Download a CINP Task Force report based on a review of evidence

International Journal of Neuropsychopharmacology (2007), 10, S1–S207. Copyright f 2007 CINP
doi:10.1017/S1461145707008255
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, Jeffrey Lieberman10, Yoshibumi Nakane11, Roger M. Pinder12,
Alan F. Schatzberg13, Jaromı́r Švestka14
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-Rössler22.
The text was edited by :
Thomas C. Baghai2, Heinz Grunze2,3 and Norman Sartorius1
The names of the persons who produced the first 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 : [email protected]
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 : [email protected]
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 : [email protected]
Affiliations :
1
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 Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom
2
S U P PL E M E N T
CINP
S2
CINP Antidepressant Task Force 2007
4
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), Tägermoosstrasse
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, Jihlavská 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, Universitätsspital 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 effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .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 Specific age- and gender-related conditions (Thomas C. Baghai, Kareem Ghalib, Heinz Grunze,
Frank Padberg, Anita Riecher-Rössler). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S85
10.1 Gender-related differences (Heinz Grunze, Anita Riecher-Rössler) . . . . . . . . . . . . . . . . . . . . . . . . . . . .S85
10.2 Age-related differences (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-effectiveness 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 effective 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 different 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 different 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 CINP’s
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 effectiveness 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 first drafts of the
text are given in the table of contents : in their present
form, however, the chapters often differ significantly
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 effort 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
Möller.
CINP Antidepressant Task Force 2007
The method used to produce the first draft of the
chapters of this review and the sources of data used
are described in chapter 4.1. What makes this effort
different 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 scientific 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
differences of opinion over whether to include description of other treatment methods, the Task Force
finally decided to provide a brief description of these
methods in the text of the review and to place more
detailed information in the annexes (19.3–19.8). 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 significance is often put forward as being sufficient for
recommendations about clinical practice. A statistically significant difference, however, is not always
equal to a clinically meaningful difference ; 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 reflect 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 effective means of
intervention to resolve or significantly reduce the
problem.
Depressive disorders satisfied the first 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 significant 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 significantly increase the risk of suicide and of suicidal
attempts.
S6
CINP Antidepressant Task Force 2007
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
effective intervention that can reduce or eliminate the
problem and is suitable for widespread application.
Until recently that criterion had not been satisfied for
the majority of mental disorders. Although public
health authorities succeeded in preventing some
mental disorders (e.g. cretinism in areas where iodine
deficiency 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 effective. Electroconvulsive therapy (ECT) helped in treating people
with certain forms of depressive disorders and
schizophrenia, but the number of those who could not
benefit from ECT vastly surpassed the numbers of
those who could. Thus this intervention did not fit
the criterion of wide applicability. Psychotherapy
helped many, but the number of experts qualified to
apply it were – and still are – small in most parts of
the world. Psychotherapeutic strategies and techniques have become sufficiently well defined 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 different
(Bolton et al., 2003).
1
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 ;
Steffens 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.
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
significant proportion of people with depressive disorders even when applied by general medical staff
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 effectively 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 first prescribed antidepressant, but some others will still remain unwell.
There is thus considerable room for further improvement of the effectiveness 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 effective 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 effects. The general
public and the media supported this notion as well. In
several countries, direct advertisements to consumers
CINP Antidepressant Task Force 2007
may have played a role (Berndt, 2005). The Prime
Minister of Norway took a few weeks off 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 staff thought about depression, it was also a step towards a different
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 figure 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 affected people’s 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 suffer
from them but also benefits society and patients’ families were neither widely known nor sufficiently 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 month’s 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 effects of new drugs for patients
in populations outside the major industrialized countries2.
Some studies did show differences in dosage and
effects of medications given to patients living in
countries with varying climate, nutrition and general
morbidity patterns, but definitive studies of the effect
of drugs on patients from different 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 scientific
literature come from other than high-income countries. The US and UK alone contribute 50 % of the accessible scientific 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 findings (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 justification for their use reflects
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 defined in ICD-10 (World Health Organization, 1992)
2
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 influence on other receptor systems
Pharmacological
group
Generic name
Primary
pharmacodynamic
mode of action
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
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
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
Additional
effects
5-HT2C
(M1)
DRI
(M1)
5-HT2,3 ; +5-HT1
5-HT2C
H1, a1, a2
(M1)
MAI, APD
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
SRI, 5-HT2
NAR
(M1)
M1, a1
M1, a1
H1, a1
H1, (M1), a1
For abbreviations see p. 9.
3
St. John’s wort is not included in the list of antidepressants because of
it has no proven efficacy 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 Parkinson’s 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 flupentixol.
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 fields 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 difficult 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 :
$
$
$
Are antidepressant medications effective in alleviating symptoms of depression and in preventing
relapses of depressive illness ? (predominantly
chapters 9 and 7)
Are the side effects of antidepressant drugs currently in use so severe that they outweigh the benefits of these drugs ? (chapters 7.3 and 9.1.1.3)
Is the treatment of depressive disorders with antidepressant drugs cost-effective for individuals and
societies ? (chapter 14)
$
$
S9
What areas of scientific 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 suffer
from depressive illnesses.
4.
4.1
Method used to produce the review
Consensus process
The challenge for the CINP Task Force created in May
2005 was to review the evidence on the use, effectiveness 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 different 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 first-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 affinity ; (++)=
appreciable receptor binding affinity ; (+++)=strong receptor binding affinity ; +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 effects ; N-TetraCA=tetracyclic antidepressant with primary noradrenergic effects ;
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 effects ;
SRI=serotonin reuptake inhibition ; SRS=serotonin reuptake stimulation ; SSRI=selective serotonin reuptake inhibitor ;
S-TCA=tricyclic antidepressant with primary serotonergic effects ; S-TetraCA=tetracyclic antidepressant with primary
serotonergic effects.
S10
CINP Antidepressant Task Force 2007
Table 2. Classification 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
ICD-10
Major depressive disorder
A. Single episode (296.2x)
B. Recurrent (296.3x)
A. Depressive episode (F32)
B. Recurrent depressive disorder (F33)
Severity :12
$
$
$
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. Significant 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
specific plan for committing suicide
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 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-confidence
Ideas of guilt and unworthiness
Agitation or retardation
Ideas or acts of self-harm or suicide
Sleep disturbances
Loss of appetite
B. The symptoms cause clinically significant 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)
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 fields, such as
the chapter on psychopharmacotherapy of children
(first 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
reflect the actual scientific 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)
Specific condition
$
$
$
$
$
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
Schizoaffective 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 8–12 experts from the
country in which the meeting was held and 8–10 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
Suggestions concerning the organization of national meetings are
given in Annex 10.
S11
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
The data considered in the development of this technical review have been extracted from different 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 für
Psychiatrie, Psychotherapie und Nervenheilkunde,
DGPPN), Praxisleitlinien in Psychiatrie und Psychotherapie, Behandlungsleitlinie affektive 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.
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 differences
(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 scientific 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 (1966–2004) and
Embase (1974–2004).
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 first randomization period were considered.
Data collection and analysis :
$
$
$
$
$
$
4.3
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 efficacy 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 final 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 fixed-effects approach, and presented Peto odds ratio (PetoOR) and standardized mean
difference (SMD).
Additional sources of information
In addition to scientific 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 flawless, and translating RCT
results to everyday clinical practice is sometimes
problematic. One major cause may be that the
15
EUFAMI is a not-for-profit 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.
population of patients included in RCTs differs significantly 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 affiliated 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.
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 specific social subgroups of patients
without health insurance.
CINP Antidepressant Task Force 2007
Statistical significance and clinical effectiveness are
not synonymous (for a definition, see Box 6) and not
always closely correlated. The so-called efficacy gap
between outcomes in clinical trials and in primary care
may be influenced by patient compliance, family and
social supports, and negative media reporting on
antidepressants (Wade, 2006). Another source of confusion is the use of refined statistical methods to
demonstrate the therapeutic efficacy and effectiveness
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 efficacy of antidepressants into the direction of limited efficacy, and
thus may impact treatment related considerations,
potentially underestimating the efficacy 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 influence 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 Force’s 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 company’s 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 different
cultural and climatic conditions. Biological differences, e.g. in metabolism, differences in food intake,
different patterns of physical morbidity as well as
cross-cultural differences in concepts of health and in
the expression of depressive episodes all lead to differences in treatment outcome. The use of medication
may differ 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 suffering from major depression or depressive disorders according to the Diagnostic and
Statistical Manual of Mental Disorders, 4th revision
(DSM-IV), or the International Statistical Classification
of Diseases and Related Health Problems, 10th revision (ICD-10). By defining specific subgroups of
patients suffering from depressive disorders, both
operationalized diagnostic systems may influence
treatment outcome. In addition, as mentioned above,
a relatively high placebo response rate in patients
suffering from depressive disorders has an impact on
efficacy studies of substances with possible antidepressant effects 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
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CINP Antidepressant Task Force 2007
studies are significantly positive in favor of a specific
medication does not mean that both drugs are equal in
efficacy. 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 difference in the Hamilton Rating Scale
for Depression (HAMD) of 2 may still be significant,
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
difference of 6 may lack statistical significance. In the
case of superiority in comparison with placebo treatment, both statistical significance and effect size are
very important factors influencing clinical effectiveness. 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 differ substantially from
study to study due to different allowances of rescue
medication, settings, severity of illness and so on.
Thus, relevant findings 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 difficult 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 efficacy of antidepressants.
Therefore, proving efficacy 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 effect, 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
sufficient 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,
dedicates several chapters on specific 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 one’s 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.
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-deficiency 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 specific antidepressant therapies are classified 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 Classification 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 five 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
S15
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
B : Maintenance
of effect
(Relapse
prevention)
C : Prevention
of recurrence
(Prophylaxis)
EMEA gives specific
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 different
fixed doses of the test
substance should be used to
determine the lower end of
the effective 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
fulfill both A and B
Double-blind comparison
against placebo, minimum
duration 1 year.
US (FDA) (U.S. Food and Drug
Administration, 2006)
South Africa (MCC) (Medicines
Control Council, 2007)
MCC gives no specific
‘ 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 effectiveness for new ‘Data presented in support of the
safety and efficacy of the
drugs’
medicine should be derived from
FDA demands no specific 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 efficacy of the
dose-comparison control
medicine can be established in
No specific 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 specific 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 fulfill 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, differences in the clinical picture of
depressive disorders influence both the choice and
outcome of specific 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).
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CINP Antidepressant Task Force 2007
Table 5. Symptomatology of depressive disorders (American
Psychiatric Association, 1994 ; World Health Organization,
1992 ; World Health Organization, 2005b)
Category of
depressive symptoms
Affective 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 deficits
Memory deficits
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 influence also
therapeutic outcome during antidepressant therapies.
Nevertheless the diagnostic systems help to compare
similar populations suffering from depressive disorders and to evaluate treatment effects worldwide.
In this chapter the effects of diagnostic categories
and subgroups on treatment outcome are described
not only on basis of scientific 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
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.
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 specific
classes of antidepressants.
5.2.1
Unipolar depression
A significant 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 differences 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 difficult diagnostic problems.
These difficulties may be further aggravated by the
presence of other conditions such as anxiety or personality disorders. The following sections describe
specific subtypes of depressive symptoms that may
influence antidepressant therapy. For other subtypes
of depression that respond similarly to treatment, no
differentiation appears to be warranted.
5.2.1.1 Severity of the disease
Depressive episodes can be classified 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 Montgomery–Åsberg rating scales for depression (Montgomery and Åsberg, 1979).
This subdivision is of clinical importance because
there is some consensus in the literature that mild
depressive syndromes should be treated by
CINP Antidepressant Task Force 2007
S17
Table 6. Diagnostic indications for specific 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
Specific indications
Mild to moderate unipolar
depression
$
Severe unipolar depression,
depression with melancholic
features
$
Depression with psychotic symptoms
$
$
$
$
$
Psychomotor agitation and
retardation/katatonic features
$
$
$
Specific features
Usually treatment with established
antidepressants, but treatment with
St. John’s wort possible
$
$
Good tolerability of phytotherapeutics
Only St. John’s wort showed sufficient
efficacy
Dually acting antidepressants
(TCAs, SNRIs, NaSSA)
ECT
$
Better efficacy in comparison to SSRIs
$
Better efficacy in comparison to
antidepressants
Usually combination therapy using
antidepressants and antipsychotics
Lithium augmentation
Highest effectiveness of ECT
Some reports support the effectiveness
of a SSRI monotherapy
$
High rate of treatment refractoriness
Augmentation strategies should be
considered at early stages to enhance
efficacy
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 effectiveness of ECT
$
$
$
$
Atypical features
$
MAOIs and SSRIs as first line treatments
$
Seasonal features
$
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
efficacious (TCAs, SNRIs, NARI, NaSSA)
Earlier use of psychosocial therapies in
combination with antidepressants
$
$
$
Depression with chronic pain
$
Adjustment disorders
$
Bipolar depression
$
SSRIs or MAOIs as a first line
treatment recommended
$
Combination with mood stabilizers
recommended
$
Monotherapy with mood stabilizers
possible
Dysthymia and double depression
$
Recurrent brief depression
$
Early combination of antidepressants
with psychotherapy recommended
No established treatment regimes
supported by RCTs
psychotherapy without additional biological therapies
such as pharmacotherapy or electroconvulsive therapy (ECT). In moderate depression non-biological
$
$
$
$
$
Acute sedating effects relieving rapidly
the patient’s restlessness are useful in
clinical routine
Avoiding sedation in case of
psychomotor retardation is useful
Katatonic features may predict rapid
ECT effects
Better clinical effectiveness in
comparison to other antidepressants
Suicidality may be enhanced during
bright light therapy
Possibly higher remission rates
Better relieve of pain syndromes
RCTs are rare, but clinical experience
suggests effectiveness of
antidepressants
TCAs and other dually acting
antidepressants such as SNRIs may
increase the switch risk
Combination may enhance effectiveness
especially in chronic depression
Higher risk for suicidal ideation
treatments are also the first choice in some guidelines,
although, moderately depressed patients respond
equally well to antidepressant medication. Moreover,
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CINP Antidepressant Task Force 2007
there is a distinct probability that patients with mild to
moderate depression may respond to phytotherapeutics such as St. John’s 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 suffering 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 benefit
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 significant efficacy (Anton and Burch, 1990 ; Rothschild et al.,
1993). SSRI monotherapy reportedly is efficacious during acute and maintenance treatment (Zanardi et al.,
1996 ; Zanardi et al., 1997). ECT has been recommended
as a possible first-line treatment because of its high
effectiveness 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
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 effect 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
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 first-line treatment
option that is superior to other pharmacological treatment (Andrews and Nemeroff, 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 first-line treatment.
5.2.1.3.1 Severe psychomotor agitation and
retardation
5.2.1.3.4
Severe psychomotor retardation, stupor, immobility
or, in contrast, severe agitation (called catatonic
Patients suffering from depression that recurs on
a regular, annual basis during fall or early winter
Seasonal features
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 efficacy (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
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 difficult. Somatoform disorders, fibromyalgia and similar
conditions characterized by pain are often accompanied by depressed mood. Effective 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 Wiffen, 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 efficacy in anecdotal reports, only SNRI and TCA have proven efficacy according a recent Cochrane review (Saarto and
Wiffen, 2007). It seems plausible that antidepressants
with both serotonergic and noradrenergic properties
could be particularly effective in treating pain and
painful physical symptoms. Higher remission rates in
these subgroups of depressed patients have recently
19
There exists no clear cut definition 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 off values
using the CGI or HAMD scale (e.g. as done in Laakmann et al., 1996
and 1998).
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 offer patients
suffering from adjustment disorder therapeutic regimes other than those that offered to patients with
depressive disorders. This is especially true during
the period of acute treatment. Although controlled
efficacy trials in adjustment disorders are rare, both
clinical experience and retrospective studies (Hameed
et al., 2005) suggest no difference 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 inflated
self-esteem are normally present together with decreased need for sleep, hyperactivity, psychomotor
agitation, racing thoughts with flight 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
patient’s history must include at least one episode of
hypomania (a period of manic symptoms of lesser
severity that lasts at least 2–4 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
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CINP Antidepressant Task Force 2007
possible to make a diagnosis of bipolar disorder, up to
50 % of younger patients suffering from depression at
the first 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 efficacy and effectiveness 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 efficacy, 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 definition of ‘ switch ’, the switch rates in
scientific 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 efficacy 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 (Möller et al., 2006).
5.2.2.2 Dysthymia and depressive disorder in
combination with dysthymia21
Diagnostic criteria for dysthymia and depressive disorders differ 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 scientific basis
for this suggestion is still a matter of debate.
21
From a scientific perspective, there is presently insufficient reason
to define ‘ double depression ’ as a specific subgroup of depressive
disorders.
depression, although it produces very similar levels of
disabilities. Also, an additional and superimposing
major depressive episode can occur in patients already
suffering from dysthymia, diagnosed then as a ‘ double
depression ’ or ‘double major depressive disorder ’.
When a dysthymic episode follows a depressive episode, the differential diagnosis of both disorders is
difficult 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 efficacy
in major depressive disorders. Different 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),
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 efficacious 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
significantly affects 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 reflection in treatment plans.
5.2.3.1 Other psychiatric disorders24
5.2.3.1.1
Anxiety disorders
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 suffering from
depressive disorders (Hasin et al., 2005). Up to now,
however, it has not been sufficiently 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 differences
in the clinical course and severity of disease compared
with patients suffering from depressive disorders
alone (Grunhaus et al., 1994).
Because comorbid conditions can diminish the
clinical effectiveness of antidepressant pharmacotherapy (Grunhaus et al., 1986), they should be
considered in treatment plans. Administering antidepressants with demonstrated efficacy for both
diagnostic entities (e.g. in the case of depressive and
anxiety disorders, SSRIs such as paroxetine
(Montgomery, 1992)), together with implementing
specific psychotherapeutic options for depression
and anxiety, seems to be a useful strategy (see also
chapters 13 and 19.9).
5.2.3.1.2
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 influence 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 effects 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 first must be considered when it can be done
directly (e.g. substitution of thyroid hormones in case
Substance abuse
25
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
S21
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,
different 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
Organic illness
Neurological disorders
$
$
$
$
$
$
$
$
$
$
$
$
Endocrine disorders
$
$
$
$
$
Other medical disorders
$
$
$
$
$
$
28
Pharmacogenic depression
$
$
$
$
$
$
Stroke
Dementia
Epilepsy
Huntington’s chorea
Hydrocephalus
Central nervous system (CNS) infectious diseases
CNS neoplasias
Parkinson’s disease
Narcolepsy
Sleep apnea
Trauma
Wilson’s disease
Adrenal disorders (Cushing’s disease, Addison’s 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 confirm 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 effect 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 suffering from CVD is relatively
low. Moreover, the comorbidity of depressive disorders and CVD significantly influences 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 suffering from myocardial infarction and depression is still limited (Jaffe 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 influencing 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 influencing 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 sufficiently,
although, both a significantly 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 influence on cardiac conductance, rhythm or output.
Most modern antidepressants fit this profile, including
SSRIs, NARIs and dual-action substances. In addition,
because depression may worsen coronary blood flow
(Lederbogen et al., 2001), it seems plausible to make
use of the diminishing effects of SSRIs on platelet aggregation (Maurer-Spurej et al., 2004) to achieve further benefit for patients suffering from depression and
cardiovascular disease.
5.2.4.1.3
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 influence of depression on
therapeutic adherence and the risk of vascular complications and disability have been described. The
effectiveness of antidepressant treatments in diabetic
patients has been shown, but the potential benefit
for blood glucose and HbA1c levels remains unclear
(Evans et al., 2005). Antidepressants and antipsychotics with sedating properties due to antihistaminergic
effects 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).
Renal disorders
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 effects
and toxic effects 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 effects and blood level monitoring are useful tools
to prevent overdoses. If renal failure progresses to
end-stage renal disease and hemodialysis, hemoperfusion or hemofiltration are necessary, lower antidepressant plasma levels are possible, and dose
adjustment may be required considering blood levels,
efficacy and side effects.
5.2.4.1.4
5.2.4.1.2 Endocrinological disorders and diabetes
mellitus
S23
Hepatic disorders
Patients suffering 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 specific 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
substances also require dose adaptation in patients
suffering from liver disease to prevent side effects
and intolerable toxicity which may occur because of
a lower clearance of antidepressants and metabolites,
and consequently prolonged elimination times
(Demolis et al., 1996 ; Joffe 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, Parkinson’s
disease and multiple sclerosis (Kanner, 2005b). In
addition, a side effect 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 suffering from
epilepsy, cautious treatment using the lowest efficacious 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 fluvoxamine seem to exhibit the lowest risk for seizures
(Pisani et al., 1999). In addition, pharmacokinetic interactions between antidepressants and antiepileptic
drugs are to be expected, especially with carbamazepine.
5.2.4.2.2
Stroke and dementia
Patients suffering 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 suffer 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 Alzheimer’s disease (AD) (Derouesne
and Lacomblez, 2004) and other forms of dementia are
often seen but are rarely distinguishable from apathy,
loss of drive and affective disturbances that are among
the symptoms of Alzheimer’s 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 efficacy 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 first 6 months poststroke significantly 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 first 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 effects. For this reason SSRIs, NARIs,
SNRIs and NaSSAs would appear to compare favorably with TCAs.
5.2.4.2.3
Parkinson’s disease
The risk for depressive disorders in patients suffering
from Parkinson’s disease (PD) (Hantz et al., 1994)
is controversial. A high prevalence of depression
in PD (20–40 %) 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 beneficial for patients and
improves the overall quality of life (Anon., 2002 ;
Weintraub et al., 2005). Both SSRIs and SNRIs are
generally well tolerated and efficacious (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 effect
on depression may in some cases be only modest
(Amsterdam, 2003). The potential benefit 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 suffering 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 effects has been reported in susceptible patients (Schillevoort et al.,
2002). These effects 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 suffering from multiple sclerosis
often show affective 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
Depression is one of the most frequent comorbid disorders in chronic migraine (Mercante et al., 2005).
S25
Comorbid migraine significantly influences 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 (fluoxetine) have shown effectiveness 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 suffer
psychiatric comorbidities such as depressive disorders
(Butt et al., 2006). In addition, specific somatic therapies such as interferones or antibiotics may increase
the risk of developing severe depressive symptoms.
Infectious diseases affecting 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 immunodeficiency
virus (HIV), acquired immunodeficiency 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.
S26
CINP Antidepressant Task Force 2007
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 suffering 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 efficacy 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
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-Pacific 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 different 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 affective 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 difficulties 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
CINP Antidepressant Task Force 2007
30
25
20
15
10
5
0
Prevalence (%)
Ankara, Turkey
Nagasaki, Japan
Athens, Greece
Paris, France
Bangalore, India
Rio de Janeiro, Brazil
Berlin, Germany
Santiago, Chile
Groningen, Netherlands
Seattle, USA
Ibadan, Nigeria
Shanghai, China
Mainz, Germany
Verona, Italy
Manchester, UK
Figure 1. Differential prevalence of depression in primary
health care in different WHO centers (Goldberg and
Lecrubier, 1995 ; Üstün 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
confirms 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 figures in studies
performed between 1961 and 1978 are at least 9 times
greater than the highest figures 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
effective 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
differences have been reported ; women are affected
twice as often as men (Kessler, 2003). In addition,
S27
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 affected by age and
gender of patients (see also chapter 10). The mean
duration of depressive episodes was 16 weeks. About
90 % of patients are suffering 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 effects (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 (2–7 %), 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 effective 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
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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
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 Möller, 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 different 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 suffering 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 different 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-specific 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
cost-effectiveness, 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
first 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 suffer 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 sufficient
knowledge and experience to diagnose depression,
e.g. general practitioners or at least trained nurses. If
resources allow, identification 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 Classification of Diseases and Related
Health Problems, 10th revision (ICD-10) (World
Health Organization, 1992), to improve confidence in
and reliability of diagnosis of depression. Structured
interviews, such as the Structured Clinical Interview
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 identification of depression in adults in primary care settings,
although evidence for children and adolescents is insufficient. 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
Clinical feature
None Mild Moderate Severe
( %)
( %) ( %)
( %)
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
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
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 first 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 Korff, 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)
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Assessment should be offered 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 first manifests with a depressive
episode, patients and relatives should be questioned
for emerging (hypo)manic symptoms both at the
initial taking of the patient’s 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
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
sufficient care for depressed patients.
possibility of direct hospital admission, health and
insurance policies in different countries may not yet
reflect this standard ; elsewhere, a lack of resources
makes it difficult. Nevertheless, considering the
consequences of inadequate diagnosis and treatment
(including treatment settings) for prolonged illness,
chronicity and finally potential suicide, measures
must be taken to ensure these standards worldwide.
