidepressants are provided within chapters 9.1.2 to 9.1.10. Especially in severely depressed, hospitalized patients mixed S/NTCAs compare favorably with SSRIs (Anderson, 1998 ; Anderson, 2000a ; Danish University Antidepressant Group, 1986 ; Danish University Antidepressant Group, 1990) and the RIMA moclobemide (Danish University Antidepressant Group, 1993), whereas SSRIs and MAOIs appear to be superior in depressive disorders with anergic or atypical features (see chapters 9.1.2.1 and 9.1.5.1). The inuence of gender and depression subtype on antidepressant response is unclear, but higher age does seem to predict a better response to TCAs (Parker, 2002 ; Parker et al., 2003). From a clinical point of view, but again without sufcient support in the literature (Sartorius, 1974), TCAs
51

TCAs are available in both oral and i.v. forms. There is no scientic evidence for a dierential ecacy prole between them. See chapter 9.1.1.2.3 for a more detailed description of i.v. administration of antidepressants.

CINP Antidepressant Task Force 2007 by microdialysis following chronic (14-day) administration clearly demonstrate that there is no signicant change in serotonin release (Malagie et al., 2000). Previous studies had shown that, following chronic administration, tianeptine induces adaptive changes in cortical, but not hippocampal serotonin transporters (Pineyro et al., 1995a ; Pineyro et al., 1995b). Experimental studies now indicate that tianeptine has neuroprotective eects that contribute to its antidepressant properties (Defrance et al., 1988 ; McEwen and Olie, 2005). In this respect it resembles other classes of antidepressants (see chapter 8 for details). Thus, changes in neurogenesis and neuroplasticity of the hippocampus, cortex and amygdala may play a prominent role in the ecacy of tianeptine. In addition, tianeptine has been shown to change the neuronal architecture of the hippocampus and amygdala, and the rate of apoptosis in the hippocampus and temporal cortex, and to restore hippocampal volume following exposure to chronic stress (McEwen and Olie, 2005). Such eects have been explained in terms of modulation of glutamatergic transmission (see also chapter 8.2) (Kole et al., 2002 ; Reagan et al., 2004). In other words, experimental evidence suggests that changes in glutamatergic function reect adaptive changes to stress of the glutamate transporter that are located on glial cells ; any change in serotonergic function following tianeptine is therefore likely to be indirect. 9.1.4.1 Ecacy The ecacy of tianeptine in most published studies was comparable to SSRIs (Kasper and Olie, 2002) ; only one RCT showed an advantage of uoxetine in elderly patients (Guel et al., 1999). Comparison with other antidepressants such as amitriptyline (Guel et al., 1989 ; Invernizzi et al., 1994) and mianserin (Brion et al., 1996) also turned up no signicant dierences in ecacy. 9.1.4.2 Safety and tolerability Tianeptine does not appear to be associated with severe anticholinergic or cardiovascular side eects (Loo and Deniker, 1988). Specic advantages in the case of comorbidities such as cardiovascular disorders (Pogosova et al., 2004) and Parkinsons (Levin, 2006) disease have been described. The overall tolerability prole compared with SSRIs has been shown to be favorable, especially in the case of paroxetine (Kasper and Olie, 2002 ; Lepine et al., 2001). Nor have any detectably signicant dierences (in comparison with uoxetine) been reported (Loo et al., 2001). 9.1.5 Selective serotonin reuptake inhibitors 9.1.5.1 Ecacy

S65

Today, in many countries, SSRIs are the antidepressant substances prescribed most frequently as a rst-line treatment (Ostacher et al., 2005). Good ecacy has been described for each of the currently available substances, regardless of the etiology or severity of depression. Although several reports suggest that some drugs may be superior to SSRIs (venlafaxine (Cipriani et al., 2005b ; Cipriani et al., 2006 ; Smith et al., 2002 ; Thase et al., 2001), milnacipran (Puech et al., 1997), mirtazapine (Thase et al., 2006a)), it is dicult to interpret what these results mean clinically. For example, escitalopram has been shown to have comparable ecacy to venlafaxine (Kennedy et al., 2006). Escitalopram also demonstrates a statistically signicant, but clinically speaking minimal superiority over the other SSRI, citalopram (Bech et al., 2004 ; Lepola et al., 2004 ; Moore et al., 2005). Consequently, use of escitalopram has been recommended (Montgomery, 2006), especially in severe depression (Llorca et al., 2005). Another RCT reports the superiority of escitalopram over both citalopram and paroxetine (Boulenger et al., 2006). Prior metaanalyses showed neither signicant nor clinically relevant dierences in ecacy (Edwards and Anderson, 1999). But a recently published pooled analysis of all available study data to date found signicant advantages of escitalopram in comparison with several SSRIs, e.g. citalopram, uoxetine and sertraline, and in comparison with the SNRI venlafaxine (Kasper et al., 2006). Nevertheless, more RCTs are needed to evaluate the clinical relevance of these ndings, draw nal conclusions and make specic recommendations. Despite of the fact that SSRIs have shown no overall relevant inferiority compared with TCAs in a variety of randomized controlled trials (Moller et al., 1998) and meta-analyses (Geddes et al., 2000), there is some evidence of better ecacy and clinical eectiveness of TCAs in the subgroup of inpatients compared with outpatients (Anderson, 1998 ; Anderson, 2000a). This is especially true in comparing the TCA amitriptyline with SSRIs, taking into account that in most cases inpatients show a higher severity of the disease and a higher proportion of patients suer from melancholic features of depression. SSRIs and irreversible MAOIs also show an overall similar ecacy in the treatment of depression. Indeed, except among outpatients suering from depression with atypical features (chapter 5.2.1.3.3), MAOIs give better results (Thase et al., 1995). In

S66

CINP Antidepressant Task Force 2007

Table 18. Clinical highlights and dierences among SSRIs based predominantly on clinical experience and consensus (modied according to Stahl, 1997 ; Stahl, 2006) Generic name Citalopram (Bezchlibnyk-Butler et al., 2000) Specic clinical features of SSRIs One of the most selective SSRIs Possibly lower incidence of sexual dysfunction Possibly better tolerability in the elderly Low interaction potential One of the most selective and best-tolerated SSRIs Possibly rapid onset of action and high eect size during antidepressant treatment ; good eect in anxious depression and comorbid anxiety disorders Good eect in atypical depression Good eect in patients with fatigue and low energy Long half-life, weekly administration possible Good eect in anxious depression and comorbid anxiety disorders ; potential advantages in psychotic depression Possibly lower incidence of sexual dysfunction Discontinuation eects after rapid tapering Good eect in anxious depression and comorbid anxiety disorders Mild anticholinergic action Discontinuation eects more likely than for other SSRIs Good eect in atypical depression ; least selective over dopamine Low interaction potential More gastrointestinal side eects, but best documented cardiovascular safety

Escitalopram (Baldwin, 2002)

Fluoxetine (Calil, 2001)

Fluvoxamine (Ware, 1997)

Paroxetine (Green, 2003)

Sertraline (Khouzam et al., 2003)

addition, MAOIs show advantages during ultra-highdose treatment in patients suering from treatmentresistant depression, whereas increasing the SSRI doses has no substantial benecial eect (Adli et al., 2005). Despite their similarities, various SSRIs do have specic dierences (Table 18). 9.1.5.2 Safety and tolerability53 Dierent SSRIs show dierent safety proles. Nevertheless, the safety and tolerability prole of SSRIs as a pharmacological group of compounds compares very favorably with TCAs (Mace and Taylor, 2000). Specically, anticholinergic side eects especially are more common during TCA therapy. Therefore, lesser cardiovascular toxicity together with a lower risk for constipation and reduction of urinary ow can be expected. Also, anticholinergic side eects on the visual system, such as enhanced risk for worsening of angle-closure glaucoma and accommodation disturbances, are rare with SSRIs54. Only paroxetine shows greater anticholinergic side eects
All possible interactions of antidepressants with other pharmacotherapeutics are beyond of scope of this review ; the interactions described represent a selection and are not exhaustive.
53

and more adverse events, e.g. compared with the more selective escitalopram (Boulenger et al., 2006). The result is a lower discontinuation rate (Peretti et al., 2000) during SSRI treatment. In addition, SSRIs have proven safer than TCAs in cases of overdose (Barbey and Roose, 1998 ; Cheeta et al., 2004 ; Mason et al., 2000), which is benecial during antidepressant treatment, especially in suicidal patients. In addition, a simplied dose regimen compared with TCA therapy diminishes the danger of antidepressant therapies being below therapeutic dose ranges. These factors all contribute to an ecacious and cost` eective rst-line therapy in depression vis-a-vis TCAs despite higher prescription costs (Goldstein and Goodnick, 1998). Nevertheless, clinicians need to be aware of the particular side-eect prole of SSRIs (Ferguson, 2001 ; Lader, 1996). The most frequent side eects following short-term treatment are gastrointestinal disturbances such as nausea, diarrhea and emesis. Also common are restlessness and agitation, sleep disturbances, dizziness and headache. During long-term SSRI
54 In cases of acute angle-closure (closed-angle, narrow-angle) glaucoma, paroxetine is contraindicated due to greater anticholinergic side eects compared with other SSRIs (Bennett and Wyllie, 1999).

CINP Antidepressant Task Force 2007 treatment sexual dysfunction, including loss of libido, anorgasmia and disturbances of erectile or ejaculatory function in men, are signicant limitations of SSRI therapy. Some studies show these aspects to be less prominent with uvoxamine therapy than with other SSRIs (Waldinger et al., 1998). Delayed ejaculation appears to occur more with paroxetine (MontejoGonzalez et al., 1997). Disorientation, restlessness and myoclonus together with hyperreexia, tremor and pain syndromes together with unstable vital signs represent the potentially fatal serotonin syndrome (Boyer and Shannon, 2005). It may occur predominantly as an interaction of combining SSRIs with MAOIs or other serotonergic substances (e.g. S-TCAs or triptans used during acute therapy of migraine attacks), even during time intervals before and after treatment in dependency of the half-life of the substances, but also during SSRI monotherapy. In most cases, therefore, a washout period of 2 weeks (uoxetine ; 6 weeks before MAOI therapy) is recommended, and combining SSRIs and MAOIs is contraindicated. But there are published reports of good tolerability of combined therapy with SSRIs and triptans, possibly due to the fact that some triptans do not cross the blood-brain barrier after oral administration (Blier and Bergeron, 1995 ; Goldberg et al., 1999). Rare side eects are weight gain, anticholinergic eects and extrapyramidal motor side eects (EPMSs). Caution must be exercised in prescribing SSRIs for patients suering from Parkinsons disease (Lemke, 2002), but there is no good evidence that SSRIs are associated with a worsening of motor features in Parkinsons (Burn, 2002 ; Lemke et al., 2004). A very rare adverse event during SSRI therapy of younger patients, though not uncommon in the elderly, is inappropriate secretion of antidiuretic hormone (ADH) with possible electrolyte imbalance and hyponatremia leading to increased risk of seizures (Arinzon et al., 2002 ; Degner et al., 2004 ; Finfgeld, 2003). In addition, combined use of SSRIs and substances that increase the risk of bleeding events is discouraged owing to blockade of serotonin reuptake in platelets and subsequent platelet dysfunction (Serebruany, 2006). Risk of gastrointestinal hemorrhage in particular may be enhanced if nonsteroidal antiphlogistics or aspirin are combined with SSRIs (Weinrieb et al., 2005). Discontinuation symptoms can occur after SSRI treatment (Haddad, 2001) but seem to be rare events following treatment with uoxetine, due to its long half-life, and some other SSRIs, e.g. sertraline (Sir et al., 2005) and escitalopram (Baldwin et al., 2005) (see also chapter 9.1.1.3.2). 9.1.6 Selective serotonin and noradrenaline reuptake inhibitors 9.1.6.1 Ecacy

S67

SNRIs represent a group of newer antidepressants that act dually on serotonin and norepinephrine reuptake. Today, three substances of this group are available : venlafaxine, milnacipran and duloxetine. Compared with venlafaxine, duloxetine more potently blocks serotonin and noradrenaline transporters in vitro and in vivo (Bymaster et al., 2001). This is especially true for the noradrenaline reuptake-inhibiting eect after application of lower doses. Judging the comparative ecacy and clinical eectiveness is dicult because overall, newer antidepressants probably do not dier substantially with respect to these parameters for treatment of major depressive disorder (Hansen et al., 2005). Moreover, the available three SNRIs have been suggested to have similar ecacy (Stahl et al., 2005). Response rates during venlafaxine and duloxetine treatment were comparable, but patients treated with venlafaxine show a favorable trend in reaching remission (Vis et al., 2005). In comparison with the SSRIs sertraline (Sir et al., 2005) and escitalopram (Bielski et al., 2004 ; Montgomery et al., 2004b), venlafaxine demonstrated comparable ecacy eects in treatment of depressive disorders and quality of life. Venlafaxine has also proved to signicantly reduce depressive symptoms compared with uoxetine (Clerc et al., 1994). Several meta-analyses have also suggested superior ecacy of venlafaxine over SSRIs (Cipriani et al., 2005b ; Cipriani et al., 2006 ; Smith et al., 2002), but because most of the studies investigated the ecacy of uoxetine and paroxetine in comparison with SNRIs, the results must be evaluated carefully before conclusions about the ecacy of SSRIs as a pharmacological class can be drawn. The described superiority is reported to be enhanced when not only treatment response but also remission is used as an ecacy criterion (Stahl et al., 2005 ; Thase et al., 2001), but to date no sucient evidence for a faster response of SNRIs in comparison to SSRIs has been published. In addition, better ecacy and tolerability of escitalopram over venlafaxine have been reported in the context of remission rates (Montgomery and Andersen, 2006), whereas a meta-analysis found no signicant dierences (Kennedy et al., 2006) (for review see Friedli et al., 2000 ; Miller et al., 2003 ; Scott and Freeman, 1992 ; Thase, 2004). Meta-analyses have shown milnacipran to have an antidepressant ecacy similar to that of imipramine and signicantly superior to that of SSRIs (Puech et al., 1997). Direct comparisons between duloxetine and paroxetine in

S68

CINP Antidepressant Task Force 2007 Agency, 2006 ; National Institute for Health and Clinical Excellence, 2004). 9.1.7 Selective noradrenaline reuptake inhibitors

RCTs showed, controversially, both superiority of the SNRIs (Goldstein et al., 2004) and no signicant dierences (Detke et al., 2004). Studies show duloxetine to have eectiveness similar to escitalopram (Hirschfeld and Vornik, 2004). In contrast, direct comparisons between SNRIs (venlafaxine and milnacipran) and TCAs turned up no signicant or clinically relevant dierences in ecacy (Samuelian and Hackett, 1998 ; Van Ameringen55 et al., 2002). Direct comparison of venlafaxine and mirtazapine showed only trends in favor of mirtazapine but no signicant dierences (Guel et al., 2001). Besides its ecacy in treating depression, duloxetine has also been reported to signicantly reduce painful physical symptoms (Detke et al., 2002). 9.1.6.2 Safety and tolerability SNRI treatment has a favorable tolerability prole compared with TCAs ; most adverse events occur early in treatment and tend to decrease or disappear with continued treatment (Stahl et al., 2005). Venlafaxine is similar to sertraline in terms of treatment ecacy and quality of life, but sertraline showed a more favorable tolerability prole with respect to discontinuation symptoms and the risk of elevated blood pressure (Sir et al., 2005). This risk seems to be less prominent in newer SNRIs such as duloxetine and milnacipran (Stahl et al., 2005). Nevertheless, duloxetine tends to have more adverse events than paroxetine (Detke et al., 2004 ; Goldstein et al., 2004). An extended release (ER) formulation of venlafaxine has tolerability advantages over the immediate release (IR) formulation (Norman and Olver, 2004 ; Olver et al., 2004) (see chapter 9.1.1.2). Hypertension may occur more frequently with high doses of venlafaxine than with low doses (Thase et al., 2006b). Discontinuation of the SSRI escitalopram results in a lower rate of reported discontinuation symptoms (Baldwin et al., 2005). In most studies SNRIs proved more ecacious than SSRIs and had better tolerability than TCAs, which at least in the case of milnacipran probably has a positive impact on the cost-eectiveness of treatment (Dardennes et al., 1999) (for more details on the cost-eectiveness of SNRIs see chapter 14.4.2). The fatal toxicity index for venlafaxine in cases of overdose seems to be in between that of SSRIs and TCAs (Koski et al., 2005), leading to the recommendation that venlafaxine be reserved as a second-line treatment after SSRIs (Medicines and Healthcare products Regulatory

9.1.7.1 Ecacy Controlled data directly comparing the single available NARI reboxetine56 with other antidepressants are rare. One study looking at reboxetine and sertraline found no dierence in response after 5 weeks of treatment, whereas reboxetine was found to be advantageous for remission between weeks 2 and 4, and at week 5 (Eker et al., 2005). Reboxetine was found to be similar to uoxetine in ecacy for depressive disorders, and more eective in a subgroup of severely depressed patients (Massana et al., 1999). Among patients suering from post-stroke depression, reboxetine was less ecacious in anxious depressed patients than citalopram, but more ecacious in retarded depressed patients (Rampello et al., 2004). In addition, reboxetine is reported to be at least as eective as other classes of antidepressants, including TCAs, and again in a subgroup of patients, in depressed patients with melancholic features, TCA was found to have advantages over reboxetine (Montgomery, 1998). 9.1.7.2 Safety and tolerability In all published studies, reboxetine showed a good safety and tolerability prole (Burrows et al., 1998). Reboxetine is safer and more tolerable than TCAs. NARI use was not associated with an increased risk of seizures, orthostatic hypotension or cardiovascular side eects. In addition, sexual dysfunction appears to be less common with reboxetine than with the SSRI uoxetine (Clayton et al., 2003). Reboxetine has a different side eect prole than SSRIs, with advantages in terms of agitation, nervousness, anxiety and gastrointestinal events (Montgomery, 1998). Patients treated with reboxetine sometimes experience agitation and sleep disturbances ; they may also be troubled by hyperhidrosis. Despite the low anticholinergic activity of reboxetine, its a-receptor agonistic eects may aect micturation. In that event concomitant treatment with tamsulosin, an a1A-adrenoceptor antagonist, may prevent such patients from discontinuing reboxetine. Increased heart rate and blood pressure have also been reported. Weight loss occurs only rarely.

55

The Medline database contains the wrong spelling Van Amerongen .

56 Reboxetine is available in Europe and Australia, but as mentioned above, to date it has not been marketed in the US.

CINP Antidepressant Task Force 2007 9.1.8 a-Receptor-blocking tetracyclic antidepressants 9.1.8.1 Ecacy To date the structurally similar tetracyclic antidepressants mianserin and mirtazapine represent the group of a2-receptor-blocking antidepressants. Mianserin was developed before mirtazapine and shows a higher anity for the a1-adrenoceptor and more inuence on noradrenaline (NA) reuptake (Kelder et al., 1997). Mianserin exerts only weak NA reuptake-inhibiting eects. Mirtazapine is characterized as its own class of antidepressant with noradrenergic and specic serotonergic properties (NaSSA). The a2-antagonistic eect of mirtazapine results in serotonergic activation, whereas the a1-antagonistic eect of mianserin counteracts the a2-antagonistic eect. Both mianserin (Moller et al., 1995) and mirtazapine (Benkert et al., 2002) are described as being at least as eective as TCAs and have some advantages over other newer antidepressants (Szegedi and Schwertfeger, 2005). In addition to its antidepressant eects, mirtazapine signicantly improves sleep parameters associated with insomnia (Thase, 1999a). Mirtazapine also shows much more rapid onset of action than SSRIs (Benkert et al., 2000 ; Benkert et al., 2002 ; Blier, 2001 ; Blier, 2003 ; Quitkin et al., 2001 ; Tran et al., 2003). But owing to the retrospective character of some of these studies, further clarication is required of the hypothesis that these eects are caused not only by the sedating properties of mirtazapine but also its specic eects on other symptoms of depression. An RCT in elderly patients showed mirtazapine to have an earlier onset of action compared with the SSRI paroxetine (Schatzberg et al., 2002). It is better at reducing depressive symptoms than uoxetine (Wheatley et al., 1998). Compared with other recently developed antidepressants, such as dual-action SNRIs and selective NARIs, mirtazapine shows no convincing dierences in terms of overall ecacy or speed of onset (Moller, 2000 ; Olver et al., 2001). Nevertheless, from a clinical point of view, a signicant advantage (and simultaneously a disadvantage, as described in chapter 9.1.8.2) of NaSSAs is their pharmacodynamic prole, including antihistaminergic properties, which are useful in treating depression-related sleep disturbances without the use of additional hypnotic substances. Mirtazapine is also available in the galenic form of fast dissolving tablets (see chapter 9.1.1.2). 9.1.8.2 Safety and tolerability NaSSAs have a substantially better side-eect prole than a variety of TCAs (Blier, 2003 ; Montgomery,

S69

1995 ; Tran et al., 2003). The safety of NaSSAs is similar to that of SSRIs (Olver et al., 2001), but typical serotonergic side eects such as sexual dysfunction and gastrointestinal complaints are less frequently present in mirtazapine-treated patients (Montgomery, 1995). The most frequently reported adverse events during mirtazapine therapy are antihistaminergic eects, such as initial somnolence and dizziness, together with increased appetite and cumulative weight gain over the long term (Tran et al., 2003). The weight gain often reduces patients compliance and may sometimes even facilitate development of a metabolic syndrome. Serious and potentially fatal side eects are rare, but clinicians need to be aware of the potential of both antidepressants to cause or enhance severe neutropenia (Ozcanli et al., 2005). In addition, mianserin is reported to carry a risk for agranulocytosis (Farmer, 1990 ; Girard, 1990 ; Launay et al., 2000). This is especially true in patients with an enhanced susceptibility for these side eects (see chapter 9.1.1.3.4) and in combination therapies (Imbarlina et al., 2004). 9.1.9 Serotonin modulating antidepressants 9.1.9.1 Ecacy Nefazodone and its structural analog trazodone block 5-HT2 receptors, but only weakly inhibit the reuptake of serotonin and noradrenaline (Blier et al., 2006). One of the active metabolites of serotonin modulating antidepressants (SMAs) has 5-HT1 agonistic properties. The drugs are reported to work as well as the TCA imipramine and other older antidepressants (Cyr and Brown, 1996 ; Ellingrod and Perry, 1995). Nefazodone and trazodone are also as eective as the SSRIs uoxetine, sertraline and paroxetine (Avila et al., 2003 ; Sussman et al., 2001). Trazodone is reported to be as eective as the SNRI venlafaxine in ameliorating depressive symptoms, and better at relieving sleep disturbances. It is less good, however, at improving cognitive disturbances and retardation (Cunningham et al., 1994). The NaSSA mirtazapine shows signicant clinical advantages compared with trazodone in terms of overall ecacy (van Moaert et al., 1995). The sedating properties of nefazodone and trazodone make them particularly suitable for agitated patients and patients suering from insomnia (Boerner and Moller, 1999 ; Thase, 1999a). 9.1.9.2 Safety and tolerability SMAs have a safety margin similar to TCAs, but a more favorable tolerability prole (Lader, 1996), with lower anticholinergic and antihistaminic activity (Taylor et al., 1995). The specicity of action of SMAs

S70

CINP Antidepressant Task Force 2007 (Workman and Short, 1993). Despite a few contradictory results, its good ecacy combined with a lower switch risk than SNRIs argues for recommending bupropion especially in the treatment of bipolar depression (Post et al., 2006 ; Thase, 2005). 9.1.10.2 Safety and tolerability Compared with patients treated with the SSRI sertraline, patients treated with bupropion show a lower rate of serotonergic side eects, such as sexual dysfunction, gastrointestinal complaints, insomnia and agitation (Coleman et al., 1999 ; Croft et al., 1999 ; Kavoussi et al., 1997). Particularly in male patients, sexual dysfunction may be prominent and can be reduced by using an ER formulation of bupropion. In addition, side eects are reportedly fewer with bupropion than with uoxetine (Coleman et al., 2001). Patients given doxepin had predominantly more anticholinergic and antihistaminergic side eects than those given TCAs (Feighner et al., 1986). Bupropion has also been classied as a B-group antidepressant for use during pregnancy. Although the risk for generalized seizures is considered to be a rare consequence of bupropion treatment (Montgomery, 2005), it must be taken into account in treatment plans using bupropion (Ross and Williams, 2005). This risk may be further enhanced under conditions that increase the chance of seizures, such as alcohol withdrawal, anorexia and bulimia (Horne et al., 1988). Indeed, in cases of accidental or intentional overdose, generalized seizures seem to be a relatively frequent complication (Pesola and Avasarala, 2002 ; Shepherd et al., 2004). 9.1.11 Herbal preparations used in the treatment of depression Although herbal treatments make up a reasonable share of antidepressant prescriptions in some countries, e.g. Germany, whether they should be classied as antidepressants is a matter of ongoing controversy (Bauer et al., 2002c). The main reason is that RCTs have not shown these medications to be useful in cases of severe depression. An additional reason is the uncertainty regarding their precise pharmacological mechanism of action. Nevertheless, a variety of herbal substances with possible antidepressant eects have been investigated in less-sophisticated studies and less severely depressed patients. For most of these substances, e.g. Kava-Kava extract, no antidepressant eects could be demonstrated. For others, RCTs have shown antidepressant eects (Akhondzadeh et al., 2005), but to date, no placebo-controlled replication studies have been published.

on neurotransmitter systems is believed to be the reason for the enhanced safety and tolerability of the drugs (Nemero, 1994). The side-eect prole of SMAs is also dierent from that of SSRIs ; the most commonly reported side eects are sedation, dry mouth, nausea, somnolence and dizziness (Cunningham et al., 1994 ; Cyr and Brown, 1996). Trazodone may enhance the risk of priapism. Patients taking SMAs report fewer complaints of nervousness, insomnia and sexual dysfunction compared with SSRIs (Preskorn, 1995). Nevertheless, several case reports show that the potential of nefazodone to cause severe hepatotoxicity and even fulminant hepatic failure (Conway et al., 2004 ; Schirren and Baretton, 2000 ; Tzimas et al., 2003) makes reliable clinical monitoring crucial (Lucena et al., 2003). The original producer has withdrawn nefazodone from the market, but in some countries, including the US, generic versions of the drug are available. Trazodone is still available in eastern countries, such as China and Hong Kong, Indonesia, Japan, Korea and Thailand. 9.1.10 Dopamine and noradrenaline reuptake inhibitors57

9.1.10.1 Ecacy The mechanism of action of DNRIs is still not completely clear or understood. The FDA classies DNRIs as B-category antidepressants. In a variety of countries bupropion is approved only for smoking cessation, but not as an antidepressant. Nevertheless, it is used o-label for combination therapies, especially in the case of treatment-resistant depression. Bupropion shows signicant antidepressant ecacy at least equal to the SSRIs sertraline (Coleman et al., 1999 ; Croft et al., 1999 ; Kavoussi et al., 1997), uoxetine (Coleman et al., 2001 ; Feighner et al., 1991 ; Workman and Short, 1993) and paroxetine (Weihs et al., 2000). The same is true of comparison with the TCA doxepin (Feighner et al., 1986), but the improvement in sleep parameters was more pronounced in the doxepin group. Likewise, no dierence in ecacy is evident between bupropion and the TCAs amitriptyline (Remick et al., 1982) and imipramine (Workman and Short, 1993). The same comparative study revealed no dierences in ecacy between bupropion and the SNRI venlafaxine and the SMA trazodone
57

The mechanism of action of bupropion is still unclear. It may be related to inhibition of presynaptic dopamine and noradrenaline (norepinephrine) reuptake transporters (Foley et al., 2006), but positron emission tomography (PET) studies in humans show no eects on dopamine or noradrenaline transporters at therapeutic doses (Kugaya et al., 2003 ; Learned-Coughlin et al., 2003 ; Meyer et al., 2002).

CINP Antidepressant Task Force 2007 9.1.11.1 St. Johns wort 9.1.11.1.1 Ecacy

S71

The most studied of the herbal substances is St. Johns wort (Hypericum perforatum). It is worth noting that many dierent preparations of St. Johns wort are available over-the-counter, and these dier in the number, concentration and balance of active and inactive, helpful and potentially harmful constituents. Both serotonergic mechanisms and MAO inhibition have been proposed as antidepressant modes of action (Deltito and Beyer, 1998). In addition, mechanisms similar to those of SSRIs, but to a lesser extent, have been reported (Kasper and Schulz, 1999). Despite some controversy in ndings (Shelton et al., 2001a), studies conclude that Hypericum is suitable for treatment of mild to moderate depressive syndromes (Kalb et al., 2001 ; Kasper, 2001 ; Lecrubier et al., 2002 ; Uebelhack et al., 2004 ; Wong et al., 1998) if preparations provide sucient concentrations of hypericin. In some countries, it has already been approved for that indication. In randomized controlled studies, Hypericum was therapeutically equivalent to the SSRIs uoxetine (Behnke et al., 2002 ; Schrader, 2000), paroxetine (Szegedi et al., 2005) and sertraline (Brenner et al., 2000 ; Gastpar et al., 2005). Indirect comparisons with uoxetine show no relevant dierences in ecacy (Volz and Laux, 2000). Even advantages of Hypericum over uoxetine have been demonstrated (Fava et al., 2005a), but neither active compound exhibited statistically signicant superiority over placebo. Nevertheless, remission rates were higher in SSRItreated patients (Bjerkenstedt et al., 2005). Therapeutic equivalence to imipramine and superiority over placebo have been shown in the treatment of mild to moderate depression (Philipp et al., 1999 ; Woelk, 2000). Recent meta-analyses show inconsistent results (Linde et al., 2005). Hypericum reportedly shows eectiveness similar to low-dose TCA (Kim et al., 1999) or SSRI therapy (Kasper and Dienel, 2002), but problems of design in some studies prohibit denite conclusions. 9.1.11.1.2 Safety and tolerability

of include photosensitization (Kasper, 2001 ; Kasper and Schulz, 1999). Because Hypericum involves serotonergic mechanisms and monoamine oxidase inhibition, concurrent use of SSRIs and MAOIs should be avoided (Deltito and Beyer, 1998). Treatment with Hypericum, which induces both CYP3A4 and the drug transporter protein P-glycoprotein, can result in pharmacokinetic interactions with serious clinical consequences, such as loss of activity of comedication (Henderson et al., 2002 ; Hennessy et al., 2002 ; Izzo and Ernst, 2001). This outcome has been demonstrated for digoxin (Johne et al., 1999) and cyclosporine (Ruschitzka et al., 2000) owing to induction of hepatic metabolizing enzymes, and for contraceptives, especially in case of low-dose oral contraception (Murphy et al., 2005). To date no results have been published concerning discontinuation symptoms following tapering of Hypericum. 9.1.11.2 Kampo Kampo (a traditional Japanese herbal medicine) formulas are widely used along with modern medicines as adjunctive strategies in Japan (Kanba et al., 1998 ; Kanba et al., 1999). A kampo formula is made from two or more herbs that have various pharmacological activities. Kampo prescriptions should not only be selected according to traditional theory but also be prescribed based on symptoms. The Japanese Ministry of Health, Labor and Welfare has approved more than 100 kampo prescriptions for use in clinical practice. Some open studies have shown the ecacy of kampo formulas for patients with neurosis and mild major depression. Also, Yamada and Kanba have reported six outpatients with premenstrual dysphoric disorder (PMDD) who were treated successfully with Kamishoyosan (Yamada and Kanba, 2002). For major depression, schizophrenia and other mental disorders, kampo formulas are used with psychotropics, such as antidepressants and antipsychotics. For example, partial remitted major depressive disorder was treated successfully with Rokumigan or Hachimijiogan (Yamada et al., 2005). These substances are also used for the treatment of adverse events induced by psychotropics. Twenty outpatients with SSRI-induced nausea and dyspepsia were successfully treated with Goreisan (Yamada et al., 2003b). 9.1.11.3 Morinda ocinalis, Jieyu and Banxia Houpu decoction (Chinese traditional herbal medicine) Morinda ocinalis (Cui et al., 1995) and a decoction/ brew of Banxia Houpu (Luo et al., 2000) are herbal medicines that have been used since ancient times

Comparative studies show signicantly better tolerability of Hypericum compared with SSRIs and TCAs (Bjerkenstedt et al., 2005 ; Szegedi et al., 2005 ; Woelk, 2000). In particular, Hypericum was devoid of anticholinergic side eects, sedation, gastrointestinal disturbances and sexual dysfunction (TrautmannSponsel and Dienel, 2004). The substance is considered to be safer than TCAs with regard to cardiac function (Czekalla et al., 1997). Nevertheless, risks to be aware

S72

CINP Antidepressant Task Force 2007 MAOI tranylcypromine to be eective for refractory depression. Data concerning other selective compounds are insucient to allow any denitive conclusion on the benet of high-dose treatment. Recently published reviews summarize the actual knowledge about switching strategies (Ruhe et al., 2006b) and dose escalating strategies (Ruhe et al., 2006a) which are especially recommended in case of partial response. Factors in addition to pharmacological treatment resistance that may lead to less favorable outcomes include psychiatric comorbidity, e.g. alcohol and substance abuse, personality disorders and anxiety and panic disorder (Adli et al., 2005). Sharan and Saxena (Sharan and Saxena, 1998) have identied several other factors predictive for poor response, including a family history of aective disorders, severity of depression, suicide attempts, number of previous episodes, long duration of depression prior to treatment, negative life events and poor social support. Awareness of these factors and adequate action, e.g. addition of psychotherapy with negative life events, are an a priori requisite for making pharmacological changes. In addition it is essential to be aware of all factors inuencing the patients compliance (Demyttenaere et al., 2001a ; Demyttenaere et al., 2001b). Treatmentresistant depression may also inuence vulnerability to other mental disorders. For example, the incidence of dementia is signicantly increased in older patients with insuciently treated depression (Shim and Yang, 2006). In support of these results, magnetic resonance imaging (MRI) ndings showing decreased hippocampal volumes in treatment-refractory depressed patients, and enhanced neuronal plasticity and cellular resilience may indicate a new direction for developing novel, improved therapeutics for dicultto-treat depression (Manji et al., 2003). Figure 3 summarizes a stepwise approach for managing non-response to an initital antidepressant. 9.1.12.2 General introduction to combination and augmentation When a previous monotherapy has not been ecacious at all, even after a trial with maximum dosage, switching medication is usually recommended (Kennedy et al., 2001). A recently published analysis of the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial pointed out that approximately 25 % of patients non-responsive to citalopram benet from switching either to sertraline, bupropion or venlafaxine (Rush et al., 2006c).

in traditional Chinese medicine to treat depressionassociated symptoms. Jieyu pill and decoction have been investigated in patients suering from depressive symptoms and showed antidepressant properties in randomized, but not placebo-controlled studies (Feng et al., 2004 ; Shen et al., 2004). To date, putative antidepressant eects and possible mechanisms of action of Morinda ocinalis and Banxia Houpu have been investigated in animal models of depression (Li et al., 2001 ; Zhang et al., 2002). In addition, phase III clinical trials are ongoing. It is thus premature draw nal conclusions about the possible antidepressant ecacy and eectiveness of these compounds. 9.1.12 Strategies in the event of non-response to antidepressant treatments : combination and augmentation 9.1.12.1 The concept of non-response to antidepressant treatment Patients who do not respond to at least two antidepressant monotherapies (in some wider denitions even one) are usually referred to as treatment resistant. However, reasons for this treatment resistance or non-response to antidepressant treatment (see also Box 7, denition of pharmacotherapy-resistant depression) may vary and often do not reect true resistance to treatment. The denition by Ananth (Ananth, 1998) as a failure to respond adequately to two successive courses of monotherapy with pharmacologically dierent antidepressants given in adequate dose for sucient length of time includes a number of prerequisites : correct diagnosis, adequate treatment in terms of dosage, duration and compliance, and unsuccessful previous therapy. Before switching antidepressants, sucient length of treatment (see chapter 9.1) and the adequacy of dosage should be considered. If in doubt, TDM (see chapter 9.1.1.1.3) may be helpful to ensure adequate blood levels of medication (Corruble and Guel, 2000). Switching strategies after unsuccessful antidepressant trials often results in low remission rates (Fava et al., 2006). Adli et al. (Adli et al., 2005) conducted a systematic review of whether dose escalation leads to additional benet following failure of a medium dose. They concluded that available data suggest dierential ecacy of various pharmacological classes at more than medium dosage. Direct evidence shows no increase of ecacy with high-dose selective serotonin reuptake inhibitor (SSRI) treatment ; however, indirect evidence suggests enhanced therapeutic ecacy with high-dose tricyclic antidepressants. Few clinical data show ultra-high-dose treatment with the irreversible

CINP Antidepressant Task Force 2007

Inadequate response to first antidepressant

S73

9.1.12.2.1

Combination treatment

9.1.12.2.1.1 Combination of dierent antidepressants 9.1.12.2.1.1.1 Ecacy Although we lack scientic evidence to dene specic and eective next-step treatment options for treatment-resistant depressive disorders (Rush et al., 2004), combination of antidepressants is a very common strategy in such cases (de la Gandara et al., 2005a ; Schatzberg, 2004). Generally, antidepressants with dierent pharmacological proles are combined. In a recent literature search, Dodd et al. (Dodd et al., 2005) identied only 8 randomized trials between 1978 and 2004 that studied combinations of antidepressants, 5 of them including uoxetine. In addition, 16 open-label trials were identied, most of them using again at least one SSRI. Combining antidepressants with predominant serotonergic and noradrenergic properties, e.g. prescribing SSRIs and SNRIs, is also one of the most frequent clinical therapeutic options (de la Gandara et al., 2005a). SSRIs and NaSSAs are also frequently used in combination. A combination of the SSRI uoxetine and the tetracyclic a2-blocker mianserin showed superior ecacy over placebo in several studies (Dam et al., 1998 ; Ferreri et al., 2001). Especially in the case of prior treatment resistance, combining two dual-action substances, such as mirtazapine and venlafaxine, can be of clinical use, but more controlled studies conrming the superior eectiveness of these combinations are required (de la Gandara et al., 2005b ; Rojo et al., 2005). Further reasons for combining dierent antidepressants are specic side-eect proles, e.g. using antihistaminergic properties of one antidepressant for early amelioration of sleep disturbances or improvement of appetite, especially in geriatric depression. 9.1.12.2.1.1.2 Safety and tolerability Combining two or even more antidepressants can enhance tolerability (King et al., 1994), owing to clinical eectiveness of lower doses : sexual dysfunction due to SSRI treatment may be reduced using lower dosages within combination strategies. For example, bupropion showed a reduced rate of sexual dysfunction compared with some SSRIs (Coleman et al., 1999 ; Coleman et al., 2001 ; Croft et al., 1999). At the same time, a variety of possible pharmacokinetic interactions (Baumann, 1996) enhances risk for severe adverse events, e.g. increased TCA toxicity due to cytochrome P-450 inhibition by uoxetine or uvoxamine (for more details see chapter 9.1.1.1). The fact that TDM of these compounds is not widely practiced

Reevaluate diagnosis Exclude comorbid medical or psychiatric disorder Review dose

Disease apparently resistant to optimal/sufficient dose*

Increase dose of first antidepressant

nonresponse

Continue increased dose for 4 weeks Partial response Reevaluate dose and continue optimized regimen for further 2 weeks Still partial response Combine with antidepressant from a different pharmacological class or augment with a nonantidepressant (e.g. lithium)

Switch to an antidepressant from a different pharmacologic class or dual action agent

No further improvement

Figure 3. A stepwise approach to managing patients with inadequate response to antidepressant therapy (adopted from Hirschfeld et al., 2002). * TDM should be implemented in routine care (Mann et al., 2006b). It is especially recommended in case of treatment failures.

However, when response is partial, it may be unwise to discontinue premedication and risk worsening of symptoms. Thus, combination with another antidepressant or augmentation should be considered. Sucient evidence now exists that combining antidepressants or augmentation strategies could be more eective than monotherapy in some patients (Kennedy et al., 2001). Combination treatment is dened as addition of another medication without expecting potentiation of ecacy of the previous drug (see Box 10). Benets as well as side eects are additive. Usually, a medication with an alternative and dierent pharmacology or a drug with a dual mechanism of action is chosen for combination treatment (see also chapter 9.1.12.2.1). In contrast, augmentation means adding another agent that by itself may be not specically helpful as a primary treatment of depression but that may enhance responsiveness to a given antidepressant (see Box). Examples for these strategies, ordinarily used in antidepressant non- or only partially responsive patients, include lithium, thyroid hormones, pindolol and buspirone, and more recently, also some atypical antipsychotics. Table 19 summarizes common augmentation strategies.

S74

CINP Antidepressant Task Force 2007

Box 10. Denition of combination and augmentation treatment

$ $

Combination treatment : combination of two or more treatments, each of which represents an antidepressant alone. Augmentation treatment : eciency amplication of an antidepressant treatment with a substance that alone does not exert sucient antidepressant activity to be used as a monotherapy.

makes this risk more likely. Further increased risk is associated with additional somatic diseases that require additional pharmacologic treatment. 9.1.12.2.1.2 Combination of ECT and antidepressants 9.1.12.2.1.2.1 Ecacy A further option in enhancing the eectiveness of antidepressant treatments may be concomitant use of ECT in combination with antidepressants. Such a step may be necessary due to possible non-responsiveness to ECT in 1525 % of depressed patients (Husain et al., 2004). However, study results regarding a putative benet of combining ECT with TCAs (Lauritzen et al., 1996 ; Nelson and Benjamin, 1989) and the lack of benet of other concomitant medication, like SSRIs, are still controversial (Lauritzen et al., 1996). In particular, investigations of the ecacy of modern antidepressants in combination with ECT, e.g. the dual-action substances mirtazapine and venlafaxine, are rare (Baghai et al., 2006b ; Farah, 1997). Owing to the severity of depressive syndromes in patients following medication treatment failure, the clinical recommendation is to combine ECT with antidepressants at moderate doses over the entire course of treatment. When that is not possible, antidepressants should be used at least during the last 2 weeks of ECT treatment to prevent exacerbation of depression following ECT during the usual latency until antidepressant response is achieved following initiating pharmacotherapy or to use continuation ECT (see chapter 12.2.3). 9.1.12.2.1.2.2 Safety and tolerability Combining ECT with TCAs and SSRIs has been described as a safe procedure (Lauritzen et al., 1996 ; Nelson and Benjamin, 1989). Moreover, safety data on such combinations are available : in a recent study venlafaxine at dosages lower than 300 mg/day was shown to be safe in combination with ECT. In highdose treatments above 300 mg/day, side eects of a cardiovascular nature, such as transient asystolia and bradycardia, were more frequent when ECT was combined with propofol anesthesia (Gonzalez-Pinto et al., 2002). Combination of ECT and MAOIs should be treated with particular caution. In fact, it should

be avoided, if possible, owing to enhanced risk for sometimes lethal complications, especially shortly after starting pharmacological treatment (Naguib and Koorn, 2002). At the very least a 2-week washout period should be observed. The combination of ECT with lithium increases the risks associated with anesthesia (Hill et al., 1976 ; Hill et al., 1977 ; Reimherr et al., 1977), the risk of prolonged seizures (Sartorius et al., 2005) and the risk of cognitive disturbances. But it represents only a relative contraindication due to reports of safe use of this combination and the specic risk of discontinuing lithium treatment. 9.1.12.2.2 Augmentation treatment

Augmentation strategies have some advantages over switching antidepressants. They eliminate the period of transmission from one antidepressant to another and build on the partial response. Consequently, if they work, they can be rapidly eective ; they may, however, also raise tolerability and safety issues. As combination treatment has been dealt with extensively in the previous chapter (see chapter 9.1.12.2.1), we will now concentrate only on the dierent augmentation strategies tested in unipolar depression. 9.1.12.2.3 Lithium

Of all the strategies listed in Table 19, lithium augmentation is the best described (Bauer et al., 2003 ; Bschor and Bauer, 2006 ; Zullino and Baumann, 2001). A multitude of open and 12 randomized placebocontrolled trials, including a meta-analysis (Bauer et al., 2003), support the ecacy of lithium augmentation in the acute treatment of treatment-resistant unipolar depression. Lithium has been found to augment the therapeutic eects of a broad spectrum of antidepressants, including TCAs (Bauer et al., 2003 ; Bauer and Dopfmer, 1999) and SSRIs (Joe et al., 1993 ; Katona et al., 1995). The meta-analysis by Bauer and Dopfmer (Bauer and Dopfmer, 1999) also demon strated that lithium augmentation is superior to placebo augmentation, with a response rate of about 4050 % at week 3 or 4 across studies, but only 20 % of patients respond as early as week 1. To allow full assessment of patient response, lithium augmentation should be administered for at least 4 weeks, ensuring

CINP Antidepressant Task Force 2007

Table 19. Biological treatment strategies for partial and non-responding patients with major depressive disorders. Modied from WFSBP Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1 (Bauer et al., 2002c) Treatment strategy Pharmacological augmentation Lithium Lamotrigine, valproate, carbamazepine Amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone Pindolol Buspirone Stimulants Pergolide Bromocriptine Pramipexole Reserpine Hormone augmentation Triiodothyronine (T3) L-Thyroxine (T4) Estrogen (only women) Dehydroepiandrosterone (DHEA) Miscellaneous Ketokonazole, metyrapone L-Tryptophan, 5-hydroxytryptophan V-3 fatty acids Folic acid (only women) Non-pharmacological Electroconvulsive therapy [Repetitive transcranial magnetic stimulation] [Vagus nerve stimulation] Phototherapy (bright light therapy) Wakefulness therapy (sleep deprivation) Physical exercise Mechanisms/drug classication

S75

Mood stabilizer Anticonvulsants/mood stabilizer Antipsychotic agents, 5-HT2 antagonism 5-HT1A autoreceptor antagonist, b-receptor blocker 5-HT1A and D2-receptor agonist Dopamine and noradrenaline release and reuptake inhibition Dopamine (D1/D2) agonist Dopamine (D2) agonist Dopamine (D2/D3) agonist Reuptake inhibition of biogenic amines Thyroid hormone Thyroid hormone Ovarian steroid hormone Adrenal androgen hormone Peripheral cortisol suppression Essential amino acid, 5-HI precursor Food supplement Vitamin Electric stimulation to elicit an epileptiform seizure in brain Non-invasive stimulation of the cerebral cortex Autonomic signals to limbic and cortical function Chronotherapeutics Chronotherapeutics Supportive procedure

serum levels of 0.60.8 mmol/l (Bauer et al., 2002c). Once stabilized on the combination, it is unwise to withdraw lithium for at least a year (Bauer et al., 2000). However, the utility of lithium augmentation may be limited by side eects, e.g. polyuria, muscular weakness and tremor. Especially in older patients lithium toxicity may occur even within therapeutic plasma levels and might present itself with a clinical picture that is not always easy to dierentiate from an increase in severity of depression. Electroencephalogram (EEG) may be a helpful monitoring tool for dierential diagnosis in this clinical situation (Gallinat et al., 2000). Whether the potential neurotoxicity of lithium plays a major role in clinical practice or even has a distinct neuroprotective eect cannot yet be concluded. Patients on lithium therapy should be closely monitored and regularly assessed for the presence of side eects from the central nervous system (CNS) even

when their serum lithium levels are within therapeutic levels. Research may be needed to develop better ways to monitor lithium, possibly by substituting plasma levels with other, more reliable indices. A candidate index could be red blood cell lithium levels. This issue has been discussed in an extensive review recently (Fountoulakis et al., 2006). It is also unclear whether lithium augmentation has the same ecacy across age groups. Some publications point to a low response rate and a high rate of severe side eects in the elderly. 9.1.12.2.4 Thyroid hormones

At least 13 prospective trials (9 open and 4 controlled double-blind studies) support the usefulness of triiodothyronine (T3), with most studies employing 2535.5 mg/day (Bauer et al., 2002c). Women especially seem to respond favorably to thyroid hormone

S76

CINP Antidepressant Task Force 2007 studies (Barbee and Jamhour, 2002), as well as in one small double-blind study (Barbosa et al., 2003). Most of these studies (Barbosa et al., 2003 ; Blier and Ward, 2003), however, were conducted in mixed samples of unipolar and bipolar II patients. Absent a separate analysis, it is impossible to draw any clear conclusions as far as unipolar treatment-resistant depression is concerned. In summary, the evidence for the usefulness of augmentation with anticonvulsants remains weak. 9.1.12.2.6 Pindolol

augmentation (Altshuler et al., 2001). A three-arm, double-blind controlled study showed equal ecacy of augmentation with T3 and lithium, and superiority to placebo (Joe et al., 1993). A recently published STAR*D report conrmed the similar ecacy of T3 and lithium with lower rates of adverse events and slightly (but nonsignicant) higher remission rates in the T3 group (Nierenberg et al., 2006a). However, as not all controlled double-blind studies showed signicant results in favor of T3, a subsequent meta-analysis found inconsistent results favoring T3 augmentation (Aronson et al., 1996). Recently, augmentation with L-thyroxine (T4) has been postulated as an alternative to T3, and open studies and functional neuroimaging support the ecacy of this approach (Bauer et al., 2002a ; Bauer et al., 2005). Double-blind controlled studies are still missing, however. When adding T4, evidence so far suggests that supraphysiological dosages should be used ; comparison of only 150mg/day of T4 with 37.5 mg/day of T3 showed signicantly lower response rates for T4 (24 vs. 53 %) (Joe and Singer, 1990). In some studies, dosage up to 500 mg/ day of T4 have been used with good ecacy and satisfactory tolerability (Bauer et al., 1998). However, the use of T4 in treatment-resistant unipolar depression is still experimental, and for now evidence is on the side of T3. 9.1.12.2.5 Anticonvulsants

Surprisingly little has been published regarding a potential augmentative eect of anticonvulsants in unipolar depression. Open studies of valproate (Davis et al., 1996 ; Svestka et al., 1990) and carbamazepine (Post et al., 1986) suggest antidepressant properties (Normann et al., 2002 ; Post et al., 1986). However, verication by double-blind studies is still missing, and in addition, studies of augmentation with carbamazepine show that it induces metabolism of venlafaxine and citalopram, and that it may be necessary to increase the dose of the antidepressant (Ciusani et al., 2004 ; Steinacher et al., 2002). In a double-blind add-on study to paroxetine in non-treatment-resistant patients, lamotrigine showed a faster onset of response but no signicant dierence in the outcome after 10 weeks (Normann et al., 2002). As far as treatment-resistant depression is concerned, however, there is some evidence from open studies for the augmentative ecacy of carbamazepine (Cullen et al., 1991 ; Rybakowski et al., 1999 ; Varney et al., 1993). The augmentative ecacy of lamotrigine has been reported both in open and retrospective

A potential role of 5-HT1A agonists in treating depression and anxiety has been a major focus of research in the past decade (Blier and Ward, 2003). Pindolol is a b-adrenoreceptor antagonist. It also blocks 5-HT1A and 5-HT1B/1D receptors, and therefore should prevent the negative feedback eect of increased somatodendritic serotonin (Dawson and Nguyen, 2000). As a consequence, this action may accelerate the onset of antidepressant action (Artigas et al., 2001 ; Artigas et al., 2006). A meta-analysis by Ballesteros and Callado (Ballesteros and Callado, 2004) of nine randomized controlled studies on the augmentative eects of pindolol for SSRIs showed increased response with pindolol after 2 weeks. After 6 weeks no dierence in outcome was observed. Despite positive open studies, three out of four controlled trials have failed to show advantage over placebo in treatment-refractory patients (Moreno et al., 1997 ; Perez et al., 1999 ; Segrave and Nathan, 2005). Only one small study applying once-daily high-dose pindolol (7.5 mg) demonstrated a signicant advantage (Sokolski et al., 2004). In their review on pindolol augmentation, Segrave and Nathan (Segrave and Nathan, 2005) speculate that the 2.5-mg twice daily (t.i.d.) dose of pindolol that has been used in all but one of these investigations may be suboptimal for achieving reliable and signicant occupancy of 5-HT1A autoreceptors, as shown by positron emission tomography (PET) data (Rabiner et al., 2001) and may explain the contradictory nature of the results of investigations of pindolol augmentation. 9.1.12.2.7 Buspirone

Buspirone is a partial 5-HT1A agonist that is believed to activate postsynaptic 5-HT1A receptors and thus may enhance the action of SSRIs. In addition, it has been reported that it exerts anity to D4 and to a lesser extent to D1 and D2 receptors with a1- and a2antagonistic activity (Millan et al., 2000). A major metabolite of buspirone enhances norepinephrine

CINP Antidepressant Task Force 2007 release. Therefore, buspirone may also exert a dual mechanism of action. However, in two double-blind placebo-controlled studies, buspirone augmentation both to uoxetine and citalopram failed to demonstrate signicant benet over placebo (Appelberg et al., 2001 ; Landen et al., 1998) The study by Appelberg, however, suggests at least a potential benet in more severe depression in a post hoc subanalysis (Appelberg et al., 2001). Recently, the STAR*D study investigated the ecacy of buspirone versus bupropion augmentation in SSRI non-responders. In most outcomes, the rate of improvement was similar for both strategies, but buspirone was associated with more tolerability problems (Trivedi et al., 2006a). Clearly, further controlled studies are required to clarify the role of 5-HT1A agonist in augmenting antidepressants. 9.1.12.2.8 Tandospirone

S77

Similar to buspirone, tandospirone is a 5-HT1A receptor agonist used in treating anxiety disorders. In a Japanese study, the ecacy of augmentation of clomipramine by tandospirone in 36 untreated outpatients with major depressive disorder was evaluated and compared with clomipramine monotherapy and clomipramine plus diazepam. Outcome after 6 weeks, measured with the HAMD (17 items, HAMD17) and the Hamilton Anxiety Rating Scale (14 items ; HAMA-14) showed no statistically signicant dierence. However, at 2 weeks, the percentage improvement of the HAMD-17 score in the tandospirone plus clomipramine group tended to be higher, though not statistically signicant, than in the other groups (Yamada et al., 2003a). More studies are required to ascertain whether augmentation of antidepressants by tandospirone for a few weeks might enhance the onset of antidepressant response. 9.1.12.2.9 Second-generation antipsychotics

First-generation medium-potency antipsychotics, such as sulpiride, have been shown to accelerate and improve antidepressant (SSRI) treatment (Uchida et al., 2005). More recently, the use of atypical antipsychotics (see Table 19) to augment antidepressants in non-psychotic depressive disorder has also been advocated. In addition, antidepressant eects of monotherapy with some of those substances have been published both for bipolar (Post and Calabrese, 2004) and unipolar depression (Amore and Jori, 2001). Zhang et al. demonstrated that in the rat prefrontal cortex the combination of olanzapine and uoxetine produced robust, sustained increases in extracellular

levels of dopamine and norepinephrine up to 36128 % and 27216 % of the baseline, respectively, which were signicantly greater than either drug alone (Zhang et al., 2000). Thus, the combination of olanzapine and uoxetine has been tested in several controlled studies both in unipolar and, more extensively, bipolar depression. A small placebocontrolled study of olanzapine added on to uoxetine supports this strategy (Shelton et al., 2001b). In a second study the olanzapine/uoxetine combination was superior to olanzapine alone in the treatment of depression with psychotic features (Rothschild et al., 2004). Moreover, a larger double-blind study that compared monotherapy with uoxetine, nortriptyline and olanzapine against olanzapine/uoxetine combination in patients with treatment-resistant depression also signicantly favored the antidepressant/antipsychotic combination (Shelton et al., 2005). A large open study showed acute responsiveness of previously SSRI (citalopram) treatment-resistant patients to augmentation with low doses (0.252 mg/ day, depending on age) of risperidone (Nemero et al., 2004). After a 6-week augmentation phase, 68.1 % of the patients with treatment-resistant depression receiving add-on risperidone were classied as responders. However, signicant superiority against citalopram monotherapy was not maintained in the subsequent double-blind continuation phase. Recently, another placebo-controlled study on risperidone augmentation that included 97 patients who met criteria for unipolar non-psychotic major depression and failed to respond, or only partially responded, to at least a 5-week trial of an adequate dose of antidepressant monotherapy. Primary outcome (remission status) was determined by a Montgomery Asberg Depression Rating Scale (MADRS) rating f10 to denote remission. At the end of 4 weeks of treatment 51.6 % of the risperidone augmentation group remitted compared with 24.2 % of the placebo augmentation group (p=0.011) (Nemero et al., 2004). Augmentation with risperidone has also been compared with addition of bupropion as a second antidepressant to SSRIs in a small, double-blind study. Although there was no signicant dierence in any outcome score at the end of the study (week 6), risperidone produced a more robust eect as early as week 1 (Papakostas et al., 2004). A non-inferiority trial comparing amisulpride with paroxetine treatment of major depression found no statistically signicant dierences between the treatment groups (Cassano and Jori, 2002). Open and retrospective data also support the augmentative

S78

CINP Antidepressant Task Force 2007 MAOIs and augmentation of serotonergic antidepressants in treatment-resistant depression (for an overview see Nelson, 2000) and in seasonal depression refractory to light treatment (Lam et al., 1997). However, unambiguous controlled studies are still lacking. Since an open pilot trial by Wharton with methylphenidate in treatment-resistant depression (Wharton et al., 1971), the use of stimulants has been documented in case series and one larger retrospective chart review suggesting ecacy in treatmentrefractory depression (Stotz et al., 1999). Yet the only randomized controlled study carried out so far of methylphenidate in treatment-resistant depression (Zhang et al., 2000) could not nd a signicant advantage over placebo. More recently, modanil has been tested in an open pilot study as an add-on to antidepressants and showed a 43 % response rate (Rasmussen et al., 2005). In a placebo-controlled study, however, it showed signicant improvement in SSRI partial responders for fatigue and sleepiness, but only a trend to better outcomes in depression rating scales (Fava et al., 2005b). Clearly, more randomized, conrmative studies are needed. Dopamine agonists such as pramipexole also demonstrated antidepressant activity in clinical trials (Corrigan et al., 2000 ; Goldberg et al., 2004). Besides countering agitation and sleep disturbances, benzodiazepines may also have other augmentative eects on antidepressant treatment (Furukawa et al., 2000 ; Furukawa et al., 2001b). But their longterm use is clearly discouraged due to their inherent risk of addiction. In some instances, e.g. perimenopausal depression, augmentation with estrogen has been recommended based on small pilot studies (Morgan et al., 2005 ; Rasgon et al., 2002 ; Schneider et al., 1997 ; Schneider et al., 2001). By the same token, estrogen carries health risks such as increased risk of endometrial and breast cancer, and thrombosis. A recent randomized doubleblind pilot study tested antidepressant augmentation with the selective estrogen receptor modulator raloxifene, showing good tolerability of raloxifene and a non-signicant trend to higher remission rates after 8 weeks (Grigoriadis et al., 2005). Clearly, more controlled studies with adequate sample sizes are required. Also, in women only, the substitution of folic acid (folate) improved the antidepressant action of uoxetine (Coppen and Bailey, 2000). In addition, augmentation strategies using testosterone or dehydroepiandrosterone (DHEA) have been reported (Fava, 2001).

ecacy of quetiapine, ziprasidone (Papakostas et al., 2004) and aripiprazole (Barbee et al., 2004 ; Papakostas et al., 2005 ; Papakostas, 2005 ; Simon and Nemero, 2005), although controlled studies have yet to be published. In conclusion, although it is possible to describe the augmentative eects of several atypical antipsychotics, controlled evidence is still sparse, comparator studies to established strategies such as lithium augmentation are lacking and we still need more clinical experience of the utility of this approach in treatment-resistant depression. 9.1.12.2.10 V-3 polyunsaturated fatty acids

Following publication of a potential epidemiological link between low sh intake and depression (Hibbeln, 1998), low V-3 fatty acid levels in depression and in women during the perinatal period have been found (Rees et al., 2005). In four of seven double-blind randomized controlled trials, signicant improvement of depressive symptoms was seen after regular ingestion of eicosapentaenoic acid, an V-3 fatty acid, as an adjunct to antidepressant treatment compared with placebo (Nemets et al., 2002 ; Peet and Horrobin, 2002) (for detailed information see the reviews of Sontrop and Campbell, 2006, and Parker et al., 2006). Relatively high doses between 0.5 and 2.8 g/day have been used to achieve antidepressant eects (Freeman et al., 2006 ; Peet and Horrobin, 2002). Owing also to publication of negative results (Silvers et al., 2005), to date it remains unclear whether this therapeutic option has clear antidepressant eects. Furthermore, we do not know whether it could be effective independent of other antidepressant treatments or ecacious only in patients with abnormally low V-3 fatty acid levels. To date the safety and tolerability prole of V-3 fatty acid therapies seems to be excellent. Good tolerability has been reported even in post-partum depression (Freeman et al., 2006). Diarrhea is a very common side eect without markedly enhanced danger ; it can, however, inuence blinding procedures in double-blind studies. A somatic benet for depressed patients, who often are at enhanced cardiovascular risk, has been proposed and needs to be further investigated (Frasure-Smith et al., 2004). 9.1.12.2.11 Other augmentation strategies

L-Tryptophan and 5-hydroxytryptophan used as serotonin precursors have been studied in depressive disorders with equivocal results. Some smaller studies employing L-tryptophan showed potentiation of

CINP Antidepressant Task Force 2007 9.1.12.2.12 Summary

S79

Except for lithium and T3, there is still a lack of good methodological studies supporting other pharmacological augmentation strategies. This area has begun to receive more scientic attention, and ongoing studies like STAR*D (Fava et al., 2003 ; Nierenberg et al., 2006a ; Trivedi et al., 2004), the Texas Medication Algorithm Project (Rush et al., 2003a ; Trivedi et al., 2004) and the Berliner Algorithmus Projekt (Adli et al., 2002 ; Adli et al., 2003) will supply further evidence for augmentation strategies and develop evidence-based algorithms for treatment-refractory patients. Other national medication algorithms for the treatment of depressive disorders have also recently come into existence, e.g. in Korea (Lee et al., 2006) and in Australia (Ellis, 2004). Using treatment algorithms predominantly progressing from simpler to more complex strategies may help to improve response rates up to 90 % (Thase and Rush, 1997). 9.1.13 New developments and novel pharmacological treatment approaches The therapeutic latency, the non-response rate of approximately 30 % and the side eects of all antidepressants available so far are important reasons to continuee the search for further treatment options for depressive disorders. Priorities of interest include developing new drugs with fewer side eects and possibly faster response due to the possibility of using higher-dose regimes (Norman and Leonard, 1994). The following sections describe some pharmacological principles that are currently not being used clinically and that may disclose novel approaches in the treatment of depression (Baghai et al., 2006c ; Rupprecht et al., 2004). 9.1.13.1 Inuence on melatonergic neurotransmission Melatonin secretion underpins precise circadian rhythms (Lesieur et al., 1998). It is regulated via the cyclic AMP (cAMP) signal transduction cascade (Foulkes et al., 1997). A variety of animal studies and clinical trials in depressed patients suggest that agomelatine, a synthetic melatonergic MT1 and MT2 receptor agonist (Audinot et al., 2003 ; Yous et al., 1992) with 5-HT2C receptor antagonist (Millan et al., 2003) properties within the CNS, has antidepressant eects (Tuma et al., 2002). The antidepressant properties of agomelatine and its good tolerability prole have been demonstrated in several clinical trials (Kennedy and Emsley, 2006 ; Loo et al., 2002 ; Montgomery et al., 2004c ; Olie and Kasper, 2007) that compared it with

established antidepressants such as paroxetine and venlafaxine, and with placebo. In particular, sleeprelated complaints improved without sedation during the daytime. In a further randomized double-blind, multicenter study, the absence of discontinuation symptoms in sustained remitted patients was shown following agomelatine therapy (Montgomery et al., 2004c). Agomelatine thus represents a promising novel strategy in the treatment of depression. 9.1.13.2 Serotonergic antidepressants A promising strategy that was not developed further was gepirone, an azapirone similar to buspirone that acts as a partial agonist at 5-HT1A receptors (Silva and Brandao, 2000 ; Van Reeth et al., 1999). In animal studies gepirone shows anxiolytic and antidepressant properties (Silva and Brandao, 2000 ; Van Reeth et al., 1999). Thus far, three placebo controlled double-blind studies in depressed patients have been published. In all trials gepirone proved superior to placebo in the treatment of depression ; it also showed good tolerability (Feiger, 1996 ; Feiger et al., 2003 ; Wilcox et al., 1996). Although these data support possible antidepressant properties of gepirone, the manufacturer has halted its development. Development of other serotonergic substances as antidepressants, such as ipsapirone, esinoxan and tandospirone, has also been stopped. Only tandospirone has been marketed, in Japan, as an anxiolytic drug. 9.1.13.3 Tachykinin receptor antagonists The peptide family of tachykinins (Stout et al., 2001), in particular substance P (SP), have drawn attention to new developments within antidepressant pharmacotherapy (Kramer et al., 1998 ; Stout et al., 2001). The tachykinin NK1 receptor is the receptor for SP, which is co-localized with monoamines in several regions of the CNS (Stout et al., 2001). Furthermore, intracerebroventricular administration of SP causes increased concentrations of catecholamine, and it has been shown that NK1-receptor knockout mice exhibit reduced anxiety and stress-related behavior (Stout et al., 2001). Stimulation of enhanced hippocampal neurogenesis, too, an eect also observed after application of established antidepressants, has been reported (Kramer et al., 1998 ; Stout et al., 2001). Despite the fact that several synthetic NK1-receptor antagonists are available (Stout et al., 2001), only the results of clinical trials with two substances have been published. In a double-blind study, an NK1 antagonist was compared with SSRI treatment and showed

S80

CINP Antidepressant Task Force 2007 1991 ; Sovner and Fogelman, 2002 ; Thakore and Dinan, 1995 ; Wolkowitz et al., 1993). In a placebo-controlled study, hints of the putative antidepressant ecacy of ketoconazole were found only in hypercortisolemic, but not in normocortisolemic, patients (Wolkowitz et al., 1999a). Another placebo-controlled double-blind study in treatment-resistant depression has shown insucient antidepressant ecacy (Malison et al., 1999). Similar antidepressant eects have also been shown for metyrapone in case reports and open trials (Ghadirian et al., 1995 ; Murphy et al., 1991 ; Murphy, 1991 ; Raven et al., 1996), as well as in placebocontrolled double-blind studies. A study of eight patients found a reduction in the score of the MADRS of more than 50 % within 2 weeks of treatment (ODwyer et al., 1995). A comparison of metyrapone with placebo in addition to serotonergic antidepressant therapy resulted in signicant acceleration of antidepressant eects (Jahn et al., 2004). Denite proof of the antidepressant properties of ketoconazole and metyrapone, however, is still lacking. A further limitation of therapy using steroid synthesis inhibitors is the risk of developing adrenal gland insuciency, and substitution of hydrocortisone may be required during treatment (ODwyer et al., 1995). Nevertheless, at least in hypercortisolemic and severely depressed patients, this experimental therapeutic approach can be considered in the case of severe treatment resistance. 9.1.13.4.3 Neuroactive steroids

superiority over placebo (Kramer et al., 1998). The scores of both Hamilton depression and anxiety rating scales were signicantly reduced. A further study demonstrated no superiority of MK 869 over placebo. A subsequent substance was examined, and a signicant, but relatively small superiority in reducing HAMD scores compared with placebo was found (Kramer, 2002). A recent study conrmed the antidepressant properties of yet another NK1 antagonist (Kramer et al., 2004), but this rst promising antidepressant approach was not conrmed by clinical data in further studies. These uncertainties necessitate replicating the ndings. Nevertheless, NK1 antagonism appears to be a promising new antidepressant treatment principle with an excellent tolerability prole. To date, the rst NK1 antagonist has been approved by the authorities not as an antidepressant, but as an antiemetic. 9.1.13.4 Treatment strategies inuencing the hypothalamic pituitary adrenal system 9.1.13.4.1 Corticotropin-releasing hormone receptor antagonists Up to now, one corticotropin-releasing hormone (CRH1) receptor antagonist (R121919) has been investigated. In an open trial examining the safety and tolerability, not ecacy, of this compound in 20 depressed patients, a distinct reduction in HAMD and HAMA scores was evident within 4 weeks of treatment (Zobel et al., 2000). The activity of the hypothalamic pituitary adrenal (HPA) system was not altered following administration of the CRH1 receptor antagonist. This indicates that the compound selectively blocked CRH1 receptors, while the HPA system is also under control of CRH2 receptors. Tapering o of the study medication resulted in a certain deterioration of the depressive syndrome. The compound was withdrawn from further development owing to the nding of increased liver enzymes in routine laboratory screening. Due to the lack of placebo-controlled double-blind studies, further clinical trials using other CRH1 receptor antagonists are required to clarify the possible antidepressant potential of these substances. 9.1.13.4.2 Steroid synthesis inhibitors

Inhibitors of steroid synthesis such as the fungicide ketoconazole and metyrapone have been reported to exert antidepressive eects. Case series and open trials reported antidepressant eects of ketoconazole (Anand et al., 1995 ; Ghadirian et al., 1995 ; Murphy,

Neuroactive steroids modulate neurotransmitter receptors (Rupprecht and Holsboer, 1999) and show antidepressant and anxiolytic properties in animal studies (Bitran et al., 1991 ; Khisti et al., 2000). Antidepressants, in particular SSRIs, enhance the concentration of endogenous 3a-reduced neuroactive steroids within dierent areas of the brain (Rupprecht and Holsboer, 1999). These mechanisms may play a role in antidepressant treatment. However, synthetic analogs of 3a-reduced neuroactive steroids for the therapy of psychiatric disorders in humans are not yet available. DHEA is a neuroactive steroid that displays both antagonistic properties at c-amino butyric acid (GABAA) receptors and antiglucocorticoid eects (Rupprecht, 1997 ; Rupprecht and Holsboer, 1999 ; Wolkowitz et al., 1999b). One open study (Wolkowitz et al., 1997) suggested possible antidepressant eects of DHEA. An early placebo-controlled double-blind study performed using an add-on treatment of DHEA in depressed patients showed a signicant reduction

CINP Antidepressant Task Force 2007 in HAMD scores (Wolkowitz et al., 1999b). Yet DHEA concentrations were found to be enhanced in depressed patients compared with healthy volunteers (Heuser et al., 1998), which seems to contradict the indication of DHEA as treatment option in depressive disorders. 9.1.13.4.4 Glucocorticoid receptor antagonists

S81

Synthetic glucocorticoid receptor antagonists block the eects of cortisol at glucocorticoid receptors. In initial casuistic studies the glucocorticoid-/progesteronereceptor antagonist mifepristone, used in some countries to terminate rst-trimester pregnancy, improved depressive symptoms in antidepressant treatmentresistant depression (Murphy et al., 1993). An openlabel study in patients with psychotic depression showed a reduction in the Brief Psychiatric Rating Scale (BPRS) scores in the majority of the patients (Belano et al., 2002), but reported no statistically signicant dierences. Symptom amelioration could be seen after 7 days in high-dose treatment groups. A placebo-controlled case series in ve patients suering from psychotic depression showed a reduction in HAMD score up to 26 % (Belano et al., 2001), but again, only a non-signicant trend to a difference between verum and placebo could be seen. A recent study demonstrated a statistically signicant inuence of mifepristone on psychotic symptoms measured using the BPRS, but no signicant dierences in other depression rating scales (DeBattista et al., 2006). Because of the antagonistic eects of mifepristone at progesterone receptors, the use of this substance as an antidepressant seems to be limited. Further investigations using the selective glucocorticoid receptor antagonist Org 34517 have been carried out. Initial clinical experience supports the possible antidepressant ecacy of glucocorticoid receptor antagonists. Nevertheless, the results of placebo-controlled doubleblind studies of sucient power and over a suciently long treatment period are needed before the antidepressant potential of these substances can be reliably assessed. 9.2 Continuation and maintenance therapy with antidepressants, mood stabilizers and other medication The need for continuation treatment has also been clearly demonstrated by placebo-controlled studies. Relapse rates ranged from 31 to 80 % for remitted patients who were switched to placebo compared with 031 % of those who received active tricyclic

medication (Prien, 1990 ; Prien and Kupfer, 1986). Studies with SSRI continuation, amineptine, nefazodone and reboxetine have reported similar results. Tables 20 and 21, modied from Fakra et al (2006) depicts continuation and maintenance studies from 1988 to 2006, when most controlled maintenance studies with new antidressants had been conducted. As a rule of thumb, continuation of antidepressant treatment prevented roughly 50 % of the recurrences that occured under placebo, regardless of the duration of the study or the pharmacological nature of the antidepressant drug. Similarly, a systematic review by Hirschfeld (Hirschfeld, 2001) found that approximately one-third to one-half of patients successfully stabilized in acute-phase treatment will relapse if medication is not sustained throughout the continuation period, and only 1015 % will relapse if medication is continued. Therefore, it is recommended to continue the successful initial antidepressant or combination treatment at the same dose during the continuation phase (Thase, 1999b). For patients who remit on antidepressant together with lithium as augmentative treatment, combined treatment during continuation has been suggested to be more ecacious than antidepressants alone (Bauer et al., 2000 ; Bschor et al., 2002). Although usually cited as compelling evidence for prophylactic treatment, the meta-analysis of Geddes et al. (2003) has a stronger focus on continuation treatment and prevention of early relapse. Of the 31 randomized trials included in this meta-analysis, most trials went on for 12 months and were conducted in acute responders to antidepressant treatment. Thus, they are truly continuation treatment studies. However, a few studies lasting up to 3 years also support the persistence of eectiveness. Although not true for the majority of patients, some studies have suggested that continuous antidepressant treatment destabilizes patients (see Hirschfeld, 2000). However, at the end of his review Fava concluded that at present we have no sound data that antidepressant drugs may worsen the course of depression and, if they do, whether the phenomena is generalized or very limited. Thus, unless the individual history of a patient shows evidence of negative eects from long-term antidepressant treatment, continuation therapy should be oered to every patient following recovery from a depressed episode. The situation may be dierent for other subtypes of depression, e.g. bipolar depression with a rapid-cycling course ; these special conditions are, however, beyond the scope of this review.

S82

CINP Antidepressant Task Force 2007

Table 20. Maintenance treatment using one antidepressant in comparison to placebo Length of treatment phase Study Montogomery (1988) Frank (1990) Robinson (1991) Number of subjects 456 initial 220 maint 182 complete 128 maint 106 complete 88 initial 47 maint 35 complete 20 maint 19 complete 436 initial 204 maint 500 initial 214 maint 166 complete 253 initial 145 maint 121 complete 427 initial 269 maint 264 complete 371 initial 288 maint 165 complete 172/141135 283 initial 143 maint 41 complete 230 initial 121 maint 121 complete 318 initial 113 maint 76 complete 195 initial 116 maint Acute 6 weeks Contin 18 weeks Mainten 1 year Drug Fluoxetine Recurrence rate Drug 26 % Placebo 57 %

Until remission Until remission

17 weeks 16 weeks

3 years 2 years

Imipramine Phenelzine

40 % 29 %

81 % 81 %

Kupfer (1992) Terra (1998) Rouillon (2000)

Imipramine (3)5 years 6 weeks Until remission 8 weeks 18 weeks 4 months 1 year 1 year Fluvoxamine Milnacipram 18 % 12.7 % 16.3 % 67 % 35.1 % 23.6 %

Gilaberte (2001)

24 weeks

48 weeks

Fluoxetine

20 %

40 %

Hochstrasser (2001) Lepine (2004)

Montgomery (1988) Versiani (1999) Reynolds (1999) Klysner (2002)

69 weeks 16 weeks Until (max remission 77 weeks) 46 months 18 months Followed by a 2 months placebo period 8 weeks 1 year 6 weeks Until remission 8 weeks 23+23 weeks 16 weeks 16 weeks

48 weeks

Citalopram

22 %

76 %

Sertraline

16.9 %

33.3 %

Paroxetine Reboxetine 3 years >48 weeks Nortriptyline Citalopram

16 % 21.8 % 29 % (80120 ng/l) 32 %

43 % 56 % 40 % (4060 ng/l) 67 %

Wilson (2003)

8 weeks

1620 weeks

100 weeks

Sertraline

44.6 %

54.4 %

Reynolds (2006)

Until remission

16 weeks

2 year

Paroxetine +/x psychotherapy

36.5 %

64.2 %

The ultimate goal with any psychiatric disorder is to prevent recurrence of acute symptomatology and improve functionality and quality of life in patients. Clearly, this goal is no dierent with unipolar depression. The prophylactic eect of continuing antidepressant medication has been demonstrated in a multitude of studies (Geddes et al., 2003 ; Hirschfeld, 2000) (see Figure 4).

As already detailed in chapter 7 on the goals of treatment, long-term prophylactic treatment following continuation treatment is recommended in patients with a history of recurring episodes. Besides preventing relapses, antidepressants may add value by virtue of their neuroprotective properties (Sheline et al., 2003). Taken together, approximately 60 % of patients at risk will experience a recurrent episode of

CINP Antidepressant Task Force 2007

Advantage of mirtazapine over amitriptyline and placebo for time to relapse in the survival analysis, and against placebo for the number of relapses No signicant dierence between two treatments Open study, comparable ecacy, but nortriptyline produced fewer residual depressive symptoms and side-eects

S83

6 weeks 20 weeks Up to 2 years Randomization during all treatment phases

Table 21. Maintenance treatment studies comparing two antidepressants

116 initial 12 weeks 12 weeks 18 months 59 conti Randomization during all treatment phases (elderly patients)

Length of treatment phase

6 weeks 1 year Double-blind phase

24 months

depression within 1 year if untreated, whereas those who continue treatment will have a recurrence rate of between 10 and 30 % (Hirschfeld, 2001). If in doubt about the indication for maintenance treatment, an early decision in favor of long-term maintenance may improve long-term outcome : Solomon (Solomon et al., 2000) showed that the risk of a new episode increases by 16 % with each successive recurrence. If a patient has had a history of at least two (Paykel and Priest, 1992) or three episodes (Prien et al., 1984), prophylactic treatment is recommended. Guidelines agree that maintenance dosages should be similar to acute and continuation treatment unless tolerability problems force reduction of the medication. Of the 31 studies included in the meta-analysis by Geddes et al. (2003), 5 studies had a duration of 3 years and 6 a duration of 2 years. However, most of these studies included only a small number of patients and thus do not encourage rm conclusions by themselves. Among the randomized controlled studies, the study by Prien et al. (Prien et al., 1984) comparing imipramine and lithium alone or in combination against placebo supplied good evidence for the prophylactic ecacy of both the antidepressant and lithium. The ecacy of imipramine is also supported by a 36-month study of Frank et al. (Frank et al., 1990). Similar evidence for continuing prophylactic ecacy has been supplied for nortriptyline (Reynolds et al., 1999), sertraline (Keller et al., 1998) and citalopram (Klysner et al., 2002), as well as for the MAOI phenelzine (Robinson et al., 1991).

Relapse/ recurrence rate

Placebo

Parox. and Imip.> placebo 50 % more dropouts with Imip./Parox. due to side eect

Conclusion

18.7 % 21.9 %

Drug

Mirtazapine 4.1 % Amitriptyline placebo 23 %

15 % 4% 25 %

Contin

Mainten

Fluvoxamine Sertraline

Nortriptyline placebo

Paroxetine Imipramine placebo

Drug

10 % 16 %

9.2.1.1 Alternatives to long-term antidepressant treatment 9.2.1.1.1 Lithium

4 months

Acute

If patients do not respond to prophylactic antidepressant treatment or do not tolerate side eects, the rst alternative is long-term lithium maintenance therapy. Although it may be even more efcacious in bipolar disorder, and although some negative results in unipolar disorder have been published (Burgess et al., 2001a ; Burgess et al., 2001b), the ecacy of lithium in preventing relapses in unipolar recurrent depression is well established (Coppen, 2000 ; Dunner, 1998 ; Paykel, 2001 ; Schou, 1995). These ndings are also supported by two meta-analyses showing that lithium is more eective than placebo in preventing recurrence of unipolar depression (Angst et al., 2002a ; Souza and Goodwin, 1991). In

Number of subjects

717 initial 219 conti

Claghorn (1993)

Montgomery (1998) 580 initial 217 conti

Franchini (1997)

77 initial 64 conti

Study

Bump (2001)

S84

CINP Antidepressant Task Force 2007

Events/patients Number of trials Allocated antidepressant 169/912 (19%) 13/61 (21%) 113/449 (25%) 156/1034 (15%) 14/71 (20%) 465/ 2527 (18%) Placebo adjusted 313/889 (35%) 57/66 (86%) 248/432 (57%) 385/1046 (37%) 28/72 (39%) 1031/ 2505 (41%) Antidepressant events Logrank OE 57.5 15.7 70.7 94.9 6.9 (Variance of OE) (60.7) (6.0) (50.5) (80.7) (7.5) Odds ratio (95% Cl) Antidepressant : Placebo

Reduction (S.E.)

