Clinical Pharmacology in Psychiatry: From Molecular Studies to Clinical Reality

332 Pages·1989·13.398 MB·English

by  C. Braestrup, P. H. Andersen (auth.), Prof. Dr. Svein G. Dahl, Prof. Dr. Lars F. Gram (eds.)

Psychopharmacology Series 7
Clinical Pharmacology
in Psychiatry
From Molecular Studies to Clinical Reality
Editors
s.
G. Dahl L. F. Gram
With 76 Figures
Springer-Verlag Berlin Heidelberg New York
London Paris Tokyo Hong Kong
Prof. Dr. SVEING. DAHL
Professor of Pharmacology, Department of Pharmacology,
Institute of Medical Biology, University ofTroms0 School of Medicine,
9001 Troms0, Norway
Prof. Dr. LARS F. GRAM
Professor of Clinical Pharmacology, Department of Clinical Pharmacology,
School of Medicine, Odense University, 5000 Odense C, Denmark
Vols. 1 and 2 of this series appeared under the titel "Psychopharmacology Supplementum"
ISBN-13 :978-3-642-74432-7 e-ISBN-13:978-3-642-74430-3
DOl: 10.1007/978-3-642-74430-3
Library of Congress Cataloging-in-Publication Data. Clinical pharmacology in psychiatrie: from
molecular studies to clinical reality/editors, S.G.Dahl, L.F.Gram. p. em. - (Psychopharmacology
series; 7) Papers presented at the 5th International Meeting on Clinical Pharmacology in Psychiatry, held
June 26-30,1988 at the University of Troms0, Norway. Includes index. ISBN-13:978-3-642-74432-7
1. Psychopharmacology -Congresses. I. Dahl,S.G. (Svein G.), II. Gram, Lars F. III. International
Meeting on Clinical Pharmacology in Psychiatry (5th: 1988: University of Troms0) IV. Series. [DNLM:
1. Psychotropic Drugs - pharmacology - congresses. 2. Psychotropic Drugs - therapeutic use -
congresses. W1 PS773J v. 7/QV 77C6405 1988] RM300.C555 1989 615'.788-dc20 DNLM/DLC for
Library of Congress.
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Preface
This volume collects the invited lectures and some selected contributions
presented at the 5th International Meeting on Clinical Pharmacology in
Psychiatry, which was held 26-30 June 1988 at the University of Troms0,
Norway. The 24 h of daylight at the northernmost university in the world al
lowed for long, pleasant and productive sessions. The title of the conference as
well as a number of the topics covered represent a continuation of four
previous conferences, the first held in Chicago in 1979 and organized by the
late Earl U sdin and colleagues.
The earlier conferences have been documented in Clinical Pharmacology
in Psychiatry, edited by E. Usdin (Elsevier, New York, 1981), Clinical
Pharmacology in Psychiatry. Neuroleptic and Antidepressant Research, edited
by E. Usdin, S. G. Dahl, L. F. Gram and o. Lingjrerde (Macmillan Publishers
Ltd., London, 1981), Clinical Pharmacology in Psychiatry. Bridging the
Experimental-Therapeutic Gap, edited by LF. Gram, E. Usdin, S.G. Dahl,
P. Kragh-Sorensen, P. L. Morselli and F. Sjoqvist (Macmillan Publishers
Ltd., London, 1983), and Clinical Pharmacology in Psychiatry. Selectivity
in Psychotropic Drug Action - Promises or Problems? edited by S. G. Dahl,
L.F. Gram, S.M. Paul and W.Z. Potter (Psychopharmacology Series 3,
Springer, Heidelberg, 1987).
It seems to us that the key to the success of the IMCPP series, and the main
reason for its continuation, lies in its interdisciplinary approach in discussing
both clinical and basic research. The present volume contains a session on dif
ferent strategies in the development of new psychotropic drugs, from
molecular to clinical studies. The clinical advantages of the new generation of
receptor-selective drugs in psychopharmacology was the main topic of the 4th
International Meeting on Clinical Pharmacology in Psychiatry, and this
theme is updated in one of the sessions presented in this volume. Clinical
pharmacokinetics and the rationale for therapeutic plasma level monitoring of
neuroleptic and antidepressant drugs have been important topics at this and
all previous conferences. This volume extends the field with a session on
pharmacogenetics and presents the first comprehensive analysis of the role
of the sparteine-debrisoquine drug oxidation polymorphism in psycho
pharmacology, with clinical implications.