6.3
Enhanced care
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 specific 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 first 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 patient’s 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 patient’s 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
S31
Box 3. Principles of enhanced care (adapted and modified according to Goodwin, 2003)
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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 benefit 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 effects 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 offer 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 specifically
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-effective in the
short term, but this effect 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 effective and likely to be cost effective
(Gilbody et al., 2003a ; Gilbody et al., 2003b).
Response
Traditionally, treatment is divided into acute, continuation and maintenance (prophylactic) phases
(Kupfer, 2005) (see Figure 2).
Clinical trials focus on symptomatic relief measured
by specific scales, e.g. the HAMD score (Hamilton,
1967), and define response and remission in relation to
these scores (usually 50 % reduction of the baseline
score as ‘ response’ and a specific cut-off as ‘ remission ’, see Box 4). It should be kept in mind that
remission as defined in clinical trials does not necessarily correspond to remission in clinical terms.
Relapse
Free interval Recurrence
Healthy
Depressed
Spontaneous course
Acute treatment
Continuation and maintenance
treatment
Figure 2. Long-term treatment of depression (modified from
Kupfer, 1991).
Clearly, clinical management of depression goes far
beyond these criteria, which are meant to establish
evidence for efficacy of treatment. Although remission
is recognized as the optimal outcome of treatment for
depression, remission lacks a universally accepted
definition (Israel, 2006).
$
7. Goals of treatment : response, remission,
recovery
Remission
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. Definition of response and remission (Thase, 2003)
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The traditional definition of response to antidepressant therapy includes a 50 % improvement in symptoms30.
Remission is defined 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 defined as remission (e.g. HAMD score f7).
Full Recovery is defined as the full regain of social and occupational functioning without residual symptoms of depression.
Box 5. Choice of a specific drug
The availability of different antidepressants may vary from country to country (see chapter 14). Among the antidepressants
available, proven efficacy must be the first consideration. In the next step, the choice of a specific 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 finally the preference of the
patient after explaining potential advantages and disadvantages of candidate medications.
$
$
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$
30
American Psychiatric Association, 2000 ; Bauer et al.,
2002c).
From the patient’s perspective, the most important
criteria for remission are the presence of features of
positive mental health such as optimism and selfconfidence, self-satisfaction and a return to one’s
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
significant 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 suffering,
morbidity, and a high risk of recurrence and/or
chronicity. Treating patients with depression to a
state of remission is associated with a significantly
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 defined 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
Response and remission are usually measured using instruments
such as the Montgomery–Åsberg 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.
death from somatic disorders associated with depression, e.g. cardiovascular disease (Angst et al.,
2002a).
Optimal clinical effectiveness 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
Initiation of antidepressant treatment should be a first
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 effective dose to ensure good tolerability. If no side effects occur or if side effects 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 first choice of antidepressant is a selective serotonin reuptake inhibitor
(SSRI) or other, newer antidepressant with a favorable
side effect profile (Voellinger et al., 2003). Regardless
of the drug chosen, during antidepressant pharmacotherapy one must reckon with a delay of several
weeks until sufficient antidepressant effects can be
seen. Up to now no definite 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 profile 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 effects of TCA and psychotherapy – whereas Amitriptyline had early effects
on vegetative symptoms of depression psychotherapy
showed more delayed effects 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 first 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
effective antidepressant treatment initiates clinical
changes even during the first week of antidepressant
treatment (Stassen et al., 1999 ; Taylor et al., 2006).
If a treatment is not the first medication trial and
a patient has previously been on fluoxetine 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 fluoxetine 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 specific
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 (2–3) days of pausing medication is sufficient
(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
specific 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 fluoxetine and escitalopram) (Baboolal, 2004 ;
Haddad, 1998 ; Rosenbaum et al., 1998 ; Schatzberg
et al., 2006). The reported frequency of antidepressant
discontinuation syndromes varies widely from
10–60 % 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
3.81–6.68) and in particular venlafaxine and paroxetine (OR 12.16, 95 % CI 6.17–23.35 and OR 8.47, 95 %
CI 5.63–12.65, respectively) (Trenque et al., 2002).
Discontinuation syndrome may also affect 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 sufficient to suggest a possible causal relation. Sixty-four of the cases were associated with
paroxetine, 14 with fluoxetine, 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 sufficiently
long enough for a final 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 flu-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 efficacy of a
given treatment differ according to expert reviews and
guidelines. For acute treatment, recommendations
vary regarding how long the drug of first choice
S34
CINP Antidepressant Task Force 2007
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 50–75 % in moderately to severely depressed patients, which means that despite
sufficient dosage, 25–50 % of patients do not respond
sufficiently 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 difficult
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 sufficient 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 defined as a f25 % decrease in baseline
symptom severity, partial response as a 26–49 % 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 8–10
weeks to define the full extent of symptom reduction
(Bauer et al., 2002c). This contrasts with a recommendation from a round-table consensus published by Hirschfield 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 6–8 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 findings of Nierenberg et al. (2000) showing
that in patients who had not received at least 30 % reduction of symptom severity by 4 weeks on fluoxetine,
the likelihood of a response at 8 weeks was only about
12–27 %. Similarly, Stassen and Angst (1998) reported
that in a controlled study comparing moclobemide
and fluoxetine, onset of improvement occurred in
more than 70 % of patients within the first 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 insufficient 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-defined relationship exists between
drug plasma concentration and its clinical effects
(therapeutic effects, adverse effects 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 Guelfi, 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 effectiveness and side effects and in
conjunction with a clinical question, e.g. insufficient
treatment response, side effects due to overdosing and
so on. Moreover, serum level measurements should
only be performed under steady-state conditions (at
least five 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
CINP Antidepressant Task Force 2007
drug, e.g. a short (about 2–10 hours) plasma half-life
for venlafaxine, trazodone, tranylcypromine and
moclobemide, or a very extensive plasma half-life,
e.g. 3–15 days, for fluoxetine and its metabolite norfluoxetine.
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 5–8 % of Caucasians are considered to be poor metabolizers (PM) and 1–7 % are
ultrarapid metabolizers (UM) (Baumann et al., 2005) ;
the first leads to increased serum levels and the latter
to insufficient 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 influences the metabolic rate of other substances. For example, some SSRIs that inhibit CYP2D6,
especially fluoxetine and paroxetine, but also bupropion, may result in clinically significant 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. norfluoxetine, the metabolite of
fluoxetine and fluvoxamine, 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 effective and symptomatic remission has been achieved,
the usual recommendation is to continue the antidepressant in unchanged dose unless side effects 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 significantly 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 patient’s risk of relapse. The
situation may be different 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 effective antidepressant monotherapy or combination treatment for at least another
3–6 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 off at the end of
continuation is strongly advised. It has been suggested
that the tapering phase should last at least 4–6 months
(Bauer et al., 2002c).
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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)
Number of episodes that would indicate
that longer ‘maintenance’ treatment
is appropriate
UK Defeat Depression Consensus
Statement (Paykel and Priest, 1992)
4–6
o2
US Agency for Health Care Policy and
Research (Agency for Health Care Policy
and Research, 1993)
4–9
o2
British Association for Psychopharmacology
(Anderson et al., 2000)
6
o3 in the past 5 years (or o6 in total)
American Psychiatric Association
(American Psychiatric Association, 2000)
4–5
not specified
Korean Guidelines (Lee et al., 2006)
6–12
2 years up to indefinitely 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
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 difficult to achieve. Other factors that influence 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 (Müller-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
o3 in past 5 years (or o5 in total)
in recurrent depression :up to 3 years
been recommended, e.g. the WFSBP Guidelines recommend maintenance treatment of 5–10 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 influence the probability of
recurrence of a depressive episode (modified 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
findings 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 first 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 first 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 patient’s
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 benefit from
maintenance medication and may experience a
worsening of the long-term course of the illness.
According to Fava, the mechanism of this paradoxical
effect 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 effects of a drug
and may result in loss of clinical effectiveness. 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
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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 efficacy of antidepressant maintenance in clinical trial subjects, the role of long-term
antidepressant continuation in less severely depressed
patients still requires further clarification.
7.3
Managing side effects
This section focuses on general management of side
effects. Medication-specific side effects are detailed in
the specific sections on patients (see chapters 9.1.2 up
to 9.1.11).
Patients’ complaints about side effects of medications should always been taken seriously to forestall
non-adherence and uncontrolled discontinuation.
But patients do not always report side effects spontaneously, so active probing is recommended.
Therapists must be familiar with drug side-effect profiles.
7.3.1 Frequency of the occurrence of side effects
Minor side effects are common and are associated with
most medication trials. They differ 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 effects in controlled
studies comparing SSRIs and TCAs, though different
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 one’s (Anderson, 2000 ;
Anderson, 1998 ; Peretti et al., 2000 ; Wilson and
Mottram, 2004), also reflected 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 effects 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 effects are tolerable and the patient is responding either completely or at least partially and is willing
to continue with a drug despite side effects, careful
tapering of the medication is a reasonable first step. If
side effects are already occurring at unusually low
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CINP Antidepressant Task Force 2007
doses, TDM and potential identification of a poor
metabolizer status may be helpful (Baumann et al.,
2005). If, after tapering medication, side effects do not
subside or efficacy is lost, switching drugs with slow
tapering off, stopping and then titration of a new
antidepressant is advised. In general, SSRIs and mixed
serotonergic/noradrenergic antidepressants have a
more favorable side-effect profile 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 effects may be underestimated because
clinical trials often only disclose spontaneously reported side effects, and in natural settings they
may be much more common. In the context of managing side effects, psycho-education of the patient
plays an essential role. Experience of side effects 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 effects 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 effects. In the process, the mechanisms
underlying the actions of effective drugs have been
defined. 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
slices in vitro, whereas iproniazid, the first clinically
effective MAOI, inhibited the intraneuronal metabolism of these biogenic amines, gave support to the
emerging monoamine hypothesis of depression (Ban,
2001). However, despite the refinement 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 exemplified by maprotiline and reboxetine) or serotonin (selective serotonin
reuptake inhibitors, SSRIs, as exemplified by fluoxetine) (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 first effective 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 influx of calcium
ions and thereby reduce the calcium-dependent release of noradrenaline, drugs that specifically 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 modification of the tetracyclic structure of mianserin has
led to the development of a dual-action antidepressant
that lacks the gastrointestinal and neurological
side effects of the SSRIs, adverse effects 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 efficacy in the treatment of depression (Amore and Jori, 2001 ; Papakostas,
2006).
Moreover the positive influence of antidepressants
on monoamine neurotransmitter systems is not
limited to the treatment of depressive disorders.
Therapeutic effects 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 influence on specific neurotransmitters may influence the regulation of behavior
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 specificity 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 effects.
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 differences between different 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 different from other SSRIs
(Chen et al., 2005 ; Sanchez et al., 2004 ; Thase, 2006).
Despite the plethora of different 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 efficacy
but safety. Modern antidepressants are no more effective than the first tricyclics, such as imipramine or
amitriptyline.
While it is generally assumed that all effective 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 effects 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
significantly decreases the concentration of brain
serotonin, results in either no effect or a mild
dysphoria in healthy volunteers and does not affect
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 effects 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 effect (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 effects 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 significant role. Effective
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
profile 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
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CINP Antidepressant Task Force 2007
diagnosis of depression, and the different types of depression, is dependent on the symptoms ; these are
frequently complicated by comorbidity with other
psychiatric disorders. Clearly, the development of
specific 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 effects
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 profile, cognitive
and memory deficits) 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 fulfil at
least 3 criteria, namely predictive validity (an ability to
detect all treatments that are therapeutically effective),
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 fulfil the first two criteria,
it is more difficult 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 fulfil 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,
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 offspring (Weinstock, 2007).
When pregnant rats undergo daily restraint stress
for one week during the mid-gestational period, the
offspring show increased immobility in a stressful environment (such as the open field 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 beneficial 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 effectively 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
modifications 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
CINP Antidepressant Task Force 2007
studies, which have identified 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 affected, suggesting functional impairment of these regions associated with depressive
disorders (for review see Gould and Manji, 2004).
Effective antidepressant treatments have also identified 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 affected 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 modifications in neuronal architecture. Very
few publications have reported the effect of antidepressants on them.
Such observations are particularly pertinent to
the mode of action of antidepressants, as for the first
time, a cellular explanation has been proposed that
identifies 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 findings for the
development of future antidepressants ? Clearly, the
conventional approach whereby specific monoamine
S41
neurotransmitters are targeted must be reconsidered.
It can be argued that such an approach has failed to
bring about any major benefits to the depressed patient in terms of therapeutic efficacy. 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 effective 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 influence 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 effect upon serotonergic transmission and
32
S100 is a protein characterized by two calcium binding sites. There
are at least 21 different types of S100 proteins in the so-called S100
protein family.
S42
CINP Antidepressant Task Force 2007
enhance function (Culman et al., 1997). While considerable excitement was generated regarding the
antidepressant potential of the first 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 findings
have shown that most classes of antidepressants decrease the affinity 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 first
s1-receptor antagonist shown to have antidepressant
activity (Manji and Lenox, 1999 ; Roman et al., 1990),
but it could not subsequently be confirmed 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 significant 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 influence 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 efficacy 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)
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-inflammatory cytokines into the etiology of
depression. Thus, the observation that inflammatory
mediators, such as the pro-inflammatory 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 suffering 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 profile, mood, memory, appetite,
libido, cognitive function, endocrine function) may
also be caused by pro-inflammatory cytokines that are
increased in the blood and cerebrospinal fluid (CSF)
of depressed patients (Dantzer, 2004). Conversely,
chronic treatment with antidepressants attenuates the
release of pro-inflammatory cytokines from activated
macrophages both in the blood (Xia et al., 1996) and
in the brain (Obuchowicz et al., 2006). These findings
suggest that antagonists of pro-inflammatory 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).
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). Inflammatory changes in the brain are
pathological features of both dementia and depression
(Steffens et al., 1997). It would appear that an increase
in inflammation-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 effect 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 inflammatory mediators are responsible for increasing neuronal apoptosis and preventing repair of damaged neuronal networks.
Effective 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
reflect 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 efficacy 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 hypothalamic–pituitary–
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) (Nemeroff 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 first weeks of antidepressant pharmacotherapy seems to be associated
with lower rates of early treatment response (Hatzinger
et al., 2002). Furthermore, and significantly, 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 differ 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
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 fluid (CSF) of both suicide victims and in depressed patients (Nemeroff, 1996). However, despite
initial promising clinical experience, so far CRF
antagonists have shown no efficacy 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 beneficial 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
identified 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 identification of malfunctioning neurotransmitters and their
signaling systems, and correcting their defects with
novel molecules, offers 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 effects.
It is now realized that polymorphisms of the cytochrome P-450 microsomal oxidase system in the liver
are responsible for many of the genetic differences that
affect drug responsiveness and metabolism.
An important area that is related to pharmacogenetics is pharmacogenomics. Whereas pharmacogenetics is concerned with the individual patient and
how differences in metabolism and drug response are
a reflection 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 specific 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
disease and hypertension, and psychiatric illness are
polygenic and therefore influenced 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
findings, 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 effect. Nevertheless,
meta-analyses have identified several genetic variants
of candidate genes. In bipolar disorder, for example,
a variant of the MAO-A gene has been identified
(Furlong et al., 1999), although other investigators
have been unable to confirm this finding (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 influence
of stressful life events on depression (Caspi et al.,
2003). However, once again, not all investigators have
been able to replicate this finding (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 influence the risk for developing depressive disorders (Arinami et al., 1996 ; Baghai et al., 2006a),
HPA axis activity (Baghai et al., 2002) and the clinical
effectiveness of antidepressant therapies (Baghai et al.,
2001 ; Bondy et al., 2005). Also, the glucocorticoid
receptor-regulating co-chaperone FKBP5 has been
shown to influence 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
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 deficiencies, which frequently occur in late-onset depression. Such observations serve to emphasize the difficulties that exist in
attempting to identify specific 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 suffer
from potentially biologically different diagnostic
entities. This confusion may contribute to reported
difficulties in association studies. In future, better diagnostic systems or investigation of endophenotypes
may help to define genetically different 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 findings, 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
benefits and risks during the pharmacotherapy of
depression, followed by further discussion regarding
mechanism of action and specific 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
Organization’s (WHO’s) 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 efficacy that
are better tolerated than amitriptyline such as SSRIs
but that are sometimes not prescribed because of their
cost. However, despite the undoubted effectiveness
of TCAs, it soon became apparent that the anticholinergic and antihistaminergic side effects 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 effects in most
of the published studies. But interestingly also antidepressant effects of selectively anticholinergic acting
substances have been reported (Furey and Drevets,
2006).
For historical reasons, currently available antidepressants are usually classified according to their
chemical structure and mode of action. This classification 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 scientific and
historical classification. Nevertheless it may be useful
to use a different ordering scheme in evolving treatment plans and algorithms. Classification according to
33
Sociotherapy designates non-medical, social and work-related
components of the care process.
S46
CINP Antidepressant Task Force 2007
Box 6. Definitions efficacy/clinical effectiveness/efficiency
Efficacy is the power of a substance to produce the effects that it is supposed to produce (e.g. antidepressant effects).
Clinical effectiveness is the ability to successfully achieve clinical remission.
Efficiency describes the relationship between effectiveness 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 influence 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
specific 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
34
For educational purposes it could be justified to use only a
pharmacodynamic classification model of antidepressants. Due to
historical reasons and after a consensus process in addition the
classification according the chemical structure was retained.
35
Antidepressants such as fluoxetine, trimipramine, mirtazapine,
mianserin, venlafaxine and reboxetine are generally marketed as
racemic compounds. Both the pharmacological and pharmacokinetic
profiles of these substances may differ between the enantiomers, e.g.
of citalopram (Baumann et al., 2002 ; Baumann and Eap, 2001) or
fluoxetine. In the case of the latter, a different pharmacological
profile of the two enantiomers may cause differences in cardiac
tolerability (Magyar et al., 2003).
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 differences in populations of different countries play a major role in
clinical trials investigating efficacy and tolerability.
Moreover, outsourcing of clinical trials may cause
difficulties in interpreting study results ; caution is recommended, especially in cases where study results
from different 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 different countries could raise
doubts about the findings.
A summary of commonly used antidepressants, including their primary mode of action and influence on
other receptor systems, is shown in Table 1. According
the review from Sanchez et al. (1999) semiquantitative
information about receptor affinities 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 affinities concerning secondary and additional pharmacodynamic profiles
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 efficacy and tolerability, but we do not
know whether that is true for each country. Direct comparisons
between brand-name formulations and generics and between
different 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
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
Starting
dose (mg)
Dosage range
(mg/day)
25
25–75
30–60
50
100
20
25–50
25–75
120–180
75
25–75
40/6038
5–10
20
50–100
25–75
20
70
25–75
20
30
50
15
150–300
100
25–50
20
15
10
4
oral : 30
transdermal : 6
50
37.5
10
50–100
25–50
75
100
25–50
150–300
180–300
100–400
200–300
20–60
100–250
100–300
240–720
75–150
150–300
60–120
10–20
20–80
100–300
150–300
20–60
140–210
150–225
20–30
60–120
100–200
30–45
300–600
300–600
75–300
20–60
30–90
20–60
8–12
oral : 30–60
transdermal : 6–12
50–200
37.5
20–40
200–600
150–400
75–375
200–500
37
Different dosages are used on different continents and in different
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 influence
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.
S47
Despite the development of a variety of new antidepressants with different pharmacodynamic profiles,
to date the hope of better efficacy and clinical
effectiveness (see Box 6) over older antidepressants
has not been fulfilled.
In contrast to efficiency, the focus of effectiveness is
achievement as such, not the resources spent, so anything that is effective is not necessarily efficient, but
anything that is efficient also has to be effective. In
psychiatry, the distinction between efficacy (ideal use)
and clinical effectiveness (typical use) is often drawn.
Whereas efficacy may be shown in clinical trials,
clinical effectiveness has to be demonstrated in clinical
practice.
Some reports of better efficacy for some recently
developed antidepressants require further confirmation. 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 MAOI’s
concerning their clinical effectiveness. But even in
the case of a proven efficacy of antidepressants the
clinical effectiveness may be diminished due high
discontinuation rates. These seem to be influenced
by noncompliance due to side effect profiles of antidepressants (Hotopf et al., 1997). In addition, it is
necessary to evaluate the clinical relevance of small
mean differences in depression rating scales between
active substances or antidepressant and placebo treatment, even in the case of statistical significance.
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 specific 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 efficacy and tolerability of antidepressants for
large portions of the world population. Predominantly
genetic, but also cultural differences, may contribute to
a differential 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 effects 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 effects, their specific
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CINP Antidepressant Task Force 2007
Box 7. Definition of pharmacotherapy-resistant depression (modified 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 definition of appropriate treatment varies among experts. While some consider that appropriate treatment must include
two courses of pharmacotherapy with antidepressants of different groups in sufficient 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-effect profile still must be taken into account
during treatment. In addition, the latency of several
weeks until the onset of sufficient therapeutic effects
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 findings remains controversial (Blier,
2003 ; Nierenberg, 2001). In addition early drugspecific behavioral changes which may be predictive
for the clinical response (Katz et al., 2004) are not recorded sufficiently in all RCTs. Moreover, demographic factors and treatment settings appear to
influence 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 effects 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 defining treatment
resistant/refractory depression (see the definition 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 first 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 efficacy during a time
interval of at least 4–6 weeks in a sufficient 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 inefficacious, 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 definition 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 difficulty in predicting the most effective 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 (Möller, 2002), can
be a clinically useful addendum. Prescription of
anxiolytics as a monotherapy is barely effective 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 effective 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 sufficient treatment
attempts have been made with efficacious 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
effects, then describe all presently available antidepressants according their mode of action, clinical
effectiveness and main side-effect and risk profile.
9.1.1.1 Metabolism, pharmacokinetics, pharmacogenetics,
therapeutic drug monitoring and interactions of
antidepressants
9.1.1.1.1
Introduction
The pharmacological effect 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 defining 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 differences in drug
metabolism in patients. Thus it may be assumed that
drug plasma concentrations, rather than dose, reflect
concentration in the brain, and this assumption has
prompted numerous studies on the relationship of
drug plasma concentrations and clinical effects 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
S49
phase II reaction, they undergo conjugation (Table 12)
(Liston et al., 2001). Drugs such as tertiary amine TCAs
and SSRIs such as fluoxetine, 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 first 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 field 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 differ
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 differs among different ethnic groups. From a
clinical point of view, PMs have a higher risk of
experiencing adverse effects 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 influenced by comedication,
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CINP Antidepressant Task Force 2007
Table 12. Antidepressants as substrates of cytochrome P-450 (CYP)
Drug (and/or metabolite)
substrate of
Class of
antidepressants
Drug
Active (and clinically
non-relevant) metabolites
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
(2-OH-desipramine)
Dothiepine
Doxepin (a)
CYP2C19
+ (+)
+
+
+
CYP3A4,
CYP1A2,
CYP2C9
(+)
(+)
(CYP3A4,
CYP1A2,
CYP2C9)
+ (+)
+ (+)
+
CYP1A2,
CYP3A4,
CYP2C19
+
CYP2C9,
CYP1A2
+
CYP1A2,
CYP3A4
+
·
+
desmethyldoxepin (a)
Imipramine
desipramine
(2-OH-imipramine)
(2-OH-desipramine)
Lofepramine
desipramine
(2-OH-desipramine)
+ (+)
+
(+)
+
+
Maprotiline
Other forms
of CYP
CYP2D6
CYP1A2
(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)
+
CYP3A4,
CYP2B6,
CY1A2
·
+
+
·
CYP1A2,
CYP3A4
+
+ (+)
+
+
CYP3A4
+
CINP Antidepressant Task Force 2007
S51
Table 12. (cont.)
Drug (and/or metabolite)
substrate of
Class of
antidepressants
Drug
Active (and clinically
non-relevant) metabolites
CYP2D6
CYP2C19
Other forms
of CYP
+ (+)
+
+
CYP3A4
SSRIs
Citalopram (b)
desmethylcitalopram
(didesmethylcitalopram)
(citalopram propionic acid derivative)
Escitalopram
S-desmethylcitalopram
(S-didesmethylcitalopram)
(S-citalopram propionic acid derivative)
Fluoxetine (b)
norfluoxetine
Fluvoxamine
Paroxetine
Sertraline
+ (+)
+
CYP3A4
+ (+)
+
+
CYP2C9,
CYP3A4
+
+
x
-
CYP1A2
+
CYP3A4,
x2C9, x2B6
norsertraline
Other antidepressants
Bupropion
Dibenzepine
Duloxetine
x
·
+
CYP2B6
CYP1A2
(desmethylduloxetine)
x
x (+)
Milnacipran
Nefazodone
3-OH-nefazodone
m-CPP
Reboxetine (b)
Trazodone
x
+
x
+ (+)
x
CYP3A4
CYP3A4
CYP3A4,
CYP1A2
m-CPP
+
Venlafaxine (b)
+
O-desmethylvenlafaxine
(N-desmethylvenlafaxine)
(N,O-didesmethylvenlafaxine)
Viloxazine
St. John’s wort
·
·
Moclobemide
Tranylcypromine
x
·
CYP2C9,
CYP3A4
MAOIs
+
* From Baumann (in preparation), (cf. also Wilkinson, 2005).