NARI MAOI Tricyclic SSRI Other

2 4 15 10 1

Total

32

245.7

(205.4)

70% (4) 2p <0.00001

99% or

95% confidence intervals 0 1.0 1.5 2.0 0.5 Antidepressant worse Antidepressant better Treatment effect 2p <0.00001

2 Heterogeneity between five categories: 4=18.6; p =0.001

Figure 4. Cochrane meta-analysis of the ecacy of antidepressants in preventing recurrence of unipolar depression : risk of relapse, odds ratios by drug type (from Geddes et al., 2003). NARI, Noradrenaline (norepinephrine) reuptake inhibitor ; MAOI, monoamine oxidase inhibitor ; SSRI, selective serotonin reuptake inhibitor.

addition to preventing new episodes, lithium normalizes the increased mortality rates for cerebrovascular and cardiovascular disorders in aectively ill patients (Angst et al., 2002a) and reduces the risk of suicide (Angst et al., 2002a ; Goodwin et al., 2003 ; Souza and Goodwin, 1991). For a recent up-to-date review see also Muller-Oerlinghausen et al. (Muller Oerlinghausen et al., 2006). In addition, potential neuroprotective eects, including preventive eects against Alzheimers dementia, can be of interest when prescribing long-term lithium prophylaxis. The usually recommended serum lithium levels for prophylaxis in unipolar recurrent depression are 0.50.8 mmol/l, but individual variations may occur. The use of extended-release forms of lithium has been strongly encouraged, as these enable oncedaily dosing and are associated with fewer side eects, both favoring enhanced treatment adherence of patients. 9.2.1.1.2 Anticonvulsants in the prophylaxis of unipolar depression Carbamazepine has been studied in two small doubleblind comparator trials with lithium in recurrent major depression (Angst et al., 2002a ; Rush, 1999). Both studies suggested equal ecacy for lithium and carbamazepine. However, for prophylactic treatment, the propensity of carbamazepine not only to induce its own hepatic metabolism but also to accelerate

metabolization of drugs using CYP3A4 must be kept in mind. Some antidepressants, e.g. venlafaxine, mirtazapine, nefazodone, reboxetine and imipramine, are substrates of CYP3A4 and thus may not achieve sucient plasma levels when used in combination with carbamazepine. CYP1A2 and CYP2C9, which contribute to carbamazepine metabolism, may also be inhibited by uvoxamine. Given its potential interactions and lack of scientic evidence from placebo-controlled studies, carbamazepine can only be recommended as a subordinated choice when other strategies have failed. For other anticonvulsants only anecdotal reports and small case series, no controlled studies, have been published for prophylaxis in unipolar depression. 9.2.1.2 General principles of long-term prophylactic treatment As a general recommendation, prophylactic treatment of unipolar depression is not only restricted to pharmacotherapy. Maintaining a good doctor-patient relationship, monitoring adherence and psychoeducation are important as well. Whereas approximately 4070 % of patients adhere to their antidepressant drug regimen during the acute phase of therapy, only 1550 % still comply with therapy during the continuation phase (Mel et al., 1998). Automated systems have been tested in primary care setting, alerting the

CINP Antidepressant Task Force 2007 physician if a rell has been missed for a specied time. However, this approach did not improve compliance (Bambauer et al, 2006) and cannot substitute for a good doctorpatient relationhip. As preparation for long-term prophylactic treatment, patients and their relatives should be informed especially about topics such as expected course of illness, treatment options, medication ecacy and side eects, use of a daily self-reporting instrument for mood to detect early warning signs of relapse or recurrence, long-term perspectives and, if applicable, projected end of treatment. Patients should also be trained to distinguish between spontaneous, shortlasting mood uctuations (bleeps) and true emergence of a new episode, which should be treated as soon as possible (Rush, 1999). In addition, psychotherapy, especially interpersonal therapy and cognitive behavioral therapy, should be included in the overall treatment portfolio (Baghai et al., 2006c). However, a detailed description of the proven ecacy of psychotherapy in addition to medication is beyond the scope of this review.

S85

10 Specic age- and gender-related conditions 10.1 Gender-related dierences58

Gender dierences in unipolar depression are a consistent nding in several longitudinal and cross-sectional studies (for review see Kahn and Halbreich, 2005 ; Kuehner, 2003). Lifetime prevalence shows an unadjusted mean female/male ratio of 2.1, whereas the point prevalence gender ratio is 1.7 (Kuehner, 2003). This estimate of dierences in lifetime depression rates is calculated from large population-based studies comprising up to almost 45000 subjects and, for point and period prevalence rates, even up to 78000 subjects (DEPRES study (Depression Research in European Society) (Angst et al., 2002b). Several dierences in comorbidity, symptomatology and coping style between genders have been described. Starting with comorbidities, frequent disorders comorbid with depression in females include anxiety (Breslau et al., 1995), somatoform disorders and eating disorders, especially bulimia (Marcus et al., 2005), whereas men are more likely to suer from comorbid alcohol and drug abuse (Marcus et al., 2005).

58

Gender-related dierences of antidepressant pharmacotherapies during pregnancy or post-partum and breast-feeding periods are described more in detail in chapter 9.1.1.3.3.

This gender dierence may also be reected in ways of coping with depression. For example, Angst et al. found that depressed men were more likely to increase consumption of alcohol, whereas women tried to cope through emotional release and religion (Angst et al., 2002b). As far as other features of depression are concerned, recently published results of the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study (Marcus et al., 2005) also show a signicantly earlier onset of the rst major depressive episode in women, and longer current major episodes for women compared with men. In addition, depression in women may also aect their ospring : children of mothers suering from depression are at high risk for disruptive behavior and anxiety disorders as demonstrated in a large sample of the STAR*D trial (Pilowsky et al., 2006). Some features of depression appear to be more prevalent among men than among women, e.g. a tendency to overreact and to attack in anger (Winkler et al., 2005a). Criterial major depressive episodes according to DSM-IV (American Psychiatric Association, 1994), however, are more prevalent in female than in male depressed patients (Angst et al., 2002b). In the large European DEPRES I and II study, women were signicantly more likely to have ve or more criterial symptoms of depression than men (female/male ratio 1.96). Interestingly, dierences in symptomatology are already apparent in adolescent depression. Bennett et al. (2005) interviewed 383 depressed adolescents with the Childhood Version of the Schedule for Aective Disorders and Schizophrenia (K-SADS-IIIR, -IV ; Bennett et al., 2005) and the Beck Depression Inventory (BDI ; Bennett et al., 2005). In this sample, with a mean age of 15.8 years, he found that depressed girls were more likely to exhibit guilt, body image dissatisfaction, self-blame, self-disappointment, feelings of failure, concentration problems, diculty working, problems of sadness and depressed mood, fatigue and health worries than depressed boys. In contrast, depressed boys had higher clinician ratings for anhedonia, depressed morning mood and morning fatigue (Bennett et al., 2005). Explanations for these gender dierences are manifold, and several factors may contribute to them. According to Kuehner (2003), these factors include genetics, sex hormones, diering endocrine stress reactivity, a higher incidence of thyroid axis abnormalities, prior anxiety disorders, personality traits, neuropsychological factors, gender role and psychosocial factors, and life events, e.g. childhood

S86

CINP Antidepressant Task Force 2007 by other studies (Scheibe et al., 2003 ; Thiels et al., 2005) or a combined analysis of several studies (Hildebrandt et al., 2003). When interpreting data, especially from randomized controlled studies, a major methodological pitfall is the underinclusion of women in the older studies (Yonkers and Brawman-Mintzer, 2002). This makes potential ndings of gender-specic ecacy of tricyclics especially dicult to interpret. The situation is slightly dierent with SSRIs, where reported gender dierences are based on more recent studies with equal gender distribution. In a review of 30 randomized placebo-controlled trials of tricyclics conducted to obtain market authorization between 1979 and 1991, Wohlfarth et al. (2004) could not identify a gender dierence in the ecacy of tricyclics. This nding contrasts with a meta-analysis of Hamilton et al. (1995) of all published trials with imipramine, which showed signicantly dierent response rates of 62 % for men and only 51 % for women. On the other hand, several studies describe a signicantly higher response rate for women to SSRI treatment compared with men, e.g. (Baca et al., 2004). A better ecacy of SSRIs was also demonstrated by an analysis of 15 randomized placebo-controlled studies conducted at the Northwest Clinical Research Center in Bellevue, Washington, between 1996 and 2003 (Khan et al., 2005). The researchers found that women had a signicantly greater response than men to SSRIs, but not to SNRI antidepressants. The authors assume that this dierent responsiveness may be due to subtle dierences in the serotonergic system between men and women (Bano et al., 2004 ; Bell et al., 2001 ; Nishizawa et al., 1997). For other classes of medications, gender-specic dierences are less clear. For example, better response rates to monoamine oxidase inhibitors (MAOIs) in women have been described in studies that include a substantial number of depressed patients with socalled atypical features (Davidson and Pelton, 1986) (see also chapter 5.2.1.3.3). However, atypical depression characterized by dysphoria and pronounced anxiety is a more likely nding in women than men, and MAOIs had previously demonstrated a good ecacy in this condition (Henkel et al., 2006). Thus, the nding of higher responsiveness to MAOIs for women may simply be due to the interaction of depression subtype and gender. This is a good example of the careful consideration of potential covariables that is essential in identifying true gender dierences. In summary, prevalence, symptomatology, treatment response and consequences of depression are not identical in men and women, and a gender-specic

sexual abuse. So far, there are no consistent ndings for gender dierences in heritability (Kendler, 1998). Only when broadening the criteria for depressive disorders does heritability of those disorders appear to be greater in women than in men (Kendler, 1998). In elderly patients, a higher heritability for depressive symptoms may be associated with female gender (Jansson et al., 2004). In addition, gender-specic eects of genetic polymorphisms, e.g. within the angiotensin I converting enzyme (ACE) gene, may play a role in varying responsiveness and speed of onset of antidepressant action. In women, D/D and I/ D alleles have been associated with a faster onset of dierent antidepressant therapies (Baghai et al., 2003 ; Baghai et al., 2004). Overall, however, more research is needed to reach rmer conclusions concerning a gender-specic genetic preposition for depression and response to treatment. Sex hormones may play an important modulatory role in the manifestation and course of depression, and also for treatment response. There exist specic vulnerabilities and complex interactions between brain mechanisms and gonadal hormones (Halbreich and Kahn, 2006). For instance, depressive symptomatology in vulnerable women seems to increase when their physiological estradiol levels decrease, e.g. perimenstrually, in the post-partum period or during perimenopause. Just as menopause seems to negatively aect SSRI treatment response of depressed women, antidepressant treatment seems to be inuenced by estradiol levels (Pinto-Meza et al., 2006). At the same time, several studies have shown estrogen treatment to be eective in post-partum as well as perimenopausal depression (for review see Kahn and Halbreich, 2005 ; Riecher-Rossler et al., In Press). Estrogens may enhance serotonergic activity and, if combined, may induce a better responsiveness to SSRIs (Stahl, 2001) (for review see Kahn and Halbreich, 2005). Estradiol may be involved in desensitization at the 5-HT1A receptor (Bouali et al., 2003 ; Carrasco et al., 2004). Other neuroendocrine axes, such as the hypothalamicpituitaryadrenal (HPA) (Kornstein et al., 2002) and thyroid axes (Kornstein et al., 2002), may also exhibit subtle dierences between genders, thereby aecting vulnerability to depression. In general, treatment should not dier between depressed men and women, but specic precautions must be taken into account (see also chapter 9.1.1.3.3). Clinically, gender dierences in treatment response have been demonstrated in several studies (Frank et al., 1988 ; Kornstein et al., 2002 ; Yonkers and Brawman-Mintzer, 2002), but could not be conrmed

CINP Antidepressant Task Force 2007 psychiatric approach that takes into account genderspecic risk and inuencing factors (see also chapter 9.1.1.3.3) including gender roles is warranted (Riecher-Rossler, 2000). 10.2 Age-related dierences

S87

10.2.1 Using antidepressant medications to treat depression in child and adolescent populations 10.2.1.1 Introduction Identifying and treating depressive disorders in child and adolescent populations is often more complicated than in adult populations for two main reasons. First, the clinical features of depressive disorders in young patients may dier substantially from those of adult patients. Instead of manifesting neurovegetative or straightforward depressive symptoms, depressed children may exhibit behavioral problems that cause diculties in psychosocial functioning at home or at school. Identifying these behaviors related to and underlying depression requires not only evaluating the patient but also talking to parents and teachers as informants. The second diculty stems from the variety of treatment options based on relatively little evidence of ecacy and safety in children and adolescents. In addition, questions have been raised recently regarding the possibility of increased suicidal behavior in depressed youth treated with antidepressant medications (Leslie et al., 2005). All of these issues must be considered before deciding whether and how to treat young people with depression. Comprehensive guidelines about identifying and treating this age group have been published elsewhere (Birmaher et al., 1998 ; Park and Goodyer, 2000). Likewise, because comprehensive reviews of evidence-based psychotherapies for depressed youth are available (Compton et al., 2004 ; Curry, 2001), this chapter instead will discuss the safety and ecacy of antidepressants. First, we will review randomized controlled trials (RCTs) of antidepressants in depressed children and adolescents. Next, we will discuss regulatory actions taken by drug safety agencies in the US and UK. Finally, we will oer recommendations regarding pharmacologic treatment of depressed children and adolescents. While empirical studies of antidepressant medications have been conducted in depressed child and adolescent populations since the 1960s, the rst welldesigned, double-blind, placebo-controlled studies most involving tricyclic antidepressants (TCAs) did not take place until the mid- and late 1980s (Ambrosini, 2000). Since then, several RCTs, primarily

of newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), have been conducted in child and adolescent populations. No RCTs of monoamine oxidase inhibitors have been conducted in depressed child or adolescent populations. The only RCT showing positive eects in childhood depression shows therapeutic benets of V-3 fatty acids in a 16week-long clinical trial (Nemets et al., 2006). In a recently published meta-analysis the eectiveness of antidepressants in comparison to placebo in the treatment of pediatric major depressive disorder has been conrmed (Bridge et al., 2007). It has been stated that the benets of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempts. Similar conclusions were drawn due to increasing suicide rates both in the US (14 %) and the Netherlands (49 %) after decreasing SSRI prescriptions (x22 %) between the years 2003 and 2005 following warnings of U.S. and European regulatory agencies about a possible suicide risk with antidepressant use in pediatric patients (Gibbons et al., 2007). A Cochrane meta-analysis of TCAs, as well as all known published RCTs of SSRIs and atypical antidepressants, will be described below. Whenever applicable, a distinction will be made between a given drugs attributes in child (age 12 and under) and adolescent (age 13 and older) populations59. 10.2.1.1.1 Tricyclic antidepressants

Given the ample evidence for ecacy in adult populations, multiple clinical trials of TCAs including studies of amitriptyline, imipramine, nortriptyline and desipramine in the serotonergic system have been conducted. A Cochrane review of 13 of these RCTs involving over 500 young people was completed by Hazell and colleagues (Hazell et al., 2002). Across child and adolescent populations, the eect size (ES) identied by this meta-analysis was statistically signicant, but small (ES x0.31, 95 % CI x0.62 to x0.01 ; negative ES indicates a reduction in depressive symptoms). However, when subgroup analyses were conducted, no signicant benet was seen with children (ES 0.15, 95 % CI x0.34 to 0.64), but a larger advantage was seen with adolescents (ES x0.47, 95 % CI : x0.92 to x0.02). This dierential treatment response is consistent with the superior ecacy of TCAs in adult populations, and may be explained by

59

Age limits in the denitions of children and adolescents are varying between dierent countries (e.g. in Germany the legal age limit is 14 years). In the cited studies predominantly an age limit of 12 years has been used.

S88

CINP Antidepressant Task Force 2007 Clinical Global Impressions-Improvement Score (CGI-I) and the Childrens Depression Rating ScaleRevised (CDRS-R). Signicantly more youth given uoxetine responded (i.e. received ratings of 1, very much improved , or 2, much improved , on the CGII). While endpoint mean CDRS-R scores were signicantly better for uoxetine-treated youth than for those who received placebo, the dierences in terms of remission (a dichotomous measure, prospectively dened as a score of <29 on the CDRS, and potentially less sensitive to change) did not reach signicance. Response rates did not dier for children 12 and under compared with adolescents 13 and over. In comparisons with placebo, adverse events were not signicantly increased in the uoxetine-treated group. In 2002, Emslie et al. published an 8-week multisite follow-up study of 219 subjects between the ages of 8 and 18 (Emslie et al., 2002). In this trial, the CDRS-R was again used as a primary outcome measure. While the mean 22-point drop in CDRS-R scores in the uoxetine group was signicantly dierent from the 14.9-point decrease noted in the placebo group, it did not achieve primary outcome response criteria prospectively dened as a o30 % decrease in scores. However, in post hoc analyses the authors demonstrated that primary outcome would have been achieved had response been dened at o20, 40, 60 or 70 % decrease in CDRS scores, or if their calculation correctly reected the fact that the CDRS-R scale has a minimum value of 17 instead of 0 (Cheung et al., 2005). While no information was provided regarding suicidality, patients receiving uoxetine reported fewer adverse events than did those receiving placebo. Based on these results, uoxetine received US Food and Drug Administration (FDA) approval to treat depressive disorders in children and adolescents. In the double-blind relapse-prevention phase of the above-mentioned study, Emslie and colleagues continued to follow 40 subjects who remitted on uoxetine ; 20 of these uoxetine responders were assigned to continue xed-dose uoxetine, whereas 20 others were switched directly from uoxetine to placebo. Over the subsequent 32 weeks, when compared with those switched to placebo, fewer subjects who remained on uoxetine relapsed (60 vs. 34 %, respectively). Additionally, time to relapse was longer for those who remained on uoxetine compared with those who were switched to placebo (181 days vs. 71 days, p=0.046). There were no statistically signicant dierences in adverse events (Emslie et al., 2004). Fluoxetine, alone and in combination with cognitive-behavioral therapy (CBT), was compared with

maturation of neurological pathways or other developmental dierences between children, adolescents and adults (Bostic et al., 2005). Importantly, compared with placebo controls, in pediatric populations TCAs were associated with more vertigo, orthostatic hypotension and dry mouth (Hazell et al., 2002). 10.2.1.1.2 SSRIs and newer antidepressants

Given the lack of convincing evidence of eectiveness and the narrow therapeutic window of TCAs, more recent childhood depression trials have focused on SSRIs and other newer antidepressants. However, whereas 18 placebo-controlled RCTs of newer antidepressants have been conducted, only 12 have been published (Table 22). This section describes published SSRI trials with regard both to ecacy and to safety. In addition, data regarding unpublished trials were obtained from the report completed by the UKs Committee on Safety of Medicine (CSM) of the Medicines and Healthcare products Regulatory Agency (Commitee on Safety of Medicines, 2004), and a recent review of antidepressants in depression among youth (Cheung et al., 2005). 10.2.1.1.2.1 Fluoxetine The rst report about a case series of six patients, aged 1017 years, showing self-injurious ideation or behavior during uoxetine treatment of obsessivecompulsive disorder was published by (King et al., 1991). Between 1990 and 2004, four trials of uoxetine as a treatment for child and adolescent major depressive disorder were conducted, three of which were positive. The negative study of uoxetine, which was small and possibly underpowered, involved 40 adolescents from inpatient and outpatient settings. After 8 weeks on 2060 mg of uoxetine, authors did not identify signicant dierences for any of the outcome measures used ; subjects responded equally well to uoxetine or placebo. Other than weight loss, no drugassociated adverse events were reported (Simeon et al., 1990). The rst positive uoxetine study, published in 1997 by Emslie et al., compared a 20 mg xed dose of uoxetine to placebo in a group of 96 children and adolescents aged 717 (Emslie et al., 1997). Subjects were treated for 8 weeks at a single site. At the trials end, compared with placebo, subjects assigned to uoxetine scored signicantly better on both prospectively identied primary outcome measures : the

Table 22. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents Study characteristics Dose (mg) 2060 20 20 1040 Length (weeks) 8 8 8 12 Sites (n) 1 1 15 13 Results Active treatment n.a. 56 % 38.4 41 % FLX+CBT : 71.0 % FLX : 60.6 % FLX+CBT : 33.79 FLX : 36.30 66.5 % 18.98p8.24 60.5 % 9.3 n.a. x22.84 36 % 59 % x21.9 n.a. Sig. ? (Y/N) N Y Y N* Y Y Y N N N N N N Y Y N N N n.a.

Agent Fluoxetine

Author Simeon et al., 1990 Emslie et al., 1997 Emslie et al., 2002 March et al., 2004

N 40 96 219 439

Age 1318 717 818 1217

Primary outcome none assigned CGI-I (1 or 2) CDRS-R mean scores CDRS-R (>/=30 %) CGI-I (1 or 2) CDRS-R (cts)

Placebo n.a. 33 % 47.1 20 % 34.8 % 34.8 % 41.77 41.77 55.2 % 19.79p9.88 58.2 % 9.8 n.a. x20.19 24 % 61 % x20.2 n.a.

p value n.a. 0.02 <0.008 0.09 0.001 0.001 0.001 0.34 0.11 0.13 0.702 0.616 0.684 0.007 <0.5 0.310 n.a.

Sponsor n.a. NIMH Lily NIH

Paroxetine

Keller et al., 2001 Berard et al., 2006 Emslie et al., 2006

180** 286 206 376 174 244 264 40

1218 1318 717 617 717 1318 617 817

2040 2040 1050 50200 2040 1020 37.575

8 12 8 10 8 12 8 6

10 33 40 53 21 25 1

HAMD (f8 or o50 %) HAMD (cfb) MADRS (>/=50 %) K-SADS-L (cfb) CDRS-R (cfb) CDRS-R (mean reduction) CDRS-R (cfb) Kiddie-SADS-P, MADRS CDRS-R (cfb) n.a.

GSK

GSK GSK

CINP Antidepressant Task Force 2007

Sertraline Citalopram Escitalopram Venlafaxine

Wagner et al., 2003 Wagner et al., 2004 von Knorring et al., 2006 Wagner et al., 2006 Mandoki et al., 1997

Pzer Forrest

* Authors note that results would have reached signicance if response was dened as decrease in CDRS of o20, 40, 50 or 60 %. ** Trial included 275 subjects, but 95 were randomized to imipramine and are not considered in the above analysis. cfb=change from baseline ; cts=change in total score (adjusted mean) ; n.a.=not available ; GSK=GlaxoSmithKline.

S89

S90

CINP Antidepressant Task Force 2007 et al., 2006). Neither study demonstrated ecacy of paroxetine compared with placebo on primary outcome measures. In the rst study (Berard et al., 2006), which focused on adolescents aged 1318, more treatment-discontinuing adverse events and suiciderelated behavior were reported in the paroxetine group compared with placebo (11.8 vs. 7.1 % and 4.4 vs. 2.1 % respectively ; these dierences were not statistically signicant). In the second study (Emslie et al., 2006), which evaluated paroxetine in 206 children aged 717, serious adverse events were more commonly reported by children treated with paroxetine (6 subjects) versus placebo (1 subject). Additionally, treatment discontinuation due to an adverse event occurred more commonly with paroxetine (8.9 %) compared with placebo (2 %). 10.2.1.1.2.3 Sertraline In 2003, Wagner et al. published the combined results of two separate 10-week trials involving 376 child and adolescent subjects (aged 617) with depressive disorders (Wagner et al., 2003). These studies were conducted at 53 sites in ve countries, and the combined analysis was planned a priori. Although the individual trials did not reach statistical signicance on the primary outcome measure (mean reduction in CDRSR), when combined they demonstrated a small but statistically signicant eect. Of note, at the studys endpoint, the mean dierence in CDRS-R score was signicant for adolescents (sertraline : x28.95 ; placebo : x24.11 ; p=0.01) but only borderline signicant for children (sertraline : x31.44 ; placebo : x27.56 ; p=0.5). Compared with placebo, three times as many sertraline-treated subjects discontinued treatment as a result of suering adverse events. 10.2.1.1.2.4 Citalopram Wagner et al. also published results from an 8-week trial of citalopram in 174 children and adolescents (aged 717) with depressive disorders (Wagner et al., 2004). Compared with placebo, response criteria (CDRS-R f28) were achieved by signicantly more citalopram-treated depressed youth. Citalopram and placebo were discontinued due to adverse events at a similar rate (5.6 and 5.9 %, respectively). No dierences between children and adolescent populations were reported. According to the CSM report, a large unpublished trial of citalopram in depressed teenagers (aged 1318) did not demonstrate an antidepressant eect over placebo. Additionally, compared with placebo, greater percentages of citalopram-treated youth reported

placebo in the Treatment for Adolescents with Depression Study (TADS). The rst phase of this National Institute of Mental Health) (NIMH)sponsored multisite RCT followed 439 adolescents (aged 1217) with moderate to severe depression for 12 weeks. The uoxetine plus CBT condition was superior to placebo on both primary outcome measures : CDRS-R total score and CGI-I score of 1 or 2. Fluoxetine alone was statistically superior to placebo on the CGI-I variable, but not the CDRS-R. Compared with placebo, there was a statistically signicant increased risk of harm-related events a category that included suicidal and non-suicidal behavior such as self-cutting in the groups treated with uoxetine (OR 2.19 ; 95 % CI 1.034.62) ; however, there was no statistically signicant increased risk of suicide-related events in the uoxetine group. Whereas suicidal thinking decreased in all treatment groups, uoxetine plus CBT was associated with the greatest reduction (March et al., 2004). Combination treatment with CBT and uoxetine showed the greatest benet-to-risk ratio for adolescents with moderate to severe depression, and was superior to monotherapy. Moreover, uoxetine alone was more eective in treatment of depressed adolescents than CBT alone, whereas CBT alone did not dierentiate from placebo (March et al., 2004 ; Pathak et al., 2005 ; TADS study group, 2003 ; TADS study group, 2005). Note that the placebo response rate was relatively low in the TADS study (35 %) in comparison with other studies in children and adolescents, possibly due to specic inclusion criteria. 10.2.1.1.2.2 Paroxetine Keller et al. treated 180 adolescents (aged 1218) with either paroxetine or placebo in a multi-site, 8-week RCT. The HAMD-17 was the primary outcome measure ; both response (end of trial score of f8 or a >50 % reduction) and change from baseline were assessed. Whereas youth treated with paroxetine improved on primary outcome measures relative to placebo, these improvements were not statistically signicant in the case of imipramine (Keller et al., 2001). Adverse events were reported more often by patients receiving paroxetine (11 patients) versus placebo (2 patients). Additionally, paroxetine-treated patients had an increased risk of suicidal ideation compared with placebo-treated patients (5.4 vs. 0 % respectively). Two additional paroxetine studies, both conducted several years ago and previously unpublished, have recently been published (Berard et al., 2006 ; Emslie

CINP Antidepressant Task Force 2007 self-harm or suicidal thoughts, made serious suicide attempts or required hospitalization. In contrast, von Knorring et al. reported a response rate of about 60 % for both citalopram and placebo in 244 adolescents (aged 1318 years), but a better outcome in the citalopram group when the study results were controlled for the application of psychotherapy (von Knorring et al., 2006). In addition, a worsening of suicidal thoughts and a nonsignicant trend to a higher incidence of suicide-related events was seen more frequently in the placebo group. 10.2.1.1.2.5 Escitalopram Wagner and colleagues conducted an 8-week RCT of escitalopram, the S-isomer of citalopram, involving 264 young subjects aged 617 (Wagner et al., 2006). Although the results across the entire sample did not reveal signicant dierences, subgroup analysis revealed a statistically signicant drug versus placebo benet for adolescents. Rates of discontinuation due to adverse events and rates of suicide-related behavior were similar for drug and placebo. 10.2.1.1.2.6 Venlafaxine Venlafaxine, an antidepressant that inhibits reuptake of both serotonin and norepinephrine, has also been evaluated as a treatment for depressed youth. In 1997, Mandoki et al. published a trial involving 40 children and adolescents (aged 818), who received relatively low doses of venlafaxine (37.5 mg for children, 75 mg for adolescents) or placebo ; all subjects also received weekly therapy with cognitive and behavioral elements. After 6 weeks, substantial improvement was noted in all subjects ; however, there was no signicant dierence between the venlafaxine-treated subjects and those who received placebo. No serious adverse events were reported in the published paper ; however, one subject was hospitalized after developing mania (Mandoki et al., 1997). Emslie et al. conducted two RCTs of venlafaxine XR in a total of 334 subjects with depressive disorders aged 717 ; while unpublished, the results of these two trials were analyzed together and described in a recent review (Cheung et al., 2005). The combined analysis did not identify any signicant dierences between venlafaxine extended release (ER, XR) and placebo on the primary outcome variable of CDRS-R endpoint. Of note, when children (ages 711) and adolescent (ages 1217) subgroup analyses were conducted, there was a suggestion of ecacy in the adolescent group (Cheung et al., 2005). According to the CSM report, more treatment-discontinuing adverse events,

S91

including hostility and suicidality, were identied in the group treated with venlafaxine. 10.2.1.1.2.7 Mirtazapine Emslie et al. also conducted two RCTs of mirtazapine, a noradrenergic and specic serotonergic agent. These trials involved a total of 250 depressed youth (aged 717). While the results of these trials remain unpublished, a recent review indicates that no signicant CDRS-R dierences between mirtazapine and placebo conditions were noted at the end of either 8-week trial (Cheung et al., 2005). According to the CSM report, one mirtazapine-treated subject reported suicidal thoughts and one placebo-treated subject performed an act of self-mutilation. 10.2.1.1.2.8 Nefazodone Two RCTs of nefazodone, a serotonin-modulating antidepressant, were conducted by Emslie and colleagues. While neither study has been published, one trial involving 195 depressed 12- to 17-yearolds was described in a recent review (Cheung et al., 2005). In this study, benecial eects for nefazodone approached but did not achieve statistical signicance on CDRS-R primary outcome variables. No nefazodone-related serious adverse events occurred. The CSM report included no data regarding this medication. 10.2.1.1.2.9 Bupropion No RCTs have been conducted with this medication in child and adolescent populations. 10.2.1.1.2.10 V-3 fatty acids Benets of V-3 fatty acids have been shown in a 16-week-long RCT (Nemets et al., 2006). 10.2.1.2 Regulatory action by the UK and US In June 2003, after evaluating unpublished manufacturer data revealing increased suicidality associated with paroxetine, the UK Committee on Safety of Medicine (CSM) advised that paroxetine should not be used to treat depressed youth. The FDA quickly followed suit. In August 2003, the manufacturer of venlafaxine sent letters to doctors explaining that, due to lack of ecacy and potential for increases in suicidality and hostility, the drug should not be used for young people. By December 2003, the Medicines and Healthcare products Regulatory Agency (MHRA)

S92

CINP Antidepressant Task Force 2007 treatment of depression and anxiety disorders in children and adolescents. These compounds should generally not be used in this age group because clinical trials have shown an increased risk of suicidal behavior (European Medicines Agency, 2004). In June 2006, however, after further data reviews, the EMEA adopted a more favorable position towards uoxetine ; it recommended extending uoxetines indication to include children, 8 years of age or older who suer from moderate to severe depression and who do not respond to psychological therapy (European Medicines Agency, 2006) (EMEA website : http://www. emea.eu.int/). 10.2.1.3 Investigations of other sources of evidence Given the problems inherent in drawing conclusions about suicidality from studies not designed or powered for such a purpose (Emslie et al., 2005), several pharmaco-epidemiological and observational studies have been undertaken in order to further examine the link between newer antidepressants and suicide or suicidal behavior. 10.2.1.4 Antidepressants and completed suicides One frequently utilized pharmaco-epidemiologic technique involves investigating whether regional changes in rates of prescription of newer antidepressants correlate with changes in suicide rates. Several of these large, retrospective studies have been carried out (Gibbons et al., 2005 ; Gibbons et al., 2006 ; Hall et al., 2003 ; Helgason et al., 2004 ; Ludwig and Marcotte, 2005 ; Olfson et al., 2003 ; Olfson et al., 2006 ; Sondergard et al., 2006). An Australian study found substantially decreased rates of suicide in association with exposure to antidepressants, especially in older men and women, together with increased suicide rates in adolescents and young adults aged 1524 (Hall et al., 2003). More recent studies by Olfson and colleagues (Olfson et al., 2006), as well as a large FDA metaanalysis found a similar age-dependent pattern of antidepressant-associated suicide risk (US Food and Drug Administration, 2007). Other American and international studies indicate an inverse relationship between rates of SSRI prescriptions and rates of suicide in child and adolescent populations (Gibbons et al., 2005 ; Ludwig and Marcotte, 2005 ; Olfson et al., 2003). According to an analysis of WHO data performed by the American College of Neuropsychopharmacology (ACNP) Task Force on SSRIs and Suicidal Behavior in Youth, over the past 14 years the suicide rate for adolescents and young adults (aged 1524) has decreased by an average of 33 % across 15

warned against using all SSRIs, and the FDA urged extreme caution when using any newer antidepressant in pediatric populations (Leslie et al., 2005). Given their concern regarding treatment-emergent suicidality, the FDA conducted a review of independently coded safety data from 24 studies of nine of these antidepressants (uoxetine, sertraline, paroxetine, uvoxamine, citalopram, bupropion, venlafaxine, nefazodone and mirtazapine) in youth populations. Of note, these medications were prescribed in trials not only for depression but also for anxiety disorders and attention-decit hyperactivity disorder. It is important to note that, among the 4400 patients treated with SSRIs or other newer antidepressants in these studies, there were no completed suicides. However, when evaluated together, the risk of suicidality (dened as suicidal thinking and behavior) in the antidepressant trials was approximately twice that of placebo : 4 versus 2 %, respectively (risk ratio 1.95, 95 % CI 1.282.98), a nding that was supported by a recent re-analysis largely of the same studies (Wohlfarth et al., 2006). There was also a signicant eect for treatment-emergent agitation and hostility (Hammad, 2006). When the FDA restricted its analysis to trials of depressive disorders, statistically signicant dierences in suicidality and treatment-emergent agitation and hostility persisted (Hammad et al., 2006a ; see Table 23). Depressed youth treated with paroxetine were most likely to experience treatment-emergent agitation and hostility (relative risk 7.69, 95 % CI 1.8032.99). Those treated with venlafaxine XR were most likely to experience suicidality (relative risk 8.84, 95 % CI 1.1269.51). Based on the above analyses, the FDA concluded that a true risk may exist for some youth. As a result, in October 2004 the FDA issued a black box warning alerting health-care providers and consumers about an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents who are taking antidepressant medication (FDA Public Health Advisory, 2004) (FDA website). The FDA review panel included all antidepressants in its warning due to concern that limiting the black box to newer agents would encourage the use of older medications with narrower therapeutic windows and higher lethality in overdose (Gibbons et al., 2005) ; however, uoxetine remains FDA-approved for the treatment of depression in youth. In December 2004, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMEA) Scientic Committee similarly advised that newer antidepressants are not authorized Europe-wide for the

CINP Antidepressant Task Force 2007

Table 23. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents Suicide-related events Drug Nefazodone Citalopram Fluoxetine Mirtazapine Paroxetine Sertraline Venlafaxine XR Total Relative risk No events 1.37 1.53 1.58 2.15 2.16 8.84 1.66 95 % CI n.a. 0.533.50 0.743.16 0.0638.37 0.716.52 0.489.62 1.1269.51 1.022.68 Treatment-emergent agitation or hostility Relative risk 1.09 1.87 1.01* 0.52 7.69 2.92 2.86 1.79 95 % CI 0.532.25 0.3410.13 0.402.55 0.038.27 1.8032.99 0.3127.83 0.7810.44 1.162.76

S93

* FDA analysis of treatment-emergent hostility and agitation did not include data from the TADS study. Boldface=statistically signicant results.

countries (Mann et al., 2006a). While such analyses are imperfect and subject to the ecologic fallacy (Robinson, 1950), taken together, the reported studies show mixed evidence of increased suicidality or suicide rates among children and adolescents caused by SSRI use. In addition to pharmaco-epidemiologic studies, others groups have used post-mortem toxicological analyses as a means of investigating a link between completed youth suicide and antidepressant medications. Evidence from a large-scale Swedish study (Isacsson et al., 2005) and two smaller American studies (Moskos et al., 2005 ; Tardi et al., 2002) does not support an association between treating youth with antidepressants and subsequent completed suicide. 10.2.1.5 Antidepressants and suicidal behavior or non-fatal self-harm in depressed youth In addition to completed suicides, information is also available regarding suicidal behavior and non-fatal self-harm. Several retrospective studies have investigated this potential link through queries of large databases of patient information. The results of these studies are mixed. In 2004, Valuck et al. conducted a propensityadjusted cohort study to examine links between antidepressant treatment and suicide attempts in over 24000 adolescents (aged 1218) who were started on antidepressants after being newly diagnosed with depressive disorders. After adjusting for severity of symptoms, the researchers found that youth treated with SSRIs did not have statistically signicant increases in rates of suicide attempts when compared with youth treated with other or

multiple medications. Youth who continued treatment with any antidepressant for 6 months made signicantly fewer suicide attempts than those who remained on medication for less than 8 weeks. (Valuck et al., 2004). Martinez et al. conducted a nested case-control study comparing rates of fatal and non-fatal self-harm for over 146000 individuals in a large UK general practice database (Martinez et al., 2005). Identied cases were prescribed TCAs, SSRIs or other newer antidepressants for a depressive episode (unipolar or bipolar) or dysthymia. In the 6 months following index prescription, no suicides occurred in the 10- to 18-year-old cohort. However, compared with depressed youth treated with TCAs, depressed youth treated with SSRIs demonstrated weak evidence for increased rates of non-fatal self-harm (adjusted odds ratio 1.59, 95 % CI 1.012.50). Among the SSRIs evaluated, the greatest risk for non-fatal self-harm was associated with paroxetine. Jick and colleagues found a near-signicant signal for increased rates of selfharm in paroxetine-treated youth (aged 1019) in an earlier study of the same database (Jick et al., 2004). A potential criticism of these studies, but also of other naturalistic databases, is the mixed cohort of unipolar and bipolar patients. Antidepressants may induce switching into mania, which in adolescents is characteristically mixed in nature. Mixed episodes, however, are strongly associated with suicidal ideation (Dilsaver et al., 1994). In addition, the index episode in bipolar patients is characteristically depressive, and the age of onset of bipolar disorder is earlier than of unipolar disorder, leading to a potential overrepresentation of bipolar patients in such a cohort. Thus, the inclusion of bipolar adolescents may easily

S94

CINP Antidepressant Task Force 2007 conclude that the risk-benet prole is most favorable for uoxetine. Two of the studies suggest that the risk-benet prole of citalopram is also positive (Bridge et al., 2005 ; Wallace et al., 2006) ; one study suggests that the benets of sertraline may also outweigh its risks when used in treating depressed youth. In sum, the evidence about safety and ecacy of SSRIs is mixed. There is signicant evidence for the ecacy of uoextine in treating depressed adolescents. Fluoxetine is the only agent approved by regulatory agencies in the US, UK and Europe for use in depressed youth. Importantly, in the well-designed TADS study, uoextine was helpful in a group of moderate to severely depressed youth that were not signicantly helped by CBT (March et al, 2004). There is more limited evidence for the ecacy of sertraline, citalopram and escitalopram. Regarding safety, meta-analyses of RCTs suggest that SSRIs increase suicide ideation compared with placebo, but observational studies suggest that SSRIs do not increase suicide risk more than older antidepressants (Hall and Lucke, 2006). While there is no evidence of completed suicide from reported RCTs, compared with placebo, there is a higher incidence of self-harm and aggressive or impulsive actions, especially with paroxetine or venlafaxine treatment. Based on all of the preceding data, the following recommendations might be considered regarding diagnosis and treatment of youth with depressive disorders (see also Box 11). 10.2.1.7 Conclusion Although much is known about the eects of antidepressant medications in children and adolescents, research is needed to further improve our ability to treat depressed youth. In adolescents, high placebo response rates have been reported, but there is reasonable evidence for the eectiveness of uoxetine. Apart from V-3 fatty acids, there is no substantial evidence that antidepressant medication is useful in prepubertal children. The current evidence for prepubertal ecacy of antidepressants is not robust : the older postpubertal adolescents were in clinical trials, the more likely was the response to antidepressants. In addition, several questions regarding the safety of newer antidepressants remain. Regarding ecacy, more information is needed to determine which children and adolescents respond to which treatments. Current treatment studies have been characterized by high placebo response rates and suboptimal response rates. Important questions

confound the results, making conclusions regarding the risk of suicidal ideation in unipolar depressed patients problematic (Berk and Dodd, 2005a ; Berk and Dodd, 2005b). In a recent meta-analysis by Dubicka et al. (Dubicka et al., 2006) the pooled risk of self-harm and suicidal behavior from randomized trials of newer antidepressants was determined. Self-harm or suiciderelated events occurred in 71 of 1487 (4.8 %) of depressed youths treated with antidepressants versus 38 of 1254 (3.0 %) of those given placebo (xed-eect odds ratio 1.70, 95 % CI 1.132.54, p=0.01). There was a trend for individual suicidal thoughts, attempts and self-harm to occur more often in youth taking antidepressants than in those given placebo, but none of these dierences was statistically signicant. In a separate study, Simon and colleagues used a large American database to retrospectively analyze over 82000 index episodes of antidepressant treatment, 5107 of which involved youth aged 518 (Simon et al., 2006). Six months after the diagnosis of depressive disorders (coded as ICD-9 MDD, Dysthymia or Depressive Disorder NOS) and after initiating antidepressants, 3 youth and 28 adults completed suicide. Like Jick and colleagues, Simon and colleagues found a signicantly higher rate of suicide attempts in the rst week of treatment compared with subsequent weeks. However, when compared across the entire sample, there was no statistically signicant increased risk of completing suicide the rst month of treatment compared with subsequent months. Additionally, rates of serious suicide attempts, captured from 3 months before to 6 months after index antidepressant prescription, were highest in the month before antidepressants were initiated. When the newer antidepressants included in the FDA review were compared with older antidepressants not evaluated by the FDA, this decrease in suicide attempts in the month after treatment initiation was seen only with newer antidepressants. The authors state that these dierences may reect a more timely therapeutic eect of newer agents. 10.2.1.6 The use of antidepressants, and their risks and benets Several recent studies have used a meta-analysis to compare the risks and benets of individual antidepressant agents that have been subject to randomized clinical trials in depressed youth (Bridge et al., 2005 ; Wallace et al., 2006 ; Whittington et al., 2004). The authors of each of these studies

CINP Antidepressant Task Force 2007

Box 11. Useful clinical practice in the treatment of children and adolescents (and adults)
$

S95

Carefully diagnosis the patient. Comorbidities or alternate diagnoses such as bipolar disorder may aect both the safety and ecacy of drug treatment. Dierentiate between depressive disorder and depressive distress in teenagers (for screening purposes, the symptoms hopelessness, anhedonia and suicidality are the most important). After careful diagnosis, discuss the risks and benets of treatment with antidepressants and/or psychotherapy. The discussion should involve the parent(s) or guardian(s) and, whenever appropriate, the patient. The conversation should reect both the treatment-associated risks as well as the risk of untreated depression. Be aware of the better evidence for the use of medication combined with psychotherapy. If depressive symptoms are mild or if the current episode is of new or recent onset, consider a period of intensive psychosocial therapy, support and monitoring. Given the episodic nature of depression and the turbulence of youth, particularly adolescence, some depressive episodes may respond to psychotherapy, simple supportive interventions or may even remit spontaneously. However, even if symptoms remit, patients should be considered at risk for future depressive episodes and receive regular monitoring. If symptoms worsen or persist for 68 weeks, an evidence-based treatment with medication and/or a specic psychotherapy should also be initiated if only support has been oered up to that point.60 Educate the patient and family61 about what to expect from drug treatment. It is important to let them know that they may experience a drugs side eects before they experience the benets. Provide them with information about irritability, akathisia, agitation and mania, and encourage them to call with questions. The Parents Med Guide is one useful resource available on the World Wide Web (www.parentsmedguide.org) in English and Spanish. A measurement of side eects and symptoms of depression, including suicidality, using rating scales is useful. Develop a safety plan with the patient and the responsible adult. Both the child and parent/guardian should have numbers for the doctor/clinic as well as a plan for accessing emergency services. If the patient is experiencing suicidal ideation but outpatient treatment is appropriate, provide only limited amounts of medication. When initiating medication, start low and monitor carefully. Based on current evidence, uoxetine is the only drug approved for clinical use and should be used as a rst line agent. It is recommended that psychotherapy be coadministered whenever possible. While starting low, children may be able to tolerate and sometimes require doses similar to those for adults. Monitoring must be tailored to t individual clinical situations. The FDA recommends the monitoring schedule listed below, which was also used in the TADS study. Particularly in the initial weeks, in addition to monitoring for suicidality, patients and families should be asked about medication compliance and changes in behavior.
# # #

Every week for the rst 4 weeks Every other week for the next 4 weeks After 12 weeks, then as necessary

If the patient responds, treatment should continue. Continuation treatment for 36 months after remission helps reduce rates of relapse. If children or adolescents have suered previously from episodes of depression, a maintenance phase of 13 years should be strongly considered. If a medication discontinuation trial is desired after a period of sustained remission, it should be well-planned, slowly conducted and carefully monitored. If the patient does not respond, re-evaluate the diagnosis before moving on to an alternative drug strategy. If the diagnosis is conrmed, consider a trial of a dierent medication.

regarding the eects of early intervention and longterm treatment in both children and adolescents also remain. The debate over the safety of these medications will also continue. If the risk is determined to be real, investigators must identify an etiology of self-harm and suicidal behavior, and conclude whether these

behaviors can be predicted and neutralized. Given the known morbidity and mortality associated with untreated depression, all risks of treatment must be balanced against the risk of withholding treatment. Regardless of treatment status, all depressed children and adolescents will require psychoeducation and careful monitoring. 10.2.2 Antidepressant treatment in old age

The suggestions given are based more on clinical experience than on evidence-based medicine. 61 In countries where rearms are widely available, parents should be encouraged to remove rearms or other dangerous equipment from the house.

60

10.2.2.1 General clinical considerations The prevalence of depression appears to be independent of age (Patten et al., 2001 ; Steens et al., 2000),

S96

CINP Antidepressant Task Force 2007 to the side eects of antidepressants, particularly cardiovascular side eects and treatment-related cognitive dysfunction (Moskowitz and Burns, 1986). Suboptimal regimes in 43.3 % of elderly patients treated with antidepressants have been reported. These include both potentially hazardous (e.g. due to high-dose treatment with anticholinergic agents) as well as excessively low intensity and insucient treatments (Wang et al., 2005). It may also be important to distinguish between young-old (aged <75 years) and old-old (aged >75 years). Both groups show marked dierences in comorbidity (e.g. dementia), lifestyle and rates of institutional care. However, in most antidepressant trials this distinction has not been made, and patient samples in previous studies are usually heterogeneous and termed elderly, geriatric, senile or older adults, aged 55 or over (Mottram et al., 2006). 10.2.2.2 Ecacy of antidepressants in old age Numerous randomized controlled trials of antidepressant treatment in late-life depression have been conducted, including all substance classes. The rst question is whether antidepressant pharmacotherapy is eective at all in elderly patients, i.e. whether it shows therapeutic ecacy superior to placebo treatment. Roose and Schatzberg (2005) recently reviewed ve placebo-controlled trials that were selected based on quality criteria in order to assess antidepressant ecacy and eectiveness. Useful data on TCAs are very limited because previous studies have often involved inadequate dosages of TCAs (e.g. imipramine and amitriptyline), which are not recommended for the use in elderly patients (Mamdani et al., 2000). Thus, four of these randomized controlled trials (Rapaport et al., 2003 ; Roose et al., 2004 ; Schneider et al., 2003 ; Tollefson et al., 1995) compared dierent SSRIs (uoxetine, sertraline, citalopram, paroxetine), and one trial compared uoxetine and venlafaxine with placebo (Schatzberg et al., 2002). Three studies demonstrated a statistically signicant dierence in drug versus placebo response or remission rates (Rapaport et al., 2003 ; Schneider et al., 2003 ; Tollefson et al., 1995). The percentage of trials failing to show a signicant dierence between verum and placebo groups resembles results of non-geriatric trials, where medication is found to be more eective than placebo less than 50 % of the time. In 1999, among other general medical principles, the World Psychiatric Association (WPA) recommended treating depressive symptoms in the elderly with the aim of complete remission. A more recent guideline of a

but a high rate of depressive symptoms requiring treatment (Chopra et al., 2005) in old age has been reported. In clinical work, prevalence rates may be articially low owing to standardized diagnostic assessment procedures that are insuciently adapted for use in the elderly (Wittchen et al., 1994). Underdetection of subthreshold depression, which shows a high prevalence in the old age (Horowitz et al., 2005), may be one explanation. The diagnosis of depression may thus be relatively rare in elderly patients, whereas subthreshold depression, which according to the Diagnostic and Statistical Manual of Mental Disorders, 4th revision (DSM-IV), and the International Statistical Classication of Diseases and Related Health Problems, 10th revision (ICD-10), also requires antidepressant treatment, may frequently be present. However, epidemiological data show that the prevalence of depression in old age is in fact high, is often underdiagnosed and undertreated, has a high rate of recurrence and is associated with signicantly increased mortality (Katona, 1994). Because the prevalence of suicidal ideation is also relatively high in the old age, eective suicide prevention is especially needed for this age group (Pfa and Almeida, 2005 ; Raue et al., 2007). In addition, older patients experience more and longer major depressive episodestogether with increased general medical comorbidities (Husain et al., 2005). Considerable comorbidity exists with dementia, stroke and Parkinsons disease, where patients often suer from depressive symptoms. The response to antidepressant treatment in the elderly apparently does not dier from treatment response in younger patients. However, relapse rates are higher, and the longitudinal outcome is less favorable than for middle age (Mitchell and Subramaniam, 2005). Very few longitudinal studies follow the course of depressive illness in elderly people. The meta-analysis of data from 12 studies in primary care and in community secondary care showed that after 2 years, 21 % of elderly depressed patients who were at least partially diagnosed and treated by primary care physicians had died. Among survivors, almost half remained depressed (Cole et al., 1999). Moreover, inadequate training in geriatrics may worsen this situation (Bartels et al., 2003), whereas elderly patients who receive adequate antidepressant treatment experience signicantly better physical functioning (Callahan et al., 2005). The more adverse longitudinal course in old age may more plausibly be explained by medical comorbidity (see also chapter 5.2.4), immobility and psychosocial factors than by age itself (Mitchell and Subramaniam, 2005). It is also generally accepted that elderly depressed patients are particularly prone

CINP Antidepressant Task Force 2007 working group of the Royal College of Psychiatrists from the UK (Baldwin et al., 2003) also supported the ecacy of antidepressant drugs in elderly patients based on a previous Cochrane review (Wilson et al., 2001) and further meta-analyses (Gerson et al., 1999 ; McCusker et al., 1998 ; Mittmann et al., 1997). In contrast, little is known about augmentation strategies in elderly patients who have shown only modest improvement during previous treatment trials (Baldwin et al., 2003). Another question is whether one class of antidepressants is more favorable in old age than others. Roose and Schatzberg (Roose and Schatzberg, 2005) selected six trials that compared at least two dierent antidepressants for further critical review. All randomized controlled trials in this review were comparison trials of two SSRIs or one SSRI compared with a TCA or mirtazapine (Bondare et al., 2000 ; Navarro et al., 2001 ; Newhouse et al., 2000 ; Roose et al., 2004 ; Schatzberg et al., 2002). The response rates in these comparison trials were consistently higher than those seen with the same agents in placebo-controlled trials (5073 % vs. 3572 %) and may better reect the eectiveness of medication in a clinical setting (Roose and Schatzberg, 2005). These trials did not demonstrate that one antidepressant is superior to another ; nevertheless, some experts recommend the low-dose use of TCAs in the treatment of elderly patients. In a very recent Cochrane analysis (Mottram et al., 2006), 29 out of 163 identied trials were selected for further analysis, and 14 studies were selected for contributing ecacy data. Trials entering the meta-analysis of ecacy had to compare at least two active antidepressant drugs, because the meta-analysis aimed at comparing the ecacy of antidepressant classes, withdrawal rates and side-eect proles in elderly patients. The trial duration varied between 4 and 8 weeks, and only 2 trials (comparison of moclobemide with imipramine and tianeptine) were conducted over 12 weeks or more (Dunningham et al., 1994). No signicant dierences in ecacy were found between classes of antidepressants (TCAs, TCA-related drugs, SSRIs, MAOIs and atypical antidepressants). However, the trials contained relatively small numbers of patients, possibly introducing a large type-2 error, which may explain the negative nding. Higher numbers of patients withdrawn irrespective of reason or due to side eects were observed during treatment with TCAs compared with SSRIs. Electroconvulsive therapy (ECT) has also been shown to exert excellent eectiveness, which was better in younger than in older geriatric patients (Abrams, 2002 ; Greenberg and Fink, 1992 ; Oshima

S97

and Higuchi, 1999). Despite specic side eects, such as greater cognitive impairment, ecacy is greater in older than in younger patients, and reduced mortality in comparison with other treatments has been shown (Philibert et al., 1995). Further progress in understanding ECT and anesthesia has reduced the risks of of the treatment. Some authors currently are therefore of the opinion that there are no absolute medical contraindications to the use of modied ECT which is encouraged now also in geriatric patients and in patients at particular medical risk (Abrams, 2002 ; Fink, 1999). There is a broad clinical consensus that it is appropriate to include both antidepressant medication, specically SSRIs, and nonpharmacological modalities in treatment plans for severe depression in the elderly (Alexopoulos et al., 2001). 10.2.2.3 Tolerability in elderly patients The recent Cochrane analysis (Mottram et al., 2006) of side eects showed a small increased risk of gastrointestinal (including the experience of dry mouth ) and neuropsychiatric side eects (drowsiness, dizziness, lethargy) associated with classical TCAs. However, further conclusions regarding the comparison of other classes of substances have not been possible due to the methodological limitation mentioned above. Thus, only the pharmacological proles of specic drugs and their interactions with medical comorbidity and concomitant medication can determine the choice of antidepressants in elderly patients. In primary care, newer drugs that provide a superior safety prole, such as SSRIs, are gradually replacing TCAs as a rstline treatment (Gareri et al., 1998 ; Mamdani et al., 2000). Moreover, geriatric patients are more susceptible to side eects such as orthostatic hypotension and sedation. Cognitive disturbances, too, and even delirious states induced by the anticholinergic action of various antidepressants, e.g. TCAs, are more frequent. Elderly patients are at especially high risk for adverse drug reactions and drug-drug interactions (see also chapter 9.1.1.1.5) due to multimedications (Borchelt, 1995). Some side eects that raise particular concerns in younger patients, such as weight gain due to antihistaminergic eects, may be benecial for elderly patients, who often suer from anorexia and weight loss. In existing medical comorbidity, which may complicate the management of late-life depression, particular care should be paid in choosing an antidepressant. According to the guidelines from the UK (Baldwin et al., 2003), SSRIs should be preferred for depression that complicates vascular and

S98

CINP Antidepressant Task Force 2007 Robins, 1970) published a meta-analysis of studies putting a lifetime suicide risk at 15 %. This frequently quoted gure may overestimate the suicide risk, as it generalizes from high-risk hospitalized patients to all depressed patients (Boardman and Healy, 2001). Suicide rates in depressed patients in longer (>10 years) follow-up studies range from 4 % to 10.6 % (Angst et al., 2005). A meta-analysis of 27 mortality studies by Inskip (Inskip et al., 1998) using contemporary data and modern analytic techniques led to an estimate of a lifetime suicide risk of 6 % for aective disorders. Recently, Bostwick and Pankratz (Bostwick and Pankratz, 2000) found a hierarchy of lifetime suicide prevalences : 8.6 % in people ever admitted for suicidality, 4 % in patients admitted with aective disorder but not specically for suicidality, and 2.2 % in mixed inpatient and outpatient populations. Diagnostic uncertainties may also obscure accurate estimates of suicide rates for unipolar depression. A meta-analysis by Harris and Barraclough (1998) found a standard mortality ratio (SMR) of 21.24 for major depressive disorder that even exceeded the one calculated for bipolar patients. Osby et al. identied all patients with a hospital diagnosis of bipolar (n=15386) or unipolar (n=39182) disorder in Sweden from 1973 to 1995 from the inpatient register and linked with the national cause-of-death register to determine the date and cause of death. The SMRs for suicide were 15.0 for males and 22.4 for females with bipolar disorder, and 20.9 and 27.0, respectively, for unipolar disorder (Osby et al., 2001). A more precise estimate of suicide mortality may be dicult due to methodological shortcomings, as outlined by Jules Angst and colleagues (Angst et al., 2005).
$

cerebrovascular disease, mainly because of safety and tolerability. In dementia, TCAs, SSRIs and moclobemide are eective ; however, newer drugs are better tolerated and safer. For Parkinsons disease no adequate trial data are available. SSRIs may aggravate parkinsonian symptoms, but this nding has not been established (Baldwin et al., 2003). 10.2.2.4 Dosage and duration of antidepressant treatment in old age Comorbid medical conditions and concomitant medications require particular attention to pharmacodynamic and pharmacokinetic interactions. Even if no other medical disturbances are present, normal aging leads to dierences in hepatic and renal function that require extraordinary awareness. Because of reduced hepatic metabolism and renal elimination rate in the elderly, appropriate dosages are lower than in younger patients (Chiu, 1997). In frail patients treatment should commence with a slow dosage and titrate gradually to the therapeutic dosage range ( start low and go slow ). Moreover, the guidelines of the American Psychiatric Association (APA) emphasize that elderly patients typically require a lower dosage than younger patients to reach a particular blood level and tolerate a given blood level less well. However, the blood levels at which antidepressant medications are maximally eective appear to be the same as for younger patients (American Psychiatric Association, 2000 ; Wilson et al., 2001). Another critical issue is the duration of treatment in old age. Older patients apparently take longer to recover from depression and recovery goes on up to 12 weeks, provided that there has been some early improvement (Wilson et al., 2001). Currently at least 6 weeks of treatment is recommended to achieve optimal therapeutic eects (Wilson et al., 2001). However, little response (e.g. less than 25 % recovery) during the rst 4 weeks of the same treatment is associated with a low probability of remission (Mottram et al., 2006). Similar to younger patients, following remission, antidepressant medication should be continued at the same dose for at least 6 months in the case of initial episodes and longer in the case of recurrent illness, as described in Table 9 (Geddes et al., 2003). 11 Suicidality and antidepressants : depression and suicide About two-thirds of people committing suicide suer from depression. In 1970, Guze and Robins (Guze and

$ $

The most severely ill, hospitalized patient samples are selected, and these are not representative. Lifelong follow-up studies are lacking. The diagnoses in representative suicide samples are retrospective. In order to compensate for the lack of decades-long follow-up studies, risk estimates are based on exposure years that assume an unproven time-related linear risk. Perhaps the most signicant methodological problem : bipolar disorder and unipolar depression arising from an under-diagnosis of hypomania leading to an underestimate of bipolar II disorder.

The most denitive prospective, long-term, large cohort study on suicide risk in aective disorders may be that conducted by Angst et al. who followed up 406 patients with mood disorder from 1963 to

CINP Antidepressant Task Force 2007 2003 (Angst et al., 2005). By 2003, 11.1 % of these patients had committed suicide, with the highest SMR being 26.4 for unipolar depressed patients. These data underscore the prominent role of early diagnosis and treatment of depression in suicide prevention. Early diagnosis and public awareness have been proven to be eective tools in reducing suicide attempts and completed suicides in large, populationbased studies. This nding was rst demonstrated in a prospective, community-based trial in Gotland, Sweden (Rihmer et al., 1995 ; Rutz et al., 1989). The results were replicated recently (Henriksson and Isacsson, 2006) and seem also to hold true for larger, urban communities. For example, the Nurnberger Bundnis gegen Depression (Nuremberg Alliance against Depression) is a community-based, multifaceted, 2-year intervention that focuses on depression. The number of suicidal acts (fatal and non-fatal suicide attempts) showed a signicant and clinically relevant reduction compared with both a 1-year baseline and a control region (minus 24 %) (Althaus et al., 2006 ; Hegerl et al., 2006). Patients with a history of suicidal behavior suer from a greater burden of depressive illness (Claassen et al., 2006). As demonstrated by Balazs et al. (2006), the presence of such clinical features as irritability, distractibility and psychomotor agitation ( mixed depression as quoted by the authors) are, besides hopelessness (Goldston et al., 2006 ; MacLeod et al., 2005), strong predictors of suicide attempts even in patients who do not otherwise fulll diagnostic criteria for bipolar disorder. On the basis of these ndings, Rihmer and Akiskal (2006) speculated that in these patients the use of antidepressants without concomitant mood stabilizers may exacerbate a preexisting mixed state or generate de novo mixed syndromes, resulting in treatment resistance as well as a worsening of depression that ultimately may provoke suicidal behavior. In the context of this review, it may be appropriate to recommend that special caution should be exercised in patients with the symptoms of hopelessness, irritability, distractibility and agitation who are prescribed an SSRI, since agitation occurs statistically signicantly more frequently with SSRIs than with other antidepressants, e.g. TCAs. In the future, we may be even able to identify patients on riks for suicidal behaviour on a gentic basis ; a recent report demonstrated that markers within GRIK2 and GRIA3 are associated with treatment-emergent suicidal ideation during citalopram therapy (Laje et al., 2007). Dierent claims about the use of antidepressants, especially selective serotonin reuptake inhibitors

S99

(SSRIs), and suicidality have been proposed. Antidepressants may decrease suicide rates on a population basis (Ludwig and Marcotte, 2005), but at the same time they may increase suicidality (or even suicide events) in some individuals early in treatment (Healy and Whitaker, 2003). Recent reviews by Hall and Lucke (2006) and Moller (2006a, b), show some sup portive evidence for both views. A study by Yerevanian et al. (2004) demonstrated that long-term treatment with antidepressants (SSRIs and tricyclic antidepressants (TCAs)), sometimes in combination with benzodiazepines, signicantly reduces the risk of both completed and attempted suicide in more than 500 patients with major depression and dysthymic disorder. In addition, a multitude of epidemiological studies have demonstrated reduction of suicidality in regional populations in association with antidepressant prescription (Carlsten et al., 2001 ; Hall et al., 2003 ; Isacsson et al., 1997 ; Isacsson, 2000 ; Ohberg et al., 1998 ; Rihmer et al., 2000) ; for a short overview see (Hall and Lucke, 2006 ; Isacsson and Rich, 2005 ; Yerevanian et al., 2004). Investigating the suicide mortality of the 27 countries with data on annual sales of all SSRIs (and, of course, also other antidepressants) between 1980 and 2000, Ludwig and Marcotte (2005) found that after controlling for a variety of sociodemographic factors, an increase of one SSRI pill per capita in 2000 (a 13 % increase over 1999 levels) was associated with a signicant, 2.5 % reduction in suicide rates in adults. As pointed out by Rihmer and Akiskal (2006), this eect is most prominent in countries with previous high suicide rates and low rates of treated depression, and can be separated from other covariables such as alcohol consumption or unemployment rates. In Iceland (population 286000) the relatively low suicide rate (around 30 suicides per year) was not decreased despite a huge increase in the use of antidepressants (Helgason et al., 2004). When not properly conducted, however, open studies and population-based studies can easily be subject to several biases and errors in interpreting results (Moller, 2006a). It should also not be neglected that some of the recent epidemiological studies arose in response to the concerns of regulatory agencies of potential increased suicidality with antidepressants, and due to their largely uncontrolled nature, there is clearly room for an investigator bias. Randomized, control group studies, especially when placebo controlled, seem to be the best basis for statements about the suicide risk of certain antidepressants. But because suicide is, fortunately, a rare outcome in controlled studies, it cannot be reliably assessed. To improve the number of subjects and statistical power, pooled data

S100

CINP Antidepressant Task Force 2007 These limitations must be kept in mind when assessing suicidal behavior in controlled studies, both in those studies detecting a signal and those that do not. A secondary analysis by Moller of a 6-week double-blind controlled study comparing paroxetine and amitriptyline showed a marked reduction in suicidal thoughts for both medications (Moller et al., 1998). Similarly, Szanto (Szanto et al., 2003) demonstrated complete remission of suicidal ideation in elderly depressed patients after 12 weeks of either amitriptyline or paroxetine treatment. A review of data from several controlled studies by Moller (Moller, 2003) also demonstrated a greater benet of SSRIs compared with placebo in reducing suicidal ideation. But there is also conicting evidence. Concerns started in 1990 with the observation of intense suicidal preoccupation during uoxetine treatment in six patients. (Teicher et al., 1990), obviously contrasting neurobiological ndings of decreased central serotonergic neurotransmission in suicide victims (Asberg, 1976). By the end of 1991, at least four other publications appeared, expressing concerns about the emergence of intense suicidality with uoxetine. A reanalysis of the rst survey on this topic, conducted by Fava and Rosenbaum (1991) suggested that the emergence of suicidality was about three times more likely with uoxetine than with other antidepressants (ACNP, 1992). More recently Healey and Whitaker (2003) have argued that there is an increased risk of suicidal behavior in controlled trials, although the risk is relatively rare. In the Healey meta-analysis, this risk seemed to be especially increased in juveniles and adolescents as discussed previously in this review (see chapter 10.2.1). This report raised considerable public attention, especially in Great Britain and the US. To clarify this issue, the US Food and Drug Administration (FDA) commissioned an independent group of investigators at Columbia University to review all adverse events that suggested suicidal activity in controlled trials of SSRIs in children and adolescents. In 4400 depressed children and adolescents in a total of 24 studies, there were no completed suicides ; however, the risk of suicidal ideation or activity was 4 % on active medication and 2 % on placebo (US Food and Drug Administration, 2005). The exact signicance of this nding is not clear, and the FDA did not make any conclusions regarding causality. In addition, the methodological basis of the consecutive FDA black box warning (FDA Public Health Advisory, 2004) for marketed antidepressants about the use of these agents in younger patients raises questions, as outlined by Klein (2006).

subjected to meta-analysis have been used (for the general methodological problems of using metaanalyses, please refer to chapter 4.4). To date, the largest database from randomized controlled trials (RCTs) is one assessed by Hammad et al. (Hammad et al., 2006b). They evaluated the rate of suicide in placebo- and active drug-treated groups of patients with major depression and various anxiety disorders participating in short-term RCTs. Data were available for 207 trials conducted in patients with major depressive disorder (MDD), including a total of 40028 patients, and 44 trials conducted in patients with various anxiety disorders, including a total of 10972 patients. The use of neither placebo nor antidepressants in short-term RCTs was associated with an increased risk of completed suicide among patients with MDD or various anxiety disorders. Nonetheless, as the authors conclude, because of the small numbers of suicides in these trials and the subsequent lack of statistical power, an increased risk of completed suicide in association with either drug or placebo treatment cannot be denitively excluded. Thus, we can only assess other parameters that are more frequent and are linked to suicide with various degrees of certainty (and, of course, uncertainty ; Klein, 2006). Even when softening the outcome criterion towards suicidality , not completed suicide, the results of such control group studies also have to be viewed critically and considering the methodological pitfalls inherent in the design of such studies. The low basal prevalence of suicidal behavior has the consequence that, for principal statistical reasons, it is almost impossible to perform a control group study with adequate statistical power to dierentiate between the outcome results of two treatment groups, as the number of these events in a medium-sized or even a large control group study is small. This drawback could possibly be overcome by an enriched sample design ; however, most of the respective control group studies on antidepressants do not deal with samples in which the symptom suicidality/suicidal thoughts is enriched. Indeed, the opposite is true : most studies exclude at least patients with serious suicidal thoughts. The principal ethical aim, i.e. to avoid harm to the patients, conicts with the scientic objective of such studies. Thus the ideal control group design to answer the question whether antidepressants reduce suicidality cannot be realized for ethical reasons. The consequence of this dilemma might be that any indications of ecacy do not reach statistical signicance and, in addition, are far removed from actual ecacy in real-life conditions (Moller, 2006a).

CINP Antidepressant Task Force 2007 A nding similar to the FDA warning was also reported by a recent meta-analysis of 702 randomized controlled trials including more than 87000 depressive and other psychiatric patients, primarily adult patients. In this analysis Fergusson62 et al. (2005) showed a signicantly increased risk of suicide attempts (OR, 2.28), but not of completed suicides in patients taking SSRIs compared with placebo. In the pooled analysis of SSRIs versus TCAs, no dierence was detected in the odds ratio of suicide attempts. This contrasts with another meta-analysis by Gunnell et al. (2005) of 277 randomized controlled trials of SSRIs compared with placebo in 40000 adult patients submitted by pharmaceutical companies to the safety review of the Medicines and Healthcare products Regulatory Agency (MHRA). The authors found no evidence that SSRIs increase the risk of suicide. As a consequence of the conicting results in adults, the FDA recently asked manufacturers to review their adult databases on suicidal behavior in controlled antidepressant trials. In response to the FDA request, the rst metaanalyses of the specic suicide risk of newer antidepressants are now available. Acharya et al. (2006) evaluated all completed duloxetine trials in major depression until February 2004. The researchers compared the incidence of suicide-related events with duloxetine versus placebo in controlled trials, using the Mantel-Haenszel incidence dierence (MHID) and exposure time-adjusted rate dierence (MHRD) methods, and analyzed changes in HAMD Item-3 (suicidality) scores. The planned primary metaanalysis of dierences in incidence (MHID) of suicidal behaviors during randomized treatment with duloxetine versus placebo did not indicate an association of risk with treatment. Analyses using MHRD methods and outcomes (completed suicide, non-fatal suicide attempt and suicidal ideation) also failed to show either increased or decreased risk of suicidal events in association with duloxetine treatment. Changes in HAMD Item-3 suicidality scores showed more improvement with duloxetine (MHID 9.56 %, 95 % CI 4.5014.6, p<0.001) and less worsening of suicidal ideation with duloxetine (MHID 4.25 %, 95 % CI 6.55 to 1.95, p<0.001). Cheung et al. have argued that extrapolating data on antidepressants from adults to

S101

62

In a series of workshops on problematic papers, the Canadian Network for Mood and Anxiety Treatments (CANMAT) criticized the lack of heterogeneity analysis before including studies in patients whose diagnoses were unspecied. In addition, small dierences in the numbers of rare events such as suicides may lead to misinterpretation of study results.

adolescents is questionable (Cheung et al., 2006), but the same is true in the opposite direction. Thus, modeling of potential excess suicides in adults from data generated in adolescents, as done, for example, by Gunnell and Ashby (2004), is highly questionable, especially with more data now available of studies in adult populations. Following up on FDA warnings, Simon et al. (2006) analyzed computerized health plan records from a total of 82285 episodes of antidepressant treatment between 1 January 1992 and 30 June 2003. Identifying death by suicide and serious suicide attempts, they found that the risk of suicide attempts was highest in the months before starting antidepressant treatment and declined progressively after starting medication. It was not signicantly higher in the months after starting medication than in subsequent months. Comparing the 10 newer antidepressants included in the FDA black box warning with older antidepressants revealed that an increase in the risk of suicide was even more likely with the older drugs than with the newer antidepressants. In addition, a recent combined analysis of all placebocontrolled depression and anxiety studies with escitalopram found no signal for increased suicide risk with active medication treatment. On the contrary, suicidal ideation as measured with item 10 of the MADRS became signicantly lower from week 1 onwards with active treatment (Pedersen, 2005). Other important arguments against increased suicide rates with SSRIs are provided by epidemiological and toxicological studies. A controlled toxicological analysis of all suicide victims from 1992 to 1999 in Sweden showed that SSRIs were underrepresented compared with other antidepressants and that in suicide victims under the age of 15 (n=52), dierent antidepressants (but no SSRIs) were detected in seven cases (Isacsson et al., 2005). In a study of the UK General Practice Research Database, Jick et al. found no suicides at all in 6976 depressed patients, 1019 years old, who were prescribed antidepressants. Indeed, over this entire age group the database revealed 15 suicides, none of whom had been treated with antidepressants (Jick et al., 2004). Grunebaum et al. (2004) presented the results of a methodologically very sound analysis of US-American data for the years 19851999 that also took into account unemployment and alcohol consumption as confounding factors in a multivariate approach. The relationships between the suicide, antidepressant prescription, unemployment and alcoholic beverage consumption rates were studied using generalized linear models. Suicide rates by antidepressant overdose were compared in SSRIs and TCAs. From 1985 to

S102

CINP Antidepressant Task Force 2007 suicidal ideation and suicide attempts during the early phases of treatment, possibly because they cause agitation and activation particularly at that time. During these early phases, doctors should plan frequent follow-up visits and also consider a possible supporting role for family members and caregivers. In addition, doctors should give patients a realistic view about the time to onset of improvement ; overoptimistic expectations of patients and doctors may result in disappointment and consequently hopelessness and suicidality. Besides antidepressants, other medications, including lithium and antipsychotics, may also signicantly reduce suicides in patients with mood disorder, as demonstrated by a meta-analysis of Baldessarini et al. (2003) and a recent study of Angst et al. (2005). In the analysis of data of the Zurich cohort study by Angst, long-term medication treatment with antidepressants alone or with a neuroleptic, or with lithium in combination with antidepressants and/or neuroleptics, signicantly lowered suicide rates even though the subjects treated were more severely ill than those without medication. Weighing risks against the benets of antidepressants, it also has been argued that overdosing of antidepressants is potentially lethal, and thus it may be risky to supply a depressed patient with a potential means of suicide. Yet newer antidepressants especially show a large safety margin that makes lethal intoxication dicult, and several studies have shown that prescription medication is not commonly used as a means of suicide (Bradvik and Berglund, 2005 ; Henriksson et al., 2001 ; Isacsson et al., 1997). In addition, it has been demonstrated that, with the introduction of the newer antidepressants and the decreased use of older tricyclics, the rate of fatal toxicities of antidepressants has declined (Morgan et al., 2004). In summary, data on increased suicidal behaviors from randomized controlled studies are conicting, but the overwhelming evidence from epidemiological studies is in favor of reduced suicide rates with antidepressant treatment. Concerning the risk of using prescribed antidepressants as a suicide tool, the risk of lethal intoxication with antidepressants, although already rare, still declines with the replacement of the classical antidepressants by newer agents. It appears more evident that antidepressants are valuable tools in preventing suicides in depression (Goldney, 2006) instead of provoking it ; and summarized on the basis of the available evidence, any increased risk of suicide that antidepressants may produce in a subset of (mostly adolescent) depressed patients appears to be

1999, the suicide rate fell 13.5 %, with a greater decline among women, and antidepressant prescription rates increased over fourfold, with the increase mostly due to SSRIs. Prescription rates for SSRIs and other second-generation antidepressants were both inversely associated with suicide rates (p=0.03 and p=0.02, respectively). In a multivariable analysis adjusting for unemployment and alcoholic beverage consumption rates, SSRI antidepressant prescription rates remained inversely associated with the national suicide rate (p=0.03). A similar analysis of suicide data from the US performed by Gibbons et al. (2005) obtained somewhat more dierentiated results. This study focused on the years 19961998 and categorized the national county-level suicide rates according to age, sex, income, race and antidepressant prescription rates (expressed as number of pills prescribed). The overall relationship between antidepressant medication prescription and suicide rate was not signicant. Within individual classes of antidepressants, prescriptions for SSRIs and other new-generation non-SSRI antidepressants (e.g. nefazodone hydrochloride, mirtazapine, bupropion hydrochloride and venlafaxine hydrochloride) were associated with lower suicide rates (both within and between counties). A positive association between TCA prescription and suicide rates was observed, i.e. higher TCA prescription rates were associated with a higher suicide risk (which may be partially due to the higher toxicity of TCAs when taken with suicidal intent). Results were adjusted for age, sex, race, income and county-to-county variability in suicide rates. Higher suicide rates in rural areas were associated with fewer antidepressant prescriptions, lower income and relatively more prescriptions for TCAs. It should be noted that the authors also report similar results in favor of SSRI prescription in adolescents in a consecutive paper (Gibbons et al., 2006). Thus, on the basis of the cited and additional studies and meta-analyses (Fergusson et al., 2005 ; Martinez et al., 2005) Cipriani et al. (2005a) concluded for depression in adults (not in children!) that taking into account these limitations, we can get some useful insights for clinical practice. Firstly, current evidence that indicates no clear relation between SSRIs and suicide, together with available robust evidence of efcacy of treatment with antidepressant drugs in the pharmacological management of moderate to severe unipolar depression, should encourage doctors to prescribe eective doses of these drugs in such patients. Doctors should additionally be aware that SSRIs, similarly to tricyclics, may induce or worsen

CINP Antidepressant Task Force 2007 oset by the public health benets of increased diagnosis and treatment of depression.