It is our hope that the scientific presentations in this volume may stimulate
further research and development towards improved efficacy and safety of
psychotropic drugs.
Troms0, Odense, 1989 SVEIN G. DAHL· LARS F. GRAM
Acknowledgements
The 5th International Meeting on Clinical Pharmacology in Psychiatry would
not have been possible without the generous financial support received from a
number of institutions and pharmaceutical companies, which we gratefully
acknowledge:
The University of Troms0, The Norwegian Research Council for Science and
the Humanities, Astra, Beecham, Ciba-Geigy, Delagrange, Delalande,
Duphar, Eli ,Lilly, Essex, Fabre, Ferrosan Denmark, Ferrosan Sweden, I.C.I.,
I.R.I.S., Janssen, Lundbeck Foundation, Merrell Dow, Novo, Organon,
Parke-Davis, Pfizer, Rhone-Poulenc, Roche, Roussel Uc1af, Sanofi, Schering,
Upjohn.
The members of the organizing committee for the Fifth International Meeting
on Clinical Pharmacology in Psychiatry were:
Svein G. Dahl, University ofTroms0, Norway.
Lars F. Gram, Odense University, Odense, Denmark.
Stuart A. Montgomery, St Mary's Hospital, London, UK.
The members of the Scientific Advisory Committee were:
Luc P. Balant, Universite de Geneve, Geneva, Switzerland.
LeifBertilsson, Huddinge University Hospital, Huddinge, Sweden.
Herbert Y. Meltzer, Case Western Reserve University, Cleveland, Ohio,
USA.
Steven M. Paul, National Institute of Mental Health, Maryland, USA.
William Z. Potter, National Institute of Mental Health, Maryland, USA.
Pierre Simon, Societe Sanofi Recherche, Paris, France.
Edouard Zarifian, Centre Psychiatrique Esquirol, Caen, France.
We would also like to thank Eldbj0rg Heimstad and Gustav Wik, Troms0,
and the other staff members at the Department of Pharmacology, University
of Troms0 and at Asgard Psychiatric Hospital, who helped with the local
arrangements during the conference.
Contents
Strategies in Psychotropic Drug Innovation
Receptor Subtypes and Endogenous Ligands: Rational Tools in the
Search for Psychotropic Drugs?
C. BRAESTRUP and P.H. ANDERSEN. With 1 Figure. ... . . . . . . . . . . .. . . . 3
Histamine H3 Receptors in the Brain: Potent and Selective Ligands.
J. C. SCHWARTZ, J. M. ARRANG, M. GARBARG, and H. POLLARD.
With 3 Figures ................................................ 10
Targets for Neurotransmitter Receptor Research Using PET Scan:
The Neuroleptic Binding Site.
J. C. BARON, J. L. MARTINOT, H. CAMBON, J. P. BOULENGER,
M.F. POIRIER, V. CAILLARD,J. BLIN,J.D. HURET, C. LOC'H,
and B. MAZIERE. With 4 Figures .................................. 20
The Potential of Positron-Emission Tomography for Pharmacokinetic
and Pharmacodynamic Studies ofNeuroleptics.
L. FARDE, F.-A. WIESEL, L. NILSSON, and G. SEDVALL. With 2 Figures.. 32
Neurotransmitter Interactions as a Target of Drug Action.
W.Z. POTTER, J.K. HSIAO, and H. AGREN. With 1 Figure. . . .. . .. . . . .. 40
E-1 0-Hydroxynortriptyline: Effects and Disposition of a
Potential Novel Antidepressant.
L. BERTILSSON, M.-L. DAHL-PuuSTINEN, and C. NORDIN. With 3 Figures. 52
Molecular Graphics of Antidepressant Drugs and Metabolites.