· No studies available.
(a) A mixture of geometric isomers : the isomers differ in their pharmacological and pharmacokinetic profile.
(b) Chiral drugs : the isomers (of the drug and of their chiral metabolites) may differ in their pharmacological and pharmacokinetic profile.
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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 insufficient response even if doses considered adequate
Adverse effects 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 deficiency, gene multiplication)
Special populations
$
$
$
Children and adolescents
Elderly patients (o65 years)
Patients with somatic comorbidities (hepatic or renal insufficiency, 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 briefly 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
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 fixed doses and they may
inform about the reliability of the drug plasma concentration measured in a patient treated with a particular dose.
TDM of antidepressants
TDM of antidepressant drugs is widely practiced
to optimize the pharmacotherapy of depression
(Baumann et al., 2004 ; Brøsen, 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 effectiveness (Baumann et al., 2004). Table 14
represents the result of a consensus among experts
9.1.1.1.4
Pharmacogenetics and TDM
It is now generally acknowledged that pharmacogenetic tests represent a useful tool in finding 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 effects (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 confirm
that, indeed, the CYP2D6 genotype determines the
plasma concentration of some antidepressants
(Grasmäder 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 effects. 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 effects 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
Many patients are comedicated with other psychotropic and/or somatic drugs as a consequence of comorbidities or non-response to monotherapy. Patients
suffering from recurrent depression are submitted to
long-term treatment. This increases the lifetime risk of
comorbidities, which necessitate simultaneous treatment with several drugs. Adverse effects 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 (fluoxetine, paroxetine, fluvoxamine,
trimipramine etc.) and metabolites (norfluoxetine)
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 fluvoxamine
(Bertschy et al., 1991) or fluoxetine (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://
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Table 14. TDM of antidepressants : recommended plasma
concentration ranges (‘ therapeutic windows’)
(Baumann et al., 2004)
Recommended
therapeutic range
(consensus)
Drug and active metabolite
Antidepressants
Amitriptyline plus nortriptyline
Citalopram
Clomipramine plus norclomipramine
Desipramine
Doxepin plus nordoxepin
Escitalopram
Fluoxetine plus norfluoxetine
Fluvoxamine
Imipramine plus desipramine
Maprotiline
Mianserin
Mirtazapine
Moclobemide
Nortriptyline
Paroxetine
Reboxetine
Sertraline
Tranylcypromine
Trazodone
Trimipramine
Venlafaxine plus
O-desmethylvenlafaxine
Viloxazine
80–200 ng/ml
30–130 ng/ml
175–450 ng/ml
100–300 ng/ml
50–150 ng/ml
15–80 ng/ml
120–300 ng/ml
150–300 ng/ml
175–300 ng/ml
125–200 ng/ml
15–70 ng/ml
40–80 ng/ml
300–1000 ng/ml
70–170 ng/ml
70–120 ng/ml
10–100 ng/ml
10–50 ng/ml
f50 ng/ml
650–1500 ng/ml
150–350 ng/ml
195–400 ng/ml
20–500 ng/ml
medicine.iupui.edu/flockhart/table.htm (14-8-2006),
www.pharmacoclin.ch (14-8-2006)). It is striking to
observe that authors differ 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 beneficial 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
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CINP Antidepressant Task Force 2007
Table 15. Typical inhibitors and inducers of cytochrome
P-450
(DeVane, 2003 ; Entsuah and Chitra, 1997 ; Norman
and Olver, 2004 ; Olver et al., 2004).
Antidepressants and
other CYP-450 substrates
CYP inducing (+) and
inhibiting (x) properties
9.1.1.2.2
Broccoli (Brassica oleracea)
Caffeine
Carbamazepine
Cimetidine
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+
Ciprofloxacin
Clarithromycin
Dexamethasone
Dihydralazine
Diltiazem
Efavirenz
Erythromycine
Fluoxetine
Fluvoxamine
Grapefruit juice (Citrus paradisi)
Haloperidol
Indinavir
Intraconazole
Ketoconazole
Levomepromazine
MDMA (‘ecstasy’)
Mexiletine
Mifepristone
Nefazodone
Nevirapine
Norfloxazine
Omeprazole
Paroxetine
Phenobarbital
Phenytoin
Primidone
Rifampicin
Ritonavir
Rofecoxib
Saquinavir
St. John’s wort
(Hypericum perforatum)
Tobacco smoking (Nicotiana)
Valproic acid
Verapamil
CYP1A2+
CYP3Ax, CYP2C9x
CYP3Ax
patients (Behnke et al., 2003). While there is common
consensus that no differences concerning the clinical
effectiveness can be observed, tolerability advantagtes
of ER formulations in comparison to IR formulations
have been reported e.g. in case of the SNRI venlafaxine
Transdermal antidepressants
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 efficacy in comparison to orally administered selegiline (Morgan,
2007).
9.1.1.2.3
Intravenous antidepressants
Parenteral administration of antidepressants during
the first 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 confirming 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 ½ ampoule (amp) of clomipramine (1 ml,
12.5 mg) and adding 1 amp (2 ml, 25 mg) every day
to reach a maximum of 5–6 amp (125–150 mg).
Anecdotal data report higher doses up to 8–9 amp per
day (200–225 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 effects. Maprotiline is
also available in i.v. form (Drago et al., 1983 ; Kissling
et al., 1985 ; Zapletalek et al., 1982), but data regarding
its efficacy 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
(Guelfi et al., 2000 ; review : Moukaddam and
Hirschfeld, 2004). It has also been shown to be effective
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 effective 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 benefit from the bypassing of
the gastrointestinal tract and achieve better and faster
drug levels.
9.1.1.3 Summary of side effects39
Antidepressant drugs can produce common side
effects according their receptor profiles. 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-effect profile.
Anticholinergic and antihistaminergic side effects are
of particular concern, and possible cardiovascular
complications, especially in case of overdose, have
consequently limited their use (Burrows et al., 1976 ;
39
The subdivision in different classes of antidepressants including
additional effects on specific receptors can be seen in Table 1.
Together with Table 16 an individual side effect profile of each
single antidepressant can be deduced. In addition to that profile also
the used dose and the individual sensitivity of a patient influences
the probability and magnitude of side effects.
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 first-line therapy due to their favorable tolerability profile (Burrows and Norman, 1997).
Despite their fewer anticholinergic effects, however,
it is important to pay attention to the specific sideeffect profiles 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 influences
compliance (Kent, 2000). Especially during the first
days of use of antihistaminergic antidepressants,
patients must be informed about possible effects 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 deficits. After the first 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, differences 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 specific side-effect profiles based
on the effect of antidepressants on receptors and neurotransmitters. Using this table in combination with
Table 1, one can deduce the specific side-effect profile
to be expected for a specific 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
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 profiles, and direct and indirect effects of antidepressants possibly associated
with clinically relevant and compliance-influencing side effects
Influenced receptors
or neurotransmitters
Mode of action
Typical side effects (receptor)41
M1 receptor
Antimuscarinic/anticholinergic
$
$
$
$
$
$
$
$
$
H1 receptor
Antihistaminergic
$
$
$
$
$
$
a1/2-receptor
Antiadrenergic
$
NA transporter
Noradrenalin reuptake inhibition/
noradrenergic effects
$
5-HT transporter blockade/5-HT
receptor agonism
Serotonin-reuptake inhibition/
serotonergic effects
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 effects.
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.
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
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
$
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 effects 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 identified 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 (Griffith et al., 1983 ; Miller and
Griffith, 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 difficulties 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 effects 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.
44
The definition of ‘ dependence potential ’ varies among different
systems of classification. DSM-IV defines ‘ substance dependence’ in
relation to a mixed picture of tolerance, withdrawal effects and
compulsive drug-taking behavior, usually accompanied by a craving
for the positive effects of the drug.
45
In addition, antidepressants have no market value for drug
abusers, an authentic measure of abuse potential.
S57
It would, however, be surprising if, on discontinuation, psychotropic drugs did not produce some
withdrawal effects. Clearly they are often taken for
relatively long periods of time, and receptors adapt
in significant ways to their presence. Once the drug
is removed, these changes will be expressed as imbalances in neurotransmitter function and subjective
adverse effects. Typically, these effects 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 ‘flu-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 effects were more likely
with high doses and prolonged treatment. With less
than 5 weeks’ exposure, withdrawal effects 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).
Differences in the rates of discontinuation syndrome have been reported after patients stabilized on
fluoxetine, sertraline or paroxetine had their maintenance therapy interrupted with double-blind substitution for 5–8 days. The incidence of discontinuation
syndrome was lower in fluoxetine 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 affective 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 sufficient information to confirm a possible causal relation. Sixty-four
of the cases were associated with paroxetine, 14 with
fluoxetine, 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 3.81–6.68) and in particular with
the SNRI venlafaxine and the SSRI paroxetine
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CINP Antidepressant Task Force 2007
(OR 12.16, 95 % CI 6.17–23.35 and OR 8.47, 95 % CI
5.63–12.65, respectively) (Trenque et al., 2002). It
should, of course, be a critical part of the information
given to patients that such effects can arise. They can
usually be abolished by restarting the withdrawn drug
and avoided by substituting fluoxetine 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 effects 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 effects is
imprecise and is confounded by expectations under
ordinary clinical conditions. The more sensitive the
measure, the more likely it is that withdrawal effects
will be detected. It would, however, be extremely
misleading to imply that these effects 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 finding 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 effects, odd physical effects as a result of
individual differences 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 effects are often described as very severe
and unexpected. Discontinuation symptoms and
treatment interruption-emergent events were more
frequent after paroxetine compared with fluoxetine
treatment due to the different 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
discussed (Dean, 2002 ; Haddad, 1999). Withdrawal
symptoms have even (though rarely) been described
following discontinuation of herbal antidepressants
such as St. John’s wort (Beckman et al., 2000).
The apparent absence of appropriate notification
that such effects 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 suffer 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 benefit 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 benefits 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 benefit comes at the potential
cost of adverse effects. These adverse effects are
somatic symptoms on withdrawal. Extending prescription for minor symptoms or syndromes runs the
risk of the harm being perceived as greater than the
benefit. There are undoubtedly some problems with
the use and, particularly, the discontinuation of
CINP Antidepressant Task Force 2007
S59
Box 8. Discontinuation symptoms and relapse after stopping antidepressant treatments : conclusion
Antidepressant medications do not produce dependence that corresponds to criteria of the ICD-10 and the DSM-IV
classifications.
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 fluoxetine (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 difficult-to-solve therapeutic problem and require individual risk-benefit
analysis. Untreated depression is associated with impaired feto-placental function, premature delivery,
miscarriage, low fetal growth and perinatal unwanted
effects, 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 influence infants during
breast feeding (for review see Burt et al., 2001 ; Dodd
46
Definitions of dependence and addiction are still controversial
(O’Brien et al., 2006). ‘ Physical dependence’ is characterized by
symptoms of withdrawal after discontinuation of a substance ;
‘ addiction’ is most commonly is defined 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 effects.
et al., 2000 ; Suri et al., 1998). Therefore, the risk of
untreated depressive disorders causing maternal
stress that also influences 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 benefits 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
influence on behavioral development, e.g. abnormal
emotional behavior in offspring, cannot to date be
excluded. Accordingly, recent studies in new born
mice have shown an effect of serotonin and SSRI
(Fluoxetine) treatment on behavioral phenotypes,
leading to the hypothesis that these effects 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 fluoxetine or other SSRIs
(Wisner et al., 1999). Nevertheless, more neonatal
complications were seen. Children of mothers treated
with fluoxetine during the first trimester of pregnancy
showed lower maternal weight gain during pregnancy
S60
CINP Antidepressant Task Force 2007
(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
fluoxetine 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 differ 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 1–3 % 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
first 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 confirm 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 first-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
sufficiently long time for a final 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
specific safety profiles of maintenance and contin-
uation therapies during pregnancy and the postpartum period must also be considered (Ernst and
Goldberg, 2002).
9.1.1.3.4
Antidepressants and fitness to drive
Most patients treated with antidepressants are not
hospitalized, but continue to live in their community.
It is therefore important to know whether antidepressants influence activities such as car driving,
which requires intact psychomotor functioning. Some
antidepressants produce side effects that include dizziness, sedation, blurred vision, sleepiness, and difficulty 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 different studies are sometimes
difficult. The literature is surprisingly thin with regard
to studies regarding the influence 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 first 10–14 days following initiation of
treatment (Laux, 2001). A retrospective cohort study
showed that elderly patients treated with TCAs represent a higher risk group for traffic 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
S61
Table 17. Fitness to drive during application of antidepressants in healthy volunteers
Antidepressant
Study details
Outcome
Reference
Amitriptyline
Healthy volunteers, 75 mg
Louwerens et al., 1984
Dothiepin
Doxepin
Healthy volunteers, 75–150 mg
Healthy volunteers, 75 mg
Escitalopram
Healthy volunteers, 10–20 mg
Fluoxetine
Healthy volunteers, 20 mg
Imipramine
Healthy volunteers, 50 mg
Mianserin
Healthy volunteers, 30–60 mg
Mirtazapine
Healthy volunteers, 15–30 mg
Moclobemide
Healthy volunteers, 200 mg
Nefazodone
Healthy volunteers, 200 or 400 mg
Paroxetine
Healthy volunteers, 20–40 mg
Sertraline
Venlafaxine
Healthy volunteers, 100–200 mg
Healthy volunteers, 37.5–75 mg
SDLP elevation, adaptation after
1 week
SDLP not different from placebo
SDLP elevation, adaptation
after 1 week
Driving and psychomotor
performance not affected
Reduced attention, driving
performance not affected
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 different
from placebo
Highway driving performance not
impaired, slight impairment of
lateral position control after
400 mg per day
Impaired psychomotor performance,
road tracking not affected
Simulated car driving not affected
No effect on SDLP or psychomotor
performance
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
Robbe and O’Hanlon, 1995
Warrington, 1991
O’Hanlon et al., 1998
SDLP, Standard deviation of lateral position.
suffering from this disease, a first dose of 25 mg
amitriptyline significantly impaired driving performance, in comparison to placebo. After a 2-week treatment with 25 mg/day amitriptyline, tolerance had
developed as the differences between placebo vs
verum were not any more significant (the drug was
always administered in the evening, about 13h before
the test).
These effects of the TCA appear to be related to their
pharmacological properties as a1-, muscarinic and/or
H1 antagonists. As expected, due to their pharmacological profile, 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 effect 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 confirmed
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 confirms
that depressive illness per se represents a risk factor.
In contrast, escitalopram (Wingen et al., 2005),
fluoxetine (Ramaekers et al., 1995), paroxetine (Robbe
and O’Hanlon, 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
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CINP Antidepressant Task Force 2007
significantly influence 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 affinity of escitalopram for histamine receptors.
Conflicting results were obtained for venlafaxine.
While it is considered relatively safe by some authors
when tested in healthy volunteers (Ramaekers, 2003 ;
O’Hanlon 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 effect 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. fluoxetine, moclobemide) (Ramaekers,
2003).
The effect 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 effect of alcohol on skills related to driving
behavior (Landauer et al., 1969), while generally SSRIs
do not modify these alcohol effects (Baxter, 2006).
In conclusion, depressed patients must be informed
that, owing to their illness, driving performance may
definitely decrease, and that the risk of traffic accidents
is increased by alcohol or benzodiazepine consumption. Moreover, the decision to medicate with an antidepressant must be made based on the patient’s
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
drugs may impair driving capability (Veldhuijzen
et al., 2006).
9.1.2
Monoamine oxidase inhibitors48
9.1.2.1 Efficacy
A comparable efficacy profile 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 efficacy 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
suffering 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 efficacy profile, 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 significant
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-effect
burden of the SNRI/NaSSA combination compared
with irreversible MAOIs, combination therapy may
also be suitable for patients suffering from highly
treatment resistant depression (McGrath et al.,
2006), but comparative RCTs up to now are missing.
48
The following sections describe the efficacy and safety profile of
all available antidepressants. Substances are classed in groups
according to their main mode of action. Because frequency of
prescription varies among different 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
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Box 9. List of tyramine-rich foods and beverages (excerpt)
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 caffeine
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 effective 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 Parkinson’s disease, may also
exert significant antidepressant effects (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 efficacy 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 effective as TCAs
and SSRIs, but somewhat less effective 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 efficacy 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 fluoxetine requires lengthening the time interval
to 5–6 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 modifications. 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.
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CINP Antidepressant Task Force 2007
9.1.3 Non-selective monoamine reuptake
inhibitors/tricyclic antidepressants
Ever since the introduction of the first 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 Organization’s (WHO’s)
list of essential drugs (World Health Organization,
2005a). Nevertheless, in recent years tri- and tetracyclic antidepressants have lost their status as firstline treatment for depression in several developed
countries due in part to their particular side-effect
profile and the introduction of newer antidepressants
in these countries.
Even absent sufficient scientific justification 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 influence 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 Efficacy51
As described previously, TCA treatment is effective
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 influence 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 sufficient support in the literature (Sartorius, 1974), TCAs
51
TCAs are available in both oral and i.v. forms. There is no
scientific evidence for a differential efficacy profile between them.
See chapter 9.1.1.2.3 for a more detailed description of i.v.
administration of antidepressants.
with lesser sedating effects, such as clomipramine or
desipramine, appear superior in retarded and anergic
depression. TCAs with inherently stronger antihistaminergic effects, such as doxepin, amitriptyline
and dosulepine, have advantages in agitated patients
with significant sleep disturbances.
9.1.3.2 Safety and tolerability
The main concerns in using TCAs as a first-line treatment are anticholinergic and antihistaminergic side
effects possibly influencing 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 specificity and a tolerability profile that includes a lower risk of cardiovascular and neurological side effects.
Suicidal behavior may be a further reason to be
cautious in prescribing TCAs as first-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 efficacy 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 modified TCA tianeptine
Despite its modified tricyclic structure, initial studies
showed that tianeptine did not share pharmacological
properties with TCAs, MAOIs or SSRIs (Wilde and
Benfield, 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.
CINP Antidepressant Task Force 2007
by microdialysis following chronic (14-day) administration clearly demonstrate that there is no significant
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 effects 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 efficacy 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 effects 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 reflect 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 Efficacy
The efficacy of tianeptine in most published studies
was comparable to SSRIs (Kasper and Olie, 2002) ; only
one RCT showed an advantage of fluoxetine in elderly
patients (Guelfi et al., 1999). Comparison with other
antidepressants such as amitriptyline (Guelfi et al.,
1989 ; Invernizzi et al., 1994) and mianserin (Brion
et al., 1996) also turned up no significant differences
in efficacy.
9.1.4.2 Safety and tolerability
Tianeptine does not appear to be associated with
severe anticholinergic or cardiovascular side effects
(Loo and Deniker, 1988). Specific advantages in the
case of comorbidities such as cardiovascular disorders
(Pogosova et al., 2004) and Parkinson’s (Levin, 2006)
disease have been described. The overall tolerability
profile 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 significant differences (in comparison with
fluoxetine) been reported (Loo et al., 2001).
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9.1.5 Selective serotonin reuptake inhibitors
9.1.5.1 Efficacy
Today, in many countries, SSRIs are the antidepressant substances prescribed most frequently as
a first-line treatment (Ostacher et al., 2005). Good
efficacy 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 difficult to interpret what these results mean
clinically. For example, escitalopram has been shown
to have comparable efficacy to venlafaxine (Kennedy
et al., 2006). Escitalopram also demonstrates a statistically significant, 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 significant nor clinically relevant differences in efficacy (Edwards and Anderson,
1999). But a recently published pooled analysis of
all available study data to date found significant
advantages of escitalopram in comparison with several SSRIs, e.g. citalopram, fluoxetine 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 findings,
draw final conclusions and make specific recommendations.
Despite of the fact that SSRIs have shown no overall
relevant inferiority compared with TCAs in a variety
of randomized controlled trials (Möller et al., 1998)
and meta-analyses (Geddes et al., 2000), there is some
evidence of better efficacy and clinical effectiveness
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 suffer from melancholic
features of depression.
SSRIs and irreversible MAOIs also show an overall
similar efficacy in the treatment of depression.
Indeed, except among outpatients suffering from depression with atypical features (chapter 5.2.1.3.3),
MAOIs give better results (Thase et al., 1995). In
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CINP Antidepressant Task Force 2007
Table 18. Clinical highlights and differences among SSRIs based predominantly on clinical experience and consensus
(modified according to Stahl, 1997 ; Stahl, 2006)
Generic name
Specific clinical features of SSRIs
Citalopram (Bezchlibnyk-Butler et al., 2000)
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 effect size during antidepressant
treatment ; good effect in anxious depression and comorbid anxiety disorders
Good effect in atypical depression
Good effect in patients with fatigue and low energy
Long half-life, weekly administration possible
Good effect in anxious depression and comorbid anxiety disorders ; potential
advantages in psychotic depression
Possibly lower incidence of sexual dysfunction
Discontinuation effects after rapid tapering
Good effect in anxious depression and comorbid anxiety disorders
Mild anticholinergic action
Discontinuation effects more likely than for other SSRIs
Good effect in atypical depression ; least selective over dopamine
Low interaction potential
More gastrointestinal side effects, 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 suffering from treatmentresistant depression, whereas increasing the SSRI
doses has no substantial beneficial effect (Adli et al.,
2005).
Despite their similarities, various SSRIs do have
specific differences (Table 18).
9.1.5.2 Safety and tolerability53
Different SSRIs show different safety profiles.
Nevertheless, the safety and tolerability profile of
SSRIs as a pharmacological group of compounds
compares very favorably with TCAs (Mace and
Taylor, 2000). Specifically, anticholinergic side effects
especially are more common during TCA therapy.
Therefore, lesser cardiovascular toxicity together with
a lower risk for constipation and reduction of urinary
flow can be expected. Also, anticholinergic side effects
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 effects
53
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.
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 beneficial during antidepressant
treatment, especially in suicidal patients. In addition,
a simplified dose regimen compared with TCA
therapy diminishes the danger of antidepressant
therapies being below therapeutic dose ranges.
These factors all contribute to an efficacious and costeffective first-line therapy in depression vis-à-vis
TCAs despite higher prescription costs (Goldstein and
Goodnick, 1998).
Nevertheless, clinicians need to be aware of the
particular side-effect profile of SSRIs (Ferguson, 2001 ;
Lader, 1996). The most frequent side effects 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 effects 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 significant limitations of SSRI
therapy. Some studies show these aspects to be less
prominent with fluvoxamine 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 hyperreflexia, 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
(fluoxetine ; 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 effects are weight gain, anticholinergic
effects and extrapyramidal motor side effects (EPMSs).
Caution must be exercised in prescribing SSRIs
for patients suffering from Parkinson’s disease
(Lemke, 2002), but there is no good evidence that
SSRIs are associated with a worsening of motor features in Parkinson’s (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
fluoxetine, 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).
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9.1.6 Selective serotonin and noradrenaline reuptake
inhibitors
9.1.6.1 Efficacy
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 effect after
application of lower doses. Judging the comparative
efficacy and clinical effectiveness is difficult because
overall, newer antidepressants probably do not differ
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 efficacy (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 efficacy effects in treatment
of depressive disorders and quality of life. Venlafaxine
has also proved to significantly reduce depressive
symptoms compared with fluoxetine (Clerc et al., 1994).
Several meta-analyses have also suggested superior
efficacy of venlafaxine over SSRIs (Cipriani et al.,
2005b ; Cipriani et al., 2006 ; Smith et al., 2002), but
because most of the studies investigated the efficacy of
fluoxetine and paroxetine in comparison with SNRIs,
the results must be evaluated carefully before conclusions about the efficacy 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 efficacy
criterion (Stahl et al., 2005 ; Thase et al., 2001), but to
date no sufficient evidence for a faster response of
SNRIs in comparison to SSRIs has been published.