S103

12 Other treatments for depression 12.1 Psychotherapy63

Empirically supported psychotherapies are potent alternatives to and augmenters in combination with antidepressant medications. Ecacious psychotherapies may have particular benets for depressed patients, such as pregnant women, who prefer to avoid medication. In non-industrialized countries, such psychotherapies may be the only feasible, aordable treatments for depression (Bolton et al., 2003). Interpersonal psychotherapy (IPT) is a time-limited, diagnosis-focused treatment shown in repeated randomized controlled trials to have ecacy as both an acute and a maintenance treatment for major depressive disorder (Weissman et al., 2000). IPT denes depression as a treatable medical illness that is not the patients fault. It focuses on the connection between the patients mood and interpersonal life circumstances. It has been shown not only to relieve depressive symptoms but to build social skills. IPT has shown more modest benet for dysthymic disorder (Browne et al., 2002 ; Markowitz et al., 2005). One large trial has indicated the ecacy of an adaptation of IPT (Interpersonal Social Rhythms Therapy) as an adjunctive treatment for bipolar disorder (Frank et al., 2005). Other studies have found that interpersonal counseling (IPC), a short, dilute version of IPT, relieves symptoms of subsyndromal depression (Weissman et al., 2000). Cognitive and behavioral therapies (CBT) have also demonstrated ecacy in repeated randomized controlled trials for depression. Cognitive therapy focuses on the automatic irrational thoughts that arise in the depressed state, in particular the cognitive triad of negative outlooks. This consists of negative thoughts about oneself ( Im no good), the environment ( Things are overwhelming ), and the future ( Its never going to get any better ) (Beck et al., 1979). Patients learn to test the evidence for and against negative thinking, and to substitute more rational responses to the environment for overly negative depressive thinking. Cognitive techniques are frequently used in combination with behavioral interventions such as scheduling pleasurable

63

See chapter 19.8 for more detailed information in Annex 8 : Additional information on psychotherapy.

activities. The two are used together in varying combinations, but CBT is generally more common than either pure cognitive or pure behavioral therapy. Cognitive therapy appears to have an enduring eect that protects persistently against relapse even after acute treatment ends (Hollon et al., 2005a,b). Cognitive Behavioral Analysis System of Psychotherapy (CBASP ; McCullough, 2000), an amalgam of behavioral, cognitive, interpersonal, and psychodynamic techniques developed specically to treat chronic depression, equalled nefazodone in ecacy in one large trial, and the combination of CBASP plus nefazodone surpassed either treatment alone (Keller et al., 2000). As there was no placebo control condition in this study, however, the ecacy of CBASP requires further testing. In addition to acute ecacy, cognitive therapies have been shown to enhance the ecacy of antidepressants, especially in combination treatment, possibly due to an inuence on serotonin and noradrenaline levels (Gaszner, 2005). Due to a relative lack of research funding, there are far fewer trials of psychotherapy than of pharmacotherapy for the treatment of depression. Psychotherapy research is complicated by the need to manualize the therapies, to train therapists to follow these manuals, and to monitor therapist adherence in treating patients during the trial by taping and rating treatment sessions. Nonetheless, a series of randomized trials have generally shown equipotence of empirically-based psychotherapies with pharmacotherapy for non-delusional outpatients with major depression. An early, key study was the NIMH Treatment of Depression Collaborative Research Program (Elkin et al., 1989), which compared imipramine, pill placebo, IPT, and CBT in treating 250 outpatients with major depression. In that 16 week trial, all treatments showed equal overall benets, but imipramine and IPT had greater ecacy for patients with more severe depression (HAMD >20) relative to pill placebo with clinical management. On the basis of their performance in controlled ecacy trials, interpersonal psychotherapy, and cognitive and behavioral therapies (CBTs) should be included in algorithms of standard treatment for depressive disorders. IPT and CBTs have already been included in numerous professional and national treatment guidelines (Karasu et al., 1993 ; Tylee, 2006 ; van den Broek, 2005). For patients with chronic or severe depression, the combination of pharmacotherapy and one of these empirically validated psychotherapies may be preferable to either monotherapy (Rush and Thase, 1999). Also in a recently published

S104

CINP Antidepressant Task Force 2007

Box 12. Administration of ECT according WHO recommendations (World Health Organization, 2005c)
$

According WHO recommendations, just as with any other treatment, ECT should only be administered after obtaining informed consent. ECT should only be administered in the so-called modied form (which to date represents the standard procedure), i.e. with the use of anesthesia and muscle relaxation. The practice of using unmodied ECT should be stopped, but up to now this method is still used in some countries for traditional and nancial reasons.

meta-analysis the combined therapy outperformed psychotherapy, but this was only true in moderate chronic depression. No dierences were found in nonchronic depression (de Maat et al., 2007). 12.2 Electroconvulsive therapy64

Electroconvulsive therapy (ECT) is the safe induction of a series of generalized epileptic seizures for therapeutic purposes using brief-pulse stimulation techniques under anesthesia and muscle paralysis. Informed consent65 of the patient or the responsible legal guardian is mandatory (see also Box 12). Since the rst publications, the excellent therapeutic eectiveness of this method in the treatment of depression has been described in a variety of reviews and metaanalyses (Abrams, 2002 ; Baghai et al., 2005 ; ECT review group, 2003). 12.2.1 ECT as rst-line treatment

In the case of refusal of food and drink, and severe psychomotor retardation, ECT has been shown to be one of the safest therapeutic options with the fastest relief of symptoms (Gangadhar et al., 1982). Therefore, depressive stupor and inanition, as in melancholic, catatonic and/or psychotic depression, can be a rstline indication for ECT before other treatments are prescribed. If, due to other conditions, e.g. severe psychotic symptoms and/or high suicide risk, rapid improvement is crucial for the patient, ECT should

64

See chapter 19.3 for more detailed information in Annex 3 : Additional information on electroconvulsive therapy. 65 Exceptionally in the case of perilous disease, when there is no possibility of obtaining informed consent due to the character of the mental illness, ECT can also be administered after legal authorization and informed consent of the patients legal representative. Patients with stupor, manic excitement, catatonic mutism and in acute paranoid states may not be able to give written consent, and alternative consent processes, which vary with jurisdictions in dierent countries, must be applied. It is useful for physicians who are responsible for the more acute and severely ill psychiatric patients to consider ECT as a primary indication and to be acquainted with all the means for proper consent for treatment within their jurisdiction.

be considered earlier than other therapeutic options (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). In psychotic depression, the remission rate for ECT approximates 90 %, with relief experienced within 1014 days (Petrides et al., 2001). The risks of suicide that mark severe psychiatric illnesses are quickly relieved by ECT, although attention to continuation treatment is essential to sustain the benet (Kellner et al., 2005). Also, with other acute psychiatric syndromes, e.g. delirious mania and malignant catatonia, that mark systemic illnesses such as lupus erythematosus, neuroleptic malignant syndrome (NMS) and medication toxicity may require ECT as a rst-line treatment (Abrams, 2002 ; Baghai et al., 2005), especially if it is not possible to dierentiate between NMS and malignant catatonia. Intensive ECT, usually administered daily (en bloc), relieves the high rates of mortality associated with malignant catatonia and delirious mania (Fink, 1999 ; Fink and Taylor, 2003). In addition, when depression, mania and psychotic symptoms accompany systemic illnesses or are present during early pregnancy or the post-partum breastfeeding period, administration of medications is often precluded and ECT becomes a useful treatment option. In the case of severe and life-threatening adverse events of antidepressants, in psychotic depressed patients and also in the case of severe adverse events due to antipsychotics, ECT monotherapy can be a safe rst-line treatment. This recommendation also holds for patients suering from severe somatic diseases, including the risk of worsening due to antidepressant and antipsychotic pharmacotherapy (Beliles and Stoudemire, 1998 ; Franco-Bronson, 1996 ; Rothschild, 1996). In addition, long duration and chronic course of the index episode are negative outcome predictors in depressive disorders that signal a higher risk for therapy resistance to medication and ECT (Beliles and Stoudemire, 1998 ; Prudic et al., 1990) ; more patients should be informed about these possible response rate modiers as part of shared decision making concerning their antidepressant treatment. Nevertheless, the primary use of ECT is handicapped by

CINP Antidepressant Task Force 2007 severe stigma and even legal restrictions against its use in some jurisdictions (Ottoson and Fink, 2004).

S105

12.2.2 ECT as second-line treatment The most common use of ECT is in patients for whom medications have failed to elicit remission or in whom medication toxicity has interrupted the course of therapy (Abrams, 2002 ; Baghai et al., 2005). Nevertheless, patients rarely receive ECT after the rst two medication treatment failures, which are often used as a criterion for pharmacotherapy resistance (Moller, 1997 ; Prudic et al., 1996 ; Sackeim, 2001 ; Warneke, 1993). Use of ECT signicantly enhances response rates (Davidson et al., 1978 ; Folkerts et al., 1997 ; Kroessler, 1985). This nding is especially true in patients suering from psychotic depression, even if antipsychotic therapies have been applied adequately before (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001 ; Folkerts et al., 1997). Intolerable side eects of antidepressant medications, somatic comorbidities emerging during the pharmacological treatment (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001 ; Rasmussen et al., 2002) or worsening of depressive symptoms, including severe suicidality during antidepressant pharmacotherapy, can also be the reason for initiating an ECT treatment course (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001).

individual patient shows an enhanced risk for recurrence of depression during continued pharmacotherapy, including both antidepressants and mood stabilizers, C-ECT should be a part of the treatment plan (Frey et al., 2001 ; McCall, 2001 ; Rabheru and Persad, 1997). The usual clinical procedure is to prolong the treatment intervals according to individual clinical requirements. During acute treatment, a patient usually receives two or three treatments per week. Afterwards, usually one treatment per week is applied for 48 weeks, then one treatment every 2 weeks and then one treatment every 4 weeks. This frequency should be maintained for at least 6 months. A frequently used alternative strategy (the so-called cafeteria style) is the individual decision whether to administer C-ECT treatment when the rst signs of recurring depressive symptoms are reported (Abrams, 2002 ; Fink et al., 1996). Regular weekly evaluations help to judge the necessity to shorten treatmentfree intervals on an individual basis. The same evaluation is necessary during the attempt to stop ECT treatment after 6 months. As soon as depressive symptoms recur, prolongation of C-ECT should go into eect. 12.2.4 Side eects

12.2.3 Maintenance and continuation ECT66 As described in chapter 9.2 in addition to pharmacologic and psychotherapeutic continuation therapies, especially after pharmacotherapy treatment failures, ECT, too, can be an ecacious prophylactic tool (Kellner et al., 2005 ; Sartorius and Henn, 2005a,b), even given the absence of controlled studies. Continuation ECT should be considered when depressive symptoms recur, especially when adequate pharmacologic therapy fails. Even when the prior history of an

66

The terms continuation treatment and continuation ECT (C-ECT) are predominantly used to characterize maintenance treatment after successful treatment of the index phase. They are sometimes distinguished from maintenance treatment and maintenance ECT (M-ECT) (Sartorius and Henn, 2005a) based on theoretical considerations regarding switching to prophylactic treatment to prevent new episodes of depression. Because for individual patients this time point cannot be precisely dened, in the following text only the term C-ECT is used.

Varying with the anesthetic, the most frequent immediate unpleasant eects of ECT are headache, nausea and vomiting. On rare occasions, prolonged seizures that require anticonvulsant treatment may also occur (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). Due to predisposition of the patients or pharmacological interactions (lithium), the eect of muscle relaxants may be enhanced, requiring a longer period of assisted respiration (Hill et al., 1977 ; Reimherr et al., 1977). In bipolar depression ECT may induce hypomania or mania ( switch ) (Angst et al., 1992). All patients may be confused on awakening after a seizure. In addition, typical side eects that are more prominent in bilateral than in unilateral and in high-dose than in lower-dose ECT (ECT review group, 2003) are transient cognitive disturbances. These include short-term memory disturbances (van Waarde and Stek, 2001), a prolonged postictal reorientation period, memory disturbances that include anterograde or retrograde amnesia and rarely occurring eects on autobiographic long-term memory (Lisanby et al., 2000). Nearly all patients report amelioration of cognitive impairment after nishing the course of ECT treatment (Devanand et al., 1991).

S106

CINP Antidepressant Task Force 2007 based on the current view that depressive disorders aect integrated pathways that link select cortical, subcortical and limbic sites and their related neurotransmitter and molecular mediators (Padberg and Moller, 2003). However, these brain-stimulation methods use dierent windows to access the anatomically dened pathways that show functional changes during the acute episode and attempt to modulate the system in the direction of a normal regulation of mood and emotions. rTMS is currently mainly targeted to cortical prefrontal sites (George et al., 2003 ; Padberg and Moller, 2003), whereas VNS enters the system by vagal aerents to the vagal nucleus and the nucleus tractus solitarius in the brain stem that are linked to regions of the brain involved in mood regulation, such as the amygdala, hippocampus and locus coeruleus (George et al., 2003). MST employs the ECT approach of inducing generalized therapeutic convulsions in order to treat depression. However, the method induces a lower current in the CNS and attempts to be more focal compared with ECT to minimize side eects and particularly exerts its eect on frontal and prefrontal cortical and subcortical sites (Lisanby et al., 2003b). Very recently, interesting data have been presented using DBS to stimulate a subgenual cingulate region (Brodmann area 25) that is metabolically overactive in treatment-resistant depression and shows normalization in activity after recovery (Greenblatt et al., 1964 ; Lisanby et al., 2003b). However, other regions in the basal ganglia and their pathways to prefrontal limbic areas may also be putative targets in future studies. Psychosurgical interventions, such as stereotactically applied bilateral orbitomedial lesions for resistant severe depression, posssibly show similar therapeutic eects ; however, at present they are of marginal clinical signicance (Sachdev and Sachdev, 2005). Moxibustion must also be mentioned among physical treatment options for depression. But empirical data regarding this intervention are insucient, and it mainly plays a role in traditional Chinese medicine (Cheng et al., 2005). Due to the fact that placebo response rates can be high in the treatment of depression, it is sometimes dicult to approve new antidepressant treatments. Nevertheless, new non-pharmacological treatments have already been approved in some countries for the treatment of depression : TMS has been approved in Canada and Israel, and VNS is approved by the US Food and Drug Administration (FDA) as an add-on treatment for depression.

Nevertheless, recent improvements in the use of ECT include methods to maintain good therapeutic ` ecacy together with better tolerability vis-a-vis cognitive disturbances. Using modied ECT techniques (Ghaziuddin et al., 2000), including unilateral or bifrontal pulse wave stimulation, anesthesia with muscle relaxation and sucient oxygenation, these risks could be substantially reduced (Ghaziuddin et al., 2000 ; Sackeim et al., 1993 ; Sackeim et al., 2000). A variety of case reports, case series and controlled studies conrm that ECT does not cause long-lasting functional (Krause et al., 1988) or any structural damage of the central nervous system (CNS) (Devanand et al., 1991 ; Krause et al., 1988 ; Lisanby et al., 2003b). But more research is needed to investigate the longerterm cognitive side eects of ECT (Greenhalgh et al., 2005). 12.2.5 Safety

In general, ECT is one of the best-tolerated antidepressant therapies, with low risk for severe complications, even lower than TCA. The mortality rate during ECT varies between 1 : 50000 and 1 : 25000 treatments (Abrams, 2002 ; American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). Severe complications that warrant special attention are seen in less than 1 : 10000 treatments (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001 ; Nuttall et al., 2004 ; Shiwach et al., 2001). 12.3 12.3.1 Other non-pharmacological treatments Introduction

Besides new pharmacological antidepressant treatment strategies, during the last decade several new biophysical approaches have been under investigation for the treatment of major depressive illness : repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), magnetoconvulsive therapy (MST) and, very recently, deep brain stimulation (DBS). These methods have in common that they directly or indirectly target brain regions that play a role in the pathophysiology of depressive disorders. All methods except MST dier from ECT in their presumed mechanisms of action, though they have often been discussed in comparison with ECT. rTMS was originally found to improve mood in patients suering from Parkinsons disease. This led to trials in the treatment of depression. rTMS, VNS, MST and DBS have been further developed in a hypothesis-driven manner

CINP Antidepressant Task Force 2007 12.3.2 Repetitive transcranial magnetic stimulation67 Repetitive transcranial magnetic stimulation (rTMS) was originally introduced in 1985 by Barker et al. as a non-invasive tool to electromagnetically stimulate the primary motor cortex in humans (Lisanby et al., 2003b). It has turned out to be a powerful research tool in neurophysiology and cognitive neuroscience. As an antidepressant intervention rTMS is usually targeted to the dorsolateral prefrontal cortex (DLPFC) based on well-replicated ndings that show reversible functional changes in this region. The majority of studies focus on the left prefrontal cortex based on the observed asymmetry of prefrontal function associated with major depression (Lisanby et al., 2003b). A large number of dierent stimulation parameters, e.g. frequency and intensity of stimulation, have been applied in studies (Padberg and Moller, 2003), and the usual treatment duration has been 14 weeks of treatment. About 25 randomized placebo-controlled clinical trials, including about 750 patients suering from major depressive episodes, have been conducted to date investigating the safety and ecacy of rTMS as an antidepressant intervention (Berman et al., 2000b ; Dolberg et al., 2002 ; Garcia-Toro et al., 2001a ; GarciaToro et al., 2001b ; Kaumann et al., 2004 ; Loo et al., 2003 ; Miniussi et al., 2005 ; Mosimann et al., 2004 ; Nahas et al., 2003 ; Padberg et al., 1999 ; Padberg et al., 2002 ; Padberg and Moller, 2003 ; Pascual-Leone et al., 1996 ; Rossini et al., 2005). In the majority of these trials, signicant placebo/verum dierences have been observed, with antidepressant eects ranging from modest to substantial. Due to the methodological limitations of many of these trials stemming from rather small sample sizes, the diculty of controlling sham rTMS and short observation periods, the current assessment of its ecacy in the wake of initial enthusiasm about its treatment potential is more sober. Several meta-analyses have been conducted (Berman et al., 2000b ; Burt et al., 2002 ; Couturier, 2005 ; Dolberg et al., 2002 ; Ebmeier et al., 2006 ; Garcia-Toro et al., 2001a ; Martin et al., 2003 ; Pascual-Leone et al., 1996 ; Schulze-Rauschenbach et al., 2005) that support the antidepressant ecacy of rTMS, but clinical eects are not very strong, and the clinical signicance may be questionable. rTMS has also been directly compared with ECT in ve parallel design trials (Grunhaus et al., 2000 ; Grunhaus et al., 2003 ; Pridmore et al., 2000 ;

S107

Schulze-Rauschenbach et al., 2005). In these trials, rTMS was found to be as eective as ECT in patients suering from major depressive episodes without psychotic features, but to be inferior for psychotic depression (Grunhaus et al., 2000). Four trials have investigated combined treatment with active rTMS plus antidepressant compared with sham rTMS plus antidepressant to answer the question whether rTMS augments the eect of antidepressant medication (Lisanby et al., 2001b ; Rumi et al., 2005). But only one study that combined rTMS with amitriptyline found a signicant superiority of combined active treatment (Rumi et al., 2005). Apart from single studies and case reports, little is known regarding the stability of eects and potential maintenance treatment strategies (Pascual-Leone et al., 1996), and the largest body of evidence points to transient eects following completion of rTMS treatment (Pascual-Leone et al., 1996 ; Schule et al., 2003). rTMS appears to be safe and well tolerated by patients within a range of parameters dened according to a consensus (Wassermann, 1998). In conclusion, there is considerable evidence for the antidepressant ecacy of high-frequency rTMS over the left dorsolateral prefrontal cortex applied over 24 weeks, and rTMS may be applied successfully as adjuvant antidepressant intervention. However, the antidepressant ecacy of rTMS has still not been suciently proven owing to the methodological limitations of previous clinical trials. Up to now solely in Canada and in Israel it has been approved for the treatment of depression by the authorities. 12.3.3 Transcranial direct current stimulation

67 See chapter 19.4 for more detailed information in for more detailed information in Annex 4 : Additional information on transcranial magnetic stimulation.

Transcranial direct current stimulation (tDCS) is a stimulation technique with potential benets in the treatment of depression which is currently used in investigational settings. A placebo controlled RCT in 40 depressed patients suggested benecial eects of tDCS of the left dorsolateral prefrontal cortex which persisted one month after the end of the treatment (Boggio et al., 2007b). During the treatment there was no necessity for anesthesia and the overall tolerability was excellent. In addition an improvement of cognitive performance has been reported (Boggio et al., 2007a). In spite of the increasing interest in the new non-pharmacological treatment strategies (Rau et al., 2007) to date tDCS is at a very early stage of development in the treatment of depression and the reports about antidepressant eectiveness are awaiting their replication.

S108 12.3.4

CINP Antidepressant Task Force 2007 Magnetic seizure therapy patients received continuous treatment, and longterm data have been published on 205 patients after 12 months of stimulation (Rush et al., 2005b). In the acute study, no dierence in primary and secondary outcome measures between VNS and placebo treatment groups was observed (Rush et al., 2005a). To facilitate interpretation of the clinical meaning of the long-term data in terms of ecacy, a post hoc comparison study with the same inclusion criteria as the controlled VNS study was initiated, including 124 patients who received treatment as usual (TAU) (George et al., 2005). After 12 months, a clinical response was found in 29.8 % of the patients included in the VNS study, whereas only 12.5 % responded in the TAU study ; remission was achieved in 17.1 % of the VNS study compared with 6.7 % of the TAU study (George et al., 2005). Concerning the safety of VNS, the results of the studies in epilepsy were essentially conrmed. VNS carries signicant health risks, including voice alteration, cough, dyspnea, neck pain, dysphagia, laryngismus, paraesthesia and pharyngitis (Rush et al., 2005a), which may improve gradually during treatment (Rush et al., 2005b). Based on the ecacy and safety data, the VNS therapy system was recently approved by the FDA for the adjunctive long-term treatment of chronic and recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. Despite this approval, to date it is not known whether VNS exerts antidepressant eects superior to placebo or other treatments, and further controlled, parallel-design long-term trials are urgently needed. Because of its invasive nature, VNS should be strictly reserved for exceptional cases where the patients demand for this treatment is high, other interventions have failed and a clinical benet is likely. In addition, although controversial (Annegers et al., 2000 ; Schachter, 2006), a connection has been suggested between VNS (used to treat treatment-refractory epilepsy) and sudden death. 12.3.6 Deep brain stimulation

MST is a variant of rTMS that uses stronger stimulation parameters (40 % more intensity compared with standard rTMS stimulation, higher frequency and a prolonged impulse of about 0.4 ms) to intentionally induce an epileptic seizure for therapeutic purposes. It is hypothesized that MST might be a kind of convulsive therapy that retains the therapeutic ecacy of ECT with an improved side-eect prole. Indeed, MST should induce a secondary generalized seizure more focally in relevant brain regions (Lisanby et al., 2003b), as the magnetic eld can penetrate scalp and skull without hindrance. Animal studies and safety data of clinical pilot studies in depression have been published supporting this notion (Lisanby et al., 2001c ; Lisanby et al., 2003a ; Moscrip et al., 2005). Its antidepressant ecacy is currently under investigation, and so far only case reports are available (Kosel et al., 2003 ; Lisanby et al., 2001a ; Moscrip et al., 2005). MST is still at an early stage of development (Lisanby et al., 2003a) and is therefore restricted in most counties to use in experimental treatment designs. 12.3.5 Vagus nerve stimulation68

In the 1980s and 1990s vagus nerve stimulation (VNS) was developed in animal models for its putative anticonvulsant action. It was introduced into the routine treatment of therapy-resistant focal epilepsies about a decade ago. It has been approved by the FDA. Theoretical considerations regarding the functional anatomy of the vagus nerve, which projects to areas of the brain relevant for generation and control of mood and emotions, as well as observations of mood changes in epilepsy patients undergoing VNS have triggered the application of VNS in depressive disorders (George et al., 2003). VNS has been investigated in a series of open and controlled clinical trials in depressed patients participating in an industrial development program, and recently the data of the complete trial set have been published (George et al., 2005 ; Nahas et al., 2005 ; Rush et al., 2000 ; Rush et al., 2005b ; Rush et al., 2005a ; Sackeim et al., 2001b). The results of an open pilot study (Rush et al., 2000 ; Sackeim et al., 2001b) led to a double-blind randomized placebo-controlled multicenter trial that included 235 patients who received either active or placebo stimulation over a 10-week period (Rush et al., 2005a). Following the acute treatment period, all

68

See chapter 19.5 for more detailed information in Annex 5 : Additional information on vagus nerve stimulation.

Deep brain stimulation (DBS) is a well-established treatment for intractable Parkinsons disease (PD) and other movement disorders, where usually the subthalamic nucleus, the globus pallidus internus or the thalamus is stimulated (Mayberg et al., 2005). An implantable stimulation system like the VNS system is used to stereotactically target relevant brain areas and generate a functional lesion in regions that are generators of symptoms of PD and other movement

CINP Antidepressant Task Force 2007 disorders. For psychiatric disorders, published reports of treatment with DBS have been limited to cases of obsessive compulsive disorder and Gilles de la Tourette syndrome (Mayberg et al., 2005). Very recently, Mayberg and colleagues (2005) published six cases of patients treated with DBS of the subgenual cingulate cortex, hypothetically driven by previous studies showing the consistent involvement of this region in acute sadness in healthy volunteers and antidepressant treatment eects in depressed patients (Kopell et al., 2004 ; Mayberg et al., 1999 ; Mayberg et al., 2005). The authors found a striking and sustained remission of depressive symptoms in four of the six patients, associated with a marked reduction in local cerebral blood ow as well as changes in downstream limbic and cortical sites demonstrated by positron emission tomography (Mayberg et al., 2005). DBS treatment is thus far only an experimental intervention in depression, and further extensive methodological research is needed to develop this approach towards a clinically applicable treatment (Schlaepfer and Lieb, 2005). 12.3.7 Total or partial sleep deprivation69 (wakefulness therapy) Total sleep deprivation (TSD) is a non-pharmacological intervention that exerts rapid antidepressant effects in about 6070 % of depressed patients who stayed awake one complete night and the consecutive day (Benedetti et al., 2005 ; Wirz-Justice et al., 2005 ; Wu and Bunney, 1990) despite the fact that sometimes it is dicult to keep patients awake. During late-night sleep deprivation (partial sleep deprivation, PSD) patients are awakened between 1 and 2 a.m. and stay awake during the second half of the night and the complete consecutive day until at least 8 p.m. PSD is as eective and rapid as TSD and better accepted by depressed patients (Schilgen and Tolle, 1980). In contrast, early night sleep deprivation (SD) is ineective in the treatment of depression (Wu and Bunney, 1990). To date, in addition to chronotherapeutic mechanisms, the induction of hippocampal neurogenesis has also been discussed as a possible mechanism of action (Grassi et al., 2006). The clinical relevance of TSD is limited, since relapse after sleep deprivation is a frequent phenomenon observed in most patients with depression (Wu
69

S109

and Bunney, 1990). Dierent strategies for relapse prevention after SD are combination with lithium (Benedetti et al., 1999 ; Grube and Hartwich, 1990), pindolol (Smeraldi et al., 1999), bright light therapy (Colombo et al., 2000 ; Neumeister et al., 1996) or the serial administration of PSD up to twice (or thrice) a week (Kuhs et al., 1996 ; Kuhs et al., 1998). It was recently shown in several clinical trials that a phase advance of the sleep period after SD can be used to prevent relapse in about 60 % of responders (Kuhs et al., 1996 ; Lee and Chan, 1999). Nevertheless, due to the overall lower eectiveness in comparison with other antidepressant treatments and its transient eects, sleep deprivation is used in clinical routine predominantly as an augmentation strategy. 12.3.8 Bright light therapy (phototherapy)

In seasonal aective disorders (SADs), bright white light therapy shows some usefulness in the treatment of depressive symptoms (Lee and Chan, 1999 ; Rosenthal et al., 1985). For other indications, such as non-seasonal depressive disorder, further research will be needed to determine the usefulness of phototherapy (Benedetti et al., 2001 ; Compton and Nemero, 2000 ; Prasko et al., 2002). Some studies report a good benet in depressed patients receiving bright light therapy to augment antidepressant pharmacotherapy (Benedetti et al., 2003 ; Loving et al., 2002). In recent reports, phototherapy was also suggested as an ecacious adjunctive treatment in nonseasonal unipolar and bipolar depression (Martiny et al., 2005a ; Martiny et al., 2005b ; Terman and Terman, 2005). Nevertheless, due to the fact that some reports on the ecacy of light therapy are not based on rigorous study designs, more randomized controlled trials are necessary to adequately evaluate the therapeutic impact of phototherapy on non-seasonal depression (Golden et al., 2005). Because of these somewhat controversial results, due to the results of several RCTs (Lam et al., 2006 ; Ruhrmann et al., 1998) phototherapy could be considered in SAD as a rstline therapy, whereas in other forms of depression it can be tried as an augmentation strategy. 12.3.9 Exercise

See chapter 19.7 for more detailed information Annex 7 : Additional information on chronotherapeutics : light and wake therapy.

A variety of publications have discussed the theoretical background of the benecial eects of physical exercise in the treatment of depressive disorders. In addition, reviews report on and recommend exercise as a promising behavioral intervention, at least as an adjunct treatment of depression (Craft and Perna,

S110

CINP Antidepressant Task Force 2007 13 Antidepressant drugs in the treatment of anxiety disorders71 The proven ecacy of antidepressant drugs in relieving anxiety symptoms in patients with depressive disorders led naturally to investigations of their potential to relieve symptoms and reduce associated disability in patients with anxiety disorders, including generalized anxiety disorder (GAD), panic disorder, social phobia (also known as social anxiety disorder), post-traumatic stress disorder (PTSD) and obsessivecompulsive disorder (OCD). In clinical practice, the need for treatment should be determined by the severity and persistence of symptoms, and the level of disability and impact on social functioning ; choice of treatment is inuenced by patient characteristics (such as previous response, concomitant medication and contraindications), the evidence base supporting its use, patient and physician preference, and the local availability of the proposed intervention (Baldwin and Polkinghorn, 2005).

2004 ; North et al., 1990). Even long-term changes and antidepressant eectiveness of exercise during 20 weeks of treatment have been reported (Singh et al., 2001). Nevertheless, detailed reviews and a metaanalysis showed that the eectiveness of exercise in reducing symptoms of depression cannot yet be concluded owing to methodological weaknesses in studies published to date (Barbour and Blumenthal, 2005 ; Lawlor and Hopker, 2001). Preliminary evidence reported recently shows exercise to be an eective lower-cost augmentation strategy that reduces depressive symptoms in partial responders to antidepressant medication (Trivedi et al., 2006b ; Trivedi et al., 2006c). For now, exercise can only be recommended as a supplemental therapeutic option during antidepressant therapies, with additional health benets especially in the case of longer-term use. In addition, limited evidence supports the eectiveness of yoga breathing exercises as a complementary treatment of depression (Jorm et al., 2002), but at this time it is impossible to quantitatively assess its benet. 12.3.10 Acupuncture70

14 Health economics : the cost of illness 14.1 Background

Because the use of complementary and alternative therapies is overrepresented in patients suering from depressive syndromes (Kessler et al., 2001), the actual knowledge about the main therapeutic options in this eld needs to be evaluated. Acupuncture has a long history in Eastern culture, and traditional Chinese medicine describes its inuence on the bodys balance of health and energy. Traditional acupuncture involves inserting needles into specic trigger points at dierent parts of the body. Despite a variety of published studies in this eld, a recent review reports insucient evidence for determining the ecacy of acupuncture in comparison with pharmacological antidepressant treatment (Smith and Hay, 2005). Also, adequate blinding of physicians and patients in clinical trials together with standardized outcome measures are necessary before clinical and scientic recommendations can be made (Smith and Hay, 2005). An overall good safety and tolerability of acupuncture has been described. Especially in trials comparing TCA with acupuncture, the typical side eects were much less in the acupuncture groups (Luo et al., 1998). Studies comparing modern and better- tolerated antidepressants have not been published to date.

The primary and central objectives of mental health services are the alleviation of symptoms and the promotion of quality of life. However, it is also widely recognized that economic considerations need to be taken into account. One reason is the widespread recognition that the costs of mental health problems can be substantial, and that they fall widely : on those who are ill, their families, the health-care system, other service systems and the wider national economy. Costs vary across countries for a number of reasons, including dierent means of calculating them, dierences in health systems and dierences in economies, including currencies. Thus, costs cannot be easily extrapolated from one country to another, particularly from developed to developing countries. A second reason for paying more attention to economic issues is the apparently growing cost of treatment. Some of the newer modes of treatment for mental health problems including the newer medications for depression are marketed at higher prices than the older treatments they could potentially replace. This has raised questions about whether the newer treatments are cost-eective. Third, in many

See chapter 19.6 for more detailed information in Annex 6 : Additional information on acupuncture.

70

71 See chapter 19.9 for more detailed information in Annex 9 : Additional information on antidepressant drugs in the treatment of anxiety disorders.

CINP Antidepressant Task Force 2007 countries there is a better understanding of the interconnections between mental health problems, employment and social exclusion (and of the potential for eective treatments to have impacts across many areas of life), and hence growing interest in mental health among ministries responsible for employment and nance. But the fundamental, pervasive, durable and most important reason for being interested in the economics of depression is that the professional, pharmaceutical and other resources required to provide treatment and support are not enough to meet the needs. Scarcity is a permanent feature of all health systems, indeed of all societies. In the face of such scarcity, choices have to be made among alternative uses of the same resource or service. Economics and, in particular, economic evaluation aims to provide decision makers with data that can inform and assist their decisions about how to allocate available resources. 14.2 The broad costs of depression

S111

There have been numerous cost-of-illness studies for depression. Here we summarize just a few to illustrate the main economic impacts of the illness.
$

The cost of depression to a society is usually measured in a cost-of-illness study, which estimates the value of resources incurred as a result of an illness. The economic cost of an illness or condition is driven by a number of factors :
$ $ $

prevalence treatment and service support rates eects of the illness on ability to work.

The costs measured in a cost-of-illness study are therefore usually separated into direct and indirect costs. Direct costs include the costs of treating the illness ; in the case of depression these would include the cost of primary and secondary care contacts and the cost of antidepressant medication. Indirect costs include the economic impact of premature mortality (estimated in terms of lost productivity from lost life years) and the lost productivity from economic inactivity (non-availability for work how many people with depression are unemployed or otherwise inactive because of their illness), absenteeism (days taken o work as a result of depression) and presenteeism (time at work but with reduced productivity because of depression-related symptoms). The output of a costof-illness study is expressed in monetary terms and is an estimate of the total burden of a particular disease to society. Such estimates are helpful, but they are not evaluative they tell us nothing about whether treatment is needed or which treatment is most costeective.

In England, unipolar depression was estimated to cost over 9000 million in 2000, of which only 370 million was direct treatment costs. The largest cost element was productivity losses : over 1 year, 109.7 million lost working days and 2615 deaths were attributed to depression (Thomas and Morris, 2003). Depression is a substantial nancial burden compared with coronary heart disease, and is the leading single cause of death in the UK. In 1999, the estimated economic burden of depression was around 7000 million (Liu et al., 2002). Throughout Europe, 23 % of the years of healthy life lost and 50 % of years lived with disability (YLD) are caused by brain diseases. Thirty-ve per cent of disabilityadjusted life years (DALYs), a measure of lost health, are considered to be due to brain disease (Olesen and Leonardi, 2003). In addition, in Europe depression is undertreated, and antidepressant treatments are underused (Henriksson et al., 2006 ; Taleb et al., 2006). The cost of aective disorders (including both bipolar depression and unipolar depression) in the 25 countries of the European Union plus Iceland, Norway and Switzerland was modeled by AndlinSobocki and colleagues (Andlin-Sobocki et al., 2005) and estimated at E10,566 million in 2004. Nevertheless, the need for a pan-European epidemiological study to collect more complete data about the real costs of depression in Europe has been recommended (Andlin-Sobocki and Wittchen, 2005). The cost of depression in the Asia-Pacic region has also been examined. Hu et al. reviewed existing evidence and reported that the total cost of depression in Australia was US$1800 million in 1997, of which 22 % was direct treatment costs, and US$1400 million in Taiwan in 1994, of which a quarter was direct treatment costs (Hu, 2004). Another study by Hu et al. that estimates the cost of depression in China is currently in press. In Pakistan, the high cost of depression prevents the majority of depressed patients from seeking treatment, which contributes to suering from the illness and an associated loss of productivity (Gadit, 2004). The economic burden of depression in the US was relatively stable between 1990 and 2000, despite an increase in the proportion of suerers receiving treatment. The total cost in 2000 was US$8310 million, of which almost a third was in direct

S112

CINP Antidepressant Task Force 2007 or to return to work (if not originally employed) compared with patients whose symptoms had not changed. Clinical improvement was also associated with fewer work days lost though illness, but not with the typical number of hours worked per week. For people whose symptoms improved, there was a marginally signicant reduction in health-care costs, although not until the second year after initiating antidepressant treatment. The impact on employment was therefore both larger and more immediate than the impact on health service costs. Another study shows that the impact of symptom alleviation on workplace performance can be rapid (Berndt et al., 1998). Atwork performance in this US study improved for chronically depressed people as the severity of their symptoms reduced. Over two-thirds of the observed improvement in work performance was found to have occurred in the rst 4 weeks after initiating treatment with an antidepressant. In Canada, Dewa et al. found that the use of recommended antidepressants at recommended doses improved symptoms and in turn improved employment outcomes for a large sample of workers (Dewa et al., 2003). Similarly, the largesample, six-country Longitudinal Investigation of Depression Outcomes (LIDO) study found that patients with improved depression symptoms had less absenteeism (Simon et al., 2002). These employment changes are all the more signicant in the face of ending stigma and discrimination by employers against people with mental health problems (McDaid et al., 2005). 14.3 14.3.1 Methodology : economic evaluation72 Core questions

medical treatment costs (Greenberg et al., 2003). The burden of depression appears to be less than the economic cost of diabetes in the US, estimated at US$13,200 million in 2001 (American Diabetes Association, 2003). There is a dearth of cost-of-illness studies from Africa, Asia, Eastern Europe, and Latin America (Hu, 2006). The cost-of-illness literature thus reminds us that depression places a nancial burden not only on health and social services but also on the broader economy from days lost from work and productivity losses more generally (see 19.2 Annex 2 : Additional information on the types of economic evaluation). Moreover, the impact of depression on work days absent and reduced productivity while at work has income and career progression implications for individuals with the illness. Less readily measured certainly not easily expressed in monetary terms but of considerable importance are the eects of depression on performance of family and social role (Brown and Harris, 1978). In addition, the psychological distress of caregivers together with a higher intensity of depressive symptoms in patients may increase use of primary care services and, presumably, costs (Perlick et al., 2005). It is therefore important that evaluations of costs and outcomes take a wide cost perspective that includes not only health service costs, and social and non-statutory service costs, but also losses to the economy and to the individual and family. For example, the direct cost of depression in England (Thomas and Morris, 2003) included the cost of hospital contacts, general practice consultations and drug consumption, while indirect costs included morbidity costs measured in terms of absenteeism and mortality costs in terms of the number of deaths due to suicide. Private costs to family and carers were excluded in this study. Thomas et al. found that a relatively small proportion of total costs were direct treatment costs and that total costs are driven by the ability of patients to return to work (morbidity costs). However, we will see that analyses that include morbidity and mortality costs are relatively rare. Instead, most economic evaluations tend to take a health systems approach, including only costs of primary and secondary care and medication. The need for this wider perspective is illustrated by Simon et al. (Simon et al., 2000a), who reported secondary analyses of a randomized controlled trial (RCT) of an SSRI. They found that patients across both arms (SSRI and TCA) whose symptoms had improved 12 months after the start of the trial were more likely to continue in paid employment (if working at baseline)

Decision makers face two central questions when considering whether to use or recommend a particular treatment for depression. The rst is the clinical question, which asks whether an antidepressant is eective in improving patient health, or when considering two or more treatment options which of them has the better or best outcomes. Once the decision maker knows that a particular treatment is eective, she or he wants an answer to the second question : Is it costeective ? That is, does the treatment achieve the improved outcomes or quality of life at a cost that is worth paying ? These two questions (Is the treatment eective ? Is it worth it ?) sit at the heart of cost-eectiveness analysis.

72 See chapter 19.2 for more detailed information in Annex 2 : Additional information on the types of economic evaluation.

CINP Antidepressant Task Force 2007 While it is always going to be necessary to reformulate these questions in ways that make them answerable with empirical research, their simplicity should never be forgotten. However, providing answers to these questions is obviously not that simple. It must also be emphasized that cost-eectiveness analysis does what its name suggests : it looks at both costs and eectiveness (outcomes). So, comparing the costs of one treatment with another, without any evidence on outcomes, does not constitute an economic evaluation. Such an exercise might be a helpful description of service utilization patterns and associated costs, as we have just seen in looking at the cost-of-illness evidence, but it does not provide enough information to assist service professionals, managers or others facing the choice between two or more alternatives. Similarly, calculating the costs and outcomes of a single service could be interesting but cannot be classed as an economic evaluation unless those costs and outcomes are compared with equivalent data for another service, or even compared with the option of doing nothing , and so again the study cannot tell us whether the service is worth providing. Uncontrolled mirror design studies often run into this problem. It is important to emphasize as we will note again below that an interventions cost-eectiveness is relative to the comparator in the evaluation, which makes the choice of comparator crucial. 14.3.2 Types of economic evaluation There are a number of dierent modes of economic evaluation, each with their associated data needs, advantages, disadvantages and uses. Good accounts of health economic evaluation methods (although with very few mental health examples) are given by Drummond et al. (Drummond et al., 2005) and Drummond and McGuire (Drummond and McGuire, 2001). The methods used in health economic evaluations are developing quite rapidly, and consequently some of the techniques mentioned later in this report have been in use in empirical studies for only a short time. A detailed account of the methods for economic evaluation is given in Annex 2 : Additional information on the types of economic evaluation. In brief, cost-eectiveness analysis combines costs with a single disease-specic outcome measure such as a depression symptom scale. The incremental costeectiveness ratio (ICER) is computed as the dierence in cost between the two treatments divided by the dierence in outcomes. In a cost-utility analysis,

S113

eectiveness is reduced to a single outcome index of utility such as the quality-adjusted life year (QALY) or DALY. Incremental cost-utility ratios can thus be calculated and compared over dierent conditions and disease areas, allowing strategic decision makers in a health system to judge whether resources are most eectively deployed in, say, treating depression or treating breast cancer. Cost-benet analysis generates monetary valuations of outcomes to compare costs and benets directly, which in principle opens up a wider set of comparisons for decision makers, including non-health-care options. In cost-consequence analysis, costs are reported alongside a range of outcome measures in an attempt to capture the broader picture of the impact of the intervention. Finally, cost-minimization analysis involves assessment of costs only, given the already established equality of outcomes. A summary of methods for economic evaluation is given in Table 24. 14.3.3 Search strategy

We carried out a systematic review, searching on Medline, EMBASE and PsycINFO for the period January 1985 to November 2005. The search was restricted to articles with the key words depression or depressive disorder and cost and cost analysis , or cost-eectiveness or economic . Following the search of the databases, a manual search of the references of included articles was undertaken to identify any relevant studies. Information on the articles was recorded using a structured form included consideration of the following criteria :
$ $

focused on adults with depression ; included comparative analysis of alternative interventions ; undertaken within a randomized controlled trial (RCT), non-random comparison or modeling study ; considered the cost-eectiveness of antidepressants, or of care or case management when in combination with, or compared with antidepressants or of physical treatments ; included the systematic assessment of both costs and outcomes, including cost-eectiveness, cost-utility, cost-benet, cost-consequence and costminimization analysis.

14.4 Economic evidence for pharmacological treatment options The literature search retrieved almost 3000 references, although only 50 are included in the nal review.

S114

CINP Antidepressant Task Force 2007

Table 24. Methods for economic evaluation Type of analysis Cost-eectiveness Cost-utility Outcome Disease-specic outcome such as depression scale Single outcome such as QALY or DALY Advantages Meaningful and understandable analysis Can compare across diseases Disadvantages Cannot compare across diseases Not suitable in all disease areas, particularly mental health, because of diculties of utility measurement Dicult to convert health outcomes into monetary terms Dicult to draw rm conclusions if outcomes move in dierent directions Can rarely be used because outcomes are rarely known with certainty to be equal

Cost-benet Cost-consequence

Monetary Specic range of disease and other relevant outcome dimensions Outcomes must be identical to the treatment alternatives

Understandable and simple analysis Includes range of outcomes in analysis Understandable and simple analysis

Cost-minimization

Papers were excluded because they did not focus on depression, they did not include costs or they did not compare two or more alternative interventions. The relative cost-eectiveness of antidepressants is determined by a number of factors, most importantly their relative ecacy. The SSRIs and other newer antidepressants have a considerably higher purchase price than the TCAs, and higher drug costs can lead to higher total costs. However, it is unclear how long this trend will continue, as many of the SSRIs and newer antidepressants are now coming o patent and in many countries (though not all) are then sold generically at a lower price : for example, in March 2000 a 30day supply of uoxetine (Prozac1) in the UK cost 19.34, but by March 2005 the equivalent generic uoxetine price was 2.11. Cost-eectiveness is also inuenced by patient adherence. Adherence is generally low and dropout rates high among individuals commencing antidepressant treatment, which has an impact on the eectiveness of the drug. One explanation for poor adherence is the unpleasant side effects associated with the drugs ; these include as dry mouth, sedation, blurred vision and sexual dysfunction (see chapter 9.1.1.3). If the SSRIs and the other newer antidepressants have better side-eect proles than the TCAs, the newer preparations may improve adherence and outcomes and thus also improve costeectiveness. 14.4.1 Selective serotonin reuptake inhibitors

We identied 32 papers that appraised the costeectiveness of selective serotonin reuptake inhibitors

(SSRIs) for depression, though only 7 used data from prospective trials or naturalistic settings, with the remaining evidence coming from models. Simon and colleagues (Simon et al., 1996 ; Simon et al., 1999a) carried out a prospective, naturalistic, randomized trial with economic evaluation comparing alternative antidepressant therapies. Patients attending primary care clinics in the US and initiating antidepressant treatment were randomized to uoxetine (an SSRI) or desipramine or imipramine (TCAs). In the short term (6 months) treatment dropout was lower, there were fewer adverse eects and achievement of a therapeutic dose was more likely among patients randomized to receive uoxetine. However, there were no signicant dierences in clinical outcomes or quality of life, nor were there any signicant dierences in cost, because the higher drug acquisition cost of uoxetine was oset by lower outpatient and inpatient service use. A similar pattern of results was found at the 2-year follow-up. The authors concluded that restricting the rst-line use of uoxetine in primary care would probably not reduce overall treatment costs due to the lower hospital service utilization in that group. Other RCTs have compared SSRIs with other antidepressants and psychological therapies. One compared the costs and outcomes of uoxetine, citalopram and amitriptyline for major depression in central Europe and found no signicant dierences in cost or outcome between interventions (Hosak et al., 2000). The authors concluded that amitriptyline was no less expensive or more eective than citalopram or uoxetine and advised that there was no advantage to

CINP Antidepressant Task Force 2007 restricting patients from treatment with SSRIs. Another compared SSRIs, placebo and psychological treatment for common mental disorders, including depression, in Goa, India (Patel et al., 2003). Psychiatric outcomes were signicantly better with antidepressant than placebo at 2 months, but no signicant dierence was detected at 12 months. Costs were lower in the SSRI group, suggesting that antidepressants are more cost-eective than placebo. Psychological treatment resulted in worse outcomes and higher total costs than placebo. The authors argued that aordable antidepressants such as uoxetine should be the treatment of choice for common mental disorders in general health-care settings in India, since they are associated with improved clinical and economic outcomes, particularly in the long term. Retrospective analysis of existing data was used to measure the cost-eectiveness of sertraline and TCAs for depression in primary care in the UK (Forder et al., 1996). The average cost of treatment was slightly greater for those receiving TCAs due to greater use of psychiatric services. In terms of cost-eectiveness, sertraline was found to dominate TCAs for all denitions of costs and outcomes. In an attempt to clarify the relative cost-eectiveness of antidepressants as a rst choice treatment for depression in primary care, Peveler and colleagues (2005) carried out a randomized controlled trial comparing TCAs, SSRIs and the TCA-related antidepressant lofepramine. The UK-based study found no signicant dierence in costs or outcomes between groups. However, for values placed on an additional QALY of over 5000 the approach taken in examining net benets or plotting a cost-eectiveness acceptability curve treatment with SSRIs was likely to be the most cost-eective strategy. The evidence from RCTs and retrospective analyses suggests that SSRIs may be more cost-eective treatments for depression than TCAs and are more costeective than placebo. Despite higher acquisition costs, SSRIs do not appear to increase overall treatment costs, as SSRIs result in reductions in subsequent health service utilization. In addition, SSRIs may generate better outcomes. In comparison to the limited availability of economic evaluations from naturalistic settings and RCTs, there are a plethora of studies using modeling techniques to estimate the cost-eectiveness of SSRIs for depression. These models tend to use data from existing evidence for clinical eectiveness and outcomes, but expert opinion on costs and transition through the model, and are based in a variety of health systems and settings. The studies vary substantially in the

S115

quality of the data used, the robustness of assumptions employed, the techniques used to test them and generate ndings, and consequently their usefulness for this review. Assumptions need to be employed because there is inadequate data on some aspect of how the drugs will inuence outcomes, service use and costs. A decision-analytic model was used to analyze the cost-eectiveness and cost utility of SSRIs and TCAs in various combinations for depressive disorders in Canada and is a good example of how the evidence on the relative cost-eectiveness of the two types of antidepressants can be summarized (Canadian Coordinating Oce for Health Technology Assesment, 1997). The meta-analysis of available clinical evidence showed that there were no statistically signicant differences between the ecacy, completion rates and dropout rates of the antidepressants considered. The perspective of the economic evaluation was that of the health-care system, so only direct health-care costs (inpatient contacts, primary care contacts and drug costs) were included. The study suggested that from a Canadian perspective both TCAs and SSRIs should be part of an eective treatment strategy and that further research, preferably from RCTs, was needed to investigate the long-term cost-eectiveness of treatment for depressive disorders. In an early model Jonsson and Bebbington (Jonsson and Bebbington, 1994) compared the cost-eectiveness of paroxetine and imipramine in people with depression in the UK. The 12-month cost per successfully treated patient was lower with paroxetine than imipramine, indicating that paroxetine was the more costeective. The results were sensitive to assumptions concerning the relative ecacy of the drugs, particularly treatment failure, and the authors concluded that although paroxetine had a high cost per day when patient adherence and the total cost of treatment are taken into account, it was the more cost-eective option. However, these ndings were questioned a few years later when the model was reassessed with some key assumptions challenged and changed (Woods and Rizzo, 1997). With revised assumptions the model demonstrated that the TCA was at least equally if not more cost-eective than the SSRI. The authors advised that a policy of using TCAs as a rst choice antidepressant, with SSRIs reserved for those patients not doing well, appears more cost-eective than the reverse sequence. The two studies use the same data but generate dierent results, confusing the issue of cost-eectiveness and highlighting the importance of the assumptions made in economic models.

S116

CINP Antidepressant Task Force 2007 Poland in the inpatient setting, and Italy and Poland in the outpatient setting. The authors concluded that venlafaxine is a more cost-eective treatment than the alternatives and suggested that increased utilization of the compound in most settings across Europe and the Americas would have favorable impacts on health-care payer budgets. The model was re-analyzed when new data became available on the probability of relapse with dierent antidepressants (Casciano, 2003). The revised study disputed the treatment dominance of venlafaxine and concluded that venlafaxine was more eective than SSRIs but also more expensive. The cost-eectiveness of venlafaxine for people in the acute phase of major depressive disorder was evaluated in a UK outpatient setting (Freeman et al., 2000). The model demonstrated that venlafaxine oered statistically signicant improvements in depression-free days and that, from a health care perspective, the cost per depression-free day was lower for venlafaxine than for SSRIs or TCAs. Lenox-Smith and colleagues (2004) updated the Freeman model using revised data on costs and outcomes. They found that using venlafaxine as a rst-line treatment strategy, and switching to an SSRI if necessary, was a dominant treatment strategy over rst-line treatment with an SSRI, resulting in better outcomes with lower costs. A similar evaluation was undertaken in Italy (Casciano et al., 1999). The results suggested that venlafaxine was more cost-eective compared with SSRIs and TCAs for both inpatients and outpatients with respect to cost per successfully treated patient and cost per symptom-free day. Extended-release venlafaxine was found to be a cost-eective strategy among people with depression in Austria (Howard and Knight, 2004). Finally, venlafaxine for people with major depressive disorder has been evaluated in both inpatient and outpatient settings in Canada and the US (Einarson et al., 1995 ; Einarson et al., 1997 ; Trivedi et al., 2004 ; van Baardewijk et al., 2005). Results from these studies suggested that venlafaxine was more eective, but costs were either more, less or the same as with treatment with other antidepressants. The results of all the models above are highly sensitive to the assumptions made and the unit costs used. At present, and on the basis of available evidence, it is dicult to draw rm conclusions regarding the cost-eectiveness of venlafaxine for depression. In the case of duloxetine, both acute and maintenance treatment seem to be cost-eective alternatives to SSRIs and TCAs (Dardennes et al., 1999 ; Lafuma et al., 1999).

Other modeling studies present evidence of the cost-eectiveness of SSRIs compared with TCAs (Le Pen et al., 1994 ; Nuijten et al., 1995) and compared with usual care (Nuijten et al., 1998), although no statistically signicant dierences in costs are reported. However, there is evidence suggesting that SSRIs are more costly and more eective than usual care (Kind and Sorensen, 1995). When maintenance treatment with SSRIs is compared with episodic treatment with a TCA, there are improved outcomes, but alongside higher costs (Hatziandreu et al., 1994). Evidence of the cost-eectiveness of escitalopram compared with SSRIs and other newer antidepressants is accumulating. However, the majority of the evidence is from one economic model, applied to different health systems. In Austria, Belgium, Sweden, Norway and Finland, escitalopram was the dominant treatment strategy, achieving better outcomes with lower costs, both when health-care and broader societal costs are considered for patients with severe depression (Demyttenaere et al., 2005 ; Francois et al., 2002 ; Francois et al., 2003 ; Hemels et al., 2004a ; Lothgren et al., 2004). It was also cost-eective in treating severe depression in Austria (Hemels et al., 2004b). When the model was applied in the UK, escitalopram was found to be a cost-eective option compared with generic citalopram (Wade et al., 2005a ; Wade et al., 2005b) and had a cost-eectiveness prole comparable to the newer antidepressant venlafaxine. Only one prospective evaluation of escitalopram has been carried out as part of an RCT. Fernandez et al. (2005) demonstrated that escitalopram had similar ecacy to venlafaxine and patient costs were lower in the escitalopram group, though not signicantly so. In both the models and the RCT, the reduction in costs was due to reduced hospitalization in the escitalopram group. 14.4.2 Selective serotonin and noradrenaline reuptake inhibitors In common with evidence of the cost-eectiveness of SSRIs, decision and Markov models dominate economic evaluations for the newer antidepressants. The cost-eectiveness of venlafaxine for major depressive disorder has been estimated using models in a number of health-care systems : Germany, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, UK, US and Venezuela (Casciano et al., 2001 ; Doyle et al., 2001). Using results from meta-analyses, venlafaxine had the highest expected success rate and the greatest number of symptom-free days in all countries. It yielded a lower expected cost in all countries except

CINP Antidepressant Task Force 2007 14.4.3 Noradrenergic and specic serotonergic antidepressant Only one study prospectively collected and analyzed data on cost-eectiveness, focusing on mirtazapine versus paroxetine in UK primary care attenders with depression (Romeo et al., 2004). Mirtazapine treatment resulted in signicantly greater improvements in quality of life than paroxetine at 26 weeks. Although no signicant cost dierences were observed between the two groups, societal costs were lower with mirtazapine than with paroxetine. The results suggest that mirtazapine may be a cost-eective treatment choice for depression in a primary care setting. Mirtazapine for people with moderate to severe depression has been investigated in modeling studies for the UK and Austria. In the UK study Borghi and Guest (Borghi and Guest, 2000) demonstrated that mirtazapine was both more eective and less costly compared with amitriptyline and uoxetine. The higher acquisition costs of the preparation were oset by the lower costs of managing adverse events and lower health service utilization. In Austria, Brown and colleagues (Brown et al., 1999) established the cost-eectiveness of mirtazapine despite the dierences in acquisition costs compared with other antidepressants such as amitriptyline and uoxetine. 14.4.4 Serotonin-modulating antidepressants Two models have evaluated the cost utility of nefazodone in depression, from the perspective of a US managed care organization (Revicki et al., 1997) and a Canadian health insurance organization (Anton and Revicki, 1995). In both models, cost-eectiveness was estimated for a 30-year-old woman with active depression, and in both studies the ndings suggested that nefazodone is a cost-eective treatment compared with imipramine (a TCA) and uoxetine (an SSRI). The results were highly sensitive to the assumptions made in the model, particularly those concerning ecacy and dropout. 14.5 Evidence on the cost-eectiveness of antidepressants and care management Care management involves patient education, shared decision making and monitoring. The way in which individuals starting antidepressant treatment are managed clinically may inuence their outcomes and thus the cost-eectiveness of the antidepressants. Three studies have investigated the cost-eectiveness of care management versus usual care in patients

S117

starting antidepressant treatment. In two trials clinical outcomes suggest there are no signicant dierences in depression-free days or in health-care costs (Simon et al., 2000b ; Simon et al., 2002), whereas one describes superiority of care management (Wells et al., 2000). Although education alone of primary care physicians does not seem to improve patient outcomes (Gask et al., 2004 ; Thompson et al., 2000), care management or collaborative care involving doctor education, patient education and monitoring by an additional mental health worker can improve patient outcomes at modest costs (Simon et al., 2000b ; Simon et al., 2002 ; Wells et al., 2000). In additon, identication and treatment of depression among patients with a history of high medical expenditures can decrease service use, improve depression outcomes and increase work productivity, though the cost of screening is high (Katzelnick et al., 1997 ; Von Kor et al., 1998). A decision-analytic model suggested that an increase in the appropriateness of care as seen in a care management program is likely to improve functioning outcomes and increase the value of health-care spending in terms of health benets (Sturm and Wells, 1995). 14.6 Economic evidence for pharmacological treatment options The economic evidence has some limitations. First, results from clinical trials are frequently inconclusive due to short follow-up periods and inadequate power to demonstrate dierences in costs. Second, the results from economic models are strongly inuenced by the assumptions made ; in many cases conclusions change when new evidence becomes available, or when medication prices change or when a dierent view has been taken on the likelihood of an assumption (this is true particularly in modeling studies ; a differentiation between analyses performed with an industrial sponsor and analyses independent of the pharmaceutical industry has been suggested). Third, the results of economic evaluations tend to be country-specic, as nations have dierent health systems and economic conditions. Notwithstanding these points, it is possible to identify some trends in the results, as well as some areas where further research is needed. Evidence of the cost-eectiveness of SSRIs compared with TCAs is persuasive (Barbui et al., 2003). Many studies have demonstrated that SSRIs have higher acquisition costs, but lower subsequent health service costs, a pattern that may increase as SSRIs become available generically at much lower prices.

S118

CINP Antidepressant Task Force 2007

Box 13. Summary of economic evidence on antidepressant treatments What we know :

$ $ $

Some, but not all analyses suggest that SSRI treatment is more cost-eective than treatment with TCAs. On the basis of available evidence, venlafaxine and mirtazapine appear to be cost-eective alternatives to SSRIs. A new way of care, called care management, has demonstrated its value in enhancing the eectiveness of antidepressants in one out of three studies.

What we do not know :

$ $

Evidence of the cost-eectiveness of the new SSRI escitalopram compared with other SSRIs is accumulating. Large-scale real-life (RCT or observational) comparisons of newer antidepressants, such as NARIs, SNRIs or NaSSAs to SSRIs have yet to be undertaken. Modeled analyses have limited application because of the quality of the data on which they are based and the assumptions made. Most studies are based in developed countries, and given the fundamental dierences in health systems across the world, it is dicult to know whether their ndings can be generalized to other countries. Cultural factors may impact on patients adherence, prescription habits and nally on cost-eectiveness.

Evidence of the cost-eectiveness of the SSRI escitalopram is accumulating. Although it has a higher cost than the now generic citalopram, models have demonstrated that it achieves better outcomes and decreases the likelihood of an inpatient stay, resulting in lower costs. Newer antidepressants have entered a crowded market, and except in one instance, real-life (RCT or observational) comparisons to existing antidepressants have yet to be undertaken (or at least published). In common with other evidence from economic models, it is dicult to summarize the cost-eectiveness of these interventions. In many cases, the models that have been constructed have relied entirely on expert views to project the costs, and the precise methods used by the expert panels to arrive at their resource use estimates are often not described fully or clearly in the literature. These inadequacies limit the generalizability and applicability of these studies and make it dicult to draw rm conclusions. On the basis of available evidence, however, the SNRIs venlafaxine (Freeman et al., 2000) and duloxetine or (Dardennes et al., 1999 ; Lafuma et al., 1999) the NaSSA mirtazapine (Borghi and Guest, 2000) appear to be cost-eective alternatives to SSRIs. 14.7 Implications : economic evidence for pharmacological treatment options Growing awareness of the need to improve not only the eectiveness but also the cost-eectiveness of health-care interventions has produced various streams of demand for economic evidence. Two are

relevant here. There are requests for measures of the overall resource or cost impact of a particular health problem, leading to cost-of-illness and global burden studies. Much attention has recently focused on some of the non-health-care costs which, as we have seen, can be very large for many people with depression. While cost-of-illness calculations can be helpful in raising awareness of the scale and breadth of impact of mental health problems, they are no substitute for evaluations that look at both costs and outcomes. There are also demands for economic evaluations of particular treatments or policies, generating costeectiveness and similar analyses, either carried out within clinical trials or using routinely collected, naturalistic data. Well-conducted economic evaluations can contribute pertinent evidence to the discussion and development of policy and practice. They can support decisions relating to the funding and provision of services and can help to improve the eciency with which scarce health-care and related resources are allocated. In this chapter we have reviewed the economic evaluation evidence on antidepressant medications, drawing on a new systematic search of the international literature. The quality of many studies is disappointing. Among the methodological weaknesses are (for summary see Box 13) :
$

$ $

small sample sizes, leaving studies underpowered to test economic hypotheses ; narrow measurement of costs ; the relative rarity of randomized controlled trials, and hence few studies with strong internal validity ;

CINP Antidepressant Task Force 2007

$

S119

few large observational studies with appropriate standardization, and hence limitations on the external validity of some evidence ; the scarcity of cost-utility analyses and costbenet analyses, making it impossible to use the existing evidence base to make comparisons of resource eciency outside the mental health system ; widespread use of economic models that may not accurately reect the true clinical cost situation.

In many areas the economic evidence relied entirely on economic modeling. These models are based in many cases on expert views to project costs, and the precise methods used by the expert panels to arrive at their resource use estimates are not described fully and clearly in the literature. These inadequacies limit the generalizability and applicability of these studies and make it dicult to draw rm conclusions. Economic evaluations of antidepressant treatment for depression are inherently context-bound. These evaluations describe the consequences of both the illness and its treatment for service systems and social relations, and these latter will vary from country to country, and often from locality to locality. Also, the economic value of work varies across dierent countries and cultures. Making generalizations across countries is therefore more dicult than with, say, clinical evaluations. The almost complete absence of economic evidence on depression treatments for all but a very few health systems of the world is therefore a further limitation. 14.8 Economic evidence for psychological treatment options Depression is widely treated with psychological therapies, including cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), counseling and other forms of psychotherapy. Psychological therapies such as CBT and IPT have proven eectiveness in depression (see chapter 12.1), so economic evaluations essentially aim to investigate whether high initial treatment costs are oset by potentially lower drug costs and fewer visits to other health care professionals (the cost-oset question) or whether the additional costs are worth paying because of improved outcomes (the cost-eectiveness question). In standard care, psychological treatments generally tend to be delivered alongside treatment as usual, which may or may not include an antidepressant and this is reected in the evaluative literature. In some

instances, however, antidepressants have been directly compared with psychological therapies and we concentrate on this literature here. In an early economic analysis, 120 patients initiating treatment for depression were randomized to one of four interventions : CBT by a clinical psychologist, counseling and case work by a social worker, amitriptyline prescribed by a psychiatrist and usual care from a general practitioner (Scott and Freeman, 1992). After 16 weeks, there were improvements in depressive symptoms in all treatment groups, but total treatment costs were twice as much in the specialist treatment groups compared with routine care. With such a short period of follow-up, it was dicult to draw conclusions, and the authors recommended a full economic evaluation with longer follow-up and one that included a wider denition of cost. More recently, Miller and colleagues (2003) compared counseling and antidepressant therapy for the treatment of mild to moderate depression in primary care. At 12-month follow-up, there were no signicant dierences in outcomes and costs. Bootstrap analysis showed that the antidepressant intervention was the dominant cost-eective strategy for the majority of patients, indicating that the cost-eectiveness of counseling compared with treatment with an antidepressant for depression in primary care has not been proven. The cost-eectiveness of psychotherapy and medication was investigated in trials in Canada, the US and the UK. In one study, patients with dysthymia were randomized to interpersonal psychotherapy (IPT) (Klerman and Weissmann, 1987), IPT with sertraline (an SSRI) or sertraline alone in an RCT in primary care (Browne et al., 2002). Clinical outcomes at 2-year follow-up demonstrated that there were no statistically signicant dierences between sertraline alone and sertraline plus IPT, but both were signicantly more eective than IPT alone in reducing depressive symptoms. Societal costs were signicantly lower in the IPT group, but there was no synthesis of costs and eects, so the incremental cost-eectiveness of the treatment is not known. The authors stressed the importance and potential economic value of combining psychotherapy and pharmacotherapy. IPT, pharmacotherapy with nortriptyline (a TCA) or usual care were compared in a cost-eectiveness analysis in the US (Lave et al., 1998). Both IPT and the pharmacotherapy generated better outcomes than usual care at follow-up, although the pharmacotherapy group did slightly better than those assigned

S120

CINP Antidepressant Task Force 2007

Table 25. Summary of cost-eectiveness of psychological treatments for depression Psychotherapeutic method IPT

Cost-eectiveness Depends on the treatment setting ; may be cost-eective (better outcomes no dierence in cost) in secondary care but evidence from primary care less clear. When compared head-to-head with an SSRI, no evidence of cost-eectiveness Not yet proven. Evidence from primary care of improved outcomes is always accompanied by substantially higher costs. Some evidence that self-help CBT and computerized CBT may be cost-eective No signicant dierences in costs or outcomes in clinical trials, though meta-analysis suggests counseling will produce signicantly better outcomes for signicantly higher costs Cost-eective from a societal perspective, but higher costs in intervention group from a health-care perspective. Additional costs of problem-solving treatment are oset by fewer days o work in the intervention group

Reference Browne et al., 2002 ; Guthrie et al., 1999 ; Kamlet et al., 1995

CBT

Bower et al., 2000 ; Kaltenthaler et al., 2002 ; Richards et al., 2003 ; Scott and Freeman, 1992 ; Scott et al., 2003 Bower et al., 2002 ; Bower and Rowland, 2006 ; Friedli et al., 2000 ; Harvey et al., 1998 ; Miller et al., 2003 ; Scott and Freeman, 1992 ; Simpson et al., 2003 Mynors-Wallis et al., 1997

Counseling

Problem solving

to IPT. Costs were higher in the IPT and pharmacotherapy groups compared with usual care. The incremental cost per QALY gained was US$11695 for nortriptyline and US$15358 for IPT. Although the dierences were not statistically signicant, from a decision-making perspective there is a preference for the drug treatment. A modeled cost-utility analysis compared IPT, imipramine (a TCA), a combination of the two, and placebo in patients with recurrent depression (Kamlet et al., 1995). Modeling and simulation methods were used to estimate the costs and benets associated with each maintenance therapy, and the authors demonstrated that the drug maintenance treatment was cost-eective. Among patients with depression who had a partner with a criticizing attitude, signicant improvements in outcomes were found in patients randomized to couples therapy compared with those randomized to antidepressants (Le et al., 2000). There were higher treatment costs in the therapy group, but the higher costs were moderated by decreased use of other services, resulting in no signicant dierences in cost at follow-up. The authors warned that the results could not be generalized beyond individuals with depression who are living with a heterosexual partner and that conclusions were limited by large amounts of missing data in the economic evaluation. Cost-eectiveness studies concerning the role of family care are lacking,

but there is a broad consensus about the importance and value of family care during the treatment of depressive disorders. Psychotherapy is cost-eective in some patient groups (Table 25), but when compared directly with antidepressants, their cost-eectiveness needs further evaluation. The economic value of combining psychotherapy with pharmacotherapy also needs further examination. Finally, new care arrangements have demonstrated their value in enhancing the eectiveness of antidepressants, but studies have only taken place in the US and given the fundamental dierences in health systems across the world it is dicult to know whether their ndings can be generalized to other countries. The economic discussion to this point principally addresses acute treatment costs. In the very short run, psychotherapies are more labor-intensive and costly than pharmacotherapies. Over time, however, the fulcrum may shift : daily pharmacotherapy which might be continued indenitely to maintain prophylaxis against depressive relapse and recurrence, whereas psychotherapy may either be discontinued, with enduring eect (Hollon et al., 2005), or continued in less frequent (e.g. monthly) sessions. Empirically validated psychotherapies may also arguably help patients to neutralize psychosocial stressors (e.g., marital diculties) that might provoke a future

CINP Antidepressant Task Force 2007 depressive episode. Thus over the longer duration of the treatment of this usually chronic illness, it is possible that antidepressant psychotherapy might have cost advantages relative to pharmacotherapy. Studies to assess this, however, are lacking. 15 Conclusions and implications73 The Executive Committee and the Council of the Collegium Internationale Neuropsychopharmacologicum have considered the information contained in this

S121

report as well as other information available to its members and adopted a Consensus Statement about the use of antidepressants in the treatment of depressive disorders. The Consensus Statement is given here as a concluding summary of the review. In addition to providing a summary of the main ndings of the review, the Consensus Statement also indicates future action that CINP will take in this area and makes a series of recommendations to governments, professional and non-professional organizations and the media.

Antidepressant Medications in the Treatment of Depressive Disorders: A Consensus Statement by the Collegium Internationale Neuropsychopharmacologicum
The International College of Neuropsychopharmacology, Aware of the major public health importance of depressive disorders and of the suering that these disorders cause to people who have them and their families ; Cognizant that even in highly industrialized countries only a small proportion of people with depression who could benet from qualied help contact health-care services and receive adequate treatment ; Given that medical practitioners may fail to recognize depressive disorders in people who come to them seeking help and that their knowledge about the treatment of depression may be insucient ; Concerned by the ndings that the general population and health-care workers still attach stigma to depressive disorders ; Aware of the risks of suicide and physical illness that are elevated in people with depressive disorders ; Deeply concerned also by the tendency to consider depressive disorders to be minor ills of living and not illnesses that should be given appropriate care ; Considering that the potential benets of these medications used in the treatment of depressive disorders outweigh the risks presented by the side eects of their application ;
73 The CINP consensus statement has been adopted to the actual knowledge about antidepressant treatments. Due to the nature of the constant scientic progress it is planned to actualize the information presented in the review on a regular basis.

Stressing that the application of adequate treatment not only helps the persons who have the disease and their families, but also brings signicant social and economic benets to society ; Stressing also that the treatment of depressive disorders is a process in which the application of antidepressant medications, social support and psychological help and treatment must be used in a manner that will correspond to the needs of the individuals who are being treated, and of their relatives and other carers ; Recognizing that new information and knowledge about the treatment of depressive disorders is not reaching those engaged in health-care and that the general public is still insuciently informed about the frequency of depressive disorders and possibilities of their eective treatment ; DECIDES 1. To publish the CINP Task Force report based on a review of Evidence about Antidepressant Medications and other Treatments of Depressive Disorders and employ it as a platform for the development of training programs and guidelines concerning the recognition and treatment of depressive disorders ; 2. To develop specic guidelines concerning the use of antidepressant medications in the treatment of depressive disorders and to undertake all that is necessary to bring them to the attention of medical practitioners worldwide, engaging the World Health

S122

CINP Antidepressant Task Force 2007 Munchen in Germany hosted one of the regional meetings and enabled two of the editors (Dr T. C. Baghai and Prof. H. Grunze) to carry out their work on the review. Numerous individuals, institutions and the companies listed above provided the Task Force with publications and other relevant scientic materials. To all of them we express our most sincere and cordial gratitude. 17 Statement of Interest Thomas C. Baghai accepted paid speaking engagements in satellite symposia and acted as a consultant for Janssen-Cilag, Organon, Pzer and Servier. David Baldwin acted as a consultant to and/or accepted paid speaking engagements in satellite symposia from a number of companies with an interest in anxiety and depressive disorders (Asahi, Cephalon, Eli Lilly, GlaxoSmithKline (GSK), Lundbeck, Pzer, Organon, Pharmacia, Pierre Fabre, Roche, Servier, Sumitomo, Wyeth). He holds or has held research grants (on behalf of his employer) from a number of companies with an interest in anxiety and depressive disorders (Cephalon, Eli Lilly, GSK, Lundbeck, Organon, Pzer, Pharmacia, Roche, Wyeth). Barbara Barrett has acted as an independent consultant to Servier for the development of an economic model of agomelatine in the UK. Pierre Baumann has served on the advisory boards of Pzer and Lundbeck in Switzerland. He has been sponsored by almost all pharmaceutical companies involved in psychopharmacology in Switzerland to carry out studies, participate in symposia and organize congresses. He has stocks in Novartis and Roche. Ursula Brand has no conicting interests. Max Fink has no commercial contracts or appointments and receives no funding from industry sources that may inuence the conclusions of his contributions to the review. Wolfgang Fleischhacker discloses that he received speaking/consultancy honoraria from Bristol-Myers Squibb (BMS)/Otsuka, AstraZeneca, Janssen-Cilag, Lundbeck, Pzer, Servier and Wyeth. He also holds or has held research support from BMS/Otsuka, Janssen and Servier. Konstantinos Fountoulakis has received support concerning travel and accommodation expenses from various pharmaceutical companies in order to participate in medical congresses. He has also received honoraria for lectures from AstraZeneca, Janssen-Cilag, Eli Lilly and a research grant from the Pzer Foundation.

Organization and other institutions and organizations in this process ; 3. To develop materials that will be suitable for the correct information of the general public about depressive disorders and the possibilities of their treatment. AND RECOMMENDS 1. To governments to introduce educational programs concerning depressive disorders in all schools of health personnel and in in-service training of health sta to ensure that people with depressive disorders receive adequate help and treatment ; these programs should include families as well. 2. To professional societies in the eld of mental health to participate in the development of comprehensive treatment and rehabilitation programs for people with depressive disorders ; 3. To non-governmental organizations of patients and their families to participate in the development of training materials and collaborate in other ways with professional organizations and institutions engaged in the programs designed to improve the treatment of people with mental disorders ; 4. To the media to collaborate with professional organizations in the eort to bring well-balanced information about depressive disorders to the general public. 16 Acknowledgements Work on this review has been supported by unrestricted grants made to the CINP by the following companies : Bristol-Myers Squibb Company, Eli Lilly and Company, Forest Laboratories, GlaxoSmithKline, H. Lundbeck A/S, Les Laboratoires Servier and Wyeth. The funds received served to organize and cover the expenses of travel and accommodation for meetings of the Task Force as well as national and regional meetings of experts. The funds were also used for administrative support in producing the review. None of the members of the Task Force nor any of the advisers received any fees nor honoraria for their work. Prof. Xiao Zeping, President of the Shanghai Mental Health Center in Shanghai, China, Prof. Nikolaj Nesnanov, Director of the Bekhterev Psychoneurological Institute in St. Petersburg, Russia, and Dr Edgar Belfort, Administrative Secretary of the Association of Psychiatrists of Latin America (APAL) in Caracas, Venezuela, organized and hosted regional meetings related to the project. Prof. Moller, Chairman of the Psychiatric De partment of the Ludwig-Maximilians-Universitat

CINP Antidepressant Task Force 2007 Toshiaki Furukawa has received research funds and speaking fees from Asahi Kasei, Astellas, Dai-Nippon, Eisai, Eli Lilly, GSK, Janssen, Kyowa Hakko, Meiji, Organon, Pzer, Tsumura, Yoshitomi and Zelia. The Japanese Ministry of Education, Science and Technology, and the Japanese Ministry of Health, Labor and Welfare have also funded his research. Karim Ghalib has no conicts of interest. Guy M. Goodwin received grants from SanoAventis, Servier and honoraria from AstraZeneca, BMS, Eisai, Lilly, Lundbeck, Pzer, Sano-Aventis, Servier and Wyeth. He serves on the advisory boards of Lilly, Lundbeck, P1Vital, Sano-Aventis, Servier, Wyeth. He has no shares in pharmaceutical companies. He holds or has held research grants from SanoAventis, Lilly, Stanley MRI, the Bailey-Thomas Trust and the MRC (UK). Heinz Grunze receives research grants from Novartis, AstraZeneca, UCB Belgium and Pzer. He occasionally supplies services as a consultant and/or paid speaker for AstraZeneca, Sano-Aventis, Desitin, Lilly, Janssen-Cilag, BMS and Pzer. Peter Jensen currently receives investigator-initiated grants from McNeil Pharmaceuticals and unrestricted educational grants from Pzer, Lilly and McNeil, participates in speakers bureaus for CMED, the Union Chimique Belge Pharma, PsychCME, Continuing Medical Education Outtters and the Neuroscience Education Institute, and consults to Best Practice, Inc., Janssen Pharma, Novartis and the Union Chimique Belge Pharma. Shigenobu Kanba Grants or contracts : Lilly, GSK, Pzer, Asahi-Kasei, Janssen, Tsumura, Ajinomoto, Yoshitomi, Meiji, Kyowa-Hakko, Sumitomo, Organon, Otsuka. Consultant : Lilly, Pzer, Mitsubishi, Ono, Astellas, Otsuka. Martin Knapp discloses the following consulting services and research grants from the pharmaceutical industry pertinent to this review : Servier, Lilly, Organon, Sano-Aventis, Pzer, Novartis. Jerey Liebermann discloses that he holds or has held research grants from BMS/Otsuka, GSK, Janssen, Pzer and Acadia. He is also patent holder of Repligen. John C. Markowitz was a consultant in 2006 for Ono Pharmaceuticals ; in the past he has received speakers honoraria and/or consulting fees from Pzer, BMS and Forest. Yoshibumi Nakane is a supervisor of The Japanese Committee of Prevention and Treatment for Depression sponsored by Eli Lilly and Shionogi. Frank Padberg has no conicts of interests. Roger Pinder was a full-time employee of Organon until June 2004. Since then he has received honoraria

S123

and/or travel support from Organon for chairing and speaking at symposia. He also acts as non-executive Chairman of NeuroCure Ltd. (Dublin) and as a consultant to Cypress Bioscience Inc. (San Diego), Daniolabs Ltd. (Cambridge, UK), Nomura Phase4 Ventures (London) and Organon International Inc. (New Jersey, USA). Anita Riecher-Rossler discloses that she received speaking/consultancy honoraria or research grants from BMS, AstraZeneca, Janssen-Cilag, Eli Lilly and Sano-Synthelabo. Norman Sartorius acted as consultant and/or received honoraria for presentations at meetings and symposia organized by Eli Lilly, Janssen, Lundbeck, Pzer, Servier and Wyeth. Alan Schatzberg acted as a consultant to and/or accepted paid speaking engagements in satellite symposia from Abbott, Aventis, BrainCells, BMS, Corcept, Eli Lilly, Forest Labs, GSK, Janssen-Cilag, Neuronetics, Organon, Pzer, Somaxon, Somerset and Wyeth. He holds or has held research grants from Somerset and Wyeth and holds equities from BrainCells, Corcept, Merck, Organon, Pzer and Somaxon. Jaromr Svestka acted as a consultant to and/or accepted paid speaking engagements in satellite symposia from AstraZeneca, Sano-Aventis, BMS, Desitin, Eli Lilly, Janssen-Cilag, KrkaPzer, Zenziva. He received support for participation in international congresses from BMS, Eli Lilly, Janssen-Cilag, Pzer and Zentiva.

18 References
Aarre TF, Bugge P (2002). ECT for patients taking lamotrigine. European Psychiatry 17 (Suppl. 1), 135. Abrams R (2002). Electroconvulsive Therapy. Oxford : Oxford University Press. Acharya N, Rosen AS, Polzer JP, DSouza DN, Perahia DG, Cavazzoni PA, Baldessarini RJ (2006). Duloxetine : metaanalyses of suicidal behaviors and ideation in clinical trials for major depressive disorder. Journal of Clinical Psychopharmacology 26, 587594. Ackerman DL, Greenland S (2002). Multivariate metaanalysis of controlled drug studies for obsessivecompulsive disorder. Journal of Clinical Psychopharmacology 22, 309317. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M (2005). Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed ? A systematic review. European Archives of Psychiatry and Clinical Neuroscience 255, 387400. Adli M, Berghofer A, Linden M, Helmchen H, Muller-Oerlinghausen B, Mackert A, Stamm T,

S124

CINP Antidepressant Task Force 2007

Taub N, Vollebergh WA (2004). Prevalence of mental disorders in Europe : results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatrica Scandinavica. Supplementum 2127. Altar CA (1999). Neurotrophins and depression. Trends in Pharmacological Sciences 20, 5961. Althaus D, Niklewski G, Schmidtke A, Hegerl U (2006). [Changes in the frequency of suicidal behaviour after a 2-year intervention campaign.]. Nervenarzt. 10.1007/s00115-005-2031-5. Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC (2001). Does thyroid supplementation accelerate tricyclic antidepressant response ? A review and meta-analysis of the literature. American Journal of Psychiatry 158, 16171622. Ambrosini PJ (2000). A review of pharmacotherapy of major depression in children and adolescents. Psychiatric Services 51, 627633. American Diabetes Association (2003). Economic cost of diabetes in the US in 2002. Diabetes Care 26, 917932. American Diabetes Association (2005). Antidepressants Associated With Increased Risk of Diabetes in Pre-Diabetes (www.diabetes.org). Accessed 10 November 2006. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. Washington DC : American Psychiatric Press. American Psychiatric Association (2000). Practice guideline for the treatment of patients with major depressive disorder (revision). American Journal of Psychiatry 157, 145. American Psychiatric Association Committee on Electroconvulsive Therapy, Weiner RD, Coey CE, Folk J, Fochtmann LJ, Greenberg RM, Isenberg KE, Kellner CH, Sackeim HA, Moench LM (2001). The Practice of Electroconvulsive Therapy. Washington : American Psychiatric Association. Amore M, Jori MC (2001). Faster response on amisulpride 50 mg versus sertraline 50100 mg in patients with dysthymia or double depression : a randomized, double-blind, parallel group study. International Clinical Psychopharmacology 16, 317324. Amsterdam JD (2003). A double-blind, placebo-controlled trial of the safety and ecacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. Journal of Clinical Psychiatry 64, 208214. Amsterdam JD, Bodkin JA (2006). Selegiline transdermal system in the prevention of relapse of major depressive disorder : a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. Journal of Clinical Psychopharmacology 26 (6), 579586. Amsterdam JD, Shults J (2005). MAOI ecacy and safety in advanced stage treatment-resistant depression-A retrospective study. Journal of Aective Disorders 89, 183188. Anand A, Malison RT, McDougle CJ, Price LH (1995). Antiglucocorticoid treatment of refractory depression with ketoconazole : a case report. Biological Psychiatry 37, 338340.

