Selective Serotonin Reuptake Inhibitors (SSRIs): Past, Present and Future

237 Pages·1999·1.49 MB·english

by  S. Clare Stanford

6
NEUROSCIENCE INTELLIGENCE UNIT
S. Clare Stanford
Selective Serotonin
Reuptake Inhibitors
(SSRIs)
Past, Present and Future
R.G. LANDES
C O M P A N Y
N
EUROSCIENCE
I
NTELLIGENCE
U 6
NIT
Selective Serotonin Reuptake
Inhibitors (SSRIs)
Past, Present and Future
S. Clare Stanford, D. Phil.
Department of Pharmacology
University College London
London, England, U.K.
R.G. LANDES
COMPANY
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EUROSCIENCE NTELLIGENCE NIT
Selective Serotonin Reuptake Inhibitors (SSRIs)
Past, Present and Future
R.G. LANDES COMPANY
Austin, Texas, U.S.A.
Copyright ©1999 R.G. Landes Company
All rights reserved.
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ISBN: 1-57059-649-2
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Library of Congress Cataloging-in-Publication Data
Selective serototin reuptake inhibitors (SSRIs): past, present and future / [edited by]
S. Clare Stanford
p. cm. -- (Neuroscience intelligence unit)
Includes bibliographical references and index
ISBN 1-57059-649-2(alk. paper)
1. Serotonin uptake inhibitors. 2. Serotonin uptake inhibitors --
Side effects I. Stanford, S. Clare. . II. Series.
[DNLM: 1. Serotonin Uptake Inhibitors--therapeutic use.
2. Serotonin Uptake Inhibitors--pharmacology. 3. Serotonin Uptake Inhibitors --
metabolism. 4.Depressive Disorder--drug therapy.
QVRM129 S774 1999
616.85'27061--dc21
DNLM/DLC
for Library of Congress
CONTENTS
1. The Discovery Of The SSRIs: A Milestone In
Neuropsychopharmacology and Rational
Drug Design...............................................................................................1
Arvid Carlsson
Disentangling the Riddle of Dual Amine Transport ............................. 1
The Tricyclic Antidepressants and the Amine Uptake Theory............. 2
5-HT Enters the Scene............................................................................. 3
Development of the First SSRI: Zimelidine .......................................... 3
Fluoxetine and Other SSRIs.................................................................... 4
Conclusion............................................................................................... 5
2. Clinical Pharmacokinetics of SSRIs.........................................................9
Pierre Baumann, Chin B Eap and Pierre Voirol
Metabolism and Pharmacokinetic Properties of SSRIs......................... 9
Drug Blood Concentrations and Clinical Response............................ 17
Pharmacokinetic Interactions............................................................... 17
3. SSRIs In Depression: Distinctive Actions?.............................................27
Julie Newman and Andrew A. Nierenberg
Comparison with Other Antidepressants ............................................ 27
Atypical Antidepressants....................................................................... 28
Within-Group Comparison of SSRIs................................................... 30
Criteria for Selection of Preferred Treatment...................................... 37
Conclusion............................................................................................. 42
4. SSRIs and Patient Groups with Specific Treatment Problems.............47
John Hughes, Brian Lunn and John O’Brien
Children and Adolescents..................................................................... 47
Bulimia Nervosa.................................................................................... 50
Anorexia Nervosa.................................................................................. 51
Premenstrual Syndromes...................................................................... 51
Impulse-Control Disorders................................................................... 52
The Elderly............................................................................................. 53
Cost-Effectiveness of SSRIs................................................................... 57
5. SSRIs, Drug Withdrawal and Abuse: Problem or Treatment?.............65
C. Heather Ashton and Allan H. Young
The SSRI Withdrawal (Discontinuation) Syndrome .......................... 65
SSRIs in Alcohol and Drug Abuse........................................................ 69
Abuse of SSRIs....................................................................................... 74
6. SSRIs and Sexual Function.....................................................................81
Peter A. Sargent and Guy M. Goodwin
Introduction........................................................................................... 81
The Neurobiology of Sexual Function................................................. 81
Pharmacology of Sexual Function in Men and Women..................... 87
Management of Sexual Dysfunction .................................................... 89
Conclusion............................................................................................. 90
7. SSRIs and Suicide....................................................................................95
John A. Henry and Carol A. Rivas
The Relationship Between Depression and Suicide............................. 95
Evidence Linking 5-HT Dysfunction and Suicide............................... 96
Comparison of Consequences of Overdose of SSRIs
versus Other Antidepressant Agents ................................................ 97