In addition, better efficacy 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 significant
differences (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 efficacy
similar to that of imipramine and significantly
superior to that of SSRIs (Puech et al., 1997). Direct
comparisons between duloxetine and paroxetine in
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CINP Antidepressant Task Force 2007
RCTs showed, controversially, both superiority of
the SNRIs (Goldstein et al., 2004) and no significant
differences (Detke et al., 2004). Studies show duloxetine to have effectiveness similar to escitalopram
(Hirschfeld and Vornik, 2004).
In contrast, direct comparisons between SNRIs
(venlafaxine and milnacipran) and TCAs turned up
no significant or clinically relevant differences in efficacy (Samuelian and Hackett, 1998 ; Van Ameringen55
et al., 2002). Direct comparison of venlafaxine and
mirtazapine showed only trends in favor of mirtazapine but no significant differences (Guelfi et al., 2001).
Besides its efficacy in treating depression, duloxetine has also been reported to significantly reduce
painful physical symptoms (Detke et al., 2002).
9.1.6.2 Safety and tolerability
SNRI treatment has a favorable tolerability profile
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 efficacy and
quality of life, but sertraline showed a more favorable
tolerability profile 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 efficacious than SSRIs and
had better tolerability than TCAs, which at least in the
case of milnacipran probably has a positive impact on
the cost-effectiveness of treatment (Dardennes et al.,
1999) (for more details on the cost-effectiveness 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
55
The Medline database contains the wrong spelling ‘ Van
Amerongen ’.
Agency, 2006 ; National Institute for Health and
Clinical Excellence, 2004).
9.1.7
Selective noradrenaline reuptake inhibitors
9.1.7.1 Efficacy
Controlled data directly comparing the single available NARI reboxetine56 with other antidepressants are
rare. One study looking at reboxetine and sertraline
found no difference 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 fluoxetine in efficacy for depressive disorders, and more effective in a subgroup of severely
depressed patients (Massana et al., 1999). Among
patients suffering from post-stroke depression, reboxetine was less efficacious in anxious depressed patients than citalopram, but more efficacious in
retarded depressed patients (Rampello et al., 2004). In
addition, reboxetine is reported to be at least as effective 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 profile (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 effects. In addition, sexual dysfunction appears to
be less common with reboxetine than with the SSRI
fluoxetine (Clayton et al., 2003). Reboxetine has a different side effect profile 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 effects
may affect 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.
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 Efficacy
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
affinity for the a1-adrenoceptor and more influence
on noradrenaline (NA) reuptake (Kelder et al., 1997).
Mianserin exerts only weak NA reuptake-inhibiting
effects. Mirtazapine is characterized as its own class of
antidepressant with noradrenergic and specific serotonergic properties (NaSSA). The a2-antagonistic effect
of mirtazapine results in serotonergic activation,
whereas the a1-antagonistic effect of mianserin counteracts the a2-antagonistic effect.
Both mianserin (Möller et al., 1995) and mirtazapine
(Benkert et al., 2002) are described as being at least
as effective as TCAs and have some advantages
over other newer antidepressants (Szegedi and
Schwertfeger, 2005). In addition to its antidepressant
effects, mirtazapine significantly 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 clarification is required
of the hypothesis that these effects are caused not only
by the sedating properties of mirtazapine but also its
specific effects 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 fluoxetine
(Wheatley et al., 1998). Compared with other recently
developed antidepressants, such as dual-action SNRIs
and selective NARIs, mirtazapine shows no convincing differences in terms of overall efficacy or speed of
onset (Möller, 2000 ; Olver et al., 2001). Nevertheless,
from a clinical point of view, a significant advantage
(and simultaneously a disadvantage, as described in
chapter 9.1.8.2) of NaSSAs is their pharmacodynamic
profile, 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-effect profile
than a variety of TCAs (Blier, 2003 ; Montgomery,
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1995 ; Tran et al., 2003). The safety of NaSSAs is similar
to that of SSRIs (Olver et al., 2001), but typical serotonergic side effects 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 effects,
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 effects 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 effects (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 Efficacy
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 effective as the SSRIs fluoxetine, sertraline and paroxetine (Avila et al., 2003 ;
Sussman et al., 2001). Trazodone is reported to be as
effective 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 significant
clinical advantages compared with trazodone in terms
of overall efficacy (van Moffaert et al., 1995). The sedating properties of nefazodone and trazodone make
them particularly suitable for agitated patients and
patients suffering from insomnia (Boerner and Möller,
1999 ; Thase, 1999a).
9.1.9.2 Safety and tolerability
SMAs have a safety margin similar to TCAs, but
a more favorable tolerability profile (Lader, 1996),
with lower anticholinergic and antihistaminic activity
(Taylor et al., 1995). The specificity of action of SMAs
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CINP Antidepressant Task Force 2007
on neurotransmitter systems is believed to be the reason for the enhanced safety and tolerability of the drugs
(Nemeroff, 1994). The side-effect profile of SMAs is
also different from that of SSRIs ; the most commonly
reported side effects 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 Efficacy
The mechanism of action of DNRIs is still not completely clear or understood. The FDA classifies 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
off-label for combination therapies, especially in the
case of treatment-resistant depression.
Bupropion shows significant antidepressant efficacy
at least equal to the SSRIs sertraline (Coleman et al.,
1999 ; Croft et al., 1999 ; Kavoussi et al., 1997), fluoxetine (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 difference in efficacy is
evident between bupropion and the TCAs amitriptyline (Remick et al., 1982) and imipramine (Workman
and Short, 1993). The same comparative study revealed no differences in efficacy 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
effects on dopamine or noradrenaline transporters at therapeutic
doses (Kugaya et al., 2003 ; Learned-Coughlin et al., 2003 ; Meyer
et al., 2002).
(Workman and Short, 1993). Despite a few contradictory results, its good efficacy 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 effects, 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 effects are reportedly fewer with
bupropion than with fluoxetine (Coleman et al., 2001).
Patients given doxepin had predominantly more
anticholinergic and antihistaminergic side effects than
those given TCAs (Feighner et al., 1986). Bupropion
has also been classified 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 classified
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 effects have
been investigated in less-sophisticated studies and
less severely depressed patients. For most of these
substances, e.g. Kava-Kava extract, no antidepressant
effects could be demonstrated. For others, RCTs have
shown antidepressant effects (Akhondzadeh et al.,
2005), but to date, no placebo-controlled replication
studies have been published.
CINP Antidepressant Task Force 2007
9.1.11.1 St. John’s wort
9.1.11.1.1
Efficacy
The most studied of the herbal substances is St. John’s
wort (Hypericum perforatum). It is worth noting that
many different preparations of St. John’s wort are
available over-the-counter, and these differ 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 findings (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 sufficient 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
fluoxetine (Behnke et al., 2002 ; Schrader, 2000), paroxetine (Szegedi et al., 2005) and sertraline (Brenner
et al., 2000 ; Gastpar et al., 2005). Indirect comparisons
with fluoxetine show no relevant differences in efficacy (Volz and Laux, 2000). Even advantages of
Hypericum over fluoxetine have been demonstrated
(Fava et al., 2005a), but neither active compound exhibited statistically significant 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 effectiveness
similar to low-dose TCA (Kim et al., 1999) or SSRI
therapy (Kasper and Dienel, 2002), but problems of
design in some studies prohibit definite conclusions.
9.1.11.1.2
Safety and tolerability
Comparative studies show significantly 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 effects, 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
S71
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 efficacy 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 officinalis, Jieyu and Banxia Houpu
decoction (Chinese traditional herbal medicine)
Morinda officinalis (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
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CINP Antidepressant Task Force 2007
in traditional Chinese medicine to treat depressionassociated symptoms. Jieyu pill and decoction have
been investigated in patients suffering 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 effects and possible mechanisms of action of Morinda officinalis 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 final
conclusions about the possible antidepressant efficacy
and effectiveness 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 definitions
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, definition of pharmacotherapy-resistant
depression) may vary and often do not reflect true
resistance to treatment. The definition by Ananth
(Ananth, 1998) as a ‘failure to respond adequately to
two successive courses of monotherapy with pharmacologically different antidepressants given in adequate
dose for sufficient 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, sufficient 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 Guelfi, 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 benefit following failure of a medium dose.
They concluded that ‘available data suggest differential efficacy of various pharmacological classes at more
than medium dosage. Direct evidence shows no increase of efficacy with high-dose selective serotonin
reuptake inhibitor (SSRI) treatment ; however, indirect
evidence suggests enhanced therapeutic efficacy with
high-dose tricyclic antidepressants. Few clinical data
show ultra-high-dose treatment with the irreversible
MAOI tranylcypromine to be effective for refractory
depression. Data concerning other selective compounds are insufficient to allow any definitive conclusion on the benefit 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 identified several
other factors predictive for poor response, including a
family history of affective 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 influencing the patients’ compliance (Demyttenaere
et al., 2001a ; Demyttenaere et al., 2001b). Treatmentresistant depression may also influence vulnerability
to other mental disorders. For example, the incidence
of dementia is significantly increased in older patients
with insufficiently treated depression (Shim and Yang,
2006). In support of these results, magnetic resonance
imaging (MRI) findings 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 difficultto-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 efficacious
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 benefit from switching
either to sertraline, bupropion or venlafaxine (Rush
et al., 2006c).
CINP Antidepressant Task Force 2007
9.1.12.2.1
Inadequate response to first
antidepressant
9.1.12.2.1.1.1 Efficacy
Disease apparently resistant
to optimal/sufficient dose*
Increase dose of first
antidepressant
Switch to an antidepressant
from a different
pharmacologic class or dual
action agent
No further
improvement
Combination treatment
9.1.12.2.1.1 Combination of different antidepressants
Reevaluate diagnosis
Exclude comorbid medical or
psychiatric disorder
Review dose
nonresponse
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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)
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.
Sufficient evidence now exists that combining antidepressants or augmentation strategies could be more
effective than monotherapy in some patients (Kennedy
et al., 2001). Combination treatment is defined as
addition of another medication without expecting potentiation of efficacy of the previous drug (see Box 10).
Benefits as well as side effects are additive. Usually, a
medication with an alternative and different 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 specifically
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.
Although we lack scientific evidence to define specific
and effective 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
different pharmacological profiles are combined. In a
recent literature search, Dodd et al. (Dodd et al., 2005)
identified only 8 randomized trials between 1978 and
2004 that studied combinations of antidepressants, 5 of
them including fluoxetine. In addition, 16 open-label
trials were identified, 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
fluoxetine and the tetracyclic a2-blocker mianserin
showed superior efficacy 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 confirming the superior
effectiveness of these combinations are required
(de la Gandara et al., 2005b ; Rojo et al., 2005). Further
reasons for combining different antidepressants
are specific side-effect profiles, 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
effectiveness 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 fluoxetine or fluvoxamine (for more details see chapter 9.1.1.1). The fact
that TDM of these compounds is not widely practiced
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CINP Antidepressant Task Force 2007
Box 10. Definition of combination and augmentation treatment
$
$
Combination treatment : combination of two or more treatments, each of which represents an antidepressant alone.
Augmentation treatment : efficiency amplification of an antidepressant treatment with a substance that alone does not exert
sufficient 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 Efficacy
A further option in enhancing the effectiveness 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 15–25 % of depressed patients (Husain et al.,
2004). However, study results regarding a putative
benefit of combining ECT with TCAs (Lauritzen et al.,
1996 ; Nelson and Benjamin, 1989) and the lack of
benefit of other concomitant medication, like SSRIs,
are still controversial (Lauritzen et al., 1996). In
particular, investigations of the efficacy 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 effects 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 specific 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 effective ; 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 different 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 efficacy of lithium augmentation in the acute treatment of treatment-resistant
unipolar depression. Lithium has been found to augment the therapeutic effects of a broad spectrum of
antidepressants, including TCAs (Bauer et al., 2003 ;
Bauer and Döpfmer, 1999) and SSRIs (Joffe et al., 1993 ;
Katona et al., 1995). The meta-analysis by Bauer and
Döpfmer (Bauer and Döpfmer, 1999) also demonstrated that lithium augmentation is superior to placebo augmentation, with a response rate of about
40–50 % 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
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Table 19. Biological treatment strategies for partial and non-responding patients with major depressive disorders.
Modified 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
Mechanisms/drug classification
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
Hormone augmentation
Triiodothyronine (T3)
L-Thyroxine (T4)
Estrogen (only women)
Dehydroepiandrosterone (DHEA)
Thyroid hormone
Thyroid hormone
Ovarian steroid hormone
Adrenal androgen hormone
Miscellaneous
Ketokonazole, metyrapone
L-Tryptophan, 5-hydroxytryptophan
V-3 fatty acids
Folic acid (only women)
Peripheral cortisol suppression
Essential amino acid, 5-H’I’ precursor
Food supplement
Vitamin
Non-pharmacological
Electroconvulsive therapy
[Repetitive transcranial magnetic stimulation]
[Vagus nerve stimulation]
Phototherapy (bright light therapy)
Wakefulness therapy (sleep deprivation)
Physical exercise
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 0.6–0.8 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 effects, 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 differentiate from an increase
in severity of depression. Electroencephalogram (EEG)
may be a helpful monitoring tool for differential 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 effect cannot yet be concluded.
Patients on lithium therapy should be closely monitored and regularly assessed for the presence of side
effects 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 efficacy across age
groups. Some publications point to a low response rate
and a high rate of severe side effects 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
25–35.5 mg/day (Bauer et al., 2002c). Women especially seem to respond favorably to thyroid hormone
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augmentation (Altshuler et al., 2001). A three-arm,
double-blind controlled study showed equal efficacy
of augmentation with T3 and lithium, and superiority
to placebo (Joffe et al., 1993). A recently published
STAR*D report confirmed the similar efficacy of T3 and
lithium with lower rates of adverse events and slightly
(but nonsignificant) higher remission rates in the T3
group (Nierenberg et al., 2006a). However, as not all
controlled double-blind studies showed significant
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 efficacy 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 significantly
lower response rates for T4 (24 vs. 53 %) (Joffe and
Singer, 1990). In some studies, dosage up to 500 mg/
day of T4 have been used with good efficacy 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 effect 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,
verification 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 significant difference 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 efficacy of carbamazepine
(Cullen et al., 1991 ; Rybakowski et al., 1999 ; Varney
et al., 1993). The augmentative efficacy of lamotrigine
has been reported both in open and retrospective
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
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 effect 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 effects of
pindolol for SSRIs showed increased response with
pindolol after 2 weeks. After 6 weeks no difference 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 significant 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 significant 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 affinity 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 fluoxetine and citalopram failed to demonstrate significant benefit over placebo (Appelberg et al.,
2001 ; Landen et al., 1998) The study by Appelberg,
however, suggests at least a potential benefit in
more severe depression in a post hoc subanalysis
(Appelberg et al., 2001). Recently, the STAR*D study
investigated the efficacy 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
Similar to buspirone, tandospirone is a 5-HT1A receptor agonist used in treating anxiety disorders. In
a Japanese study, the efficacy 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 significant difference. 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 significant, 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 effects 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 fluoxetine
produced robust, sustained increases in extracellular
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levels of dopamine and norepinephrine up to
361¡28 % and 272¡16 % of the baseline, respectively,
which were significantly greater than either drug
alone (Zhang et al., 2000). Thus, the combination
of olanzapine and fluoxetine has been tested in several controlled studies both in unipolar and, more
extensively, bipolar depression. A small placebocontrolled study of olanzapine added on to fluoxetine
supports this strategy (Shelton et al., 2001b). In a
second study the olanzapine/fluoxetine 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 fluoxetine, nortriptyline and olanzapine against olanzapine/fluoxetine combination in patients with treatment-resistant
depression also significantly 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 (0.25–2 mg/
day, depending on age) of risperidone (Nemeroff et al.,
2004). After a 6-week augmentation phase, 68.1 %
of the patients with treatment-resistant depression
receiving add-on risperidone were classified as responders. However, significant 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–
Åsberg 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) (Nemeroff 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 significant difference in any
outcome score at the end of the study (week 6), risperidone produced a more robust effect as early as
week 1 (Papakostas et al., 2004).
A non-inferiority trial comparing amisulpride
with paroxetine treatment of major depression found
no statistically significant differences between the
treatment groups (Cassano and Jori, 2002). Open
and retrospective data also support the augmentative
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efficacy of quetiapine, ziprasidone (Papakostas et al.,
2004) and aripiprazole (Barbee et al., 2004 ; Papakostas
et al., 2005 ; Papakostas, 2005 ; Simon and Nemeroff,
2005), although controlled studies have yet to be published.
In conclusion, although it is possible to describe
the augmentative effects 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 fish 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, significant 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 effects (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 effects.
Furthermore, we do not know whether it could be effective independent of other antidepressant treatments or efficacious only in patients with abnormally
low V-3 fatty acid levels.
To date the safety and tolerability profile 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 effect without markedly enhanced danger ; it can, however, influence blinding procedures in
double-blind studies. A somatic benefit 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
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 efficacy 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 find a significant advantage over placebo.
More recently, modafinil 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
significant 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, confirmative 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 effects 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-significant 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
fluoxetine (Coppen and Bailey, 2000). In addition,
augmentation strategies using testosterone or dehydroepiandrosterone (DHEA) have been reported
(Fava, 2001).
CINP Antidepressant Task Force 2007
9.1.12.2.12
Summary
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 scientific 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 effects 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 effects 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 Influence 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 effects
(Tuma et al., 2002). The antidepressant properties of
agomelatine and its good tolerability profile 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
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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, flesinoxan 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 effect 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
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superiority over placebo (Kramer et al., 1998). The
scores of both Hamilton depression and anxiety rating
scales were significantly reduced. A further study
demonstrated no superiority of MK 869 over placebo.
A subsequent substance was examined, and a significant, but relatively small superiority in reducing
HAMD scores compared with placebo was found
(Kramer, 2002). A recent study confirmed the antidepressant properties of yet another NK1 antagonist
(Kramer et al., 2004), but this first promising antidepressant approach was not confirmed by clinical
data in further studies. These uncertainties necessitate
replicating the findings. Nevertheless, NK1 antagonism appears to be a promising new antidepressant
treatment principle with an excellent tolerability profile. To date, the first NK1 antagonist has been approved by the authorities not as an antidepressant,
but as an antiemetic.
9.1.13.4 Treatment strategies influencing 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 efficacy, 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 off of the
study medication resulted in a certain deterioration
of the depressive syndrome. The compound was
withdrawn from further development owing to the
finding 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 effects. Case series and open trials
reported antidepressant effects of ketoconazole
(Anand et al., 1995 ; Ghadirian et al., 1995 ; Murphy,
1991 ; Sovner and Fogelman, 2002 ; Thakore and Dinan,
1995 ; Wolkowitz et al., 1993). In a placebo-controlled
study, hints of the putative antidepressant efficacy 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
insufficient antidepressant efficacy (Malison et al.,
1999). Similar antidepressant effects 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 (O’Dwyer
et al., 1995). A comparison of metyrapone with placebo
in addition to serotonergic antidepressant therapy
resulted in significant acceleration of antidepressant
effects (Jahn et al., 2004). Definite 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 insufficiency, and substitution of hydrocortisone may be required during treatment (O’Dwyer
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
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 different 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 effects
(Rupprecht, 1997 ; Rupprecht and Holsboer, 1999 ;
Wolkowitz et al., 1999b). One open study (Wolkowitz
et al., 1997) suggested possible antidepressant effects
of DHEA. An early placebo-controlled double-blind
study performed using an add-on treatment of DHEA
in depressed patients showed a significant 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
Synthetic glucocorticoid receptor antagonists block the
effects of cortisol at glucocorticoid receptors. In initial
casuistic studies the glucocorticoid-/progesteronereceptor antagonist mifepristone, used in some countries to terminate first-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
(Belanoff et al., 2002), but reported no statistically
significant differences. Symptom amelioration could
be seen after 7 days in high-dose treatment groups.
A placebo-controlled case series in five patients
suffering from psychotic depression showed a reduction in HAMD score up to 26 % (Belanoff et al.,
2001), but again, only a non-significant trend to a difference between verum and placebo could be seen. A
recent study demonstrated a statistically significant
influence of mifepristone on psychotic symptoms
measured using the BPRS, but no significant differences in other depression rating scales (DeBattista
et al., 2006).
Because of the antagonistic effects 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 efficacy of glucocorticoid receptor antagonists.
Nevertheless, the results of placebo-controlled doubleblind studies of sufficient power and over a sufficiently 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 0–31 % of those who received active tricyclic
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medication (Prien, 1990 ; Prien and Kupfer, 1986).
Studies with SSRI continuation, amineptine, nefazodone and reboxetine have reported similar results.
Tables 20 and 21, modified 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 10–15 % 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 efficacious 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 effectiveness.
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
effects from long-term antidepressant treatment, continuation therapy should be offered to every patient
following recovery from a depressed episode. The
situation may be different 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.
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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)
Kupfer (1992)
Terra (1998)
Rouillon (2000)
Gilaberte (2001)
Hochstrasser
(2001)
Lepine (2004)
Montgomery
(1988)
Versiani (1999)
Reynolds (1999)
Klysner (2002)
Wilson (2003)
Reynolds (2006)
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
172/141–135
283 initial
143 maint
41 complete
230 initial
121 maint
121 complete
318 initial
113 maint
76 complete
195 initial
116 maint
Recurrence rate
Acute
Contin
Mainten
Drug
Drug
Placebo
6 weeks
18 weeks
1 year
Fluoxetine
26 %
57 %
Until
remission
Until
remission
17 weeks
3 years
Imipramine
40 %
81 %
16 weeks
2 years
Phenelzine
29 %
81 %
Imipramine
(3–)5 years
6 weeks
18 weeks
1 year
Fluvoxamine
18 %
12.7 %
67 %
35.1 %
Until
remission
4 months
1 year
Milnacipram
16.3 %
23.6 %
8 weeks
24 weeks
48 weeks
Fluoxetine
20 %
40 %
48 weeks
Citalopram
22 %
76 %
Sertraline
16.9 %
33.3 %
Paroxetine
16 %
43 %
Reboxetine
21.8 %
56 %
40 %
(40–60 ng/l)
67 %
6–9 weeks
16 weeks
Until
(max
remission
77 weeks)
4–6 months 18 months
Followed by a 2 months
placebo period
8 weeks
1 year
6 weeks
23+23 weeks
Until
remission
8 weeks
16 weeks
3 years
Nortriptyline
16 weeks
>48 weeks
Citalopram
29 %
(80–120 ng/l)
32 %
8 weeks
16–20 weeks
100 weeks
Sertraline
44.6 %
54.4 %
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 different with unipolar depression. The prophylactic effect 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
Open study, comparable efficacy, but nortriptyline
produced fewer residual depressive symptoms
and side-effects
Advantage of mirtazapine over amitriptyline and
placebo for time to relapse in the survival
analysis, and against placebo for the number of
relapses
No significant difference between two treatments
Parox. and Imip.> placebo 50 % more dropouts
with Imip./Parox. due to side effect
10 %
16 %
Nortriptyline
placebo
116 initial
12 weeks
12 weeks
18 months
59 conti
Randomization during all treatment phases
(elderly patients)
Bump (2001)
Mirtazapine
4.1 %
Amitriptyline
placebo
23 %
6 weeks
20 weeks
Up to 2 years
Randomization during all treatment phases
24 months
4 months
77 initial
64 conti
Franchini (1997)
6 weeks
1 year
Double-blind phase
717 initial
219 conti
Claghorn (1993)
Montgomery (1998) 580 initial
217 conti
18.7 %
21.9 %
Fluvoxamine
Sertraline
Paroxetine
Imipramine
placebo
15 %
4%
25 %
Placebo
Drug
Mainten
Contin
Acute
Number
of subjects
Study
Length of treatment phase
Table 21. Maintenance treatment – studies comparing two antidepressants
Drug
Relapse/
recurrence rate
Conclusion
CINP Antidepressant Task Force 2007
S83
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 firm 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 efficacy of both the
antidepressant and lithium. The efficacy of imipramine is also supported by a 36-month study of Frank
et al. (Frank et al., 1990). Similar evidence for continuing prophylactic efficacy 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).