Bauer M (2002). Eectiveness and feasibility of a standardized stepwise drug treatment regimen algorithm for inpatients with depressive disorders : results of a 2-year observational algorithm study. Journal of Clinical Psychiatry 63, 782790. Adli M, Rush AJ, Moller HJ, Bauer M (2003). Algorithms for optimizing the treatment of depression : making the right decision at the right time. Pharmacopsychiatry 36 (Suppl. 3), S222S229. Agency for Health Care Policy and Research (1993). Depression Guideline Panel : Depression in Primary Care. Rockville, MD : U.S. Department of Health and Human Services. AHCPR (Agency for Health Care Policy and Research) (1999). Evidence Report on Treatment of Depression : Newer Pharmacotherapies. Washington DC : AHCPR. Aichhorn W, Whitworth AB, Weiss U, Stuppaeck C (2004). Mirtazapine and breast-feeding. American Journal of Psychiatry 161, 2325. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, Amini H, Fallah-Pour H, Jamshidi AH, Khani M (2005). Crocus sativus L. in the treatment of mild to moderate depression : a double-blind, randomized and placebo-controlled trial. Phytotherapy Research 19, 148151. Akiskal H, Bourgeois ML, Angst J, Post R, Moller HJ, Hirschfeld RM (2000). Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. Journal of Aective Disorders 59 (Suppl. 1), 530. Akiskal HS, Benazzi F (2006). The DSM-IV and ICD-10 categories of recurrent [major] depressive and bipolar II disorders : evidence that they lie on a dimensional spectrum. Journal of Aective Disorders 92, 4554. Alarcon RD, Westermeyer J, Foulks EF, Ruiz P (1999). Clinical relevance of contemporary cultural psychiatry. Journal of Nervous and Mental Disease 187, 465471. Alexopoulos GS, Katz IR, Reynolds CF, III, Carpenter D, Docherty JP (2001). The expert consensus guideline series. Pharmacotherapy of depressive disorders in older patients. Postgrad. Med. Spec No Pharmacotherapy, 186. Alfonso J, Frick LR, Silberman DM, Palumbo ML, Genaro AM, Frasch AC (2006). Regulation of hippocampal gene expression is conserved in two species subjected to dierent stressors and antidepressant treatments. Biological Psychiatry 59, 244251. Allen JJB, Schnyer RN (1998). The ecacy of acupuncture in the treatment of major depression in women. Psychological Science 9, 397402. Alonso J, Angermeyer MC, Bernert S, Bruaerts R, Brugha TS, Bryson H, de Girolamo G, Graaf R, Demyttenaere K, Gasquet I, Haro JM, Katz SJ, Kessler RC, Kovess V, Lepine JP, Ormel J, Polidori G, Russo LJ, Vilagut G, Almansa J, Arbabzadeh-Bouchez S, Autonell J, Bernal M, Buist-Bouwman MA, Codony M, Domingo-Salvany A, Ferrer M, Joo SS, Martinez-Alonso M, Matschinger H, Mazzi F, Morgan Z, Morosini P, Palacin C, Romera B,

CINP Antidepressant Task Force 2007

Ananth J (1998). Treatment-resistant depression. Psychotherapy and Psychosomatics 67, 6170. Anderson IM (1998). SSRIS versus tricyclic antidepressants in depressed inpatients : a meta-analysis of ecacy and tolerability. Depression & Anxiety 7 (Suppl. 1), 117., 1117. Anderson IM (2000). Selective serotonin reuptake inhibitors versus tricyclic antidepressants : a meta-analysis of ecacy and tolerability. Journal of Aective Disorders 58, 1936. Anderson CS, Hackett ML, House AO (2004). Interventions for preventing depression after stroke. Cochrane Database of Systematic Reviews. CD003689. Anderson IM (1998). SSRIS versus tricyclic antidepressants in depressed inpatients : a meta-analysis of ecacy and tolerability. Depression and Anxiety 7 (Suppl. 1), 1117. Anderson IM (2000a). Selective serotonin reuptake inhibitors versus tricyclic antidepressants : a meta-analysis of ecacy and tolerability. Journal of Aective Disorders 58, 1936. Anderson IM, Nutt DJ, Deakin JF (2000). Evidence-based guidelines for treating depressive disorders with antidepressants : a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. Journal of Psychopharmacology 14, 320. Anderson J (2000b). On variability of eects for a metaanalysis of rheumatoid arthritis radiographic progression. Journal of Rheumatology 27, 540542. Andersson HI, Ejlertsson G, Leden I, Rosenberg C (1993) Chronic pain in a geographically dened general population : studies of dierences in age, gender, social class, and pain localization. Clinical Journal of Pain 9, 174182. Andlin-Sobocki P, Jonsson B, Wittchen H-U, Olesen J (2005). Cost of brain disorders in Europe. European Journal of Neurology 12, S1S27. Andlin-Sobocki P, Wittchen HU (2005). Cost of aective disorders in Europe. European Journal of Neurology 12 (Suppl. 1), 3438. Andrade L, Caraveo-Anduaga JJ, Berglund P, Bijl RV, de Graaf R, Vollebergh W, Dragomirecka E, Kohn R, Keller M, Kessler RC, Kawakami N, Kilic C, Oord D, Ustun TB, Wittchen HU (2003). The epidemiology of major depressive episodes : results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. International Journal of Methods in Psychiatric Research 12, 321. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M, Rodrigo L, Romero-Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmeron J, Martin-Vivaldi R (2005). Drug-induced liver injury : an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129, 512521. Andrews JM, Nemero CB (1994). Contemporary management of depression. American Journal of Medicine 97, 24S32S.

S125

Anghelescu I, Klawe C, Dahmen N (2002). Venlafaxine in a patient with idiopathic leukopenia and mirtazapineinduced severe neutropenia. Journal of Clinical Psychiatry 63, 838. Angst F, Stassen HH, Clayton PJ, Angst J (2002a). Mortality of patients with mood disorders : followup over 34-38 years. Journal of Aective Disorders 68, 167181. Angst J (2006). Do many patients with depression suer from bipolar disorder ? Canadian Journal of Psychiatry 51, 35. Angst J, Angst F, Gerber-Werder R, Gamma A (2005). Suicide in 406 mood-disorder patients with and without long-term medication : a 40 to 44 years follow-up. Archives of Suicide Research 9, 279300. Angst J, Angst K, Baruol I, Meinherz-Surbeck R (1992). ECT-induced and drug-induced hypomania. Convulsive Therapy 8, 179185. Angst J, Dobler-Mikola A (1985). The Zurich Study : a prospective epidemiological study of depressive, neurotic and psychosomatic syndromes. IV. Recurrent and nonrecurrent brief depression. European Archives of Psychiatry and Neurological Science 234, 408416. Angst J, Gamma A, Gastpar M, Lepine JP, Mendlewicz J, Tylee A (2002b). Gender dierences in depression. Epidemiological ndings from the European DEPRES I and II studies. European Archives of Psychiatry and Clinical Neuroscience 252, 201209. Annegers JF, Coan SP, Hauser WA, Leestma J (2000). Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality, and sudden, unexpected, unexplained death. Epilepsia 41, 549553. Anon. (2001). Extrapyramidal eects of SSRI antidepressants. Prescrire International 10, 118119. Anon. (2002). Factors impacting on quality of life in Parkinsons disease : results from an international survey. Movement Disorders 17, 6067. Anon. (2004). Mirtazapine : seizures and neutropenia. Prescrire International 13, 58. Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (2004). Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306, 879881. Anton RF, Burch EA (1990). Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. American Journal of Psychiatry 147, 12031208. Anton SF, Revicki DA (1995). The use of decision analysis in the pharmacoeconomic evaluation of an antidepressant : a cost-eectiveness study of nefazodone. Psychopharmacology Bulletin 31, 249258. Appelberg BG, Syvalahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH (2001). Patients with severe depression may benet from buspirone augmentation of selective serotonin reuptake inhibitors : results from a placebo-controlled, randomized, double-blind, placebo wash-in study. Journal of Clinical Psychiatry 62, 448452. Aranow RB, Hudson JI, Pope HG, Grady TA, Laage TA, Bell IR, Cole JO (1989). Elevated antidepressant plasma

S126

CINP Antidepressant Task Force 2007

Deiml T, Uhr M, Illig T, Wichmann HE, Modell S, Nothdurfter C, Holsboer F, Muller-Myhsok B, Moller HJ, Rupprecht R, Bondy B (2006a). Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Molecular Psychiatry 11, 10031115. Baghai TC, Eser D, Schule C, Nothdurfter C, Moller HJ, Rupprecht R (2005). Elektrokonvulsionstherapie bei depressiven Storungen. Journal Fur Neurologie, Neurochirurgie Und Psychiatrie 4/2005, 2028. Baghai TC, Marcuse A, Brosch M, Schule C, Eser D, Nothdurfter C, Steng Y, Noack I, Pietschmann K, Moller HJ, Rupprecht R (2006b). The inuence of concomitant antidepressant medication on safety, tolerability and clinical eectiveness of electroconvulsive therapy. World Journal of Biological Psychiatry 7, 8290. Baghai TC, Moller HJ, Rupprecht R (2006c). Recent progress in pharmacological and non-pharmacological treatment options of major depression. Current Pharmaceutical Design 12, 503515. Baghai TC, Schule C, Zill P, Deiml T, Eser D, Zwanzger P, Ella R, Rupprecht R, Bondy B (2004). The angiotensin I converting enzyme insertion/deletion polymorphism inuences therapeutic outcome in major depressed women, but not in men. Neuroscience Letters 363, 3842. Baghai TC, Schule C, Zwanzger P, Minov C, Schwarz MJ, de Jonge S, Rupprecht R, Bondy B (2001). Possible inuence of the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene on therapeutic outcome in aective disorders. Molecular Psychiatry 6, 258259. Baghai TC, Schule C, Zwanzger P, Minov C, Zill P, Ella R, Eser D, Oezer S, Bondy B, Rupprecht R (2002). Hypothalamic-pituitary-adrenocortical axis dysregulation in patients with major depression is inuenced by the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene. Neuroscience Letters 328, 299303. Baghai TC, Schule C, Zwanzger P, Zill P, Ella R, Eser D, Deiml T, Minov C, Rupprecht R, Bondy B (2003). Inuence of a functional polymorphism within the angiotensin I-converting enzyme gene on partial sleep deprivation in patients with major depression. Neuroscience Letters 339, 223226. Balazs J, Benazzi F, Rihmer Z, Rihmer A, Akiskal KK, Akiskal HS (2006). The close link between suicide attempts and mixed (bipolar) depression : implications for suicide prevention. Journal of Aective Disorders 91, 133138. Baldessarini RJ, Tondo L, Hennen J (2003). Lithium treatment and suicide risk in major aective disorders : update and new ndings. Journal of Clinical Psychiatry 64 (Suppl. 5), 4452. Baldwin DS (2002). Escitalopram : ecacy and tolerability in the treatment of depression. Hospital Medicine 63, 668671. Baldwin DS, Birtwistle J (1998). The side eect burden associated with drug treatment of panic disorder. Journal of Clinical Psychiatry 59 (Suppl. 8), 3944.

levels after addition of uoxetine. American Journal of Psychiatry 146, 911913. Arinami T, Li L, Mitsushio H, Itokawa M, Hamaguchi H, Toru M (1996). An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and aective disorders. Biological Psychiatry 40, 11221127. Arinzon ZH, Lehman YA, Fidelman ZG, Krasnyansky II (2002). Delayed recurrent SIADH associated with SSRIs. Annals of Pharmacotherapy 36, 11751177. Armstrong SC, Cozza KL (2000). Consultation-liaison psychiatry drug-drug interactions update. Psychosomatics 41, 155156. Aronson R, Oman HJ, Joe RT, Naylor CD (1996). Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Archives of General Psychiatry 53, 842848. Arroll B, Goodyear-Smith F, Kerse N, Fishman T, Gunn J (2005). Eect of the addition of a help question to two screening questions on specicity for diagnosis of depression in general practice : diagnostic validity study. British Medical Journal 331, 884. Artigas F, Adell A, Celada P (2006). Pindolol augmentation of antidepressant response. Current Drug Targets 7, 139147. Artigas F, Celada P, Laruelle M, Adell A (2001). How does pindolol improve antidepressant action ? Trends in Pharmacological Sciences 22, 224228. Asnis GM, De La Garza R, II (2006). Interferon-induced depression in chronic hepatitis C : a review of its prevalence, risk factors, biology, and treatment approaches. Journal of Clinical Gastroenterology 40, 322335. Audinot V, Mailliet F, Lahaye-Brasseur C, Bonnaud A, Le Gall A, Amosse C, Dromaint S, Rodriguez M, Nagel N, Galizzi JP, Malpaux B, Guillaumet G, Lesieur D, Lefoulon F, Renard P, Delagrange P, Boutin JA (2003). New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedebergs Archives of Pharmacology 367, 553561. Avery DH, Norden MJ (1998). Dawn stimulation and bright light therapy in subsyndromal seasonal aective disorder. In : Lam R (Ed.), Seasonal Aective Disorder and Beyond : Light Treatment for SAD and Non-SAD Conditions. Washington, DC : American Psychiatric Press. Avila A, Cardona X, Martin-Baranera M, Maho P, Sastre F, Bello J (2003). Does nefazodone improve both depression and Parkinson disease ? A pilot randomized trial. Journal of Clinical Psychopharmacology 23, 509513. Baboolal NS (2004). Venlafaxine withdrawal syndrome : report of seven cases in Trinidad. Journal of Clinical Psychopharmacology 24, 229231. Baca E, Garcia-Garcia M, Porras-Chavarino A (2004). Gender dierences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 28, 5765. Baghai TC, Binder EB, Schule C, Salyakina D, Eser D, Lucae S, Zwanzger P, Haberger C, Zill P, Ising M,

CINP Antidepressant Task Force 2007

Baldwin DS, Montgomery SA, Nil R, Lader M (2005). Discontinuation symptoms in depression and anxiety disorders. International Journal of Neuropsychopharmacology. 10.1017/S1461145705006358. Baldwin DS, Polkinghorn C (2005). Evidence-based pharmacotherapy of Generalized Anxiety Disorder. International Journal of Neuropsychopharmacology 8, 293302. Baldwin RC, Anderson D, Black S, Evans S, Jones R, Wilson K, Ilie S (2003). Guideline for the management of late-life depression in primary care. International Journal of Geriatric Psychiatry 18, 829838. Ballesteros J, Callado LF (2004). Eectiveness of pindolol plus serotonin uptake inhibitors in depression : a metaanalysis of early and late outcomes from randomised controlled trials. Journal of Aective Disorders 79, 137147. Bambauer KZ, Adams AS, Zhang F, Minko N, Grande A, Weisblatt R, Soumerai SB, Ross-Degnan D (2006). Physician alerts to increase antidepressant adherence : fax or ction ? Arch. Intern. Med. 166, 498504. Ban TA (2001). Pharmacotherapy of depression : a historical analysis. Journal of Neural Transmission 108, 707716. Ban TA, Healy D, Shorter E (1998). The rise of Psychopharmacology and The story on CINP. Animula Publishing House (Hungary). Ban TA (2006a). A history of the Collegium Internationale Neuro-Psychopharmacologicum (19572004). Progress in Neuro-Psychopharmacology and Biological Psychiatry 30, 599616. Ban TA (2006b). Academic psychiatry and the pharmaceutical industry. Progress in NeuroPsychopharmacology and Biological Psychiatry 30, 429441. Bano S, Akhter S, Afridi MI (2004). Gender based response to uoxetine hydrochloride medication in endogenous depression. Journal of the College of Physicians and Surgeons Pakistan 14, 161165. Barbee JG, Conrad EJ, Jamhour NJ (2004). The eectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. Journal of Clinical Psychiatry 65, 975981. Barbee JG, Jamhour NJ (2002). Lamotrigine as an augmentation agent in treatment-resistant depression. Journal of Clinical Psychiatry 63, 737741. Barbey JT, Roose SP (1998). SSRI safety in overdose. Journal of Clinical Psychiatry 59 (Suppl. 15), 4248. Barbosa L, Berk M, Vorster M (2003). A doubleblind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with uoxetine for resistant major depressive episodes. Journal of Clinical Psychiatry 64, 403407. Barbour KA, Blumenthal JA (2005). Exercise training and depression in older adults. Neurobiology of Aging 26 (Suppl. 1), 119123. Barbui C, Hotopf M, Freemantle N, Boynton J, Churchill R, Eccles MP, Geddes JR, Hardy R, Lewis G, Mason JM (2000). Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants : comparison of

S127

drug adherence. Cochrane Database of Systematic Reviews. CD002791. Barbui C, Guaiana G, Garattini S (2001). Regulatory issues in Europe. Journal of Clinical Psychopharmacology 21, 545548. Barbui C, Percudani M, Hotopf M (2003). Economic evaluation of antidepressive agents : a systematic critique of experimental and observational studies. Journal of Clinical Psychopharmacology 23, 145154. Barden N, Reul JM, Holsboer F (1995). Do antidepressants stabilize mood through actions on the hypothalamicpituitary-adrenocortical system ? Trends in Neurosciences 18, 611. Barkin RL, Barkin S (2005). The role of venlafaxine and duloxetine in the treatment of depression with decremental changes in somatic symptoms of pain, chronic pain, and the pharmacokinetics and clinical considerations of duloxetine pharmacotherapy. American Journal of Therapeutics 12, 431438. Barlow DH, Gorman JM, Shear MK, Woods SW (2000). Cognitive-behavioral therapy, imipramine, or their combination for panic disorder : a randomized controlled trial. Journal of the American Medical Association 283, 25292536. Bartels SJ, Dums AR, Oxman TE, Schneider LS, Arean PA, Alexopoulos GS, Jeste DV (2003). Evidence-based practices in geriatric mental health care : an overview of systematic reviews and meta-analyses. Psychiatric Clinics of North America 26, 971990, xxi. Bauer M, Adli M, Baethge C, Berghofer A, Sasse J, Heinz A, Bschor T (2003). Lithium augmentation therapy in refractory depression : clinical evidence and neurobiological mechanisms. Canadian Journal of Psychiatry 48, 440448. Bauer M, Baur H, Berghofer A, Strohle A, Hellweg R, Muller-Oerlinghausen B, Baumgartner A (2002a). Eects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders. Journal of Aective Disorders 68, 285294. Bauer M, Bschor T, Kunz D, Berghofer A, Strohle A, Muller-Oerlinghausen B (2000). Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. American Journal of Psychiatry 157, 14291435. Bauer M, Dopfmer S (1999). Lithium augmentation in treatment-resistant depression : meta-analysis of placebocontrolled studies. Journal of Clinical Psychopharmacology 19, 427434. Bauer M, Hellweg R, Graf KJ, Baumgartner A (1998). Treatment of refractory depression with high-dose thyroxine. Neuropsychopharmacology 18, 444455. Bauer M, London ED, Rasgon N, Berman SM, Frye MA, Altshuler LL, Mandelkern MA, Bramen J, Voytek B, Woods R, Mazziotta JC, Whybrow PC (2005). Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression. Molecular Psychiatry 10, 456469.

S128

CINP Antidepressant Task Force 2007

the treatment of mild to moderate depression. Advances in Therapy 19, 4352. Belano JK, Flores BH, Kalezhan M, Sund B, Schatzberg AF (2001). Rapid reversal of psychotic depression using mifepristone. Journal of Clinical Psychopharmacology 21, 516521. Belano JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C, Schatzberg AF (2002). An open label trial of C-1073 (mifepristone) for psychotic major depression. Biological Psychiatry 52, 386392. Belloeuf L, Le JC, Hugues FC (2000). [Paroxetine withdrawal syndrome]. Annales de Medecine Interne (Paris) 151 (Suppl. A), A52A53. Beliles K, Stoudemire A (1998). Psychopharmacologic treatment of depression in the medically ill. Psychosomatics 39, S219. Bell C, Abrams J, Nutt D (2001). Tryptophan depletion and its implications for psychiatry. British Journal of Psychiatry 178, 399405. Bellantuono C, Migliarese G, Imperadore G (2006). [Pharmacologic therapy of depression during pregnancy]. Recenti Progressi in Medicina 97, 94107. Ben-Arie O, George GC (1979). A case of tranylcypromine ( Parnate) addiction. British Journal of Psychiatry 135, 273274. Benedetti F, Barbini B, Fulgosi MC, Colombo C, Dallaspezia S, Pontiggia A, Smeraldi E (2005). Combined total sleep deprivation and light therapy in the treatment of drug-resistant bipolar depression : acute response and long-term remission rates. Journal of Clinical Psychiatry 66, 15351540. Benedetti F, Colombo C, Barbini B, Campori E, Smeraldi E (1999). Ongoing lithium treatment prevents relapse after total sleep deprivation. Journal of Clinical Psychopharmacology 19, 240245. Benedetti F, Colombo C, Barbini B, Campori E, Smeraldi E (2001). Morning sunlight reduces length of hospitalization in bipolar depression. Journal of Aective Disorders 62, 221223. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E (2003). Morning light treatment hastens the antidepressant eect of citalopram : a placebo-controlled trial. Journal of Clinical Psychiatry 64, 648653. Benedetti F, Wirz-Justice A, Terman M (2006). Personal communication. Benkert O, Grunder G, Wetzel H, Hackett D (1996). A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. Journal of Psychiatric Research 30, 441451. Benkert O, Muller M, Szegedi A (2002). An overview of the clinical ecacy of mirtazapine. Human Psychopharmacology 17 (Suppl. 1), S23S26. Benkert O, Szegedi A, Kohnen R (2000). Mirtazapine compared with paroxetine in major depression. Journal of Clinical Psychiatry 61, 656663. Benkert O, Szegedi A, Philipp M, Kohnen R, Heinrich C, Heukels A, van der Vegte-Senden M, Baker RA,

Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ (2002b). World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders. Part 2. Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World Journal of Biological Psychiatry 3, 6986. Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ, WFSBP Task Force on Tretment Guidelines for Unipolar Depressive Disorders (2002c). World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of unipolar depressive disorder. Part 1. Acute and continuation treatment of major depressive disorder. World Journal of Biological Psychiatry 3, 443. Baumann P (1996). Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clinical Pharmacokinetics 31, 444469. Baumann P, Broly F, Kosel M, Eap CB (1998). Ultrarapid metabolism of clomipramine in a therapy-resistant depressive patient, as conrmed by CYP2 D6 genotyping. Pharmacopsychiatry 31, 72. Baumann P, Eap CB (2001). Enantiomeric antidepressant drugs should be considered on individual merit. Human Psychopharmacology 16, S85S92. Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Kuss HJ, Laux G, Muller-Oerlinghausen B, Rao ML, Riederer P, Zernig G (2004). The AGNP-TDM expert group consensus guidelines : therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 37, 243265. Baumann P, Ulrich S, Eckermann G, Gerlach M, Kuss HJ, Laux G, Muller-Oerlinghausen B, Rao ML, Riederer P, Zernig G, Hiemke C (2005). The AGNP-TDM Expert Group Consensus Guidelines : focus on therapeutic monitoring of antidepressants. Dialogues in Clinical Neuroscience 7, 231247. Baumann P, Zullino DF, Eap CB (2002). Enantiomers potential in psychopharmacology : a critical analysis with special emphasis on the antidepressant escitalopram. European Neuropsychopharmacology 12, 433444. Baxter K (2006). Stockleys Drug Interactions : a Source Book of Interactions, Their Mechanisms, Clinical Importance and Management. London : Pharmaceutical Press. Bech P, Tanghoj P, Cialdella P, Andersen HF, Pedersen AG (2004). Escitalopram dose-response revisited : an alternative psychometric approach to evaluate clinical eects of escitalopram compared to citalopram and placebo in patients with major depression. International Journal of Neuropsychopharmacology 7, 283290. Beck AT (1967). Depression : Clinical, Experimental and Theoretical Aspects. New York : Harper & Row. Beck AT, Rush AJ, Shaw BF, Emery G (1979). Cognitive Therapy of Depression. New York : Guilford. Beckman SE, Sommi RW, Switzer J (2000). Consumer use of St. Johns wort : a survey on eectiveness, safety, and tolerability. Pharmacotherapy 20, 568574. Behnke K, Jensen GS, Graubaum HJ, Gruenwald J (2002). Hypericum perforatum versus uoxetine in

CINP Antidepressant Task Force 2007

Simmons JH, Schutte AJ (2006). Mirtazapine orally disintegrating tablets versus venlafaxine extended release : a double-blind, randomized multicenter trial comparing the onset of antidepressant response in patients with major depressive disorder. Journal of Clinical Psychopharmacology 26, 7578. Bennett DS, Ambrosini PJ, Kudes D, Metz C, Rabinovich H (2005). Gender dierences in adolescent depression : do symptoms dier for boys and girls ? Journal of Aective Disorders 89, 3544. Bennett HG, Wyllie AM (1999). Paroxetine and acute angleclosure glaucoma. Eye 13 (Pt 5), 691692. Berard R, Fong R, Carpenter DJ, Thomason C, Wilkinson C (2006). An international, multicenter, placebo-controlled trial of paroxetine in adolescents with major depressive disorder. Journal of Child and Adolescent Psychopharmacology 16, 5975. Berg AO (2002). Screening for depression : recommendations and rationale. American Journal of Nursing 102, 7780. Berger M, van Calker D, Riemann D (2003). Sleep and manipulations of the sleep-wake rhythm in depression. Acta Psychiatrica Scandinavica. Supplementum 8391. Berk M, Dodd S (2005a). Antidepressants and adolescents : the bipolar confound ? Human Psychopharmacology 20, 12. Berk M, Dodd S (2005b). Are treatment emergent suicidality and decreased response to antidepressants in younger patients due to bipolar disorder being misdiagnosed as unipolar depression ? Medical Hypotheses 65, 3943. Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ, Czajkowski SM, DeBusk R, Hosking J, Jae A, Kaufmann PG, Mitchell P, Norman J, Powell LH, Raczynski JM, Schneiderman N (2003). Eects of treating depression and low perceived social support on clinical events after myocardial infarction : the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. Journal of the American Medical Association 289, 31063116. Berlim MT, Turecki G (2007). What is the meaning of treatment resistant/refractory major depression (TRD) ? A systematic review of current randomized trials. European Neuropsychopharmacology 17, 696707. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000a). Antidepressant eects of ketamine in depressed patients. Biological Psychiatry 47, 351354. Berman RM, Narasimhan M, Sanacora G, Miano AP, Homan RE, Hu XS, Charney DS, Boutros NN (2000b). A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biological Psychiatry 47, 332337. Berndt ER (2005). To inform or persuade ? Direct-toconsumer advertising of prescription drugs. New England Journal of Medicine 352, 325328. Berndt ER, Finkelstein SN, Greenberg PE, Howland RH, Keith A, Rush AJ, Russell J, Keller MB (1998). Workplace performance eects from chronic depression and its treatment. Journal of Health Economics 17, 511535.

S129

Bertilsson L, Aberg-Wistedt A, Gustafsson LL, Nordin C (1985). Extremely rapid hydroxylation of debrisoquine : a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Therapeutic Drug Monitoring 7, 478480. Bertilsson L, Dahl ML, Dalen P, Al Shurbaji A (2002). Molecular genetics of CYP2D6 : clinical relevance with focus on psychotropic drugs. British Journal of Clinical Pharmacology 53, 111122. Bertilsson L, Mellstrom B, Sjoqvist F, Martensson B, Asberg M (1981). Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation : clinical implications. Lancet i, 560561. Bertschy G, Vandel S, Vandel B, Allers G, Volmat R (1991). Fluvoxamine-tricyclic antidepressant interaction : an accidental nding. European Journal of Clinical Pharmacology 40, 119120. Beutler LE, Clarkin JF, Bongar B (2000). Guidelines for the Systematic Treatment of the Depressed Patient. New York : Oxford University Press. Bezchlibnyk-Butler K, Aleksic I, Kennedy SH (2000). Citalopram : a review of pharmacological and clinical eects. Journal of Psychiatry and Neuroscience 25, 241254. Bickel A, Kornhuber J, Maihofner C, Ropohl A (2005). Exacerbation of migraine attacks during treatment with the selective serotonin reuptake inhibitor sertraline. A case report. Pharmacopsychiatry 38, 327328. Bielski RJ, Ventura D, Chang CC (2004). A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. Journal of Clinical Psychiatry 65, 11901196. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T, Muller N, Pster H, Lieb R, Mueller JC, Lohmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B (2004). Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genetics 36, 13191325. Birkenhager TK, Renes JW, Pluijms EM (2004). One-year follow-up after successful ECT : a naturalistic study in depressed inpatients. Journal of Clinical Psychiatry 65, 8791. Birmaher B, Brent DA, Benson RS (1998). Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. American Academy of Child and Adolescent Psychiatry. Journal of the American Academy of Child and Adolescent Psychiatry 37, 12341238. Bitran D, Hilvers RJ, Kellogg CK (1991). Anxiolytic eects of 3a-hydroxy-5a[b]-pregnan-20-one : endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Research 561, 157161. Bjerkenstedt L, Edman GV, Alken RG, Mannel M (2005). Hypericum extract LI 160 and uoxetine in mild to

S130

CINP Antidepressant Task Force 2007

randomized, double-blind clinical trial on the ecacy of cortical direct current stimulation for the treatment of major depression. International Journal of Neuropsychopharmacology 16. Bolton P, Bass J, Neugebauer R, Verdeli H, Clougherty KF, Wickramaratne P, Speelman L, Ndogoni L, Weissman M (2003). Group interpersonal psychotherapy for depression in rural Uganda : a randomized controlled trial. Journal of the American Medical Association 289, 31173124. Bolton P, Wilk CM, Ndogoni L (2004). Assessment of depression prevalence in rural Uganda using symptom and function criteria. Social Psychiatry and Psychiatric Epidemiology 39, 442447. Bondare W, Alpert M, Friedho AJ, Richter EM, Clary CM, Batzar E (2000). Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. American Journal of Psychiatry 157, 729736. Bondy B, Baghai TC, Zill P, Schule C, Eser D, Deiml T, Zwanzger P, Ella R, Rupprecht R (2005). Genetic variants in the angiotensin I-converting-enzyme (ACE) and angiotensin II receptor (AT1) gene and clinical outcome in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29, 10941099. Bonnabry P, Sievering J, Leemann T, Dayer P (2001). Quantitative drug interactions prediction system (Q-DIPS) : a dynamic computer-based method to assist in the choice of clinically relevant in vivo studies. Clinical Pharmacokinetics 40, 631640. Bonnet U (2003). Moclobemide : therapeutic use and clinical studies. CNS Drug Reviews 9, 97140. Borchelt M (1995). [Potential side-eects and interactions in multiple medication in elderly patients : methodology and results of the Berlin Study of Aging]. Zeitschrift Fur Gerontologie Und Geriatrie 28, 420428. Borghi J, Guest JF (2000). Economic impact of using mirtazapine compared to amitriptyline and uoxetine in the treatment of moderate and severe depression in the UK. European Psychiatry 15, 378387. Bosker FJ, Westerink BH, Cremers TI, Gerrits M, van der Hart MG, Kuipers SD, van der Pompe G, ter Horst GJ, Den Boer JA, Korf J (2004). Future antidepressants : what is in the pipeline and what is missing ? CNS Drugs 18, 705732. Bostic JQ, Rubin DH, Prince J, Schlozman S (2005). Treatment of depression in children and adolescents. Journal of Psychiatric Practice 11, 141154. Bostwick JM, Pankratz VS (2000). Aective disorders and suicide risk : a reexamination. American Journal of Psychiatry 157, 19251932. Bouali S, Evrard A, Chastanet M, Lesch KP, Hamon M, Adrien J (2003). Sex hormone-dependent desensitization of 5-HT1A autoreceptors in knockout mice decient in the 5-HT transporter. European Journal of Neuroscience 18, 22032212. Boulenger JP, Huusom AK, Florea I, Baekdal T, Sarchiapone M (2006). A comparative study of the ecacy of long-term treatment with escitalopram and paroxetine

moderate depression : a randomized, placebo-controlled multi-center study in outpatients. European Archives of Psychiatry and Clinical Neuroscience 255, 4047. Black DW, Winokur G, Nasrallah A (1993). A multivariate analysis of the experience of 423 depressed inpatients treated with electroconvulsive therapy. Convulsive Therapy 9, 112120. Blakely RD (2001). Physiological genomics of antidepressant targets : keeping the periphery in mind. Journal of Neuroscience 21, 83198323. Blanco C, Raza MS, Schneier FR, Liebowitz MR (2003). The evidence-based pharmacological treatment of social anxiety disorder. International Journal of Neuropsychopharmacology 6, 427442. Blier P (2001). Pharmacology of rapid-onset antidepressant treatment strategies. Journal of Clinical Psychiatry 62 (Suppl. 15), 1217. Blier P (2003). The pharmacology of putative early-onset antidepressant strategies. European Neuropsychopharmacology 13, 5766. Blier P (2006). Pregnancy, depression, antidepressants and breast-feeding. Journal of Psychiatry and Neuroscience 31, 226228. Blier P, Bergeron R (1995). The safety of concomitant use of sumatriptan and antidepressant treatments. Journal of Clinical Psychopharmacology 15, 106109. Blier P, Saint-Andre E, Hebert C, de Montigny C, Lavoie N, Debonnel G (2006). Eects of dierent doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers. International Journal of Neuropsychopharmacology 110. Blier P, Ward NM (2003). Is there a role for 5-HT1A agonists in the treatment of depression ? Biological Psychiatry 53, 193203. Boardman AP, Healy D (2001). Modelling suicide risk in aective disorders. European Psychiatry 16, 400405. Bodkin JA, Amsterdam JD (2002). Transdermal selegiline in major depression : a double-blind, placebo-controlled, parallel-group study in outpatients. American Journal of Psychiatry 159, 18691875. Boerner RJ, Moller HJ (1999). The importance of new antidepressants in the treatment of anxiety/depressive disorders. Pharmacopsychiatry 32, 119126. Bogdanowicz E, Kalinowski A, Swiecicki L (1991). [Treatment of depression with intravenous infusions of clomipramine and maprotiline]. Psychiatria Polska 25, 1924. Bogetto F, Bellino S, Revello RB, Patria L (2002). Discontinuation syndrome in dysthymic patients treated with selective serotonin reuptake inhibitors : a clinical investigation. CNS Drugs 16, 273283. Boggio PS, Bermpohl F, Vergara AO, Muniz AL, Nahas FH, Leme PB, Rigonatti SP, Fregni F (2007a). Go-no-go task performance improvement after anodal transcranial DC stimulation of the left dorsolateral prefrontal cortex in major depression. Journal of Aective Disorders 101, 9198. Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA, Pascual-Leone A, Fregni F (2007b). A

CINP Antidepressant Task Force 2007

in severely depressed patients. Current Medical Research and Opinion 22, 13311341. Bower P, Byford S, Sibbald B, Ward E, King M, Lloyd M, Gabbay M (2000). Randomised controlled trial of non-directive counselling, cognitive-behaviour therapy, and usual general practitioner care for patients with depression. II : cost eectiveness. British Medical Journal 321, 13891392. Bower P, Rowland N (2006). Eectiveness and cost eectiveness of counselling in primary care. Cochrane Database of Systematic Reviews 3, CD001025. Bower P, Rowland N, Mellor C, Heywood P, Godfrey C, Hardy R (2002). Eectiveness and cost eectiveness of counselling in primary care. Cochrane Database of Systematic Reviews CD001025. Boyer EW, Shannon M (2005). The serotonin syndrome. New England Journal of Medicine 352, 11121120. Bradvik L, Berglund M (2005). Suicide in severe depression related to treatment : depressive characteristics and rate of antidepressant overdose. European Archives of Psychiatry and Clinical Neuroscience 255, 245250. Bramness JG, Skurtveit S, Morland J (2003). Testing for benzodiazepine inebriationrelationship between benzodiazepine concentration and simple clinical tests for impairment in a sample of drugged drivers. European Journal of Clinical Pharmacology 59, 593601. Breivik T, Gundersen Y, Myhrer T, Fonnum F, Osmundsen H, Murison R, Gjermo P, von HS, Opstad PK (2006). Enhanced susceptibility to periodontitis in an animal model of depression : reversed by chronic treatment with the anti-depressant tianeptine. Journal of Clinical Periodontology 33, 469477. Brenner R, Azbel V, Madhusoodanan S, Pawlowska M (2000). Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression : a double-blind, randomized pilot study. Clinical Therapeutics 22, 411419. Breslau N, Schultz L, Peterson E (1995). Sex dierences in depression : a role for preexisting anxiety. Psychiatry Research 58, 112. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA (2007). Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment : a meta-analysis of randomized controlled trials. Journal of the American Medical Association 297, 16831696. Bridge JA, Salary CB, Birmaher B, Asare AG, Brent DA (2005). The risks and benets of antidepressant treatment for youth depression. Annals of Medicine 37, 404412. Briggs NC, Jeerson JW, Koenecke FH (1990). Tranylcypromine addiction : a case report and review. Journal of Clinical Psychiatry 51, 426429. Briley M (1998). Specic serotonin and noradrenaline reuptake inhibitors (SNRIs). A review of their pharmacology, clinical ecacy and tolerability. Human Psychopharmacology : Clinical and Experimental 13, 99111.

S131

Brion S, Audrain S, de Bodinat C (1996). [Major depressive episodes in patients over 70 years of age. Evaluation of the eciency and acceptability of tianeptine and mianserin]. Presse Medicale 25, 461468. Brsen K (1996). Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry. Therapeutic Drug Monitoring 18, 393396. Brown C, Battista DR, Bruehlman R, Sereika SS, Thase ME, Dunbar-Jacob J (2005). Beliefs about antidepressant medications in primary care patients : relationship to selfreported adherence. Medical Care 43, 12031207. Brown CS, Bryant SG (1988). Monoamine oxidase inhibitors : safety and ecacy issues. Drug Intelligence and Clinical Pharmacy 22, 232235. Brown GK, Beck AT, Steer RA, Grisham JR (2000). Risk factors for suicide in psychiatric outpatients : a 20-year prospective study. Journal of Consulting and Clinical Psychology 68, 371377. Brown GW, Harris T (1978). Social Origins of Depression : a Study of Psychiatric Disorder in Women. London : Tavistock Publications. Brown MC, Nimmerrichter AA, Guest JF (1999). Costeectiveness of mirtazapine compared to amitriptyline and uoxetine in the treatment of moderate and severe depression in austria. European Psychiatry 14, 230244. Browne G, Steiner M, Roberts J, Gafni A, Byrne C, Dunn E, Bell B, Mills M, Chalklin L, Wallik D, Kraemer J (2002). Sertraline and/or interpersonal psychotherapy for patients with dysthymic disorder in primary care : 6-month comparison with longitudinal 2-year follow-up of eectiveness and costs. Journal of Aective Disorders 68, 317330. Bruck P, Antao CA, Henry JA (1992). Generic prescribing of antidepressants. Journal of the Royal Society of Medicine 85, 682685. Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J, Paykel E, Versiani M, Racagni G (2002). The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. European Neuropsychopharmacology 12, 461475. Brunnauer A, Laux G, Geiger E, Soyka M, Moller HJ (2006). Antidepressants and driving ability : results from a clinical study. J. Clin. Psychiatry 67, 17761781. Bschor T, Bauer M (2006). Ecacy and mechanisms of action of lithium augmentation in refractory major depression. Current Pharmaceutical Design 12, 29852992. Bschor T, Berghofer A, Strohle A, Kunz D, Adli M, Muller Oerlinghausen B, Bauer M (2002). How long should the lithium augmentation strategy be maintained ? A 1-year follow-up of a placebo-controlled study in unipolar refractory major depression. Journal of Clinical Psychopharmacology 22, 427430. Bump GM, Mulsant BH, Pollock BG, Mazumdar S, Begley AE, Dew MA, Reynolds CF, III. (2001). Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly. Depress. Anxiety. 13, 3844.

S132

CINP Antidepressant Task Force 2007

Butt AA, Evans R, Skanderson M, Shakil AO (2006). Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis. Journal of Hepatology 44, 864868. Bymaster FP, Dresheld-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT (2001). Comparative anity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 25, 871880. Calil HM (2001). Fluoxetine : a suitable long-term treatment. Journal of Clinical Psychiatry 62 (Suppl. 22), 2429. Callahan CM, Kroenke K, Counsell SR, Hendrie HC, Perkins AJ, Katon W, Noel PH, Harpole L, Hunkeler EM, Unutzer J (2005). Treatment of depression improves physical functioning in older adults. Journal of the American Geriatrics Society 53, 367373. Campo-Arias A (2004). [Antidepressants in migraine prophylaxis : an approximation]. Revista De Neurologia 38, 864868. Canadian Coordinating Oce for Health Technology Assesment (1997). Selective Serotonin Reuptake Inhibitors (SSRIs) for Major Depresion. Part 2. The Cost-Eectiveness of SSRIs in Treatment of Depression. Ottawa : Canadian Coordinating Oce for Health Technology Assesment. Canadian Psychiatric Association and Canadian Network for Mood and Anxiety Treatments (CANMAT) (2001). Clinical guidelines for the treatment of depressive disorders. Canadian Journal of Psychiatry 46 (Suppl. 1), 5S90S. Carlsten A, Waern M, Ekedahl A, Ranstam J (2001). Antidepressant medication and suicide in Sweden. Pharmacoepidemiology and Drug Safety 10, 525530. Carney RM, Blumenthal JA, Freedland KE, Youngblood M, Veith RC, Burg MM, Cornell C, Saab PG, Kaufmann PG, Czajkowski SM, Jae AS (2004). Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosomatic Medicine 66, 466474. Carrasco GA, Barker SA, Zhang Y, Damjanoska KJ, Sullivan NR, Garcia F, DSouza DN, Muma NA, van De Kar LD (2004). Estrogen treatment increases the levels of regulator of G protein signaling-Z1 in the hypothalamic paraventricular nucleus : possible role in desensitization of 5-hydroxytryptamine1A receptors. Neuroscience 127, 261267. Casciano J, Arikian S, Tarride JE, Doyle JJ, Casciano R (1999). A pharmacoeconomic evaluation of major depressive disorder (Italy). Epidemiologia e Psichiatria Sociale 8, 220231. Casciano J, Doyle J, Arikian S, Casciano R (2001). The health economic impact of antidepressant usage from a payers perspective : a multinational study. International Journal of Clinical Practice 55, 292299. Casciano R (2003). Eectiveness measures of major depressive disorder in pharmacoeconomic evaluations. Managed Care Interface (Suppl. B), 1415.

Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G (2001a). Lithium for maintenance treatment of mood disorders. Cochrane Database of Systematic Reviews CD003013. Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G (2001b). Lithium for maintenance treatment of mood disorders [Update]. Cochrane Database of Systematic Reviews CD003013. Burke MJ, Preskorn SH (1995). Short term treatment of mood disorders with standard antidepressants. In : Bloom FE, Kupfer DJ (Eds.), Psychopharmacology : The Fourth Generation of Progress (pp. 10531065). New York : Raven Press. Burke MJ, Preskorn SH (1999). Therapeutic drug monitoring of antidepressants : cost implications and relevance to clinical practice. Clinical Pharmacokinetics 37, 147165. Burn DJ (2002). Beyond the iron mask : towards better recognition and treatment of depression associated with Parkinsons disease. Movement Disorders 17, 445454. Burrows GD (1992). Long-term clinical management of depressive disorders. Journal of Clinical Psychiatry 53 (Suppl.), 3235. Burrows GD, Davies B, Scoggins BA (1972). Plasma concentration of nortriptyline and clinical response in depressive illness. Lancet 2, 619623. Burrows GD, Hughes I, Norman T (1981). Cardiotoxicity of Antidepressants : Experimental Background. In : Wheatly D (Ed.), Stress and the Heart (pp. 131171). New York : Raven Press. Burrows GD, Maguire KP, Norman TR (1998). Antidepressant ecacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine : a review. Journal of Clinical Psychiatry 59 (Suppl. 14), 47. Burrows GD, Norman TR (1997). Antidepressants : clinical aspects. Stress Medicine 13, 167172. Burrows GD, Norman TR, Judd FK (1993). Long-term management of depressive disorders. Current Therapeutic Research 54, 832837. Burrows GD, Norman TR, Judd FK (1994). Denition and dierential diagnosis of treatment-resistant depression. International Clinical Psychopharmacology 9 (Suppl. 2), 510. Burrows GD, Norman TR, Maguire KP, Rubinstein G, Scoggins BA, Davies B (1977). A new antidepressant butriptyline : plasma levels and clinical response. Medical Journal of Australia 2, 604606. Burrows GD, Vohra J, Hunt D, Sloman JG, Scoggins BA, Davies B (1976). Cardiac eects of dierent tricyclic antidepressant drugs. British Journal of Psychiatry 129, 335341. Burt T, Lisanby SH, Sackeim HA (2002). Neuropsychiatric applications of transcranial magnetic stimulation : a meta analysis. International Journal of Neuropsychopharmacology 5, 73103. Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E (2001). The use of psychotropic medications during breast-feeding. American Journal of Psychiatry 158, 10011009.

CINP Antidepressant Task Force 2007

Caspi A, Sugden K, Mott TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003). Inuence of life stress on depression : moderation by a polymorphism in the 5-HTT gene. Science 301, 386389. Cassano GB, Jori MC (2002). Ecacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression : a randomized, double-blind, parallel group study. International Clinical Psychopharmacology 17, 2732. Cassano GB, Musetti L, Perugi G, Soriani A, Mignani V, McNair DM, Akiskal HS (1988). A proposed new approach to the clinical subclassication of depressive illness. Pharmacopsychiatry 21, 1923. Castren E (2005). Is mood chemistry ? Nature Reviews. Neuroscience 6, 241246. Ceskova E, Nahunek K, Rysanek R, Svestka J (1983). [Clinical experience with clomipramine (Hydiphen) and desipramine (Petytyl) by parenteral administration in the treatment of endogenous depression with signs of pharmacoresistance]. Cesk. Psychiatr. 79, 94101. Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Johnson KA, Jones KL (1999). Weight gain in infants breastfed by mothers who take uoxetine. Pediatrics 104, e61. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA (2006). Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New England Journal of Medicine 354, 579587. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL (1996). Birth outcomes in pregnant women taking uoxetine. New England Journal of Medicine 335, 10101015. Charney DS, Grothe DR, Smith SL, Brady KT, KaltsounisPuckett J, Wright CW, Laird LK, Rush AJ (2002). Overview of psychiatric disorders and the role of newer antidepressants. Journal of Clinical Psychiatry 63, 39. Chatterjee U, Poddar A, Ameen S (2006). Evidence-Based Psychotherapy (http://www.psyplexus.com/mhr/ evidence_based_psychotherapy.html). Accessed 10 February 2007). Cheeta S, Schifano F, Oyefeso A, Webb L, Ghodse AH (2004). Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998-2000. British Journal of Psychiatry 184, 4147. Chen F, Larsen MB, Sanchez C, Wiborg O (2005). The S-enantiomer of R,S-citalopram increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. European Neuropsychopharmacology 15, 193198. Chen S, Chou WH, Blouin RA, Mao Z, Humphries LL, Meek C, Neill JR, Martin WL, Hays LR, Wedlund PJ (1996). The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism : screening costs and inuence on clinical outcomes in psychiatry. Clinical Pharmacology and Therapeutics 60, 522534. Cheng K, Yan H, Duan KJ (2005). [Advances in clinical and mechanism studies of acupuncture and moxibustion for treatment of depression]. Zhongguo Zhen Jiu 25, 221223.

S133

Cheung AH, Emslie GJ, Mayes TL (2005). Review of the ecacy and safety of antidepressants in youth depression. Journal of Child Psychology and Psychiatry, and Allied Disciplines 46, 735754. Cheung AH, Emslie GJ, Mayes TL (2006). The use of antidepressants to treat depression in children and adolescents. Canadian Medical Association Journal 174, 193200. Chisholm D, Healey A, Knapp M (1997). QALYs and mental health care. Social Psychiatry and Psychiatric Epidemiology 32, 6875. Chiu E (2004). Epidemiology of depression in the Asia Pacic region. Australasian Psychiatry 12 (Suppl.), S410. Chiu HF (1997). Antidepressants in the elderly. International Journal of Clinical Practice 51, 369374. Chopra MP, Zubritsky C, Knott K, Have TT, Hadley T, Coyne JC, Oslin DW (2005). Importance of subsyndromal symptoms of depression in elderly patients. American Journal of Geriatric Psychiatry 13, 597606. Cipriani A, Barbui C, Brambilla P, Furukawa TA, Hotopf M, Geddes JR (2006). Are all antidepressants really the same ? The case of uoxetine : a systematic review. Journal of Clinical Psychiatry 67, 850864. Cipriani A, Barbui C, Geddes JR (2005a). Suicide, depression, and antidepressants. British Medical Journal 330, 373374. Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M, Hotopf M, Malvini L, Barbui C (2005b). Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database of Systematic Reviews CD004185. Ciusani E, Zullino DF, Eap CB, Brawand-Amey M, Brocard M, Baumann P (2004). Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine : pharmacokinetic and clinical aspects. Journal of Psychopharmacology 18, 559566. Claassen CA, Trivedi MH, Rush AJ, Husain MM, Zisook S, Young E, Leuchter A, Wisniewski SR, Balasubramani GK, Alpert J (2006). Clinical dierences among depressed patients with and without a history of suicide attempts : Findings from the STAR*D trial. Journal of Aective Disorders 97, 7784. Claghorn JL and Feighner JP. (1993). A double-blind comparison of paroxetine with imipramine in the long-term treatment of depression. Journal of Clinical Psychopharmacology 13, 23S27S. Clark RE, Xie H, Brunette MF (2004). Benzodiazepine prescription practices and substance abuse in persons with severe mental illness. Journal of Clinical Psychiatry 65, 151155. Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK, Brown MT, Schwartz GE (2003). Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder. International Clinical Psychopharmacology 18, 151156. Clement Jerdi M, Daali Y, Kondo Oestreicher M, Cherkaoui S, Dayer P (2005). A simplied analytical method for a

S134

CINP Antidepressant Task Force 2007

anxiety and depressive disorders in children and adolescents : an evidence-based medicine review. Journal of the American Academy of Child and Adolescent Psychiatry 43, 930959. Conus P, Bondol G, Eap CB, Macciardi F, Baumann P (1996). Pharmacokinetic uvoxamine-clomipramine interaction with favorable therapeutic consequences in therapy-resistant depressive patient. Pharmacopsychiatry 29, 108110. Conway CR, McGuire JM, Baram VY (2004). Nefazodoneinduced liver failure. Journal of Clinical Psychopharmacology 24, 353354. Coppen A (2000). Lithium in unipolar depression and the prevention of suicide. Journal of Clinical Psychiatry 61 (Suppl. 9), 5256. Coppen A, Bailey J (2000). Enhancement of the antidepressant action of uoxetine by folic acid : a randomised, placebo controlled trial. Journal of Aective Disorders 60, 121130. Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000). Comparison of pramipexole, uoxetine, and placebo in patients with major depression. Depression and Anxiety 11, 5865. Corruble E, Guel JD (2000). Does increasing dose improve ecacy in patients with poor antidepressant response : a review. Acta Psychiatrica Scandinavica 101, 343348. Coryell W (1996). Psychotic depression. Journal of Clinical Psychiatry 57 (Suppl. 3), 2731. Coryell W (1998). The treatment of psychotic depression. Journal of Clinical Psychiatry 59 (Suppl. 1), 2227. Coryell W, Pfohl B, Zimmerman M (1985). Outcome following electroconvulsive therapy : a comparison of primary and secondary depression. Convulsive Therapy 1, 1014. Couturier JL (2005). Ecacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression : a systematic review and meta-analysis. Journal of Psychiatry and Neuroscience 30, 8390. Cozza KL, Armstrong SC (2005). Concise Guide to the Cytochrome P450 System. Drug Interaction Principles for Medical Practice. Washington : Amer Psychiatric Pub Inc. Craft LL, Perna FM (2004). The benets of exercise for the clinically depressed. Primary Care Companion to the Journal of Clinical Psychiatry 6, 104111. Croft H, Settle EJ, Houser T, Batey SR, Donahue RM, Ascher JA (1999). A placebo-controlled comparison of the antidepressant ecacy and eects on sexual functioning of sustained-release bupropion and sertraline. Clinical Therapeutics 21, 643658. Cui C, Yang M, Yao Z, Cao B, Luo Z, Xu Y, Chen Y (1995). [Antidepressant active constituents in the roots of Morinda ocinalis How]. Zhongguo Zhong Yao Za Zhi 20, 363. Cullen M, Mitchell P, Brodaty H, Boyce P, Parker G, Hickie I, Wilhelm K (1991). Carbamazepine for treatmentresistant melancholia. Journal of Clinical Psychiatry 52, 472476.

phenotyping cocktail of major CYP450 biotransformation routes. Journal of Pharmaceutical and Biomedical Analysis 35, 12031212. Clerc GE, Ruimy P, Verdeau-Palles J (1994). A double-blind comparison of venlafaxine and uoxetine in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient Study Group. International Clinical Psychopharmacology 9, 139143. Cohen LS, Nonacs R, Viguera AC, Reminick A (2004). Diagnosis and treatment of depression during pregnancy. CNS Spectrums 9, 209216. Cole MG, Bellavance F, Mansour A (1999). Prognosis of depression in elderly community and primary care populations : a systematic review and meta-analysis. American Journal of Psychiatry 156, 11821189. Coleman CC, Cunningham LA, Foster VJ, Batey SR, Donahue RM, Houser TL, Ascher JA (1999). Sexual dysfunction associated with the treatment of depression : a placebo-controlled comparison of bupropion sustained release and sertraline treatment. Annals of Clinical Psychiatry 11, 205215. Coleman CC, King BR, Bolden-Watson C, Book MJ, Segraves RT, Richard N, Ascher J, Batey S, Jamerson B, Metz A (2001). A placebo-controlled comparison of the eects on sexual functioning of bupropion sustained release and uoxetine. Clinical Therapeutics 23, 10401058. Collantes-Estevez E, Fernandez-Perez C (2003). Improved control of osteoarthritis pain and self-reported health status in non-responders to celecoxib switched to rofecoxib : results of PAVIA, an open-label post-marketing survey in Spain. Current Medical Research and Opinion 19, 402410. Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E (1999). Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression. Psychiatry Research 86, 267270. Colombo C, Lucca A, Benedetti F, Barbini B, Campori E, Smeraldi E (2000). Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression : replication of main eects and interaction. Psychiatry Research 95, 4353. Committee for Proprietary Medicinal Products (2002) Concept paper on the revision of the committee for proprietary medicinal products (CPMP) note for guidance on medicinal products for the treatment of depression. Document id : cpmp/ewp/518/97 (http:/ / www.emea.eu.int). Accessed 22 June 2007. Commitee on Safety of Medicines (2004). Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants. (http:/ / www.mhra.gov.uk/home/groups/pl-p/documents/ drugsafetymessage/con019472.pdf). Accessed 24 January 2006. Compton MT, Nemero CB (2000). The treatment of bipolar depression. Journal of Clinical Psychiatry 61 (Suppl. 9), 5767. Compton SN, March JS, Brent D, Albano AM, Weersing R, Curry J (2004). Cognitive-behavioral psychotherapy for

CINP Antidepressant Task Force 2007

Culman J, Klee S, Ohlendorf C, Unger T (1997). Eect of tachykinin receptor inhibition in the brain on cardiovascular and behavioral responses to stress. Journal of Pharmacology and Experimental Therapeutics 280, 238246. Cummings JL, Masterman DL (1999). Depression in patients with Parkinsons disease. International Journal of Geriatric Psychiatry 14, 711718. Cunningham LA, Borison RL, Carman JS, Chouinard G, Crowder JE, Diamond BI, Fischer DE, Hearst E (1994). A comparison of venlafaxine, trazodone, and placebo in major depression. Journal of Clinical Psychopharmacology 14, 99106. Curran S (1995). Eect of paroxetine on seizure length during electroconvulsive therapy. Acta Psychiatrica Scandinavica 92, 239240. Curry JF (2001). Specic psychotherapies for childhood and adolescent depression. Biological Psychiatry 49, 10911100. Curtin F, Berney P, Kaufmann C (2002). Moclobemide discontinuation syndrome predominantly presenting with inuenza-like symptoms. J Psychopharmacol. 16, 271272. Cuzzell JZ (2006). Paroxetine may increase risk for congenital malformations. Dermatology Nursing 18, 68. Cyr M, Brown CS (1996). Nefazodone : its place among antidepressants. Annals of Pharmacotherapy 30, 10061012. Czekalla J, Gastpar M, Hubner WD, Jager D (1997). The eect of hypericum extract on cardiac conduction as seen in the electrocardiogram compared to that of imipramine. Pharmacopsychiatry 30 (Suppl. 2), 8688. Dam J, Ryde L, Svejso J, Lauge N, Lauritsen B, Bech P (1998). Morning uoxetine plus evening mianserin versus morning uoxetine plus evening placebo in the acute treatment of major depression. Pharmacopsychiatry 31, 4854. Danish University Antidepressant Group (1986). Citalopram : clinical eect prole in comparison with clomipramine. A controlled multicenter study. Danish University Antidepressant Group. Psychopharmacology 90, 131138. Danish University Antidepressant Group (1990). Paroxetine : a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant eect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. Journal of Aective Disorders 18, 289299. Danish University Antidepressant Group (1993). Moclobemide : a reversible MAO-A-inhibitor showing weaker antidepressant eect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. Journal of Aective Disorders 28, 105116. Dantzer R (2004). Cytokine-induced sickness behaviour : a neuroimmune response to activation of innate immunity. European Journal of Pharmacology 500, 399411. Darcourt G, Souetre E, Pringuey D, Robert P, Feuillade P, Belugou JL (1992). [Disorders of circadian rhythms in depression]. Encephale 18 Spec No. 4, 473478. Dardennes R, Berdeaux G, Lafuma A, Fagnani F (1999). Comparison of the cost-eectiveness of milnacipran

S135

(a SNRI) with TCAs and SSRIs : a modeling approach. European Psychiatry 14, 152162. Dardennes RM, Even C, Ballon N, Bange F (1998). Serotonin syndrome caused by a clomipramine-moclobemide interaction. Journal of Clinical Psychiatry 59, 382383. Davidson J, McLeod M, Law-Yone B, Linnoila M (1978). A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression. Archives of General Psychiatry 35, 639642. Davidson J, Pearlstein T, Londborg P, Brady KT, Rothbaum B, Bell J, Maddock R, Hegel MT, Farfel G (2001). Ecacy of sertraline in preventing relapse of posttraumatic stress disorder : results of a 28-week double-blind, placebocontrolled study. American Journal of Psychiatry 158, 19741981. Davidson J, Pelton S (1986). Forms of atypical depression and their response to antidepressant drugs. Psychiatry Research 17, 8795. Davidson JR, Connor KM, Hertzberg MA, Weisler RH, Wilson WH, Payne VM (2005). Maintenance therapy with uoxetine in posttraumatic stress disorder : a placebocontrolled discontinuation study. Journal of Clinical Psychopharmacology 25, 166169. Davidson JR, McLeod MN, Turnbull CD, Miller RD (1981). A comparison of phenelzine and imipramine in depressed inpatients. Journal of Clinical Psychiatry 42, 395397. Davis JM, Wang Z, Janicak PG (1993). A quantitative analysis of clinical drug trials for the treatment of aective disorders. Psychopharmacol. Bull. 29, 175181. Davis LL, Frazier E, Husain MM, Warden D, Trivedi M, Fava M, Cassano P, McGrath PJ, Balasubramani GK, Wisniewski SR, Rush AJ (2006). Substance use disorder comorbidity in major depressive disorder : a conrmatory analysis of the STAR*D cohort. American Journal on Addictions 15, 278285. Davis LL, Kabel D, Patel D, Choate AD, Foslien-Nash C, Gurguis GN, Kramer GL, Petty F (1996). Valproate as an antidepressant in major depressive disorder. Psychopharmacology Bulletin 32, 647652. Dawling S, Lynn K, Rosser R, Braithwaite R (1982). Nortriptyline metabolism in chronic renal failure : metabolite elimination. Clinical Pharmacology and Therapeutics 32, 322329. Dawson LA, Nguyen HQ (2000). The role of 5-HT(1A) and 5-HT(1B/1D) receptors on the modulation of acute uoxetine-induced changes in extracellular 5-HT : the mechanism of action of (+/x)pindolol. Neuropharmacology 39, 10441052. De la Gandara J, Aguera L, Rojo JE, Ros S, de Pedro JM (2005a). Use of antidepressant combinations : which, when and why ? Results of a Spanish survey. Acta Psychiatrica Scandinavica. Supplementum 3236. De la Gandara J, Rojo JE, Ros S, Aguera L, de Pedro JM (2005b). Neuropharmacological basis of combining antidepressants. Acta Psychiatrica Scandinavica. Supplementum 1113, 36.

S136

CINP Antidepressant Task Force 2007

Kawakami N, Ono Y, Takeshima T, Uda H, Karam EG, Fayyad JA, Karam AN, Mneimneh ZN, Medina-Mora ME, Borges G, Lara C, de Graaf R, Ormel J, Gureje O, Shen Y, Huang Y, Zhang M, Alonso J, Haro JM, Vilagut G, Bromet EJ, Gluzman S, Webb C, Kessler RC, Merikangas KR, Anthony JC, Von Kor MR, Wang PS, Brugha TS, Aguilar-Gaxiola S, Lee S, Heeringa S, Pennell BE, Zaslavsky AM, Ustun TB, Chatterji S (2004). Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. Journal of the American Medical Association 291, 25812590. Demyttenaere K, Enzlin P, Dewe W, Boulanger B, De BJ, De TW, Mesters P (2001a). Compliance with antidepressants in a primary care setting, 1 : Beyond lack of ecacy and adverse events. Journal of Clinical Psychiatry 62 (Suppl. 22), 3033. Demyttenaere K, Enzlin P, Dewe W, Boulanger B, De BJ, De TW, Mesters P (2001b). Compliance with antidepressants in a primary care setting, 2 : the inuence of gender and type of impairment. Journal of Clinical Psychiatry 62 (Suppl. 22), 3437. Demyttenaere K, Hemels ME, Hudry J, Annemans L (2005). A cost-eectiveness model of escitalopram, citalopram, and venlafaxine as rst-line treatment for major depressive disorder in Belgium. Clinical Therapeutics 27, 111124. Depression Guideline Panel (1993). Depression in Primary Care : Detection and Diagnosis. Rockville, MD : Agency for Health Care Policy and Research. Derouesne C, Lacomblez L (2004). [Depression and dementia]. Psychologie et Neuropsychiatrie Du Vieillissement 2 (Suppl. 1), S35S42. DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD (1999). Medications versus cognitive behavior therapy for severely depressed outpatients : mega-analysis of four randomized comparisons. American Journal of Psychiatry 156, 10071013. DeRubeis RJ, Hollon SD, Amsterdam JD, Shelton RC, Young PR, Salomon RM, OReardon JP, Lovett ML, Gladis MM, Brown LL, Gallop R (2005). Cognitive therapy vs medications in the treatment of moderate to severe depression. Archives of General Psychiatry 62, 409416. Descamps-Francois C, Yous S, Chavatte P, Audinot V, Bonnaud A, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D (2003). Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands. Journal of Medicinal Chemistry 46, 11271129. Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA (2002). Duloxetine, 60 mg once daily, for major depressive disorder : a randomized double-blind placebo-controlled trial. Journal of Clinical Psychiatry 63, 308315. Detke MJ, Wiltse CG, Mallinckrodt CH, McNamara RK, Demitrack MA, Bitter I (2004). Duloxetine in the acute and long-term treatment of major depressive disorder : a placebo- and paroxetine-controlled trial. European Neuropsychopharmacology 14, 457470.

De Leon J (2006). AmpliChip CYP450 test : personalized medicine has arrived in psychiatry. Expert Review of Molecular Diagnostics 6, 277286. De Leon J, Armstrong SC, Cozza KL (2006). Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics 47, 7585. De Leon J, Susce MT, Murray-Carmichael E (2006b). The AmpliChip CYP450 genotyping test : Integrating a new clinical tool. Molecular Diagnosis & Therapy 10, 135151. De Maat SM, Dekker J, Schoevers RA, de JF (2007). Relative ecacy of psychotherapy and combined therapy in the treatment of depression : a meta-analysis. European Psychiatry 22, 18. De Mello MF, de Jesus Mari J, Bacaltchuk J, Verdeli H, Neugebauer R (2005). A systematic review of research ndings on the ecacy of interpersonal therapy for depressive disorders. European Archives of Psychiatry and Clinical Neuroscience 255, 7582. Dean AJ (2002). Are antidepressants addictive ? Drug and Alcohol Review 21, 317319. DeBattista C, Belano J, Glass S, Khan A, Horne RL, Blasey C, Carpenter LL, Alva G (2006). Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biological Psychiatry 60, 13431349. Defrance R, Marey C, Kamoun A (1988). Antidepressant and anxiolytic activities of tianeptine : an overview of clinical trials. Clinical Neuropharmacology 11 (Suppl. 2), S74S82. Degner D, Grohmann R, Kropp S, Ruther E, Bender S, Engel RR, Schmidt LG (2004). Severe adverse drug reactions of antidepressants : results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 37 (Suppl. 1), S39S45. Delgado PL (2004). How antidepressants help depression : mechanisms of action and clinical response. Journal of Clinical Psychiatry 65 (Suppl. 4), 2530. Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Moreno FA, Heninger GR, Charney DS (1999). Tryptophan-depletion challenge in depressed patients treated with desipramine or uoxetine : implications for the role of serotonin in the mechanism of antidepressant action. Biological Psychiatry 46, 212220. Deltito J, Beyer D (1998). The scientic, quasi-scientic and popular literature on the use of St. Johns Wort in the treatment of depression. Journal of Aective Disorders 51, 345351. Demolis JL, Angebaud P, Grange JD, Coates P, FunckBrentano C, Jaillon P (1996). Inuence of liver cirrhosis on sertraline pharmacokinetics. British Journal of Clinical Pharmacology 42, 394397. Demyttenaere K (1998). Noncompliance with antidepressants : whos to blame ? International Clinical Psychopharmacology 13 (Suppl. 2), S19S25. Demyttenaere K, Bruaerts R, Posada-Villa J, Gasquet I, Kovess V, Lepine JP, Angermeyer MC, Bernert S, de Girolamo G, Morosini P, Polidori G, Kikkawa T,

CINP Antidepressant Task Force 2007

Devanand DP, Sackeim HA, Prudic J (1991). Electroconvulsive therapy in the treatment-resistant patient. Psychiatric Clinics of North America 14, 905923. DeVane CL (2003). Immediate-release versus controlledrelease formulations : pharmacokinetics of newer antidepressants in relation to nausea. Journal of Clinical Psychiatry 64 (Suppl. 18), 1419. Dewa CS, Hoch JS, Lin E, Paterson M, Goering P (2003). Pattern of antidepressant use and duration of depression-related absence from work. British Journal of Psychiatry 183, 507513. Diaz-Olavarrieta C, Cummings JL, Velazquez J, Garcia de la Cadena C (1999). Neuropsychiatric manifestations of multiple sclerosis. Journal of Neuropsychiatry and Clinical Neurosciences 11, 5157. Dilsaver SC (1988). Monoamine oxidase inhibitor withdrawal phenomena : symptoms and pathophysiology. Acta Psychiatrica Scandinavica 78, 17. Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Krajewski KJ (1994). Suicidality in patients with pure and depressive mania. American Journal of Psychiatry 151, 13121315. DiMascio A, Weissman MM, Pruso BA, Neu C, Zwilling M, Klerman GL (1979). Dierential symptom reduction by drugs and psychotherapy in acute depression. Archives of General Psychiatry 36, 14501456. Dingemanse J, Kneer J, Fotteler B, Groen H, Peeters PA, Jonkman JH (1995). Switch in treatment from tricyclic antidepressants to moclobemide : a new generation monoamine oxidase inhibitor. Journal of Clinical Psychopharmacology 15, 4148. Dingemanse J, Wallnofer A, Gieschke R, Guentert T, Amrein R (1998). Pharmacokinetic and pharmacodynamic interactions between uoxetine and moclobemide in the investigation of development of the serotonin syndrome. Clinical Pharmacology and Therapeutics 63, 403413. Dodd S, Buist A, Norman TR (2000). Antidepressants and breast-feeding : a review of the literature. Paediatric Drugs 2, 183192. Dodd S, Horgan D, Malhi GS, Berk M (2005). To combine or not to combine ? A literature review of antidepressant combination therapy. Journal of Aective Disorders 89, 111. Dolberg OT, Dannon PN, Schreiber S, Grunhaus L (2002). Transcranial magnetic stimulation in patients with bipolar depression : a double blind, controlled study. Bipolar Disorders 4 (Suppl. 1), 9495. Doogan DP, Caillard V (1992). Sertraline in the prevention of depression. British Journal of Psychiatry 160, 217222. Doyle JJ, Casciano J, Arikian S, Tarride JE, Gonzalez MA, Casciano R (2001). A multinational pharmacoeconomic evaluation of acute major depressive disorder (MDD) : a comparison of cost-eectiveness between venlafaxine, SSRIs and TCAs. Value in Health 4, 1631. Drago F, Motta A, Grossi E (1983). Intravenous maprotiline in severe and resistant primary depression : a double-blind comparison with clomipramine. Journal of International Medical Research 11, 7884.

S137

Drummond M, McGuire A (2001). Economic Evaluation in Health Care : Merging Theory With Practice. Oxford : Oxford University Press. Drummond M, Sculpher MJ, Torrance GW, OBrien BJ, Stoddart GL (2005). Methods for the Economic Evaluation of Health Care Programmes. Oxford : Oxford University Press. Dubicka B, Hadley S, Roberts C (2006). Suicidal behaviour in youths with depression treated with new-generation antidepressants : meta-analysis. British Journal of Psychiatry 189, 3938., 393398. Dugbartey AT, Dugbartey MT, Apedo MY (1998). Delayed neuropsychiatric eects of malaria in Ghana. Journal of Nervous and Mental Disease 186, 183186. Duggal HS, Gates C, Pathak PC (2004). Olanzapine-induced neutropenia : mechanism and treatment. Journal of Clinical Psychopharmacology 24, 234235. Duman RS, Monteggia LM (2006). A neurotrophic model for stress-related mood disorders. Biological Psychiatry 59, 11161127. Dunner DL (1998). Lithium carbonate : maintenance studies and consequences of withdrawal. Journal of Clinical Psychiatry 59 (Suppl. 6), 4855 ; discussion 56. Dunningham W, de Aguiar WM, de Lourdes Costa Pinto M (1994). A double-blind Brazilian study of ecacy and safety of moclobemide versus imipramine in the treatment of patients with geriatric depression. Arquivos Brasileiros De Medicina 68, 402405. Eaton WW (2002). Epidemiologic evidence on the comorbidity of depression and diabetes. Journal of Psychosomatic Research 53, 903906. Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE (1996). Depression and risk for onset of type II diabetes. A prospective population-based study. Diabetes Care 19, 10971102. Ebmeier KP, Donaghey C, Steele JD (2006). Recent developments and current controversies in depression. Lancet 367, 153167. ECT review group (2003). Ecacy and safety of electroconvulsive therapy in depressive disorders : a systematic review and meta-analysis. Lancet 361, 799808. Edwards JG, Anderson I (1999). Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 57, 507533. Egger T, Dormann H, Ahne G, Pahl A, Runge U, Azaz-Livshits T, Neubert A, Criegee-Rieck M, Gassmann KG, Brune K (2005). Cytochrome P450 polymorphisms in geriatric patients : impact on adverse drug reactions : a pilot study. Drugs and Aging 22, 265272. Einarson TR, Addis A, Iskedjian M (1997). Pharmacoeconomic analysis of venlafaxine in the treatment of major depressive disorder. Pharmacoeconomics 12, 286296. Einarson TR, Arikian S, Sweeney S, Doyle J (1995). A model to evaluate the cost-eectiveness of oral therapies in the management of patients with major depressive disorders. Clinical Therapeutics 17, 136153.

S138

CINP Antidepressant Task Force 2007

Ernst CL, Goldberg JF (2002). The reproductive safety prole of mood stabilizers, atypical antipsychotics, and broadspectrum psychotropics. Journal of Clinical Psychiatry 63 (Suppl. 4), 4255. European Medicines Agency CfMPfHU (2004). CHMP Meeting on Paroxetine and Other SSRIs (http:// www.emea.europa.eu/pdfs/human/press/pr/ 19257004en.pdf). Accessed 7 January 2007. Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR, Nemero CB, Bremner JD, Carney RM, Coyne JC, DeLong MR, Frasure-Smith N, Glassman AH, Gold PW, Grant I, Gwyther L, Ironson G, Johnson RL, Kanner AM, Katon WJ, Kaufmann PG, Keefe FJ, Ketter T, Laughren TP, Leserman J, Lyketsos CG, McDonald WM, McEwen BS, Miller AH, Musselman D, OConnor C, Petitto JM, Pollock BG, Robinson RG, Roose SP, Rowland J, Sheline Y, Sheps DS, Simon G, Spiegel D, Stunkard A, Sunderland T, Tibbits PJ, Valvo WJ (2005). Mood disorders in the medically ill : scientic review and recommendations. Biological Psychiatry 58, 175189. Fakra E, Fonseca DD, Livolsi S, Destoppeleire C, Lancon C (2006) Long term studies of depression : what is relevant for the physician ? European Journal Psychiatry 20, 242257. Fallon BA, Liebowitz MR, Campeas R, Schneier FR, Marshall R, Davies S, Goetz D, Klein DF (1998). Intravenous clomipramine for obsessive-compulsive disorder refractory to oral clomipramine : a placebocontrolled study. Archives of General Psychiatry 55, 918924. Fallon BA, Nields JA (1994). Lyme disease : a neuropsychiatric illness. American Journal of Psychiatry 151, 15711583. Fan XD (1992). [Function of lymphocyte beta-adrenergic receptor in depression]. Zhonghua Shen Jing Jing Shen Ke Za Zhi 25, 3224, 382. Farah A (1997). Mirtazapine and ECT combination therapy. Convulsive Therapy 13, 116117. Farmer R (1990). Mianserin and agranulocytosis. Lancet 336, 1010. Fattaccini CM, Bolanos-Jimenez F, Gozlan H, Hamon M (1990). Tianeptine stimulates uptake of 5hydroxytryptamine in vivo in the rat brain. Neuropharmacology 29, 18. Fava GA (2003a). Can long-term treatment with antidepressant drugs worsen the course of depression ? Journal of Clinical Psychiatry 64, 123133. Fava GA, Ruini C (2002). The sequential approach to relapse prevention in unipolar depression. World Psychiatry 1, 1015. Fava M (2001). Augmentation and combination strategies in treatment-resistant depression. Journal of Clinical Psychiatry 62 (Suppl. 18), 411. Fava M (2002). Somatic symptoms, depression, and antidepressant treatment. Journal of Clinical Psychiatry 63, 305307. Fava M (2003b). Diagnosis and denition of treatment-resistant depression. Biological Psychiatry 53, 649659.

Einarson TR, Einarson A (2005). Newer antidepressants in pregnancy and rates of major malformations : a meta-analysis of prospective comparative studies. Pharmacoepidemiology and Drug Safety 14, 823827. Eker SS, Akkaya C, Akgoz S, Sarandol A, Kirli S (2005). [Comparison of reboxetine and sertraline in terms of ecacy and safety in major depressive disorder]. Turk Psikiyatri Dergisi 16, 153163. Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, Glass DR, Pilkonis PA, Leber WR, Docherty JP (1989). National Institute of Mental Health Treatment of Depression Collaborative Research Program. General eectiveness of treatments. Archives of General Psychiatry 46, 971982. Ellingrod VL, Perry PJ (1995). Nefazodone : a new antidepressant. American Journal of Health-System Pharmacy 52, 27992812. Ellis P (2004). Australian and New Zealand clinical practice guidelines for the treatment of depression. Australian and New Zealand Journal of Psychiatry 38, 389407. Emslie GJ, Heiligenstein JH, Hoog SL, Wagner KD, Findling RL, McCracken JT, Nilsson ME, Jacobson JG (2004). Fluoxetine treatment for prevention of relapse of depression in children and adolescents : a doubleblind, placebo-controlled study. Journal of the American Academy of Child and Adolescent Psychiatry 43, 13971405. Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, Jacobson JG (2002). Fluoxetine for acute treatment of depression in children and adolescents : a placebo-controlled, randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry 41, 12051215. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, Rintelmann J (1997). A double-blind, randomized, placebo-controlled trial of uoxetine in children and adolescents with depression. Archives of General Psychiatry 54, 10311037. Emslie GJ, Ryan ND, Wagner KD (2005). Major depressive disorder in children and adolescents : clinical trial design and antidepressant ecacy. Journal of Clinical Psychiatry 66 (Suppl. 7), 1420. Emslie GJ, Wagner KD, Kutcher S, Krulewicz S, Fong R, Carpenter DJ, Lipschitz A, Machin A, Wilkinson C (2006). Paroxetine treatment in children and adolescents with major depressive disorder : a randomized, multicenter, double-blind, placebo-controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry 45, 709719. Ensom MHH, Chang TKH, Patel P (2001). Pharmacogenetics : the therapeutic drug monitoring of the future ? Clinical Pharmacokinetics 40, 783802. DeVane CL (2003). Immediate-release versus controlledrelease formulations : pharmacokinetics of newer antidepressants in relation to nausea. Journal of Clinical Psychiatry 64 (Suppl. 18), 1419.

CINP Antidepressant Task Force 2007

Fava M (2003c). The role of the serotonergic and noradrenergic neurotransmitter systems in the treatment of psychological and physical symptoms of depression. Journal of Clinical Psychiatry 64 (Suppl. 13), 2629. Fava M (2006). Prospective studies of adverse events related to antidepressant discontinuation. Journal of Clinical Psychiatry 67 (Suppl. 4), 1421. Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW, Zajecka J, Murck H, Rosenbaum JF (2005a). A double-blind, randomized trial of St Johns wort, uoxetine, and placebo in major depressive disorder. Journal of Clinical Psychopharmacology 25, 441447. Fava M, Davidson KG (1996). Denition and epidemiology of treatment-resistant depression. Psychiatric Clinics of North America 19, 179200. Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF (1997). Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. American Journal of Psychiatry 154, 17601762. Fava GA, Ruini C, Belaise C (2007). The concept of recovery in major depression. Psychol. Med. 37, 307317. Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ (2003). Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatric Clinics of North America 26, 45794. x. Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ, Thase ME, Warden D, Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH (2006). A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients : a STAR*D report. American Journal of Psychiatry 163, 11611172. Fava M, Thase ME, DeBattista C (2005b). A multicenter, placebo-controlled study of modanil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. Journal of Clinical Psychiatry 66, 8593. FDA Public Health Advisory (2004). Suicidality in Children and Adolescents Being Treated With Antidepressant Medications. (http://www.fda.gov/cder/drug/ antidepressants/SSRIPHA200410.htm). Accessed 7 January 2007). Feiger AD (1996). A double-blind comparison of gepirone extended release, imipramine, and placebo in the treatment of outpatient major depression. Psychopharmacology Bulletin 32, 659665. Feiger AD, Heiser JF, Shrivastava RK, Weiss KJ, Smith WT, Sitsen JM, Gibertini M (2003). Gepirone extended-release : new evidence for ecacy in the treatment of major depressive disorder. Journal of Clinical Psychiatry 64, 243249. Feiger AD, Rickels K, Rynn MA, Zimbro DL, Robinson DS (2006). Selegiline transdermal system for the treatment of major depressive disorder : an 8-week, double-blind, placebo-controlled, exible-dose titration trial. Journal of Clinical Psychiatry 67(9), 13541361.

