Table Of ContentAntidepressants
Contemporary Neuroscience
Antidepressants: New Pharmacological Strategies, edited by Phil Skolnick, 1997
Molecular Mechanisms of Dementia, edited by Wilma Wasco
and Rudolph E. Tanzi, 1997
Neurotransmitter Transporters: Structure, Function, and Regulation,
edited by Maarten E. A. Reith, 1997
Motor Activity and Movement Disorders: Research Issues and Applications,
edited by Paul R. Sanberg, Klaus-Peter Ossenkopp, and Martin Kavaliers, 1996
Neurotherapeutics: Emerging Strategies, edited by Linda M. Pullan
and Jitendra Patel, 1996
Neuron-Glia Interrelations During Phylogeny: II. Plasticity
and Regeneration, edited by Antonia Vernadakis
and Betty I. Roots, 1995
Neuron-Glia Interrelations During Phylogeny: 1. Phylogeny
and Ontogeny of Glial Cells, edited by Antonia Vernadakis
and Betty I. Roots, 1995
The Biology of Neuropeptide Y and Related Peptides, edited
by William F. Colmers and Claes Wahlestedt, 1993
Psychoactive Drugs: Tolerance and Sensitization, edited
by A. J. Goudie and M. W. Emmett-Oglesby, 1989
Experimental Psychopharmacology, edited by Andrew J. Greenshaw
and Colin T. Dourish, 1987
Developmental Neurobiology of the Autonomic Nervous System, edited
by Phyllis M. Gootman, 1986
The Auditory Midbrain, edited by Lindsay Aitkin, 1985
Neurobiology of the Trace Elements, edited by Ivor E. Dreosti
and Richard M. Smith
Vol. 1: Trace Element Neurobiology and Deficiencies, 1983
Vol. 2: Neurotoxicology and Neuropharmacology, 1983
Antidepressants
New Pharmacological Strategies
Edited by
Phil Skolnick
National Institutes of Health, Bethesda, MD
Springer Science+Business Media, LLC
© 1997 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 1997
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Library of Congress Cataloging in Publication Data
Antidepressants: new pharmacological strategies/edited by Phil Skolnick.
p. cm.--{Contemporary neuroscience)
Includes bibliographical references and index.
ISBN 978-1-61737-048-9 ISBN 978-1-59259-474-0 (eBook)
DOI 10.1007/978-1-59259-474-0
I. Antidepressants. l. Skolnick, Phil. II. Series.
[DNLM: I. Antidepressive agents. QV 77.5 A62897 1997]
RM332.A579 1997
616.85'27061--dc21
DNLM/DLC
for Library of Congress 97-16900
CIP
Preface
Forty years ago, the first reports appeared describing the antidepressant properties
of iproniazid and imipramine. Equal measures of serendipity and astute clinical obser
vation led to the discovery of these "first-generation" antidepressants. Thus, the anti
depressant properties of iproniazid (an analog of isoniazid) were first recognized in
patients being treated for tuberculosis, while imipramine was synthesized in an attempt
to improve on the therapeutic properties of another tricyclic molecule, chlorpromazine.
The demonstration that these first-generation antidepressants affect the disposition
and metabolism of biogenic amines led to a revolution in biological psychiatry, result
ing in new theories and testable hypotheses about the origins of affective disorders.
These early studies led in the synthesis of new compounds in an attempt to improve the
therapeutic qualities of first-generation agents. The fruits of these efforts include a
group of "second-generation" antidepressants, such as the serotonin-specific reuptake
inhibitors (SSRls) and reversible inhibitors of monoamine oxidase (RIMAs). A "third
generation" of antidepressants is now available, possessing both serotonin and nor
epinephrine reuptake blocking properties, but apparently devoid of many other phar
macological properties common to tricyclic antidepressants. The principal advantage
of these second- and third-generation agents is an improved side-effect profile com
pared to first-generation antidepressants. These newer agents are clearly superior to
placebo, but SSRls (for example) appear to be no more efficacious antidepressants
than imipramine and, though still controversial, may be less effective than traditional
therapies in severely depressed (melancholic) patients (1-4).
In order to achieve a clear improvement over current antidepressants, two major
therapeutic objectives must be met. First, a reduction in the rate ofnonresponders from
the -30% reported in most carefully controlled studies. Second, a reduction (and in the
ideal, elimination) of the "therapeutic lag" encountered with traditional antidepres
sants. This therapeutic lag remains one of the great enigmas of antidepressant therapy.
Aside from the obvious benefit to the patient, therapies that reduce the latency between
onset of treatment and significant remission of symptoms will undoubtedly result in a
better understanding of the molecular mechanisms of antidepressant action.