9.2.1.1 Alternatives to long-term antidepressant
treatment
9.2.1.1.1
Lithium
If patients do not respond to prophylactic antidepressant treatment or do not tolerate side effects,
the first alternative is long-term lithium maintenance therapy. Although it may be even more efficacious in bipolar disorder, and although some
negative results in unipolar disorder have been published (Burgess et al., 2001a ; Burgess et al., 2001b), the
efficacy of lithium in preventing relapses in unipolar
recurrent depression is well established (Coppen,
2000 ; Dunner, 1998 ; Paykel, 2001 ; Schou, 1995). These
findings are also supported by two meta-analyses
showing that lithium is more effective than placebo
in preventing recurrence of unipolar depression
(Angst et al., 2002a ; Souza and Goodwin, 1991). In
CINP Antidepressant Task Force 2007
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Events/patients
Antidepressant events
Number
of trials
Allocated
antidepressant
Placebo
adjusted
Logrank
O–E
(Variance
of O–E)
NARI
2
(60.7)
4
–15.7
(6.0)
Tricyclic
15
–70.7
(50.5)
SSRI
10
–94.9
(80.7)
Other
1
313/889
(35%)
57/66
(86%)
248/432
(57%)
385/1046
(37%)
28/72
(39%)
–57.5
MAOI
169/912
(19%)
13/61
(21%)
113/449
(25%)
156/1034
(15%)
14/71
(20%)
–6.9
(7.5)
465/
2527
(18%)
1031/
2505
(41%)
–245.7
(205.4)
Total
99% or
32
Odds ratio
(95% Cl)
Antidepressant : Placebo
Reduction
(S.E.)
70% (4)
2p <0.00001
95% confidence intervals
Heterogeneity between five categories: χ42=18.6; p =0.001
0
1.0
1.5
2.0
0.5
Antidepressant worse
Antidepressant better
Treatment effect 2p <0.00001
Figure 4. Cochrane meta-analysis of the efficacy 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 affectively
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 Müller-Oerlinghausen et al. (MüllerOerlinghausen et al., 2006). In addition, potential
neuroprotective effects, including preventive effects
against Alzheimer’s dementia, can be of interest
when prescribing long-term lithium prophylaxis.
The usually recommended serum lithium levels
for prophylaxis in unipolar recurrent depression
are 0.5–0.8 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 effects,
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 efficacy 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
sufficient plasma levels when used in combination
with carbamazepine. CYP1A2 and CYP2C9, which
contribute to carbamazepine metabolism, may also
be inhibited by fluvoxamine. Given its potential
interactions and lack of scientific 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
40–70 % of patients adhere to their antidepressant
drug regimen during the acute phase of therapy, only
15–50 % still comply with therapy during the continuation phase (Melfi et al., 1998). Automated systems
have been tested in primary care setting, alerting the
CINP Antidepressant Task Force 2007
physician if a refill has been missed for a specified
time. However, this approach did not improve compliance (Bambauer et al, 2006) and cannot substitute
for a good doctor–patient 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 efficacy and side
effects, 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 fluctuations (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 efficacy of psychotherapy in addition to medication is beyond the scope
of this review.
10 Specific age- and gender-related conditions
10.1
Gender-related differences58
Gender differences in unipolar depression are a
consistent finding 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 differences 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 differences 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 suffer from
comorbid alcohol and drug abuse (Marcus et al., 2005).
58
Gender-related differences of antidepressant pharmacotherapies
during pregnancy or post-partum and breast-feeding periods are
described more in detail in chapter 9.1.1.3.3.
S85
This gender difference may also be reflected 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 significantly earlier
onset of the first major depressive episode in women,
and longer current major episodes for women compared with men. In addition, depression in women
may also affect their offspring : children of mothers
suffering 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
significantly more likely to have five or more criterial
symptoms of depression than men (female/male ratio
1.96).
Interestingly, differences in symptomatology are
already apparent in adolescent depression. Bennett
et al. (2005) interviewed 383 depressed adolescents
with the Childhood Version of the Schedule for
Affective 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, difficulty
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 differences are
manifold, and several factors may contribute to
them. According to Kuehner (2003), these factors include genetics, sex hormones, differing 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
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CINP Antidepressant Task Force 2007
sexual abuse. So far, there are no consistent findings
for gender differences 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-specific
effects 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
different antidepressant therapies (Baghai et al., 2003 ;
Baghai et al., 2004). Overall, however, more research
is needed to reach firmer conclusions concerning a
gender-specific 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 specific
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 affect SSRI treatment response of depressed women, antidepressant treatment seems to
be influenced by estradiol levels (Pinto-Meza et al.,
2006). At the same time, several studies have shown
estrogen treatment to be effective 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 hypothalamic–pituitary–adrenal
(HPA) (Kornstein et al., 2002) and thyroid axes
(Kornstein et al., 2002), may also exhibit subtle differences between genders, thereby affecting vulnerability
to depression.
In general, treatment should not differ between depressed men and women, but specific precautions
must be taken into account (see also chapter 9.1.1.3.3).
Clinically, gender differences 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 confirmed
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 findings of gender-specific
efficacy of tricyclics especially difficult to interpret.
The situation is slightly different with SSRIs, where
reported gender differences 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 difference in the efficacy of
tricyclics. This finding contrasts with a meta-analysis
of Hamilton et al. (1995) of all published trials with
imipramine, which showed significantly different response rates of 62 % for men and only 51 % for women.
On the other hand, several studies describe a significantly higher response rate for women to SSRI treatment compared with men, e.g. (Baca et al., 2004).
A better efficacy 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 significantly greater response than men to SSRIs,
but not to SNRI antidepressants. The authors assume
that this different responsiveness may be due to subtle
differences 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-specific
differences 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 finding in women than
men, and MAOIs had previously demonstrated a good
efficacy in this condition (Henkel et al., 2006). Thus,
the finding 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
differences.
In summary, prevalence, symptomatology, treatment response and consequences of depression are
not identical in men and women, and a gender-specific
CINP Antidepressant Task Force 2007
psychiatric approach that takes into account genderspecific risk and influencing factors (see also chapter
9.1.1.3.3) – including gender roles – is warranted
(Riecher-Rössler, 2000).
10.2
Age-related differences
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 differ substantially from those of adult
patients. Instead of manifesting neurovegetative or
straightforward depressive symptoms, depressed
children may exhibit behavioral problems that cause
difficulties 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 difficulty stems from
the variety of treatment options based on relatively
little evidence of efficacy 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 efficacy 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 offer 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 first 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
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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 effects in childhood depression
shows therapeutic benefits of V-3 fatty acids in a 16week-long clinical trial (Nemets et al., 2006).
In a recently published meta-analysis the effectiveness of antidepressants in comparison to placebo in
the treatment of pediatric major depressive disorder
has been confirmed (Bridge et al., 2007). It has been
stated that the benefits 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
drug’s 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 efficacy 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 effect size (ES)
identified by this meta-analysis was statistically significant, 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 significant benefit 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 differential treatment response
is consistent with the superior efficacy of TCAs
in adult populations, and may be explained by
59
Age limits in the definitions of children and adolescents are
varying between different 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.
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CINP Antidepressant Task Force 2007
maturation of neurological pathways or other developmental differences 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 effectiveness
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 efficacy and to safety. In
addition, data regarding unpublished trials were obtained from the report completed by the UK’s
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 first report about a case series of six patients,
aged 10–17 years, showing self-injurious ideation or
behavior during fluoxetine treatment of obsessivecompulsive disorder was published by (King et al.,
1991).
Between 1990 and 2004, four trials of fluoxetine as a
treatment for child and adolescent major depressive
disorder were conducted, three of which were positive.
The negative study of fluoxetine, which was small
and possibly underpowered, involved 40 adolescents
from inpatient and outpatient settings. After 8 weeks
on 20–60 mg of fluoxetine, authors did not identify
significant differences for any of the outcome
measures used ; subjects responded equally well to
fluoxetine or placebo. Other than weight loss, no drugassociated adverse events were reported (Simeon
et al., 1990).
The first positive fluoxetine study, published in
1997 by Emslie et al., compared a 20 mg fixed dose of
fluoxetine to placebo in a group of 96 children and
adolescents aged 7–17 (Emslie et al., 1997). Subjects
were treated for 8 weeks at a single site. At the trial’s
end, compared with placebo, subjects assigned
to fluoxetine scored significantly better on both prospectively identified primary outcome measures : the
Clinical Global Impressions-Improvement Score
(CGI-I) and the Children’s Depression Rating ScaleRevised (CDRS-R). Significantly more youth given
fluoxetine ‘responded ’ (i.e. received ratings of 1, ‘very
much improved ’, or 2, ‘much improved ’, on the CGII). While endpoint mean CDRS-R scores were significantly better for fluoxetine-treated youth than for
those who received placebo, the differences in terms of
‘ remission ’ (a dichotomous measure, prospectively
defined as a score of <29 on the CDRS, and potentially
less sensitive to change) did not reach significance.
Response rates did not differ for children 12 and under
compared with adolescents 13 and over. In comparisons with placebo, adverse events were not significantly increased in the fluoxetine-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
fluoxetine group was significantly different from the
14.9-point decrease noted in the placebo group, it did
not achieve primary outcome ‘ response’ criteria prospectively defined as a o30 % decrease in scores.
However, in post hoc analyses the authors demonstrated that primary outcome would have been
achieved had response been defined at o20, 40, 60 or
70 % decrease in CDRS scores, or if their calculation
correctly reflected 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 fluoxetine reported
fewer adverse events than did those receiving
placebo. Based on these results, fluoxetine 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 fluoxetine ; 20 of these fluoxetine responders were assigned
to continue fixed-dose fluoxetine, whereas 20 others
were switched directly from fluoxetine to placebo.
Over the subsequent 32 weeks, when compared with
those switched to placebo, fewer subjects who remained on fluoxetine relapsed (60 vs. 34 %, respectively). Additionally, time to relapse was longer for
those who remained on fluoxetine compared with
those who were switched to placebo (181 days vs. 71
days, p=0.046). There were no statistically significant
differences in adverse events (Emslie et al., 2004).
Fluoxetine, alone and in combination with cognitive-behavioral therapy (CBT), was compared with
Table 22. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents
Study characteristics
N
Age
Dose
(mg)
Results
Length
(weeks)
Sites
(n)
Agent
Author
Fluoxetine
Simeon et al., 1990
Emslie et al., 1997
40
96
13–18
7–17
20–60
20
8
8
1
1
Emslie et al., 2002
March et al., 2004
219
439
8–18
12–17
20
10–40
8
12
15
13
Primary outcome
none assigned
CGI-I (1 or 2)
CDRS-R mean scores
CDRS-R (›>/=30 %)
CGI-I (1 or 2)
CDRS-R (cts)
Paroxetine
Keller et al., 2001
180**
12–18
20–40
8
10
Berard et al., 2006
286
13–18
20–40
12
33
Emslie et al., 2006
206
7–17
10–50
8
40
HAMD (f8 or ›o50 %)
HAMD (cfb)
MADRS (›>/=50 %)
K-SADS-L (cfb)
CDRS-R (cfb)
Active
treatment
Placebo
p value
Sig. ?
(Y/N)
n.a.
56 %
38.4
41 %
FLX+CBT : 71.0 %
FLX : 60.6 %
FLX+CBT : 33.79
FLX : 36.30
n.a.
33 %
47.1
20 %
34.8 %
34.8 %
41.77
41.77
n.a.
0.02
<0.008
0.09
0.001
0.001
0.001
0.34
N
Y
Y
N*
Y
Y
Y
N
n.a.
NIMH
66.5 %
18.98p8.24
60.5 %
9.3
n.a.
55.2 %
19.79p9.88
58.2 %
9.8
n.a.
0.11
0.13
0.702
0.616
0.684
N
N
N
N
N
GSK
GSK
GSK
Sponsor
Lily
NIH
Wagner et al., 2003
376
6–17
50–200
10
53
CDRS-R (mean reduction)
x22.84
x20.19
0.007
Y
Pfizer
Wagner et al., 2004
von Knorring et al., 2006
174
244
7–17
13–18
20–40
8
12
21
CDRS-R (cfb)
Kiddie-SADS-P, MADRS
36 %
59 %
24 %
61 %
<0.5
Y
N
Forrest
Escitalopram
Wagner et al., 2006
264
6–17
10–20
8
25
CDRS-R (cfb)
x21.9
x20.2
0.310
N
Venlafaxine
Mandoki et al., 1997
40
8–17
37.5–75
6
1
n.a.
n.a.
n.a.
n.a.
N
* Authors note that results would have reached significance if response was defined 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.
n.a.
CINP Antidepressant Task Force 2007
Sertraline
Citalopram
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S90
CINP Antidepressant Task Force 2007
placebo in the Treatment for Adolescents with
Depression Study (TADS). The first phase of this
National Institute of Mental Health) (NIMH)sponsored multisite RCT followed 439 adolescents
(aged 12–17) with moderate to severe depression for
12 weeks. The fluoxetine 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
significant increased risk of harm-related events – a
category that included suicidal and non-suicidal behavior such as self-cutting – in the groups treated with
fluoxetine (OR 2.19 ; 95 % CI 1.03–4.62) ; however, there
was no statistically significant increased risk of
suicide-related events in the fluoxetine group.
Whereas suicidal thinking decreased in all treatment
groups, fluoxetine plus CBT was associated with the
greatest reduction (March et al., 2004). Combination
treatment with CBT and fluoxetine showed the
greatest benefit-to-risk ratio for adolescents with
moderate to severe depression, and was superior to
monotherapy. Moreover, fluoxetine alone was more
effective in treatment of depressed adolescents than
CBT alone, whereas CBT alone did not differentiate
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
specific inclusion criteria.
10.2.1.1.2.2 Paroxetine
Keller et al. treated 180 adolescents (aged 12–18) 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
significant 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
et al., 2006). Neither study demonstrated efficacy of
paroxetine compared with placebo on primary outcome measures. In the first study (Berard et al., 2006),
which focused on adolescents aged 13–18, 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 differences were not statistically significant). In the second study (Emslie et al.,
2006), which evaluated paroxetine in 206 children
aged 7–17, 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 6–17) with depressive disorders (Wagner et al., 2003). These studies were conducted at 53 sites in five countries, and the combined
analysis was planned a priori. Although the individual trials did not reach statistical significance on the
primary outcome measure (mean reduction in CDRSR), when combined they demonstrated a small but
statistically significant effect. Of note, at the study’s
endpoint, the mean difference in CDRS-R score was
significant for adolescents (sertraline : x28.95 ; placebo : x24.11 ; p=0.01) but only borderline significant
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 suffering 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 7–17) with depressive disorders (Wagner et al.,
2004). Compared with placebo, response criteria
(CDRS-R f28) were achieved by significantly 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 differences between children and adolescent populations
were reported.
According to the CSM report, a large unpublished
trial of citalopram in depressed teenagers (aged 13–18)
did not demonstrate an antidepressant effect over
placebo. Additionally, compared with placebo, greater
percentages of citalopram-treated youth reported
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 13–18 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 nonsignificant 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 6–17 (Wagner et al., 2006).
Although the results across the entire sample did not
reveal significant differences, subgroup analysis revealed a statistically significant drug versus placebo
benefit 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 8–18), 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 significant
difference 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 7–17 ; 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 significant differences between
venlafaxine extended release (ER, XR) and placebo on
the primary outcome variable of CDRS-R endpoint.
Of note, when children (ages 7–11) and adolescent
(ages 12–17) subgroup analyses were conducted,
there was a suggestion of efficacy in the adolescent
group (Cheung et al., 2005). According to the CSM
report, more treatment-discontinuing adverse events,
S91
including hostility and suicidality, were identified 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 specific serotonergic agent. These
trials involved a total of 250 depressed youth (aged
7–17). While the results of these trials remain unpublished, a recent review indicates that no significant
CDRS-R differences 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, beneficial effects for nefazodone
approached but did not achieve statistical
significance 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
Benefits 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 efficacy 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)
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CINP Antidepressant Task Force 2007
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 (fluoxetine, sertraline, paroxetine, fluvoxamine, 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-deficit 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 ’ (defined 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 1.28–2.98), a finding that was supported by a recent re-analysis largely of the same
studies (Wohlfarth et al., 2006). There was also a significant effect for treatment-emergent agitation and
hostility (Hammad, 2006).
When the FDA restricted its analysis to trials of depressive disorders, statistically significant differences
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
1.80–32.99). Those treated with venlafaxine XR were
most likely to experience suicidality (relative risk 8.84,
95 % CI 1.12–69.51).
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, fluoxetine
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) Scientific
Committee similarly advised that newer antidepressants ‘are not authorized Europe-wide for the
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 fluoxetine ; it
recommended extending fluoxetine’s indication to include children, ‘8 years of age or older who suffer
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 15–24 (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
15–24) has decreased by an average of 33 % across 15
CINP Antidepressant Task Force 2007
S93
Table 23. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents
Suicide-related events
Treatment-emergent agitation or hostility
Drug
Relative risk
95 % CI
Relative risk
95 % CI
Nefazodone
Citalopram
Fluoxetine
Mirtazapine
Paroxetine
Sertraline
Venlafaxine XR
No events
1.37
1.53
1.58
2.15
2.16
8.84
n.a.
0.53–3.50
0.74–3.16
0.06–38.37
0.71–6.52
0.48–9.62
1.12–69.51
1.09
1.87
1.01*
0.52
7.69
2.92
2.86
0.53–2.25
0.34–10.13
0.40–2.55
0.03–8.27
1.80–32.99
0.31–27.83
0.78–10.44
Total
1.66
1.02–2.68
1.79
1.16–2.76
* FDA analysis of treatment-emergent hostility and agitation did not include data from the TADS study.
Boldface=statistically significant 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 ; Tardiff 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 12–18) 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
significant 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 significantly 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). Identified
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 1.01–2.50). Among the SSRIs evaluated, the greatest risk for non-fatal self-harm was
associated with paroxetine. Jick and colleagues found
a near-significant signal for increased rates of selfharm in paroxetine-treated youth (aged 10–19) 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
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 (fixed-effect
odds ratio 1.70, 95 % CI 1.13–2.54, 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 differences was statistically significant.
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 5–18
(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 significantly higher rate of
suicide attempts in the first week of treatment compared with subsequent weeks. However, when compared across the entire sample, there was no
statistically significant increased risk of completing
suicide the first 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 differences
may reflect a more timely therapeutic effect of newer
agents.
10.2.1.6 The use of antidepressants, and their risks
and benefits
Several recent studies have used a meta-analysis
to compare the risks and benefits 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
conclude that the risk-benefit profile is most favorable
for fluoxetine. Two of the studies suggest that the
risk-benefit profile of citalopram is also positive
(Bridge et al., 2005 ; Wallace et al., 2006) ; one
study suggests that the benefits of sertraline may also
outweigh its risks when used in treating depressed
youth.
In sum, the evidence about safety and efficacy of
SSRIs is mixed. There is significant evidence for the
efficacy of fluoextine 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, fluoextine was helpful in a group of
moderate to severely depressed youth that were
not significantly helped by CBT (March et al, 2004).
There is more limited evidence for the efficacy 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 effects 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 effectiveness of fluoxetine.
Apart from V-3 fatty acids, there is no substantial
evidence that antidepressant medication is useful in
prepubertal children. The current evidence for prepubertal efficacy 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 efficacy, 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
CINP Antidepressant Task Force 2007
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Box 11. Useful clinical practice in the treatment of children and adolescents (and adults)
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Carefully diagnosis the patient. Comorbidities or alternate diagnoses such as bipolar disorder may affect both the safety
and efficacy of drug treatment. Differentiate 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 benefits 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
reflect 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 6–8 weeks, an evidence-based
treatment with medication and/or a specific psychotherapy should also be initiated if only support has been offered 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 drug’s side effects before they experience the benefits. Provide them with information about irritability,
akathisia, agitation and mania, and encourage them to call with questions. The Parent’s Med Guide is one useful resource
available on the World Wide Web (www.parentsmedguide.org) in English and Spanish. A measurement of side effects 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, fluoxetine is the only drug
approved for clinical use and should be used as a first 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 fit 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 first 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 3–6 months after remission helps reduce
rates of relapse. If children or adolescents have suffered previously from episodes of depression, a ‘maintenance’ phase of
1–3 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 confirmed, consider a trial of a different medication.
regarding the effects 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
60
The suggestions given are based more on clinical experience than
on evidence-based medicine.
61
In countries where firearms are widely available, parents should
be encouraged to remove firearms or other dangerous equipment
from the house.
10.2.2.1 General clinical considerations
The prevalence of depression appears to be independent of age (Patten et al., 2001 ; Steffens et al., 2000),
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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
artificially low owing to standardized diagnostic
assessment procedures that are insufficiently 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 Classification 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 significantly increased mortality (Katona, 1994). Because the prevalence of suicidal ideation is also relatively high in
the old age, effective suicide prevention is especially
needed for this age group (Pfaff 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 Parkinson’s disease, where
patients often suffer from depressive symptoms. The
response to antidepressant treatment in the elderly
apparently does not differ 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
significantly 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
to the side effects of antidepressants, particularly
cardiovascular side effects 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 insufficient
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 differences 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 Efficacy of antidepressants in old age
Numerous randomized controlled trials of antidepressant treatment in late-life depression have been
conducted, including all substance classes. The first
question is whether antidepressant pharmacotherapy
is effective at all in elderly patients, i.e. whether it
shows therapeutic efficacy superior to placebo treatment. Roose and Schatzberg (2005) recently reviewed
five placebo-controlled trials that were selected based
on quality criteria in order to assess antidepressant
efficacy and effectiveness. 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 different
SSRIs (fluoxetine, sertraline, citalopram, paroxetine),
and one trial compared fluoxetine and venlafaxine
with placebo (Schatzberg et al., 2002). Three studies
demonstrated a statistically significant difference 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 significant difference between verum and
placebo groups resembles results of non-geriatric
trials, where medication is found to be more effective
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
CINP Antidepressant Task Force 2007
working group of the Royal College of Psychiatrists
from the UK (Baldwin et al., 2003) also supported the
efficacy 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 different
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 (Bondareff 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
(50–73 % vs. 35–72 %) and may better reflect the effectiveness 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 identified trials were selected for further analysis, and 14 studies were selected for contributing efficacy data. Trials entering the meta-analysis of efficacy
had to compare at least two active antidepressant
drugs, because the meta-analysis aimed at comparing
the efficacy of antidepressant classes, withdrawal rates
and side-effect profiles 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 significant differences
in efficacy 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 finding. Higher numbers of patients
withdrawn irrespective of reason or due to side effects
were observed during treatment with TCAs compared
with SSRIs.
Electroconvulsive therapy (ECT) has also been
shown to exert excellent effectiveness, which was
better in younger than in older geriatric patients
(Abrams, 2002 ; Greenberg and Fink, 1992 ; Oshima
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and Higuchi, 1999). Despite specific side effects,
such as greater cognitive impairment, efficacy 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 modified 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,
specifically 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 effects showed a small increased risk of gastrointestinal (including the experience of ‘dry mouth ’) and
neuropsychiatric side effects (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 profiles of specific 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 profile,
such as SSRIs, are gradually replacing TCAs as a firstline treatment (Gareri et al., 1998 ; Mamdani et al.,
2000). Moreover, geriatric patients are more susceptible to side effects 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 effects that raise particular concerns
in younger patients, such as weight gain due to antihistaminergic effects, may be beneficial for elderly
patients, who often suffer 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
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CINP Antidepressant Task Force 2007
cerebrovascular disease, mainly because of safety and
tolerability. In dementia, TCAs, SSRIs and moclobemide are effective ; however, newer drugs are better
tolerated and safer. For Parkinson’s disease no adequate trial data are available. SSRIs may aggravate
parkinsonian symptoms, but this finding 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 differences 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 effective 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 effects (Wilson et al., 2001).
However, little response (e.g. less than 25 % recovery)
during the first 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 suffer
from depression. In 1970, Guze and Robins (Guze and
Robins, 1970) published a meta-analysis of studies
putting a lifetime suicide risk at 15 %. This frequently
quoted figure 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 affective
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 affective
disorder but not specifically 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. Ösby et al.
identified 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 (Ösby et al., 2001).
A more precise estimate of suicide mortality may be
difficult due to methodological shortcomings, as outlined by Jules Angst and colleagues (Angst et al.,
2005).
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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 significant methodological problem : bipolar disorder and unipolar depression arising from an under-diagnosis of hypomania leading
to an underestimate of bipolar II disorder.
The most definitive prospective, long-term, large
cohort study on suicide risk in affective 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 effective tools in reducing suicide attempts and completed suicides in large, populationbased studies. This finding was first 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 Nürnberger
Bündnis 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 significant 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 suffer
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 fulfill diagnostic
criteria for bipolar disorder. On the basis of these
findings, 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 significantly 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).
Different claims about the use of antidepressants,
especially selective serotonin reuptake inhibitors
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(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 Möller (2006a, b), show some supportive 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, significantly 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 significant, 2.5 % reduction in suicide rates in adults. As pointed out by
Rihmer and Akiskal (2006), this effect 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
(Möller, 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
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CINP Antidepressant Task Force 2007
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 definitively 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 differentiate 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, conflicts with the scientific
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 efficacy do not reach
statistical significance and, in addition, are far removed from actual efficacy in real-life conditions
(Möller, 2006a).