S139

Feighner J, Hendrickson G, Miller L, Stern W (1986). Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder. Journal of Clinical Psychopharmacology 6, 2732. Feighner JP, Gardner EA, Johnston JA, Batey SR, Khayrallah MA, Ascher JA, Lineberry CG (1991). Doubleblind comparison of bupropion and uoxetine in depressed outpatients. Journal of Clinical Psychiatry 52, 329335. Feighner JP, Herbstein J, Damlouji N (1985). Combined MAOI, TCA, and direct stimulant therapy of treatmentresistant depression. Journal of Clinical Psychiatry 46, 206209. Feinstein A, OConnor P, Gray T, Feinstein K (1999). Pathological laughing and crying in multiple sclerosis : a preliminary report suggesting a role for the prefrontal cortex. Multiple Sclerosis 5, 6973. Feng BL, Wang QC, Li ZY (2004). [Inuence of Jieyu Huoxue Decoction on rehabilitation of patients with depression after cerebral infarction]. Zhong Xi Yi Jie He Xue Bao 2, 182184. Ferguson JM (2001). SSRI antidepressant medications : adverse eects and tolerability. Primary Care Companion to the Journal of Clinical Psychiatry 3, 2227. Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, Hutton B (2005). Association between suicide attempts and selective serotonin reuptake inhibitors : systematic review of randomised controlled trials. British Medical Journal 330, 396. Fernandez JL, Montgomery S, Francois C (2005). Evaluation of the cost eectiveness of escitalopram versus venlafaxine XR in major depressive disorder. Pharmacoeconomics 23, 155167. Ferreri M, Lavergne F, Berlin I, Payan C, Puech AJ (2001). Benets from mianserin augmentation of uoxetine in patients with major depression nonresponders to uoxetine alone. Acta Psychiatrica Scandinavica 103, 6672. Fineberg NA, Gale TM (2005). Evidence-based pharmacotherapy of obsessive-compulsive disorder. International Journal of Neuropsychopharmacology 8, 107129. Finfgeld DL (2003). SSRI-related hyponatremia among aging adults. Journal of sychosocial Nursing and Mental Health Services 41, 1216. Fink M (1990). Is catatonia a primary indication for ECT ? Convulsive Therapy 6, 14. Fink M (1992). Catatonia and DSM-IV. Convulsive Therapy 8, 159162. Fink M (1999). Electroshok : Restoring the Mind. New York : Oxford University Press. Fink M, Abrams R, Bailine S, Jae R (1996). Ambulatory electroconvulsive therapy : report of a task force of the association for convulsive therapy. Association for Convulsive Therapy. Convulsive Therapy 12, 4255. Fink M, Sackeim HA (1996). Convulsive therapy in schizophrenia ? Schizophrenia Bulletin 22, 2739. Fink M, Taylor MA (2003). Catatonia : a Clinicians Guide to Diagnosis and Treatment. Cambridge : Cambridge University Press.

S140

CINP Antidepressant Task Force 2007

for the treatment of depression and estimation of the budgetary impact. Journal of Medical Economics 5, 91107. Francois C, Toumi M, Aakhus AM, Hansen K (2003). A pharmacoeconomic evaluation of escitalopram, a new selective serotonin reuptake inhibitor. Comparison of cost-eectiveness between escitalopram, citalopram, uoxetine, and venlafaxine for the treatment of depression in Norway. European Journal of Health Economics 4, 1219. Frank E, Carpenter LL, Kupfer DJ (1988). Sex dierences in recurrent depression : are there any that are signicant ? American Journal of Psychiatry 145, 4145. Frank E, Kupfer DJ, Perel JM, Cornes C, Jarrett DB, Mallinger AG, Thase ME, McEachran AB, Grochocinski VJ (1990). Three-year outcomes for maintenance therapies in recurrent depression. Archives of General Psychiatry 47, 10931099. Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, Grochocinski V, Houck P, Scott J, Thompson W, Monk T (2005). Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Archives of General Psychiatry 62, 9961004. Frasure-Smith N, Lesperance F, Julien P (2004). Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biological Psychiatry 55, 891896. Frasure-Smith N, Lesperance F, Talajic M (1993). Depression following myocardial infarction. Impact on 6-month survival. Journal of the American Medical Association 270, 18191825. Frazer A (2001). Serotonergic and noradrenergic reuptake inhibitors : prediction of clinical eects from in vitro potencies. Journal of Clinical Psychiatry 62, 1623. Freeman H, Arikian S, Lenox-Smith A (2000). Pharmacoeconomic analysis of antidepressants for major depressive disorder in the United Kingdom. Pharmacoeconomics 18, 143148. Freeman MP, Hibbeln JR, Wisner KL, Brumbach BH, Watchman M, Gelenberg AJ (2006). Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression. Acta Psychiatrica Scandinavica 113, 3135. Frey R, Schreinzer D, Heiden A, Kasper S (2001). [Use of electroconvulsive therapy in psychiatry]. Nervenarzt 72, 661676. Frey R, Schreinzer D, Stimp T, Vycudilik W, Berzlanovich A, Kasper S (2002). [Fatal poisonings with antidepressive drugs and neuroleptics. Analysis of a correlation with prescriptions in Vienna 1991 to 1997]. Nervenarzt 73, 629636. Friedli K, King MB, Lloyd M (2000). The economics of employing a counsellor in general practice : analysis of data from a randomised controlled trial. British Journal of General Practice 50, 276283. Fromm MF (2000). P-glycoprotein : a defense mechanism limiting oral bioavailability anad CNS accumulation of

Finkelstein FO, Watnick S, Finkelstein SH, Wuerth D (2002). The treatment of depression in patients maintained on dialysis. Journal of Psychosomatic Research 53, 957960. Fleck MP, Lafer B, Sougey EB, Del Porto JA, Brasil MA, Juruena MF (2003). [Guidelines of the Brazilian Medical Association for the treatment of depression (complete version)]. Revista Brasileira De Psiquiatria 25, 114122. Foley KF, DeSanty KP, Kast RE (2006). Bupropion : pharmacology and therapeutic applications. Expert Review of Neurotherapeutics 6, 12491265. Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S, Schulze-Monking H (1997). Electroconvulsive therapy vs. paroxetine in treatment-resistant depression : a randomized study. Acta Psychiatrica Scandinavica 96, 334342. Forder J, Kavanagh S, Fenyo A (1996). A comparison of the cost-eectiveness of sertraline versus tricyclic antidepressants in primary care. Journal of Aective Disorders 38, 97111. Foulkes NS, Borjigin J, Snyder SH, Sassone-Corsi P (1997). Rhythmic transcription : the molecular basis of circadian melatonin synthesis. Trends in Neurosciences 20, 487492. Fountoulakis KN, Iacovides A, Nimatoudis I, Kaprinis G, Ierodiakonou C (1999). Comparison of the diagnosis of melancholic and atypical features according to DSM-IV and somatic syndrome according to ICD-10 in patients suering from major depression. European Psychiatry 14, 426433. Fountoulakis KN, Iacovides A, St Kaprinis G (2004). Combined oral venlafaxine and intravenous clomipramine-A : successful temporary response in a patient with extremely refractory depression. Canadian Journal of Psychiatry 49, 7374. Fountoulakis KN, Vieta E, Bouras C, Notaridis G, Giannakopoulos P, Kaprinis G, Akiskal HS (2006). Lithium toxicity. A systematic review of existing data. Annals of General Psychiatry 4, S329. Frampton JE and Plosker GL (2007). Selegiline transdermal system : in the treatment of major depressive disorder. Drugs 67, 25765. Franchini L, Gasperini M, Perez J, Smeraldi E, Zanardi R. (1997). A double-blind study of long-term treatment with sertraline or uvoxamine for prevention of highly recurrent unipolar depression. J Clin Psychiatry. 58, 104107. Franchini L, Gasperini M, Perez J, Smeraldi E, Zanardi R (1998). Dose-response ecacy of paroxetine in preventing depressive recurrences : a randomized, double-blind study. Journal of Clinical Psychiatry 59, 229232. Franco-Bronson K (1996). The management of treatmentresistant depression in the medically ill. Psychiatric Clinics of North America 19, 329350. Francois C, Sinronen H, Toumi M (2002). Introduction of escitalopram, a new SSRI in Finland : comparison of cost-eectiveness between the other SSRs and SNRI

CINP Antidepressant Task Force 2007

drugs. International Journal of Clinical Pharmacology and Therapeutics 38, 6974. Furey ML and Drevets WC (2006). Antidepressant ecacy of the Antimuscarinic drug scopolamine : a randomized, placebo.-controlled clinical trial. Archives of General Psychiatry 63, 11211129. Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC (1999). Analysis of the monoamine oxidase A (MAOA) gene in bipolar aective disorder by association studies, meta-analyses, and sequencing of the promoter. American Journal of Medical Genetics 88, 398406. Furukawa T, McGuire H, Barbui C (2003). Low dosage tricyclic antidepressants for depression. Cochrane Database of Systematic Reviews CD003197. Furukawa T, Streiner DL, Young LT (2000). Antidepressant plus benzodiazepine for major depression. Cochrane Database of Systematic Reviews CD001026. Furukawa TA, Streiner DL, Young LT (2001a). Antidepressant plus benzodiazepine for major depression. Cochrane Database of Systematic Review.s CD001026. Furukawa TA, Streiner DL, Young LT (2001b). Is antidepressant-benzodiazepine combination therapy clinically more useful ? A meta-analytic study. Journal of Aective Disorders 65, 173177. Furukawa TA, Watanabe N, Churchill R (2006). Psychotherapy plus antidepressant for panic disorder with or without agoraphobia : systematic review. British Journal of Psychiatry 188, 305312. Gadit AA (2004). Out-of-pocket expenditure for depression among patients attending private community psychiatric clinics in Pakistan. Journal of Mental Health Policy and Economics 7, 2328. Gallagher P, Young AH (In Press). Mifepristone (RU-486) treatment for depression and psychosis : a review of the therapeutic implications. Neuropsychiatric Disease and Treatment. Gallagher SM, Allen JJ, Hitt SK, Schnyer RN, Manber R (2001). Six-month depression relapse rates among women treated with acupuncture. Complementary Therapies in Medicine 9, 216218. Gallarda T (1999). [Alzheimers disease and depression]. Encephale 25 Spec No. 5, 1417. Gallinat J, Boetsch T, Padberg F, Hampel H, Herrmann WM, Hegerl U (2000). Is the EEG helpful in diagnosing and monitoring lithium intoxication ? A case report and review of the literature. Pharmacopsychiatry 33, 169173. Gangadhar BN, Kapur RL, Kalyanasundaram S (1982). Comparison of electroconvulsive therapy with imipramine in endogenous depression : a double blind study. British Journal of Psychiatry 141, 367371. Garcia-Toro M, Mayol A, Arnillas H, Capllonch I, Ibarra O, Crespi M, Mico J, Lafau O, Lafuente L (2001a). Modest adjunctive benet with transcranial magnetic stimulation in medication-resistant depression. Journal of Aective Disorders 64, 271275. Garcia-Toro M, Pascual-Leone A, Romera M, Gonzalez A, Mico J, Ibarra O, Arnillas H, Capllonch I, Mayol A, Tormos JM (2001b). Prefrontal repetitive transcranial

S141

magnetic stimulation as add on treatment in depression. Journal of Neurology, Neurosurgery and Psychiatry 71, 546548. Gardiner SJ, Begg EJ (2005). Pharmacogenetic testing for drug metabolizing enzymes : is it happening in practice ? Pharmacogenetics and Genomics 15, 365369. Gardiner SJ, Begg EJ (2006). Pharmacogenetics, drugmetabolizing enzymes, and clinical practice. Pharmacological Reviews 58, 521590. Gardner DM, Lynd LD (1998). Sumatriptan contraindications and the serotonin syndrome. Annals of Pharmacotherapy 32, 3338. Gareri P, Stilo G, Bevacqua I, Mattace R, Ferreri G, De Sarro G (1998). Antidepressant drugs in the elderly. General Pharmacology 30, 465475. Garner EM, Kelly MW, Thompson DF (1993). Tricyclic antidepressant withdrawal syndrome. Annals of Pharmacotherapy 27, 10681072. Gask L, Dowrick C, Dixon C, Sutton C, Perry R, Torgerson D, Usherwood T (2004). A pragmatic cluster randomized controlled trial of an educational intervention for GPs in the assessment and management of depression. Psychological Medicine 34, 6372. Gastpar M, Ngo KT, Gilsdorf U, Baumann P (1986). Comparison of oral and intravenous treatment of depressive states : preliminary results of a WHO collaborative study. Clinical Neuropharmacology 9 (Suppl. 4), 434436. Gastpar M, Singer A, Zeller K (2005). Ecacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry 38, 7886. Gaszner P (2005). About the menopausal depression. Neuropsychopharmacologia Hungarica 7, 208214. Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM (2003). Relapse prevention with antidepressant drug treatment in depressive disorders : a systematic review. Lancet 361, 653661. Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J (2000). SSRIs versus other antidepressants for depressive disorder. Cochrane Database of Systematic Reviews CD001851. Geerlings MI, Schoevers RA, Beekman AT, Jonker C, Deeg DJ, Schmand B, Ader HJ, Bouter LM, Van TW (2000). Depression and risk of cognitive decline and Alzheimers disease. Results of two prospective community-based studies in The Netherlands. British Journal of Psychiatry 176, 568575. Gendreau RM, Thorn MD, Gendreau JF, Kranzler JD, Ribeiro S, Gracely RH, Williams DA, Mease PJ, McLean SA, Clauw DJ (2005). Ecacy of milnacipran in patients with bromyalgia. Journal of Rheumatology 32, 19751985. Gentile S (2005). The safety of newer antidepressants in pregnancy and breastfeeding. Drug Safety 28, 137152. George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, Howland R, Kling MA, Moreno F, Rittberg B, Dunner D, Schwartz T,

S142

CINP Antidepressant Task Force 2007

depression in primary care. Quality and Safety in Health Care 12, 149155. Gilmer WS, Trivedi MH, Rush AJ, Wisniewski SR, Luther J, Howland RH, Yohanna D, Khan A, Alpert J (2005). Factors associated with chronic depressive episodes : a preliminary report from the STAR-D project. Acta Psychiatrica Scandinavica 112, 425433. Girard M (1990). Mianserin side-eects. Lancet 336, 1439. Glassman A, Shapiro PA, Ford DE, Culpepper L, Finkel MS, Swenson JR, Bigger JT, Rollman BL, Wise TN (2003). Cardiovascular health and depression. Journal of Psychiatric Practice 9, 409421. Glassman AH (2005). Does treating post-myocardial infarction depression reduce medical mortality ? Archives of General Psychiatry 62, 711712. Glassman AH, Bigger JT, Ganey M, Shapiro PA, Swenson JR (2006). Onset of major depression associated with acute coronary syndromes : relationship of onset, major depressive disorder history, and episode severity to sertraline benet. Archives of General Psychiatry 63, 283288. Goforth HW, Holsinger T (2007). Rapid relief of severe major depressive disorder by use of preoperative ketamine and electroconvulsive therapy. Journal of ECT 23, 2325. Goldberg D, Lecrubier Y (1995). Form and frequency of mental disorders across centres. In : Ustun TB, Sartorius N (Eds.), Mental Illness in General Health Care : an International Study (pp. 323334). Chichester : John Wiley. Goldberg JF (2003). When do antidepressants worsen the course of bipolar disorder ? Journal of Psychiatric Practice 9, 181194. Goldberg JF, Burdick KE, Endick CJ (2004). Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatmentresistant bipolar depression. American Journal of Psychiatry 161, 564566. Goldberg MR, Lowry RC, Musson DG, Birk KL, Fisher A, De Puy ME, Shadle CR (1999). Lack of pharmacokinetic and pharmacodynamic interaction between rizatriptan and paroxetine. Journal of Clinical Pharmacology 39, 192199. Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, Suppes T, Wisner KL, Nemero CB (2005). The ecacy of light therapy in the treatment of mood disorders : a review and meta-analysis of the evidence. American Journal of Psychiatry 162, 656662. Golden RN, Hsiao JK, Lane E, Ekstrom D, Rogers S, Hicks R, Potter WZ (1990). Abnormal neuroendocrine responsivity to acute i.v. clomipramine challenge in depressed patients. Psychiatry Research 31, 3947. Goldney RD (2006). Suicide and antidepressants : what is the evidence ? Australian and New Zealand Journal of Psychiatry 40, 381385. Goldstein BJ, Goodnick PJ (1998). Selective serotonin reuptake inhibitors in the treatment of aective disorders III. Tolerability, safety and pharmacoeconomics. Journal of Psychopharmacology 12, S55S87.

Carpenter L, Burke M, Ninan P, Goodnick P (2005). A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biological Psychiatry 58, 364373. George MS, Rush AJ, Sackeim HA, Marangell LB (2003). Vagus nerve stimulation (VNS) : utility in neuropsychiatric disorders. International Journal of Neuropsychopharmacology 6, 7383. Georgotas A, McCue RE, Hapworth W, Friedman E, Kim OM, Welkowitz J, Chang I, Cooper TB (1986). Comparative ecacy and safety of MAOIs versus TCAs in treating depression in the elderly. Biological Psychiatry 21, 11551166. Gerson S, Belin TR, Kaufman A, Mintz J, Jarvik L (1999). Pharmacological and psychological treatments for depressed older patients : a meta-analysis and overview of recent ndings. Harvard Review of Psychiatry 7, 128. Ghadirian AM, Engelsmann F, Dhar V, Filipini D, Keller R, Chouinard G, Murphy BEP (1995). The psychotropic eects of inhibitors of steroid biosynthesis in depressed patients refractory to treatment. Biological Psychiatry 37, 369375. Ghaziuddin N, Laughrin D, Giordani B (2000). Cognitive side eects of electroconvulsive therapy in adolescents. Journal of Child and Adolescent Psychopharmacology 10, 269276. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ (2007). Early evidence on the eects of regulators suicidality warnings on SSRI prescriptions and suicide in children and adolescents. American Journal of Psychiatry 164, 13561363. Gibbons RD, Hur K, Bhaumik DK, Mann JJ (2005). The relationship between antidepressant medication use and rate of suicide. Archives of General Psychiatry 62, 165172. Gibbons RD, Hur K, Bhaumik DK, Mann JJ (2006). The relationship between antidepressant prescription rates and rate of early adolescent suicide. American Journal of Psychiatry 163, 18981904. Gibson AC (1974). Letter : Agranulocytosis after treatment with clomipramine infusion. British Journal of Psychiatry 125, 111112. Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM (2004). Antidepressants for bipolar depression : a systematic review of randomized, controlled trials. American Journal of Psychiatry 161, 15371547. Gilaberte I, Montejo AL, de la GJ, Perez-Sola V, Bernardo M, Massana J, Martin-Santos R, Santiso A, Noguera R, Casais L, Perez-Camo V, Arias M, Judge R. (2001). Fluoxetine in the prevention of depressive recurrences : a double-blind study. Journal of Clinical Psychopharmacology 21, 417424. Gilbody S, Whitty P, Grimshaw J, Thomas R (2003a). Educational and organizational interventions to improve the management of depression in primary care : a systematic review. Journal of the American Medical Association 289, 31453151. Gilbody SM, Whitty PM, Grimshaw JM, Thomas RE (2003b). Improving the detection and management of

CINP Antidepressant Task Force 2007

Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C, Demitrack MA (2004). Duloxetine in the treatment of depression : a double-blind placebo-controlled comparison with paroxetine. Journal of Clinical Psychopharmacology 24, 389399. Goldston DB, Reboussin BA, Daniel SS (2006). Predictors of suicide attempts : state and trait components. Journal of Abnormal Psychology 115, 842849. Gonzalez-Pinto A, Gutierrez M, Gonzalez N, Elizagarate E, Perez De Heredia JL, Mico JA (2002). Ecacy and safety of venlafaxine-ECT combination in treatment-resistant depression. Journal of Neuropsychiatry and Clinical Neurosciences 14, 206209. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D (2003). Suicide risk in bipolar disorder during treatment with lithium and divalproex. Journal of the American Medical Association 290, 14671473. Goodwin GM (2003). Evidence-based guidelines for treating bipolar disorder : recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 17, 149173. Gould TD, Manji HK (2004). The molecular medicine revolution and psychiatry : bridging the gap between basic neuroscience research and clinical psychiatry. Journal of Clinical Psychiatry 65, 598604. Grasmader K, Verwohlt PL, Rietschel M, Dragicevic A, Muller M, Hiemke C, Freymann N, Zobel A, Maier W, Rao ML (2004). Impact of polymorphisms of cytochromeP450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical eects of antidepressants in a naturalistic clinical setting. European Journal of Clinical Pharmacology 60, 329336. Grassi ZG, Cipriani S, Balgkouranidou I, Scattoni R (2006). One night sleep deprivation stimulates hippocampal neurogenesis. Brain Research Bulletin 69, 375381. Gravenor DS, Leclerc JR, Blake G (1986). Tricyclic antidepressant agranulocytosis. Canadian Journal of Psychiatry 31, 661. Green B (2003). Focus on paroxetine. Current Medical Research and Opinion 19, 1321. Green RC, Cupples LA, Kurz A, Auerbach S, Go R, Sadovnick D, Duara R, Kukull WA, Chui H, Edeki T, Grith PA, Friedland RP, Bachman D, Farrer L (2003). Depression as a risk factor for Alzheimer disease : the MIRAGE Study. Archives of Neurology 60, 753759. Greenberg L, Fink M (1992). The use of electroconvulsive therapy in geriatric patients. Clinics in Geriatric Medicine 8, 349354. Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA, Corey-Lisle PK (2003). The economic burden of depression in the United States : how did it change between 1990 and 2000 ? Journal of Clinical Psychiatry 64, 14651475. Greenblatt M, Grosser GH, Wechsler HA (1964). Dierential response of hospitalized depressed patients in somatic therapy. American Journal of Psychiatry 935943. Greenhalgh J, Knight C, Hind D, Beverley C, Walters S (2005). Clinical and cost-eectiveness of electroconvulsive

S143

therapy for depressive illness, schizophrenia, catatonia and mania : systematic reviews and economic modelling studies. Health Technology Assessment 9, 156, iiiiv. Grith JD, Carranza J, Grith C, Miller LL (1983). Bupropion : clinical assay for amphetamine-like abuse potential. Journal of Clinical Psychiatry 44, 206208. Grigoriadis S, Kennedy SH, Srinivisan J, McIntyre RS, Fulton K (2005). Antidepressant augmentation with raloxifene. Journal of Clinical Psychopharmacology 25, 9698. Grogan R, Wagner DR, Sullivan T, Labar D (1995). Generalized nonconvulsive status epilepticus after electroconvulsive therapy. Convulsive Therapy 11, 5156. Grote NK, Frank E (2003). Dicult-to-treat depression : the role of contexts and comorbidities. Biological Psychiatry 53, 660670. Grube M, Hartwich P (1990). Maintenance of antidepressant eect of sleep deprivation with the help of lithium. European Archives of Psychiatry and Clinical Neuroscience 240, 6061. Grundemar L, Hakanson R (1994). Neuropeptide Y eector systems : perspectives for drug development. Trends in Pharmacological Sciences 15, 153159. Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ (2004). Antidepressants and suicide risk in the United States, 19851999. Journal of Clinical Psychiatry 65, 14561462. Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz R, Ziv R, Lefkifker E (2000). Repetitive transcranial magnetic stimulation is as eective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder : an open study. Biological Psychiatry 47, 314324. Grunhaus L, Pande AC, Brown MB, Greden JF (1994). Clinical characteristics of patients with concurrent major depressive disorder and panic disorder. American Journal of Psychiatry 151, 541546. Grunhaus L, Rabin D, Greden JF (1986). Simultaneous panic and depressive disorder : response to antidepressant treatments. Journal of Clinical Psychiatry 47, 47. Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN (2003). A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic major depression. Biological Psychiatry 53, 324331. Grunze H, Kasper S, Goodwin G, Bowden C, Baldwin D, Licht R, Vieta E, Moller HJ (2002). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of bipolar disorders. Part I. Treatment of bipolar depression. World Journal of Biological Psychiatry 3, 115124. Guel JD, Ansseau M, Timmerman L, Korsgaard S (2001). Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. Journal of Clinical Psychopharmacology 21, 425431. Guel JD, Bouhassira M, Bonett-Perrin E, Lancrenon S (1999). [The study of the ecacy of uoxetine versus

S144

CINP Antidepressant Task Force 2007

Halbreich U, Kahn LS (2006). Atypical depression, somatic depression and anxious depression in women : Are they gender-preferred phenotypes ? Journal of Aective Disorders Hall WD, Lucke J (2006). How have the selective serotonin reuptake inhibitor antidepressants aected suicide mortality ? Australian and New Zealand Journal of Psychiatry 40, 941950. Hall WD, Mant A, Mitchell PB, Rendle VA, Hickie IB, McManus P (2003). Association between antidepressant prescribing and suicide in Australia, 19912000 : trend analysis. British Medical Journal 326, 1008. Hameed U, Schwartz TL, Malhotra K, West RL, Bertone F (2005). Antidepressant treatment in the primary care oce : outcomes for adjustment disorder versus major depression. Annals of Clinical Psychiatry 17, 7781. Hamilton JA, Grant M, Jensvold MF (1995). Sex and the treatment of depression : when does it matter ? In : Jensvold MF, Halbreich U, Hamilton JA (Eds.), Psychopharmacology of Women : Sex, Gender and Hormonal Considerations. Washington DC : American Psychiatric Press. Hamilton M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662. Hamilton M (1967). Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology 6, 278296. Hammad TA (2006). Relationship Between Psychotropic Drugs and Pediatric Suicidality (http://www.fda.gov/ ohrms/dockets/ac/04/brieng/2004-4065B1-10-TAB08Hammads-Review.pdf). Accessed 24 January 2006. Hammad TA, Laughren T, Racoosin J (2006a). Suicidality in pediatric patients treated with antidepressant drugs. Archives of General Psychiatry 63, 332339. Hammad TA, Laughren TP, Racoosin JA (2006b). Suicide rates in short-term randomized controlled trials of newer antidepressants. Journal of Clinical Psychopharmacology 26, 203207. Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS (2005). Ecacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Annals of Internal Medicine 143, 415426. Hantz P, Caradoc-Davies G, Caradoc-Davies T, Weatherall M, Dixon G (1994). Depression in Parkinsons disease. American Journal of Psychiatry 151, 10101014. Harkin A, Kelly JP, Leonard BE (2006). A review of the relevance and validity of olfactory bulbectomy as a model of depression. Clinical Neuroscience Research 3, 253262. Harris EC, Barraclough B (1998). Excess mortality of mental disorder. British Journal of Psychiatry 173 :1153., 1153. Harvey BH, McEwen BS, Stein DJ (2003). Neurobiology of antidepressant withdrawal : implications for the longitudinal outcome of depression. Biological Psychiatry 54, 11051117. Harvey I, Nelson SJ, Lyons RA, Unwin C, Monaghan S, Peters TJ (1998). A randomized controlled trial and economic evaluation of counselling in primary care. British Journal of General Practice 48, 10431048. Hasegawa S, Watanabe A, Nguyen KQ, Debonnel G, Diksic M (2005). Chronic administration of citalopram in

tianeptine in the treatment of elderly depressed patients followed in general practice]. Encephale 25, 265270. Guel JD, Pichot P, Dreyfus JF (1989). Ecacy of tianeptine in anxious-depressed patients : results of a controlled multicenter trial versus amitriptyline. Neuropsychobiology 22, 4148. Guel JD, Strub N, Loft H (2000). Ecacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and ecacy data from a double-blind, double-dummy trial. Journal of Aective Disorders 58, 201209. Guillem E, Lepine JP (2003). [Does addiction to antidepressants exist ? About a case of one addiction to tianeptine]. Encephale 29, 456459. Guma M, Clemente F, Segura A, Costa J (1999). [The serotoninergic syndrome : moclobemide and citalopram]. Medicina Clnica 113, 677678. Gunnell D, Ashby D (2004). Antidepressants and suicide : what is the balance of benet and harm. British Medical Journal 329, 3438. Gunnell D, Saperia J, Ashby D (2005). Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults : meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRAs safety review. British Medical Journal 330, 385. Gureje O, Lasebikan VO, Kola L, Makanjuola VA (2007). Lifetime and 12-month prevalence of mental disorders in the Nigerian Survey of Mental Health and Wellbeing. British Journal of Psychiatry. Guthrie E, Moorey J, Margison F, Barker H, Palmer S, McGrath G, Tomenson B, Creed F (1999). Costeectiveness of brief psychodynamic-interpersonal therapy in high utilizers of psychiatric services. Archives of General Psychiatry 56, 519526. Guze SB, Robins E (1970). Suicide and primary aective disorders. British Journal of Psychiatry 117, 437438. DOI : 10.1016/j.jad.2006.09.023. Hackett ML, Anderson CS, House AO (2004). Interventions for treating depression after stroke. Cochrane Database of Systematic Reviews CD003437. Haddad P (1998). The SSRI discontinuation syndrome. Journal of Psychopharmacology 12, 305313. Haddad P (1999). Do antidepressants have any potential to cause addiction ? Journal of Psychopharmacology 13, 300307. Haddad PM (2001). Antidepressant discontinuation syndromes. Drug Safety 24, 183197. Haddjeri N, Blier P, de Montigny C (1998). Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. Journal of Neuroscience 18, 1015010156. Hager ED, Dziambor H, Winkler P, Hohmann D, Macholdt K (2002). Eects of lithium carbonate on hematopoietic cells in patients with persistent neutropenia following chemotherapy or radiotherapy. Journal of Trace Elements in Medicine and Biology 16, 9197.

CINP Antidepressant Task Force 2007

olfactory bulbectomy rats restores brain 5-HT synthesis rates : an autoradiographic study. Psychopharmacology (Berlin) 179, 781790. Hasin DS, Goodwin RD, Stinson FS, Grant BF (2005). Epidemiology of major depressive disorder : results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Archives of General Psychiatry 62, 10971106. Hasler G, Drevets WC, Manji HK, Charney DS (2004). Discovering endophenotypes for major depression. Neuropsychopharmacology 29, 17651781. Hatziandreu EJ, Brown RE, Revicki DA, Turner R, Martindale J, Levine S, Siegel JE (1994). Cost utility of maintenance treatment of recurrent depression with sertraline versus episodic treatment with dothiepin. Pharmacoeconomics 5, 249268. Hatzinger M, Hemmeter UM, Baumann K, Brand S, Holsboer-Trachsler E (2002). The combined DEX-CRH test in treatment course and long-term outcome of major depression. Journal of Psychiatric Research 36, 287297. Hazell P, OConnell D, Heathcote D, Henry D (2002). Tricyclic drugs for depression in children and adolescents. Cochrane Database of Systematic Reviews. CD002317. Healy D (2006). Manufacturing consensus. Culture, Medicine and Psychiatry 30, 135156. Healy D, Whitaker C (2003). Antidepressants and suicide : risk-benet conundrums. Journal of Psychiatry and Neuroscience 28, 331337. Hebenstreit GF, Fellerer K, Fichte K, Fischer G, Geyer N, Meya U, Hernandez M, Schony W, Schratzer M, Soukop W (1989). Rolipram in major depressive disorder : results of a double-blind comparative study with imipramine. Pharmacopsychiatry 22, 156160. Hegerl U, Althaus D, Schmidtke A, Niklewski G (2006). The alliance against depression : 2-year evaluation of a community-based intervention to reduce suicidality. Psychological Medicine 36, 12251233. Helgason T, Tomasson H, Zoega T (2004). Antidepressants and public health in Iceland. Time series analysis of national data. British Journal of Psychiatry 184, 157162. Helmchen H (1974). Symptomatology of therapy-resistant depressions. Pharmakopsychiatrie, NeuroPsychopharmakologie 7, 145155. Hemels ME, Kasper S, Walter E, Einarson TR (2004a). Cost-eectiveness analysis of escitalopram : a new SSRI in the rst-line treatment of major depressive disorder in Austria. Current Medical Research and Opinion 20, 869878. Hemels ME, Kasper S, Walter E, Einarson TR (2004b). Cost-eectiveness of escitalopram versus citalopram in the treatment of severe depression. Annals of Pharmacotherapy 38, 954960. Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002). St Johns wort (Hypericum perforatum) : drug interactions and clinical outcomes. British Journal of Clinical Pharmacology 54, 349356.

S145

Hendset M, Haslemo T, Rudberg I, Refsum H, Molden E (2006). The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs. Pharmacopsychiatry 39, 121127. Henkel V, Mergl R, Allgaier AK, Kohnen R, Moller HJ, Hegerl U (2006). Treatment of depression with atypical features : a meta-analytic approach. Psychiatry Research 141, 89101. Henkel V, Moller HJ (2005). What Are the Most Eective Diagnostic and Therapeutic Strategies for the anagement of Depression in Specialist Care ? A Health Evidence Network Report (http:/ /www.euro.who.int/document/ e86602.pdf). Accessed 24 May 2005. Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D, Mulcahy F, Feely J (2002). St Johns wort increases expression of P-glycoprotein : implications for drug interactions. British Journal of Clinical Pharmacology 53, 7582. Henriksson S, Asplund R, Boethius G, Hallstrom T, Isacsson G (2006). Infrequent use of antidepressants in depressed individuals (an interview and prescription database study in a dened Swedish population 20012002). European Psychiatry 21, 355360. Henriksson S, Boethius G, Isacsson G (2001). Suicides are seldom prescribed antidepressants : ndings from a prospective prescription database in Jamtland county, Sweden, 198595. Acta Psychiatrica Scandinavica 103, 301306. Henriksson S, Isacsson G (2006). Increased antidepressant use and fewer suicides in Jamtland county, Sweden, after a primary care educational programme on the treatment of depression. Acta Psychiatrica Scandinavica 114, 159167. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S (2006). Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine : an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. American Journal of Psychiatry 163, 185194. Heresco-Levy U, Javitt DC, Geln Y, Gorelik E, Bar M, Blanaru M, Kremer I (2006). Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. Journal of Aective Disorders 93, 239243. Heuser I, Deuschle M, Luppa P, Schweiger U, Standhardt H, Weber B (1998). Increased diurnal plasma concentrations of dehydroepiandrosterone in depressed patients. Journal of Clinical Endocrinology and Metabolism 83, 31303133. Hibbeln JR (1998). Fish consumption and major depression. Lancet 351, 1213. Hickie I, Scott E, Naismith S, Ward PB, Turner K, Parker G, Mitchell P, Wilhelm K (2001). Late-onset depression : genetic, vascular and clinical contributions. Psychological Medicine 31, 14031412. Hildebrandt MG, Steyerberg EW, Stage KB, Passchier J, Kragh-Soerensen P (2003). Are gender dierences important for the clinical eects of antidepressants ? American Journal of Psychiatry 160, 16431650.

S146

CINP Antidepressant Task Force 2007

Holsboer F (2001). Antidepressant drug discovery in the postgenomic era. World Journal of Biological Psychiatry 2, 165177. Holsboer F, Barden N (1996). Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocrine Reviews 17, 187205. Horne RL, Ferguson JM, Pope HGJ, Hudson JI, Lineberry CG, Ascher J, Cato A (1988). Treatment of bulimia with bupropion : a multicenter controlled trial. Journal of Clinical Psychiatry 49, 262266. Horowitz A, Reinhardt JP, Kennedy GJ (2005). Major and subthreshold depression among older adults seeking vision rehabilitation services. American Journal of Geriatric Psychiatry 13, 180187. Hosak L, Tuma I, Hanus H, Straka L (2000). Costs and outcomes of use of amitriptyline, citalopram and uoxetine in major depression : exploratory study. Acta Medica (Hradec Kralove) 43, 133137. Hotopf M, Hardy R, Lewis G (1997). Discontinuation rates of SSRIs and tricyclic antidepressants : a meta-analysis and investigation of heterogeneity. British Journal of Psychiatry 170, 120127. Howard P, Knight C (2004). A clinical and cost-eectiveness comparison of venlafaxine and selective serotonin reuptake inhibitors (SSRIs) in the management of patients with major depresive disorders from the perspective of an Austrian sickness fund. Journal of Medical Economics 7, 93106. Hu TW (2004). The economic burden of depression and reimbursement policy in the Asia Pacic region. Australasian Psychiatry 12 (Suppl.), S11S15. Hu TW (2006). Perspectives : an international review of the national cost estimates of mental illness, 19902003. Journal of Mental Health Policy and Economics 9, 313. Huizink AC, Mulder EJ, Buitelaar JK (2004). Prenatal stress and risk for psychopathology : specic eects or induction of general susceptibility ? Psychol. Bull. 130, 115142. Hung CI, Liu CY, Fuh JL, Juang YY, Wang SJ (2006). Comorbid migraine is associated with a negative impact on quality of life in patients with major depression. Cephalalgia 26, 2632. Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, Biggs MM, OConnor K, Rasmussen K, Litle M, Zhao W, Bernstein HJ, Smith G, Mueller M, McClintock SM, Bailine SH, Kellner CH (2004). Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT) : a Consortium for Research in ECT (CORE) report. Journal of Clinical Psychology 65, 485491. Husain MM, Rush AJ, Sackeim HA, Wisniewski SR, McClintock SM, Craven N, Holiner J, Mitchell JR, Balasubramani GK, Hauger R (2005). Age-related characteristics of depression : a preliminary STAR*D report. American Journal of Geriatric Psychiatry 13, 852860. Hutton HE, Lyketsos CG, Zenilman JM, Thompson RE, Erbelding EJ (2004). Depression and HIV risk behaviors

Hill GE, Wong KC, Hodges MR (1976). Potentiation of succinylcholine neuromuscular blockade by lithium carbonate. Anesthesiology 44, 439442. Hill GE, Wong KC, Hodges MR (1977). Lithium carbonate and neuromuscular blocking agents. Anesthesiology 46, 122126. Himmelhoch JM, Thase ME, Mallinger AG, Houck P (1991). Tranylcypromine versus imipramine in anergic bipolar depression. American Journal of Psychiatry 148, 910916. Hirschfeld RM (2000). Antidepressants in long-term therapy : a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatrica Scandinavica. Supplementum 403, 3538. Hirschfeld RM (2001). Clinical importance of long-term antidepressant treatment. British Journal of Psychiatry (Suppl.), 42, S4S8. Hirschfeld RM, Montgomery SA, Aguglia E, Amore M, Delgado PL, Gastpar M, Hawley C, Kasper S, Linden M, Massana J, Mendlewicz J, Moller HJ, Nemero CB, Saiz J, Such P, Torta R, Versiani M (2002). Partial response and nonresponse to antidepressant therapy : current approaches and treatment options. Journal of Clinical Psychiatry 63, 826837. Hirschfeld RM, Montgomery SA, Keller MB, Kasper S, Schatzberg AF, Moller HJ, Healy D, Baldwin D, Humble M, Versiani M, Montenegro R, Bourgeois M (2000). Social functioning in depression : a review. J Clin. Psychiatry 61, 268275. Hirschfeld RM, Vornik LA (2004). Newer antidepressants : review of ecacy and safety of escitalopram and duloxetine. Journal of Clinical Psychiatry 65 (Suppl. 4), 4652. Hochstrasser B, Isaksen PM, Koponen H, Lauritzen L, Mahnert FA, Rouillon F, Wade AG, Andersen M, Pedersen SF, Swart JC, Nil R (2001). Prophylactic eect of citalopram in unipolar, recurrent depression : placebo-controlled study of maintenance therapy. British Journal of Psychiatry. 178 :30410., 304310. Hoenig J (1980). The early manifestations of depression : Diagnostic hints. In : Ayd FJ (Ed.), Clinical Depression : Diagnostic and Therapeutic Challenges (pp. 121). Baltimore : Ayd Medical Communications. Hollon SD, DeRubeis RJ, Shelton RC, Amsterdam JD, Salomon RM, OReardon JP, Lovett ML, Young PR, Haman KL, Freeman BB, Gallop R (2005). Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Archives of General Psychiatry 62, 417422. Hollon SD, Jarrett RB, Nierenberg AA, Thase ME, Trivedi M, Rush AJ (2005). Psychotherapy and medication in the treatment of adult and geriatric depression : which monotherapy or combined treatment ? Journal of Clinical Psychiatry 66, 455468. Hollon SD, Thase ME, Markowitz JC (2002). Treatment and prevention of depression. Psychological Science in the Public Interest 3, 3977.

CINP Antidepressant Task Force 2007

among patients in a sexually transmitted disease clinic. American Journal of Psychiatry 161, 912914. Imbarlina MJ, Sarkar S, Marwah S, Parepally H, Johnston PR, Brar JS, Chengappa KN (2004). Leukopenia in clozapine treated patients may be induced by other drugs : a case series. European Psychiatry 19, 506509. Ingelman-Sundberg M, Oscarson M, McLellan RA (1999). Polymorphic human cytochrome P450 enzymes : an opportunity for individualized drug treatment. Trends in Pharmacological Sciences 20, 342349. Inskip HM, Harris EC, Barraclough B (1998). Lifetime risk of suicide for aective disorder, alcoholism and schizophrenia. British Journal of Psychiatry 172, 3537. Invernizzi G, Aguglia E, Bertolino A, Casacchia M, Ciani N, Marchesi GF, Nardini M, Rapisarda V (1994). The ecacy and safety of tianeptine in the treatment of depressive disorder : results of a controlled double-blind multicentre study vs. amitriptyline. Neuropsychobiology 30, 8593. Isacsson G (2000). Suicide prevention : a medical breakthrough ? Acta Psychiatrica Scandinavica 102, 113117. Isacsson G, Holmgren P, Ahlner J (2005). Selective serotonin reuptake inhibitor antidepressants and the risk of suicide : a controlled forensic database study of 14,857 suicides. Acta Psychiatrica Scandinavica 111, 286290. Isacsson G, Holmgren P, Druid H, Bergman U (1997). The utilization of antidepressants : a key issue in the prevention of suicide : an analysis of 5281 suicides in Sweden during the period 19921994. Acta Psychiatrica Scandinavica 96, 94100. Isacsson G, Rich CL (2005). Antidepressant drug use and suicide prevention. International Review of Psychiatry 17, 153162. Isbister GK, Dawson A, Whyte IM, Prior FH, Clancy C, Smith AJ (2001). Neonatal paroxetine withdrawal syndrome or actually serotonin syndrome ? Archives of Disease in Childhood. Fetal and Neonatal Edition 85, F147F148. Ising M, Horstmann S, Kloiber S, Lucae S, Binder EB, Kern N, Kunzel HE, Pfennig A, Uhr M, Holsboer F (2006). Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression : a potential biomarker ? Biological Psychiatry. 10.1016/j.biopsych.2006.07.039. Israel JA (2006). Remission in depression : denition and initial treatment approaches. Journal of Psychopharmacology 20, 510. Izzo AA, Ernst E (2001). Interactions between herbal medicines and prescribed drugs : a systematic review. Drugs 61, 21632175. Jacobson NS, Dobson KS, Truax PA, Addis ME, Koerner K, Gollan JK, Gortner E, Prince SE (1996). A component analysis of cognitive-behavioral treatment for depression. Journal of Consulting and Clinical Psychology 64, 295304. Jae AS, Krumholz HM, Catellier DJ, Freedland KE, Bittner V, Blumenthal JA, Calvin JE, Norman J, Sequeira R, OConnor C, Rich MW, Sheps D, Wu C (2006). Prediction of medical morbidity and mortality after acute myocardial

S147

infarction in patients at increased psychosocial risk in the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) study. American Heart Journal 152, 126135. Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K (2004). Metyrapone as additive treatment in major depression : a double-blind and placebo-controlled trial. Archives of General Psychiatry 61, 12351244. Janicak PG, Davis JM, Gibbons RD, Ericksen S, Chang S, Gallagher P (1985). Ecacy of ECT : a meta-analysis. American Journal of Psychiatry 142, 297302. Jansson M, Gatz M, Berg S, Johansson B, Malmberg B, McClearn GE, Schalling M, Pedersen NL (2004). Gender dierences in heritability of depressive symptoms in the elderly. Psychological Medicine 34, 471479. Jaquenoud Sirot E, van der Velden JW, Rentsch K, Eap CB, Baumann P (2006). Therapeutic Drug Monitoring and Pharmacogenetic Tests as Tools in Pharmacovigilance. Drug Safety 29, 735768. Jesberger JA, Richardson JS (1988). Brain output dysregulation induced by olfactory bulbectomy : an approximation in the rat of major depressive disorder in humans ? International Journal of Neuroscience 38, 241265. Jick H, Kaye JA, Jick SS (2004). Antidepressants and the risk of suicidal behaviors. Journal of the American Medical Association 292, 338343. Jin H, Hampton AJ, Yu X, Heaton RK, Shi C, Marcotte TP, Young C, Sadek J, Wu Z, Grant I (2006). Depression and suicidality in HIV/AIDS in China. Journal of Aective Disorders 94, 269275. Joe P, Larsen FS, Pedersen V, Ring-Larsen H, AaesJorgensen T, Sidhu J (1998). Single-dose pharmacokinetics of citalopram in patients with moderate renal insuciency or hepatic cirrhosis compared with healthy subjects. European Journal of Clinical Pharmacology 54, 237242. Joe RT, Singer W (1990). A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Research 32, 241251. Joe RT, Singer W, Levitt AJ, MacDonald C (1993). A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Archives of General Psychiatry 50, 387393. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I (1999). Pharmacokinetic interaction of digoxin with an herbal extract from St Johns wort (Hypericum perforatum). Clinical Pharmacology and Therapeutics 66, 338345. Jonsson A, Holmgren P, Ahlner J (2004). Fatal intoxications in a Swedish forensic autopsy material during 19922002. Forensic Science International 143, 5359. Jonsson B, Bebbington PE (1994). What price depression ? The cost of depression and the cost-eectiveness of pharmacological treatment. British Journal of Psychiatry 164, 665673. Jorge RE, Robinson RG, Arndt S, Starkstein S (2003). Mortality and poststroke depression : a placebo-controlled trial of antidepressants. American Journal of Psychiatry 160, 18231829.

S148

CINP Antidepressant Task Force 2007

Kanner AM (2005b). Should neurologists be trained to recognize and treat comorbid depression of neurologic disorders ? Yes. Epilepsy and Behavior 6, 303311. Karasu TB, Docherty JP, Gelenberg A, Kupfer DJ, Merriam AE, Shadoan R (1993). Practice guideline for major depressive disorder in adults. American Journal of Psychiatry 150, 126. Karp JF, Scott J, Houck P, Reynolds CF, III, Kupfer DJ, Frank E (2005). Pain predicts longer time to remission during treatment of recurrent depression. Journal of Clinical Psychiatry 66, 591597. Kasper S (2001). Hypericum perforatum : a review of clinical studies. Pharmacopsychiatry 34 (Suppl. 1), S51S55. Kasper S, Dienel A (2002). Cluster analysis of symptoms during antidepressant treatment with Hypericum extract in mildly to moderately depressed out-patients. A metaanalysis of data from three randomized, placebocontrolled trials. Psychopharmacology 164, 301308. Kasper S, Muller-Spahn F (2002). Intravenous antidepressant treatment : focus on citalopram. European Archives of Psychiatry and Clinical Neuroscience 252, 105109. Kasper S, Olie JP (2002). A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression. European Psychiatry 17 (Suppl. 3), 331340. Kasper S, Rogers SL, Madden PA, Joseph-Vanderpool JR, Rosenthal NE (1990). The eects of phototherapy in the general population. Journal of Aective Disorders 18, 211219. Kasper S, Schulz V (1999). [High dose St. Johns wort extract as a phytogenic antidepressant]. Wiener Medizinische Wochenschrift 149, 191196. Kasper S, Spadone C, Verpillat P, Angst J (2006). Onset of action of escitalopram compared with other antidepressants : results of a pooled analysis. International Clinical Psychopharmacology 21, 105110. Kato T (2001). Molecular genetics of bipolar disorder. Neuroscience Research 40, 105113. Katona CL (1994). Approaches to the management of depression in old age. Gerontology 40 (Suppl. 1), 59. Katona CL (1997). Depression and Physical Illness. Chichester, England : John Wiley. Katona CL, Abou-Saleh MT, Harrison DA, Nairac BA, Edwards DR, Lock T, Burns RA, Robertson MM (1995). Placebo-controlled trial of lithium augmentation of uoxetine and lofepramine. British Journal of Psychiatry 166, 8086. Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N, Frazer A (2004). Onset and early behavioral eects of pharmacologically dierent antidepressants and placebo in depression. Neuropsychopharmacology 29, 566579. Katzelnick DJ, Kobak KA, Greist JH, Jeerson JW, Henk HJ (1997). Eect of primary care treatment of depression on service use by patients with high medical expenditures. Psychiatric Services 48, 5964. Kaumann CD, Cheema MA, Miller BE (2004). Slow right prefrontal transcranial magnetic stimulation as

Jorm AF, Christensen H, Griths KM, Rodgers B (2002). Eectiveness of complementary and self-help treatments for depression. Medical Journal of Australia 176 (Suppl.), S84S96. Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, Kennedy MA (2003). Age-dependent antidepressant pharmacogenomics : polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to uoxetine and nortriptyline. International Journal of Neuropsychopharmacology 6, 339346. Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL, Leon AC, Mueller TI, Rice JA, Keller MB (1998a). A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Archives of General Psychiatry 55, 694700. Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL, Leon AC, Mueller TI, Rice JA, Keller MB (1998b). Major depressive disorder : a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. Journal of Aective Disorders 50, 97108. Judge R, Parry MG, Quail D, Jacobson JG (2002). Discontinuation symptoms : comparison of brief interruption in uoxetine and paroxetine treatment. International Clinical Psychopharmacology 17, 217225. Kahn LS, Halbreich U (2005). The eect of estrogens on depression. In : Bergemann N, Riecher-Rossler A (Eds.), Estrogen Eects in Psychiatric Disorders (pp. 145173). Wien : Springer. Kahn RS, van Praag HM (1992). Panic disorder : a biological perspective. European Neuropsychopharmacology 2(1), 120. Kalb R, Trautmann-Sponsel RD, Kieser M (2001). Ecacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial. Pharmacopsychiatry 34, 96103. Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J (2002). A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety. Health Technology Assessment 6, 189. Kamlet MS, Paul N, Greenhouse J, Kupfer D, Frank E, Wade M (1995). Cost utility analysis of maintenance treatment for recurrent depression. Controlled Clinical Trials 16, 1740. Kanba S, Yamada K, Mizushima H, Asai M (1998). Use of herbal medicine for treating psychiatric disorders in Japan. Psychiatry and Clinical Neurosciences 52 (Suppl.), S331S333. Kanba S, Yamada K, Mizushima H, Murata T, Asai M (1999). Use of herbal medicine for treating psychiatric disorders in Japan. In : Kanba S, Richelson E (Eds.), Herbal Medicine in Mental Health. New York : Brunner-Mazel. Kanner AM (2003). When did neurologists and psychiatrists stop talking to each other ? Epilepsy and Behavior 4, 597601. Kanner AM (2005a). Depression in epilepsy : a neurobiologic perspective. Epilepsy Currents 5, 2127.

CINP Antidepressant Task Force 2007

a treatment for medication-resistant depression : a double-blind, placebo-controlled study. Depression and Anxiety 19, 5962. Kavoussi RJ, Segraves RT, Hughes AR, Ascher JA, Johnston JA (1997). Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. Journal of Clinical Psychiatry 58, 532537. Kelder J, Funke C, De Boer T, Delbressine L, Leysen D, Nickolson V (1997). A comparison of the physicochemical and biological properties of mirtazapine and mianserin. Journal of Pharmacy and Pharmacology 49, 403411. Keller MB (1999). The long-term treatment of depression. Journal of Clinical Psychiatry 60 (Suppl. 17), 4145, discussion 4648. Keller MB, Boland RJ (1998). Implications of failing to achieve successful long-term maintenance treatment of recurrent unipolar major depression. Biological Psychiatry 44, 348360. Keller MB, Kocsis JH, Thase ME, Gelenberg AJ, Rush AJ, Koran L, Schatzberg A, Russell J, Hirschfeld R, Klein D, McCullough JP, Fawcett JA, Kornstein S, LaVange L, Harrison W (1998). Maintenance phase ecacy of sertraline for chronic depression : a randomized controlled trial. Journal of the American Medical Association 280, 16651672. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemero CB, Russell JM, Thase ME, Trivedi MH, Zajecka J (2000). A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. New England Journal of Medicine 342, 14621470. Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, McCaerty JP (2001). Ecacy of paroxetine in the treatment of adolescent major depression : a randomized, controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry 40, 762772. Kellner CH, Fink M, Knapp R, Petrides G, Husain M, Rummans T, Mueller M, Bernstein H, Rasmussen K, OConnor K, Smith G, Rush AJ, Biggs M, McClintock S, Bailine S, Malur C (2005). Relief of expressed suicidal intent by ECT : a consortium for research in ECT study. American Journal of Psychiatry 162, 977982. Kendler KS (1998). Gender dierences in the genetic epidemiology of major depression. Journal of GenderSpecic Medicine 1, 2831. Kennedy SH, Andersen HF, Lam RW (2006). Ecacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR : a meta-analysis. Journal of Psychiatry and Neuroscience 31, 122131. Kennedy SH, Emsley R (2006). Placebo-controlled trial of agomelatine in the treatment of major

S149

depressive disorder. European Neuropsychopharmacology 16, 93100. Kennedy SH, Lam RW, Cohen NL, Ravindran AV (2001). Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Canadian Journal of Psychiatry 46 (Suppl. 1), 38S58S. Kent JM (2000). SNaRIs, NaSSAs, and NaRIs : new agents for the treatment of depression. Lancet 355, 911918. Kessler RC (2003). Epidemiology of women and depression. Journal of Aective Disorders 74, 513. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS (2003). The epidemiology of major depressive disorder : results from the National Comorbidity Survey Replication (NCS-R). Journal of the American Medical Association 289, 30953105. Kessler RC, Soukup J, Davis RB, Foster DF, Wilkey SA, Van Rompay MI, Eisenberg DM (2001). The use of complementary and alternative therapies to treat anxiety and depression in the United States. American Journal of Psychiatry 158, 289294. Khan A, Brodhead AE, Schwartz KA, Kolts RL, Brown WA (2005). Sex dierences in antidepressant response in recent antidepressant clinical trials. Journal of Clinical Psychopharmacology 25, 318324. Khisti RT, Chopde CT, Jain SP (2000). Antidepressant-like eect of the neurosteroid 3a-hydroxy-5a-pregnan-20-one in mice forced swim test. Pharmacology, Biochemistry and Behavior 67, 137143. Khouzam HR, Emes R, Gill T, Raroque R (2003). The antidepressant sertraline : a review of its uses in a range of psychiatric and medical conditions. Comprehensive Therapy 29, 4753. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, Carroll BJ (2000). Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 11, 215219. Kim HL, Streltzer J, Goebert D (1999). St. Johns wort for depression : a meta-analysis of well-dened clinical trials. Journal of Nervous and Mental Disease 187, 532538. Kim RB (2006). Transporters and drug discovery : why, when and how. Molecular Pharmaceutics 3, 2632. Kimmel PL, Peterson RA (2005). Depression in end-stage renal disease patients treated with hemodialysis : tools, correlates, outcomes, and needs. Seminars in Dialysis 18, 9197. Kind P, Sorensen J (1995). Modelling the cost-eectiveness of the prophylactic use of SSRIs in the treatment of depression. International Clinical Psychopharmacology 10 (Suppl. 1), 4148. King DE, Finestone DH, Peden JG (1994). Combination antidepressant therapy in primary care. Archives of Family Medicine 3, 10881092. King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P, Scahill L (1991). Emergence of self-destructive phenomena in children and adolescents during uoxetine treatment. Journal of the American Academy of Child and Adolescent Psychiatry 30, 179186.

S150

CINP Antidepressant Task Force 2007

refractory major depression. Neuropsychopharmacology 28, 20452048. Koski A, Vuori E, Ojanpera I (2005). Newer antidepressants : evaluation of fatal toxicity index and interaction with alcohol based on Finnish postmortem data. International Journal of Legal Medicine 119, 344348. Kramer MS (2002). Clinical update : substance P antagonists in patients with major depression. European Psychiatry 17, 10. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NMJ (1998). Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 16401645. Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild AJ, Snavely D, Ghosh K, Ball WA, Reines SA, Munjack D, Apter JT, Cunningham L, Kling M, Bari M, Getson A, Lee Y (2004). Demonstration of the ecacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29, 385392. Krauchi K, Cajochen C, Mori D, Graw P, Wirz-Justice A (1997). Early evening melatonin and S-20098 advance circadian phase and nocturnal regulation of core body temperature. American Journal of Physiology 272, R1178R1188. Krause P, Genz A, Knorr W (1988). [Prospective study of the late sequelae of electroconvulsive treatment]. Psychiatrie, Neurologie Und Medizinische Psychologie 40, 532536. Kripke DF (1998). Light treatment for nonseasonal depression : speed, ecacy, and combined treatment. Journal of Aective Disorders 49, 109117. Krishnan KR, McDonald WM (1995). Arteriosclerotic depression. Medical Hypotheses 44, 111115. Kroessler D (1985). Relative ecacy rates for therapies of delusional depression. Convulsive Therapy 1, 173182. Krupnick JL, Sotsky SM, Simmens S, Moyer J, Elkin I, Watkins J, Pilkonis PA (1996). The role of the therapeutic alliance in psychotherapy and pharmacotherapy outcome : ndings in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. Journal of Consulting and Clinical Psychology 64, 532539. Krystal J (2007). Ketamine and the potential role for rapid-acting antidepressant medications. Swiss Medical Weekly 137, 215216. Krystal AD, Coey CE (1997). Neuropsychiatric considerations in the use of electroconvulsive therapy. Journal of Neuropsychiatry and Clinical Neurosciences 9, 283292. Kuehner C (2003). Gender dierences in unipolar depression : an update of epidemiological ndings and possible explanations. Acta Psychiatrica Scandinavica 108, 163174. Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM, Seibyl JP, Innis RB (2003). Changes in

Kirchheiner J, Brsen K, Dahl ML, Gram LF, Kasper S, Roots I, Sjoqvist F, Spina E, Brockmoller J (2001). CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants : a rst step towards subpopulation-specic dosages. Acta Psychiatrica Scandinavica 104, 173192. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmoller J (2004). Pharmacogenetics of antidepressants and antipsychotics : the contribution of allelic variations to the phenotype of drug response. Molecular Psychiatry 9, 442473. Kissling W, Moller HJ, Lauter H, Binz U, Wendt G (1985). Double-blind comparison of intravenous versus oral maprotiline : antidepressant activity, plasma levels, side eects. Pharmacopsychiatry 15, 9697. Kitada M (2003). Genetic polymorphism of cytochrome P450 enzymes in Asian populations : focus on CYP2D6. International Journal of Clinical Pharmacology Research 23, 3135. Klein DF (2006). The awed basis for FDA post-marketing safety decisions : the example of anti-depressants and children. Neuropsychopharmacology 31, 689699. Klerman GL, Cole JO (1965). Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacological Reviews 17, 101141. Klerman GL, Weissmann MM (1987). Interpersonal psychotherapy (IPT) and drugs in the treatment of depression. Pharmacopsychiatry 20, 37. Klysner R, Bent-Hansen J, Hansen HL, Lunde M, Pleidrup E, Poulsen DL, Andersen M, Petersen HE (2002). Ecacy of citalopram in the prevention of recurrent depression in elderly patients : placebo-controlled study of maintenance therapy. British Journal of Psychiatry 181, 2935. Knuuttila JE, Toronen P, Castren E (2004). Eects of antidepressant drug imipramine on gene expression in rat prefrontal cortex. Neurochemical Research 29, 12351244. Kole MH, Swan L, Fuchs E (2002). The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. European Journal of Neuroscience 16, 807816. Konstantinidis A, Stastny J, Ptak-Butta J, Hilger E, Winkler D, Barnas C, Neumeister A, Kasper S (2002). Intravenous mirtazapine in the treatment of depressed inpatients. European Neuropsychopharmacology 12, 5760. Kopell BH, Greenberg B, Rezai AR (2004). Deep brain stimulation for psychiatric disorders. Journal of Clinical Neurophysiology 21, 5167. Koran LM, Pallanti S, Paiva RS, Quercioli L (1998). Pulse loading versus gradual dosing of intravenous clomipramine in obsessive-compulsive disorder. European Neuropsychopharmacology 8, 121126. Kornstein SG, Sloan DM, Thase ME (2002). Gender-specic dierences in depression and treatment response. Psychopharmacology Bulletin 36, 99112. Kosel M, Frick C, Lisanby SH, Fisch HU, Schlaepfer TE (2003). Magnetic seizure therapy improves mood in

CINP Antidepressant Task Force 2007

human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology 28, 413420. Kuhs H, Farber D, Borgstadt S, Mrosek S, Tolle R (1996). Amitriptyline in combination with repeated late sleep deprivation versus amitriptyline alone in major depression. A randomised study. Journal of Aective Disorders 37, 3141. Kuhs H, Kemper B, Lippe-Neubauer U, Meyer-Dunker J, Tolle R (1998). Repeated sleep deprivation once versus twice a week in combination with amitriptyline. Journal of Aective Disorders 47, 97103. Kuhs H, Tolle R (1991). Sleep deprivation therapy. Biological Psychiatry 29, 11291148. Kupfer DJ (1991). Long-term treatment of depression. Journal of Clinical Psychiatry 52 (Suppl.), 2834. Kupfer DJ (2005). The pharmacological management of depression. Dialogues in Clinical Neuroscience 7, 191205. Kupfer DJ, Charney DS (2003). Dicult-to-treat depression. Biological Psychiatry 53, 633634. Kupfer DJ, Frank E, Perel JM, Cornes C, Mallinger AG, Thase ME, McEachran AB, Grochocinski VJ (1992). Fiveyear outcome for maintenance therapies in recurrent depression. Archives of General Psychiatry 49, 769773. Kupfer DJ, Pollock BG, Perel JM, Jarrett DB, McEachran AB, Miewald JM (1991). Immediate eects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients. Psychiatry Research 36, 279289. Kupfer DJ, Rush AJ (1983). Recommendations for depression publications. Archives of General Psychiatry 40, 1031. Laakmann G, Faltermaier-Temizel M, Bossert-Zaudig S, Baghai T (1996). Are benzodiazepines antidepressants ? Psychopharmacology 124, 291292. Laakmann G, Schule C, Baghai T, Kieser M (1998). St. Johns wort in mild to moderate depression : the relevance of hyperforin for the clinical ecacy. Pharmacopsychiatry 31 (Suppl. 1), 5459. Lader MH (1996). Tolerability and safety : essentials in antidepressant pharmacotherapy. Journal of Clinical Psychiatry 57 (Suppl. 2), 3944. Lafuma A, Dardennes R, Fagnani F, Pribil C, Bisserbe JC, Berdeaux G (1999). [Clinico-economic assessment of milnacipran in the prevention of depressive episodes]. Encephale 25, 401407. Laje G, Paddock S, Manji H, Rush AJ, Wilson AF, Charney D, McMahon FJ (2007). Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. American Journal of Psychiatry 164, 15301538. Lam R, Levitt AJ, Kraus RP, Rudradeo CB, Morehouse RL, Hasey G, Levitan RD (1999). Management issues. In : Lam R, Levitt AJ (Eds.), Canadian Consensus Guidelines for the Treatment of Seasonal Aective Disorder (pp. 96114). Vancouver, BC : Clinical and Academic Publishing. Lam RW, Levitt AJ, Levitan RD, Enns MW, Morehouse R, Michalak EE, Tam EM (2006). The Can-SAD study : a randomized controlled trial of the eectiveness of light therapy and uoxetine in patients with winter seasonal

S151

aective disorder. American Journal of Psychiatry 163, 805812. Lam RW, Levitan RD, Tam EM, Yatham LN, Lamoureux S, Zis AP (1997). L-tryptophan augmentation of light therapy in patients with seasonal aective disorder. Canadian Journal of Psychiatry 42, 303306. Lambert MT, Trutia C, Petty F (1998). Extrapyramidal adverse eects associated with sertraline. Progress in Neuro-Psychopharmacology and Biological Psychiatry 22, 741748. Landauer AA, Milner G, Patman J (1969). Alcohol and amitriptyline eects on skills related to driving behavior. Science 163, 14671468. Landen M, Bjorling G, Agren H, Fahlen T (1998). A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. Journal of Clinical Psychiatry 59, 664668. Larsen JK (1988). MAO inhibitors : pharmacodynamic aspects and clinical implications. Acta Psychiatrica Scandinavica. Supplementum 345, 7480. Launay D, Queyrel V, Hatron PY, Michon-Pasturel U, Caron J, Hachulla E, Devulder B (2000). [Agranulocytosis connected with the taking of mianserin : a complication to be feared in the aged]. Revue De Medecine Interne 21, 642643. Lauritzen L, Odgaard K, Clemmesen L, Lunde M, Ohrstrom J, Black C, Bech P (1996). Relapse prevention by means of paroxetine in ECT-treated patients with major depression : a comparison with imipramine and placebo in mediumterm continuation therapy. Acta Psychiatrica Scandinavica 94, 241251. Laux G (2001). Driving performance under antidepressants. World Journal of Biological Psychiatry 2, 186. Laux G (2002). [Psychiatric disorders and tness to drive an automobile. An overview]. Nervenarzt 73, 231238. Laux G, Reimer F (1979). [Treatment of therapy resistant depressions with high dose clomipramine]. International Pharmacopsychiatry 14, 294299. Lave JR, Frank RG, Schulberg HC, Kamlet MS (1998). Cost-eectiveness of treatments for major depression in primary care practice. Archives of General Psychiatry 55, 645651. Lawlor DA, Hopker SW (2001). The eectiveness of exercise as an intervention in the management of depression : systematic review and meta-regression analysis of randomised controlled trials. British Medical Journal 322, 763767. Le Pen C, Levy E, Ravily V, Beuzen JN, Meurgey F (1994). The cost of treatment dropout in depression. A cost-benet analysis of uoxetine vs. tricyclics. Journal of Aective Disorders 31, 118. Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher J, Schmith VD, Langstrom B (2003). In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biological Psychiatry 54, 800805.

S152

CINP Antidepressant Task Force 2007

Leonard BE (2001). Brain cytokines and the psychopathology of depression. In : Leonard BE (Ed.), Antidepressants (pp. 109120). Basel : Birkaeuser. Leonard BE, Myint A (2006a). Changes in the immune system in depression and dementia : causal or coincidental eects ? Dialogues in Clinical Neuroscience 8, 163174. Leonard BE, Myint AM (2006b). Inammation and depression : is there a causal connection with dementia ? Neurotoxicity Research 10, 112. Leonard BE, Song C (1999). Stress, depression, and the role of cytokines. Advances in Experimental Medicine & Biology 461, 251265. Leonard BE, Song C (2002). Changes in the immune system in rodent models of depression. International Journal of Neuropsychopharmacology 5, 345356. Lepine JP, Altamura C, Ansseau M, Gutierrez JL, Bitter I, Lader M, Waintraub L (2001). Tianeptine and paroxetine in major depressive disorder, with a special focus on the anxious component in depression : an international, 6-week double-blind study dagger. Human Psychopharmacology 16, 219227. Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM, Boyer P (2004). A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. American Journal of Psychiatry 161, 836842. Lepola U, Wade A, Andersen HF (2004). Do equivalent doses of escitalopram and citalopram have similar ecacy ? A pooled analysis of two positive placebo-controlled studies in major depressive disorder. International Clinical Psychopharmacology 19, 149155. Leproult R, Van Onderbergen A, Lhermite-Baleriaux M, Van Cauter E, Copinschi G (2005). Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clinical Endocrinology 63, 298304. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 15271531. Lesch KP, Gutknecht L (2004). Focus on The 5-HT1A receptor : emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. International Journal of Neuropsychopharmacology 7, 381385. Lesieur D, Leclerc V, Chavatte P, Marcot C, Renard P, Guardiola-Lemaitre B (1998). Melatonin : a pertinent prototype for therapeutic intervention. Therapie 53, 429437. Leslie LK, Newman TB, Chesney PJ, Perrin JM (2005). The Food and Drug Administrations deliberations on antidepressant use in pediatric patients. Pediatrics 116, 195204. Leterme L, Singlan YS, Auclair V, Le BR, Frimas V (2003). [Misuse of tianeptine : ve cases of abuse]. Annales De Medecine Interne 154 Spec No. 2, S58S63.

Lecrubier Y (2007). Widespread underrecognition and undertreatment of anxiety and mood disorders : results from 3 European studies. Journal of Clinical Psychiatry 68(2), :3641. Lecrubier Y, Clerc G, Didi R, Kieser M (2002). Ecacy of St. Johns wort extract WS 5570 in major depression : a doubleblind, placebo-controlled trial. American Journal of Psychiatry 159, 13611366. Lederbogen F, Deuschle M, Heuser I (1999). [Depression : a cardiovascular risk factor]. Internist 40, 11191121. Lederbogen F, Gilles M, Maras A, Hamann B, Colla M, Heuser I, Deuschle M (2001). Increased platelet aggregability in major depression ? Psychiatry Research 102, 255261. LeDoux JE (2000). Emotion circuits in the brain. Annual Review of Neuroscience 23, 155184. LeDrew K, Phillips L, Hogan M, MacCallum A (2005). Lamotrigine-induced neutropenia. Canadian Journal of Psychiatry 50, 242. Lee MS, Lim SW, Cha JH, Chung SK, Kim KS, Kasper S, Executive Committee for the Korean Medication Algorithm Project for Major Depressive Disorder (2006). Korean medication algorithm for major depressive disorder. International Journal of Psychiatry in Clinical Practice 10, 186194. Lee TM, Chan CC (1999). Dose-response relationship of phototherapy for seasonal aective disorder : a metaanalysis. Acta Psychiatrica Scandinavica 99, 315323. Le J, Vearnals S, Brewin CR, Wol G, Alexander B, Asen E, Dayson D, Jones E, Chisholm D, Everitt B (2000). The London Depression Intervention Trial : randomised controlled trial of antidepressants v. couple therapy in the treatment and maintenance of people with depression living with a partner : clinical outcome and costs. British Journal of Psychiatry 177, 95100. Leinonen E, Skarstein J, Behnke K, Agren H, Helsdingen JT (1999). Ecacy and tolerability of mirtazapine versus citalopram : a double-blind, randomized study in patients with major depressive disorder. Nordic Antidepressant Study Group. International Clinical Psychopharmacology 14, 329337. Lejoyeux M, Rodiere-Rein C, Ades J (1992). [Withdrawal syndrome from antidepressive drugs. Report of 5 cases]. Encephale 18, 251255. Lemke MR (2002). Eect of reboxetine on depression in Parkinsons disease patients. Journal of Clinical Psychiatry 63, 300304. Lemke MR, Fuchs G, Gemende I, Herting B, Oehlwein C, Reichmann H, Rieke J, Volkmann J (2004). Depression and Parkinsons disease. Journal of Neurology 251 (Suppl. 6), VI/24VI/27. Lenox-Smith A, Conway P, Knight C (2004). Cost eectiveness of representatives of three classes of antidepressants used in major depression in the UK. Pharmacoeconomics 22, 311319. Leonard BE (1988). Biochemical aspects of therapyresistant depression. British Journal of Psychiatry 152, 453459.

CINP Antidepressant Task Force 2007

Levin OS (2006). [Coaxil (tianeptine) in the treatment of depression in Parkinsons disease]. Zhurnal Nevrologii i Psikhiatrii Imeni S. S. Korsakova 106, 2025. Lexchin J, Bero LA, Djulbegovic B, Clark O (2003). Pharmaceutical industry sponsorship and research outcome and quality : systematic review. British Medical Journal 326, 11671170. Lexchin J, Light DW (2006). Commercial inuence and the content of medical journals. British Medical Journal 332, 14441447. Li YF, Yuan L, Xu YK, Yang M, Zhao YM, Luo ZP (2001). Antistress eect of oligosaccharides extracted from Morinda ocinalis in mice and rats. Acta Pharmacologica Sinica 22, 10841088. Lieberman A (2006). Depression in Parkinsons disease : a review. Acta Neurologica Scandinavica 113, 18. Liebrenz M, Borgeat A, Leisinger R, Stohler R (2007). Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Swiss. Med. Wkly. 137, 234236. Lin JH (2003). Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Advanced Drug Delivery Reviews 55, 5381. Linde K, Berner M, Egger M, Mulrow C (2005). St Johns wort for depression : meta-analysis of randomised controlled trials. British Journal of Psychiatry 186, 99107. Linkowski P, Mendlewicz J, Kerkhofs M, Leclerq R, Goldstein J, Brasseur M, Copinschi G, Van Cauter E (1987). 24-hour proles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness : eect of antidepressant treatment. Journal of Clinical Endocrinology and Metabolism 65, 141152. Linnoila M, Virkkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK (1983). Low cerebrospinal uid 5-hydroxyindoleacetic acid concentration dierentiates impulsive from nonimpulsive violent behavior. Life Science 33, 26092614. Lisanby SH, Luber B, Finck AD, Schroeder C, Sackeim HA (2001a). Deliberate seizure induction with repetitive transcranial magnetic stimulation in nonhuman primates. Archives of General Psychiatry 58, 199200. Lisanby SH, Luber B, Schlaepfer TE, Sackeim HA (2003a). Safety and feasibility of magnetic seizure therapy (MST) in major depression : randomized within-subject comparison with electroconvulsive therapy. Neuropsychopharmacology 28, 18521865. Lisanby SH, Maddox JH, Prudic J, Devanand DP, Sackeim HA (2000). The eects of electroconvulsive therapy on memory of autobiographical and public events. Archives of General Psychiatry 57, 581590. Lisanby SH, Morales O, Payne N, Kwon E, Fitzsimons L, Luber B, Nobler MS, Sackeim HA (2003b). New developments in electroconvulsive therapy and magnetic seizure therapy. CNS Spectrums 8, 529536. Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Burt T, Sackeim HA (2001b). Augmentation of sertraline antidepressant treatment with transcranial magnetic stimulation. Biological Psychiatry 49, 81S.

S153

Lisanby SH, Schlaepfer TE, Fisch HU, Sackeim HA (2001c). Magnetic seizure therapy of major depression. Archives of General Psychiatry 58, 303305. Liston HL, Markowitz JS, DeVane CL (2001). Drug glucuronidation in clinical psychopharmacology. Journal of Clinical Psychopharmacology 21, 500515. Liu JLY, Maniadakis N, Gray A, Rayner M (2002). The economic burden of coronary heart disease in the UK. Heart 88, 597603. Livingston MG, Livingston HM (1996). Monoamine oxidase inhibitors. An update on drug interactions. Drug Safety 14, 219227. Llorca PM, Azorin JM, Despiegel N, Verpillat P (2005). Ecacy of escitalopram in patients with severe depression : a pooled analysis. International Journal of Clinical Practice 59, 268275. Loo CK, Mitchell PB, Croker VM, Malhi GS, Wen W, Gandevia SC, Sachdev PS (2003). Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychological Medicine 33, 3340. Loo H, Deniker P (1988). Position of tianeptine among antidepressive chemotherapies. Clinical Neuropharmacology 11 (Suppl. 2), S97102. Loo H, Hale A, Dhaenen H (2002). Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder : a placebo-controlled dose range study. International Clinical Psychopharmacology 17, 239247. Loo H, Saiz-Ruiz J, Costa e Silva JA, Ansseau M, Herrington R, Vaz-Serra A, Dilling H, De Risio S (2001). Ecacy and safety of tianeptine in the treatment of depressive disorders in comparison with uoxetine. Human Psychopharmacology 16, S31S38. Lothgren M, Hemels M, Francois C, Jonsson B (2004). A cost-eectiveness analysis of escitalopram as rst line treatment of depression in Sweden. Primary Care Psychiatry 9, 161. Lotufo-Neto F, Trivedi M, Thase ME (1999). Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology 20, 226247. Louwerens JW, Brookhuis KA, OHanlon JF (1984). The Eects of the Antidepressants Oxaprotiline, Mianserin, Amitriptyline and Doxepin Upon Actual Driving Performance. Groningen, The Netherlands : Trac Research Centre. Loving RT, Kripke DF, Shuchter SR (2002). Bright light augments antidepressant eects of medication and wake therapy. Depression and Anxiety 16, 13. Lucena MI, Carvajal A, Andrade RJ, Velasco A (2003). Antidepressant-induced hepatotoxicity. Expert Opinion on Drug Safety 2, 249262. Lucht MJ, Kleinschmidt R, Maier W, Rietschel M (2000). Agranulocytosis during treatment with mianserin and venlafaxine. Journal of Clinical Psychopharmacology 20, 490491.

S154

CINP Antidepressant Task Force 2007

Malhotra AK, Murphy GMJ, Kennedy JL (2004). Pharmacogenetics of psychotropic drug response. American Journal of Psychiatry 161, 780796. Malison RT, Anand A, Pelton GH, Kirwin P, Carpenter L, McDougle CJ, Heninger GR, Price LH (1999). Limited ecacy of ketoconazole in treatment-refractory major depression. Journal of Clinical Psychopharmacology 19, 466470. Mamdani MM, Parikh SV, Austin PC, Upshur RE (2000). Use of antidepressants among elderly subjects : trends and contributing factors. American Journal of Psychiatry 157, 360367. Manber R, Allen JJ, Morris MM (2002). Alternative treatments for depression : empirical support and relevance to women. Journal of Clinical Psychiatry 63, 628640. Manber R, Schnyer RN, Allen JJ, Rush AJ, Blasey CM (2004). Acupuncture : a promising treatment for depression during pregnancy. Journal of Aective Disorders 83, 8995. Mancama D, Kerwin RW (2003). Role of pharmacogenomics in individualising treatment with SSRIs. CNS Drugs 17, 143151. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL (1997). Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacology Bulletin 33, 149154. Manji HK, Drevets WC, Charney DS (2001). The cellular neurobiology of depression. Nature Medicine 7, 541547. Manji HK, Lenox RH (1999). Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain : molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biological Psychiatry 46, 13281351. Manji HK, Quiroz JA, Sporn J, Payne JL, Denico K, Gray A, Zarate CAJ, Charney DS (2003). Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for dicult-to-treat depression. Biological Psychiatry 53, 707742. Mann JJ, Aarons SF, Wilner PJ, Keilp JG, Sweeney JA, Pearlstein T, Frances AJ, Kocsis JH, Brown RP (1989). A controlled study of the antidepressant ecacy and side eects of (-)-deprenyl. A selective monoamine oxidase inhibitor. Archives of General Psychiatry 46, 4550. Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaer D, Wagner KD (2006a). ACNP Task Force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology 31, 473492. Mann K, Hiemke C, Schmidt LG, Bates DW (2006b). Appropriateness of therapeutic drug monitoring for antidepressants in routine psychiatric inpatient care. Therapeutic Drug Monitoring 28, 8388. Manning DW, Markowitz JC, Frances AJ (1992). A Review of Combined Psychotherapy and Pharmacotherapy in the Treatment of Depression. J Psychother Pract Res 1, 103116. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J

Ludwig J, Marcotte DE (2005). Anti-depressants, suicide, and drug regulation. Journal of Policy Analysis and Management 24, 249272. Luo H, Jia Y, Feng X, Zhao X, Tang LC (1995). Advances in clinical research on common mental disorders with computer controlled electro-acupuncture treatment. Neurochemistry in Clinical Application 109122. Luo H, Jia Y, Li Z (1985). Electro-acupuncture vs. amitriptyline in the treatment of depressive states. Journal of Traditional Chinese Medicine 5, 38. Luo H, Jia YK, Wu X, Dai W (1990a). Electro-acupuncture in the treatment of depressive psychosis. International Journal of Clinical Acupuncture 1, 713. Luo H, Meng F, Jia Y, Zhao X (1998). Clinical research on the therapeutic eect of the electro-acupuncture treatment in patients with depression. Psychiatry and Clinical Neurosciences 52, S338S340. Luo H, Shen Y, Jia Y (1988). [Clinical study of electroacupuncture on 133 patients with depression in comparison with tricyclic amitriptyline]. Zhong Xi Yi Jie He Za Zhi 8, 7780, 68. Luo H, Shen Y, Zhou D, Jia Y (1990b). A comparative study of the treatment of depression by electroacupuncture and amitriptyline. Acupuncture 1, 2026. Luo L, Nong WJ, Kong LD, Jiang QG, Tan RX (2000). Antidepressant eects of Banxia Houpu decoction, a traditional Chinese medicinal empirical formula. Journal of Ethnopharmacology 73, 277281. Mace S, Taylor D (2000). Selective serotonin reuptake inhibitors : a review of ecacy and tolerability in depression. Expert Opinion on Pharmacotherapy 1, 917933. MacLeod AK, Tata P, Tyrer P, Schmidt U, Davidson K, Thompson S (2005). Hopelessness and positive and negative future thinking in parasuicide. British Journal of Clinical Psychology 44, 495504. MacMillan HL, Patterson CJ, Wathen CN, Feightner JW, Bessette P, Elford RW, Feig DS, Langley J, Palda VA, Patterson C, Reeder BA, Walton R (2005). Screening for depression in primary care : recommendation statement from the Canadian Task Force on Preventive Health Care. Canadian Medical Association Journal 172, 3335. Magyar J, Rusznak Z, Harasztosi C, Kortvely A, Pacher P, Banyasz T, Pankucsi C, Kovacs L, Szucs G, Nanasi PP, Kecskemeti V (2003). Dierential eects of uoxetine enantiomers in mammalian neural and cardiac tissues. International Journal of Molecular Medicine 11, 535542. Maj M, Starace F, Sartorius N (1993). Mental Disorders in HIV-1 Infection and AIDS. Bern : Huber. Malagie I, Deslandes A, Gardier AM (2000). Eects of acute and chronic tianeptine administration on serotonin outow in rats : comparison with paroxetine by using in vivo microdialysis. European Journal of Pharmacology 403, 5565. Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience 20, 91049110.