S. G. DAHL, 0. EDVARDSEN, and E. HEIMSTAD. With 5 Figures. . . . . . . .. 60
Negative Symptoms in Schizophrenia: A Target for
New Drug Development.
H. Y. MELTZER and J. ZUREICK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 68
x Contents
Clinical Significance of Receptor-Selective Drugs
Clinical Effects of Selective Serotonin Reuptake Inhibitors.
P. BECR ...................................................... 81
Effects ofSerotonergic Agonists on Neuroendocrine Responses of
Rhesus Monkeys and Patients with Depression and Anxiety Disorders.
G. R. HENINGER, D. S. CHARNEY, L.H. PRICE, P. DELGADO, S. WOODS,
and W. GooDMAN ............................................. 94
Theoretical and Practical Implications of a Controlled Trial of an
1X2-Adrenoceptor Antagonist in the Treatment of Depression.
S. A. MONTGOMERY ............................................ 105
Selective Dopamine Dl and D2 Receptor Antagonists.
J. HYTTEL, J. ARNT, and M. VAN DEN BERGHE. With 3 Figures .......... 109
Animal Pharmacology ofRac1opride, a Selective Dopamine D2
Antagonist.
H. HALL, S. O. OGREN, C. KOHLER, and O. MAGNUSSON. With 5 Figures . 123
Benzodiazepine Receptor Subtypes and Their Possible Clinical
Significance.
W. SmGHART .................................................. 131
Pharmacogenetics in Psychopharmacology
Genetic Polymorphisms of Drug-Metabolizing Enzymes:
Molecular Mechanisms.
U. A. MEYER, U. ZANGER, R. SKODA, and D. M. GRANT. With 1 Figure .. 141
Genetic Polymorphism in Drug Oxidation.
W. KALOW .......•.....•..•....••............................ 148
The Use of Human Liver Banks in Pharmacogenetic Research.
C. VON BAHR, F. P. GUENGERICH, G. MOVIN, and C. NORDIN.
With 4 Figures ................................................ 163
Inhibitors of the Microsomal Oxidation of Psychotropic Drugs:
Selectivity and Clinical Significance.
L. F. GRAM and K. BR0SEN. With 3 Figures . . . . . . . . . . . . . . . . . . . . . . . .. 172
Pharmacogenetics of Antidepressants.
F. SJOQVIST. With 9 Figures ...................................... 181
Contents XI
Pharmacokinetic and Clinical Significance of Genetic Variability
in Psychotropic Drug Metabolism.
K. BR0SEN and L. F. GRAM. With 5 Figures ......................... 192
Inhibition of Desipramine 2-Hydroxylation by Quinidine and Quinine
in Rapid and Slow Debrisoquine Hydroxylators.
E. SPINA, E. STEINER, E. DUMONT, and R. DAHLQVIST. With 1 Figure .... 201
Debrisoquine Oxidation Phenotype in Psychiatric Patients.
J. BENiTEZ, B. PINAS, M.A. GARCiA, C. MARTiNEZ, A. LLERENA,
and J. CoBALEDA. With 2 Figures .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 206
Role of Pharmacogenetics in Drug Development.
L. P. BALANT and A. E. BALANT-GoRGIA ........................... 211
Clinical Significance of Pharmacokinetic Variability
Clinical Implications of the Pharmacokinetics of
Tricyclic Antidepressants.
J.C. NELSON, C. MAZURE, and P.I. JATLOW ........................ 219
Detection of Populations at Risk Using Drug Monitoring Data.
A.E. BALANT-GoRGIA, M. GEx-FABRY, and L.P. BALANT ............. 228
Hydroxy Metabolites of Tricyclic Antidepressants:
Evaluation of Relative Cardiotoxicity.
B. G. POLLOCK and J. M. PEREL. With 1 Figure ...................... 232
Therapeutic Drug Monitoring of Tricyclic Antidepressants:
A Means of Avoiding Toxicity.