Appraisal of Evidence for Prevention, versus Aggravation,
of Suicide by SSRIs; Comparison with Other Antidepressant
Agents............................................................................................... 105
Conclusion........................................................................................... 106
8. Mechanism of Action of Different Classes of Antidepressants:
Evidence from 5-HT Challenge Studies...............................................111
Ian M. Anderson and Christopher Mortimore
Preclinical Background ....................................................................... 111
5-HT Challenge Tests in Humans...................................................... 112
Effect of Antidepressant Treatment on Responses to 5-HT
Challenge Tests................................................................................ 115
Conclusion........................................................................................... 119
9. SSRI-Induced Functional Changes in Serotonergic
Neurons..................................................................................................127
Ildefonso Hervás, Andreu Raurich, Luz Romero,
Roser Cortés and Francesc Artigas
Inhibition of 5-HT Reuptake, Serotonergic Cell Firing
and 5-HT Release ............................................................................ 127
Regional Selectivity of the Inhibitory Action of SSRIs
on 5-HT Release.............................................................................. 128
Functional Changes in Serotonergic Neurons Induced
by the Chronic Administration of SSRIs........................................ 131
Potentiation of the Effects of SSRIs by 5-HT Autoreceptor
Antagonists: Experimental Studies................................................. 134
SSRIs Plus Pindolol Combinations: Clinical Studies......................... 135
Mechanism of Action of Pindolol ...................................................... 136
Future Perspectives.............................................................................. 138
10. SSRI-Induced Changes in Catecholaminergic Transmission.............147
Clare Stanford
SSRIs and Extracellular Catecholamines............................................ 147
Monoamine Transporters................................................................... 148
Substrate Selectivity and Inhibitor Sensitivity of Cloned
Transporters .................................................................................... 150
Substrate Selectivity and Inhibitor Sensitivity of Native
Transporters .................................................................................... 152
The Selectivity of SSRIs as Inhibitors of 5-HT Uptake...................... 152
Modulation of Catecholamine Release by SSRIs............................... 153
Chronic Treatments............................................................................ 164
Conclusion........................................................................................... 164
11. The Mechanism of Action of SSRIs: A New Hypothesis.....................171
Lori L. Davis, Kimberly A. Yonkers, Madhukar Trivedi,
GeraldL.Kramer and Frederick Petty
Serotonergic Neurotransmission........................................................ 172
Preclinical Models of Depression and Relationship
with 5-HT ........................................................................................ 173
Learned Helplessness and 5-HT......................................................... 173
Comparison of SSRIs and Other Antidepressant Agents.................. 175
SSRI Spectrum of Therapeutic Action ............................................... 176
Monoamine and Brain Homeostasis: A New Hypothesis
in Understanding Psychiatric Disorders........................................ 177
Biological Abnormalities in 5-HT and Theories
of Depression................................................................................... 177
A Role for 5-HT in Depression........................................................... 178
Functional Brain Imaging Studies of the Serotonergic
System in Depression...................................................................... 179
Premenstrual Dysphoric Disorder and 5-HT.................................... 180
A Novel Neurotransmitter Balance and Equilibrium Theory
of Mental Illness.............................................................................. 181
12. SSRIs: Where Now, Where Next?.........................................................187
David J. Heal and Sharon C. Cheetham
Analysis of the Impact of the SSRIs on the Antidepressants
Market.............................................................................................. 187
An Evaluation of the SSRIs Against the Criteria for the ‘Ideal’
Antidepressant Drug....................................................................... 194
The Use of SSRIs to Treat Conditions Other Than
Depression....................................................................................... 201
New Strategies for Addressing Key Unmet Needs
of Current Antidepressant Drug Therapy...................................... 203
SSRIs: Current and Future Status....................................................... 209
Index.......................................................................................................219
EDITOR
S. Clare Stanford, D. Phil.
Department of Pharmacology
University College London
London, England, U.K.