CINP Antidepressant Task Force 2007

(2004). Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression : treatment for Adolescents With Depression Study (TADS) randomized controlled trial. Journal of the American Medical Association 292, 807820. Marcus SM, Young EA, Kerber KB, Kornstein S, Farabaugh AH, Mitchell J, Wisniewski SR, Balasubramani GK, Trivedi MH, Rush AJ (2005). Gender dierences in depression : ndings from the STAR*D study. Journal of Aective Disorders 87, 141150. Markowitz JC (1993). Psychotherapy of the Postdysthymic Patient. The Journal of Psychotherapy Practice and Research 2, 157163. Markowitz JC, Kocsis JH, Bleiberg KL, Christos PJ, Sacks M (2005). A comparative trial of psychotherapy and pharmacotherapy for pure dysthymic patients. Journal of Aective Disorders 89, 167175. Martell CR, Addis ME, Jacobson NS (2001). Depression in Context : Strategies for Guided Action. New York : W. W. Norton. Martenyi F, Brown EB, Zhang H, Koke SC, Prakash A (2002). Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder. British Journal of Psychiatry 181, 315320. Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V, Kulisevsky J (2003). Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. British Journal of Psychiatry 182, 480491. Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, Evans S, Gunnell D (2005). Antidepressant treatment and the risk of fatal and non-fatal self harm in rst episode depression : nested case-control study. British Medical Journal 330, 389. Martiny K (2004). Adjunctive bright light in non-seasonal major depression. Acta Psychiatrica Scandinavica. Supplementum 728. Martiny K, Lunde M, Unden M, Dam H, Bech P (2005a). Adjunctive bright light in non-seasonal major depression : results from clinician-rated depression scales. Acta Psychiatrica Scandinavica 112, 117125. Martiny K, Lunde M, Unden M, Dam H, Bech P (2005b). Adjunctive bright light in non-seasonal major depression : results from patient-reported symptom and well-being scales. Acta Psychiatrica Scandinavica 111, 453459. Martiny K, Lunde M, Unden M, Dam H, Bech P (2006). The lack of sustained eect of bright light in non-seasonal major depression. Psychological Medicine 12471252. Marzolini C, Paus E, Buclin T, Kim RB (2004). Polymorphisms in human MDR1 (P-glycoprotein) : recent advances and clinical relevance. Clinical Pharmacology and Therapeutics 75, 1333. Mason J, Freemantle N, Eccles M (2000). Fatal toxicity associated with antidepressant use in primary care. British Journal of General Practice 50, 366370. Massana J, Moller HJ, Burrows GD, Montenegro RM (1999). Reboxetine : a double-blind comparison with uoxetine

S155

in major depressive disorder. International Clinical Psychopharmacology 14, 7380. Mattia C, Paoletti F, Coluzzi F, Boanelli A (2002). New antidepressants in the treatment of neuropathic pain. A review. Minerva Anestesiologica 68, 105114. Maurer-Spurej E, Pittendreigh C, Solomons K (2004). The inuence of selective serotonin reuptake inhibitors on human platelet serotonin. Thrombosis and Haemostasis 91, 119128. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT (1999). Reciprocal limbic-cortical function and negative mood : converging PET ndings in depression and normal sadness. American Journal of Psychiatry 156, 675682. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH (2005). Deep brain stimulation for treatment-resistant depression. Neuron 45, 651660. McCall WV (2001). Electroconvulsive therapy in the era of modern psychopharmacology. International Journal of Neuropsychopharmacology 4, 315324. McCall WV, Reboussin DM, Weiner RD, Sackeim HA (2000). Titrated moderately suprathreshold vs xed high-dose right unilateral electroconvulsive therapy : acute antidepressant and cognitive eects. Archives of General Psychiatry 57, 438444. McCullough JP (2000). Treatment for chronic depression : Cognitive Behavioral Analysis System of Psychotherapy. New York : Guilford Press. McCullough JP (2003). Treatment for chronic depression using Cognitive Behavioral Analysis System of Psychotherapy (CBASP). Journal of Clinical Psychology 59, 833846. McCusker J, Cole M, Keller E, Bellavance F, Berard A (1998). Eectiveness of treatments of depression in older ambulatory patients. Archives of Internal Medicine 158, 705712. McDaid D, Curran C, Knapp M (2005). Promoting mental well-being in the workplace : a European policy perspective. International Review of Psychiatry 17, 365373. McDonald WM, Richard IH, DeLong MR (2003). Prevalence, etiology, and treatment of depression in Parkinsons disease. Biological Psychiatry 54, 363375. McEwen BS, Olie JP (2005). Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant : tianeptine. Molecular Psychiatry 10, 525537. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ (2006). Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression : a STAR*D report. American Journal of Psychiatry 163, 15311541. Medawar C, Hardon A (2004). Medicines Out of Control ? Antidepressants and the Conspiracy of Goodwill. Amsterdam : Aksant Academic Publisher.

S156

CINP Antidepressant Task Force 2007

management of bipolar disorder. Archives of General Psychiatry 60, 904912. Millan MJ, Brocco M, Gobert A, Dekeyne A (2005). Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties : role of 5-HT2C receptor blockade. Psychopharmacology 177, 448458. Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D (2003). The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. Journal of Pharmacology and Experimental Therapeutics 306, 954964. Millan MJ, Gobert A, Newman-Tancredi A, Lejeune F, Cussac D, Rivet JM, Audinot V, Adhumeau A, Brocco M, Nicolas JP, Boutin JA, Despaux N, Peglion JL (2000). S18327 (1-[2-[4-(6-uoro-1, 2-benzisoxazol-3-yl)piperid-1yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1)- and alpha(2)-adrenergic receptors : I. Receptorial, neurochemical, and electrophysiological prole. Journal of Pharmacology and Experimental Therapeutics 292, 3853. Miller L, Grith J (1983). A comparison of bupropion, dextroamphetamine, and placebo in mixed-substance abusers. Psychopharmacology 80, 199205. Miller P, Chilvers C, Dewey M, Fielding K, Gretton V, Palmer B, Weller D, Churchill R, Williams I, Bedi N, Duggan C, Lee A, Harrison G (2003). Counseling versus antidepressant therapy for the treatment of mild to moderate depression in primary care : economic analysis. International Journal of Technology Assessment in Health Care 19, 8090. Miniussi C, Bonato C, Bignotti S, Gazzoli A, Gennarelli M, Pasqualetti P, Tura GB, Ventriglia M, Rossini PM (2005). Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency : an ecacious therapy for major drug-resistant depression ? Clinical Neurophysiology 116, 10621071. Miovic M, Block S (2007). Psychiatric disorders in advanced cancer. Cancer 110, 16651676. Misri S, Kostaras X (2002). Benets and risks to mother and infant of drug treatment for postnatal depression. Drug Safety 25, 903911. Mitchell AJ, Subramaniam H (2005). Prognosis of depression in old age compared to middle age : a systematic review of comparative studies. American Journal of Psychiatry 162, 15881601. Mitchell PB (2000). Therapeutic drug monitoring of psychotropic medications. British Journal of Clinical Pharmacology 49, 303312. Mitchell PB (2004). Therapeutic drug monitoring of non-tricyclic antidepressant drugs. Clinical Chemistry and Laboratory Medicine 42, 12121218. Mitte K, Noack P, Steil R, Hautzinger M (2005). A meta-analytic review of the ecacy of drug treatment in

Medicines and Healthcare products Regulatory Agency (2006). Updated Prescribing Advice for Venlafaxine : Information for Healthcare Professionals (http:/ / www.mhra.gov.uk/home/idcplg ?IdcService=SS_ GET_PAGE&ssDocName=CON2023846& ssSourceNodeId=242&ssTargetNodeId=221). Accessed 26 October 2006. Medicines Control Council (2007). Guidelines for the Registration of Medicines (http://www.mccza.com/ showdocument.asp ?Cat=17&Desc=Guidelines%20%20Human%20Medicines). Accessed 2 November 2007. Medina-Mora ME, Borges G, Lara Munoz C, Benjet C, Blanco Jaimes J, Fleiz Bautista C, Villatoro Velazquez J, Rojas Guiot E, Zambrano Ruiz J, Casanova Rodas L, Aguillar-Gaxiola S (2003). Prevalencia de trastornos mentales y uso de servicios : Resultados de la Encuesta Nacional de Epidemiologa Psiquiatrica en Mexico. Salud Mental 26, 116. Meijer WEE, Bouvy ML, Heerdink ER, Urquhart J, Leufkens HGM (2001). Spontaneous lapses in dosing during chronic treatment with selective serotonin reuptake inhibitors. British Journal of Psychiatry 179, 519522. Mel CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S, Sredl K (1998). The eects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Archives of General Psychiatry 55, 11281132. Menecier P, Menecier-Ossia L, Bern P (1997). [Fluoxetine dependence and tolerance. Apropos of a case]. Encephale 23, 400401. Meng F, Luo H, Shen Y, Shu L, Liu J (1994). Plasma NE concentration and 24 hours urinary MHPG-SO4 excretion changes after electro-acupuncture treatment in endogenous depression. World Journal of Acupuncture 4, 218225. Meng QF, Luo HC, Halbreich U (2002). Concepts, techniques, and clinical applications of acupuncture. Psychiatric Annals 32, 4549. Mennini T, Mocaer E, Garattini S (1987). Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn-Schmiedebergs Archives of Pharmacology 336, 478482. Menza M (2006). STAR*D : the results begin to roll in. American Journal of Psychiatry 163, 1123. Menza M, Marin H, Kaufman K, Mark M, Lauritano M (2004). Citalopram treatment of depression in Parkinsons disease : the impact on anxiety, disability, and cognition. Journal of Neuropsychiatry and Clinical Neurosciences 16, 315319. Mercante JP, Peres MF, Guendler V, Zukerman E, Bernik MA (2005). Depression in chronic migraine : severity and clinical features. Arquivos De Neuro-Psiquiatria 63, 217220. Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S (2002). Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology 163, 102105. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL (2003). A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient

CINP Antidepressant Task Force 2007

generalized anxiety disorder. Journal of Clinical Psychopharmacology 25, 141150. Mittmann N, Herrmann N, Einarson TR, Busto UE, Lanctot KL, Liu BA, Shulman KI, Silver IL, Narango CA, Shear NH (1997). The ecacy, safety and tolerability of antidepressants in late life depression : a meta-analysis. Journal of Aective Disorders 46, 191217. Moller HJ (1997). Therapieresistenz unter Antidepressiva : Denition, Epidemiologie und Risikofaktoren. In : Bauer M, Berghofer A (Eds.), Therapieresistente Depressionen (pp. 315). Berlin, Heidelberg : Springer. Moller HJ (2000). Are all antidepressants the same ? Journal of Clinical Psychiatry 61 (Suppl. 6), 2428. Moller HJ (2002). Anxiety associated with comorbid depression. Journal of Clinical Psychiatry 63 (Suppl. 14), 2226. Moller HJ (2003). Suicide, suicidality and suicide prevention in aective disorders. Acta Psychiatrica Scandinavica. Supplementum 7380. Moller HJ (2006a). Evidence for benecial eects of antidepressants on suicidality in depressive patients : a systematic review. European Archives of Psychiatry and Clinical Neuroscience 256, 329343. Moller HJ (2006b). Is there evidence for negative eects of antidepressants on suicidality in depressive patients ? A systematic review. European Archives of Psychiatry and Clinical Neuroscience 256, 476496. Moller HJ, Gallinat J, Hegerl U, Arato M, Janka Z, Pug B, Bauer H (1998). Double-blind, multicenter comparative study of sertraline and amitriptyline in hospitalized patients with major depression. Pharmacopsychiatry 31, 170177. Moller HJ, Grunze H, Broich K (2006). Do recent ecacy data on the drug treatment of acute bipolar depression support the position that drugs other than antidepressants are the treatment of choice ? A conceptual review. European Archives of Psychiatry and Clinical Neuroscience 256, 116. Moller HJ, Kasper S, Muller H, Kissling W, Fuger J, Ruhrmann S (1995). A controlled study of the ecacy and safety of mianserin and amitriptyline in depressive inpatients. Pharmacopsychiatry 28, 249252. Monroe SM, Simons AD (1991). Diathesis-stress theories in the context of life stress research : implications for the depressive disorders. Psychological Bulletin 110, 406425. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, Ledesma A, Bousono M, Calcedo A, Carrasco JL, Ciudad J, Daniel E, de la Gandara J, Derecho J, Franco M, Gomez MJ, Macias JA, Martin T, Perez V, Sanchez JM, Sanchez S, Vicens E (1997). SSRI-induced sexual dysfunction : uoxetine, paroxetine, sertraline, and uvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. Journal of Sex and Marital Therapy 23, 176194. Montgomery DB, Roberts A, Green M, Bullock T, Baldwin D, Montgomery SA (1994). Lack of ecacy of uoxetine in recurrent brief depression and suicidal attempts.

S157

European Archives of Psychiatry and Clinical Neuroscience 244, 211215. Montgomery JH, Byerly M, Carmody T, Li B, Miller DR, Varghese F, Holland R (2004a). An analysis of the eect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia. Controlled Clinical Trials 25, 598612. Montgomery SA (1992). The advantages of paroxetine in dierent subgroups of depression. International Clinical Psychopharmacology 6 (Suppl. 4), 91100. Montgomery SA (1995). Safety of mirtazapine : a review. International Clinical Psychopharmacology 10 (Suppl. 4), 3745. Montgomery SA (1998). Chairmans overview. The place of reboxetine in antidepressant therapy. Journal of Clinical Psychiatry 59 (Suppl. 14), 2629. Montgomery SA (1999). New developments in the treatment of depression. Journal of Clinical Psychiatry 60 (Suppl. 14), 1015. Montgomery SA (2005). Antidepressants and seizures : emphasis on newer agents and clinical implications. International Journal of Clinical Practice 59, 14351440. Montgomery SA (2006). Guidelines in major depressive disorder, and their limitations. International Journal of Psychiatry in Clinical Practice 10, 39. Montgomery SA, Andersen HF (2006). Escitalopram versus venlafaxine XR in the treatment of depression. International Clinical Psychopharmacology 21, 297309. Montgomery SA, Asberg M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389. Montgomery SA, Dufour H, Brion S, Gailledreau J, Laqueille X, Ferrey G, Moron P, Parant-Lucena N, Singer L, Danion JM (1988). The prophylactic ecacy of uoxetine in unipolar depression. British Journal of Psychiatry (Suppl.) 6976. Montgomery SA, Huusom AK, Bothmer J (2004b). A randomised study comparing escitalopram with venlafaxine XR in primary care patients with major depressive disorder. Neuropsychobiology 50, 5764. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I (2004c). Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine : a randomized, double-blind, placebo-controlled discontinuation study. International Clinical Psychopharmacology 19, 271280. Montgomery SA, Prost JF, Solles A, Briley M (1996). Ecacy and tolerability of milnacipran : an overview. International Clinical Psychopharmacology 11 (Suppl. 4), 4751. Montgomery SA, Reimitz PE, Zivkov M. (1998). Mirtazapine versus amitriptyline in the long-term treatment of depression : a double-blind placebo-controlled study. Int Clin Psychopharmacol. 13, 6373. Moore N, Verdoux H, Fantino B (2005). Prospective, multicentre, randomized, double-blind study of the ecacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. International Clinical Psychopharmacology 20, 131137.

S158

CINP Antidepressant Task Force 2007

Mulder H, Herder A, Wilmink FW, Tamminga WJ, Belitser SV, Egberts AC (2006). The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice. Pharmacoepidemiology and Drug Safety 15, 107114. Muller-Oerlinghausen B, Ahrens B, Felber W (2006). The suicide-preventive and mortality reducing eect of lithium. In : Bauer M, Grof P, Muller-Oerlinghausen B (Eds.), Lithium in Neuropsychiatry : The Comprehensive Guide (pp. 179192). Oxfordshire, UK : Informa Healthcare. Mulsant BH, Sweet RA, Rosen J, Pollock BG, Zubenko GS, Flynn T, Begley AE, Mazumdar S, Reynolds CF, III (2001). A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. Journal of Clinical Psychiatry 62, 597604. Mundo E, Bareggi SR, Pirola R, Bellodi L (1999). Eect of acute intravenous clomipramine and antiobsessional response to proserotonergic drugs : is gender a predictive variable ? Biological Psychiatry 45, 290294. Murphy BEP (1991). Treatment of major depression with steroid suppressive drugs. Journal of Steroid Biochemistry and Molecular Biology 39, 239244. Murphy BEP, Dhar V, Ghadirian AM, Chouinard G, Keller R (1991). Response to steroid suppression in major depression resistant to antidepressant therapy. Journal of Clinical Psychopharmacology 11, 121126. Murphy BEP, Filipini D, Ghadirian AM (1993). Possible use of glucocorticoid receptor antagonists in the treatment of major depression : preliminary results using RU 486. Journal of Psychiatry and Neuroscience 18, 209213. Murphy PA, Kern SE, Stanczyk FZ, Westho CL (2005). Interaction of St. Johns Wort with oral contraceptives : eects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 71, 402408. Musselman DL, Evans DL, Nemero CB (1998). The relationship of depression to cardiovascular disease : epidemiology, biology, and treatment. Archives of General Psychiatry 55, 580592. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007). Kynurenine pathway in major depression : evidence of impaired neuroprotection. Journal of Aective Disorders 98, 143156. Mynors-Wallis L, Davies I, Gray A, Barbour F, Gath D (1997). A randomised controlled trial and cost analysis of problem-solving treatment for emotional disorders given by community nurses in primary care. British Journal of Psychiatry 170, 113119. Naguib M, Koorn R (2002). Interactions between psychotropics, anaesthetics and electroconvulsive therapy : implications for drug choice and patient management. CNS Drugs 16, 229247. Nahas Z, Kozel FA, Li X, Anderson B, George MS (2003). Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar aective disorder : a

Moreno FA, Gelenberg AJ, Bachar K, Delgado PL (1997). Pindolol augmentation of treatment-resistant depressed patients. Journal of Clinical Psychiatry 58, 437439. Morgan PT (2007). Treatment-resistant depression : response to low-dose transdermal but not oral selegiline. Journal of Clinical Psychopharmacology 27, 313314. Morgan ML, Cook IA, Rapkin AJ, Leuchter AF (2005). Estrogen augmentation of antidepressants in perimenopausal depression : a pilot study. Journal of Clinical Psychiatry 66, 774780. Morgan O, Griths C, Baker A, Majeed A (2004). Fatal toxicity of antidepressants in England and Wales, 19932002. Health Statistics Quarterly 1824. Morilak DA, Frazer A (2004). Antidepressants and brain monoaminergic systems : a dimensional approach to understanding their behavioural eects in depression and anxiety disorders. International Journal of Neuropsychopharmacology 7, 193218. Morrison A, Levy R (2004). Toward individualized pharmaceutical care of East Asians : the value of genetic testing for polymorphisms in drug-metabolizing genes. Pharmacogenomics 5, 673689. Moscicki EK (1999). Epidemiology of suicide. In : Jacobs D (Ed.), The Harvard Medical School Guide to Suicide Assessment and Intervention (pp. 4051). San Francisco : Jossey-Bass. Moscrip TD, Terrace HS, Sackeim HA, Lisanby SH (2005). Randomized controlled trial of the cognitive side-eects of magnetic seizure therapy (MST) and electroconvulsive shock (ECS). International Journal of Neuropsychopharmacology 9, 111. Mosimann UP, Schmitt W, Greenberg BD, Kosel M, Muri RM, Berkho M, Hess CW, Fisch HU, Schlaepfer TE (2004). Repetitive transcranial magnetic stimulation : a putative add-on treatment for major depression in elderly patients. Psychiatry Research 126, 123133. Moskos M, Olson L, Halbern S, Keller T, Gray D (2005). Utah youth suicide study : psychological autopsy. Suicide and Life-Threatening Behavior 35, 536546. Moskowitz H, Burns M (1986). Cognitive performance in geriatric subjects after acute treatment with antidepressants. Neuropsychobiology 15 (Suppl. 1), 3843. Mosolov SN (1998). [Clinical pharmacology of antidepressants (review)]. Terapevticheskii Arkhiv 70, 7176. Mottram P, Wilson K, Strobl J (2006). Antidepressants for depressed elderly. Cochrane Database of Systematic Reviews. CD003491. Moukaddam NJ, Hirschfeld RM (2004). Intravenous antidepressants : a review. Depression and Anxiety 19, 19. Muhlbacher M, Konstantinidis A, Kasper S, Eichberger G, Hinterhuber H, Hofmann P, Nimmerrichter A, Schubert H, Egger C, Nickel M, Stuppaeck C (2006). Intravenous mirtazapine is safe and eective in the treatment of depressed inpatients. Neuropsychobiology 53, 8387.

CINP Antidepressant Task Force 2007

pilot study of acute safety and ecacy. Bipolar Disorders 5, 4047. Nahas Z, Marangell LB, Husain MM, Rush AJ, Sackeim HA, Lisanby SH, Martinez JM, George MS (2005). Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. Journal of Clinical Psychiatry 66, 10971104. Nahunek K, Svestka J, Ceskova E (1983). [Comparison of the onset of the therapeutic eect of clomipramine and desipramine after oral and intravenous administration in patients with endogenous depression]. Ceskoslovenska Psychiatrie 79, 164168. Narushima K, Chan KL, Kosier JT, Robinson RG (2003). Does cognitive recovery after treatment of poststroke depression last ? A 2-year follow-up of cognitive function associated with poststroke depression. American Journal of Psychiatry 160, 11571162. Narushima K, Paradiso S, Moser DJ, Jorge R, Robinson RG (2007). Eect of antidepressant therapy on executive function after stroke. British Journal of Psychiatry 190, 260265. Narushima K, Robinson RG (2003). The eect of early versus late antidepressant treatment on physical impairment associated with poststroke depression : is there a time-related therapeutic window ? Journal of Nervous and Mental Diseases 191, 645652. National Institute for Health and Clinical Excellence (2004). CG23 Depression : NICE Guideline (http:/ /www.nice. org.uk/page.aspx ?o=cg023niceguideline). Accessed 26 October 2006. National Institute of Mental Health (1976). CGI : Clinical Global Impressions. In : Guy WBRR (Ed.), Manual for the ECDEU Assessment Battery (pp. 12-112-6). Chevy Chase, MD : National Institute of Mental Health. Navarro V, Gasto C, Torres X, Marcos T, Pintor L (2001). Citalopram versus nortriptyline in late-life depression : a 12-week randomized single-blind study. Acta Psychiatrica Scandinavica 103, 435440. Nease DE, Maloin JM (2003). Depression screening : a practical strategy. Journal of Family Practice 52, 118124. Nelson JC (2000). Augmentation strategies in depression 2000. Journal of Clinical Psychiatry 61 (Suppl. 2), 1319. Nelson JC (2006). The STAR*D study : a four-course meal that leaves us wanting more. American Journal of Psychiatry 163, 18641866. Nelson JP, Benjamin L (1989). Ecacy and safety of combined ECT and tricyclic antidepressant drugs in the treatment of depressed geriatric patients. Convulsive Therapy 5, 321329. Nemero CB (1994). Evolutionary trends in the pharmacotherapeutic management of depression. Journal of Clinical Psychiatry 55 (Suppl.), 315. Nemero CB (1996). The corticotropin-releasing factor (CRF) hypothesis of depression : new ndings and new directions. Molecular Psychiatry 1, 336342. Nemero CB, Gharabawi GM, Canuso CM (2004). Augmentation with risperidone in chronic resistant

S159

depression : a double-blind placebo-controlled maintenance trial. Neuropsychopharmacology 29, 5159. Nemero CB, Widerlov E, Bisette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W (1984). Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226, 13421343. Nemets B, Stahl Z, Belmaker RH (2002). Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. American Journal of Psychiatry 159, 477479. Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RH (2006). Omega-3 treatment of childhood depression : a controlled, double-blind pilot study. American Journal of Psychiatry 163, 10981100. Nestler EJ (1998). Antidepressant treatments in the 21st century. Biological Psychiatry 44, 526533. Neumeister A, Goessler R, Lucht M, Kapitany T, Bamas C, Kasper S (1996). Bright light therapy stabilizes the antidepressant eect of partial sleep deprivation. Biological Psychiatry 39, 1621. Newhouse PA, Krishnan KR, Doraiswamy PM, Richter EM, Batzar ED, Clary CM (2000). A double-blind comparison of sertraline and uoxetine in depressed elderly outpatients. Journal of Clinical Psychiatry 61, 559568. Niedermaier N, Bohrer E, Schulte K, Schlattmann P, Heuser I (2004). Prevention and treatment of poststroke depression with mirtazapine in patients with acute stroke. Journal of Clinical Psychiatry 65, 16191623. Nierenberg AA (2001). Do some antidepressants work faster than others ? Journal of Clinical Psychiatry 62 (Suppl. 15), 2225. Nierenberg AA, Amsterdam JD (1990). Treatment-resistant depression : denition and treatment approaches. Journal of Clinical Psychiatry 51 (Suppl.), 3947. Nierenberg AA, Farabaugh AH, Alpert JE, Gordon J, Worthington JJ, Rosenbaum JF, Fava M (2000). Timing of onset of antidepressant response with uoxetine treatment. American Journal of Psychiatry 157, 14231428. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ (2006a). A comparison of lithium and T(3) augmentation following two failed medication treatments for depression : a STAR*D report. American Journal of Psychiatry 163, 15191530. Nierenberg AA, Petersen TJ, Alpert JE (2003). Prevention of relapse and recurrence in depression : the role of long-term pharmacotherapy and psychotherapy. Journal of Clinical Psychiatry 64 (Suppl. 15), 1317. Nierenberg AA, Trivedi MH, Fava M, Biggs MM, Shores-Wilson K, Wisniewski SR, Balasubramani GK, Rush AJ (2007). Family history of mood disorder and characteristics of major depressive disorder : A STAR(*)D (sequenced treatment alternatives to relieve depression) study. Journal of Psychiatric Research 41, 214221.

S160

CINP Antidepressant Task Force 2007

the response of major depression to electroconvulsive therapy : a C.O.R.E. Report. American Journal of Geriatric Psychiatry 9, 382390. ODwyer A-M, Lightman SL, Marks MN, Checkley SA (1995). Treatment of major depression with metyrapone and hydrocortisone. Journal of Aective Disorders 33, 123128. OHanlon JF, Robbe HW, Vermeeren A, van LC, Danjou PE (1998). Venlafaxines eects on healthy volunteers driving, psychomotor, and vigilance performance during 15-day xed and incremental dosing regimens. Journal of Clinical Psychopharmacology 18, 212221. Obuchowicz E, Kowalski J, Labuzek K, Krysiak R, Pendzich J, Herman ZS (2006). Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures. International Journal of Neuropsychopharmacology 9, 2735. Ohberg A, Vuori E, Klaukka T, Lonnqvist J (1998). Antidepressants and suicide mortality. Journal of Aective Disorders 50, 225233. Olesen J, Leonardi M (2003). The burden of brain diseases in Europe. European Journal of Neurology 10, 471477. Olfson M, Shaer D, Marcus SC, Greenberg T (2003). Relationship between antidepressant medication treatment and suicide in adolescents. Archives of General Psychiatry 60, 978982. Olfson M, Marcus SC, Shaer D (2006). Antidepressant drug therapy and suicide in severely depressed children and adults : A case-control study. Archives of General Psychiatry 63, 865872. Olie JP, Kasper S (2007). Ecacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. International Journal of Neuropsychopharmacology 10, 661673. Olver JS, Burrows GD, Norman TR (2001). Third-generation antidepressants : do they oer advantages over the SSRIs ? CNS Drugs 15, 941954. Olver JS, Burrows GD, Norman TR (2004). The treatment of depression with dierent formulations of venlafaxine : a comparative analysis. Human Psychopharmacology 19, 916. Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS, Terman JS, Terman M (2002). An open trial of morning light therapy for treatment of antepartum depression. American Journal of Psychiatry 159, 666669. Osby U, Brandt L, Correia N, Ekbom A, Sparen P (2001). Excess mortality in bipolar and unipolar disorder in Sweden. Archives of General Psychiatry 58, 844850. Oshima A, Higuchi T (1999). Treatment guidelines for geriatric mood disorders. Psychiatry and Clinical Neurosciences 53 (Suppl.), S55S59. Ostacher MJ, Human J, Perlis R, Nierenberg AA (2005). Evidence-based pharmacotherapy of major depressive disorder. In : Stein DJ, Lerer B, Stahl SM (Eds.), Evidence-Based Psychopharmacology (pp. 121). Cambridge : Cambridge University Press. Ostenfeld I (1973). [Treatment of endogenous depression by deprivation of sleep]. Ugeskrift for Laeger 135, 26322633.

Nijhuis IJ, Kok-Van Rooij GW, Bosschaart AN (2001). Withdrawal reactions of a premature neonate after maternal use of paroxetine. Archives of Disease in Childhood. Fetal and Neonatal Edition 84, F77. Nilsson FM, Kessing LV (2004). Increased risk of developing stroke for patients with major aective disorder : a registry study. European Archives of Psychiatry and Clinical Neuroscience 254, 387391. Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, Blier P, Diksic M (1997). Dierences between males and females in rates of serotonin synthesis in human brain. Proceedings of the National Academy of Sciences USA 94, 53085313. Nonacs R, Cohen LS (2003). Assessment and treatment of depression during pregnancy : an update. Psychiatric Clinics of North America 26, 547562. Norman TR, Leonard BE (1994). Fast-acting antidepressants : can the need be met ? CNS Drugs 2, 120131. Norman TR, Olver JS (2004). New formulations of existing antidepressants : advantages in the management of depression. CNS Drugs 18, 505520. Normann C, Hummel B, Scharer LO, Horn M, Grunze H, Walden J (2002). Lamotrigine as adjunct to paroxetine in acute depression : a placebo-controlled, double-blind study. Journal of Clinical Psychiatry 63, 337344. North TC, McCullagh P, Tran ZV (1990). Eect of exercise on depression. Exercise and Sport Sciences Reviews 18, 379415. Novick JS, Stewart JW, Wisniewski SR, Cook IA, Manev R, Nierenberg AA, Rosenbaum JF, Shores-Wilson K, Balasubramani GK, Biggs MM, Zisook S, Rush AJ (2005). Clinical and demographic features of atypical depression in outpatients with major depressive disorder : preliminary ndings from STAR*D. Journal of Clinical Psychiatry 66, 10021011. Nuijten M, Hadjadjeba L, Evans C, van den Berg J (1998). Cost eectiveness of uvoxamine in the treatment of recurrent depression in France. Pharmacoeconomics 14, 433445. Nuijten MJ, Hardens M, Souetre E (1995). A Markov process analysis comparing the cost eectiveness of maintenance therapy with citalopram versus standard therapy in major depression. Pharmacoeconomics 8, 159168. Nutt DJ (2002). The neuropharmacology of serotonin and noradrenaline in depression. International Clinical Psychopharmacology 17 (Suppl. 1), S112. Nutt DJ (2003). Death and dependence : current controversies over the selective serotonin reuptake inhibitors. Journal of Psychopharmacology 17, 355364. Nuttall GA, Bowersox MR, Douglass SB, McDonald J, Rasmussen LJ, Decker PA, Oliver WC, Rasmussen KG (2004). Morbidity and mortality in the use of electroconvulsive therapy. Journal of ECT 20, 237241. OBrien CP, Volkow N, Li TK (2006). Whats in a word ? Addiction versus dependence in DSM-V. American Journal of Psychiatry 163, 764765. OConnor MK, Knapp R, Husain M, Rummans TA, Petrides G, Smith G, Mueller M, Snyder K, Bernstein H, Rush AJ, Fink M, Kellner C (2001). The inuence of age on

CINP Antidepressant Task Force 2007

Ottoson JO, Fink M (2004). The Ethics in Electroconvulsive Therapy. New York : Brunner/Routledge. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D (2006). Depression and risk for Alzheimer disease : systematic review, meta-analysis, and metaregression analysis. Archives of General Psychiatry 63, 530538. Ozcanli T, Unsalver B, Ozdemir S, Ozmen M (2005). Sertraline- and mirtazapine-induced severe neutropenia. American Journal of Psychiatry 162, 1386. Pacher P, Kohegyi E, Kecskemeti V, Furst S (2001). Current trends in the development of new antidepressants. Current Medicinal Chemistry 8, 89100. Padberg F, Moller HJ (2003). Repetitive transcranial magnetic stimulation : does it have potential in the treatment of depression ? CNS Drugs 17, 383403. Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel P, Ella R, Rupprecht P, Thoma H, Hampel H, Toschi N, Moller HJ (2002). Repetitive transcranial magnetic stimulation (rTMS) in major depression : relation between ecacy and stimulation intensity. Neuropsychopharmacology 27, 638645. Padberg F, Zwanzger P, Thoma H, Kathmann N, Haag C, Greenberg BD, Hampel H, Moller HJ (1999). Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression : comparative study of fast, slow and sham rTMS. Psychiatry Research 88, 163171. Pallanti S, Quercioli L, Koran LM (2002). Citalopram intravenous infusion in resistant obsessive-compulsive disorder : an open trial. Journal of Clinical Psychiatry 63, 796801. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C (2004). Combined pharmacotherapy and psychological treatment for depression : a systematic review. Archives of General Psychiatry 61, 714719. Papakostas GI (2005). Augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder. Essential Psychopharmacology 6, 209220. Papakostas GI (2006). Dopaminergic-based pharmacotherapies for depression. Eur. Neuropsychopharmacol. 16, 391402. Papakostas GI, Petersen TJ, Kinrys G, Burns AM, Worthington JJ, Alpert JE, Fava M, Nierenberg AA (2005). Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. Journal of Clinical Psychiatry 66, 13261330. Papakostas GI, Petersen TJ, Nierenberg AA, Murakami JL, Alpert JE, Rosenbaum JF, Fava M (2004). Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. Journal of Clinical Psychiatry 65, 217221. Park RJ, Goodyer IM (2000). Clinical guidelines for depressive disorders in childhood and adolescence. European Child and Adolescent Psychiatry 9, 147161. Parker G (2002). Dierential eectiveness of newer and older antidepressants appears mediated by an age eect on the

S161

phenotypic expression of depression. Acta Psychiatrica Scandinavica 106, 168170. Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D (2006). Omega-3 fatty acids and mood disorders. American Journal of Psychiatry 163, 969978. Parker G, Parker K, Austin MP, Mitchell P, Brotchie H (2003). Gender dierences in response to diering antidepressant drug classes : two negative studies. Psychological Medicine 33, 14731477. Parry BL, Curran ML, Stuenkel CA, Yokimozo M, Tam L, Powell KA, Gillin JC (2000). Can critically timed sleep deprivation be useful in pregnancy and postpartum depressions ? Journal of Aective Disorders 60, 201212. Pascual-Leone A, Rubio B, Pallardo F, Catala MD (1996). Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 347, 233237. Patel V, Chisholm D, Rabe-Hesketh S, Dias-Saxena F, Andrew G, Mann A (2003). Ecacy and cost-eectiveness of drug and psychological treatments for common mental disorders in general health care in Goa, India : a randomised, controlled trial. Lancet 361, 3339. Pathak S, Kratochvil CJ, Rogers GM, Silva S, Vitiello B, Weller EB, March JS (2005). Comparative ecacy of cognitive behavioral therapy, uoxetine, and their combination in depressed adolescents : initial lessons from the treatment for adolescents with depression study. Current Psychiatry Reports 7, 429434. Patten S, Cipriani A, Brambilla P, Nose M, Barbui C (2005). International dosage dierences in uoxetine clinical trials. Canadian Journal of Psychiatry 50, 3138. Patten SB (2006). Does almost everybody suer from a bipolar disorder ? Canadian Journal of Psychiatry 51, 68. Patten SB, Barbui C (2004). Drug-induced depression : a systematic review to inform clinical practice. Psychotherapy and Psychosomatics 73, 207215. Patten SB, Metz LM (1997). Depression in multiple sclerosis. Psychotherapy and Psychosomatics 66, 286292. Patten SB, Sedmak B, Russell ML (2001). Major depression : prevalence, treatment utilization and age in Canada. Canadian Journal of Clinical Pharmacology 8, 133138. Paul IA, Nowak G, Layer RT, Popik P, Skolnick P (1994). Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. Journal of Pharmacology and Experimental Therapeutics 269, 95102. Pauwels PJ (2000). Diverse signalling by 5hydroxytryptamine (5-HT) receptors. Biochemical Pharmacology 60, 17431750. Pavlovic DM, Milovic AM (1999). [Clinical characteristics and therapy of neurosyphilis in patients who are negative for human immunodeciency virus]. Srpski Arhiv Za Celokupno Lekarstvo 127, 236240. Paykel ES (2001). Continuation and maintenance therapy in depression. British Medical Bulletin 57, 145159. Paykel ES, Brugha T, Fryers T (2005). Size and burden of depressive disorders in Europe. European Neuropsychopharmacology 15, 411423.

S162

CINP Antidepressant Task Force 2007

Pezawas L, Angst J, Kasper S (2005). Recurrent brief depression revisited. International Review of Psychiatry 17, 6370. Pezawas L, Stamenkovic M, Kasper S (2001). [Recurrent brief depressive episodes. Epidemiology, clinical aspects, diagnosis and therapy]. Nervenarzt 72, 169180. Pfa JJ, Almeida OP (2005). Detecting suicidal ideation in older patients : identifying risk factors within the general practice setting. British Journal of General Practice 55, 269273. Philibert RA, Richards L, Lynch CF, Winokur G (1995). Eect of ECT on mortality and clinical outcome in geriatric unipolar depression. Journal of Clinical Psychiatry 56, 390394. Philipp M, Kohnen R, Hiller KO (1999). Hypericum extract versus imipramine or placebo in patients with moderate depression : randomised multicentre study of treatment for eight weeks. British Medical Journal 319, 15341538. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). Potential role of pharmacogenomics in reducing adverse drug reactions : a systematic review. Journal of the American Medical Association 286, 22702279. Phillips SD, Ringo P (1995). Phenelzine and venlafaxine interaction. American Journal of Psychiatry 152, 14001401. Pilowsky DJ, Wickramaratne PJ, Rush AJ, Hughes CW, Garber J, Malloy E, King CA, Cerda G, Sood AB, Alpert JE, Wisniewski SR, Trivedi MH, Talati A, Carlson MM, Liu HH, Fava M, Weissman MM (2006). Children of currently depressed mothers : a STAR*D ancillary study. Journal of Clinical Psychiatry 67, 126136. Pincus HA, Zarin DA, Tanielian TL, Johnson JL, West JC, Pettit AR, Marcus SC, Kessler RC, McIntyre JS (1999). Psychiatric patients and treatments in 1997 : ndings from the American Psychiatric Practice Research Network. Archives of General Psychiatry 56, 441449. Pineyro G, Deveault L, Blier P, Dennis T, de Montigny C (1995a). Eect of acute and prolonged tianeptine administration on the 5-HT transporter : electrophysiological, biochemical and radioligand binding studies in the rat brain. Naunyn-Schmiedebergs Archives of Pharmacology 351, 111118. Pineyro G, Deveault L, de Montigny C, Blier P (1995b). Eect of prolonged administration of tianeptine on 5-HT neurotransmission : an electrophysiological study in the rat hippocampus and dorsal raphe. Naunyn-Schmiedebergs Archives of Pharmacology 351, 119125. Pinto-Meza A, Usall J, Serrano-Blanco A, Suarez D, Haro JM (2006). Gender dierences in response to antidepressant treatment prescribed in primary care. Does menopause make a dierence ? Journal of Aective Disorders 93, 5360. Pisani F, Spina E, Oteri G (1999). Antidepressant drugs and seizure susceptibility : from in vitro data to clinical practice. Epilepsia 40 (Suppl. 10), S48S56. Pogosova GV, Zhidko NI, Krasnitskii VB, Tikhomirova EA, Odintsova AS, Akhmedzhanov NM, Baichorov IK (2004). [Clinical ecacy of tianeptine in patients with ischemic

Paykel ES, Priest RG (1992). Recognition and management of depression in general practice : consensus statement. British Medical Journal 305, 11981202. Pearlman C, Obedian E (1995). ECT-valproic acid interaction. General Hospital Psychiatry 17, 456457. Pedersen AG (2005). Escitalopram and suicidality in adult depression and anxiety. International Clinical Psychopharmacology 20, 139143. Peet M (1994). Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. British Journal of Psychiatry 164, 549550. Peet M, Horrobin DF (2002). A dose-ranging study of the eects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Archives of General Psychiatry 59, 913919. Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, van Tilburg W (2001). Depression and cardiac mortality : results from a community-based longitudinal study. Archives of General Psychiatry 58, 221227. Peretti S, Judge R, Hindmarch I (2000). Safety and tolerability considerations : tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatrica Scandinavica. Supplementum 403, 1725. Perez V, Soler J, Puigdemont D, Alvarez E, Artigas F (1999). A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Grup de Recerca en Trastorns Afectius. Archives of General Psychiatry 56, 375379. Perlick DA, Hohenstein JM, Clarkin JF, Kaczynski R, Rosenheck RA (2005). Use of mental health and primary care services by caregivers of patients with bipolar disorder : a preliminary study. Bipolar Disorders 7, 126135. Perlis RH, Perlis CS, Wu Y, Hwang C, Joseph M, Nierenberg AA (2005). Industry sponsorship and nancial conict of interest in the reporting of clinical trials in psychiatry. American Journal of Psychiatry 162, 19571960. Pesola GR, Avasarala J (2002). Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. Journal of Emergency Medicine 22, 235239. Petrides G, Fink M, Husain MM, Knapp RG, Rush AJ, Mueller M, Rummans TA, OConnor KM, Rasmussen KGJ, Bernstein HJ, Biggs M, Bailine SH, Kellner CH (2001). ECT remission rates in psychotic versus nonpsychotic depressed patients : a report from CORE. Journal of ECT 17, 244253. Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, Chatwin J, Goddard J, Thornett A, Smith H, Campbell M, Thompson C (2005). A randomised controlled trial to compare the cost-eectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine. Health Technology Assessment 9, 1134, iii. Pevet P (2002). Melatonin. Dialogues in Clinical Neuroscience 4, 5772.

CINP Antidepressant Task Force 2007

heart disease and comorbid depression]. Kardiologiia 44, 2024. Porche DJ, Willis DG (2006). Depression in HIV-infected men. Issues in Mental Health Nursing 27, 391401. Post RM, Altshuler LL, Leverich GS, Frye MA, Nolen WA, Kupka RW, Suppes T, McElroy S, Keck PE, Denico KD, Grunze H, Walden J, Kitchen CM, Mintz J (2006). Mood switch in bipolar depression : comparison of adjunctive venlafaxine, bupropion and sertraline. British Journal of Psychiatry 189, 124131. Post RM, Calabrese JR (2004). Bipolar depression : the role of atypical antipsychotics. Expert Review of Neurotherapeutics 4, S27S33. Post RM, Uhde TW, Roy-Byrne PP, Joe RT (1986). Antidepressant eects of carbamazepine. American Journal of Psychiatry 143, 2934. Praschak-Rieder N, Neumeister A, Hesselmann B, Willeit M, Barnas C, Kasper S (1997). Suicidal tendencies as a complication of light therapy for seasonal aective disorder : a report of three cases. Journal of Clinical Psychiatry 58, 389392. Prasko J, Horacek J, Klaschka J, Kosova J, Ondrackova I, Sipek J (2002). Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression. Neuroendocrinology Letters 23, 109113. Preskorn SH (1995). Comparison of the tolerability of bupropion, uoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine. Journal of Clinical Psychiatry 56 (Suppl. 6), 1221. Price LH, Conwell Y, Nelson JC (1983). Lithium augmentation of combined neuroleptic-tricyclic treatment in delusional depression. American Journal of Psychiatry 140, 318322. Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M (2000). Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode. International Journal of Neuropsychopharmacology 3, Prien RF (1990). Ecacy of continuation drug therapy of depression and anxiety : issues and methodologies. Journal of Clinical Psychopharmacology 10, 86S90S. Prien RF, Kupfer DJ (1986). Continuation drug therapy for major depressive episodes : how long should it be maintained ? American Journal of Psychiatry 143, 1823. Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, Johnson WE (1984). Drug therapy in the prevention of recurrences in unipolar and bipolar aective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Archives of General Psychiatry 41, 10961104. Procyshyn RM, Chau A, Fortin P, Jenkins W (2004). Prevalence and outcomes of pharmaceutical industrysponsored clinical trials involving clozapine, risperidone, or olanzapine. Canadian Journal of Psychiatry 49, 601606. Prudic J, Haskett RF, Mulsant B, Malone KM, Pettinati HM, Stephens S, Greenberg R, Rifas SL, Sackeim HA (1996). Resistance to antidepressant medications and short-term

S163

clinical response to ECT. American Journal of Psychiatry 153, 985992. Prudic J, Sackeim HA, Devanand DP (1990). Medication resistance and clinical response to electroconvulsive therapy. Psychiatry Research 31, 287296. Puech A, Montgomery SA, Prost JF, Solles A, Briley M (1997). Milnacipran, a new serotonin and noradrenaline reuptake inhibitor : an overview of its antidepressant activity and clinical tolerability. International Clinical Psychopharmacology 12, 99108. Puozzo C, Albin H, Vincon G, Deprez D, Raymond JM, Amouretti M (1998). Pharmacokinetics of milnacipran in liver impairment. European Journal of Drug Metabolism and Pharmacokinetics 23, 273279. Purebl G, Birkas E, Csoboth C, Szumska I, Kopp MS (2006). The relationship of biological and psychological risk factors of cardiovascular disorders in a large-scale national representative community survey. Behavioral Medicine 31, 133139. Quitkin FM, McGrath PJ, Stewart JW, Deliyannides D, Taylor BP, Davies CA, Klein DF (2005). Remission rates with 3 consecutive antidepressant trials : eectiveness for depressed outpatients. Journal of Clinical Psychiatry 66, 670676. Quitkin FM, Taylor BP, Kremer C (2001). Does mirtazapine have a more rapid onset than SSRIs ? Journal of Clinical Psychiatry 62, 358361. Rabheru K (2001). The use of electroconvulsive therapy in special patient populations. Canadian Journal of Psychiatry 46, 710719. Rabheru K, Persad E (1997). A review of continuation and maintenance electroconvulsive therapy. Canadian Journal of Psychiatry 42, 476484. Rabiner EA, Bhagwagar Z, Gunn RN, Sargent PA, Bench CJ, Cowen PJ, Grasby PM (2001). Pindolol augmentation of selective serotonin reuptake inhibitors : PET evidence that the dose used in clinical trials is too low. American Journal of Psychiatry 158, 20802082. Rajagopalan M, Little J (1999). Discontinuation symptoms with nefazodone. Australian & New Zealand Journal of Psychiatry 33, 594597. Ramaekers JG (2003). Antidepressants and driver impairment : empirical evidence from a standard on-the-road test. Journal of Clinical Psychiatry 64, 2029. Ramaekers JG, Muntjewer ND, OHanlon JF (1995). A comparative study of acute and subchronic eects of dothiepin, uoxetine and placebo on psychomotor and actual driving performance. British Journal of Clinical Pharmacology 39, 397404. Ramaekers JG, Muntjewer ND, van Veggel LM, Uiterwijk MMC, OHanlon JF (1998). Eects of Nocturnal Doses of Mirtazapine and Mianserin on Sleep and on Daytime Psychomotor and Driving Performance in Young, Healthy Volunteers. Human Psychopharmacology : Clinical and Experimental 13, S87S97. Ramaekers JG, Swijgman HF, OHanlon JF (1992). Eects of moclobemide and mianserin on highway driving, psychometric performance and subjective parameters,

S164

CINP Antidepressant Task Force 2007

Ravindran AV, Anisman H, Merali Z, Charbonneau Y, Telner J, Bialik RJ, Wiens A, Ellis J, Griths J (1999). Treatment of primary dysthymia with group cognitive therapy and pharmacotherapy : clinical symptoms and functional impairments. American Journal of Psychiatry 156, 16081617. Ravizza L (1979). [Clinical and biochemical contributions on the eect of maprotiline and clomipramine in depressive states (preliminary observation)]. Psychiatria Clinica 12, 164172. Ray WA, Fought RL, Decker MD (1992). Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. American Journal of Epidemiology 136, 873883. Reagan LP, Rosell DR, Wood GE, Spedding M, Munoz C, Rothstein J, McEwen BS (2004). Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus : reversal by tianeptine. Proceedings of the National Academy of Sciences USA 101, 21792184. Rees AM, Austin MP, Parker G (2005). Role of omega-3 fatty acids as a treatment for depression in the perinatal period. Australian and New Zealand Journal of Psychiatry 39, 274280. Reimherr FW, Hodges MR, Hill GE, Wong KC (1977). Prolongation of muscle relaxant eects by lithium carbonate. American Journal of Psychiatry 134, 205206. Reme CE, Grimm C, Hafezi F, Wenzel A (2001). Lamp standards and ocular safety. In : Partonen T, Magnosson A (Eds.), Seasonal Aective Disorder (pp. 7983). New York : Oxford University Press. Remick RA, Campos PE, Misri S, Miles JE, Van Wyck FJ (1982). A comparison of the safety and ecacy of bupropion HCL and amitriptyline hcl in depressed outpatients. Progress in Neuro-Psychopharmacology and Biological Psychiatry 6, 523527. Revicki DA, Brown RE, Keller MB, Gonzales J, Culpepper L, Hales RE (1997). Cost-eectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings. Journal of Clinical Psychiatry 58, 4758. Reynolds CF, III, Dew MA, Pollock BG, Mulsant BH, Frank E, Miller MD, Houck PR, Mazumdar S, Butters MA, Stack JA, Schlernitzauer MA, Whyte EM, Gildengers A, Karp J, Lenze E, Szanto K, Bensasi S, Kupfer DJ (2006). Maintenance treatment of major depression in old age. New England Journal of Medicine 354, 11301138. Reynolds CF, III, Frank E, Perel JM, Imber SD, Cornes C, Miller MD, Mazumdar S, Houck PR, Dew MA, Stack JA, Pollock BG, Kupfer DJ (1999). Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression : a randomized controlled trial in patients older than 59 years. Journal of the American Medical Association 281, 3945. Richards A, Barkham M, Cahill J, Richards D, Williams C, Heywood P (2003). PHASE : a randomised, controlled trial of supervised self-help cognitive behavioural therapy in primary care. British Journal of General Practice 53, 764770.

relative to placebo. Psychopharmacology (Berlin) 106 (Suppl.), S62S67. Ramana R, Paykel ES, Cooper Z, Hayhurst H, Saxty M, Surtees PG (1995). Remission and relapse in major depression : a two-year prospective follow-up study. Psychological Medicine 25, 11611170. Rampello L, Chiechio S, Nicoletti G, Alvano A, Vecchio I, Raaele R, Malaguarnera M (2004). Prediction of the response to citalopram and reboxetine in post-stroke depressed patients. Psychopharmacology 173, 7378. Rampono J, Kristensen JH, Hackett LP, Paech M, Kohan R, Ilett KF (2000). Citalopram and demethylcitalopram in human milk ; distribution, excretion and eects in breast fed infants. British Journal of Clinical Pharmacology 50, 263268. Rao KM, Gangadhar BN, Janakiramaiah N (1993). Nonconvulsive status epilepticus after the ninth electroconvulsive therapy. Convulsive Therapy 9, 128129. Rapaport MH, Schneider LS, Dunner DL, Davies JT, Pitts CD (2003). Ecacy of controlled-release paroxetine in the treatment of late-life depression. Journal of Clinical Psychiatry 64, 10651074. Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl DP, Purohit DP, Gorman JM, Haroutunian V (2006). Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Archives of General Psychiatry 63, 161167. Rasgon NL, Altshuler LL, Fairbanks LA, Dunkin JJ, Davtyan C, Elman S, Rapkin AJ (2002). Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. Journal of Clinical Psychiatry 63 (Suppl. 7), 4548. Rasmussen KG, Sampson SM, Rummans TA (2002). Electroconvulsive therapy and newer modalities for the treatment of medication-refractory mental illness. Mayo Clinic Proceedings 77, 552556. Rasmussen NA, Schroder P, Olsen LR, Brodsgaard M, Unden M, Bech P (2005). Modanil augmentation in depressed patients with partial response to antidepressants : a pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nordic Journal of Psychiatry 59, 173178. Rau A, Grossheinrich N, Palm U, Pogarell O, Padberg F (2007). Transcranial and deep brain stimulation approaches as treatment for depression. Clinical EEG and Neuroscience 38, 105115. Raue PJ, Meyers BS, Rowe JL, Heo M, Bruce ML (2007). Suicidal ideation among elderly homecare patients. International Journal of Geriatric Psychiatry 22, 3237. Ravaris CL, Robinson DS, Ives JO, Nies A, Bartlett D (1980). Phenelzine and amitriptyline in the treatment of depression. A comparison of present and past studies. Archives of General Psychiatry 37, 10751080. Raven PW, ODwyer A-M, Taylor NF, Checkley SA (1996). The relationship between the eects of metyrapone treatment on depressed mood and urinary steroid proles. Psychoneuroendocrinology 21, 277286.

CINP Antidepressant Task Force 2007

Richelson E (2001). Pharmacology of antidepressants. Mayo Clinic Proceedings 76, 511527. Rickards H (2005). Depression in neurological disorders : Parkinsons disease, multiple sclerosis, and stroke. Journal of Neurology, Neurosurgery and Psychiatry 76 (Suppl. 1), i48i52. Ridout F, Meadows R, Johnsen S, Hindmarch I (2003). A placebo controlled investigation into the eects of paroxetine and mirtazapine on measures related to car driving performance. Human Psychopharmacology 18, 261269. Riecher-Rossler A (2000). [Mental diseases in women some arguments for a gender-sensitive psychiatry and psychotherapy]. Zeitschrift Fur Psychosomatische Medizin Und Psychotherapie 46, 129139. Riecher-Rossler A, Kuhl H, Bitzer J (In Press). Psychische Storungen in Zeiten hormoneller Umstellung eine selektive Uebersicht. Neuropsychiatrie. Riemann D, Schnitzler M, Hohagen F, Berger M (1994). [Depression and sleep : the status of current research]. Fortschritte Der Neurologie-Psychiatrie 62, 458478. Rihmer Z, Akiskal H (2006). Do antidepressants t(h)reat(en) depressives ? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. Journal of Aective Disorders 94, 313. Rihmer Z, Appleby L, Rihmer A, Belso N (2000). Decreasing suicide in Hungary. British Journal of Psychiatry 177, 84. Rihmer Z, Rutz W, Pihlgren H (1995). Depression and suicide on Gotland. An intensive study of all suicides before and after a depression-training programme for general practitioners. Journal of Aective Disorders 35, 147152. Risch NJ (2000). Searching for genetic determinants in the new millennium. Nature 405, 847856. Robbe HW, OHanlon JF (1995). Acute and subchronic eects of paroxetine 20 and 40 mg on actual driving, psychomotor performance and subjective assessments in healthy volunteers. European Neuropsychopharmacology 5, 3542. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, Farmer A, Jablenski A, Pickens R, Regier DA (1988). The Composite International Diagnostic Interview : an epidemiologic Instrument suitable for use in conjunction with dierent diagnostic systems and in dierent cultures. Archives of General Psychiatry 45, 10691077. Robinson DS, Lerfald SC, Bennett B, Laux D, Devereaux E, Kayser A, Corcella J, Albright D (1991). Continuation and maintenance treatment of major depression with the monoamine oxidase inhibitor phenelzine : a double-blind placebo-controlled discontinuation study. Psychopharmacology Bulletin 27, 3139. Robinson WS (1950). Ecological correlations and the behavior of individuals. American Sociological Review 15, 351357. Rocca P, Fonzo V, Ravizza L, Rocca G, Scotta M, Zanalda E, Bogetto F (2002). A comparison of paroxetine and

S165

amisulpride in the treatment of dysthymic disorder. Journal of Aective Disorders 70, 313317. Rodin G, Katz M, Lloyd N, Green E, Mackay JA, Wong RK (2007). Treatment of depression in cancer patients. Currrnt Oncology 14, 180188. Rodriguez C, Puerta G (1997). Prevalencia de dintomas de depresion y ansiedad en los pacientes de consulta no psiquiatrica. Revista Colombiana De Psiquiatra XXVI, 273288. Rohland BM, Carroll BT, Jacoby RG (1993). ECT in the treatment of the catatonic syndrome. Journal of Aective Disorders 29, 255261. Rojo JE, Ros S, Aguera L, de la Gandara J, de Pedro JM (2005). Combined antidepressants : clinical experience. Acta Psychiatrica Scandinavica. Supplementum 2531, 36. Roman FJ, Pascaud X, Martin B, Vauche D, Junien JL (1990). JO 1784, a potent and selective ligand for rat and mouse brain sigma-sites. Journal of Pharmacy and Pharmacology 42, 439440. Romeo R, Patel A, Knapp M, Thomas C (2004). The cost-eectiveness of mirtazapine versus paroxetine in treating people with depression in primary care. International Clinical Psychopharmacology 19, 125134. Roose SP, Sackeim HA, Krishnan KR, Pollock BG, Alexopoulos G, Lavretsky H, Katz IR, Hakkarainen H (2004). Antidepressant pharmacotherapy in the treatment of depression in the very old : a randomized, placebo-controlled trial. American Journal of Psychiatry 161, 20502059. Roose SP, Schatzberg AF (2005). The ecacy of antidepressants in the treatment of late-life depression. Journal of Clinical Psychopharmacology 25, S1S7. Roschke J, Wolf C, Muller MJ, Wagner P, Mann K, Grozinger M, Bech S (2000). The benet from whole body acupuncture in major depression. Journal of Aective Disorders 57, 7381. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB (1998). Selective serotonin reuptake inhibitor discontinuation syndrome : a randomized clinical trial. Biological Psychiatry 44, 7787. Rosenbaum JF, Zajecka J (1997). Clinical management of antidepressant discontinuation. Journal of Clinical Psychiatry 58 (Suppl. 7), 3740. Rosenthal NE, Sack DA, Carpenter CJ, Parry BL, Mendelson WB, Wehr TA (1985). Antidepressant eects of light in seasonal aective disorder. American Journal of Psychiatry 142, 163170. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsome DA, Wehr TA (1984). Seasonal aective disorder : a description of the syndrome and preliminary ndings with light therapy. Archives of General Psychiatry 41, 7280. Ross S, Williams D (2005). Bupropion : risks and benets. Expert Opinion on Drug Safety 4, 9951003. Rossello J, Bernal G (1999). The ecacy of cognitivebehavioral and interpersonal treatments for depression in Puerto Rican adolescents. Journal of Consulting and Clinical Psychology 67, 734745.

S166

CINP Antidepressant Task Force 2007

Rupprecht R, Baghai TC, Moller HJ (2004). [New developments in pharmacotherapy of depression]. Nervenarzt 75, 273280. Rupprecht R, Holsboer F (1999). Neuroactive steroids : mechanisms of action and neuropsychopharmacological perspectives. Trends in Neurosciences 22, 410416. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G (2000). Acute heart transplant rejection due to Saint Johns wort. Lancet 355, 548549. Rush AJ (1999). Strategies and tactics in the management of maintenance treatment for depressed patients. Journal of Clinical Psychiatry 60 (Suppl. 14), 2126 ; discussion 3135. Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, Trivedi MH, Suppes T, Miller AL, Biggs MM, Shores-Wilson K, Witte BP, Shon SP, Rago WV, Altshuler KZ (2003a). Texas Medication Algorithm Project, phase 3 (TMAP-3) : rationale and study design. Journal of Clinical Psychiatry 64, 357369. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G (2004). Sequenced treatment alternatives to relieve depression (STAR*D) : rationale and design. Controlled Clinical Trials 25, 119142. Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RKJ, Goodman R (2000). Vagus nerve stimulation (VNS) for treatment-resistant depressions : a multicenter study. Biological Psychiatry 47, 276286. Rush AJ, Kraemer HC, Sackeim HA, Fava M, Trivedi MH, Frank E, Ninan PT, Thase ME, Gelenberg AJ, Kupfer DJ, Regier DA, Rosenbaum JF, Ray O, Schatzberg AF (2006a). Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology 31, 18411853. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG (2005a). Vagus nerve stimulation for treatment-resistant depression : a randomized, controlled acute phase trial. Biological Psychiatry 58, 347354. Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, Lavori P, Howland R, Kling MA, Rittberg B, Carpenter L, Ninan P, Moreno F, Schwartz T, Conway C, Burke M, Barry JJ (2005b). Eects of 12 months of vagus nerve stimulation in treatment-resistant depression : a naturalistic study. Biological Psychiatry 58, 355363. Rush AJ, Thase ME, Dube S (2003b). Research issues in the study of dicult-to-treat depression. Biological Psychiatry 53, 743753. Rush AJ, Thase ME (1999). Psychotherapies for depressive disorders : a review. In : Maj M, Sartorius N (Eds.), Depressive Disorders : WPA Series Evidence and Experience in Psychiatry (pp. 161206). Chichester : John Wiley & Sons.

Rossini D, Lucca A, Zanardi R, Magri L, Smeraldi E (2005). Transcranial magnetic stimulation in treatment-resistant depressed patients : a double-blind, placebo-controlled trial. Psychiatry Research 137, 110. Roth A, Fonagy P (2004). What Works for Whom ? New York : Guilford Press. Rothschild AJ (1996). Management of psychotic, treatment-resistant depression. Psychiatric Clinics of North America 19, 237252. Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell JT (1993). Ecacy of the combination of uoxetine and perphenazine in the treatment of psychotic depression. Journal of Clinical Psychiatry 54, 338342. Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD (2004). A double-blind, randomized study of olanzapine and olanzapine/uoxetine combination for major depression with psychotic features. Journal of Clinical Psychopharmacology 24, 365373. Rouillon F, Warner B, Pezous N, Bisserbe JC (2000). Milnacipran ecacy in the prevention of recurrent depression : a 12-month placebo-controlled study. Milnacipran recurrence prevention study group. International Clinical Psychopharmacology 15, 133140. Roxanas MG, Machado JF (1998). Serotonin syndrome in combined moclobemide and venlafaxine ingestion. Medical Journal of Australia 168, 523524. Roy-Byrne PP, Uhde TW, Post RM (1986). Eects of one nights sleep deprivation on mood and behavior in panic disorder. Patients with panic disorder compared with depressed patients and normal controls. Archives of General Psychiatry 43, 895899. Rudorfer MV, Potter WZ (1997). The role of metabolites of antidepressants in the treatment of depression [review]. CNS Drugs 7, 273312. Ruhe HG, Huyser J, Swinkels JA, Schene AH (2006a). Dose escalation for insucient response to standard-dose selective serotonin reuptake inhibitors in major depressive disorder : systematic review. British Journal of Psychiatry 189, 309316. Ruhe HG, Huyser J, Swinkels JA, Schene AH (2006b). Switching antidepressants after a rst selective serotonin reuptake inhibitor in major depressive disorder : a systematic review. Journal of Clinical Psychiatry 67, 18361855. Ruhrmann S, Kasper S, Hawellek B, Martinez B, Hoich G, Nickelsen T, Moller HJ (1998). Eects of uoxetine versus bright light in the treatment of seasonal aective disorder. Psychological Medicine 28, 923933. Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Mansur C, Myczkowski ML, Moreno RA, Marcolin MA (2005). Transcranial magnetic stimulation accelerates the antidepressant eect of amitriptyline in severe depression : a double-blind placebo-controlled study. Biological Psychiatry 57, 162166. Rupprecht R (1997). The neuropsychopharmacological potential of neuroactive steroids. Journal of Psychiatric Research 31, 297314.

CINP Antidepressant Task Force 2007

Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006b). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps : a STAR*D report. American Journal of Psychiatry 163, 19051917. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M (2006c). Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. New England Journal of Medicine 354, 12311242. Rush AJ, Zimmerman M, Wisniewski SR, Fava M, Hollon SD, Warden D, Biggs MM, Shores-Wilson K, Shelton RC, Luther JF, Thomas B, Trivedi MH (2005c). Comorbid psychiatric disorders in depressed outpatients : demographic and clinical features. Journal of Aective Disorders 87, 4355. Rutz W, von Knorring L, Walinder J (1989). Frequency of suicide on Gotland after systematic postgraduate education of general practitioners. Acta Psychiatrica Scandinavica 80, 151154. Rybakowski JK, Suwalska A, Chlopocka-Wozniak M (1999). Potentiation of antidepressants with lithium or carbamazepine in treatment-resistant depression. Neuropsychobiology 40, 134139. Saarto T, Wien PJ (2005, 2007). Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews. CD005454. Saatcioglu O, Erim R, Cakmak D (2006). [A case of tianeptine abuse]. Turk Psikiyatri Dergisi 17, 7275. Sachdev PS, Sachdev J (2005). Long-term outcome of neurosurgery for the treatment of resistant depression. Journal of Neuropsychiatry and Clinical Neurosciences 17, 478485. Sachs GS, Lafer B, Stoll AL, Banov M, Thibault AB, Tohen M, Rosenbaum JF (1994). A double-blind trial of bupropion versus desipramine for bipolar depression. Journal of Clinical Psychiatry 55, 391393. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME (2007). Eectiveness of adjunctive antidepressant treatment for bipolar depression. New England Journal of Medicine 356, 17111722. Sackeim HA (2001). The denition and meaning of treatment-resistant depression. Journal of Clinical Psychiatry 62 (Suppl. 16), 1017. Sackeim HA, Decina P, Kanzler M, Kerr B, Malitz S (1987). Eects of electrode placement on the ecacy of titrated, low-dose ECT. American Journal of Psychiatry 144, 14491455. Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, Greenberg RM, Crowe RR, Cooper TB, Prudic J (2001a). Continuation pharmacotherapy in the prevention of relapse following electroconvulsive

S167

therapy : a randomized controlled trial. Journal of the American Medical Association 285, 12991307. Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ, McElhiney MC, Coleman EA, Settembrino JM (1993). Eects of stimulus intensity and electrode placement on the ecacy and cognitive eects of electroconvulsive therapy. New England Journal of Medicine 328, 839846. Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, Fitzsimons L, Moody BJ, Clark J (2000). A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at dierent stimulus intensities. Archives of General Psychiatry 57, 425434. Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, Johnson CR, Seidman S, Giller C, Haines S, Simpson RKJ, Goodman RR (2001b). Vagus nerve stimulation (VNS) for treatment-resistant depression : ecacy, side eects, and predictors of outcome. Neuropsychopharmacology 25, 713728. Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005). Brain-derived neurotrophic factor and antidepressant drugs have dierent but coordinated eects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. Journal of Neuroscience 25, 10891094. Sallee FR, Koran LM, Pallanti S, Carson SW, Sethuraman G (1998). Intravenous clomipramine challenge in obsessivecompulsive disorder : predicting response to oral therapy at eight weeks. Biological Psychiatry 44, 220227. Sallee FR, Vrindavanam NS, Deas-Nesmith D, Carson SW, Sethuraman G (1997). Pulse intravenous clomipramine for depressed adolescents : double-blind, controlled trial. American Journal of Psychiatry 154, 668673. Samuelian JC, Hackett D (1998). A randomized, double-blind, parallel-group comparison of venlafaxine and clomipramine in outpatients with major depression. Journal of Psychopharmacology 12, 273278. Sanacora G, Mason GF, Krystal JH (2000). Impairment of GABAergic transmission in depression : new insights from neuroimaging studies. Critical Reviews in Neurobiology 14, 2345. Sanchez C, Bogeso KP, Ebert B, Reines EH, Braestrup C (2004). Escitalopram versus citalopram : the surprising role of the R-enantiomer. Psychopharmacology 174, 163176. Sanchez C, Hyttel J (1999). Comparison of the eects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cellular and Molecular Neurobiology 19, 467489. Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, Hen R, Heath MJ (2001). Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxietyrelated behaviors and increases serotonergic function. Proceedings of the National Academy of Sciences USA 98, 19121917. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003). Requirement of hippocampal neurogenesis

S168

CINP Antidepressant Task Force 2007

Koenig A, Loeschke K (2003). Adherence and mental side eects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 37, 443451. Schatzberg AF (2004). Pharmacologic treatments of major depression : are two mechanisms really better than one ? Journal of Clinical Psychiatry 65 (Suppl. 4), 34. Schatzberg AF, Blier P, Delgado PL, Fava M, Haddad PM, Shelton RC (2006). Antidepressant discontinuation syndrome : consensus panel recommendations for clinical management and additional research. Journal of Clinical Psychiatry 67 (Suppl. 4), 2730. Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, Zajecka J (1997). Serotonin reuptake inhibitor discontinuation syndrome : a hypothetical denition. Discontinuation Consensus panel. J Clin. Psychiatry 58 (Suppl. 7), 510. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM (2002). Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. American Journal of Geriatric Psychiatry 10, 541550. Scheibe S, Preuschhof C, Cristi C, Bagby RM (2003). Are there gender dierences in major depression and its response to antidepressants ? Journal of Aective Disorders 75, 223235. Schilgen B, Tolle R (1980). Partial sleep deprivation as therapy for depression. Archives of General Psychiatry 37, 267271. Schillevoort I, van Puijenbroek EP, de Boer A, Roos RA, Jansen PA, Leufkens HG (2002). Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors : a case-control study using spontaneous reports. International Clinical Psychopharmacology 17, 7579. Schirren CA, Baretton G (2000). Nefazodone-induced acute liver failure. American Journal of Gastroenterology 95, 15961597. Schlaepfer TE, Lieb K (2005). Deep brain stimulation for treatment of refractory depression. Lancet 366, 14201422. Schmauss M, Kapfhammer HP, Meyr P, Ho P (1988). Combined MAO-inhibitor and tri- (tetra) cyclic antidepressant treatment in therapy resistant depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 12, 523532. Schneider LS, Nelson JC, Clary CM, Newhouse P, Krishnan KR, Shiovitz T, Weihs K (2003). An 8-week multicenter, parallel-group, double-blind, placebocontrolled study of sertraline in elderly outpatients with major depression. American Journal of Psychiatry 160, 12771285. Schneider LS, Small GW, Clary CM (2001). Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. American Journal of Geriatric Psychiatry 9, 393399. Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemero CB, Meyers BS (1997). Estrogen replacement and response to uoxetine in a multicenter geriatric

for the behavioral eects of antidepressants. Science 301, 805809. Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R (2005b). Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome : a database analysis. Lancet 365, 482487. Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R (2005a). Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome : a database analysis. Lancet 365, 482487. Sapolsky RM (2000). Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Archives of General Psychiatry 57, 925935. Sartorius A, Henn FA (2005a). [Continuation ECT]. Psychiatrische Praxis 32, 408411. Sartorius A, Henn FA (2005b). Treating depressive disorders with continuation electroconvulsive therapy. Nervenarzt 76, 13631369. Sartorius A, Wolf J, Henn FA (2005). Lithium and ECT : concurrent use still demands attention : three case reports. World Journal of Biological Psychiatry 6, 121124. Sartorius N (1974). Description and classication of depressive disorders. Contributions for the denition of the therapy-resistance and of therapy resistant depressions. Pharmakopsychiatrie, NeuroPsychopharmakologie 7, 7679. Sartorius N (1986). Cross-cultural research on depression. Psychopathology 19 (Suppl. 2), 611. Sartorius N (1993). WHOs work on the epidemiology of mental disorders. Social Psychiatry and Psychiatric Epidemiology 28, 147155. Sartorius N (1995). Recent changes in suicide rates in selected eastern European and other European countries. International Psychogeriatrics 7, 301308. Sartorius N (2001). The economic and social burden of depression. Journal of Clinical Psychiatry 62 (Suppl. 15), 811. Sartorius N, Ustun TB, Costa e Silva JA, Goldberg D, Lecrubier Y, Ormel J, Von Kor M, Wittchen HU (1993). An international study of psychological problems in primary care. Preliminary report from the World Health Organization Collaborative Project on Psychological Problems in General Health Care. Archives of General Psychiatry 50, 819824. Saxena S, Paraje G, Sharan P, Karam G, Sadana R (2006). The 10/90 divide in mental health research : trends over a 10-year period. British Journal of Psychiatry 188, 8182. Schachter SC (2006). Therapeutic eects of vagus nerve stimulation in epilepsy and implications for sudden unexpected death in epilepsy. Clinical Autonomic Research 16, 2932. Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Schmidt F, Grunze H, Lieb K (2002). Interferon alpha (IFNalpha) and psychiatric syndromes : a review. Progress in Neuro-Psychopharmacology and Biological Psychiatry 26, 731746. Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N, Heldwein W, Soyka M, Grunze H,

CINP Antidepressant Task Force 2007

depression trial. Fluoxetine Collaborative Study Group. American Journal of Geriatric Psychiatry 5, 97106. Schoenmakers EAJM, Robbe HW, OHanlon JF (1989). Acute and Subchronic Eects of the Antidepressants Levoprotiline and Doxepin on the Performance of Healthy Volunteers in Psychometric and Actual Driving Tests. Maastricht, The Netherlands : University of Maastricht, Institute for Human Psychopharmacology. Schou M (1995). Prophylactic lithium treatment of unipolar and bipolar manic-depressive illness. Psychopathology 28 (Suppl. 1), 8185. Schrader E (2000). Equivalence of St Johns wort extract (Ze 117) and uoxetine : a randomized, controlled study in mild-moderate depression. International Clinical Psychopharmacology 15, 6168. Schule C, Zwanzger P, Baghai T, Mikhaiel P, Thoma H, Moller HJ, Rupprecht R, Padberg F (2003). Eects of antidepressant pharmacotherapy after repetitive transcranial magnetic stimulation in major depression : an open follow-up study. Journal of Psychiatric Research 37, 145153. Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop WJ (2000). Association between depression and mortality in older adults : the Cardiovascular Health Study. Archives of Internal Medicine 160, 17611768. Schulze TG, Muller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt H, Grassle M, Papassotiropoulos A, Heun R, Nothen MM, Maier W, Lesch KP, Rietschel M (2000). Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. American Journal of Medical Genetics 96, 801803. Schulze-Rauschenbach SC, Harms U, Schlaepfer TE, Maier W, Falkai P, Wagner M (2005). Distinctive neurocognitive eects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in major depression. British Journal of Psychiatry 186, Schuurman AG, Van den AM, Ensinck KT, Metsemakers JF, Knottnerus JA, Leentjens AF, Buntinx F (2002). Increased risk of Parkinsons disease after depression : a retrospective cohort study. Neurology 58, 15011504. Schwarz MJ, Ackenheil M (2002). The role of substance P in depression : therapeutic indications. Dialogues in Clinical Neuroscience 4, 2129. Scott AI, Freeman CP (1992). Edinburgh primary care depression study : treatment outcome, patient satisfaction, and cost after 16 weeks. British Medical Journal 304, 883887. Scott AI, Perini AF, Shering PA, Whalley LJ (1991). In-patient major depression : is rolipram as eective as amitriptyline ? European Journal of Clinical Pharmacology 40, 127129. Scott J, Palmer S, Paykel E, Teasdale J, Hayhurst H (2003). Use of cognitive therapy for relapse prevention in chronic depression. Cost-eectiveness study. British Journal of Psychiatry 182, 221227. Segal ZV, Kennedy SH, Cohen NL (2001a). Clinical guidelines for the treatment of depressive disorders. V.

S169

Combining psychotherapy and pharmacotherapy. Canadian Journal of Psychiatry 46 (Suppl. 1), 59S62S. Segal ZV, Whitney DK, Lam RW (2001b). Clinical guidelines for the treatment of depressive disorders. III. Psychotherapy. Canadian Journal of Psychiatry 46 (Suppl. 1), 29S37S. Segrave R, Nathan PJ (2005). Pindolol augmentation of selective serotonin reuptake inhibitors : accounting for the variability of results of placebo-controlled double-blind studies in patients with major depression. Human Psychopharmacology 20, 163174. Seguin CA (1986). Psiquiatria Tradicional y Psiquiatria Folklorica. In : Vidal G, Alarcon RD (Eds.), Psiquiatria (pp. 630640). Buenos Aires : Editorial Medica Panamericana. Serebruany VL (2006). Selective serotonin reuptake inhibitors and increased bleeding risk : are we missing something ? American Journal of Medicine 119, 113116. Serretti A, Artioli P, Quartesan R (2005). Pharmacogenetics in the treatment of depression : pharmacodynamic studies. Pharmacogenetics and Genomics 15, 6167. Serretti A, Cusin C, Lattuada E, di Bella D, Catalano M, Smeraldi E (1999). Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Molecular Psychiatry 4, 280283. Sharan P, Saxena S (1998). Treatment-resistant depression : clinical signicance, concept and management. National Medical Journal of India 11, 6979. Shea MT, Widiger TA, Klein MH (1992). Comorbidity of personality disorders and depression : implications for treatment. Journal of Consulting and Clinical Psychology 60, 857868. Sheehan JD, Shelley RK (1990). Leucopenia secondary to carbamazepine despite concurrent lithium treatment. British Journal of Psychiatry 157, 911912. Sheline YI, Gado MH, Kraemer HC (2003). Untreated depression and hippocampal volume loss. American Journal of Psychiatry 160, 15161518. Shelton RC (2001). Steps Following Attainment of Remission : Discontinuation of Antidepressant Therapy. Prim. Care Companion. J Clin. Psychiatry 3, 168174. Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U (2001a). Eectiveness of St Johns wort in major depression : a randomized controlled trial. Journal of the American Medical Association 285, 19781986. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY (2001b). A novel augmentation strategy for treating resistant major depression. American Journal of Psychiatry 158, 131134. Shelton RC, Williamson DJ, Corya SA, Sanger TM, Van Campen LE, Case M, Briggs SD, Tollefson GD (2005). Olanzapine/Fluoxetine Combination for TreatmentResistant Depression : A Controlled Study of SSRI and

S170

CINP Antidepressant Task Force 2007

Simon GE, Savarino J, Operskalski B, Wang PS (2006). Suicide risk during antidepressant treatment. American Journal of Psychiatry 163, 4147. Simon GE, Von Kor M (1998). Suicide mortality among patients treated for depression in an insured population. American Journal of Epidemiology 147, 155160. Simon GE, Von Kor M, Heiligenstein JH, Revicki DA, Grothaus L, Katon W, Wagner EH (1996). Initial antidepressant choice in primary care. Eectiveness and cost of uoxetine vs tricyclic antidepressants. Journal of the American Medical Association 275, 18971902. Simon GE, Von Kor M, Ludman EJ, Katon WJ, Rutter C, Unutzer J, Lin EH, Bush T, Walker E (2002). Costeectiveness of a program to prevent depression relapse in primary care. Medical Care 40, 941950. Simon GE, Von Kor M, Piccinelli M, Fullerton C, Ormel J (1999b). An international study of the relation between somatic symptoms and depression. New England Journal of Medicine 341, 13291335. Simon GE, Von Kor M, Rutter C, Wagner E (2000b). Randomised trial of monitoring, feedback, and management of care by telephone to improve treatment of depression in primary care. British Medical Journal 320, 550554. Simon JS, Nemero CB (2005). Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. Journal of Clinical Psychiatry 66, 12161220. Simpson HB, Liebowitz MR, Foa EB, Kozak MJ, Schmidt AB, Rowan V, Petkova E, Kjernisted K, Huppert JD, Franklin ME, Davies SO, Campeas R (2004). Posttreatment eects of exposure therapy and clomipramine in obsessive-compulsive disorder. Depression and Anxiety 19, 225233. Simpson S, Corney R, Fitzgerald P, Beecham J (2003). A randomized controlled trial to evaluate the eectiveness and cost-eectiveness of psychodynamic counselling for general practice patients with chronic depression. Psychological Medicine 33, 229239. Sinclair JM, Harriss L, Baldwin DS, King EA (2005). Suicide in depressive disorders : a retrospective case-control study of 127 suicides. Journal of Aective Disorders 87, 107113. Sindrup SH, Otto M, Finnerup NB, Jensen TS (2005). Antidepressants in the treatment of neuropathic pain. Basic and Clinical Pharmacology and Toxicology 96, 399409. Singh NA, Clements KM, Singh MA (2001). The ecacy of exercise as a long-term antidepressant in elderly subjects : a randomized, controlled trial. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 56, M497M504. Sir A, DSouza RF, Uguz S, George T, Vahip S, Hopwood M, Martin AJ, Lam W, Burt T (2005). Randomized trial of sertraline versus venlafaxine XR in major depression : ecacy and discontinuation symptoms. Journal of Clinical Psychiatry 66, 13121320. Slattery DA, Hudson AL, Nutt DJ (2004). Invited review : the evolution of antidepressant mechanisms. Fundamental and Clinical Pharmacology 18, 121.