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 Möller of a
6-week double-blind controlled study comparing
paroxetine and amitriptyline showed a marked reduction in suicidal thoughts for both medications
(Möller 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 Möller
(Möller, 2003) also demonstrated a greater benefit of
SSRIs compared with placebo in reducing suicidal
ideation.
But there is also conflicting evidence. Concerns
started in 1990 with the observation of intense suicidal
preoccupation during fluoxetine treatment in six
patients. (Teicher et al., 1990), obviously contrasting
neurobiological findings 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 fluoxetine. A
reanalysis of the first survey on this topic, conducted
by Fava and Rosenbaum (1991) suggested that the
emergence of suicidality was about three times more
likely with fluoxetine 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 significance of this finding 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).
CINP Antidepressant Task Force 2007
A finding 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 significantly 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 difference 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 conflicting 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 first metaanalyses of the specific 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 difference (MHID)
and exposure time-adjusted rate difference (MHRD)
methods, and analyzed changes in HAMD Item-3
(suicidality) scores. The planned primary metaanalysis of differences 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
4.50–14.6, 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
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 unspecified. In addition, small
differences in the numbers of rare events such as suicides may lead
to misinterpretation of study results.
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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 significantly
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 significantly 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), different
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, 10–19
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 1985–1999 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
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CINP Antidepressant Task Force 2007
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 differentiated results. This study focused on
the years 1996–1998 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 significant. 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 efficacy of treatment with antidepressant drugs in the
pharmacological management of moderate to severe
unipolar depression, should encourage doctors to
prescribe effective doses of these drugs in such
patients. Doctors should additionally be aware that
SSRIs, similarly to tricyclics, may induce or worsen
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 significantly
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 Zürich 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, significantly lowered suicide rates even though the
subjects treated were more severely ill than those
without medication.
Weighing risks against the benefits 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 difficult, 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 conflicting,
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
CINP Antidepressant Task Force 2007
offset by the public health benefits of increased diagnosis and treatment of depression.
12 Other treatments for depression
12.1
Psychotherapy63
Empirically supported psychotherapies are potent
alternatives to and augmenters in combination
with antidepressant medications. Efficacious psychotherapies may have particular benefits for depressed patients, such as pregnant women, who prefer
to avoid medication. In non-industrialized countries,
such psychotherapies may be the only feasible,
affordable 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 efficacy as both an
acute and a maintenance treatment for major depressive disorder (Weissman et al., 2000). IPT defines
depression as a treatable medical illness that is not the
patient’s fault. It focuses on the connection between
the patient’s 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 benefit for dysthymic disorder
(Browne et al., 2002 ; Markowitz et al., 2005). One large
trial has indicated the efficacy 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 efficacy 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 (‘ I’m no good’), the
environment (‘ Things are overwhelming ’), and the
future (‘ It’s 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.
S103
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
effect ’ 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 specifically
to treat chronic depression, equalled nefazodone in
efficacy 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 efficacy of
CBASP requires further testing.
In addition to acute efficacy, cognitive therapies
have been shown to enhance the efficacy of antidepressants, especially in combination treatment,
possibly due to an influence 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 benefits, but imipramine and IPT had greater efficacy for patients with
more severe depression (HAMD >20) relative to pill
placebo with clinical management.
On the basis of their performance in controlled efficacy 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
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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 modified form (which to date represents the standard procedure),
i.e. with the use of anesthesia and muscle relaxation.
The practice of using unmodified ECT should be stopped, but up to now this method is still used in some countries for
traditional and financial reasons.
meta-analysis the combined therapy outperformed
psychotherapy, but this was only true in moderate
chronic depression. No differences 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 first publications, the excellent therapeutic effectiveness 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 first-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 firstline 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 patient’s 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 different 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 10–14 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 benefit (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 first-line treatment
(Abrams, 2002 ; Baghai et al., 2005), especially if it is
not possible to differentiate 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 first-line
treatment. This recommendation also holds for
patients suffering 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 modifiers 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).
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 first
two medication treatment failures, which are often
used as a criterion for pharmacotherapy resistance
(Möller, 1997 ; Prudic et al., 1996 ; Sackeim, 2001 ;
Warneke, 1993). Use of ECT significantly enhances
response rates (Davidson et al., 1978 ; Folkerts et al.,
1997 ; Kroessler, 1985). This finding is especially true in
patients suffering 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 effects 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).
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 efficacious 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 defined, in
the following text only the term ‘ C-ECT ’ is used.
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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 4–8 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 first 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 effect.
12.2.4
Side effects
Varying with the anesthetic, the most frequent
immediate unpleasant effects 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 effect 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 effects 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 effects on autobiographic long-term memory (Lisanby et al., 2000). Nearly all patients report
amelioration of cognitive impairment after finishing the course of ECT treatment (Devanand et al.,
1991).
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CINP Antidepressant Task Force 2007
Nevertheless, recent improvements in the use of
ECT include methods to maintain good therapeutic
efficacy together with better tolerability vis-à-vis
cognitive disturbances. Using modified ECT techniques (Ghaziuddin et al., 2000), including unilateral
or bifrontal pulse wave stimulation, anesthesia with
muscle relaxation and sufficient 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 confirm 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 effects 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 differ 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 suffering from
Parkinson’s disease. This led to trials in the treatment
of depression. rTMS, VNS, MST and DBS have been
further developed in a hypothesis-driven manner
based on the current view that depressive disorders
affect integrated pathways that link select cortical,
subcortical and limbic sites and their related neurotransmitter and molecular mediators (Padberg and
Möller, 2003). However, these brain-stimulation
methods use different ‘windows ’ to access the
anatomically defined 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 Möller, 2003), whereas
VNS enters the system by vagal afferents 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 effects and
particularly exerts its effect 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 effects ; however, at present they are of
marginal clinical significance (Sachdev and Sachdev,
2005). Moxibustion must also be mentioned among
physical treatment options for depression. But empirical data regarding this intervention are insufficient,
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
difficult 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.
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 findings 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 different stimulation parameters, e.g. frequency and intensity of stimulation, have been applied in studies (Padberg and Möller, 2003), and the
usual treatment duration has been 1–4 weeks of treatment.
About 25 randomized placebo-controlled clinical
trials, including about 750 patients suffering from
major depressive episodes, have been conducted to
date investigating the safety and efficacy of rTMS as an
antidepressant intervention (Berman et al., 2000b ;
Dolberg et al., 2002 ; Garcia-Toro et al., 2001a ; GarciaToro et al., 2001b ; Kauffmann 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 Möller, 2003 ; Pascual-Leone et al.,
1996 ; Rossini et al., 2005). In the majority of these
trials, significant placebo/verum differences have
been observed, with antidepressant effects ranging
from modest to substantial. Due to the methodological
limitations of many of these trials stemming from
rather small sample sizes, the difficulty of controlling
sham rTMS and short observation periods, the current
assessment of its efficacy 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 efficacy of rTMS, but clinical effects are
not very strong, and the clinical significance may be
questionable. rTMS has also been directly compared
with ECT in five parallel design trials (Grunhaus et al.,
2000 ; Grunhaus et al., 2003 ; Pridmore et al., 2000 ;
67
See chapter 19.4 for more detailed information in for more
detailed information in Annex 4 : Additional information on
transcranial magnetic stimulation.
S107
Schulze-Rauschenbach et al., 2005). In these trials,
rTMS was found to be as effective as ECT in patients
suffering 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 effect of antidepressant medication
(Lisanby et al., 2001b ; Rumi et al., 2005). But only one
study that combined rTMS with amitriptyline found a
significant superiority of combined active treatment
(Rumi et al., 2005). Apart from single studies and
case reports, little is known regarding the stability
of effects and potential maintenance treatment strategies (Pascual-Leone et al., 1996), and the largest
body of evidence points to transient effects following
completion of rTMS treatment (Pascual-Leone et al.,
1996 ; Schüle et al., 2003). rTMS appears to be
safe and well tolerated by patients within a range
of parameters defined according to a consensus
(Wassermann, 1998).
In conclusion, there is considerable evidence for
the antidepressant efficacy of high-frequency rTMS
over the left dorsolateral prefrontal cortex applied
over 2–4 weeks, and rTMS may be applied successfully as adjuvant antidepressant intervention. However, the antidepressant efficacy of rTMS has still
not been sufficiently 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
Transcranial direct current stimulation (tDCS) is a
stimulation technique with potential benefits in the
treatment of depression which is currently used in
investigational settings. A placebo controlled RCT in
40 depressed patients suggested beneficial effects 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 effectiveness are awaiting their
replication.
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CINP Antidepressant Task Force 2007
12.3.4
Magnetic seizure therapy
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 efficacy of
ECT with an improved side-effect profile. Indeed, MST
should induce a secondary generalized seizure more
focally in relevant brain regions (Lisanby et al., 2003b),
as the magnetic field 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 efficacy 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.
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 difference 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 efficacy, 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 confirmed. VNS carries significant 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 efficacy 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 effects 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 patient’s demand for this
treatment is high, other interventions have failed and a
clinical benefit 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
Deep brain stimulation (DBS) is a well-established
treatment for intractable Parkinson’s 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 effects 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 flow 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 60–70 % 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 difficult 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
effective and rapid as TSD and better accepted by depressed patients (Schilgen and Tolle, 1980). In contrast,
early night sleep deprivation (SD) is ineffective 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
See chapter 19.7 for more detailed information Annex 7 :
Additional information on chronotherapeutics : light and wake
therapy.
S109
and Bunney, 1990). Different 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 effectiveness in comparison
with other antidepressant treatments and its transient
effects, sleep deprivation is used in clinical routine
predominantly as an augmentation strategy.
12.3.8
Bright light therapy (phototherapy)
In seasonal affective 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
Nemeroff, 2000 ; Prasko et al., 2002). Some studies report a good benefit 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 efficacious 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 efficacy 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 firstline therapy, whereas in other forms of depression
it can be tried as an augmentation strategy.
12.3.9
Exercise
A variety of publications have discussed the theoretical background of the beneficial effects 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,
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2004 ; North et al., 1990). Even long-term changes and
antidepressant effectiveness of exercise during
20 weeks of treatment have been reported (Singh et al.,
2001). Nevertheless, detailed reviews and a metaanalysis showed that the effectiveness 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 effective
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 benefits especially in the case of longer-term
use. In addition, limited evidence supports the effectiveness 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
benefit.
12.3.10
Acupuncture70
Because the use of complementary and alternative
therapies is overrepresented in patients suffering from
depressive syndromes (Kessler et al., 2001), the actual
knowledge about the main therapeutic options in this
field needs to be evaluated. Acupuncture has a long
history in Eastern culture, and traditional Chinese
medicine describes its influence on the body’s balance
of health and energy. Traditional acupuncture involves inserting needles into specific trigger points at
different parts of the body.
Despite a variety of published studies in this field, a
recent review reports insufficient evidence for determining the efficacy 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 scientific 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 effects were
much less in the acupuncture groups (Luo et al., 1998).
Studies comparing modern and better- tolerated antidepressants have not been published to date.
70
See chapter 19.6 for more detailed information in Annex 6 :
Additional information on acupuncture.
13 Antidepressant drugs in the treatment of
anxiety disorders71
The proven efficacy 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 influenced 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).
14 Health economics : the cost of illness
14.1
Background
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 different means of calculating them, differences in health systems and differences 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-effective. Third, in many
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
effective treatments to have impacts across many areas
of life), and hence growing interest in mental health
among ministries responsible for employment and
finance.
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
$
$
$
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 broad costs of depression
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
effects 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 off
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 costeffective.
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$
$
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 financial 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-five 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 affective 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-Pacific 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 suffering 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 sufferers receiving
treatment. The total cost in 2000 was US$8310
million, of which almost a third was in direct
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CINP Antidepressant Task Force 2007
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 financial 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 effects 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)
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
significant 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 first 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 significant 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
Decision makers face two central questions when
considering whether to use or recommend a particular
treatment for depression. The first is the clinical question, which asks whether an antidepressant is effective
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 effective, she or
he wants an answer to the second question : Is it costeffective ? 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 effective ? Is it
worth it ?) sit at the heart of cost-effectiveness 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-effectiveness
analysis does what its name suggests : it looks at both
costs and effectiveness (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 intervention’s cost-effectiveness 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 different 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-effectiveness analysis combines costs with
a single disease-specific outcome measure such as
a depression symptom scale. The incremental costeffectiveness ratio (ICER) is computed as the difference in cost between the two treatments divided
by the difference in outcomes. In a cost-utility analysis,
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effectiveness 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 different conditions and
disease areas, allowing strategic decision makers in a
health system to judge whether resources are most
effectively deployed in, say, treating depression
or treating breast cancer. Cost-benefit analysis generates monetary valuations of outcomes to compare
costs and benefits 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-effectiveness ’ 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-effectiveness 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-effectiveness,
cost-utility, cost-benefit, 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 final review.
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CINP Antidepressant Task Force 2007
Table 24. Methods for economic evaluation
Type of analysis
Outcome
Advantages
Disadvantages
Cost-effectiveness
Disease-specific outcome such
as depression scale
Single outcome such as QALY
or DALY
Meaningful and understandable
analysis
Can compare across diseases
Cannot compare across diseases
Cost-benefit
Monetary
Cost-consequence
Specific 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
Cost-utility
Cost-minimization
Understandable and simple
analysis
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-effectiveness of antidepressants is
determined by a number of factors, most importantly
their relative efficacy. 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 off 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 fluoxetine (Prozac1) in the UK cost
£19.34, but by March 2005 the equivalent generic
fluoxetine price was £2.11. Cost-effectiveness is also
influenced by patient adherence. Adherence is generally low and dropout rates high among individuals
commencing antidepressant treatment, which has an
impact on the effectiveness 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-effect profiles
than the TCAs, the newer preparations may improve
adherence and outcomes and thus also improve costeffectiveness.
14.4.1
Selective serotonin reuptake inhibitors
We identified 32 papers that appraised the costeffectiveness of selective serotonin reuptake inhibitors
Not suitable in all disease areas,
particularly mental health,
because of difficulties of utility
measurement
Difficult to convert health
outcomes into monetary terms
Difficult to draw firm conclusions
if outcomes move in different
directions
Can rarely be used because
outcomes are rarely known
with certainty to be equal
(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 fluoxetine
(an SSRI) or desipramine or imipramine (TCAs). In the
short term (6 months) treatment dropout was lower,
there were fewer adverse effects and achievement of a
therapeutic dose was more likely among patients randomized to receive fluoxetine. However, there were
no significant differences in clinical outcomes or
quality of life, nor were there any significant differences in cost, because the higher drug acquisition cost
of fluoxetine was offset 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 first-line use of fluoxetine 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 fluoxetine, citalopram
and amitriptyline for major depression in central
Europe and found no significant differences in cost or
outcome between interventions (Hosak et al., 2000).
The authors concluded that amitriptyline was no less
expensive or more effective than citalopram or fluoxetine 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 significantly better with
antidepressant than placebo at 2 months, but no significant difference was detected at 12 months. Costs
were lower in the SSRI group, suggesting that antidepressants are more cost-effective than placebo.
Psychological treatment resulted in worse outcomes
and higher total costs than placebo. The authors argued that affordable antidepressants such as fluoxetine 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-effectiveness 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-effectiveness,
sertraline was found to dominate TCAs for all definitions of costs and outcomes.
In an attempt to clarify the relative cost-effectiveness
of antidepressants as a first 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 significant difference in costs or outcomes between
groups. However, for values placed on an additional
QALY of over £5000 – the approach taken in examining net benefits or plotting a cost-effectiveness acceptability curve – treatment with SSRIs was likely to
be the most cost-effective strategy.
The evidence from RCTs and retrospective analyses
suggests that SSRIs may be more cost-effective treatments for depression than TCAs and are more costeffective 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-effectiveness of SSRIs for
depression. These models tend to use data from existing evidence for clinical effectiveness 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
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quality of the data used, the robustness of assumptions employed, the techniques used to test them and
generate findings, 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
influence outcomes, service use and costs.
A decision-analytic model was used to analyze the
cost-effectiveness 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-effectiveness of the two types
of antidepressants can be summarized (Canadian
Coordinating Office for Health Technology Assesment,
1997). The meta-analysis of available clinical evidence
showed that there were no statistically significant differences between the efficacy, 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 effective treatment strategy and that further
research, preferably from RCTs, was needed to investigate the long-term cost-effectiveness of treatment for
depressive disorders.
In an early model Jönsson and Bebbington (Jönsson
and Bebbington, 1994) compared the cost-effectiveness
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 costeffective. The results were sensitive to assumptions
concerning the relative efficacy 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-effective
option. However, these findings 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-effective than the SSRI. The
authors advised that a policy of using TCAs as a first
choice antidepressant, with SSRIs reserved for those
patients not doing well, appears more cost-effective
than the reverse sequence. The two studies use the
same data but generate different results, confusing
the issue of cost-effectiveness and highlighting the
importance of the assumptions made in economic
models.
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Other modeling studies present evidence of the
cost-effectiveness 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 significant differences in costs are reported. However, there is evidence suggesting that
SSRIs are more costly and more effective 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-effectiveness 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-effective 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-effective option compared with generic citalopram (Wade et al., 2005a ;
Wade et al., 2005b) and had a cost-effectiveness profile
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
efficacy to venlafaxine and patient costs were lower in
the escitalopram group, though not significantly 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-effectiveness
of SSRIs, decision and Markov models dominate
economic evaluations for the newer antidepressants.
The cost-effectiveness 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
Poland in the inpatient setting, and Italy and Poland
in the outpatient setting. The authors concluded
that venlafaxine is a more cost-effective 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 different antidepressants (Casciano,
2003). The revised study disputed the treatment
dominance of venlafaxine and concluded that venlafaxine was more effective than SSRIs but also more
expensive.
The cost-effectiveness 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
offered statistically significant 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 first-line treatment strategy, and switching to an SSRI if necessary, was a
dominant treatment strategy over first-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-effective 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-effective 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
effective, 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 difficult to draw firm conclusions regarding the
cost-effectiveness of venlafaxine for depression. In
the case of duloxetine, both acute and maintenance
treatment seem to be cost-effective alternatives
to SSRIs and TCAs (Dardennes et al., 1999 ; Lafuma
et al., 1999).
CINP Antidepressant Task Force 2007
14.4.3 Noradrenergic and specific serotonergic
antidepressant
Only one study prospectively collected and analyzed
data on cost-effectiveness, focusing on mirtazapine
versus paroxetine in UK primary care attenders with
depression (Romeo et al., 2004). Mirtazapine treatment
resulted in significantly greater improvements in
quality of life than paroxetine at 26 weeks. Although
no significant cost differences were observed between
the two groups, societal costs were lower with mirtazapine than with paroxetine. The results suggest that
mirtazapine may be a cost-effective 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 effective and less costly
compared with amitriptyline and fluoxetine. The
higher acquisition costs of the preparation were
offset 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-effectiveness of mirtazapine despite
the differences in acquisition costs compared with
other antidepressants such as amitriptyline and
fluoxetine.
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-effectiveness was
estimated for a 30-year-old woman with active depression, and in both studies the findings suggested
that nefazodone is a cost-effective treatment compared
with imipramine (a TCA) and fluoxetine (an SSRI).
The results were highly sensitive to the assumptions
made in the model, particularly those concerning efficacy and dropout.
14.5 Evidence on the cost-effectiveness 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 influence their outcomes and
thus the cost-effectiveness of the antidepressants.
Three studies have investigated the cost-effectiveness
of care management versus usual care in patients
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starting antidepressant treatment. In two trials clinical
outcomes suggest there are no significant differences
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, identification 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 Korff 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 benefits (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 differences in costs. Second, the results
from economic models are strongly influenced by the
assumptions made ; in many cases conclusions change
when new evidence becomes available, or when
medication prices change or when a different 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-specific, as nations have different 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-effectiveness 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.
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Box 13. Summary of economic evidence on antidepressant treatments
What we know :
$
$
$
Some, but not all analyses suggest that SSRI treatment is more cost-effective than treatment with TCAs.
On the basis of available evidence, venlafaxine and mirtazapine appear to be cost-effective alternatives to SSRIs.
A new way of care, called care management, has demonstrated its value in enhancing the effectiveness of antidepressants
in one out of three studies.
What we do not know :
$
$
$
$
Evidence of the cost-effectiveness 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 differences in health systems across the world,
it is difficult to know whether their findings can be generalized to other countries. Cultural factors may impact on patients’
adherence, prescription habits and finally on cost-effectiveness.
Evidence of the cost-effectiveness 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 difficult to summarize the
cost-effectiveness 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 difficult to draw
firm 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-effective alternatives to
SSRIs.
14.7 Implications : economic evidence for
pharmacological treatment options
Growing awareness of the need to improve not
only the effectiveness but also the cost-effectiveness
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 costeffectiveness 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
efficiency 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
$
$
$
few large observational studies with appropriate
standardization, and hence limitations on the external validity of some evidence ;
the scarcity of cost-utility analyses and costbenefit analyses, making it impossible to use the
existing evidence base to make comparisons of
resource efficiency outside the mental health system ;
widespread use of economic models that may not
accurately reflect 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 difficult to draw firm
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 different countries and cultures. Making generalizations across
countries is therefore more difficult 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 effectiveness in depression (see chapter 12.1), so economic
evaluations essentially aim to investigate whether
high initial treatment costs are offset by potentially
lower drug costs and fewer visits to other health care
professionals (the cost-offset question) or whether the
additional costs are worth paying because of improved outcomes (the cost-effectiveness 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 reflected in the evaluative literature. In some
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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
difficult to draw conclusions, and the authors recommended a full economic evaluation with longer
follow-up and one that included a wider definition
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 significant
differences in outcomes and costs. Bootstrap analysis
showed that the antidepressant intervention was the
dominant cost-effective strategy for the majority of
patients, indicating that the cost-effectiveness of
counseling compared with treatment with an antidepressant for depression in primary care has not been
proven.
The cost-effectiveness 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 significant differences between
sertraline alone and sertraline plus IPT, but both
were significantly more effective than IPT alone in reducing depressive symptoms. Societal costs were significantly lower in the IPT group, but there was
no synthesis of costs and effects, so the incremental
cost-effectiveness 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-effectiveness
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
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Table 25. Summary of cost-effectiveness of psychological treatments for depression
Psychotherapeutic
method
Cost-effectiveness
Reference
IPT
Depends on the treatment setting ; may be cost-effective
(better outcomes no difference in cost) in secondary care but
evidence from primary care less clear. When compared
head-to-head with an SSRI, no evidence of cost-effectiveness
Browne et al., 2002 ; Guthrie et al., 1999 ;
Kamlet et al., 1995
CBT
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-effective
Bower et al., 2000 ; Kaltenthaler et al.,
2002 ; Richards et al., 2003 ; Scott and
Freeman, 1992 ; Scott et al., 2003
Counseling
No significant differences in costs or outcomes in clinical
trials, though meta-analysis suggests counseling will
produce significantly better outcomes for significantly
higher costs
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
Problem solving
Cost-effective from a societal perspective, but higher costs in
intervention group from a health-care perspective.
Additional costs of problem-solving treatment are offset by
fewer days off work in the intervention group
Mynors-Wallis et al., 1997
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
differences were not statistically significant, 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 benefits associated
with each maintenance therapy, and the authors
demonstrated that the drug maintenance treatment
was cost-effective. Among patients with depression
who had a partner with a criticizing attitude, significant improvements in outcomes were found in
patients randomized to couples therapy compared
with those randomized to antidepressants (Leff
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 significant differences 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-effectiveness
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-effective in some patient
groups (Table 25), but when compared directly with
antidepressants, their cost-effectiveness 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 effectiveness of antidepressants, but studies have only taken place in the
US and – given the fundamental differences in health
systems across the world – it is difficult to know whether their findings 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 indefinitely to maintain prophylaxis
against depressive relapse and recurrence, whereas
psychotherapy may either be discontinued, with ‘enduring effect ’ (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 difficulties) 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
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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 findings 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 suffering 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
benefit from qualified 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 insufficient ;
Concerned by the findings 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 benefits of these medications
used in the treatment of depressive disorders outweigh the
risks presented by the side effects 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 scientific 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 significant social and economic benefits
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 insufficiently informed about the frequency of depressive
disorders and possibilities of their effective 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 specific 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
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CINP Antidepressant Task Force 2007
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 staff 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 field 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 effort 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. Möller, Chairman of the Psychiatric Department of the Ludwig-Maximilians-Universität
München 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 scientific 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, Pfizer 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, Pfizer,
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, Pfizer, 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
Pfizer 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 conflicting interests.
Max Fink has no commercial contracts or appointments and receives no funding from industry sources
that may influence 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, Pfizer, 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 Pfizer
Foundation.