Chapter 10
CONTRIBUTORS
Ian M. Anderson M.B.B.S., M.R.C.P., Sharon C. Cheetham, Ph.D.
M.R.C.Psych., M.D. Knoll Pharmaceuticals
University of Manchester Research and Development
Department of Psychiatry Nottingham, England, U.K.
Manchester Royal Infirmary Chapter 12
Manchester, England,U.K.
Chapter 8 Roser Cortés, Ph.D.
Department of Neurochemistry
Instituto de Investigaciones
Francesc Artigas, Ph.D.
Biomédicas de Barcelona
Rosseló 161
CSIC (IDIBAPS)
Barcelona, Spain
Barcelona,Spain
Chapter 9
Chapter 9
C. Heather Ashton, D.M. F.R.C.P.
Lori L. Davis, M.D.
Department of Psychiatry
Department of Veterans Affairs
University of Newcastle-upon-Tyne
and
Royal Victoria Infirmary
Department of Psychiatry
Newcastle-upon-Tyne, England, U.K.
University of Alabama
Chapter 5
Birmingham, Alabama, U.S.A.
Chapter 11
Pierre Baumann, Dr rer. nat.
Unité de Biochimie et
Psychopharmacologie Clinique Chin B Eap, Ph.D.
Département Universitaire de Unité de Biochimie et
Psychiatrie Adulte Psychopharmacologie Clinique
Prilly-Lausanne, Switzerland Département Universitaire
Chapter 2 de Psychiatrie Adulte
Prilly-Lausanne, Switzerland
Arvid Carlsson Ph.D., M.D. Chapter 2
Department of Pharmacology
University of Göteborg Guy Goodwin, D. Phil., FRCPsych.,
Göteborg, Sweden FRCPEdin.
Chapter 1 University Department of Psychiatry
Warneford Hospital
University of Oxford
Oxford, England, U.K.
Chapter 6
David J. Heal, Ph.D., D.Sc. Christopher Mortimore, MB., B.Chir.,
Knoll Pharmaceuticals M.R.C.Psych.
Research and Development University of Manchester
Nottingham, England, U.K. Department of Psychiatry
Chapter 12 Manchester Royal Infirmary
Manchester, England, U.K.
John A. Henry, F.R.C.P., Chapter 8
L.R.C.P.(Eng), M.B.B.S.
Academic Department of Accident
Julie Newman, M.D.
and Emergency Medicine
Depression and Clinical
Imperial College School of Medicine
Research Program
St. Mary’s Hospital
Massachusetts General Hospital
London, England, U.K.
Boston, Massachusetts, U.S.A.
Chapter 7
Chapter 3
Ildefonso Hervás, B.Sc.
Andrew A. Nierenberg, M.D.
Department of Neurochemistry
Depression and Clinical
Instituto de Investigaciones
Research Program
Biomédicas de Barcelona
Massachusetts General Hospital
CSIC (IDIBAPS)
Boston, Massachusetts, U.S.A.
Barcelona, Spain
Chapter 3
Chapter 9
John O’Brien, M.R.C.Psych., D.M.
John Hughes, M.B., B.S., M.R.C.Psych.
University of Newcastle-upon-Tyne
Department of Psychiatry
Newcastle General Hospital
University of Newcastle-upon-Tyne
Newcastle-upon-Tyne, England, U.K.
Royal Victoria Infirmary
Chapter 4
Newcastle-upon-Tyne, England, U.K.
Chapter 4
Frederick Petty, Ph.D., M.D.
Department of Veterans Affairs
Gerald L. Kramer
Medical Center
Department of Veterans Affairs
University of Texas
University of Texas
Southwestern Medical School
Southwestern Medical School
Dallas, Texas, U.S.A.
Dallas, Texas, U.S.A.
Chapter 11
Chapter 11
Andreu Raurich, B.Sc.