S. H. PREsKORN ................................................ 237
Neuroleptic Drug Levels in Erythrocytes and in Plasma:
Implications for Therapeutic Drug Monitoring.
D. L. GARVER. With 3 Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 244
Active Metabolites ofNeuroleptics in Plasma and CSF:
Implications for Therapeutic Drug Monitoring.
E. MARTENSSON and G. NYBERG. With 4 Figures .................... 257
Hydroxyhaloperidol and Clinical Outcome in Schizophrenia.
A. C. ALTAMURA, M. MAURI, R. CAVALLARO, M. G. REGAZZETTI,
and S. R. BAREGGI. With 3 Figures ........... . . . . . . . . . . . . . . . . . . . .. 263
XII Contents
Plasma Level Monitoring for Maintenance Neuroleptic Therapy.
S.R. MARDER, T. VANPUTTEN, and M. ARAVAGIRI. With 6 Figures ..... 269
Perphenazine Serum Levels in Patients on Standard Doses.
F. HAFFNER. With 1 Figure ...................................... 280
Dose-Finding Problems with Psychotropic Drugs
From Animal Experiments to Clinical Dosing: Some Aspects of
Preclinical Development of Antidepressants.
A. DELINI-STULA. With 1 Figure .................................. 287
Evaluation of Clinical and Biological Parameters in Healthy Volunteers:
More than Pharmacokinetics and Side Effects?
A.J. PUECH, P. DANJOU, D. WAROT, G. BENSIMON, and L. LACOMBLEZ 296
Dose Finding and Serum Concentrations ofNeuroleptics in the
Treatment of Schizophrenic Patients.
F.-A. WIESEL, G. ALFREDSSON, and E. JONSSON. With 4 Figures ........ 303
Post-Marketing Surveillance of Psychotropic Drugs.
R. BRINKMANN. With 1 Figure ................................... 311
List of Participants ............... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 317
Subject Index ................................................. 325
List of Contributors
You will find the addresses at the beginning of the respective contribution
Agren,H. 40 Garver, D.L. 244
Alfredsson, G. 303 Gex-Fabry, M. 228
Altamura, A.c. 263 Goodman, W. 94
Andersen, P .H. 3 Gram, L.F. 172, 192
Aravagiri, M. 269 Grant, D.M. 141
Amt,J. 109 Guengerich, F.P. 163
Arrang, J.M. 10 Haffner, F. 280
Balant, L.P.· 211,228 Hall, H. 123
Balant-Gorgia, A.E. 211, 228 Heimstad, E. 60
Bareggi, S.R. 263 Heninger, G.R. 94
Baron, J. C. 20 Hsiao, J.K 40
Bech, P. 81 Huret, J.D. 20
Benitez, J. 206 Hyttel, J. 109
Bensimon, G. 296 Jadow, P.I. 219
Bertilsson, L. 52 Jonsson, E. 303
Blin, J. 20 lCalow, W. 148
Boulenger, J.P. 20 lCohler, C. 123
Braestrup, C. 3 Lacomblez, L. 296
Brinkmann, R. 311 Llerena, A. 206
Bresen,lC. 172,192 Loc'h, C. 20
Caillard, V. 20 Magnusson, O. 123
Cambon, H. 20 Marder, S.R. 269
Cavallaro, R. 263 Martensson, E. 257
Charney, D.S. 94 Martinez, C. 206
Cobaleda, J. 206 Martinot, J.L. 20
Dahl, S.G. 60 Mauri, M. 263
Dahl-Puustinen, M.-L. 52 Maziere, B. 20
Dahlqvist, R. 201 Mazure, C. 219
Danjou, P. 296 Meltzer, H.Y. 68
Delgado, P. 94 Meyer, U.A. 141
Delini-Stula, A. 287 Montgomery, S.A. 105
Dumont, E. 201 Movin, G. 163
Edvardsen, 0. 60 Nelson, J.C. 219
Farde, L. 32 Nilsson, L. 32
Garbarg, M. 10 Nordin, C. 52,163
Garcia, M.A. 206 Nyberg, G. 257