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, Pfizer, 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 conflicts of interest.
Guy M. Goodwin received grants from SanofiAventis, Servier and honoraria from AstraZeneca,
BMS, Eisai, Lilly, Lundbeck, Pfizer, Sanofi-Aventis,
Servier and Wyeth. He serves on the advisory boards
of Lilly, Lundbeck, P1Vital, Sanofi-Aventis, Servier,
Wyeth. He has no shares in pharmaceutical companies. He holds or has held research grants from SanofiAventis, Lilly, Stanley MRI, the Bailey-Thomas Trust
and the MRC (UK).
Heinz Grunze receives research grants from
Novartis, AstraZeneca, UCB Belgium and Pfizer. He
occasionally supplies services as a consultant and/or
paid speaker for AstraZeneca, Sanofi-Aventis, Desitin,
Lilly, Janssen-Cilag, BMS and Pfizer.
Peter Jensen currently receives investigator-initiated
grants from McNeil Pharmaceuticals and unrestricted
educational grants from Pfizer, Lilly and McNeil,
participates in speakers’ bureaus for CMED, the Union
Chimique Belge Pharma, PsychCME, Continuing
Medical Education Outfitters 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,
Pfizer, Asahi-Kasei, Janssen, Tsumura, Ajinomoto,
Yoshitomi, Meiji, Kyowa-Hakko, Sumitomo, Organon,
Otsuka. Consultant : Lilly, Pfizer, 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, Sanofi-Aventis, Pfizer, Novartis.
Jeffrey Liebermann discloses that he holds or has held
research grants from BMS/Otsuka, GSK, Janssen,
Pfizer 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 speaker’s
honoraria and/or consulting fees from Pfizer, 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 conflicts 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-Rössler discloses that she received
speaking/consultancy honoraria or research grants
from BMS, AstraZeneca, Janssen-Cilag, Eli Lilly and
Sanofi-Synthelabo.
Norman Sartorius acted as consultant and/or received honoraria for presentations at meetings and
symposia organized by Eli Lilly, Janssen, Lundbeck,
Pfizer, 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, Pfizer, Somaxon, Somerset
and Wyeth. He holds or has held research grants
from Somerset and Wyeth and holds equities from
BrainCells, Corcept, Merck, Organon, Pfizer and
Somaxon.
Jaromı́r Švestka acted as a consultant to and/or accepted paid speaking engagements in satellite symposia from AstraZeneca, Sanofi-Aventis, BMS, Desitin,
Eli Lilly, Janssen-Cilag, KrkaPfizer, Zenziva. He
received support for participation in international
congresses from BMS, Eli Lilly, Janssen-Cilag, Pfizer
and Zentiva.
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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 specific 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 reflected 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 insufficient scientific evidence
about the effectiveness 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 suffering 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 different 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 benefits 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
benefit, 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
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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 five patients out of ten responding to the antidepressant compared with four responding to the placebo,
with the assessment of benefits 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-specific
factors. We are unable to quantify the contribution of the
various non-specific factors involved, while in contrast we
can quantify the specific drug contribution. But this specific
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 specifically responds to an antidepressant and nine either don’t respond specifically 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 benefits.
I think it would be preferable to flag up the preliminary
and provisional nature of the results. They point to the fact
that antidepressants have benefits. 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 difference between the response to active
treatment and response to a placebo. This would bring in
areas like pharmacogenetics and questions about the effects
of specific treatments on different constitutional or personality types rather than simply the effects of these agents on
some disease process.
I think there is a signal failure in the field 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 first trials on Prozac, all of which essentially
repeat the formula of trying to show a small difference 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 offered to advance the science of psychopathology and also in terms of the science of clinical therapeutics.
The report bases almost everything on minimal rating scale
changes. In terms of any hard outcomes that these clinical
trials offer, 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 figures 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 offer the only hard outcomes we have. If even a proportion of the adverse responses
were factored in it is doubtful that the economic benefits
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 offered in the report on this specific 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 specific issues like
this there were the more general issues that have enveloped
the field recently, referred to by Dr Belmaker, such as increasing difficulties with articles being ghost written, with
conflicts 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 can’t believe that CINP
members with their particular backgrounds would be very
happy for the organization to adopt such an ethical position.’
CINP Antidepressant Task Force 2007
Some of David Healy’s 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
difficult 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 Healy’s
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 specific 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
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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 specific recommendations for pharmacotherapy. The CINP antidepressants task force agreed to to include those
recommendations because they represented unreferenced treatment schedules. Specific 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 effective 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-offset 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 difficulties or research funding limitations.
One of these cost-only methods is the cost-offset 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-offset 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 fixed or even shrinking budget (at
least in the short run), are treatment changes affordable ?
19.2.2
Cost-effectiveness analysis
Probably the most intuitive and straightforward
modes of economic evaluation are cost-effectiveness
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CINP Antidepressant Task Force 2007
New treatment more costly
A
Old treatment
dominates
New treatment
less effective
0
Trade-off needed:
compare cost
difference and
outcome difference
B
X
Trade-off needed:
compare cost
difference and
outcome difference
New treatment
more effective
X
New treatment
dominates – more
effective and less costly
New treatment less costly
Figure 5. Cost-effectiveness 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 specific patient groups. A
cost-effectiveness 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 difference in costs between the two treatments being evaluated with the
difference in (primary) outcome (the incremental costeffectiveness ratio or ICER).
A common finding is that a new treatment is both
more effective (the outcome profiles 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-effectiveness ‘plane’
(Figure 5) illustrates the range of possible CEA results
and the difficult decision-making task in some circumstances.
The cost-effectiveness 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 effective (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 find 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 benefit approach, linked to the construction of cost-effectiveness acceptability curves
(CEACs). These show the probability that a new intervention will be reviewed by the decision maker as
cost-effective for each prespecified 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 costeffectiveness 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-benefit)
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 effects 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 insufficiently 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-benefit analysis
Cost-benefit analysis (CBA) asks whether a treatment
or policy is socially worthwhile in the broadest
sense : Do the benefits 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 benefits
are valued in the same (monetary) units. If benefits
exceed costs, the evaluation would recommend providing the treatment, and vice versa. With two or
more alternatives, the treatment with the greatest
net benefit would be deemed the most efficient.
CBAs are thus intrinsically attractive, but conducting
them is especially problematic because of the difficulties associated with valuing outcomes in monetary
terms.
Recent methodological advances in health economics offer 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 difficult to apply
in mental health contexts. Another approach used to
value health interventions is ‘ conjoint analysis ’. Individuals are asked to rank different real- world scenarios, which may consist of several dimensions
(including, for instance, health outcomes, time inputs,
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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 specifically
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 different 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-effectiveness
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 influenced by
the personal predilections or value positions of a few
individuals, and (potentially) reflective of societal
values.
19.2.6
Cost-minimization analysis
Another ‘cost-only ’ approach is cost-minimization
analysis, which seeks to find 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-effectiveness
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CINP Antidepressant Task Force 2007
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-effectiveness analysis, where evidence on effectiveness
demonstrates no difference 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 first publication of a placebo
controlled double-blind study indicating the efficacy
of ECT in the treatment of depression (Greenblatt et al.,
1964), the excellent therapeutic effectiveness 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 first-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 first-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 10–14 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
the benefit (Kellner et al., 2005). Also other acute
psychiatric syndromes, e.g. malignant catatonia or a
neuroleptic malignant syndrome (NMS) may show
rapid benefit from ECT as a first-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 firstline treatment. This recommendation also holds for
patients suffering 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
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 (Möller, 1997 ; Prudic et al., 1996 ;
Sackeim, 2001 ; Warneke, 1993). Use of ECT significantly enhances response rates (Davidson et al., 1978 ;
Folkerts et al., 1997 ; Kroessler, 1985). This finding is
especially true in patients suffering 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 effects 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
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Table 26. Indications74 for electroconvulsive therapy (adopted from Baghai et al., 2005)
Category of ECT indications
Indication
ECT as a first-line treatment
$
$
$
$
$
$
ECT as a second-line treatment
Medication treatment failures in :
$
$
$
$
$
ECT as a last-resort treatment
Febrile catatonia*
Malignant neuroleptic syndrome*
Severe depressive episode**
Schizoaffective psychosis**
Schizophrenia**, ***
In the case of life-threatening or intolerable side effects of
psychopharmacological treatments
$
$
$
$
$
Depression
Schizoaffective 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 Parkinson’s disease
* 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 Efficacy of ECT in depressive syndromes of
differential etiology
19.3.3.1 Unipolar depression
The general efficacy 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 50–60 % 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 suffering from psychotic depression) were found in major depressed
patients treated with optimized ECT (Husain et al.,
74
ECT is indicated as a first- 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 scientific evidence from RCTs and
meta-analyses have been published (ECT review group, 2003 ;
Tharyan, 2000 ; Tharyan and Adams, 2005).
2004 ; Kellner et al., 2005 ; O’Connor 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 efficacious 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 effective than unilateral
ECT (ECT review group, 2003 ; Sackeim et al., 1987 ;
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CINP Antidepressant Task Force 2007
Sackeim et al., 1993). But unilateral ECT may achieve
efficacy rates equal to bilateral ECT if the dose regime
is 6–8 times above the titrated seizure threshold
(McCall et al., 2000 ; Sackeim et al., 2000).
(American Psychiatric Association Committee on
Electroconvulsive Therapy et al., 2001).
19.3.3.2 Bipolar depression
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 ; O’Connor et al., 2001). Nevertheless, in the case
of resistance to pharmacotherapy, ECT should not be
withheld from patients suffering 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.
ECT is an effective 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 effects and to prevent a switch into mania in
high-risk patients. In this case, an enhanced risk for
cognitive and medical side effects 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 specific 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 suffering 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 beneficial use of ECT
during OCD continuation therapy has been reported
19.3.3.5 Comorbid personality disorder
19.3.3.6 Organic depression due to somatic disorders
Patients suffering 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 Coffey, 1997) in comparison with MDD.
Nevertheless, ECT is clinically effective in patients
suffering from depression after cerebral infarction
(‘ poststroke depression ’) (Krystal and Coffey, 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
The majority of patients referred for ECT have had
multiple trials of medication. Despite this experience,
high remission rates to effective 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 effectiveness 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,
findings from study of a putative benefit 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 efficacy 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 effects 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 effective 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 4–8 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 first
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 ;
75
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 defined, in the
following text only the term ‘ C-ECT ’ is used.
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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 effects
19.3.7.1 Somatic side effects
The most frequent immediate unpleasant effects 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 suffering 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 30–180
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 effectiveness 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 finger or toe pulse oxymetry is
necessary to prevent hypoxia. Aching muscles can be
prevented by adequate muscle relaxation and are reported rarely.
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CINP Antidepressant Task Force 2007
Table 27. Clinical conditions requiring special attention before and during ECT (adopted from Baghai et al., 2005)
Category
Clinical condition
Enhanced intracerebral pressure*
Cerebral infarction*
Myocardial infarction*
Intracerebral tumor*
Any life-threatening anesthesia risk*
Cardiovascular disorders
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 insufficiency, heart-valve abnormalities,
not sufficiently 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 inflammations, 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 efficacy
Medical disorders
Neurological disorders
Orthopedic disorders
Esophageal hernia
Concomitant pharmacological treatment
* In former times considered as absolute contraindications ; today an individual risk/benefit-analysis is necessary.
In patients suffering 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 effects
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 significantly reduce the switch risk.
19.3.7.2 Cognitive side effects
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
effects 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 differentiated from rarely occurring
effects on autobiographic long-term memory (Lisanby
et al., 2000). In addition, cognitive deficits that are
not a product of memory disturbances, such as concentration or attention deficits can occur. It can be
difficult in an individual patient to differentiate cognitive side effects 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 Coffey, 1997).
Sometimes patients experience profound and sustained memory loss, sufficient 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
efficacy together with better tolerability concerning
cognitive disturbances. Modified ECT techniques
(Ghaziuddin et al., 2000), including unilateral and
bifrontal pulse wave stimulation, anesthesia with
muscle relaxation and sufficient 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 effects 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 confirm 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 sufficiently, these conditions become relative
contraindications, and a risk-benefit 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, insufficiently 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 effects for ECT and anesthesia should be taken
into consideration. In the case of specific risks, interdisciplinary counseling may be necessary. Next, the
higher somatic risk must be compared with the risk of
insufficiently treated or prolonged psychiatric illness.
Patients and relatives or responsible legal guardians
need to be informed about risk-benefit 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.,
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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
findings that show reversible functional changes in
this region using different 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 different stimulation
parameters, e.g. frequency and intensity of stimulation, have been applied in studies, and very few
studies have compared different treatment modalities
(Padberg and Möller, 2003). The usual treatment duration has been 1–4 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 suffering from
major depressive episodes, have been conducted to
date investigating the safety and efficacy 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 ; Kauffmann 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 Möller, 2003 ;
Pascual-Leone et al., 1996 ; Rossini et al., 2005). In
the majority of these trials, significant placebo/verum
differences have been observed, with antidepressant
effects ranging from modest to substantial. Due to the
methodological limitations of many of these trials
stemming from rather small sample sizes, the difficulty of controlling sham rTMS used as placebo condition, modified 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 differ 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 efficacy of rTMS,
but the clinical effects found are not very strong and
the clinical significance may be questionable. rTMS
has also been directly compared with ECT in five
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 effective as ECT in patients suffering
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from major depressive episodes without psychotic
features, but to be inferior for psychotic depression
(Grunhaus et al., 2000). Surprisingly, only one study
compared different rTMS modalities with antidepressant pharmacotherapy (clomipramine) ; however, no meaningful interpretation of the results in
terms of efficacy 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 effect of antidepressant medication (Lisanby et al., 2001b ; Rumi et al., 2005). Only
one study that combined rTMS with amitriptyline
reported significant superiority of combined active
treatment (Rumi et al., 2005), whereas the other trials,
which applied SSRIs and other substances, failed to
show a significant difference between treatment
groups. These results may support the idea of rTMS
being particularly effective 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 effects and potential
maintenance treatment strategies (Pascual-Leone et al.,
1996). The largest body evidence points to transient
effects following completion of rTMS treatment
(Pascual-Leone et al., 1996 ; Schüle et al., 2003).
rTMS appears to be safe and well tolerated by
patients within a range of parameters defined according to a consensus (Wassermann, 1998). Side effects
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 effects 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 Möller, 2003 ; Rush
et al., 2000).
In conclusion, considerable evidence argues for the
antidepressant efficacy of high-frequency rTMS over
the left dorsolateral prefrontal cortex applied over 2–4
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 effects 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 efficacy of
rTMS has still not been sufficiently 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 first open study (D-01) showed clinically
meaningful effects over a period of 2 years, with response rates between 42 and 45 % (defined 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 first 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).
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
efficacy criteria of the acute study were the number of
responders in the treatment groups. No difference between those groups was found in the acute study (15 %
response in the active vs. 10 % response in the placebo
group), nor were significant differences among the
secondary efficacy criteria (self- and observer ratings)
observed (Rush et al., 2005a). The negative finding 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
efficacy, 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 confirmed.
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 efficacy 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 effects
superior to placebo is still limited and mainly based on
long-term data compared with naturalistic treatment.
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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 efficacy of VNS in depression. Because of its invasive nature, VNS should
be reserved for special clinical cases where the
patient’s demand for this treatment is high, several
other interventions have failed and a clinical benefit
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
Efficacy
Due to the fact that the use of complementary and
alternative therapies is overrepresented in patients
suffering from depressive syndromes (Kessler et al.,
2001), the actual knowledge about the main therapeutic options in this field need to be evaluated. The
history of acupuncture in Eastern culture goes back
more than 4000 years, and traditional Chinese medicine describes its influence on the balance of health
and energy in the human body. The original practice
involves inserting needles into specific trigger points
at different parts of the body. Electro-acupuncture
(EA) includes electrical stimulation of classical trigger
points using sine wave and undulatory wave stimulation of different frequencies. An influence 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 field, a
recent review describes insufficient evidence to determine the efficacy 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 suffering from depression were treated with
traditional acupuncture or the TCA amitriptyline. No
significant differences 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
effects in the treatment groups showed no significant
differences. A better therapeutic effect on anxiety and
cognitive symptoms following acupuncture has been
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described (Allen and Schnyer, 1998). Similarly, a
variety of Chinese RCTs found no significant differences 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-specific acupuncture
showed significantly more improvement than the
group receiving non-specific acupuncture, but no significant difference from the placebo condition in
waiting-list patients could be seen (Allen and Schnyer,
1998). A single blind study also compared depressionspecific and non-specific acupuncture with mianserin
monotherapy in a total of 70 patients. Additionally,
acupuncture improved depression more than treatment with mianserin. No differences between either
forms of acupuncture could be seen (Roschke et al.,
2000). Moreover, specific acupuncture showed a
greater and lasting amelioration of symptoms in
women suffering from depression during pregnancy
(Manber et al., 2004). Other authors describe some
evidence for the clinical effectiveness 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 different 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
scientific 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 effects 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
(sleep deprivation), sleep-phase advance therapy and
light therapy (Wirz-Justice et al., 2005).
19.7.1
Wake therapy
Numerous studies have confirmed that the majority of
patients with depression who abstain from a night’s
sleep obtain immediate relief from depression (Kuhs
and Tölle, 1991 ; Ostenfeld, 1973 ; Wu and Bunney,
1990), often with full, although temporary remission.
This effect appears to be most pronounced in patients
with bipolar illness and in those with diurnal or dayto-day mood variation (Kuhs and Tölle, 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 night’s
waking (total sleep deprivation) or staying awake in
the latter part of the night (partial sleep deprivation).
A procedural elaboration, which sustains the first-day
benefit, 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 effect of sleep deprivation include combination with antidepressant drugs, pindolol, lithium
and the use of bright light therapy, all of which have
been shown to effectively 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 Tölle, 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 field needs larger trials
with suitable control groups to assess the absolute
magnitude of the wake therapy effect and trials of
longer duration to assess the relapse pattern in different 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 affective 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
effort, and its antidepressant effect and chronobiological effects 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-filtered diffuse white fluorescent light. Narrow-band spectra with blue or
green appearance have been investigated, but the data
are insufficient to recommend their use. Additionally,
there is a suspected retinal hazard of blue-light exposure, which may damage retinal structures and exacerbate age-related macular degeneration (Remé
et al., 2001). Light boxes come in many designs, but
larger screens that emit diffuse 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 benefit 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 deficient. This method uses far
lower light intensity than in post-awakening bright
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light therapy, yet has shown efficacy 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 effective,
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 effect has been confirmed, 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
effect 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 8–12
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 (Remé et al., 2001). Acute side effects 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 efficacy 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 differential benefits may exist among
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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 benefits 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 define 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 efficacy
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 efficacy, 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 effect even for acute psychotherapy, a lasting protective benefit not seen when
pharmacotherapy is discontinued (Hollon et al., 2005).
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
efficacious 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 finding
requires replication, as it is the only CBASP trial
published to date. IPT and CBT have shown less benefit than pharmacotherapy for dysthymic patients
(Markowitz et al., 2005 ; Ravindran et al., 1999), albeit
combined IPT and sertraline was cost-effective 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, differential attrition
and other methodological difficulties. Large sample
sizes are required to find differences between active
monotherapies and combined treatment. Nonetheless,
no research trial has shown combined treatment to be
less efficacious 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 efficacy of the SSRI fluoxetine 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
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 benefit from adjunctive psychotherapy (Markowitz, 1993) to expand
their social confidence 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 Differential 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 defines 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 differing
appeals and benefits for different 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-significant differences 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 differential 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 effects 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 benefit. In nonindustrialized countries, such psychotherapies may be
the only feasible, affordable treatments for depression
(Bolton et al., 2003). Psychotherapies adapted to different cultures must address the specific needs and
sensitivities of individuals in those cultures.
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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 effectively. Patient preference is a predictor of treatment
outcome and hence deserves consideration in treatment selection.
On the basis of their performance in controlled
efficacy 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 influence the
field of mental health in response to demands for accountability and to address the well-documented disparity between scientific 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 effectiveness 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 efficacy (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.
Efficacious 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 effective
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
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alone, however, have similar efficacy and acceptability
(de Mello et al., 2005 ; Markowitz et al., 2005). This
absence of an adjunctive effect for psychotherapy
seems counterintuitive.
Note that several characteristics of patients and
disorders have been related to differential 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
effective 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 efficacy 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 influenced 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 efficacious in acute treatment (Baldwin
and Polkinghorn, 2005 ; Mitte et al., 2005). The small
number of comparator-controlled studies reveals
no consistent differences in efficacy 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 significant 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 efficacy
in acute treatment, but the comparative efficacy 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 efficacy than with either treatment given alone
(Baldwin and Polkinghorn, 2005).
19.9.2
Panic disorder
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 efficacious in acute
treatment. Comparator-controlled studies provide
some evidence for the efficacy of mirtazapine and
moclobemide. The side-effect 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 significant advantage for staying on active
medication (fluoxetine, 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 efficacy 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 efficacy 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 effective
CINP Antidepressant Task Force 2007
than pharmacotherapy alone and was as effective as
psychotherapy (Furukawa et al., 2006). Therefore,
either combined therapy or psychotherapy alone has
been recommended as a first-line treatment for panic
disorder.
19.9.3 Social phobia
Systematic reviews and placebo-controlled RCTs indicate that a range of antidepressants are efficacious,
including most SSRIs (escitalopram, fluoxetine, fluvoxamine, 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 significant 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 efficacy 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 efficacy 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 efficacy of some SSRIs (fluoxetine,
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
significant advantage for staying on active medication,
for fluoxetine (Davidson et al., 2005 ; Martenyi
et al., 2002) and sertraline (Davidson et al., 2001).
The comparative efficacy of psychological and pharmacological treatments, in either acute or long-term
treatment, is uncertain (Baldwin and Polkinghorn,
2005).
19.9.5
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Obsessive-compulsive disorder
Systematic reviews and meta-analyses of randomized
placebo-controlled trials indicate that the TCA clomipramine and the SSRIs (citalopram, escitalopram,
fluoxetine, fluvoxamine, paroxetine and sertraline) are
efficacious in acute treatment. The efficacy 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 efficacy 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 significant advantage for staying on active
medication (clomipramine, paroxetine, sertraline and
fluoxetine, 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 efficacy
of exposure therapy with clomipramine compared
with exposure alone is inconsistent, but fluvoxamine
has been shown to enhance the efficacy 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
Armenia, Azerbaijan, Belarus,
Georgia, Kazakhstan, Kyrgyz
Republic, Russia, Ukraine, Uzbekistan
Munich,
Germany
Austria, Denmark, Germany, Greece,
Croatia, Czech Republic, Hungary,
Poland, Serbia, Slovakia, Switzerland
Shanghai, China
Australia, China, Hong Kong, Indonesia,
Japan, Korea, Pakistan, Philippines,
Singapore, Taiwan, Thailand
Caracas,
Venezuela
Argentina, Bolivia, Brazil, Chile,
Colombia, Costa Rica, Dominican
Republic, Ecuador, El Salvador,
Honduras, Mexico, Nicaragua, Panama,
Peru, Uruguay, Venezuela
Paris, France
France, Egypt, Luxembourg, Morocco,
Spain, Sweden, Tunisia, Turkey
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CINP Antidepressant Task Force 2007
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.
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.
Participants
Publication of findings
Participants in national meetings should be experts
representing the fields of psychiatry, pharmacology,
internal medicine and general practice, government
officials 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 12–15 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.
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 findings 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.
The agenda and method of work
19.12 Annex 12 : Additional information on the
European Federation of Associations of Families
of People with Mental Illness (EUFAMI)
19.11 Annex 11 : Suggestions concerning the
organization of national review meetings
Aims of the meeting
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 reflect 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.
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 finding 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.
EUFAMI’s 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 financial support for families
and carers as an integral part of their budget. EUFAMI
also works to establish a charter of rights of families
CINP Antidepressant Task Force 2007
of carers and offers its services in teaching health
professions and planning services for the mentally ill.
19.12.1
$
$
$
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 effort to improve mental health conditions in
their own territories, while fully respecting their
national or regional autonomy.
19.12.2
$
$
$
$
$
$
$
$
EUFAMI’s principles
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.
19.12.3
$
EUFAMI’s aims
EUFAMI’s mission
Contribute to removing the stigma surrounding
mental illness by promoting positive images to
counteract ignorance and misinformation.
Highlight examples of good practice in the field of
mental illness in order to promote good practice
throughout Europe ; identify examples of bad practice in the field 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.