Nortriptyline Resistance. Journal of Clinical Psychiatry 66, 12891297. Shen ZM, Zhu ML, Zhao AQ (2004). [Comparative observation on ecacy of jieyu pill and maprotiline in treating depression]. Zhongguo Zhong Xi Yi Jie He Za Zhi 24, 415417. Shepherd G, Velez LI, Keyes DC (2004). Intentional bupropion overdoses. Journal of Emergency Medicine 27, 147151. Shepherd M, Sartorius N (1989). Non-Specic Aspects of Treatment. Toronto : Hans Huber. Shim YS, Yang DW (2006). Depression as prognostic factor : 6 months follow-up in a geriatric institution. Archives of Gerontology and Geriatrics 43, 277283. Shimbo D, Davidson KW, Haas DC, Fuster V, Badimon JJ (2005). Negative impact of depression on outcomes in patients with coronary artery disease : mechanisms, treatment considerations, and future directions. Journal of Thrombosis and Haemostasis 3, 897908. Shiwach RS, Reid WH, Carmody TJ (2001). An analysis of reported deaths following electroconvulsive therapy in Texas, 19931998. Psychiatric Services 52, 10951097. Silva RC, Brandao ML (2000). Acute and chronic eects of gepirone and uoxetine in rats tested in the elevated plus-maze : an ethological analysis. Pharmacology, Biochemistry and Behavior 65, 209216. Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson RA (2005). Randomised double-blind placebo-controlled trial of sh oil in the treatment of depression. Prostaglandins, Leukotrienes, and Essential Fatty Acids 72, 211218. Silverstone T (2001). Moclobemide vs. imipramine in bipolar depression : a multicentre double-blind clinical trial. Acta Psychiatrica Scandinavica 104, 104109. Sim K, Lee NB, Chua HC, Mahendran R, Fujii S, Yang SY, Chong MY, Si T, He YL, Lee MS, Sung KM, Chung EK, Chan YH, Shinfuku N, Tan CH, Sartorius N, Baldessarini RJ (2006). Newer antidepressant drug use in East Asian psychiatric treatment settings : REAP (Research on East Asia Psychotropic Prescriptions) Study. British Journal of Clinical Pharmacology. Published Online : 36 October 2006. DOI : 10.1111/j.1365-2125.2006.02780.x. Simeon JG, Dinicola VF, Ferguson HB, Copping W (1990). Adolescent depression : a placebo-controlled uoxetine treatment study and follow-up. Progress in Neuro-Psychopharmacology and Biological Psychiatry 14, 791795. Simon GE, Heiligenstein J, Revicki D, Von Kor M, Katon WJ, Ludman E, Grothaus L, Wagner E (1999a). Long-term outcomes of initial antidepressant drug choice in a real world randomized trial. Archives of Family Medicine 8, 319325. Simon GE, Revicki D, Heiligenstein J, Grothaus L, Von Kor M, Katon WJ, Hylan TR (2000a). Recovery from depression, work productivity, and health care costs among primary care patients. General Hospital Psychiatry 22, 153162.

CINP Antidepressant Task Force 2007

Smeraldi E, Benedetti F, Barbini B, Campori E, Colombo C (1999). Sustained antidepressant eect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial. Neuropsychopharmacology 20, 380385. Smith CA, Hay PP (2005). Acupuncture for depression. Cochrane Database of Systematic Reviews CD004046. Smith D, Dempster C, Glanville J, Freemantle N, Anderson I (2002). Ecacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants : a meta-analysis. British Journal of Psychiatry 180, 396404. Smith KA, Fairburn CG, Cowen PJ (1997). Relapse of depression after rapid depletion of tryptophan. Lancet 349, 915919. Smith RS (1991). The macrophage theory of depression. Medical Hypotheses 35, 298306. Sogaard J, Lane R, Latimer P, Behnke K, Christiansen PE, Nielsen B, Ravindran AV, Reesal RT, Goodwin DP (1999). A 12-week study comparing moclobemide and sertraline in the treatment of outpatients with atypical depression. Journal of Psychopharmacology 13, 406414. Sokolski KN, Conney JC, Brown BJ, DeMet EM (2004). Once-daily high-dose pindolol for SSRI-refractory depression. Psychiatry Research 125, 8186. Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, Coryell W, Warshaw M, Turvey C, Maser JD, Endicott J (2000). Multiple recurrences of major depressive disorder. American Journal of Psychiatry 157, 229233. Sondergaard MP, Jarden JO, Martiny K, Andersen G, Bech P (2006). Dose response to adjunctive light therapy in citalopram-treated patients with post-stroke depression. A randomised, double-blind pilot study. Psychotherapy and Psychosomatics 75, 244248. Sondergard L, Kvist K, Andersen PK, Kessing LV (2006). Do antidepressants precipitate youth suicide ? A nationwide pharmacoepidemiological study. European Child and Adolescent Psychiatry Sontrop J, Campbell MK (2006). omega-3 polyunsaturated fatty acids and depression : a review of the evidence and a methodological critique. Preventive Medicine 42, 413. Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF, Elkin I, Watkins JT, Imber SD, Leber WR, Moyer J (1991). Patient predictors of response to psychotherapy and pharmacotherapy : ndings in the NIMH Treatment of Depression Collaborative Research Program. American Journal of Psychiatry 148, 9971008. Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, Racagni G, Zohar J, Mendlewicz J (1999). Treatment resistant depression : methodological overview and operational criteria. European Neuropsychopharmacology 9, 8391. Souza FG, Goodwin GM (1991). Lithium treatment and prophylaxis in unipolar depression : a meta-analysis. British Journal of Psychiatry 158, 66675., 666675. Sovner R, Fogelman S (2002). Ketoconazole therapy for atypical depression. Journal of Clinical Psychiatry 57, 227228.

S171

Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, Langtt JT, Walczak TS, Pacia SV, Ebrahimi N, Frobish D (2003). Initial outcomes in the Multicenter Study of Epilepsy Surgery. Neurology 61, 16801685. Spoont MR (1992). Modulatory role of serotonin in neural information processing : implications for human psychopathology. Psychol. Bull. 112, 330350. Stahl SM (1997). Psychopharmacology of Antidepressants. London : Martin Dunitz. Stahl SM (1998a). Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic eects and side eects. Journal of Aective Disorders 51, 215235. Stahl SM (1998b). Selecting an antidepressant by using mechanism of action to enhance ecacy and avoid side eects. Journal of Clinical Psychiatry 59, 2329. Stahl SM (2001). Eects of estrogen on the central nervous system. Journal of Clinical Psychiatry 62, 317318. Stahl SM (2006). Essential Psychopharmacology : The Prescribers Guide. Cambridge : Cambridge University Press. Stahl SM, Grady MM, Moret C, Briley M (2005). SNRIs : their pharmacology, clinical ecacy, and tolerability in comparison with other classes of antidepressants. CNS Spectrums 10, 732747. Starkstein SE, Petracca G, Teson A, Chemerinski E, Merello M, Migliorelli R, Leiguarda R (1996). Catatonia in depression : prevalence, clinical correlates, and validation of a scale. Journal of Neurology, Neurosurgery and Psychiatry 60, 326332. Stassen HH, Angst J (1998). Delayed onset of action of antidepressants : fact or ction ? CNS Drugs 9, 177184. Stassen HH, Angst J, Delini-Stula A (1996). Delayed onset of action of antidepressant drugs ? Survey of results of Zurich meta-analyses. Pharmacopsychiatry 29(3), 8796. Stassen HH, Angst J, Delini-Stula A (1997). Onset of action under antidepressant treatment. European Psychiatry 12(4), 163165. Stassen HH, Angst J, Delini-Stula A (1999). Fluoxetine versus moclobemide : cross-comparison between the time courses of improvement. Pharmacopsychiatry 32, 5660. Steens DC, Plassman BL, Helms MJ, Welsh-Bohmer KA, Saunders AM, Breitner JC (1997). A twin study of late-onset depression and apolipoprotein E epsilon 4 as risk factors for Alzheimers disease. Biological Psychiatry 41, 851856. Steens DC, Skoog I, Norton MC, Hart AD, Tschanz JT, Plassman BL, Wyse BW, Welsh-Bohmer KA, Breitner JC (2000). Prevalence of depression and its treatment in an elderly population : the Cache County study. Archives of General Psychiatry 57, 601607. Steimer W, Muller B, Leucht S, Kissling W (2001). Pharmacogenetics : a new diagnostic tool in the management of antidepressive drug therapy. Clinica Chimica Acta 308, 3341. Stein DJ, Kupfer D, Schatzberg A (2006). Textbook of Mood Disorders. Washington : American Psychiatric Press.

S172

CINP Antidepressant Task Force 2007

Szegedi A, Muller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O (2003). Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. Journal of Clinical Psychiatry 64, 413420. Szegedi A, Schwertfeger N (2005). Mirtazapine : a review of its clinical ecacy and tolerability. Expert Opinion on Pharmacotherapy 6, 631641. Szuba MP, Baxter LR, Altshuler LL, Allen EM, Guze BH, Schwartz JM, Liston EH (1994). Lithium sustains the acute antidepressant eects of sleep deprivation : preliminary ndings from a controlled study. Psychiatry Research 51, 283295. TADS study group (2003). The Treatment for Adolescents With Depression Study (TADS) : rationale, design, and methods. Journal of the American Academy of Child and Adolescent Psychiatry 42, 531542. TADS study group (2005). The Treatment for Adolescents With Depression Study (TADS) : demographic and clinical characteristics. Journal of the American Academy of Child and Adolescent Psychiatry 44, 2840. Taleb M, Rouillon F, Hegerl U, Hamdani N, Gorwood P (2006). Programmes against depression. Encephale 32, 915. Tamminga CA, Nemero CB, Blakely RD, Brady L, Carter CS, Davis KL, Dingledine R, Gorman JM, Grigoriadis DE, Henderson DC, Innis RB, Killen J, Laughren TP, McDonald WM, Murphy GMJ, Paul SM, Rudorfer MV, Sausville E, Schatzberg AF, Scolnick EM, Suppes T (2002). Developing novel treatments for mood disorders : accelerating discovery. Biological Psychiatry 52, 589609. Tardi K, Marzuk PM, Leon AC (2002). Role of antidepressants in murder and suicide. American Journal of Psychiatry 159, 12481249. Tatsumi M, Groshan K, Blakely RD, Richelson E (1997). Pharmacological prole of antidepressants and related compounds at human monoamine transporters. Eur. J. Pharmacol. 340, 249258. Taylor CB, Youngblood ME, Catellier D, Veith RC, Carney RM, Burg MM, Kaufmann PG, Shuster J, Mellman T, Blumenthal JA, Krishnan R, Jae AS (2005). Eects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Archives of General Psychiatry 62, 792798. Taylor DP, Carter RB, Eison AS, Mullins UL, Smith HL, Torrente JR, Wright RN, Yocca FD (1995). Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug. Journal of Clinical Psychiatry 56 (Suppl. 6), 311. Taylor MA, Fink M (2003). Catatonia in psychiatric classication : a home of its own. American Journal of Psychiatry 160, 12331241. Tayor MA, Fink M (2006). Melancholia : The Diagnosis, Pathophysiology and Treatment of Depressive Illness. Cambridge : Cambridge University Press. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z (2006). Early onset of selective serotonin reuptake inhibitor antidepressant action : systematic review and meta-analysis. Archives of General Psychiatry 63, 12171223.

Stein DJ, Zungu-Dirwayi N, Der Linden GJ, Seedat S (2000). Pharmacotherapy for posttraumatic stress disorder. Cochrane Database of Systematic Reviews. CD002795. Steinacher L, Vandel P, Zullino DF, Eap CB, BrawandAmey M, Baumann P (2002). Carbamazepine augmentation in depressive patients non-responding to citalopram : a pharmacokinetic and clinical pilot study. European Neuropsychopharmacology 12, 255260. Sterne JA, Gavaghan D, Egger M (2000). Publication and related bias in meta-analysis : power of statistical tests and prevalence in the literature. Journal of Clinical Epidemiology 53, 11191129. Stotz G, Woggon B, Angst J (1999). Psychostimulants in the therapy of treatment-resistant depression. Review of the literature and ndings from a retrospective study in 65 depressed patients. Dialogues in Clinical Neuroscience 1, 165174. Stout SC, Owens MJ, Nemero CB (2001). Neurokinin(1) receptor antagonists as potential antidepressants. Annual Review of Pharmacology and Toxicology 41, 877906. Sturm R, Wells KB (1995). How can care for depression become more cost-eective ? Journal of the American Medical Association 273, 5158. Sugahara H, Tokunaga S, Kondo T, Akamine M, Yoshimasu K, Fujisawa K, Fukudome K, Kanemitsu Y, Kubo C (2005). Comparative adherence to antidepressant drugs in a non-psychiatric outpatient clinic setting in Japan. Primary Care and Community Psychiatry 10, 5762. Sulser F, Vetulani J, Mobley PL (1978). Mode of action of antidepressant drugs. Biochemical Pharmacology 27, 257261. Suri A, Reddy S, Gonzales C, Knadler MP, Branch RA, Skinner MH (2005). Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects. International Journal of Clinical Pharmacology and Therapeutics 43, 7884. Suri RA, Altshuler LL, Burt VK, Hendrick VC (1998). Managing psychiatric medications in the breast-feeding woman. Medscape Womens Health 3, 1. Sussman N, Ginsberg DL, Biko J (2001). Eects of nefazodone on body weight : a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials. Journal of Clinical Psychiatry 62, 256260. Svenningsson P, Chergui K, Rachle I, Flajolet M, Zhang X, El YM, Vaugeois JM, Nomikos GG, Greengard P (2006). Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311, 7780. Svestka J, Rysanek R, Ceskova E (1990). Sodium valproate in the treatment of endogenous depression. Activitas Nervosa Superior 32, 231232. Szanto K, Mulsant BH, Houck P, Dew MA, Reynolds CF, III (2003). Occurrence and course of suicidality during shortterm treatment of late-life depression. Archives of General Psychiatry 60, 610617. Szegedi A, Kohnen R, Dienel A, Kieser M (2005). Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St Johns wort) : randomised controlled double blind non-inferiority trial versus paroxetine. British Medical Journal 330, 503.

CINP Antidepressant Task Force 2007

Teicher MH, Glod C, Cole JO (1990). Emergence of intense suicidal preoccupation during uoxetine treatment. American Journal of Psychiatry 147, 207210. Terman M, Terman JS (1999). Bright light therapy : side eects and benets across the symptom spectrum. Journal of Clinical Psychiatry 60, 799808. Terman M, Terman JS (2005). Light therapy for seasonal and nonseasonal depression : ecacy, protocol, safety, and side eects. CNS Spectrums 10, 647663. Terman M, Terman JS, Raerty B (1990). Experimental design and measures of success in the treatment of winter depression by bright light. Psychopharmacology Bulletin 26, 505510. Terra JL, Montgomery SA (1998) Fluvoxamine prevents recurrence of depression : results of a long-term, doubleblind, placebo-controlled study. International Clinical Psychopharmacology 13, 5562. Thakore JH, Dinan TG (1995). Cortisol synthesis inhibition : a new treatment strategy for the clinical and endocrine manifestations of depression. Biological Psychiatry 37, 364368. Tharyan P (2000). Electroconvulsive therapy for schizophrenia. Cochrane Database of Systematic Reviews. CD000076. Tharyan P, Adams CE (2005). Electroconvulsive therapy for schizophrenia. Cochrane Database of Systematic Reviews. CD000076. Thase ME (1999a). Antidepressant treatment of the depressed patient with insomnia. Journal of Clinical Psychiatry 60 (Suppl. 17), 2831. Thase ME (1999b). Redening antidepressant ecacy toward long-term recovery. Journal of Clinical Psychiatry 60 (Suppl. 6), 1519. Thase ME (2003). Evaluating antidepressant therapies : remission as the optimal outcome. Journal of Clinical Psychiatry 64 (Suppl. 13), 1825. Thase ME (2004). Comparing the ecacy of the newer antidepressants. In : Gilaberte I (Ed.), Nuevas Perspectivas En La Depresion (pp. 253284). Madrid : Aula Medica Endiciones. Thase ME (2005). Bipolar depression : issues in diagnosis and treatment. Harvard Review of Psychiatry 13, 257271. Thase ME (2006). Managing depressive and anxiety disorders with escitalopram. Expert Opinion on Pharmacotherapy 7, 429440. Thase ME, Baker RA, Simmons JH, Van Willigenburg AP, Schutte AJ (2006a). Eects of mirtazapine versus SSRIs on core symptoms of depression. Journal of Aective Disorders 91, S83. Thase ME, Entsuah AR, Rudolph RL (2001). Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. British Journal of Psychiatry 178, 234241. Thase ME, Greenhouse JB, Frank E, Reynolds CF, III, Pilkonis PA, Hurley K, Grochocinski V, Kupfer DJ (1997). Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Archives of General Psychiatry 54, 10091015.

S173

Thase ME, Mallinger AG, McKnight D, Himmelhoch JM (1992). Treatment of imipramine-resistant recurrent depression, IV : A double-blind crossover study of tranylcypromine for anergic bipolar depression. American Journal of Psychiatry 149, 195198. Thase ME, Ninan PT (2002). New goals in the treatment of depression : moving toward recovery. Psychopharmacology Bulletin 36 (Suppl. 2), 2435. Thase ME, Rush AJ (1997). When at rst you dont succeed : sequential strategies for antidepressant nonresponders. Journal of Clinical Psychiatry 58 (Suppl. 13), 2329. Thase ME, Shelton RC, Khan A (2006b). Treatment with venlafaxine extended release after SSRI nonresponse or intolerance : a randomized comparison of standard- and higher-dosing strategies. Journal of Clinical Psychopharmacology 26, 250258. Thase ME, Trivedi MH, Rush AJ (1995). MAOIs in the contemporary treatment of depression. Neuropsychopharmacology 12, 185219. The European Agency for the Evaluation of Medicinal Products (2002). Evaluation of Medicines for Human Use (http:/ /www.emea.europa.eu/pdfs/human/ewp/ 051897en.pdf). Accessed 2 November 2007. Thiels C, Linden M, Grieger F, Leonard J (2005). Gender dierences in routine treatment of depressed outpatients with the selective serotonin reuptake inhibitor sertraline. International Clinical Psychopharmacology 20, 17. Thomas CM, Morris S (2003). Cost of depression among adults in England in 2000. British Journal of Psychiatry 183, 514519. Thomas CS, Read DA (1990). Mianserin, agranulocytosis and suicide. Lancet 336, 1511. Thompson C, Kinmonth AL, Stevens L, Peveler RC, Stevens A, Ostler KJ, Pickering RM, Baker NG, Henson A, Preece J, Cooper D, Campbell MJ (2000). Eects of a clinical-practice guideline and practice-based education on detection and outcome of depression in primary care : Hampshire Depression Project randomised controlled trial. Lancet 355, 185191. Thompson SG (1994). Why sources of heterogeneity in meta-analysis should be investigated. British Medical Journal 309, 13511355. Tollefson GD, Bosomworth JC, Heiligenstein JH, Potvin JH, Holman S (1995). A double-blind, placebo-controlled clinical trial of uoxetine in geriatric patients with major depression. The Fluoxetine Collaborative Study Group. International Psychogeriatrics 7, 89104. Tossani E, Cassano P, Fava M (2005). Depression and renal disease. Seminars in Dialysis 18, 7381. Tran PV, Bymaster FP, McNamara RK, Potter WZ (2003). Dual monoamine modulation for improved treatment of major depressive disorder. Journal of Clinical Psychopharmacology 23, 7886. Trautmann-Sponsel RD, Dienel A (2004). Safety of Hypericum extract in mildly to moderately depressed outpatients : a review based on data from three randomized, placebo-controlled trials. Journal of Aective Disorders 82, 303307.

S174

CINP Antidepressant Task Force 2007

into the brain of mice. Journal of Psychiatric Research 37, 179185. Uhr M, Steckler T, Yassouridis A, Holsboer F (2000). Penetration of amitriptyline, but not of uoxetine, into brain is enhanced in mice with blood-brain barrier deciency due to Mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 22, 380387. Ural AU, Avcu F, Gokcil Z, Nevruz O, Cetin T (2005). Leucopenia and thrombocytopenia possibly associated with lamotrigine use in a patient. Epileptic Disorders 7, 3335. US Food and Drug Administration (2006). Applications for FDA Approval to Market a new Drug (http:/ / www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm ?fr=314.126). Accessed 2 November 2007. US Food and Drug Administration (2007). FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications (http://www.fda.gov/bbs/topics/NEWS/2007/ NEW01624.html). Accessed 9 June 2007. US Food and Drug Administration (2005). Templates for Antidepressant Black Box Warning and Medication Guide Posted on FDA Website, February 3, 2005. US Preventive Services Task Force AfHRaQ (2002). Screening for depression : recommendations and rationale. Annals of Internal Medicine 136, 760764. Ustun TB, Sartorius N (1995). Mental Illness in General Health Care : An International Study. Chichester, United Kingdom : John Wiley. Vaidya VA, Siuciak JA, Du F, Duman RS (1999). Hippocampal mossy ber sprouting induced by chronic electroconvulsive seizures. Neuroscience 89, 157166. Valenstein M, Taylor KK, Austin K, Kales HC, McCarthy JF, Blow FC (2004). Benzodiazepine use among depressed patients treated in mental health settings. American Journal of Psychiatry 161, 654661. Valuck RJ, Libby AM, Sills MR, Giese AA, Allen RR (2004). Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder : a propensity-adjusted retrospective cohort study. CNS Drugs 18, 11191132. van Amerongen AP, Ferrey G, Tournoux A (2002). A randomised, double-blind comparison of milnacipran and imipramine in the treatment of depression. Journal of Aective Disorders 72, 2131. van Baardewijk M, Vis PM, Einarson TR (2005). Cost eectiveness of duloxetine compared with venlafaxine-XR in the treatment of major depressive disorder. Current Medical Research and Opinion 21, 12711279. van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B (1997). A meta-analysis of the treatment of panic disorder with or without agoraphobia : a comparison of psychopharmacological, cognitivebehavioral, and combination treatments. Journal of Nervous and Mental Disease 185, 510516. van Calker D, Berger M (2000). Aektive Erkrankungen. Richtlinienentwurf Der DGPPN. Darmstadt : Steinkop.

Trenque T, Piednoir D, Frances C, Millart H, Germain ML (2002). Reports of withdrawal syndrome with the use of SSRIs : a case/non-case study in the French Pharmacovigilance database. Pharmacoepidemiology and Drug Safety 11, 281283. Trescoli-Serrano C, Smith NK (1996). Sertraline-induced agranulocytosis. Postgraduate Medical Journal 72, 446. Trindade E, Menon D, Topfer LA, Coloma C (1998). Adverse eects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants : a meta-analysis. CMAJ. 159, 12451252. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ (2006a). Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine 354, 12431252. Trivedi MH, Greer TL, Grannemann BD, Chambliss HO, Jordan AN (2006b). Exercise as an augmentation strategy for treatment of major depression. Journal of Psychiatric Practice 12, 205213. Trivedi MH, Greer TL, Grannemann BD, Church TS, Galper DI, Sunderajan P, Wisniewski SR, Chambliss HO, Jordan AN, Finley C, Carmody TI (2006c). TREAD : TReatment with Exercise Augmentation for Depression : study rationale and design. Clinical Trials 3, 291305. Trivedi MH, Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, Key T, Biggs MM, Shores-Wilson K, Witte B, Suppes T, Miller AL, Altshuler KZ, Shon SP (2004). Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Archives of General Psychiatry 61, 669680. Tuma S, Strubbe JJ, Mocaer E, Koolhaas JM (2002). S20098 aects the free-running rhythms of body temperature and activity and decreases light-induced phase delay of circadian rhythms of the rat. Chronobiology International 18, 781799. Tuunainen A, Kripke DF, Endo T (2004). Light therapy for non-seasonal depression. Cochrane Database of Systematic Reviews. CD004050. Tylee A (2006). Identifying and managing depression in primary care in the United kingdom. Journal of Clinical Psychiatry 67 (Suppl. 6), 4145. Tzimas GN, Dion B, Deschenes M (2003). Early onset, nefazodone-induced fulminant hepatic failure. American Journal of Gastroenterology 98, 16631664. Uchida H, Takeuchi H, Suzuki T, Nomura K, Watanabe K, Kashima H (2005). Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder. Journal of Clinical Psychopharmacology 25, 545551. Uebelhack R, Gruenwald J, Graubaum HJ, Busch R (2004). Ecacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression : a double-blind, randomized, placebo-controlled clinical trial. Advances in Therapy 21, 265275. Uhr M, Grauer MT (2003). abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine

CINP Antidepressant Task Force 2007

van den Broek WW (2005). [The practice guideline Depressive disorder (rst revision) from the Dutch College of General Practitioners ; a response from the perspective of psychiatry]. Nederlands Tijdschrift Voor Geneeskunde 149, 509510. van Heeringen K, Zivkov M (1996). Pharmacological treatment of depression in cancer patients. A placebocontrolled study of mianserin. British Journal of Psychiatry 169, 440443. van Laar MW, Volkerts ER, Van Willigenburg AP (1992). Therapeutic eects and eects on actual driving performance of chronically administered buspirone and diazepam in anxious outpatients. Journal of Clinical Psychopharmacology 12, 8695. van Laar MW, van Willigenburg AP, Volkerts ER (1995). Acute and subchronic eects of nefazodone and imipramine on highway driving, cognitive functions, and daytime sleepiness in healthy adult and elderly subjects. Journal of Clinical Psychopharmacology 15, 3040. van Laar MW, Volkerts ER (1998). Driving and benzodiazepine use Evidence that they do not mix. CNS Drugs 10, 383396. van Moaert M, de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmotte J, Mendlewicz J (1995). Mirtazapine is more eective than trazodone : a double-blind controlled study in hospitalized patients with major depression. International Clinical Psychopharmacology 10, 39. van Os TW, Ormel J, Van den Brink RH, Jenner JA, Van der Meer K, Tiemens BG, van der Doorn W, Smit A, van den Brink W (1999). Training primary care physicians improves the management of depression. General Hospital Psychiatry 21, 168176. van Os TW, Van den Brink RH, Van der Meer K, Ormel J (2006). The care provided by general practitioners for persistent depression. European Psychiatry 21, 8792. van Reeth O, Olivares E, Zhang Y, Tripathi B, Turek FW (1999). Chronobiotic eects of gepirone, a potential antidepressant with 5HT1A receptor partial agonist properties. Behavioural Pharmacology 10, 119130. van Waarde JA, Stek ML (2001). [Electroconvulsive therapy eective and safe in 55 patients aged 56 years and older with mood disorders and physical comorbidity]. Nederlands Tijdschrift Voor Geneeskunde 145, 16931697. Vandel P, Regina W, Bonin B, Sechter D, Bizouard P (1999). [Abuse of tianeptine. A case report]. Encephale 25, 672673. Varney NR, Garvey MJ, Cook BL, Campbell DA, Roberts RJ (1993). Identication of treatment-resistant depressives who respond favorably to carbamazepine. Annals of Clinical Psychiatry 5, 117122. Veldhuijzen DS, van Wijck AJ, Verster JC, Kalkman CJ, Kenemans JL, Olivier B, Volkerts ER (2006). The impact of chronic pain patients psychotropic drug knowledge and warning labels on the decision whether to drive a car or not. Trac Injury Prevention 7, 360364. Versiani M, Mehilane L, Gaszner P, Arnaud-Castiglioni R (1999). Reboxetine, a unique selective NRI, prevents

S175

relapse and recurrence in long-term treatment of major depressive disorder. Journal of Clinical Psychiatry 60, 400406. Vesta KS, Medina PJ (2003). Valproic acid-induced neutropenia. Annals of Pharmacotherapy 37, 819821. Vis PM, van Baardewijk M, Einarson TR (2005). Duloxetine and venlafaxine-XR in the treatment of major depressive disorder : a meta-analysis of randomized clinical trials. Annals of Pharmacotherapy 39, 17981807. Visser PJ, Verhey FR, Ponds RW, Kester A, Jolles J (2000). Distinction between preclinical Alzheimers disease and depression. Journal of the American Geriatrics Society 48, 479484. Voderholzer U, Valerius G, Schaerer L, Riemann D, Giedke H, Schwarzler F, Berger M, Wiegand M (2003). Is the antidepressive eect of sleep deprivation stabilized by a three day phase advance of the sleep period ? A pilot study. European Archives of Psychiatry and Clinical Neuroscience 253, 6872. Voellinger R, Berney A, Baumann P, Annoni JM, Bryois C, Buclin T, Bula C, Camus V, Christin L, Cornuz J, de Goumoens P, Lamy O, Strnad J, Burnand B, Stiefel F (2003). Major depressive disorder in the general hospital : adaptation of clinical practice guidelines. General Hospital Psychiatry 25, 185193. Vohra J, Burrows G, Hunt D, Sloman G (1975). The eect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. European Journal of Cardiology 3, 219227. Vohra J, Burrows GD (1974). Cardiovascular complications of tricyclic antidepressant overdosage. Drugs 8, 432437. Volz HP, Laux P (2000). Potential treatment for subthreshold and mild depression : a comparison of St. Johns wort extracts and uoxetine. Comprehensive Psychiatry 41, 133137. Volz HP, Stoll KD (2004). Clinical trials with sigma ligands. Pharmacopsychiatry 37 (Suppl. 3), S214S220. von Knorring AL, Olsson GI, Thomsen PH, Lemming OM, Hulten A (2006). A randomized, double-blind, placebocontrolled study of citalopram in adolescents with major depressive disorder. Journal of Clinical Psychopharmacology 26, 311315. von Kor M, Katon W, Bush T, Lin EH, Simon GE, Saunders K, Ludman E, Walker E, Unutzer J (1998). Treatment costs, cost oset, and cost-eectiveness of collaborative management of depression. Psychosomatic Medicine 60, 143149. Vovin RI, Fakturovich AI (1985). [Sleep deprivation as a method of treating endogenous depression]. Zhurnal Nevropatologii i Psikhiatrii Imeni S. S. Korsakova 85, 560565. Wade AG (2006). Closing the antidepressant ecacy gap between clinical trials and real patient populations. International Journal of Psychiatry in Clinical Practice 10, 2531. Wade AG, Toumi I, Hemels ME (2005a). A pharmacoeconomic evaluation of escitalopram versus citalopram in the treatment of severe depression in the United Kingdom. Clinical Therapeutics 27, 486496.

S176

CINP Antidepressant Task Force 2007

serotonin synthesis in the olfactory bulbectomized rat brain : an autoradiographic study. Brain Research Bulletin 69, 101108. Wedding U, Koch A, Rohrig B, Pientka L, Sauer H, Hoken K, Maurer I (2007). Requestioning depression in patients with cancer : contribution of somatic and aective symptoms to Becks Depression Inventory. Annals of Oncology. 5 September 2007 [epub ahead of print]. Ween JE (2005). Prophylactic mirtazapine may help to prevent post-stroke depression in people with good cognitive function. Evidence-Based Mental Health 8, 74. Weihs KL, Settle EC, Batey SR, Houser TL, Donahue RM, Ascher JA (2000). Bupropion sustained release versus paroxetine for the treatment of depression in the elderly. Journal of Clinical Psychiatry 61, 196202. Weinrieb RM, Auriacombe M, Lynch KG, Lewis JD (2005). Selective serotonin re-uptake inhibitors and the risk of bleeding. Expert Opinion on Drug Safety 4, 337344. Weinstock M (2007). Gender dierences in the eects of prenatal stress on brain development and behaviour. Neurochemical Research 32, 17301740. Weintraub D, Morales KH, Moberg PJ, Bilker WB, Balderston C, Duda JE, Katz IR, Stern MB (2005). Antidepressant studies in Parkinsons disease : a review and meta-analysis. Movement Disorders 20, 11611169. Weissman MM, Markowitz JC, Klerman GL (2000). Comprehensive Guide to Interpersonal Psychotherapy. New York : Basic Books. Wells KB, Sherbourne C, Schoenbaum M, Duan N, Meredith L, Unutzer J, Miranda J, Carney MF, Rubenstein LV (2000). Impact of disseminating quality improvement programs for depression in managed primary care : a randomized controlled trial. Journal of the American Medical Association 283, 212220. Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O, Nimrod C, Walker M (2006). Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. American Journal of Obstetrics and Gynecology 194, 961966. Westermeyer J (1989). Addiction to tranylcypromine (Parnate) : a case report. American Journal of Drug and Alcohol Abuse 15, 345350. Wharton RN, Perel JM, Dayton PG, Malitz S (1971). A potential clinical use for methylphenidate with tricyclic antidepressants. American Journal of Psychiatry 127, 16191625. Wheatley DP, van Moaert M, Timmerman L, Kremer CM (1998). Mirtazapine : ecacy and tolerability in comparison with uoxetine in patients with moderate to severe major depressive disorder. Mirtazapine-Fluoxetine Study Group. Journal of Clinical Psychiatry 59, 306312. White AD, Andrews EB (1999). The Pregnancy Registry program at Glaxo Wellcome Company. Journal of Allergy and Clinical Immunology 103, S362S363. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E (2004). Selective serotonin reuptake inhibitors in childhood depression : systematic review of published versus unpublished data. Lancet 363, 13411345.

Wade AG, Toumi I, Hemels ME (2005b). A probabilistic costeectiveness analysis of escitalopram, generic citalopram and venlafaxine as a rst-line treatment of major depressive disorder in the UK. Current Medical Research and Opinion 21, 631642. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D (2003). Ecacy of sertraline in the treatment of children and adolescents with major depressive disorder : two randomized controlled trials. Journal of the American Medical Association 290, 10331041. Wagner KD, Jonas J, Findling RL, Ventura D, Saikali K (2006). A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression. Journal of the American Academy of Child and Adolescent Psychiatry 45, 280288. Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE (2004). A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. American Journal of Psychiatry 161, 10791083. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B (1998). Eect of SSRI antidepressants on ejaculation : a double-blind, randomized, placebo-controlled study with uoxetine, uvoxamine, paroxetine, and sertraline. Journal of Clinical Psychopharmacology 18, 274281. Walker R, Swartz CM (1994). Electroconvulsive therapy during high-risk pregnancy. General Hospital Psychiatry 16, 348353. Wallace AE, Neily J, Weeks WB, Friedman MJ (2006). A cumulative meta-analysis of selective serotonin reuptake inhibitors in pediatric depression : did unpublished studies inuence the ecacy/safety debate ? Journal of Child and Adolescent Psychopharmacology 16, 3758. Wang PS, Schneeweiss S, Brookhart MA, Glynn RJ, Mogun H, Patrick AR, Avorn J (2005). Suboptimal antidepressant use in the elderly. Journal of Clinical Psychopharmacology 25, 118126. Ware MR (1997). Fluvoxamine : a review of the controlled trials in depression. Journal of Clinical Psychiatry 58 (Suppl. 5), 1523. Warneke L (1993). Managing resistant depression. When patients do not respond to therapy. Canadian Family Physician 39, 843850. Warner CH, Bobo W, Warner C, Reid S, Rachal J (2006). Antidepressant discontinuation syndrome. American Family Physician 74, 449456. Warrington SJ (1991). Clinical implications of the pharmacology of sertraline. International Clinical Psychopharmacology 6 (Suppl. 2), 1121. Wassermann EM (1998). Risk and safety of repetitive transcranial magnetic stimulation : report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 57, 1996. Electroencephalography and Clinical Neurophysiology 108, 116. Watanabe A, Hasegawa S, Nishi K, Nguyen KQ, Diksic M (2006). Chronic buspirone treatment normalizes regional

CINP Antidepressant Task Force 2007

Wichers M, Maes M (2002). The psychoneuroimmunopathophysiology of cytokine-induced depression in humans. International Journal of Neuropsychopharmacology 5, 375388. Wilcox CS, Ferguson JM, Dale JL, Heiser JF (1996). A double-blind trial of low- and high-dose ranges of gepirone-ER compared with placebo in the treatment of depressed outpatients. Psychopharmacology Bulletin 32, 335342. Wilde MI, Beneld P (1995). Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic ecacy in depression and coexisting anxiety and depression. Drugs 49, 411439. Wilkinson GR (2005). Drug metabolism and variability among patients in drug response. New England Journal of Medicine 352, 22112221. Willner P (1990). Animal models of depression : an overview. Pharmacology & Therapeutics 45, 425455. Wilson K, Mottram P (2004). A comparison of side eects of selective serotonin reuptake inhibitors and tricyclic antidepressants in older depressed patients : a meta-analysis. International Journal of Geriatric Psychiatry 19, 754762. Wilson KC, Mottram PG, Ashworth L, Abou-Saleh MT (2003). Older community residents with depression : long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study. British Journal of Psychiatry 182, 492497. Wilson K, Mottram P, Sivanranthan A, Nightingale A (2001). Antidepressant versus placebo for depressed elderly. Cochrane Database of Systematic Reviews. CD000561. Wingen M, Bothmer J, Langer S, Ramaekers JG (2005). Actual driving performance and psychomotor function in healthy subjects after acute and subchronic treatment with escitalopram, mirtazapine, and placebo : a crossover trial. Journal of Clinical Psychiatry 66, 436443. Wingen M, Ramaekers JG, Schmitt JA (2006). Driving impairment in depressed patients receiving long-term antidepressant treatment. Psychopharmacology 188, 8491. Winkler D, Pjrek E, Kasper S (2005a). Anger attacks in depression evidence for a male depressive syndrome. Psychotherapy and Psychosomatics 74, 303307. Winkler D, Pjrek E, Praschak-Rieder N, Willeit M, Pezawas L, Konstantinidis A, Stastny J, Kasper S (2005b). Actigraphy in patients with seasonal aective disorder and healthy control subjects treated with light therapy. Biological Psychiatry 58, 331336. Wirz-Justice A, Benedetti F, Berger M, Lam RW, Martiny K, Terman M, Wu JC (2005). Chronotherapeutics (light and wake therapy) in aective disorders. Psychological Medicine 35, 939944. Wirz-Justice A, Graw P, Krauchi K, Sarrafzadeh A, English J, Arendt J, Sand L (1996). Natural light treatment of seasonal aective disorder. Journal of Aective Disorders 37, 109120. Wisner KL, Gelenberg AJ, Leonard H, Zarin D, Frank E (1999). Pharmacologic treatment of depression during

S177

pregnancy. Journal of the American Medical Association 282, 12641269. Wisner KL, Zarin DA, Holmboe ES, Appelbaum PS, Gelenberg AJ, Leonard HL, Frank E (2000). Risk-benet decision making for treatment of depression during pregnancy. American Journal of Psychiatry 157, 19331940. Witkin JM, Marek GJ, Johnson BG, Schoepp DD (2007). Metabotropic glutamate receptors in the control of mood disorders. CNS & Neurological Disorders Drug Targets 6, 87100. Wittchen HU (1994). Reliability and validity studies of the WHO Composite International Diagnostic Interview (CIDI) : a critical review. Journal of Psychiatric Research 28, 5784. Wittchen HU, Knauper B, Kessler RC (1994). Lifetime risk of depression. British Journal of Psychiatry (Suppl.) 1622. Wittchen HU, Pittrow D (2002). Prevalence, recognition and management of depression in primary care in Germany : the Depression 2000 study. Human Psychopharmacology 17 (Suppl. 1), S111. Woelk H (2000). Comparison of St Johns wort and imipramine for treating depression : randomised controlled trial. British Medical Journal 321, 536539. Wohlfarth T, Storosum JG, Elferink AJ, van Zwieten BJ, Fouwels A, van den Brink W (2004). Response to tricyclic antidepressants : independent of gender ? American Journal of Psychiatry 161, 370372. Wohlfarth TD, van Zwieten BJ, Lekkerkerker FJ, Gispen-de Wied CC, Ruis JR, Elferink AJ, Storosum JG (2006). Antidepressants use in children and adolescents and the risk of suicide. European Neuropsychopharmacology 16, 7983. Wohlreich MM, Mallinckrodt CH, Watkin JG, Wilson MG, Greist JH, Delgado PL, Fava M (2005a). Immediate switching of antidepressant therapy : results from a clinical trial of duloxetine. Annals of Clinical Psychiatry 17, 259268. Wohlreich MM, Martinez JM, Mallinckrodt CH, Prakash A, Watkin JG, Fava M (2005b). An open-label study of duloxetine for the treatment of major depressive disorder : comparison of switching versus initiating treatment approaches. Journal of Clinical Psychopharmacology 25, 552560. Wolfe SM, Sasich LD, Lurie P, Hope RE, Barbehenn E, Knapp DE, Ardati A, Shubin S, Ku DB (2005). Worst Pills, Best Pills. A Consumers Guide to Avoiding Drug-Induced Death or Illness. New York, London, Toronto, Sydney : Public Citizen Foundation and Public Citizens Health Research Group. Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R, Canick J (1999a). Antiglucocorticoid treatment of depression : double-blind ketoconazole. Biological Psychiatry 45, 10701074. Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E (1999b). Double-blind treatment of major depression with dehydroepiandrosterone. American Journal of Psychiatry 156, 646649.

S178

CINP Antidepressant Task Force 2007

Yamada K, Kanba S (2002). Herbal medicine (kami-shoyo-san) in the treatment of premenstrual dysphoric disorder. Journal of Clinical Psychopharmacology 22, 442. Yamada K, Yagi G, Kanba S (2003a). Clinical ecacy of tandospirone augmentation in patients with major depressive disorder : a randomized controlled trial. Psychiatry and Clinical Neurosciences 57, 183187. Yamada K, Yagi G, Kanba S (2003b). Eectiveness of Goreisan (TJ-17) for treatment of SSRI-induced nausea and dyspepsia : preliminary observations. Clinical Neuropharmacology 26, 112114. Yamada K, Yagi G, Kanba S (2005). Eectiveness of herbal medicine (Rokumigan and Hachimijiogan) for fatigue or loss of energy in patients with partial remitted major depressive disorder. Psychiatry and Clinical Neurosciences 59, 610612. Yang X, Liu X, Luo H, Jia Y (1994). Clinical observation on needling extrachannel points in treating mental depression. Journal of Traditional Chinese Medicine 14, 1418. Yatham LN (2005). Atypical antipsychotics for bipolar disorder. Psychiatric Clinics of North America 28, 325347. Yerevanian BI, Koek RJ, Feusner JD, Hwang S, Mintz J (2004). Antidepressants and suicidal behaviour in unipolar depression. Acta Psychiatrica Scandinavica 110, 452458. Yonkers KA, Brawman-Mintzer O (2002). The pharmacologic treatment of depression : is gender a critical factor ? Journal of Clinical Psychiatry 63, 610615. Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeier B, Lesieur D, Guardiola-Lemaitre B (1992). Novel naphthalenic ligands with high anity for the melatonin receptor. Journal of Medicinal Chemistry 35, 14841486. Zanardi R, Franchini L, Gasperini M, Perez J, Smeraldi E (1996). Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. American Journal of Psychiatry 153, 16311633. Zanardi R, Franchini L, Gasperini M, Smeraldi E, Perez J (1997). Long-term treatment of psychotic (delusional) depression with uvoxamine : an open pilot study. International Clinical Psychopharmacology 12, 195197. Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E, Dotoli D, Smeraldi E (2001). Factors aecting uvoxamine antidepressant activity : inuence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biological Psychiatry 50, 323330. Zanardi R, Smeraldi E (2005). A double-blind, randomised, controlled clinical trial of acetyl-l-carnitine vs. amisulpride in the treatment of dysthymia. European Neuropsychopharmacology 16, 281287. Zapletalek M, Zbytovsky J, Kudrnova K (1982). Clinical experience with maprotilin and maprotilin/clomipramine infusions in resistant depression. Activitas Nervosa Superior 24, 7376. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63, 856864.

Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine L, Weingartner H (1993). Ketoconazole administration in hypercortisolemic depression. American Journal of Psychiatry 150, 810812. Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T, Raum WJ, Ormiston S, Johnson R, Canick J, Brizendine L, Weingartner H (1997). Dehydroepiandrosterone (DHEA) treatment of depression. Biological Psychiatry 41, 311318. Wong AH, Smith M, Boon HS (1998). Herbal remedies in psychiatric practice. Archives of General Psychiatry 55, 10331044. Wong ML, Licinio J (2004). From monoamines to genomic targets : a paradigm shift for drug discovery in depression. Nature Reviews. Drug Discovery 3, 136151. Woods SW, Rizzo JA (1997). Cost-eectiveness of antidepressant treatment reassessed. British Journal of Psychiatry 170, 257263. Workman EA, Short DD (1993). Atypical antidepressants versus imipramine in the treatment of major depression : a meta-analysis. Journal of Clinical Psychiatry 54, 512. World Health Organization (1992). The ICD-10 Classication of Mental and Behavioural Disorders : Clinical Descriptions and Diagnostic Guidelines. Geneva, Switzerland. World Health Organization (2001). Conquering Depression. (http:/ /www.searo.who.int/en/Section1174/ Section1199/Section1567/Section1826_8096.htm). Accessed 1 November 2006. World Health Organization (2002). The Global Burden of Disease Project (www.who.int). Accessed 30 January 2007. World Health Organization (2005a). WHO Model List of Essential Medicines (http:/ /www.who.int/medicines/ publications/essentialmedicines/en.). Accessed 14 November 2006. World Health Organization (2005b). WHO Report on Mental Health : Depression (http:/ /www.who.int/mental_health/ management/depression/denition/en/). Accessed 14 November 2006. World Health Organization (2005c). WHO Resource Book on Mental Health, Human Rights and Legislation. Geneva : WHO. World Psychiatric Association (2006). WPA Educational Program on Depressive Disorder Module 2 (Depressive Disorders in Physical Illness) (http:/ /www.wpanet.org/ sectorial/edu4a.html). Accessed 30 July 2006. Wu JC, Bunney WE (1990). The biological basis of an antidepressant response to sleep deprivation and relapse : review and hypothesis. American Journal of Psychiatry 147, 1421. Wulsin LR, Singal BM (2003). Do depressive symptoms increase the risk for the onset of coronary disease ? A systematic quantitative review. Psychosomatic Medicine 65, 201210. Xia Z, DePierre JW, Nassberger L (1996). Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells. Immunopharmacology 34, 2737.

CINP Antidepressant Task Force 2007

Zarate CA, Tohen M, Baraibar G (1997). Combined valproate or carbamazepine and electroconvulsive therapy. Annals of Clinical Psychiatry 9, 1925. Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP (2000). Synergistic eects of olanzapine and other antipsychotic agents in combination with uoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 23, 250262. Zhang ZQ, Yuan L, Yang M, Luo ZP, Zhao YM (2002). The eect of Morinda ocinalis How, a Chinese traditional medicinal plant, on the DRL 72-s schedule in rats and the forced swimming test in mice. Pharmacology, Biochemistry and Behavior 72, 3943. Zhou D, Grecksch G, Becker A, Frank C, Pilz J, Huether G (1998). Serotonergic hyperinnervation of the frontal cortex in an animal model of depression, the bulbectomized rat. Journal of Neuroscience Research 54, 109116. Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Attiullah N, Boerescu D (2006). How

S179

should remission from depression be dened ? The depressed patients perspective. American Journal of Psychiatry 163, 148150. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F (2000). Eects of the high-anity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression : the rst 20 patients treated. Journal of Psychiatric Research 34, 171181. Zobel AW, Yassouridis A, Frieboes R-M, Holsboer F (1999). Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. American Journal of Psychiatry 156, 949951. Zourkova A, Hadasova E (2003). Paroxetine-induced conversion of cytochrome P450 2D6 phenotype and occurence of adverse eects. General Physiology & Biophysics 22, 103113. Zullino D, Baumann P (2001). Lithium augmentation in depressive patients not responding to selective serotonin reuptake inhibitors. Pharmacopsychiatry 34, 119127.

19 Annexes 19.1 Annex 1 : Opinions and suggestions that could not be fully accommodated in the review The Task Force and the editors have carefully considered the comments and suggestions made by the Advisory Group, participants in meetings and by experts consulted on specic issues. Most of the comments and suggestions could be accommodated by changes or additions to the text. There were, however, some views that could not be fully reected in the review. They are listed below, in alphabetical order by author. Max Fink suggested not publishing an annex containing information about psychotherapy within the CINP review because of insucient scientic evidence about the eectiveness of several forms of psychotherapy in the treatment of depression. The CINP antidepressants task force agreed not to publish an extensive review about the use and usefulness of psychotherapy in depression because this would be beyond the scope of a technical review about antidepressants. Nevertheless, there was broad consensus in the task force and the advisory board that some psychotherapy forms, e.g. IPT (interpersonal therapy) and CBT (cognitive behavioral therapy), represent an important therapeutic option for many patients suering from depression that should be taken into consideration in treatment plans together with antidepressant medication. A short chapter and an annex about the psychotherapy of depression therefore have been included. Because David Healy has concerns about the review on principle, the CINP antidepressants Task Force decided to present his views without abridgment :
HEALY : My principal concern with the report that I have read lies with the interpretation it puts on clinical trial data. The report adopts one of several possible interpretations, and ideally it might have considered how the evidence looks from a number of dierent points of view. I think the interpretation adopted is arguably the least supportable one, and this is of some consequence as the interpretation of these clinical trials feeds through to the views adopted as regards the possible economic benets of antidepressants and their use in comorbid conditions etc. The report adopts the position that a relatively modest superiority over placebo in a selected number of clinical trials means that antidepressants work. While most practicing clinicians have little doubt that antidepressants can be of benet, the RCTs that are appealed to here do not demonstrate that antidepressants work. For the most part they have employed samples of convenience and it is not clear how generalizable the results from these studies might be particularly to populations with comorbid physical disorders. Second, the studies are only a selection of those undertaken ; a great number of studies demonstrating even less or no superiority of the antidepressant compared with placebo have not been published and accordingly have not been factored into the claims made here. The response to this point that these unpublished studies will often have involved failed assay systems does not take care of the issue in this context. It may be reasonable to appeal to failed assay systems in a regulatory context, which requires

S180

CINP Antidepressant Task Force 2007

The report bases almost everything on minimal rating scale changes. In terms of any hard outcomes that these clinical trials oer, one of the few hard outcomes is the data on suicidal act and completed suicide rates. When these are looked at, as the expert working group report from the MHRA in Britain, in 2004, reveals, there is a 2.6-fold increased rate of completed suicides in adults after treatment compared to placebo and a 2.4-fold increased rate of completed suicides or other suicidal acts on active treatment compared to placebo. These gures should raise questions for someone about the validity of constructing economic models that depend solely on rating scale results. Adverse responses such as completed suicides have not to the best of my knowledge been factored into the economic modes detailed in this report, but the adverse events from nausea to suicide oer the only hard outcomes we have. If even a proportion of the adverse responses were factored in it is doubtful that the economic benets claimed could be substantiated. There are a number of further points to note with this issue of suicides and suicidal acts that are at odds with the interpretation oered in the report on this specic point. The report covers the issue of pediatric suicidality primarily. It makes some mistakes. It claims that there were no suicides in the pediatric trials. In fact there were no known suicides in the set of pediatric trials submitted for registration purposes, but a very large number of patients dropped out because of adverse responses and were not followed up. It would be more correct to say there were no known suicides rather than there were no suicides. There were of course several pediatric suicides in controlled trials of recent antidepressants. But these occurred in trials other than the pediatric registration trials to which the report refers. There have also been published clinical reports from reputable clinical centers on suicides in children and adolescents dating back 15 years now. There are a large number of other substantive issues that the report essentially left in abeyance such as the issue of dependence and withdrawal. Aside from specic issues like this there were the more general issues that have enveloped the eld recently, referred to by Dr Belmaker, such as increasing diculties with articles being ghost written, with conicts of interest etc., with data selection, data suppression and data from non-existent patients. In summary, if the object of this exercise or one likely outcome of the exercise is to put into the hands of planners results that will bear the weight of policy, then the report that I have seen is a dangerous structure that I would have thought is likely to collapse in the not too distant future with only a few pillars left standing such as the pillar on ECT. If the report is taken seriously by anyone within the pharmaceutical industry involved with drug development rather than just marketing, it will hamper innovative drug development. CINP can stand back and say in the words of the Tom Lehrer song that it is not their department to consider what uses the report might be put to, but I cant believe that CINP members with their particular backgrounds would be very happy for the organization to adopt such an ethical position.

demonstrations of a treatment signal, but these are not failed studies in a wider clinical context. Any wider assessment of what antidepressants might do or their utility needs to take these negative studies into account. The greater problem, however, in the approach taken lies with the apparent willingness to adopt an interpretation which sees ve patients out of ten responding to the antidepressant compared with four responding to the placebo, with the assessment of benets dependant on rating scale data only, as evidence that the drugs work. One of several alternate interpretations of the 50 % response to antidepressants versus 40 % response to placebo in terms of the therapeutic response in the antidepressant group is that 80 % of the response to the antidepressant comes from non-specic factors. We are unable to quantify the contribution of the various non-specic factors involved, while in contrast we can quantify the specic drug contribution. But this specic drug contribution is only 20 % of the therapeutic response. One can make the argument that if the money and culture in psychiatry is to follow the evidence, it should follow the evidence of the 80 % rather than the 20 %. This can be put another way. Of every ten people entered into clinical trials one specically responds to an antidepressant and nine either dont respond specically to the antidepressant or fail to respond at all or respond adversely. Taking the approach that the authors in this report have taken privileges the response of one individual against the responses of nine and this is clearly problematic in terms of a report that may go to policy makers and others purporting to be a report that if implemented will lead to benets. I think it would be preferable to ag up the preliminary and provisional nature of the results. They point to the fact that antidepressants have benets. They do not indicate that much science has been done in this area but rather that a great deal of science remains to be done. We should be attempting to establish for instance who responds to SSRIs versus who responds to antidepressants active on other systems. Selecting out responsive patients would be quite likely to lead to a much greater dierence between the response to active treatment and response to a placebo. This would bring in areas like pharmacogenetics and questions about the eects of specic treatments on dierent constitutional or personality types rather than simply the eects of these agents on some disease process. I think there is a signal failure in the eld that we have permitted 800 odd trials or more to be done and published and perhaps an equal number to be done and left unpublished, since the rst trials on Prozac, all of which essentially repeat the formula of trying to show a small dierence between active treatment and placebo, without even in a small proportion of trials moving forward to determining who the treatment responsive groups of patients might be. This is an issue on which Tom Ban has written cogently. He has argued, and I would agree, that we have failed both in terms of the opportunity oered to advance the science of psychopathology and also in terms of the science of clinical therapeutics.

CINP Antidepressant Task Force 2007 Some of David Healys critiques have been integrated in the review, e.g. additional chapters about suicidality and antidepressants in adult patients (see chapter 11) and dependence and withdrawal (see chapter 9.1.1.3.2). Some of his concerns have been discussed more extensively, e.g. the problem of unpublished studies (see chapter 4.4), the new trends in pharmacogenetic research to establish methods for an individualized antidepressant therapy (see chapter 8.3) and the problem of comorbid physical disorders in depressed patients (see chapter 5.2.4). Because other dicult issues such as the existing problem of misconduct in clinical science and subjective evaluation of study results concerning responder rates in clinical trials cannot be resolved completely, the CINP antidepressants task force decided to report David Healys view in full to empower readers to draw their own conclusions about these issues. Ulrich Hegerl suggested changing the structure of the review and discussing antidepressant medications before the chapters about diagnosis and epidemiology because medications are already mentioned within the description of specic manifestations of depression. The CINP antidepressants task force decided not to change the structure of the document based on agreement that it is important to establish treatment plans after the correct diagnosis of depressive disorders and concomitant or comorbid diseases. Florence Thibaut suggested including recommendations for clinicians with the level of evidence at the end of each chapter. The CINP antidepressants task force decided to leave out recommendations and to publish only a review about the usefulness of antidepressant medications that will constitute the basis for treatment recommendations formulated at a national level. Wayne Katon suggested not including studies using modeling techniques in the economics chapter. He suggested adding other studies and references in the economics chapter, and he did not agree with the statement that the comparison of psychotherapy and medication reveals economic advantages for antidepressants. The economics experts within the CINP antidepressants task force agreed to present the results of modeling studies together with other kinds of economic studies, including a subchapter about differences in methodologies of economic evaluations. Because the use and usefulness of psychotherapy was not the main focus of this review, the CINP antidepressants task force agreed not to expand the chapter about psychotherapy. Markus Kosel suggested adding references about DBS in the treatment of OCD. The CINP

S181

antidepressants task force agreed not to include such studies because predominantly the pharmacological and non-pharmacological treatment of depressive disorders has been evaluated in the present review. Min-Soo Lee suggested including specic recommendations for pharmacotherapy. The CINP antidepressants task force agreed to to include those recommendations because they represented unreferenced treatment schedules. Specic treatment recommendations will be integrated as mentioned at a later stage of the project, but not in the current review. Shigenobu Kanba suggested not mentioning ECT three times in the review. The CINP antidepressants task force and the advisory board agreed to mention ECT in the chapter about combination therapies in treatment-resistant depression, in a short chapter about ECT, and in an additional and more extensive annex about this treatment method, because at present ECT still represents a very eective treatment method for severe and treatment-resistant depressive disorders. 19.2 Annex 2 : Additional information on the types of economic evaluation 19.2.1 Cost-oset studies

The simplest of economic studies are concerned only with costs, not (usually) because they see outcomes as irrelevant but because, in relation to the treatments or services under study, the health and quality of life outcomes have already been established from other research, or are (currently) not measurable because of conceptual diculties or research funding limitations. One of these cost-only methods is the cost-oset study, which compares costs incurred with (other) costs saved. For instance, a new antidepressant may have a higher acquisition cost (higher price) compared with an older drug, but may reduce the need for inpatient admissions and thus lead to cost savings downstream. While a cost-oset study is not an economic evaluation, and therefore cannot answer the Is it worth it ? question, it nevertheless addresses an issue that is often fundamental to health system decision making : Within a xed or even shrinking budget (at least in the short run), are treatment changes aordable ? 19.2.2 Cost-eectiveness analysis

Probably the most intuitive and straightforward modes of economic evaluation are cost-eectiveness

S182

CINP Antidepressant Task Force 2007

New treatment more costly

Old treatment dominates New treatment less effective 0 Trade-off needed: compare cost difference and outcome difference

Trade-off needed: compare cost difference and outcome difference New treatment more effective

B X

New treatment dominates more effective and less costly New treatment less costly

Figure 5. Cost-eectiveness of antidepressant treatment (from Woods and Rizzo, 1997).

and cost-consequences analyses. Both types of analysis measure outcomes using instruments and scales familiar to clinical researchers. Both are employed to help decision makers choose between alternative interventions available to or aimed at specic patient groups. A cost-eectiveness analysis (CEA) looks at a single outcome dimension such as the number of life years saved, the number of depression-free days or the duration of time in remission and then computes and compares the ratio of the dierence in costs between the two treatments being evaluated with the dierence in (primary) outcome (the incremental costeectiveness ratio or ICER). A common nding is that a new treatment is both more eective (the outcome proles are better than for the older or comparator treatment) and simultaneously more expensive. Decision makers therefore face the challenge of weighing up the outcomes against the higher expenditure necessary to secure them. The decision is far from straightforward in these cases. The widely used cost-eectiveness plane (Figure 5) illustrates the range of possible CEA results and the dicult decision-making task in some circumstances. The cost-eectiveness plane in Figure 5 shows the possible combinations of outcomes and costs when comparing two interventions or treatments. The point marked B indicates that the new treatment (say a new antidepressant drug) is both more eective (it has better outcomes) and less costly than the old treatment. The task for the decision maker looks quite straightforward in these circumstances : recommend wider use of the new treatment. However, many evaluations nd that new treatment modes produce better outcomes than older interventions but at a higher cost (illustrated by point A). The choice facing the decision maker is now more complex : are the better outcomes worth the higher costs ?

To aid such decision making, economists have developed cost-utility analysis (see below) and more recently the net benet approach, linked to the construction of cost-eectiveness acceptability curves (CEACs). These show the probability that a new intervention will be reviewed by the decision maker as cost-eective for each prespecied or implicit valuation of an outcome improvement. Comparisons are then possible across quite disparate clinical areas (comparing, for example, depression treatment with dementia treatment ; or psychiatry with oncology). This kind of decision context is exactly the one faced by decision makers one or two steps removed from the patient interface. An obvious weakness with the strict costeectiveness methodology is the enforced focus on a single outcome dimension (in order to compute ratios) when we know that many people with depression have multiple needs for support and when most clinicians might expect to achieve improvements in meeting more than one need. Carrying multiple outcomes forward in an analysis is less tractable analytically, but three options are available, associated with three other modes of economic evaluation. One option which is cost-consequences analysis is to retain all or most outcome dimensions (measured using standard clinical scales). The other two options weight the outcomes, either in terms of money (cost-benet) or in terms of utility (cost-utility). A weakness noted earlier is that the comparator in a trial may not be appropriate, not giving decision makers the evidence base they need (in their local circumstances, or more generally). 19.2.3 Cost-utility analysis

An increasingly used evaluative mode that seeks to reduce outcomes to a single dimension is cost-utility analysis (CUA), which measures and then values the impact of an intervention in terms of improvements in preference-weighted, health-related quality of life. The value of the quality of life improvement is measured in units of utility , usually expressed by a combined index of the mortality and quality of life eects of an intervention. The best-known and most robust index is the quality-adjusted life year (QALY). CUAs have a number of distinct advantages, including using a unidimensional measure of impact, a generic measure which allows comparisons to be made across diagnostic or clinical groups (e.g. comparing psychiatry with oncology or cardiology), and a fully explicit methodology for weighting preferences and valuing health states. But these same features are sometimes

CINP Antidepressant Task Force 2007 seen as disadvantages : the utility measure may be too reductionist, the generic quality of life indicator may be insuciently sensitive to the kinds of change expected in depression treatment, and a transparent approach to scale construction paradoxically opens the approach to criticism from those who question the values thereby obtained (Chisholm et al., 1997). On the other hand, CUAs avoid the potential ambiguities with multidimensional outcomes in costconsequences studies and are obviously more general than the single-outcome CEA. The transparency of approach is also to be welcomed. The result is an incremental cost-utility ratio for each intervention, relative to some comparator, which can be compared with similar ratios for other interventions (potentially from across the widest diagnostic range, i.e. not just from mental health). These cost-per-QALY ratios can then inform health-care resource allocation decisions or priority setting. 19.2.4 Cost-benet analysis Cost-benet analysis (CBA) asks whether a treatment or policy is socially worthwhile in the broadest sense : Do the benets exceed the costs ? This kind of analysis would allow decision makers to consider the merits not only of allocating resources within health care, but also to consider whether it would be more appropriate to invest in other sectors such as housing, education or even the military. All costs and benets are valued in the same (monetary) units. If benets exceed costs, the evaluation would recommend providing the treatment, and vice versa. With two or more alternatives, the treatment with the greatest net benet would be deemed the most ecient. CBAs are thus intrinsically attractive, but conducting them is especially problematic because of the diculties associated with valuing outcomes in monetary terms. Recent methodological advances in health economics oer ways to obtain direct valuations of health outcomes by patients, relatives or the general public. These techniques ask individuals to state the amount they would be prepared to pay (hypothetically) to achieve a given health state or health gain, or observe actual behavior and impute the implicit values. However, they are likely to be quite dicult to apply in mental health contexts. Another approach used to value health interventions is conjoint analysis . Individuals are asked to rank dierent real- world scenarios, which may consist of several dimensions (including, for instance, health outcomes, time inputs,

S183

discomfort, possible externalities and stigma), and by including cost as one of these dimensions, a monetary value can be elicited. While complex, this conjoint analysis approach has the advantage of not specically asking individuals to put a monetary value on health states or health gain, which can make the technique easier to administer than traditional willingness-topay studies. 19.2.5 Cost-consequences analysis

A cost-consequences analysis has the ability to evaluate policies and practices in a way that arguably comes quite close to everyday reality, but it also has some limitations. For each treatment alternative a cost-consequences evaluation computes total (and component) costs and measures change along every one of the relevant outcome dimensions. The cost and outcome results are then reviewed by decision makers ; the dierent outcomes are weighed up (informally and subjectively) and compared with costs. For example, the researcher could compute a series of ICERs (one for each measured outcome) for presentation to the decision maker. The decision calculus is therefore certainly much less tidy and more complicated than when using cost-eectiveness ratios or monetary or utility measures of impact (see below), but it could be argued that decision makers in health-care systems from strategic policy-makers at the macro level to individual psychiatrists at the micro level face these kinds of decisions daily. On the other hand, the process of weighing up the various outcomes by the decision maker is subjective, hidden and technocratic , whereas the choice of the single outcome dimension in a CEA and the weighting algorithms in other evaluative modes (described below) are transparent, less likely to be inuenced by the personal predilections or value positions of a few individuals, and (potentially) reective of societal values. 19.2.6 Cost-minimization analysis

Another cost-only approach is cost-minimization analysis, which seeks to nd which of a number of treatment options has the lowest cost. A costminimization analysis is carried out in one of two ways. It often proceeds in the knowledge that previous research has shown outcomes to be identical in the treatment or policy alternatives being evaluated. In this sense the approach is really more accurately described as an interrupted cost-eectiveness

S184

CINP Antidepressant Task Force 2007 the benet (Kellner et al., 2005). Also other acute psychiatric syndromes, e.g. malignant catatonia or a neuroleptic malignant syndrome (NMS) may show rapid benet from ECT as a rst-line treatment (Abrams, 2002 ; Baghai et al., 2005). Intensive ECT, usually administered daily (en bloc), relieves the high rates of mortality associated with malignant catatonia and delirious mania (Fink, 1999 ; Fink and Taylor, 2003). In the case of severe and life-threatening adverse events of antidepressants and in psychotic depressed patients ECT monotherapy can be a safe rstline treatment. This recommendation also holds for patients suering from severe somatic diseases, including the risk of worsening due to antidepressant and antipsychotic pharmacotherapy (Beliles and Stoudemire, 1998 ; Franco-Bronson, 1996 ; Rothschild, 1996). In addition, long duration and chronic course of the index episode are negative outcome predictors in depressive disorders that signal a higher risk for therapy resistance to medication and ECT (Beliles and Stoudemire, 1998 ; Prudic et al., 1990). Nevertheless, the primary use of ECT is handicapped by severe stigma and even legal restrictions against its use in some jurisdictions (Ottoson and Fink, 2004). 19.3.2 ECT as second-line treatment

analysis (see above). The other way a cost-minimization analysis can proceed is to compare costs without any regard for outcomes. Such an approach is narrow and potentially misleading and should never be encouraged : it is not an economic evaluation. Well-conducted cost-minimization analysis can therefore be thought of as a special type of cost-eectiveness analysis, where evidence on eectiveness demonstrates no dierence between two or more interventions. In most instances, however, clinical and quality of life outcomes will not be equivalent, and more complex evaluations are required, which can make them far more informative, but correspondingly more complex to conduct. 19.3 Annex 3 : Additional information on electroconvulsive therapy Electroconvulsive therapy (ECT) is the safe induction of a series of generalized epileptic seizures for therapeutic purposes using brief-pulse stimulation techniques under anesthesia and muscle paralysis. Informed consent of the patient or the responsible legal guardian is mandatory. Since the rst publication of a placebo controlled double-blind study indicating the ecacy of ECT in the treatment of depression (Greenblatt et al., 1964), the excellent therapeutic eectiveness of this method has been described in extensive studies (Abrams, 2002 ; Baghai et al., 2005). These studies are summarized in a variety of reviews and meta-analyses (Abrams, 2002 ; Baghai et al., 2005 ; ECT review group, 2003). 19.3.1 ECT as rst-line treatment

In the case of refusal of food and drink, and severe psychomotor retardation, ECT has been shown to be one of the safest therapeutic options with fast relief of symptoms (Gangadhar et al., 1982). Therefore, depressive stupor and inanition, as in melancholic, catatonic and/or psychotic depression, can be a rst-line indication for ECT. If, due to other conditions, e.g. severe psychotic symptoms and/or high suicide risk, rapid improvement is crucial for the patient, ECT should be considered earlier than other therapeutic options (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). In psychotic depression, the remission rate for ECT approximates 90 %, with relief experienced within 1014 days (Ottoson and Fink, 2004 ; Petrides et al., 2001). The risks of suicide that mark severe psychiatric illnesses are quickly relieved by ECT, although attention to continuation treatment is essential to sustain

Even if patients receive ECT only in rare cases immediately after reaching criteria for pharmacotherapy resistance, those treatment failures are the most frequent ECT indication (Moller, 1997 ; Prudic et al., 1996 ; Sackeim, 2001 ; Warneke, 1993). Use of ECT signicantly enhances response rates (Davidson et al., 1978 ; Folkerts et al., 1997 ; Kroessler, 1985). This nding is especially true in patients suering from psychotic depression, even if antipsychotic therapies have been applied adequately (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001 ; Folkerts et al., 1997). Intolerable side eects of antidepressant medications, somatic comorbidities emerging during the pharmacological treatment (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001 ; Rasmussen et al., 2002) or worsening of depressive symptoms, including severe suicidality during an antidepressant pharmacotherapy, can also be the reason for initiating an ECT treatment course (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). First- and second-line indications and rare last resort indications are summarized in Table 26.

CINP Antidepressant Task Force 2007

Table 26. Indications74 for electroconvulsive therapy (adopted from Baghai et al., 2005) Category of ECT indications ECT as a rst-line treatment Indication
$ $ $ $ $ $

S185

Febrile catatonia* Malignant neuroleptic syndrome* Severe depressive episode** Schizoaective psychosis** Schizophrenia**, *** In the case of life-threatening or intolerable side eects of psychopharmacological treatments

ECT as a second-line treatment

Medication treatment failures in :

$ $ $ $ $

Depression Schizoaective psychosis Schizophrenia Mania Depression or psychotic symptoms in case of organic diseases Treatment-resistant obsessive compulsive disorder (OCD) Treatment-resistant dyskinesias Treatment resistant Gilles de la Tourette syndrome Treatment-resistant epilepsy Treatment resistant Parkinsons disease

ECT as a last-resort treatment

$ $ $ $ $

* Fink and Taylor, 2003. ** With suicidality that cannot be handled even on protected wards, psychotic symptoms, depressive stupor, with positive symptoms or acute danger of self-harm or harm to others or with severe reduction in oral intake. *** Fink and Sackeim, 1996.

19.3.3 Ecacy of ECT in depressive syndromes of dierential etiology 19.3.3.1 Unipolar depression The general ecacy and superiority of ECT compared with antidepressant pharmacotherapy has been described in controlled clinical trials and meta-analyses (ECT review group, 2003). Response rates between 80 and 90 % (Prudic et al., 1990 ; Prudic et al., 1996) and even 100 % (Sackeim et al., 2000) have been reported. Also, lower response rates of about 5060 % have been described in patients after several medication treatment failures receiving unilateral ECT (Sackeim et al., 2000). Nevertheless, in a recent study sustained response rates of 80 %, superior to pharmacotherapy response rates (up to 70 %), and remission rates of 75 % (up to 87 % for study completers suering from psychotic depression) were found in major depressed patients treated with optimized ECT (Husain et al.,
74

ECT is indicated as a rst- or second-line treatment on the basis of broad clinical consensus on the basis of open label studies, case series and case reports. Exceptions are the indications depression and schizophrenia, for whom scientic evidence from RCTs and meta-analyses have been published (ECT review group, 2003 ; Tharyan, 2000 ; Tharyan and Adams, 2005).

2004 ; Kellner et al., 2005 ; OConnor et al., 2001 ; Petrides et al., 2001). A 20 % better improvement compared with tricyclic antidepressants and a 45 % better improvement compared with monamine-oxidase inhibitors (MAOIs) (Janicak et al., 1985) as well as a better improvement in comparison with the selective serotonin reuptake inhibitor (SSRI) paroxetine (Folkerts et al., 1997) have been described. In addition, a more rapid improvement in comparison with pharmacotherapeutic approaches has been reported (Abrams, 2002 ; Petrides et al., 2001 ; Prudic et al., 1996 ; Sackeim et al., 1993). Most patients show a faster treatment response during ECT in comparison with pharmacotherapy (Sackeim et al., 1987). But also an advantage in speed of response in similarly ecacious pharmacotherapeutic approaches, such as lithium augmentation (Sackeim et al., 1993) after tricyclic antidepressant (TCA) treatment failure, has been described. Especially for patients who receive ECT after pharmacotherapy treatment has failed, longer treatment intervals until complete remission are to be expected. Earlier reports showed lower-stimulation-energy bilateral ECT to be more eective than unilateral ECT (ECT review group, 2003 ; Sackeim et al., 1987 ;

S186

CINP Antidepressant Task Force 2007 (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). 19.3.3.5 Comorbid personality disorder Comorbid personality disorder is a predictor of poor response to ECT, and the recommendation for ECT should be made cautiously in such patients (Abrams, 2002 ; OConnor et al., 2001). Nevertheless, in the case of resistance to pharmacotherapy, ECT should not be withheld from patients suering from MDD with comorbid personality disorder (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). Rather, the information about lower response rates must be included in the patients information about the estimated treatment outcome. 19.3.3.6 Organic depression due to somatic disorders Patients suering from secondary depression associated with somatic diseases show lower response rates to biological therapies such as pharmacotherapy and ECT (Black et al., 1993 ; Coryell et al., 1985 ; Krystal and Coey, 1997) in comparison with MDD. Nevertheless, ECT is clinically eective in patients suering from depression after cerebral infarction ( poststroke depression ) (Krystal and Coey, 1997 ; Sackeim et al., 1987 ; Sackeim et al., 2000). Of course, for this patient group organic risk factors must be considered especially carefully during interdisciplinary neurological and psychiatric evaluations. 19.3.4 Combination of ECT and antidepressants

Sackeim et al., 1993). But unilateral ECT may achieve ecacy rates equal to bilateral ECT if the dose regime is 68 times above the titrated seizure threshold (McCall et al., 2000 ; Sackeim et al., 2000). 19.3.3.2 Bipolar depression ECT is an eective antidepressant therapy whether depressive episodes occur due to unipolar depression or bipolar disorder (Abrams, 2002 ; American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). As described in chapter 5.2.2.1 an enhanced switch risk, including the occurrence of hypomania or mania is associated with every highly effective antidepressant treatment. Infrequent switches from depression to mania may also occur during the course of ECT (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). But owing to a lack of randomized controlled trials and switch rates up to 30 %, regardless of the antidepressant therapy, this clinical observation has also been discussed as an artifact (Tayor and Fink, 2006). In contrast to antidepressant pharmacotherapy, the electroconvulsive treatment has not to be stopped due to the anti-manic properties of ECT. Furthermore, ECT may be combined with lithium treatment to augment lithium eects and to prevent a switch into mania in high-risk patients. In this case, an enhanced risk for cognitive and medical side eects must be taken into account (Zarate et al., 1997). In the event of urgent indication for mood stabilizers, even combined use of ECT and anticonvulsants is possible and may yield clinical advantages in specic circumstances (Aarre and Bugge, 2002 ; Pearlman and Obedian, 1995 ; Zarate et al., 1997). 19.3.3.3 Dysthymia and double depression Chronic depression in the case of dysthymia alone is not an indication for ECT treatment. Nevertheless, if the diagnostic criteria for MDD or double depression are present, dysthymia is not a predictor for a poor ECT response (Abrams, 2002 ; American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). 19.3.3.4 Depressive syndromes in OCD Patients suering from OCD who do not respond to pharmacotherapy may respond following ECT predominantly if OCD is accompanied by depressive symptoms (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001), which often is the case. Also, the benecial use of ECT during OCD continuation therapy has been reported

The majority of patients referred for ECT have had multiple trials of medication. Despite this experience, high remission rates to eective ECT up to 90 % in psychotic depression can be expected (Abrams, 2002 ; Husain et al., 2004 ; Petrides et al., 2001). The use of bilateral or high-dose unilateral stimulation can enhance the eectiveness of ECT treatment (Husain et al., 2004 ; Sackeim et al., 2000). A further option for augmenting an ECT treatment course may be the concomitant prescription of antidepressants. However, ndings from study of a putative benet of combining ECT with TCAs (Lauritzen et al., 1996 ; Nelson and Benjamin, 1989) and the lack of advantages of other concomitant medications, like SSRIs, are still controversial (Lauritzen et al., 1996). In particular, the ecacy of modern antidepressants in combination with ECT, e.g. the dual-action substances mirtazapine, venlafaxine and duloxetine, has never been investigated in controlled studies. Nevertheless, some safety data are available, e.g. venlafaxine at doses

CINP Antidepressant Task Force 2007 lower than 300 mg/day has been shown to be safe in combination with ECT. In high-dose treatments above 300 mg/day, side eects of a cardiovascular nature, such as transient asystolia and bradycardia, were more frequent if venlafaxine treatment was combined with propofol anesthesia during ECT (Gonzales-Pinto et al., 2002). 19.3.5 Continuation ECT75 As described in chapter 9.2, in addition to pharmacologic and psychotherapeutic continuation therapies, especially after pharmacotherapy treatment failure, ECT is an also eective continuation treatment (Fink et al., 1996 ; Kellner et al., 2005 ; Sartorius and Henn, 2005a ; Sartorius and Henn, 2005b), even given the absence of controlled studies. Continuation ECT should be considered when depressive symptoms recur despite adequate pharmacological continuation therapy. Even when the prior history of an individual patient shows enhanced risk for recurrence of depression during continued pharmacotherapy, including both antidepressants and mood stabilizers, C-ECT should be part of the treatment plan (Frey et al., 2001 ; McCall, 2001 ; Rabheru and Persad, 1997). The usual clinical procedure is to prolong the treatment intervals according to individual clinical requirements. During acute treatment, a patient usually receives two or three treatments per week. Afterwards, usually one treatment per week is applied for 48 weeks, then one treatment every 2 weeks and then one treatment every 4 weeks. This frequency should be maintained for at least 6 months. A frequently used alternative strategy (the so-called cafeteria style) is the individual decision whether to administer C-ECT treatment when the rst signs of recurring depressive symptoms are reported (Abrams, 2002 ; Fink et al., 1996). Regular weekly evaluations help to judge the necessity to shorten or prolong treatment-free intervals on an individual basis. 19.3.6 Safety In general, ECT is one of the best-tolerated antidepressant therapies, with low risk for severe complications, even lower than TCAs (Abrams, 2002 ;
The terms continuation treatment and continuation ECT (C-ECT) are predominantly used to characterize maintenance treatment after successful treatment of the index phase. They are sometimes distinguished from maintenance treatment and maintenance ECT (M-ECT) (Sartorius and Henn, 2005a) based on theoretical considerations regarding switching to prophylactic treatment to prevent new episodes of depression. Because for individual patients this time point cannot be precisely dened, in the following text only the term C-ECT is used.
75

S187

American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). The reported mortality rate during ECT varies between 1 : 50000 and 1 : 25000 treatments (Abrams, 2002 ; American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). Severe complications that warrant special attention are seen in less than one in 10 000 treatments (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). ECT therefore is considered to be one of the safest medical procedures performed under anesthesia. Clinical conditions requiring special attention before and during ECT described in (Abrams, 2002 ; Baghai et al., 2005) are summarized in Table 27. 19.3.7 Side eects

19.3.7.1 Somatic side eects The most frequent immediate unpleasant eects of ECT are headache, nausea and vomiting (varying with the anesthetic). Headache is reported in up to 45 % of patients and can be treated symptomatically using analgesics such as acetylsalicylic acid or paracetamol or, if severe, by changing the induction medications. Patients suering from regular migraine attacks are predisposed for postictal headache following ECT. In this case triptans, e.g. sumatriptan, can be applied orally or intranasally (Angst et al., 1992). Nausea occurs rarely following intravenous anesthesia and can be treated using metoclopramide. Other rare complications of ECT are cardiovascular events emerging from anesthesia. On rare occasions, the seizure is prolonged beyond the anticipated 30180 seconds (American Psychiatric Association Committee on Electroconvulsive Therapy et al., 2001). This risk is considerably enhanced in patients receiving theophylline (Grogan et al., 1995 ; Rao et al., 1993). The treating anesthesiologist or psychiatrist will end the seizure by administering intravenous benzodiazepines (e.g. diazepam, lorazepam), anesthetics or other anticonvulsants. This event is best managed by ictal and postictal electroencephalogram monitoring (Grogan et al., 1995), which can also be of use in treating non-convulsive seizures, which rarely occur after ECT (Grogan et al., 1995 ; Rao et al., 1993). In the case of prolonged eectiveness of muscle relaxants due to predisposition or lithium therapy (Hill et al., 1977 ; Reimherr et al., 1977), longer assisted respiration and subsequent measurement of oxygen saturation using nger or toe pulse oxymetry is necessary to prevent hypoxia. Aching muscles can be prevented by adequate muscle relaxation and are reported rarely.