Despite the indisputable evidence that most clinically effective antidepressants per
turb monoaminergic pathways, there has been a resurgence of interest in the mecha
nisms responsible for antidepressant action. This interest stems from the inability of
monoaminergic mechanisms to provide a heuristic framework capable of adequately
explaining the significant proportion of patients who do not respond to current antide
pressants and the time required for a therapeutic response. The very strategy of target
ing compounds to block·biogenic uptake and metabolism may result in the two most
v
vi Preface
significant limitations common to currently used antidepressants. Thus, we may be
compelled to focus on alternative mechanisms and strategies in order to overcome these
limitations. This objective is both worthy and timely, since it has been estimated that
the current cost of depression (from absenteeism, lost productivity, lost earnings, treat
ment, and rehabilitation) exceeds $40 billion in the United States. Moreover, the mar
ket for second-generation antidepressants (e.g., SSRIs such as sertraline, paroxetine,
and fluoxetine) has been estimated at $4 billion. The objective of this book is to bring
together novel concepts of antidepressant therapy that are either not grounded on bio
genic amine-based hypotheses or attempt to exploit new insights from the laboratory to
improve current, biogenic amine-based therapies.
REFERENCES
1. Danish University Antidepressant Group (1986) Cita1opram: clinical effect profile in com
parison with clomipramine. A controlled multicenter study. Psychopharmacol. 90,
131-138.
2. Danish University Antidepressant Group (1990) Paroxetine: a selective serotonin reuptake
inhibitor showing better tolerance, but weaker efficacy than clomipramine in a controlled
multicenter study. J. Affect. Dis. 18,289-299.
3. Roose, S. P., Glassman, A. H., Attia, E., and Woodring, S. (1994) Comparative efficacy of
selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Amer.
J. Psychiat. 151, 1735-1739.
4. Kasper, S. and Heiden, A. (1995) Do SSRls differ in their antidepressant efficacy. Human
Psychopharmacol. 10, S 163-S 172.
Phil Skolnick
Contents
Preface ................................................................................................................... v
List of Contributors ............................................................................................ ix
1 Strategies to Optimize the Antidepressant Action of Selective
Serotonin Reuptake Inhibitors
Luz Romero, Josep Ma Casanovas, Ildefons Hervas, Roser Cortes,
and Francesc Artigas ...................................................................................... 1
2 Antidepressant Properties of Specific Serotonin-Noradrenaline
Reuptake Inhibitors
Michael Briley and Chantal Moret ................................................................ 35
3 5-HT-Moduline: Novel Therapeutic Strategyfor Antidepressant Action
Gilles Fillion, Laure Seguin, Olivier Massot, Jean-Claude
Rousselle, Marie-Paule Fillion, Isabelle Cloez-Tayarani,
Brigitte Grimaldi, Jean-Christophe Seznec,
and Nicole Prudhomme ............................................................................... 53
4 Reversible Inhibitors of Monoamine Oxidase A (RIMAs):
Where Can We Go from Here?
Vivette Glover .................................................................................................... 69
5 Calcium Channel Antagonists in Mood Disorders
Olgierd Pucilowski ........................................................................................... 81
6 Functional NMDA Antagonists: A New Class of Antidepressant
Agents
Ramon Trullas ................................................................................................. 103
7 Is an Adaptation of NMDA Receptors an Obligatory Step
in Antidepressant Action?
Nuo-Yu Huang, Richard T. Layer, and Phil Skolnick .............................. 125
8 NMDA Receptors and Affective Disorders
Ian A. Paul ........................................................................................................ 145
9 The Potential Contribution of Sigma Receptors to Antidepressant
Actions
Brian E. Leonard .............................................................................................. 159
10 A Role for CREB in Antidepressant Action
Ronald S. Duman, Masashi Nibuya, and Vidita A. Vaidya ................... 173
vii
Contents
VIll
11 Antidepressants: Beyond the Synapse
S. Paul Rossby and Fridolin Sulser ............................................................. 195
12 Animal Models to Detect Antidepressants: Are New Strategies
Necessary to Detect New Agents?