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19.13 Annex 13 : List of Advisors
AGUILAR Mario, Vice-President, Honduran
Society of Psychiatry
[email protected]
ALEMAN Luis Enrique, Secretary of the
Nicaraguan Society of Psychiatry, Masaya
[email protected] ; [email protected]
ALLAIN Hervé, Laboratoire de Pharmacologie,
Université de Rennes I – Faculté de Médecine, 35043
Rennes Cedex, France
[email protected]
ALLILAIRE Jean-François, Chef du Service de
Psychiatrie (Adultes), Consultation Chaslin, Hôpital
de la Salpêtrière, 47, Bd de l’Hôpital, 75651 Paris
Cedex 13, France
[email protected]
ALVAREZ M. Carmen, General Secretary,
Venezuelan Society
[email protected]
ANSSEAU Marc, Chairman of the, Department of
Psychiatry, University of Liège, B-4000 Liège, Belgium
[email protected]
AVEDISOVA Alla, Head of New Drugs Division,
Serbsky Centre for Social and Forensic Psychiatry,
Moscow, 123367, Russia
[email protected]
AZORIN Jean-Michel, SHU Psychiatrie Adultes,
Hôpital de Sainte-Marguerite, 13274 Marseille Cedex
09, France
[email protected]
BAUER Michael, Head of the Department
of Psychiatry and Psychotherapy,
Universitätsklinikum Carl Gustav Carus, D-01307
Dresden, Germany
[email protected]
BAUMANN Pierre, University Department of
Psychiatry, Site de Cery, CH-1008 Prilly-Lausanne,
Switzerland
[email protected]
BECH Per, Psychiatric Research Unit, Frederiksborg
General Hospital, 3400 Hillerød, Denmark
[email protected]
BELFORT Edgard, WPA Zonal Representative,
WFMH Board of Directors, Caracas 1010, Venezuela
[email protected] ; [email protected]
BELMAKER R.H., Beersheva Mental Health Center,
Beersheva, Israel
[email protected]
BERK Michael, Barwon Health and Geelong Clinic,
Swanston Centre, The University of Melbourne,
Geelong, Victoria 3220, Australia
[email protected]
S200
CINP Antidepressant Task Force 2007
BLIER Pierre, University of Ottawa, Institute of
Mental Health Research, Ottawa ON K1Z 7K4, Canada
[email protected]
BOBROV Alexander, Head of the Department of
Psychiatry, Irkutsk State Institute of Postgraduate
Education for Physicians, Irkutsk, 664079, Russia
[email protected]
BOULENGER Jean-Philippe, Service Universitaire
de Psychiatrie Adulte, INSERM Equipe E-361, Hopital
La Colombière, CHU de Montpellier : 39 Avenue
Charles Flahault, F-34295-Montpellier Cedex 5
[email protected]
BRASIL Marco Antonio, Past-President, Brazilian
Association of Psychiatry, Rio de Janeiro
[email protected]
BURROWS Graham D., The University of
Melbourne, Department of Psychiatry, Austin
Hospital, Heidelberg, Victoria 3084, Australia
[email protected]
CAI Zhuoji, President, Chinese Mental Health
Association, Beijing
[email protected]
CALDERON Jose, President, Panama Society of
Psychiatry
[email protected]
CALDERON Minerva, Forensic Psychiatry,
Forensic Medical Institute
[email protected]
CALIL Helena Maria, Department of
Psychobiology, Paulista Faculty of Medicine, Federal
University of São Paulo, São Paulo, Brazil
[email protected]
CANNEVA Jean, President of UNAFAM, France
[email protected]
CASTRO Rojas Rigoberto, President, Costa Rican
Psychiatric Association, San José
[email protected]
CARROLL Bernard, Pacific Behavioral Research
Foundation, P.O. Box 223040, Carmel, CA 93922-3040,
USA
[email protected]
CHENG Nengneng, Pharmacology School, Fudan
University, P. R. China
[email protected]
CHONG Mian-Yoon, Chairman, Department of
Psychiatry, Chang Gung Memorial Hospital,
Niao-Sung Hsiang, Kaohsiung County 83342,
Taiwan
[email protected]
CORDOBA Rodrigo, General Director, CISNE
[email protected]
CORREA Eduardo, Professor, Chile University
[email protected]
CORRUBLE Emmanuelle, Service de Psychiatrie,
CHU de Bicêtre, 94270 Le Kremlin Bicêtre,
France
[email protected]
COWEN PJ, Neurosciences Building, Warneford
Hospital, Oxford OX3 7JX, UK
[email protected]
DANIELYAN Konstantin, Head of the Psychiatry,
Psychotherapy & Medical Psychology Department,
National Institute of Health of RA Armenia
[email protected]
DANION Anne, Child Psychiatrist, Strasbourg,
France
[email protected]
DELGADO Fabrizio, President of the Ecuadorian
Association of Psychiatry
[email protected]
DE VANE C. Lindsay, Department of Psychiatry &
Behavioral Sciences, Director, Laboratory of Drug
Disposition and Pharmacogenetics, Medical
University of South Carolina, USA
[email protected]
DOUKI Saı̈da, Chef de Service de
Psychiatrie, Hôpital Razi, 2010 La Manouba,
Tunis, Tunisia
[email protected]
EVSEGNEEV Roman, Head, Department of
Psychiatry, Byelorussian Medical Academy for
Postgraduate Education, President, Byelorussian
Psychiatric Association, Belarus
[email protected]
FALISSARD Bruno, Epidemiologist and
Psychiatrist, Paris, France
[email protected]
FERNANDEZ Alberto, Researcher, Neuroscience
Institute
[email protected]
FINK Max, M.D., Psychiatry and Neurology
Emeritus at Stony Brook University, Long Island,
St. James, NY 11780-0457, USA
mafi[email protected]
FLORES Julio, Adviser Psychiatrist, Central
Nervous System, Venezuela
ffl[email protected]
FRITZE Jürgen, Leitender Arzt,Verband der
privaten Krankenversicherung e.V. (German
Association of Private Health Insurers), 50968 Köln,
Germany
[email protected] ; [email protected]
FOUNTOULAKIS K.N., 3rd Department of
Psychiatry, Arisotle University of Thessaloniki,
55132 Aretsou Thessaloniki, Greece
[email protected]
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
[email protected]
GALLEGOS Rogelio, Mexican Health National
Service Representative, Mexico
[email protected]
GASTELUMENDI Eduardo, Director,
Neurosciences Institute ; Past-President of the
Peruvian Society of Psychiatry
[email protected]
GASZNER Peter, Országos Pszichiátriai És
Neurológiai Intézet, 1021 Budapest, Hungary
[email protected]
GAVIRIA Silvia
[email protected]
GERARD Alain, Psychiatrist, Paris, France
[email protected]
GINNARI ANTICH Guillermo, President,
Venezuelan Society of Psychiatry, Caracas
[email protected]
GODARD Nathalie, Child Psychiatrist, Director
of a private institution, Garches, France
GONZALEZ Celso, Psychiatrist Researcher,
University General Hospital
[email protected]
GOODWIN Frederick, 5712 Warwick Place,
Chevy Chase, MD 20815, USA
[email protected]
GORWOOD Philip, Paris, France
[email protected]
GRIGORIEVA Elena A, Head of the Department of
Psychiatry, Yaroslavl Medical Academy, Yaroslavl,
150000, Russia
[email protected]
GU Niufan, Shanghai Mental Health Center,
Shanghai, 200030
[email protected]
GUREJE Oye, Head of the Department of
Psychiatry, University College Hospital, Ibadan,
Nigeria
[email protected]
HAEN Ekkehard, Psychiatrische Universitätsklinik,
Medizinische Einrichtungen des Bezirks Oberpfalz,
93053 Regensburg, Germany
[email protected]
HEALY David, North Wales Department of
Psychological Medicine, Cardiff University,
Hergest Unit, Ysbyty Gwynedd, Bangor, Wales
LL57 2PW, UK
[email protected]
S201
HE Yanling, Shanghai Mental Health Center,
Shanghai, 200030
[email protected] ; [email protected]
HEGERL Ulrich, Klinik und Poliklinik für
Psychiatrie und Psychotherapie, Universitätsklinikum
Leipzig, Johannisallee 20, D-04317 Leipzig, Germany
[email protected]
HINDMARCH Ian, HPRU Medical Research
Centre, University of Surrey, Guildford, Surrey
GU2 7XP, UK
[email protected]
HÖSCHL 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.
[email protected]
HWANG Tae-Yeon, Director, WHO Collaborating
Center for Psychosocial Rehabilitation and
Community Mental Health, Yongin Mental Hospital,
Korea
[email protected] ; [email protected]
IRMANSYAH, Psychiatrist, Department of
Psychiatry, Faculty of Medicine, University of
Indonesia, Jakarta 10430, Indonesia
[email protected]
ISACSSON Goran, Karolinska Institute, Huddinge
University Hospital, S-141 86 Stockholm, Sweden
[email protected]
ISMAYILOV Nadir, Azerbaijan Medical University,
Baku
[email protected]
IVANOV Michail, Head of the Department
of Psychopharmacotherapy of the Bekhterev Psychoneurological Institute, St-Petersburg 192019, Russia
[email protected]
IVONOVIC Fernando, Head of Bipolar Disorders
Unit, Chile University
[email protected]
JAKOVLEVIC Miro, Department of Psychiatry,
School of Medicine, University of Zagreb,
Zagreb – Rebro, Croatia
[email protected]
JIANG Kaida, Shanghai Mental Health Center,
Shanghai, 200030
[email protected]
KANBA Shigenobu, Department of
Neuropsychiatry, Kyushu University, Fukuoka,
812-8582, Japan
[email protected]
KASAKOVTSEV Boris, Deputy Head of the section
of legislative regulation of specialized medical care,
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CINP Antidepressant Task Force 2007
Ministry of Public Health and Social Development,
Moscow, Russia
[email protected]
KASPER Siegfried, Department of General
Psychiatry, University of Vienna,
A-1090 Vienna, Austria
[email protected]
KATON Wayne J., M.D., Vice Chair of the
Department of Psychiatry and Behavioral Sciences,
University of Washington, WA 98195, USA
[email protected]
KECK Paul E., Jr., Department of Psychiatry,
University of Cincinnati College of Medicine,
Cincinnati, OH 45267-0559, USA
[email protected]
KENNEDY Sidney H, University Health Network,
Toronto, Ontario M5G 2C4, Canada.
[email protected]
Christian KLESSE, Uniklinik für Psychiatrie und
Psychosomatik, 79104 Freiburg, Germany
[email protected]
KOSEL Markus, Klinik für Psychiatrie,
Uniklinikum, 53105 Bonn, Germany
[email protected]
KRAMMLING Franz-Georg, BKK LV Bayern, 81476
München, Germany
[email protected]
KRASNOV Valery, Director of the Moscow Research
Institute of Psychiatry 107076 Moscow, Russia
[email protected], [email protected]
KUPFER David J., University of Pittsburgh Western
Psychiatric Institute and Clinic, Pittsburgh,
Pennsylvania 15261, USA
[email protected]
KUTCHER, Stan Dalhousie University
Department of Psychiatry 5909 Veterans Memorial
Lane 9th Floor, AJLB Halifax, Nova Scotia B3H 2E2,
Canada
[email protected]
LAM Raymond W., Division of Clinical
Neuroscience, Department of Psychiatry, University
of BC, Vancouver, BC, Canada
[email protected]
LANDER Hugo, President, Argentinean Society of
Psychiatrists
[email protected]
LANDOWSKI Jerzy, Chief, Clinic of Psychiatric
and Neurotic Disorders, Department of Psychiatry,
Medical University of Gdańsk, 80-211 Gdańsk, Poland
[email protected]
LAPREA Isabel, Child and Adolescent Psychiatrist,
UCV
[email protected]
LEE Min-Soo, Department of Psychiatry, Korea
University College of Medicine, Seoul, 136-705 Korea
[email protected]
LEPINE Jean-Pierre, Hôpital Fernand Widal,
Assistance Publique, Hôpitaux de Paris, INSERM U
705, 75475 Paris, France
[email protected]
LEVINA Nelly, Chief of the All-Russian Society of
disabled mentally ill and their relatives ‘ New
Choices ’, Moscow 107076, Russia
[email protected]
LI Lingjiang, Director of the Mental Health Institute,
Xiangya Medical School, Central South University,
Changsha, Hunan 410011
[email protected]
LOPEZ-IBOR Juan José, Clinica López Ibor, E-28035
Madrid, Spain
[email protected]
MA Hong, Institute of Mental Health, Peking
University, Beijing 100083
[email protected]
MACIAS Nestor, Board Member, Venezuelan
Society of Psychiatry
[email protected], [email protected]
MAGZUMOVA Shakhnoza, Uzbekistan
[email protected]
MAJ Mario, Director of the Institute of Psychiatry,
University of Naples, 80138 Napoli, Italy
[email protected]
MALYAROV Sergiy, Head of the Liaison and
Research Department Kiev City Psychiatric Hospital
#2, Kiev 02660, Ukraine
[email protected] or [email protected]
MANJI Husseini K., Director, Mood and Anxiety
Disorders Program, Chief, Laboratory of Molecular
Pathophysiology, NIMH, Porter Neuroscience
Research Center, Bethesda, MD 20892, USA
[email protected]
MARTINEZ Danilo, Coordinator, Postgraduate
Psychiatry Training Program, Military Hospital
[email protected] ; [email protected]
MARTINY Klaus, Psychiatric Research Unit,
Hilleroed Hospital, Hilleroed, 3400, Denmark
[email protected]
MAZZARELLA Xiorela, Caracas Psychiatric
Hospital, Head Unit No. 3, Caracas, Venezuela
[email protected] ;
[email protected]
MELLA Cesar, Vice-President, Latin American
Psychiatric Association
[email protected]
MILLET Bruno, Adult Psychiatry of Rennes
Centre Hospitalier Guillaume Regnier
CINP Antidepressant Task Force 2007
108, avenue du Général Leclerc BP 226,
35011 Rennes Cedex, France
[email protected]
MINHAS Fareed, Head, Institute of Psychiatry,
Rawalpindi General Hospital, Rawalpindi, Pakistan
[email protected]
MÖLLER Hans-Jürgen, Chairman of the Psychiatric
Hospital of the University Munich, 80336 München,
Germany
[email protected]
MONTAÑO Everth, President, Bolivian Society of
Psychiatry
[email protected]
MOSOLOV Sergey, Head of the Department of
Therapy of Mental Disorders, Moscow Research
Institute of Psychiatry, Moscow 107076, Russia
[email protected]
MOUSSAOUI Driss, Faculté de Médecine de
Casablanca, Centre Psychiatrique Universitaire Ibn
Rushd, Casablanca, Moprocco
[email protected]
NETTER Petra, Department of Psychology,
University of Giessen, 35394 Giessen, Germany
[email protected]
NEZNANOV Nikolay, Director of the Bekhterev
Psychoneurological Institute, St-Petersburg 192019,
Russia
[email protected] ; [email protected]
NURMAGAMBETOVA Saltanat, Almaty,
Kazakhstan 480012
[email protected]
OKASHA Ahmed, Director of WHO Collaborating
Center, Institute of Psychiatry, Ain Shams University,
Kasr El Nil, Cairo – Egypt
[email protected]
ORAL Timuçin, Bakirköy Ruh ve Sinir Hastaliklari
Hastanesi, Bakirköy Istanbul, Turkey
[email protected]
PADILLA Franklin, Vice-President, Venezuelan
Society ; Director, Postgraduate Psychiatry Training
Programme, Caracas Psychiatric Hospital, Caracas,
Venezuela
[email protected]
PÁLOVÁ Eva, Department of Psychiatry,
University of P.J. Šafárik, 040 6 Košice, Slovakia
[email protected]
PARKER Gordon, School of Psychiatry, University
of New South Wales, Northwood, NSW 2066, Australia
[email protected]
PAUNOVIĆ Vladimir R., Institute of Psychiatry,
Clinical Center of Serbia, 11000 Belgrade, Serbia &
Montenegro
[email protected]
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PIDKORYTOV Valeriy, Chief, Department of
Clinical, Social and Child Psychiatry Institute of
Neurology, Psychiatry and Narcology AMS of
Ukraine, 61068 Kharkiv, Ukraine
[email protected]
POIRIER Marie-France, Hôpital Sainte-Anne, SHU/
U796, Paris, France
[email protected]
POUY Artigas, General Secretary, Latin American
Psychiatric Association
[email protected]
PULL Charles, Service de Neuropsychiatrie, Centre
Hospitalier de Luxembourg, 1210 Luxembourg
[email protected]
QUIRION Remi, Douglas Hospital Research
Centre, McGill University, Verdun, Quebec H4H 1R3,
Canada
[email protected]
REMSCHMIDT Helmuth, Philipp Universität,
Head, Klinik für Kinder- und Jugend Psychiatrie,
35033 Marburg, Germany
[email protected] ;
[email protected]
REQUENA Alvaro, Head, Department of
Psychiatry, Venezuelan Red Cross
[email protected]
RIECHER Anita, Psychiatrische Poliklinik,
Universitätsspital Basel, 4031 Basel, Switzerland
[email protected]
RIHMER Zoltan, Magyar Jakob, Tere, 6. 1/1, 1122
Budapest, Hungary
[email protected]
RIVERA TREJO Gerardo, President, El Salvador
Society of Psychiatry
[email protected]
ROBERT Philippe, CHU – Hôpital Pasteur, 06002
Nice Cedex, France
[email protected]
RODRIGUEZ Miguel Angel, Publication,
Venezuelan Society of Psychiatry
[email protected]
RODRIGUEZ Olga, Child and Adolescent Training
Postgraduate Program, Tachira Hospital
[email protected]
ROBERT Philippe, Nice, France
[email protected]
RUBIN Robert, Los Angeles, CA 90025-7821, USA
[email protected]
RUIZ Pedro, Vice Chair for Clinical Affairs,
Department of Psychiatry and Behavioral Sciences,
University of Texas-Houston Mental Sciences
Institute, Houston, TX 77030, USA
[email protected]
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CINP Antidepressant Task Force 2007
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
[email protected]
SALAZAR Gerardo Carmelo B, Department of
Neurosciences, Lucena United Doctors Hospital,
Manila, The Philippines
[email protected]
SALAZAR Ismael, Director of the Mental Health
Hospital Social Security
[email protected] ; [email protected]
SALETU Bernd, Section of Sleep Research
and Pharmacopsychiatry, Department of Psychiatry,
Medical University of Vienna, 1090 Vienna, Austria
[email protected]
SANCHEZ Carlos, Assistant, Latin American
Psychiatric Association
[email protected]
SCHLAEPFER Thomas E., Psychiatry & Mental
Hygiene, Department of Psychiatry, University
Hospital, Bonn 53105, Germany
[email protected]
SECHTER Daniel, Besançon, France
[email protected]
SEMKE Valentin, Director of the Institute of
Psychiatry of the Tomsk Scientific Centre, Siberian
Division of the Russian Academy of Medical Science,
Tomsk, Russia
[email protected]
SIMON Gregory, Group Health Cooperative of
Puget Sound, Centre for Health Studies. Seattle, WA
98101, USA
[email protected]
STEFFEN Sigrid, Vice-President, European
Federation of Associations of Families of Mentally Ill
People (EUFAMI), 5020 Salzburg, Austria
kus.steff[email protected]
STUPPÄCK Christoph, Universitätsklinik für
Psychiatrie 1, Christian-Doppler-Klinik, Salzburg,
5020 Salzburg, Austria
[email protected]
SULTANOV Agabek A., Gashumbekoğlu, Manager
of the chair of Psychiatry Medical University, Baku,
Azerbaijan
[email protected]
SUN Xueli, 7# Xiao Xue Road, Chengdu, Sichuan
610041
[email protected] ; [email protected]
TAN Chay-Hoon, Department of Psychological
Medicine, National University Hospital, Singapore
119074
[email protected]
TANG Siu-Wa, Chair of the Department of
Psychiatry University of Hong Kong
[email protected]
TEN Vladimir, Head, Department of Clinical
Psychology and Psychiatry Kyrgyz State Medical
Academy, Bishkek 720023, Kyrgyz Republic
[email protected]
THASE Michael E., University of Pittsburgh
Medical Center, Pittsburgh PA 15213-2593, USA
[email protected]
THIBAUT Florence, University Hospital Ch.
Nicolle, INSERM, Rouen, France
[email protected]
UDOMRATN Pichet, President, The Psychiatric
Association of Thailand (PAT), Department of
Psychiatry, Faculty of Medicine, Prince of
Songkla University, Hat Yai, Songkhla 90110,
Thailand
[email protected]
VAHIP Simavi, Affective Disorders Unit, Ege
University Department of Psychiatry Bornova-Izmir
TR-35100, Turkey
[email protected]
VAN PRAAG Herman M., Huize Berghorst, 7315
HD Apeldoorn, The Netherlands
[email protected]
VIETA PASCUAL Eduard, Director of Research,
Clinical Institute of Neuroscience, Director of
Bipolar Disorders Program, Hospital Clinic,
University of Barcelona, IDIBAPS, 08036 Barcelona,
Spain
[email protected]
WANG Liwei, Shanghai Mental Health Center,
Shanghai, 200030, P. R. China
[email protected]
WATANABE Yasuo, Department of
Pharmacology/Pharmacotherapy, Nihon
Pharmaceutical University, Saitama 362-0806,
Japan
[email protected] ; [email protected]
WIED Viktor D., Deputy Director of the Bekhterev
Psychoneurological Institute, St. Petersburg 192019,
Russia
[email protected]
WOOLEY Stéphanie, Présidente, Association
France Dépression, 4, rue Vigée Lebrun, 75 015
Paris, France
YAN Heqin, Director, Shanghai Mental Health
Centre, Shanghai
[email protected] ; [email protected]
YI Chengdong, Director General, Shanghai
Food and Drug Administration Bureau, Shanghai
[email protected]
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.
[email protected]
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
[email protected]
XIAO Zeping, Shanghai Mental Health Center,
Shanghai, 200030, P. R. China
[email protected]
XIE Bin, Shanghai Mental Health Center, Shanghai,
200030, P. R. China
[email protected]
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XU Yifeng, Shanghai Mental Health Center,
Shanghai, 200030, P.R. China
[email protected]
YU, Xin, Director of the Institute of Mental Health,
Peking University 100083, Beijing, P.R. China
[email protected]
ZHANG Li, Director, CDC on Mental Health,
Ministry of Health, Beijing, P.R. China
[email protected]
ZHANG Mingyuan, Shanghai Mental Health
Center, Shanghai, 200030, P.R. China
[email protected]
ZHOU Dongfeng, President, Chinese Psychiatry
Association
[email protected]
ZVARTAU Edvin, Vice-rector, St.-Petersburg State
Medical University, St. Petersburg, Russia
[email protected]
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=Alzheimer’s disease
ADH=antidiuretic hormone
ADHD=attention-deficit hyperactivity disorder
AHCPR=Agency for Health Care Policy and
Research
AIDS=acquired immune deficiency 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-benefit analysis
CBASP=Cognitive Behavioral Analysis System of
Psychotherapy
CBT=cognitive behavioral psychotherapy
CD=combined depression (MDD and RBD)
CGI-I=Clinical Global Impressions-Improvement
Score
CDRS-R=Children’s Depression Rating
Scale-Revised
CEA=cost-effectiveness analysis
CEAC=cost-effectiveness 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 fluid
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 für Psychiatrie,
Psychotherapie und Nervenheilkunde
DHEA=dehydroepiandrosterone
DLPFC=dorsolateral prefrontal cortex
DNRI=dopamine and noradrenaline reuptake
inhibitor
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CINP Antidepressant Task Force 2007
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=effect 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 immunodeficiency virus
HPA=hypothalamic pituitary adrenal
ICD=international classification of diseases
ICER=incremental cost-effectiveness 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
Affective Disorders and Schizophrenia
LIDO=Longitudinal Investigation of Depression
Outcomes
M1=blockade of cholinergic muscarinic receptors
MAI=monoamine oxidase A inhibition
MADRS=Montgomery–Åsberg 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 difference
MHRA=Medicines and Healthcare products
Regulatory Agency
MHRD=Mantel–Haenszel exposure time-adjusted
rate difference
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=modified 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 effects
N-TetraCA=tetracyclic antidepressant with
primary noradrenergic effects
OCD=obsessive compulsive disorder
OR=odds ratio
PD=Parkinson’s 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 effects
SP=substance P
SRI=serotonin reuptake inhibition
CINP Antidepressant Task Force 2007
SRS=serotonin reuptake stimulation
SSRI=selective serotonin reuptake inhibitor
TADS=Treatment for Adolescents with
Depression Study
SAD=seasonal affective 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 effects
S-TetraCA=tetracyclic antidepressant with
primary serotonergic effects
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
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