S188

CINP Antidepressant Task Force 2007

Table 27. Clinical conditions requiring special attention before and during ECT (adopted from Baghai et al., 2005) Category Enhanced intracerebral pressure* Cerebral infarction* Myocardial infarction* Intracerebral tumor* Any life-threatening anesthesia risk* Cardiovascular disorders Clinical condition At present Not older than 3 months Not older than 3 months Including intracerebral edema At present Cardiac arrhythmias, instable angina pectoris, myocardial infarction (older than 3 months), myocardial insuciency, heart-valve abnormalities, not suciently treated hyper- or hypotonia, aortal aneurysm Disturbance of blood coagulation, severe liver diseases, severe pulmonary diseases, pheochromocytoma Intracerebral neoplasias, intracranial bleeding, intracerebral vascular malformations, cerebral ischemia, cerebral inammations, hydrocephalus, dementias, diseases of the basal ganglia, craniotomies, severe cerebral traumas Osteoporosis Increased aspiration risk ; intubation recommended If enhancing the ECT risks or reducing ECT ecacy

Medical disorders Neurological disorders

Orthopedic disorders Esophageal hernia Concomitant pharmacological treatment

* In former times considered as absolute contraindications ; today an individual risk/benet-analysis is necessary.

In patients suering from bipolar depression ECT, like any other antidepressant agent (Angst et al., 1992), can induce hypomania or mania ( switch ) (Angst et al., 1992). Concomitant lithium therapy (Zarate et al., 1997) can be used despite the higher risk of side eects such as prolonged muscle relaxation and confusional states. The use of mood stabilizers, such as valproate, lamotrigine or carbamazepine (if required, at lower doses than usual), is possible despite the anticonvulsant properties of these agents (Zarate et al., 1997). Both methods can signicantly reduce the switch risk. 19.3.7.2 Cognitive side eects All patients are confused on awakening after a seizure. The duration and severity of the post-seizure delirium vary with age (older patients have more severe and more prolonged periods of confusion), dosage and type of anesthetic, and the characteristics of the medications, both psychoactive and systemic, that have been prescribed. Special attention is paid to sedatives and anxiolytics, antipsychotics and lithium, which may enhance the confusional syndrome. Transient cognitive disturbances are typical side eects that are more prominent in bilateral than in unilateral and in high-dose than in lower-dose ECT (ECT review group, 2003). These include short-term memory disturbances in up to 30 % of patients treated (van Waarde and Stek, 2001). Postictal delirium, including a prolonged reorientation period and memory disturbances such as anterograde and retrograde

amnesia, can be dierentiated from rarely occurring eects on autobiographic long-term memory (Lisanby et al., 2000). In addition, cognitive decits that are not a product of memory disturbances, such as concentration or attention decits can occur. It can be dicult in an individual patient to dierentiate cognitive side eects of an ECT treatment from cognitive disturbances caused by depression itself (Lisanby et al., 2003a). A variety of patients report amelioration of cognitive impairment after a course of ECT treatment (Devanand et al., 1991). As described, the rate of cognitive disturbances depends on dose and application of electrical stimulation (Devanand et al., 1991 ; Krystal and Coey, 1997). Sometimes patients experience profound and sustained memory loss, sucient to interfere with their ability to return to work. Such instances are rare, but constitute the principal burden of complaints against the use of ECT (Abrams, 2002 ; Ottoson and Fink, 2004). Nevertheless, recent improvements in the use of ECT include methods to maintain good therapeutic ecacy together with better tolerability concerning cognitive disturbances. Modied ECT techniques (Ghaziuddin et al., 2000), including unilateral and bifrontal pulse wave stimulation, anesthesia with muscle relaxation and sucient oxygenation, could substantially reduce these risks (Ghaziuddin et al., 2000 ; Sackeim et al., 1993 ; Sackeim et al., 2000). If cognitive disturbances occur despite these precautions, rapid improvement within 1 and up to

CINP Antidepressant Task Force 2007 4 weeks can be observed in most cases (Ghaziuddin et al., 2000). Follow-up investigations showed a complete reversibility of cognitive side eects following an ECT course (Ghaziuddin et al., 2000 ; Krause et al., 1988) and even improvement in comparison with the time interval before ECT treatment (Baghai et al., 2005 ; Krause et al., 1988). A variety of case reports, case series and controlled studies conrm that ECT does not cause long-lasting functional impairment (Krause et al., 1988) or any structural damage of the central nervous system (Devanand et al., 1991 ; Krause et al., 1988 ; Lisanby et al., 2003b). 19.3.8 Clinical precautions and special considerations After many decades of research and clinical experience, clinicians have developed protocols for the safe treatment of patients who warrant ECT regardless of age, medical status or physical condition. Conditions that carry higher somatic risks include recent myocardial or cerebral infarction, high intracranial pressure, normal pressure hydrocephalus with risk for herniation and every other untreated severe medical and life-threatening anesthesiological risk. If treated suciently, these conditions become relative contraindications, and a risk-benet analysis must be performed for each patient on an individual and interdisciplinary basis. Other conditions associated with enhanced cardiovascular risk include coronary artery disease, arrhythmias, insuciently treated hypertonia and aneurysms. Other medical conditions, such as severe lung and liver diseases, disturbances of blood coagulation and untreated pheochromocytoma, also enhance the risk associated with ECT and anesthesia. Neurological diseases, including intracranial tumors and bleeding, vascular malformations, cerebral ischemia, acute infections and others enhance treatment risk. In general, each factor that enhances the risk of side eects for ECT and anesthesia should be taken into consideration. In the case of specic risks, interdisciplinary counseling may be necessary. Next, the higher somatic risk must be compared with the risk of insuciently treated or prolonged psychiatric illness. Patients and relatives or responsible legal guardians need to be informed about risk-benet ratios so they can share in the decision making. 19.4 Annex 4 : Additional information on transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) was originally introduced in 1985 by Barker et al. as a noninvasive tool to electromagnetically stimulate the primary motor cortex in humans (Lisanby et al.,

S189

2003b). More recently, repetitive TMS (rTMS) has become a powerful research tool in neurophysiology and cognitive neuroscience. rTMS is usually targeted to the dorsolateral prefrontal cortex based on well-replicated ndings that show reversible functional changes in this region using dierent neuroimaging techniques. The majority of studies focus on the left prefrontal cortex based on the observed asymmetry of prefrontal function associated with major depression (Lisanby et al., 2003b). A large number of dierent stimulation parameters, e.g. frequency and intensity of stimulation, have been applied in studies, and very few studies have compared dierent treatment modalities (Padberg and Moller, 2003). The usual treatment dur ation has been 14 weeks of treatment, and in most studies rTMS has been used as an add-on intervention with a stable antidepressant medication. Some 25 randomized placebo-controlled clinical trials, including about 750 patients suering from major depressive episodes, have been conducted to date investigating the safety and ecacy of rTMS as an antidepressant intervention (Berman et al., 2000b ; Burt et al., 2002 ; Dolberg et al., 2002 ; Garcia-Toro et al., 2001a ; Garcia-Toro et al., 2001b ; Kaumann et al., 2004 ; Loo et al., 2003 ; Miniussi et al., 2005 ; Mosimann et al., 2004 ; Nahas et al., 2003 ; Padberg et al., 1999 ; Padberg et al., 2002 ; Padberg and Moller, 2003 ; Pascual-Leone et al., 1996 ; Rossini et al., 2005). In the majority of these trials, signicant placebo/verum dierences have been observed, with antidepressant eects ranging from modest to substantial. Due to the methodological limitations of many of these trials stemming from rather small sample sizes, the diculty of controlling sham rTMS used as placebo condition, modied double-blind designs with the person applying rTMS being aware of the condition and patient and rating psychiatrist being blinded, and the short observation periods, the level of evidence currently provided by the available data still needs improvement. Several meta-analyses have been conducted that dier largely in the studies selected and the methodology of analysis used (Burt et al., 2002 ; Couturier, 2005 ; Ebmeier et al., 2006 ; Martin et al., 2003 ; Pascual-Leone et al., 1996 ; SchulzeRauschenbach et al., 2005). Most of these metaanalyses support the antidepressant ecacy of rTMS, but the clinical eects found are not very strong and the clinical signicance may be questionable. rTMS has also been directly compared with ECT in ve parallel design trials (Grunhaus et al., 2000 ; Grunhaus et al., 2003 ; Pridmore et al., 2000 ; SchulzeRauschenbach et al., 2005). In these trials rTMS was found to be as eective as ECT in patients suering

S190

CINP Antidepressant Task Force 2007 the left dorsolateral prefrontal cortex applied over 24 weeks, and rTMS may also be successfully used as an adjuvant antidepressant intervention. Patients with psychotic symptoms appear to respond only poorly to rTMS. There is no evidence that rTMS-associated antidepressant eects are stable beyond the end of rTMS treatment. Thus, continuation therapy should be planned and initiated as recommended by current clinical guidelines. Since the antidepressant ecacy of rTMS has still not been suciently proven owing to the methodological limitations of previous clinical trials, the results of several ongoing placebo-controlled multicenter trials in the US and Germany are expected to clarify the role of rTMS within the range of antidepressant interventions. 19.5 Annex 5 : Additional information on vagus nerve stimulation In the 1980s and 1990s vagus nerve stimulation (VNS) was developed in animal models for its putative anticonvulsant action. It was approved by the FDA and introduced into the routine treatment of therapyresistant focal epilepsies about a decade ago. Theoretical considerations regarding the functional anatomy of the vagus nerve also projecting to areas of the brain relevant for generation and control of mood and emotions, but also observations of mood changes in epilepsy patients undergoing VNS, have triggered the application of VNS in depressive disorders (George et al., 2003). A NeuroCybernetic Prosthesis (NCP) System is used for VNS that consists of a pulse generator implanted into the thoracic wall and subcutaneously implanted bipolar leads linked to the left vagal nerve. This system has been investigated in a series of open and controlled clinical trials as part of an industrial development program, and the data of the complete trial set have been published (George et al., 2005 ; Nahas et al., 2005 ; Rush et al., 2000 ; Rush et al., 2005b ; Rush et al., 2005a ; Sackeim et al., 2001b). The rst open study (D-01) showed clinically meaningful eects over a period of 2 years, with response rates between 42 and 45 % (dened as at least 50 % reduction of baseline HAMD scores) and remission rates between 21 and 22 % (Rush et al., 2000 ; Sackeim et al., 2001b). However, all patients included in the rst open study received additional antidepressant medication, which also was changed over time. The promising results of this open pilot study led to a double-blind randomized placebo-controlled multicenter trial (D-02 study) that included 235 patients who received either active or placebo stimulation during a 10-week period (Rush et al., 2005a).

from major depressive episodes without psychotic features, but to be inferior for psychotic depression (Grunhaus et al., 2000). Surprisingly, only one study compared dierent rTMS modalities with antidepressant pharmacotherapy (clomipramine) ; however, no meaningful interpretation of the results in terms of ecacy was possible due to small sizes of treatment groups (Lisanby et al., 2001b). Four trials have investigated combined treatment with active rTMS plus antidepressant compared with sham rTMS plus antidepressant to answer the question whether rTMS augments the eect of antidepressant medication (Lisanby et al., 2001b ; Rumi et al., 2005). Only one study that combined rTMS with amitriptyline reported signicant superiority of combined active treatment (Rumi et al., 2005), whereas the other trials, which applied SSRIs and other substances, failed to show a signicant dierence between treatment groups. These results may support the idea of rTMS being particularly eective combined with distinct neuropharmacological actions, and this hypothesis should be systematically addressed by future studies. Apart from single studies and case reports, little is known regarding the stability of eects and potential maintenance treatment strategies (Pascual-Leone et al., 1996). The largest body evidence points to transient eects following completion of rTMS treatment (Pascual-Leone et al., 1996 ; Schule et al., 2003). rTMS appears to be safe and well tolerated by patients within a range of parameters dened according to a consensus (Wassermann, 1998). Side eects include the risk of seizure, which increases with higher intensity and higher frequency of stimulation as well as shorter intertrain intervals. Since safety criteria for limiting these stimulation parameters have been published, no additional seizures have been reported within these limits. Among the side eects that are frequently observed are slight local painful stimulation artifacts on the scalp, transient headaches following stimulation and single cases of autonomous arousal reactions, including dizziness and fainting (personal communications). Clinical contraindications include implanted devices (pacemakers), intracranial articles of ferromagnetic material, a history of epileptic seizures and brain injuries or surgery. Particular attention should also be paid to the psychiatric side effects of rTMS, including the risk for switching into hypomania and manic states, particularly in patients with bipolar disorder, and de novo induction of psychotic symptoms (Padberg and Moller, 2003 ; Rush et al., 2000). In conclusion, considerable evidence argues for the antidepressant ecacy of high-frequency rTMS over

CINP Antidepressant Task Force 2007 After completion of the acute treatment period, all patients received continuous treatment, and long-term data on 205 patients following 12 months of stimulation were recently published (Rush et al., 2005b). Patients of the placebo group also received active treatment during the long-term period, and changes in the concomitant treatment (medication and psychotherapy) were allowed according to clinical requirements ( treatment as usual , TAU). The primary ecacy criteria of the acute study were the number of responders in the treatment groups. No dierence between those groups was found in the acute study (15 % response in the active vs. 10 % response in the placebo group), nor were signicant dierences among the secondary ecacy criteria (self- and observer ratings) observed (Rush et al., 2005a). The negative nding in the acute study was discussed as being due to the low stimulation intensity applied in the active group (0.67 mA vs. 0.96 mA in the D-01 study). To make sense of the clinical meaning of the long-term data in terms of ecacy, a comparison study was initiated (D-04) that included 124 patients receiving only TAU (George et al., 2005). This study had the same inclusion criteria as the D-02 study : chronic depressive episode (duration longer than 2 years) or recurrent depression (more than four episodes, including the current episode), an HAMD baseline score >20 and nonresponse after two to four appropriate antidepressant medication trials. After 12 months, a clinical response was found in 29.8 % of the patients included in the D-02 study, whereas only 12.5 % responded in the D-04 study ; remission was achieved in 17.1 % of the D-02 study compared with 6.7 % of the D-04 study (George et al., 2005). Concerning the safety of VNS, the results of the studies in epilepsy were essentially conrmed. Following the acute period, the D-02 study found voice alterations, increased cough, dyspnea, neck pain, dysphagia, laryngismus, paraesthesia and pharyngitis (Rush et al., 2005a). During long-term treatment over 1 year most of these adverse events showed a clear decline (Rush et al., 2005b). Based on the ecacy and safety data, the VNS therapy system was recently approved by the FDA for the adjuvant, long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. Despite the recent FDA approval, the body of evidence testifying that VNS exerts antidepressant eects superior to placebo is still limited and mainly based on long-term data compared with naturalistic treatment.

S191

A placebo-controlled trial is urgently needed to clarify the issues arising from the D-02 acute study, and to provide more data for the ecacy of VNS in depression. Because of its invasive nature, VNS should be reserved for special clinical cases where the patients demand for this treatment is high, several other interventions have failed and a clinical benet is likely. VNS should only be used where thorough medical follow-up can be guaranteed. 19.6 Annex 6 : Additional information on acupuncture 19.6.1 Ecacy

Due to the fact that the use of complementary and alternative therapies is overrepresented in patients suering from depressive syndromes (Kessler et al., 2001), the actual knowledge about the main therapeutic options in this eld need to be evaluated. The history of acupuncture in Eastern culture goes back more than 4000 years, and traditional Chinese medicine describes its inuence on the balance of health and energy in the human body. The original practice involves inserting needles into specic trigger points at dierent parts of the body. Electro-acupuncture (EA) includes electrical stimulation of classical trigger points using sine wave and undulatory wave stimulation of dierent frequencies. An inuence on breceptor function (Fan, 1992) and central serotonergic (Fan, 1992) and noradrenergic (Meng et al., 1994) functions in depressed patients responding to EA has been suggested. Despite a variety of published studies in this eld, a recent review describes insucient evidence to determine the ecacy of acupuncture in comparison with pharmacological antidepressant treatment (Smith and Hay, 2005). The cause for this uncertainty is the methodological quality of the investigations published up to now. Nevertheless, some of these controlled studies are presented below to describe the present state of information. In a comparative randomized controlled trial 20 patients suering from depression were treated with traditional acupuncture or the TCA amitriptyline. No signicant dierences between the treatment groups could be seen, but due to the relatively small number of patients, the study seems to be underpowered (Yang et al., 1994). Further studies investigated EA in comparison with amitriptyline and placebo in an analysis of two separate study parts. Again, therapeutic eects in the treatment groups showed no signicant dierences. A better therapeutic eect on anxiety and cognitive symptoms following acupuncture has been

S192

CINP Antidepressant Task Force 2007 (sleep deprivation), sleep-phase advance therapy and light therapy (Wirz-Justice et al., 2005). 19.7.1 Wake therapy

described (Allen and Schnyer, 1998). Similarly, a variety of Chinese RCTs found no signicant dierences between EA or computerized EA and amitriptyline treatment (Luo et al., 1985 ; Luo et al., 1988 ; Luo et al., 1990b ; Luo et al., 1990a ; Luo et al., 1998) (see (Luo et al., 1995 ; Meng et al., 2002) for review). A further study compared acupuncture for depression with acupuncture for other complaints and a group of patients waiting for treatment (n=35). Patients receiving depression-specic acupuncture showed signicantly more improvement than the group receiving non-specic acupuncture, but no signicant dierence from the placebo condition in waiting-list patients could be seen (Allen and Schnyer, 1998). A single blind study also compared depressionspecic and non-specic acupuncture with mianserin monotherapy in a total of 70 patients. Additionally, acupuncture improved depression more than treatment with mianserin. No dierences between either forms of acupuncture could be seen (Roschke et al., 2000). Moreover, specic acupuncture showed a greater and lasting amelioration of symptoms in women suering from depression during pregnancy (Manber et al., 2004). Other authors describe some evidence for the clinical eectiveness of acupuncture, but mention that further studies are needed before recommendations can be made (Gallagher et al., 2001 ; Manber et al., 2002). Note also that to be able to compare dierent investigations will require not only randomized controlled trials of adequate power but also a detailed description of standardized procedures in acupuncture. Finally, adequate blinding of physicians and patients together with standardized outcome measures are also needed before clinical and scientic recommendations can be made (Smith and Hay, 2005). 19.6.2 Safety and tolerability

An overall good safety and tolerability of acupuncture has been described. Especially in trials comparing TCA with acupuncture, typical side eects were much less in the acupuncture groups (American Psychiatric Association, 1994). Studies comparing modern and better-tolerated antidepressants have not been published up to now. 19.7 Annex 7 : Additional information on chronotherapeutics : light and wake therapy Chronotherapeutics refers to treatments that modulate the circadian and seasonal rhythms of mood and sleep regulation. These manipulations include wake therapy

Numerous studies have conrmed that the majority of patients with depression who abstain from a nights sleep obtain immediate relief from depression (Kuhs and Tolle, 1991 ; Ostenfeld, 1973 ; Wu and Bunney, 1990), often with full, although temporary remission. This eect appears to be most pronounced in patients with bipolar illness and in those with diurnal or dayto-day mood variation (Kuhs and Tolle, 1991). The mechanism of action is unknown but may rest on the reduction of REM sleep, which is believed to be depressogenic (Riemann et al., 1994). Wake therapy has been and remains in many countries a standard method for treating depression, most often as an augmentation strategy with drug treatment. Wake therapy is used either in the form of a whole nights waking (total sleep deprivation) or staying awake in the latter part of the night (partial sleep deprivation). A procedural elaboration, which sustains the rst-day benet, is to use sleep deprivation followed by a sleep phase advance in which the habitual sleep time is gradually approached over several nights (Berger et al., 2003 ; Voderholzer et al., 2003). Used on its own, a substantial number of patients will relapse into depression when resuming normal sleep (Wu and Bunney, 1990). However, new methods have been developed over the last decade that are designed to maintain the antidepressant response of wake therapy (Neumeister et al., 1996 ; Wirz-Justice et al., 2005). The simplest form simply repeats wake therapy for a number of nights, with recovery nights interspersed. A simple and well-tested protocol repeats wake therapy three times over a period of 5 days (Colombo et al., 2000). Other methods to sustain the antidepressant eect of sleep deprivation include combination with antidepressant drugs, pindolol, lithium and the use of bright light therapy, all of which have been shown to eectively reduce the relapse into depression after wake therapy (Benedetti et al., 1999 ; Colombo et al., 2000 ; Smeraldi et al., 1999 ; Szuba et al., 1994). Even though wake therapy is almost exclusively used in an inpatient setting for both inpatients and visiting outpatients, one study has been carried out using home wake treatment (Loving et al., 2002). The switch rate into mania for bipolar patients is no higher than with the use of antidepressant drugs (Colombo et al., 1999), and the suicide risk does not appear to be increased (Kuhs and Tolle, 1991 ; Vovin and Fakturovich, 1985). Caution is, however, warranted in

CINP Antidepressant Task Force 2007 the course of wake therapy due to occasional steep mood swings experienced in the course of the protocol. There is some evidence to suggest that patients with high levels of anxiety and panic attacks improve less from wake therapy and that they may develop panic attacks on the day after sleep deprivation (RoyByrne et al., 1986). The research eld needs larger trials with suitable control groups to assess the absolute magnitude of the wake therapy eect and trials of longer duration to assess the relapse pattern in dierent patient groups. A treatment manual (Benedetti et al., 2006) and guidelines are in preparation. 19.7.2 Light therapy The modern and systematic use of light treatment in psychiatry stems from the observation by Rosenthal and colleagues in the early 1980s of recurrent winter depression and the subsequent evidence that light treatment alleviated the depressive symptoms (Rosenthal et al., 1984). Seasonal aective disorder (SAD) is now incorporated in the DSM-IV diagnostic system as a subtype of major depression ( with seasonal pattern ) (American Psychiatric Association, 1994). Light therapy has seen an extensive research eort, and its antidepressant eect and chronobiological eects have now been established in several systematic reviews and in many clinical studies (Golden et al., 2005 ; Kripke, 1998 ; Terman and Terman, 2005 ; Tuunainen et al., 2004 ; Winkler et al., 2005b). Light treatment has been used in SAD as a monotherapy and and in non-seasonal depression (chronic and recurrent) both as a monotherapy and as augmentation with drugs. Light treatment is performed by the use of a light box that produces 10000 lux, wide-screen, ultraviolet-ltered diuse white uorescent light. Narrow-band spectra with blue or green appearance have been investigated, but the data are insucient to recommend their use. Additionally, there is a suspected retinal hazard of blue-light exposure, which may damage retinal structures and ex acerbate age-related macular degeneration (Reme et al., 2001). Light boxes come in many designs, but larger screens that emit diuse light are best tolerated and maximize desired stimulation of the peripheral retina. Light treatment from ambulatory, battery-powered light visors is available, but controlled data have not shown a benet relative to placebo dim light. Another variant is gradually incremental dawn simulation that mimics outdoor sunrise in the bedroom, where the signal is often absent or decient. This method uses far lower light intensity than in post-awakening bright

S193

light therapy, yet has shown ecacy in several trials of SAD, where a simulated springtime sunrise is presented in winter (Avery and Norden, 1998). Finally, going outdoors into natural sunlight can be eective, assuming good weather conditions and seasonal availability of early morning sunlight (Wirz-Justice et al., 1996). Treatment duration is in the range of 30 minutes to 1 hour, preferably in the morning upon awakening. A dose-response eect has been conrmed, thus enabling treatment regimens with shorter exposure duration at higher intensity (Sondergaard et al., 2006 ; Terman et al., 1990). For SAD, the duration of treatment extends throughout the dark season in order to forestall relapse (Lam et al., 1999). For non-seasonal depression, light therapy presumably works as an accelerating agent in combination with drugs, although recent evidence indicates only a short-lived positive eect when the lights are discontinued (Martiny, 2004 ; Martiny et al., 2006). Light treatment in non-seasonal depression should thus optimally be used until remission is reached and sustained for at least 812 weeks of daily treatment ; it can easily be resumed if there is subsequent relapse. The use of light treatment thus far has not shown any long-term damage to the visual system (Reme et al., 2001). Acute side eects are limited to milder degrees of headache and blurring of vision, and nausea and irritability, which can be alleviated by decreasing light intensity or increasing the distance from the screen. Hypomania can occur but is often of milder degree and short-lived when light is discontinued. Patients with bipolar disorder should use light therapy only in conjunction with moodstabilizing medication (Terman and Terman, 1999). 19.8 Annex 8 : Additional information on psychotherapy Empirically supported psychotherapies are potent alternatives to and augmenters in combination with antidepressant medications. Although psychotherapies have received less study than pharmacotherapies, randomized controlled studies have demonstrated the ecacy of some psychosocial interventions, acutely and as maintenance treatments, both as monotherapies and in combination with medication as antidepressant treatments. The empirically based psychotherapies, principally cognitive behavioral therapy (CBT) (Beck et al., 1979), interpersonal psychotherapy (IPT) (Weissman et al., 2000) and behavioral therapy (e.g. Martell et al., 2001), have advantages and disadvantages relative to pharmacotherapy, and dierential benets may exist among

S194

CINP Antidepressant Task Force 2007 This presumably indicates that psychotherapy provides patients with methods for handling new psychosocial problems, potential triggers of depressive episodes that arise in their lives after acute treatment ends. The empirical evidence for psychotherapy as monotherapy for chronic depression is sparser and less strong. The Cognitive Behavioral Analysis System of Psychotherapy (CPASP) (McCullough, 2003) was as ecacious as nefazodone both acutely and as maintenance treatment in one large (n=681) study of chronic depressive disorders ; the combination of nefazodone and CBASP was superior to either monotherapy (Keller et al., 2000). This impressive nding requires replication, as it is the only CBASP trial published to date. IPT and CBT have shown less benet than pharmacotherapy for dysthymic patients (Markowitz et al., 2005 ; Ravindran et al., 1999), albeit combined IPT and sertraline was cost-eective relative to pharmacotherapy alone in one study (Browne et al., 2002). 19.8.2 Combination treatment with antidepressant medication and psychotherapy Combined treatment studies often have been confounded by inadequate power, dierential attrition and other methodological diculties. Large sample sizes are required to nd dierences between active monotherapies and combined treatment. Nonetheless, no research trial has shown combined treatment to be less ecacious than antidepressant monotherapy (Manning et al., 1992). Given health economics considerations, combined treatment may best be reserved for patients with chronic, highly comorbid, severe depressions, or those at high suicide risk (Hollon et al., 2005 ; Rush, 1999). In an open trial in menopausal depressed women cognitive therapies have been shown to enhance the ecacy of the SSRI uoxetine especially in combination treatments. As a possible mechanism of action a better normalization of serotonin and noradrenaline levels has been suggested (Gaszner, 2005). 19.8.3 Psychotherapy as adjunct to pharmacotherapy

these psychotherapies for depressed patients with particular moderating factors. Most psychotherapy outcome research has involved individual psychotherapy, although group and family therapies have received some study. Empirically validated treatments are time-limited, diagnosis-focused and address current life problems rather than the past. Of the many forms of extant psychotherapy, only a few have received empirical assessment ; the antidepressant benets of the remainder remain unclear. 19.8.1 Psychotherapies as primary treatment for mood disorders After decades of psychotherapists avoiding structured research, researchers in the 1970s began to conduct randomized controlled trials (RCTs) of psychotherapies for non-delusional outpatients with depressive disorders. In addition to incorporating research paradigms from pharmacotherapy trials (e.g. random assignment, blinded independent assessment), researchers wrote manuals to dene particular treatment approaches, such as CBT and IPT. Treatment sessions were recorded to ensure therapist adherence to the treatment approach, which was reinforced by frequent supervision. Psychotherapies were initially compared with waiting lists or low-contact conditions, but increasingly also to active treatments, including antidepressant medication (e.g. Elkin et al., 1989). These trials yielded repeated evidence of the ecacy of CBT and IPT as treatments for depressive disorders (Hollon et al., 2005), leading to their incorporation into national and professional treatment guidelines (American Psychiatric Association, 2000 ; Depression Guideline Panel, 1993 ; Karasu et al., 1993 ; Roth and Fonagy, 2004). Lacking funding from an industry, psychotherapy researchers have conducted fewer trials than pharmacotherapy researchers. In general, empirically supported psychotherapies have demonstrated similar response and remission rates to pharmacotherapy for outpatients with depressive disorders. They treat mood and demoralization more quickly than neurovegetative symptoms of depression, the reverse of the pattern seen for antidepressant medications. Beyond acute ecacy, IPT and CBT have been shown to provide prophylaxis against relapse and recurrence when prescribed as less frequently scheduled (e.g. monthly) maintenance treatments (Frank et al., 1990 ; Hollon et al., 2005). Studies of CBT suggest an enduring eect even for acute psychotherapy, a lasting protective benet not seen when pharmacotherapy is discontinued (Hollon et al., 2005).

Some depressed patients remit on antidepressant medication and require no additional treatment. Others, particularly chronically depressed patients, may improve symptomatically yet still function less than optimally, or feel unsure about social risks or career decisions. Such patients may benet from adjunctive psychotherapy (Markowitz, 1993) to expand their social condence or behavioral repertoire. In addition, so-called sequential therapy, the use of CBT

CINP Antidepressant Task Force 2007 after remission achieved with antidepressants for acute treatment, may be of use (see (Fava and Ruini, 2002) for review). 19.8.4 Dierential therapeutics Behavioral therapy helps patients to schedule pleasurable activities while avoiding painful ones. Cognitive therapy, usually combined with behavioral techniques, helps patients to identify cognitive distortions with depressive biases, thoughts that are unnecessarily painful, pessimistic and which inhibit potentially valuable activity. IPT denes depression as a medical disorder and focuses on the connection between mood and social situations or life circumstances ; it has been shown to build social skills. Understandably, these therapies may have diering appeals and benets for dierent depressed individuals. A few RCTs have directly compared IPT and CBT (Elkin et al., 1989 ; Rossello and Bernal, 1999) or cognitive therapy and behavioral therapy (Jacobson et al., 1996). While showing non-signicant dierences in outcome, these trials allowed evaluation of moderators of treatment outcome. For example, patients with poor concentration may respond better to IPT than CBT, whereas those with a paucity of social skills may fare better in CBT than IPT (Sotsky et al., 1991). Far more research of dierential therapeutics is needed. 19.8.5 Comparing medications and psychotherapies Medications work faster than psychotherapies and are easier to administer to large populations, although the therapeutic alliance is equally important for both antidepressant modalities (Krupnick et al., 1996). Empirically validated psychotherapies lack medication interactions, and have low adverse eects and little risk of inducing mania in depressed bipolar patients. They may address social stressors, such as marital pressures, that could potentially trigger future episodes. Psychotherapies have potential advantages for depressed women during pregnancy and nursing ; may be better accepted by adolescents, particularly given recent concerns about serotonin reuptake inhibitors in this population ; and although not well tested for depressed children, may be indicated inasmuch as medication has not shown benet. In nonindustrialized countries, such psychotherapies may be the only feasible, aordable treatments for depression (Bolton et al., 2003). Psychotherapies adapted to different cultures must address the specic needs and sensitivities of individuals in those cultures.

S195

Psychotherapies are not intended to treat depression with psychotic features, nor as monotherapy for bipolar I disorder (Frank et al., 2005 ; Miklowitz et al., 2003). Some severely depressed patients may be too depleted to engage in psychotherapy eectively. Patient preference is a predictor of treatment outcome and hence deserves consideration in treatment selection. On the basis of their performance in controlled ecacy trials, IPT and CBT should be included in algorithms of standard treatment for depressive disorders. 19.8.6 The attitude to CBT and IPT in Korea

Evidence-based medicine has begun to inuence the eld of mental health in response to demands for accountability and to address the well-documented disparity between scientic evidence and actual practice (Chatterjee et al., 2006). Psychotherapy is widely practiced but has been less intensively studied than pharmacotherapy because it has no industry to fund it. Nevertheless, several prominent studies have demonstrated the eectiveness of psychological approaches in patients with depression. Practice guidelines published by several countries, including the UK (National Institute for Health and Clinical Excellence, 2004), US (Beutler et al., 2000) and Canada (Segal et al., 2001b ; Segal et al., 2001a) suggest that psychotherapies for depression such as CBT and IPT are equivalent to drugs in terms of ecacy (DeRubeis et al., 1999 ; DeRubeis et al., 2005 ; Hollon et al., 2002). In Korea, pharmacotherapy for depression is widely used. CBT was introduced, but few RCTs of CBT in patients with depression have been published. Moreover, little is known about IPT among mental health professionals. Probably the most serious problems are the lack of IPT therapists (or supervisors) and a lack of systematic training programs. Our task is to resolve these problems. Ecacious psychotherapies such as CBT and IPT are both primary treatments and alternatives to pharmacotherapy for depression. The issue of combined psychotherapy and pharmacotherapy deserves consideration. Many clinicians recommend combined treatment for patients with depression, based simply on the belief that combined treatment is more eective than either pharmacotherapy alone or psychotherapy alone. However, a meta-analysis showed that combined therapy is superior to psychotherapy alone for treatment of more severe, recurrent depression (Thase et al., 1997). Combined treatment and antidepressant

S196

CINP Antidepressant Task Force 2007 no consistent dierences in ecacy between active compounds (Mitte et al., 2005). Psychological symptoms of anxiety may respond better to antidepressant drugs than to benzodiazepines (Baldwin and Polkinghorn, 2005). Double-blind studies in patients who have undergone acute treatment indicate that continuing with an SSRI or SNRI is associated with a further increase in overall response rates. Relapseprevention studies in patients who have responded to previous acute treatment reveal a signicant advantage for staying on active medication (escitalopram or paroxetine), compared with switching to placebo, for up to 6 months (Baldwin and Polkinghorn, 2005). When delivered singly, pharmacological and psychological treatments have broadly similar ecacy in acute treatment, but the comparative ecacy of drug and psychological approaches over the long term is not established. It is uncertain whether combining drug and psychological treatments is associated with greater ecacy than with either treatment given alone (Baldwin and Polkinghorn, 2005). 19.9.2 Panic disorder

alone, however, have similar ecacy and acceptability (de Mello et al., 2005 ; Markowitz et al., 2005). This absence of an adjunctive eect for psychotherapy seems counterintuitive. Note that several characteristics of patients and disorders have been related to dierential treatment response. Some studies show that psychotherapy helps to keep patients in pharmacotherapy (Pampallona et al., 2004) and to discontinue medication without increasing the risk for subsequent relapse or recurrence (Hollon et al., 2005). Combined treatment is likely to be recommended for patients with more complex or chronic disorders, or with a clinically unsatisfactory response to either monotherapy (Hollon et al., 2005). Yet whether combined treatment is more eective than either monotherapy is controversial. Further studies are required. 19.9 Annex 9 : Additional information on antidepressant drugs in the treatment of anxiety disorders The proven ecacy of antidepressant drugs in relieving anxiety symptoms in patients with depressive disorders naturally led to investigations of their potential to relieve symptoms and reduce associated disability in patients with anxiety disorders, including generalized anxiety disorder (GAD), panic disorder, social phobia (also known as social anxiety disorder), post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). In clinical practice, the need for treatment should be determined by the severity and persistence of symptoms, and the level of disability and impact on social functioning ; choice of treatment is inuenced by patient characteristics (such as previous response, concomitant medication and contraindications), the evidence base supporting its use, patient and physician preference, and the local availability of the proposed intervention (Baldwin and Polkinghorn, 2005). In general, in comparison with mood disorders higher doses and longer time of treatment are required to achieve response in anxiety disorders. 19.9.1 Generalized anxiety disorder

In GAD, systematic reviews and placebocontrolled randomized controlled trials (RCTs) indicate that some SSRIs (escitalopram, paroxetine and sertraline), the SNRI venlafaxine, and the TCA imipramine are all ecacious in acute treatment (Baldwin and Polkinghorn, 2005 ; Mitte et al., 2005). The small number of comparator-controlled studies reveals

Randomized double-blind placebo-controlled trials of antidepressants indicate that all SSRIs, some TCAs (clomipramine, imipramine), and the SNRIs venlafaxine and the NARI reboxetine are ecacious in acute treatment. Comparator-controlled studies provide some evidence for the ecacy of mirtazapine and moclobemide. The side-eect burden associated with SSRI treatment in panic disorder is somewhat less than with other classes of psychotropic drugs (Baldwin and Birtwistle, 1998). Following acute treatment, continuing with SSRIs or clomipramine is associated with an increase in overall response rates, and placebocontrolled and other relapse-prevention studies in patients who have responded to acute treatment reveal a signicant advantage for staying on active medication (uoxetine, paroxetine, sertraline, imipramine) compared with switching to placebo, for up to 6 months (Baldwin and Polkinghorn, 2005). Pooled analyses and RCTs indicate that drug and psychological treatments, delivered singly, have similar ecacy in acute treatment, but suggest that CBT may be superior to TCAs in preventing symptomatic relapse (van Balkom et al., 1997). It has been mentioned that there is some uncertainty whether combining drug and psychological treatments is associated with greater overall ecacy than with either treatment given alone (Barlow et al., 2000 ; van Balkom et al., 1997), but a recently published meta-analysis showed that combined therapy was more eective

CINP Antidepressant Task Force 2007 than pharmacotherapy alone and was as eective as psychotherapy (Furukawa et al., 2006). Therefore, either combined therapy or psychotherapy alone has been recommended as a rst-line treatment for panic disorder. 19.9.3 Social phobia Systematic reviews and placebo-controlled RCTs indicate that a range of antidepressants are ecacious, including most SSRIs (escitalopram, uoxetine, uvoxamine, paroxetine and sertraline), the SNRI venlafaxine, the MAOI phenelzine, and the RIMA moclobemide. Double-blind studies indicate that continuing SSRI or SNRI treatment from 12 weeks to 24 weeks is associated with an increase in overall treatment response rates. Placebo-controlled relapseprevention studies in patients who have responded to previous acute treatment reveal a signicant advantage for staying on antidepressant medication (escitalopram, paroxetine and sertraline), compared with switching to placebo for up to 6 months (Baldwin and Polkinghorn, 2005 ; Blanco et al., 2003). When delivered singly, pharmacological and psychological treatments have broadly similar ecacy in acute treatment, but acute treatment with cognitive therapy may be associated with reduced risk of symptomatic relapse at follow-up. It is uncertain whether combining drug and psychological treatments is associated with greater overall ecacy than with either treatment given alone (Baldwin and Polkinghorn, 2005 ; Blanco et al., 2003). 19.9.4 Post-traumatic stress disorder Randomized, placebo-controlled trials provide evidence for the ecacy of some SSRIs (uoxetine, paroxetine and sertraline), the SNRI venlafaxine, the TCAs amitriptyline and imipramine, the MAOI phenelzine and mirtazapine on some outcome measures (Baldwin and Polkinghorn, 2005 ; Stein et al., 2000). Following response to acute treatment, continuing with venlafaxine or sertraline treatment over 6 months is associated with a gradual increase in overall treatment response. Placebo-controlled relapse-prevention studies in patients who have responded to previous acute treatment reveal a signicant advantage for staying on active medication, for uoxetine (Davidson et al., 2005 ; Martenyi et al., 2002) and sertraline (Davidson et al., 2001). The comparative ecacy of psychological and pharmacological treatments, in either acute or long-term treatment, is uncertain (Baldwin and Polkinghorn, 2005). 19.9.5 Obsessive-compulsive disorder

S197

Systematic reviews and meta-analyses of randomized placebo-controlled trials indicate that the TCA clomipramine and the SSRIs (citalopram, escitalopram, uoxetine, uvoxamine, paroxetine and sertraline) are ecacious in acute treatment. The ecacy of clomipramine appears marginally superior to that of SSRIs in meta-analysis (Ackerman and Greenland, 2002), but the tolerability of SSRIs is generally superior (Fineberg and Gale, 2005). Fixed-dose comparator studies provide inconsistent evidence for a dose-response relationship with SSRIs, higher doses being associated with greater ecacy in some, but not all evaluations (Fineberg and Gale, 2005). Long-term (up to 12 months) double-blind studies show an advantage for continuing with medication in patients responding to acute treatment. Most relapse-prevention studies in patients who have responded to acute treatment reveal a signicant advantage for staying on active medication (clomipramine, paroxetine, sertraline and uoxetine, at higher dose), compared with switching to placebo (Fineberg and Gale, 2005). Combining treatment approaches may be superior to psychological approaches or serotonergic antidepressant treatment given alone. The evidence for enhanced ecacy of exposure therapy with clomipramine compared with exposure alone is inconsistent, but uvoxamine has been shown to enhance the ecacy of exposure therapy and CBT. Relapse rates may be greater after initial treatment with a pharmacological rather than a psychological intervention (Simpson et al., 2004). 19.10 Annex 10 : List of regional meetings and countries represented
Regional meeting Participating countries St. Petersburg, Russia Munich, Germany Shanghai, China Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyz Republic, Russia, Ukraine, Uzbekistan Austria, Denmark, Germany, Greece, Croatia, Czech Republic, Hungary, Poland, Serbia, Slovakia, Switzerland Australia, China, Hong Kong, Indonesia, Japan, Korea, Pakistan, Philippines, Singapore, Taiwan, Thailand Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Honduras, Mexico, Nicaragua, Panama, Peru, Uruguay, Venezuela France, Egypt, Luxembourg, Morocco, Spain, Sweden, Tunisia, Turkey

Caracas, Venezuela

Paris, France

S198

CINP Antidepressant Task Force 2007 A budget for the meeting should be prepared, including expenditures for travel and accommodation of the participants, the cost of translation into the national language and the cost of hiring the meeting location if necessary. No honoraria should be requested. Proposals should be sent to Prof. N. Sartorius as soon as possible so that they can be included in the summary of work and proposals that will be submitted to the CINP. Publication of ndings It is expected that each of the national meetings will produce a local publication in the national language or in English. The publication should assemble the points that will be relevant for the use of antidepressant medications in the country. Should the group decide to also publish the Technical Review in the national language the convener should inform the CINP accordingly. The national reports will be brought together, and their ndings will be published in an international journal together with an update of the Technical Review (should an update prove to be necessary). The publications will be posted on the CINP website, together with the review. 19.12 Annex 12 : Additional information on the European Federation of Associations of Families of People with Mental Illness (EUFAMI) EUFAMI, the European Federation of Associations of Families of People with Mental Illness, is the representative body for voluntary organizations throughout Europe, promoting the interests and wellbeing of people with mental illness and their carers. Founded in 1992, EUFAMI is a democratic, memberled organization, registered in Brussels, under Belgian law. EUFAMI was formed by members of carer organizations who, overwhelmed by the trauma of severe mental illness in the family, and nding their ability to cope undermined, shared their experience of helplessness and frustration, and resolved to work together to help themselves and the people that they care for. Today, EUFAMI has 48 member organizations from 1 non-European and 26 European countries. EUFAMIs aims are to ensure the continuous improvement throughout Europe and by association around the world of the quality of care and welfare for people with mental illness and their families. To meet this need, EUFAMI lobbies governments to provide appropriate nancial support for families and carers as an integral part of their budget. EUFAMI also works to establish a charter of rights of families

19.11 Annex 11 : Suggestions concerning the organization of national review meetings Aims of the meeting The national meetings should help to bring together the experience and evidence about the use of antidepressant medications in the treatment of depressive disorders obtained in the countries where the meetings are taking place. Participants Participants in national meetings should be experts representing the elds of psychiatry, pharmacology, internal medicine and general practice, government ocials dealing with mental health and with questions of medications, representatives of family or patient organizations, and persons representing insurance and the pharmaceutical industry. In all, it is expected that 1215 participants will take part in the national meetings. Subsequently, it would be useful to bring the results of the review to the knowledge of larger audiences, both professional and non-professional, representing the stakeholders involved in the care for people with depressive disorders. The agenda and method of work All the participants should receive the CINP Technical Review in the language that they can easily use. The CINP Technical Review has been translated into Chinese, English, French, Russian and Spanish. It is also probable that an Arabic version will be prepared shortly. In some instances, a translation into the national language will be necessary. The meetings should take place after the participants have had a chance to examine the review and prepare their notes and proposals about additions, comments and changes that would reect the national experience and evidence obtained locally and which has not been included in the review. The agenda should include a detailed examination of the CINP Technical Review and a discussion that will lead to the formulation of a national report to be added to and considered in conjunction with the review. Administrative steps The convener of the national meeting should prepare a list of participants, a detailed agenda and a timetable for the meeting indicating its location and proposed dates. The proposal should also list the members of the CINP Task Force or other experts that the convener would like to invite as resource persons to the meeting.

CINP Antidepressant Task Force 2007 of carers and oers its services in teaching health professions and planning services for the mentally ill. 19.12.1
$

S199

19.13 Annex 13 : List of Advisors AGUILAR Mario, Vice-President, Honduran Society of Psychiatry maguilarhn@yahoo.com ALEMAN Luis Enrique, Secretary of the Nicaraguan Society of Psychiatry, Masaya lueman@ibw.com.ni ; hijproye@ibw.com.ni ALLAIN Herve, Laboratoire de Pharmacologie, Universite de Rennes I Faculte de Medecine, 35043 Rennes Cedex, France Herve.Allain@univ-rennes1.fr ALLILAIRE Jean-Francois, Chef du Service de Psychiatrie (Adultes), Consultation Chaslin, Hopital ` de la Salpetriere, 47, Bd de lHopital, 75651 Paris Cedex 13, France jf.allilaire@psl.ap-hop-paris.fr ALVAREZ M. Carmen, General Secretary, Venezuelan Society tatatiu@movistar.net.ve ANSSEAU Marc, Chairman of the, Department of ` ` Psychiatry, University of Liege, B-4000 Liege, Belgium psychiatrie@ulg.ac.be AVEDISOVA Alla, Head of New Drugs Division, Serbsky Centre for Social and Forensic Psychiatry, Moscow, 123367, Russia aavedisova@hotmail.com AZORIN Jean-Michel, SHU Psychiatrie Adultes, Hopital de Sainte-Marguerite, 13274 Marseille Cedex 09, France clancon@ap-hm.fr BAUER Michael, Head of the Department of Psychiatry and Psychotherapy, Universitatsklinikum Carl Gustav Carus, D-01307 Dresden, Germany Michael.Bauer@uniklinikum-dresden.de BAUMANN Pierre, University Department of Psychiatry, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland pierre.baumann@chuv.ch BECH Per, Psychiatric Research Unit, Frederiksborg General Hospital, 3400 Hillerd, Denmark pebe@fa.dk BELFORT Edgard, WPA Zonal Representative, WFMH Board of Directors, Caracas 1010, Venezuela belfort.ed@cantv.net ; wpazone4@cantv.net BELMAKER R.H., Beersheva Mental Health Center, Beersheva, Israel belmaker@bgumail.bgu.ac.il BERK Michael, Barwon Health and Geelong Clinic, Swanston Centre, The University of Melbourne, Geelong, Victoria 3220, Australia mikebe@barwonhealth.org.au

EUFAMIs aims

To achieve continuous improvement throughout Europe in mental health generally, in the quality of care and welfare for mentally ill people, and in the level of support for their caring relatives and friends. To enable member associations to combine their efforts and act jointly at the European level to achieve those aims. To strengthen and assist member associations in their eort to improve mental health conditions in their own territories, while fully respecting their national or regional autonomy. EUFAMIs principles

19.12.2
$

Carers must be acknowledged as equal partners with professionals in the care team supporting the person with mental illness. Carers need support in their own right and have independent needs which must be recognized and respected. All people with mental illness should be cared for in an appropriate environment and provided with a comprehensive range of health-care and social care services. All people with mental illness should have the right to share in the opportunities, enjoyments, challenges and responsibilities of everyday life. EUFAMIs mission

19.12.3
$

Contribute to removing the stigma surrounding mental illness by promoting positive images to counteract ignorance and misinformation. Highlight examples of good practice in the eld of mental illness in order to promote good practice throughout Europe ; identify examples of bad practice in the eld of mental illness and campaign for positive change. Lobby for greater equality of legislation throughout Europe in order to bring about improvements in the health and social care of people with mental illness, and in the well-being of their carers. Promote and support further research into the causes and treatment of mental illness. Campaign for adequate resources for the health and social care of people with mental illness and their carers.

S200

CINP Antidepressant Task Force 2007 CORRUBLE Emmanuelle, Service de Psychiatrie, CHU de Bicetre, 94270 Le Kremlin Bicetre, France emmanuelle.corruble@bct.ap-hop-paris.fr COWEN PJ, Neurosciences Building, Warneford Hospital, Oxford OX3 7JX, UK phil.cowen@psych.ox.ac.uk DANIELYAN Konstantin, Head of the Psychiatry, Psychotherapy & Medical Psychology Department, National Institute of Health of RA Armenia danielyan_k@yahoo.com DANION Anne, Child Psychiatrist, Strasbourg, France anne.danion@chru-strasbourg.fr DELGADO Fabrizio, President of the Ecuadorian Association of Psychiatry fdelgado@jbgye.org.ec DE VANE C. Lindsay, Department of Psychiatry & Behavioral Sciences, Director, Laboratory of Drug Disposition and Pharmacogenetics, Medical University of South Carolina, USA devanel@musc.edu DOUKI Sada, Chef de Service de Psychiatrie, Hopital Razi, 2010 La Manouba, Tunis, Tunisia saida.douki@rns.tn EVSEGNEEV Roman, Head, Department of Psychiatry, Byelorussian Medical Academy for Postgraduate Education, President, Byelorussian Psychiatric Association, Belarus bpa@cervus.unibel.by FALISSARD Bruno, Epidemiologist and Psychiatrist, Paris, France Falissard_b@wanadoo.fr FERNANDEZ Alberto, Researcher, Neuroscience Institute alberfe@amauta.rcp.net.pe FINK Max, M.D., Psychiatry and Neurology Emeritus at Stony Brook University, Long Island, St. James, NY 11780-0457, USA mank@attglobal.net FLORES Julio, Adviser Psychiatrist, Central Nervous System, Venezuela ores@organon.com.ve FRITZE Jurgen, Leitender Arzt,Verband der privaten Krankenversicherung e.V. (German Association of Private Health Insurers), 50968 Koln, Germany Juergen.Fritze@pkv.de ; Juergen.Fritze@dgn.de FOUNTOULAKIS K.N., 3rd Department of Psychiatry, Arisotle University of Thessaloniki, 55132 Aretsou Thessaloniki, Greece kfount@med.auth.gr

BLIER Pierre, University of Ottawa, Institute of Mental Health Research, Ottawa ON K1Z 7K4, Canada PBlier@rohcg.on.ca BOBROV Alexander, Head of the Department of Psychiatry, Irkutsk State Institute of Postgraduate Education for Physicians, Irkutsk, 664079, Russia bobrov_irkutsk@rambler.ru BOULENGER Jean-Philippe, Service Universitaire de Psychiatrie Adulte, INSERM Equipe E-361, Hopital ` La Colombiere, CHU de Montpellier : 39 Avenue Charles Flahault, F-34295-Montpellier Cedex 5 jp-boulenger@chu-montpellier.fr BRASIL Marco Antonio, Past-President, Brazilian Association of Psychiatry, Rio de Janeiro presidente@abpbrasil.org.br BURROWS Graham D., The University of Melbourne, Department of Psychiatry, Austin Hospital, Heidelberg, Victoria 3084, Australia graham.burrows@austin.org.au CAI Zhuoji, President, Chinese Mental Health Association, Beijing caizhuoji@126.com CALDERON Jose, President, Panama Society of Psychiatry calderon@cwpanama.net CALDERON Minerva, Forensic Psychiatry, Forensic Medical Institute micalderon@cantv.net CALIL Helena Maria, Department of Psychobiology, Paulista Faculty of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil hmcalil@psicobio.epm.br CANNEVA Jean, President of UNAFAM, France infos@unafam.org CASTRO Rojas Rigoberto, President, Costa Rican Psychiatric Association, San Jose rcastror@racsa-co.cr CARROLL Bernard, Pacic Behavioral Research Foundation, P.O. Box 223040, Carmel, CA 93922-3040, USA bcarroll@redshift.com CHENG Nengneng, Pharmacology School, Fudan University, P. R. China nncheng@shmu.edu.cn CHONG Mian-Yoon, Chairman, Department of Psychiatry, Chang Gung Memorial Hospital, Niao-Sung Hsiang, Kaohsiung County 83342, Taiwan mchong@cgmh.org.tw CORDOBA Rodrigo, General Director, CISNE rodrinel@yahoo.com CORREA Eduardo, Professor, Chile University arlegui@yahoo.com

CINP Antidepressant Task Force 2007 FURUKAWA Toshiaki, Chair of the Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 Japan furukawa@med.nagoya-cu.ac.jp GALLEGOS Rogelio, Mexican Health National Service Representative, Mexico rogeliogallegosc@hotmail.com GASTELUMENDI Eduardo, Director, Neurosciences Institute ; Past-President of the Peruvian Society of Psychiatry egastel@rcp.net.pe GASZNER Peter, Orszagos Pszichiatriai Es Neurologiai Intezet, 1021 Budapest, Hungary h12890gas@ella.hu GAVIRIA Silvia Sgaviria1@epm.net.co GERARD Alain, Psychiatrist, Paris, France al.gerard@free.fr GINNARI ANTICH Guillermo, President, Venezuelan Society of Psychiatry, Caracas gginnari@cantv.net GODARD Nathalie, Child Psychiatrist, Director of a private institution, Garches, France GONZALEZ Celso, Psychiatrist Researcher, University General Hospital celsohuc@cantv.net GOODWIN Frederick, 5712 Warwick Place, Chevy Chase, MD 20815, USA drgoodwin@aol.com GORWOOD Philip, Paris, France philip.gorwood@lmr.ap-hop-paris.fr GRIGORIEVA Elena A, Head of the Department of Psychiatry, Yaroslavl Medical Academy, Yaroslavl, 150000, Russia prof.gri-orieva@mail.ru GU Niufan, Shanghai Mental Health Center, Shanghai, 200030 guniufc@hotmail.com GUREJE Oye, Head of the Department of Psychiatry, University College Hospital, Ibadan, Nigeria gureje.o@skannet.com.ng HAEN Ekkehard, Psychiatrische Universitatsklinik, Medizinische Einrichtungen des Bezirks Oberpfalz, 93053 Regensburg, Germany ekkehard.haen@medbo.de HEALY David, North Wales Department of Psychological Medicine, Cardi University, Hergest Unit, Ysbyty Gwynedd, Bangor, Wales LL57 2PW, UK David.Healy@nww-tr.wales.nhs.uk

S201

HE Yanling, Shanghai Mental Health Center, Shanghai, 200030 heyl@sh163.net ; heyl@public9.sta.net.cn HEGERL Ulrich, Klinik und Poliklinik fur Psychiatrie und Psychotherapie, Universitatsklinikum Leipzig, Johannisallee 20, D-04317 Leipzig, Germany krausem@medizin.uni-leipzig.de HINDMARCH Ian, HPRU Medical Research Centre, University of Surrey, Guildford, Surrey GU2 7XP, UK I.hindmarch@surrey.ac.uk HOSCHL Cyril, Director, Prague Psychiatric Center, 181 03 Praha 8, Czech Republic hoschl@ pcp.lf3.cuni.cz HU Teh-Wei, Professor of Health Economics, University of California, School of Public Health, Berkeley, CA 94720, USA. thu@berkeley.edu HWANG Tae-Yeon, Director, WHO Collaborating Center for Psychosocial Rehabilitation and Community Mental Health, Yongin Mental Hospital, Korea lilymh@dreamwiz.com ; lilymh@empal.com IRMANSYAH, Psychiatrist, Department of Psychiatry, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia irmans@indo.net.id ISACSSON Goran, Karolinska Institute, Huddinge University Hospital, S-141 86 Stockholm, Sweden Goran.Isacsson@neurotec.ki.se ISMAYILOV Nadir, Azerbaijan Medical University, Baku inadir@azdata.net IVANOV Michail, Head of the Department of Psychopharmacotherapy of the Bekhterev Psychoneurological Institute, St-Petersburg 192019, Russia spbinstb@infopro.spb.su IVONOVIC Fernando, Head of Bipolar Disorders Unit, Chile University ferlore@vtr.net JAKOVLEVIC Miro, Department of Psychiatry, School of Medicine, University of Zagreb, Zagreb Rebro, Croatia pro-mente@zg.hinet.hr JIANG Kaida, Shanghai Mental Health Center, Shanghai, 200030 jiangkaida@sh163.net KANBA Shigenobu, Department of Neuropsychiatry, Kyushu University, Fukuoka, 812-8582, Japan skanba@npsych.med.kyushu-u.ac.jp KASAKOVTSEV Boris, Deputy Head of the section of legislative regulation of specialized medical care,

S202

CINP Antidepressant Task Force 2007 LEE Min-Soo, Department of Psychiatry, Korea University College of Medicine, Seoul, 136-705 Korea leeminso@korea.ac.kr LEPINE Jean-Pierre, Hopital Fernand Widal, Assistance Publique, Hopitaux de Paris, INSERM U 705, 75475 Paris, France jean-pierre.lepine@lrb.aphp.fr LEVINA Nelly, Chief of the All-Russian Society of disabled mentally ill and their relatives New Choices , Moscow 107076, Russia levinan36@mail.ru LI Lingjiang, Director of the Mental Health Institute, Xiangya Medical School, Central South University, Changsha, Hunan 410011 Lilj9016@public.cs.hn.cn LOPEZ-IBOR Juan Jose, Clinica Lopez Ibor, E-28035 Madrid, Spain jli@lopez-Ibor.com MA Hong, Institute of Mental Health, Peking University, Beijing 100083 hma@ht.rol.cn.net MACIAS Nestor, Board Member, Venezuelan Society of Psychiatry climaca@cantv.net, climaca@hotmail.com MAGZUMOVA Shakhnoza, Uzbekistan shakhnoza2001@rambler.ru MAJ Mario, Director of the Institute of Psychiatry, University of Naples, 80138 Napoli, Italy majmario@tin.it MALYAROV Sergiy, Head of the Liaison and Research Department Kiev City Psychiatric Hospital #2, Kiev 02660, Ukraine malyarov@voliacable.com or sergiy@malyarov.ln.ua MANJI Husseini K., Director, Mood and Anxiety Disorders Program, Chief, Laboratory of Molecular Pathophysiology, NIMH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA manji@nih.gov MARTINEZ Danilo, Coordinator, Postgraduate Psychiatry Training Program, Military Hospital djmartinezaraujo@tutopia.com ; danisan@telcel.net.ve MARTINY Klaus, Psychiatric Research Unit, Hilleroed Hospital, Hilleroed, 3400, Denmark kmar@fa.dk MAZZARELLA Xiorela, Caracas Psychiatric Hospital, Head Unit No. 3, Caracas, Venezuela xioremazzarella@hotmail.com ; xioremazzarella@yahoo.com MELLA Cesar, Vice-President, Latin American Psychiatric Association Cesarm2@verizon.net.do MILLET Bruno, Adult Psychiatry of Rennes Centre Hospitalier Guillaume Regnier

Ministry of Public Health and Social Development, Moscow, Russia avdeenkoas@rosminzdrav.ru KASPER Siegfried, Department of General Psychiatry, University of Vienna, A-1090 Vienna, Austria sci-genpsy@meduniwien.ac.at KATON Wayne J., M.D., Vice Chair of the Department of Psychiatry and Behavioral Sciences, University of Washington, WA 98195, USA wkaton@u.washington.edu KECK Paul E., Jr., Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, USA keckpe@ucmail.uc.edu KENNEDY Sidney H, University Health Network, Toronto, Ontario M5G 2C4, Canada. sidney.kennedy@uhn.on.ca Christian KLESSE, Uniklinik fur Psychiatrie und Psychosomatik, 79104 Freiburg, Germany christian_klesse@psyallg.ukl.uni-freiburg.de KOSEL Markus, Klinik fur Psychiatrie, Uniklinikum, 53105 Bonn, Germany markus.kosel@ukb.uni-bonn.de KRAMMLING Franz-Georg, BKK LV Bayern, 81476 Munchen, Germany krammling@bkk-lv-bayern.de KRASNOV Valery, Director of the Moscow Research Institute of Psychiatry 107076 Moscow, Russia krasnov@mtu-net.ru, vkrasnov@kapta.ru KUPFER David J., University of Pittsburgh Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania 15261, USA kupferdj@msx.upmc.edu KUTCHER, Stan Dalhousie University Department of Psychiatry 5909 Veterans Memorial Lane 9th Floor, AJLB Halifax, Nova Scotia B3H 2E2, Canada Stan.Kutcher@dal.ca LAM Raymond W., Division of Clinical Neuroscience, Department of Psychiatry, University of BC, Vancouver, BC, Canada r.lam@ubc.ca LANDER Hugo, President, Argentinean Society of Psychiatrists apsa@apsa.org.ar LANDOWSKI Jerzy, Chief, Clinic of Psychiatric and Neurotic Disorders, Department of Psychiatry, Medical University of Gdansk, 80-211 Gdansk, Poland jland@amg.gda.pl LAPREA Isabel, Child and Adolescent Psychiatrist, UCV aprefar@cantv.net

CINP Antidepressant Task Force 2007 108, avenue du General Leclerc BP 226, 35011 Rennes Cedex, France b.millet@ch-guillaumeregnier.fr MINHAS Fareed, Head, Institute of Psychiatry, Rawalpindi General Hospital, Rawalpindi, Pakistan fareedminhas@hotmail.com MOLLER Hans-Jurgen, Chairman of the Psychiatric Hospital of the University Munich, 80336 Munchen, Germany Hans-Juergen.Moeller@med.uni-muenchen.de MONTANO Everth, President, Bolivian Society of Psychiatry Montev7@hotmail.com MOSOLOV Sergey, Head of the Department of Therapy of Mental Disorders, Moscow Research Institute of Psychiatry, Moscow 107076, Russia krasnov@mtu-net.ru MOUSSAOUI Driss, Faculte de Medecine de Casablanca, Centre Psychiatrique Universitaire Ibn Rushd, Casablanca, Moprocco psych@casanet.net.ma NETTER Petra, Department of Psychology, University of Giessen, 35394 Giessen, Germany petra.netter@psychol.uni-giessen.de NEZNANOV Nikolay, Director of the Bekhterev Psychoneurological Institute, St-Petersburg 192019, Russia nezn@bekhterev.ru ; spbinstb@infopro.spb.su NURMAGAMBETOVA Saltanat, Almaty, Kazakhstan 480012 saya_n@yahoo.com OKASHA Ahmed, Director of WHO Collaborating Center, Institute of Psychiatry, Ain Shams University, Kasr El Nil, Cairo Egypt aokasha@internetegypt.com ORAL Timucin, Bakirkoy Ruh ve Sinir Hastaliklari Hastanesi, Bakirkoy Istanbul, Turkey etoral@prizma.net.tr PADILLA Franklin, Vice-President, Venezuelan Society ; Director, Postgraduate Psychiatry Training Programme, Caracas Psychiatric Hospital, Caracas, Venezuela franklinpadilla@gmail.com PALOVA Eva, Department of Psychiatry, University of P.J. Safarik, 040 6 Kosice, Slovakia palovae@ke.sknet.sk PARKER Gordon, School of Psychiatry, University of New South Wales, Northwood, NSW 2066, Australia g.parker@unsw.edu.au PAUNOVIC Vladimir R., Institute of Psychiatry, Clinical Center of Serbia, 11000 Belgrade, Serbia & Montenegro vpaunovic@sbb.co.yu

S203

PIDKORYTOV Valeriy, Chief, Department of Clinical, Social and Child Psychiatry Institute of Neurology, Psychiatry and Narcology AMS of Ukraine, 61068 Kharkiv, Ukraine pid-vs@ukr.net POIRIER Marie-France, Hopital Sainte-Anne, SHU/ U796, Paris, France mf.poirier@ch-sainte-anne.fr POUY Artigas, General Secretary, Latin American Psychiatric Association spu@mednet.org.uy PULL Charles, Service de Neuropsychiatrie, Centre Hospitalier de Luxembourg, 1210 Luxembourg aep@chl.lu QUIRION Remi, Douglas Hospital Research Centre, McGill University, Verdun, Quebec H4H 1R3, Canada quirem@douglas.mcgill.ca REMSCHMIDT Helmuth, Philipp Universitat, Head, Klinik fur Kinder- und Jugend Psychiatrie, 35033 Marburg, Germany remschm@med.uni-marburg.de ; remschm@post.med.uni-marburg.de REQUENA Alvaro, Head, Department of Psychiatry, Venezuelan Red Cross alvarorequena@cantv.net RIECHER Anita, Psychiatrische Poliklinik, Universitatsspital Basel, 4031 Basel, Switzerland ariecher@uhbs.ch RIHMER Zoltan, Magyar Jakob, Tere, 6. 1/1, 1122 Budapest, Hungary rihmer.z@opni.hu RIVERA TREJO Gerardo, President, El Salvador Society of Psychiatry gerardoriverat@yahoo.com ROBERT Philippe, CHU Hopital Pasteur, 06002 Nice Cedex, France philippe.robert15@wanadoo.fr RODRIGUEZ Miguel Angel, Publication, Venezuelan Society of Psychiatry miguelangelrh@cantv.net RODRIGUEZ Olga, Child and Adolescent Training Postgraduate Program, Tachira Hospital olrodri@mipunto.com ROBERT Philippe, Nice, France philippe.robert15@wanadoo.fr RUBIN Robert, Los Angeles, CA 90025-7821, USA Robert.rubin@va.gov RUIZ Pedro, Vice Chair for Clinical Aairs, Department of Psychiatry and Behavioral Sciences, University of Texas-Houston Mental Sciences Institute, Houston, TX 77030, USA pedro.ruiz@uth.tmc.edu

S204

CINP Antidepressant Task Force 2007 TANG Siu-Wa, Chair of the Department of Psychiatry University of Hong Kong psychiat@hku.hk TEN Vladimir, Head, Department of Clinical Psychology and Psychiatry Kyrgyz State Medical Academy, Bishkek 720023, Kyrgyz Republic psycho@freenet.kg THASE Michael E., University of Pittsburgh Medical Center, Pittsburgh PA 15213-2593, USA thaseme@upmc.edu THIBAUT Florence, University Hospital Ch. Nicolle, INSERM, Rouen, France Florence.Thibaut@chu-rouen.fr UDOMRATN Pichet, President, The Psychiatric Association of Thailand (PAT), Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand upichet@medicine.psu.ac.th VAHIP Simavi, Aective Disorders Unit, Ege University Department of Psychiatry Bornova-Izmir TR-35100, Turkey simavi.vahip@ege.edu.tr VAN PRAAG Herman M., Huize Berghorst, 7315 HD Apeldoorn, The Netherlands h.m.van.praag@vanpraag.com VIETA PASCUAL Eduard, Director of Research, Clinical Institute of Neuroscience, Director of Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain evieta@clinic.ub.es WANG Liwei, Shanghai Mental Health Center, Shanghai, 200030, P. R. China lwwang163@163.com WATANABE Yasuo, Department of Pharmacology/Pharmacotherapy, Nihon Pharmaceutical University, Saitama 362-0806, Japan yasuwat@nichiyaku.ac.jp ; yasuwatnb@aol.com WIED Viktor D., Deputy Director of the Bekhterev Psychoneurological Institute, St. Petersburg 192019, Russia wied@nm.ru WOOLEY Stephanie, Presidente, Association France Depression, 4, rue Vigee Lebrun, 75 015 Paris, France YAN Heqin, Director, Shanghai Mental Health Centre, Shanghai yanhqn@gmail.com ; yanhqn@online.sh.cn YI Chengdong, Director General, Shanghai Food and Drug Administration Bureau, Shanghai gaolei@smda.gov.cn

RUSH John A., Jr., M.D., Vice-Chair, Department of Clinical Sciences, Department of Psychiatry, University of Texas SW Medical Center, Dallas, TX 75390-7208, USA Johnn.rush@utsouthwestern.edu SALAZAR Gerardo Carmelo B, Department of Neurosciences, Lucena United Doctors Hospital, Manila, The Philippines gbsneuro@mozcom.com SALAZAR Ismael, Director of the Mental Health Hospital Social Security apal2002@hotmail.com ; isalazarg@hotmail.com SALETU Bernd, Section of Sleep Research and Pharmacopsychiatry, Department of Psychiatry, Medical University of Vienna, 1090 Vienna, Austria bernd.saletu@meduniwien.ac.at SANCHEZ Carlos, Assistant, Latin American Psychiatric Association csanchez@cantv.net SCHLAEPFER Thomas E., Psychiatry & Mental Hygiene, Department of Psychiatry, University Hospital, Bonn 53105, Germany schlaepf@jhmi.edu SECHTER Daniel, Besancon, France daniel.sechter@ufc-chu.univ-fcomte.fr SEMKE Valentin, Director of the Institute of Psychiatry of the Tomsk Scientic Centre, Siberian Division of the Russian Academy of Medical Science, Tomsk, Russia redo@mail.tomsknet.ru SIMON Gregory, Group Health Cooperative of Puget Sound, Centre for Health Studies. Seattle, WA 98101, USA simon.g@ghc.org STEFFEN Sigrid, Vice-President, European Federation of Associations of Families of Mentally Ill People (EUFAMI), 5020 Salzburg, Austria kus.steen@aon.at STUPPACK Christoph, Universitatsklinik fur Psychiatrie 1, Christian-Doppler-Klinik, Salzburg, 5020 Salzburg, Austria c.stuppaeck@salk.at SULTANOV Agabek A., Gashumbekoglu, Manager of the chair of Psychiatry Medical University, Baku, Azerbaijan gerai@hotbox.ru SUN Xueli, 7# Xiao Xue Road, Chengdu, Sichuan 610041 sunxueli@tom.com ; sunxueli58@163.com TAN Chay-Hoon, Department of Psychological Medicine, National University Hospital, Singapore 119074 phctanch@nus.edu.sg

CINP Antidepressant Task Force 2007 YOUDIM Moussa B.H., Director of Eve Topf and National Parkinson Foundation (US), Centers of Excellence for Neurodegenerative Diseases, Technion-Faculty of Medicine, Haifa, Israel. Youdim@tx.technion.ac.il YOUNG Allan Hunter, LEEF Chair in Depression Research ; Associate Director, Institute of Mental Health ; Department of Psychiatry, University of British Columbia, Vancouver, BC Canada V6T 2A1, Canada alyoung@interchange.ubc.ca XIAO Zeping, Shanghai Mental Health Center, Shanghai, 200030, P. R. China xiaozeping@gmail.com XIE Bin, Shanghai Mental Health Center, Shanghai, 200030, P. R. China myzhang@online.sh.cn 20 Abbreviations +5-HT1=serotonin 1 receptor stimulation 5-HT2=serotonin 2 receptor antagonism 5-HT2c=5-HT2c receptor antagonist 5-HT3=serotonin 3 receptor antagonism a1=a1 receptor antagonism a2=a2-receptor antagonism all. 5HTT=binding to the allosteric site of the serotonin transporter ACTH=adrenocorticotropic hormone, corticotropin ACNP=American College of Neuropsychopharmacology AD=Alzheimers disease ADH=antidiuretic hormone ADHD=attention-decit hyperactivity disorder AHCPR=Agency for Health Care Policy and Research AIDS=acquired immune deciency syndrome APA=American Psychiatric Association APD=amphetamine prodrug APOE=apolipoprotein E BAC=blood alcohol concentration Bcl-2=B-cell lymphoma 2 (anti-apoptotic protein) BDI=Beck Depression Inventory BDNF=brain-derived neurotrophic factor BPRS=Brief Psychiatric Rating Scale CANMAT=Canadian Network for Mood and Anxiety Treatments CBA=Cost-benet analysis CBASP=Cognitive Behavioral Analysis System of Psychotherapy

S205

XU Yifeng, Shanghai Mental Health Center, Shanghai, 200030, P.R. China hyyyyb@online.sh.cn YU, Xin, Director of the Institute of Mental Health, Peking University 100083, Beijing, P.R. China yuxin@bjmu.edu.cn ZHANG Li, Director, CDC on Mental Health, Ministry of Health, Beijing, P.R. China zhangli1410@sina.com ZHANG Mingyuan, Shanghai Mental Health Center, Shanghai, 200030, P.R. China myzhang@online.sh.cn ZHOU Dongfeng, President, Chinese Psychiatry Association zhoudf@public.fhnet.cn.net ZVARTAU Edvin, Vice-rector, St.-Petersburg State Medical University, St. Petersburg, Russia zvartau@spmu.rssi.ru

CBT=cognitive behavioral psychotherapy CD=combined depression (MDD and RBD) CGI-I=Clinical Global Impressions-Improvement Score CDRS-R=Childrens Depression Rating Scale-Revised CEA=cost-eectiveness analysis CEAC=cost-eectiveness acceptability curve CIDI=Composite International Diagnostic Interview CINP=Collegium Internationale Neuro-Psychopharmacologicum CNS=central nervous system COX=cyclo-oxygenase CRF=corticotropin releasing factor (=CRH) CRH=corticotropin releasing hormone (=CRF) CSF=cerebrospinal uid CSM=Committee on Safety of Medicine (UK) CUA=cost-utility analysis DA=dopamine (D2) receptor antagonist DALY=disability-adjusted life years DBS=deep brain stimulation DCS=d-cycloserine DEPRES=Depression Research in European Society DGPPN=Deutsche Gesellschaft fur Psychiatrie, Psychotherapie und Nervenheilkunde DHEA=dehydroepiandrosterone DLPFC=dorsolateral prefrontal cortex DNRI=dopamine and noradrenaline reuptake inhibitor

S206

CINP Antidepressant Task Force 2007 MINI=Mini International Neuropsychiatric Interview MRI=magnetic resonance imaging MST=magnetoconvulsive therapy MT1/MT2=melatonin 1 and melatonin 2 receptor agonist MT=melatonergic antidepressant M-TCA=modied tricyclic antidepressant NA=noradrenaline (=norepinephrine) NAR=noradrenaline-releasing properties NARI=selective noradrenaline (norepinephrine) reuptake inhibitor NaSSA=noradrenergic and selective serotonergic antidepressant NCP=NeuroCybernetic Prosthesis (System) NGF=nerve growth factor NIMH=National Institute of Mental Health NK1=neurokinin 1 NMDA=N-methyl-D-aspartate NMS=neuroleptic malignant syndrome NN=nomen nescio (unknown author) NRI=noradrenaline (norepinephrine) reuptake inhibition/inhibitor N-TCA=tricyclic antidepressant with primary noradrenergic eects N-TetraCA=tetracyclic antidepressant with primary noradrenergic eects OCD=obsessive compulsive disorder OR=odds ratio PD=Parkinsons disease PET=positron emission tomography PHQ=Patient Health Questionnaire PKC=protein kinase C PMDD=premenstrual dysphoric disorder PSD=partial sleep deprivation PTSD=post-traumatic stress disorder QALY=quality-adjusted life year RCT=randomized controlled trial RBD=recurrent brief depression RIMA=reversible inhibitor of monoamine oxidase A rTMS=repetitive transcranial magnetic stimulation SCID=Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders SMA=serotonin-modulating antidepressant SMR=standard mortality ratio SNRI=selective serotonin and noradrenaline reuptake inhibitor S/N-TCA=tricyclic antidepressant with similar serotonergic and noradrenergic eects SP=substance P SRI=serotonin reuptake inhibition

DRI=dopamine reuptake inhibition DSM=diagnostic and statistical manual of mental disorders EA=electro-acupuncture ECT=electroconvulsive therapy EMEA=European Medicines Agency ENRICHD=Enhancing Recovery in Coronary Heart Disease Patients Randomized Trial ER=extended release ES=eect size EUFAMI=European Federation of Association of Families of People with Mental Illness ESEMeD=European Study of the Epidemiology of Mental Diseases FDA=Food and Drug Administration GABA=c-amino butyric acid GAD=generalized anxiety disorder GM=glutamatergic modulator GP=general practitioner H1=blockade of histamine 1 receptors HAMA=Hamilton rating scale for anxiety HAMD=Hamilton rating scale for depression HIV=human immunodeciency virus HPA=hypothalamic pituitary adrenal ICD=international classication of diseases ICER=incremental cost-eectiveness ratio ICPE=International Consortium of Psychiatric Epidemiology IL=interleukin IPC=interpersonal counseling IPT=interpersonal psychotherapy IR=immediate release K-SADS=Childhood Version of the Schedule for Aective Disorders and Schizophrenia LIDO=Longitudinal Investigation of Depression Outcomes M1=blockade of cholinergic muscarinic receptors MAI=monoamine oxidase A inhibition MADRS=MontgomeryAsberg depression rating scale MAOI=irreversible inhibitor of monoamine oxidase A and B MAOBI=irreversible inhibitor of monoamine oxidase B MAP=mitogen-activated protein MBI=monoamine oxidase B inhibition MCC=Medical Control Council of South Africa MDD=major depressive disorder MHID=Mantel-Haenszel incidence dierence MHRA=Medicines and Healthcare products Regulatory Agency MHRD=MantelHaenszel exposure time-adjusted rate dierence

CINP Antidepressant Task Force 2007 SRS=serotonin reuptake stimulation SSRI=selective serotonin reuptake inhibitor TADS=Treatment for Adolescents with Depression Study SAD=seasonal aective disorders SD=sleep deprivation SDLP=standard deviation of lateral position STAR*D=Sequenced Treatment Alternatives to Relieve Depression S-TCA=tricyclic antidepressant with primary serotonergic eects S-TetraCA=tetracyclic antidepressant with primary serotonergic eects TAU=treatment as usual tDCS=transcranial direct current stimulation TDM=therapeutic drug monitoring TNF=tumor necrosis factor TRD=treatment resistant depression TSD=total sleep deprivation UK=United Kingdom US=United States of America VNS=vagus nerve stimulation WFSBP=World Federation of Societies of Biological Psychiatry WHO=World Health Organization WPA=World Psychiatric Association XR=extended release YLD=years lived with disability

S207