Paul Willner and Mariusz Papp .................................................................. 213
13 Molecular Strategies to Novel Antidepressant Discovery
Steven M. Paul, Xin Wu, Yanbin Liang, and Edward 1. Ginns .............. 235
Index .................................................................................................................. 251
Contributors
Department of Neurochemistry, Instituto de Investigaciones
FRANCESC ARTIGAS •
Biomedicas de Barcelona, Spain
Centre de Recherche Pierre Fabre, France
MICHAEL BRILEY •
Department of Neurochemistry, Instituto
JOSEP Ma CASANOVAS •
de Investigaciones Biomedicas de Barcelona, Spain
Unite de Pharmacologie Neuro-Immuno-Endocrinienne,
ISABELLE CLOEZ-TAYARANI •
Institut Pasteur, Paris Cedex, France
Department of Neurochemistry, Instituto de Investigaciones
ROSER CORTES •
Biomedicas de Barcelona, Spain
RONALD S. DUMAN • Laboratory of Molecular Psychiatry and Pharmacology,
Yale University School of Medicine, Connecticut Mental Health Center,
New Haven, CT
Unite de Pharmacologie Neuro-Immuno-Endocrinienne, Institut
GILLES FILllON •
Pasteur, Paris Cedex, France
Unite de Pharmacologie Neuro-Immuno-Endocrinienne,
MARIE-PAULE FILllON •
Institut Pasteur, Paris Cedex, France
EDWARD I. GINNS • Clinical Neuroscience Branch, NIMH, National Institute
of Health, Bethesda, MD
Department of Paediatrics, Queen Charlotte's and Chelsea
VIVETTE GLOVER •
Hospital, London, UK
Unite de Pharmacoiogie Neuro-Immuno-Endocrinienne, Institut
BRIGITTE GRIMALDI •
Pasteur, Paris Cedex, France
Department of Neurochemistry, Instituto de Investigaciones
ILDEFONS HERVAs •
Biomedicas de Barcelona, Spain
Laboratory of Neuroscience, National Institutes of Health,
Nuo-Yu HUANG •
Bethesda, MD
Laboratory of Neuroscience, National Institutes of Health,
RICHARD T. LAYER •
Bethesda, MD
BRIAN E. LEONARD • Pharmacology Department, University College,
Galway, Ireland
Lilly Research Laboratories, Eli Lilly and Company,
YANBIN LIANG •
Indianapolis, IN
Unite de Pharmacologie Neuro-Immuno-Endocrinienne, Institut
OUVIER MASSOT •
Pasteur, Paris Cedex, France
Centre de Recherche Pierre Fabre, France
CHANTAL MORET •
ix
x Contributors
Laboratory of Molecular Psychiatry and Pharmacology,
MASASHI NIBUYA •
Yale University School of Medicine, Connecticut Mental Health Center,
New Haven, CT
Institute of Pharmacology, Polish Academy of Sciences,
MARIUSZ PAPP •
Kwakow, Poland
IAN A. PAUL • Laboratory ofNeurobehavioral Pharmacology and Immunology,
Division of Neurobiology and Behavior Research, Department of Psychiatry,
University of Mississippi Medical Center, Jackson, MS
Lilly Research Laboratories, Eli Lilly and Company,
STEVEN M. PAUL •
Indianapolis, IN; Clinical Neuroscience Branch, NIMH, National Institute
of Health, Bethesda, MD
Unite de Pharmacologie Neuro-Immuno-Endocrinienne,
NICOLE PRUDHOMME •
Institut Pasteur, Paris Cedex, France
Department of Psychiatry, Temple University Hospital,
OLGIERD PUCILOWSKI •
Philadelphia, PA
Department of Neurochemistry, Instituto de Investigaciones
Luz ROMERO •
Biomedicas de Barcelona, Spain
Department of Psychiatry, Vanderbilt University School
S. PAUL ROSSBY •
of Medicine, Nashville, TN
Unite de Pharmacologie Neuro-Immuno-Endocrinienne,
JEAN-CLAUDE ROUSSELLE •
Institut Pasteur, Paris Cedex, France
Unite de Pharmacologie Neuro-Immuno-Endocrinienne, Institut
LAURE SEGUIN •
Pi lris Cedex, France
Unite de Pharmacologie Neuro-Immuno-Endocrinienne,
JEAN-CHRISTOPHE SEZNEC •
Institut Pasteur, Paris Cedex, France
Laboratory of Neuroscience, National Institutes of Health,
PHIL SKOLNICK •
Bethesda, MD
Departments of Psychiatry and Pharmacology, Vanderbilt
FRIDOLIN SULSER •
University School of Medicine, Nashville, TN
Neurobiology Unit, Institut d'Investigaciones Biomediques
RAMON TRULLAS •
de Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain
VIDITA A. V AIDYA • Laboratory of Molecular Psychiatry and Pharmacology,
Yale University School of Medicine, Connecticut Mental Health Center,
New Haven, CT
Department of Psychology, University of Wales, Swansea, UK
PAUL WILLNER •
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
XIN Wu •