Brian Lunn, M.B., Ch.B., M.R.C.Psych.
Department of Neurochemistry
Department of Psychiatry
Instituto de Investigaciones
University of Newcastle-upon-Tyne
Biomédicas de Barcelona
Royal Victoria Infirmary
CSIC (IDIBAPS)
Newcastle-upon-Tyne, England, U.K.
Barcelona, Spain
Chapter 4
Chapter 9
Carol A. Rivas, M.Sc. Pierre Voirol, B.Pharm.
Academic Department of Accident Unité de Biochimie et
and Emergency Medicine Psychopharmacologie Clinique
Imperial College School of Medicine Département Universitaire
St. Mary’s Hospital de Psychiatrie Adulte
London, England, U.K. Prilly-Lausanne, Switzerland
Chapter 7 Chapter 2
Luz Romero, Ph.D. Kimberly A. Yonkers, M.D.
Department of Neurochemistry Yale University
Instituto de Investigaciones West Haven, Connecticut
Biomédicas de Barcelona Chapter 11
CSIC (IDIBAPS)
Barcelona, Spain Allan H.Young, M.B. Ch.B, Ph.D.,
Chapter 9 M.R.C.Psych.
Department of Psychiatry
Peter A. Sargent, M.R.C.Psych. University of Newcastle-upon-Tyne
University Department of Psychiatry Royal Victoria Infirmary
Warneford Hospital Newcastle-upon-Tyne, England, U.K.
University of Oxford Chapter 5
Oxford, England, U.K.
Chapter 6
Madhukar Trivedi, M.D.
University of Texas
Southwestern Medical Center
Dallas, Texas, U.S.A.
Chapter 11
PREFACE
As this book makes clear, the selective serotonin reuptake inhibitors
(SSRIs) have turned out to have an impressive impact on the treatment of de-
pression and one of them, fluoxetine, has even attained cult status. This success
is a testament to the progress that has been made since the chance discovery of
the antidepressant effects of imipramine in 1957. The attributes of the SSRIs
have already been covered in several reviews of specific aspects of their phar-
macology and clinical efficacy. Yet, so far, there has been no frank appraisal of
the SSRIs which has tackled clinical and preclinical research of both their thera-
peutic actions and side-effects. The aim of this book was to plug this gap in the
literature and draw on relevant material covering the whole spectrum of their
actions: the ‘cons’ as well as the ‘pros.’ Obviously, their predecessors, the tricy-
clic antidepressants, are still the major comparator but, whenever enough is
known, the latest pharmaceutical recruits have been drawn into the analysis
too.
As with all projects of this type, this book was faced with the problem
that the constituency of readers is as diverse as the chemistry of the SSRIs them-
selves, ranging from clinicians to basic scientists; from policy-makers and
fund-holders to the health professional working at the coal-face; from those
dedicated to drug discovery and development to those responsible for teaching
in this complicated area; from the accomplished expert to the bemused stu-
dent; from the pharmacologist to (possibly) the scientific correspondent. It is
obviously impossible to satisfy all these different groups but we have done out
best by ensuring that all chapters first cover background material before mov-
ing on to the more challenging specialist research. In so doing, this book has
tried, wherever feasible, to bridge the chasms between the laboratory, the clinic
and the lecture theater.
The book starts with a personal memoir of the discovery of the first SSRI,
zimelidine, contributed by Arvid Carlsson who has been involved with these
agents since the start of the story. The following seven chapters look at SSRIs
from the clinical point of view. First, Pierre Baumann and colleagues describe
the significance of their pharmacokinetics. In Chapter 2, they compare the dif-
ferent compounds and, in particular, highlight what is known about their me-
tabolism and how this explains some of their adverse drug interactions. Here,
and throughout the book, it is made clear that the SSRIs differ from the tricyclics
in a number of respects, not least because they are a chemically unrelated group
of compounds and so it cannot be assumed that they will all share the same
phamacological profile.
In Chapter 3, Julie Newman and Andrew Nierenberg compare the SSRIs
and tricyclics in all aspects of the treatment of depression and draw attention
to the expanding list of disorders for which these drugs are proving to have a