Clinical Pharmacology in Psychiatry: Strategies in Psychotropic Drug Development

278 Pages·1993·8.953 MB·English

by  S. G. Dahl, Ø. Edvardsen, I. Sylte (auth.), Prof. Dr. Lars F. Gram, Dr. Luc P. Balant, Prof. Herbert Y. Meltzer, Prof. Svein G. Dahl (eds.)

Psychopharmacology Series 10
Clinical Pharmacology
in Psychiatry
Strategies in Psychotropic Drug Development
Edited by
L.F. Gram L.P. Balant
H.Y. Meltzer S.G. Dahl
With 29 Figures
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Prof. Dr. LARS F. GRAM
Dept. of Clinical Pharmacology, Odense University,
Winsl0wparken 19, 5000 Odense C, Denmark
Dr. Luc P. BALANT
I.U.P.G., Unite de Recherche Clinique,
47, Rue du XXXI Decembre, 1207 Geneve, Switzerland
Prof. HERBERT Y. MELTZER
Department of Psychiatry, Case Western Res. Univ.,
2040 Abington Road, Cleveland, Ohio 44106, U.S.A.
Prof. SVEIN G. DAHL
Institute of Medicinal Biology, University of Troms0,
P.O. Box 977, 9037 Troms0, Norway
Vols. 1 and 2 of this series appeared under the title "Psychopharmacology Supplementum"
ISBN-13:978-3-642-78012-7 e-ISBN-13:978-3-642-78010-3
DOl: 10.1007/978-3-642-78010-3
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© Springer-Verlag Berlin Heidelberg 1993
Softcover reprint of the hardcover 1st edition 1993
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Preface
This book contains the papers from invited lecturers as well as selected
contributions presented at the 6th International Meeting on Clinical
Pharmacology in Psychiatry (I.M.C.P.P.) held in Geneva, Switzerland, 5-7
June 1991. At this meeting the basic theme of the previous meetings in this
series (Chicago 1979, Troms0 1980, Odense 1982, Bethesda 1985, Troms0
1988) was continued, namely, to bridge the gap between experimental
development and clinical reality in psychopharmacology.
After more than 25 years of intensive research in biological psychiatry,
basic understanding of the biological mechanisms underlying major psychiatric
diseases has advanced significantly but is still far from complete. Likewise,
the hypotheses underlying the development of new psychotropics have been
refined and produced a wide spectrum of novel, yet designed compounds.
The crucial condition for all progress in this field is reliable, informative
clinical testing of new compounds.
It is our hope that this book, as a continuation of the earlier publications
in this series, provides further evidence of the ongoing interaction between
preclinical and clinical scientists, who only together can assure progress in
this exciting area of research and clinical practice.
Odense, Geneva, L.F. GRAM, L.P. BALANT,
Cleveland, Troms0 H.Y. MELTZER, and S.G. DAHL
Acknowledgements
The 6th International Meeting on Clinical Pharmacology in Psychiatry
received generous support from a number of institutions and pharmaceutical
companies, which is gratefully acknowledged:
Institutions Universitaires de Merck, Sharp and Dohme, US
Psychiatrie de Geneve Merrell Dow, France and US
Department of Clinical Novo Nordisk, Denmark
Pharmacology, Odense University Organon, The Netherlands, Sweden
Abbot, US and Switzerland
Astra, Sweden Pfizer, US
Bristol-Myers Squibb, US Pierre Fabre, France
Ciba-Geigy, Denmark, Sweden and RhOne-Poulenc, France
Switzerland Roche, Denmark, Sweden and US
Delagrange, France Sandoz, Switzerland and US
Eli Lilly, US Sanofi, France
Glaxo, UK and US Schering, FRG
Janssen, Switzerland Schering-Plough, Sweden and US
Kabi Pharma, Sweden SmithKline Beecham, UK
Lundbeck, Denmark and Troponwerke, FRG
Switzerland Upjohn, UK and US
Merck, FRG Wyeth-Ayerst, US
The members of the Organizing Committee were:
A.E. Balant-Gorgia, Switzerland L.F. Gram, Denmark
L.P. Balant, Switzerland H.Y. Meltzer, US
S.G. Dahl, Norway
The members of the Scientific Advisory Committee were:
D.E. Casey, US W.Z. Potter, US
R. Fog, Denmark F.-A. Wiesel, Sweden
F. Holsboer, FRG E. Zarifian, France
E. Paykel, UK
We would like to thank:
Symporg SA, Congress Organizers, Geneva, Switzerland, and
Henrik Horneberg, Dep. of Clinical Pharmacology, Odense University,
for excellent assistance in preparing and arranging the conference.
Contents
Molecular Modeling of Neurotransmitter Receptors
S.G. DAHL, 0. EDVARDSEN, and I. SYLTE. With 2 Figures.. .. . . . . . .. . . 1
Structure-Function Analysis
of the Three p-Adrenergic Catecholamine Receptors
A.D. STROSBERG. With 2 Figures. . . . . . . . ... . . . . . . .... . . .. . . . . . .. .. 9
Serotonin Receptor Subtypes
P.R. HARTIG, N. ADHAM, J. ZGOMBICK, M. MACCHI, H.-T. KAo,
L. SCHECHTER, T. BRANCHEK, and R. WEINSHANK. With 1 Figure
and 4 Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 15
Developmental Regulation
of 5-HT2 and 5-HT Receptor Gene Expression in Rat Brain
1c
R.D. CIARANELLO, J. AIMI, R. DEAN, R. DESAI, S. GARLOW,
M.R. HELLER, D. MORILAK, and B.L. ROTH. With 2 Figures. .. . . . . . .. 26
Relevance of 5-HT Autoreceptors for Psychotropic Drug Action
M. GOTHERT and E. SCHLICKER. With 2 Figures and 2 Tables. . . . . . . . .. 38
Brain Serotonin Subsystem Complexity and Receptor Heterogeneity:
Therapeutic Potential of Selective Serotonin Agonists and Antagonists
K.P. LESCH, C.S. AULAKH, and D.L. MURPHY. With 1 Figure
and 3 Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 52
Serotonin Receptors and Antipsychotic Drug Action
H.Y. MELTZER. With 2 Tables. . . . .... . . . . . . .. . . . . . . . . . . . . .. .. . . .. 70
The Third Dopamine Receptor (D3): New Perspectives in Therapeutics
B. GIROS, P. SOKOLOFF, M.P. MARTRES, L. LANNFELT, M. ANDRlEux,
R. BESAN<;ON, C. PILON, M.L. BOUTHENET, E. SomL, and
J.C. SCHWARTZ. With 4 Figures and 1 Table. . . . . . . . . . . . . . . . . . . . . . .. 82
x Contents
PET Examination of Central D2 Dopamine Receptor Occupancy
in Relation to Extrapyramidal Syndromes in Patients
Being Treated with Neuroleptic Drugs
L. FARDE and A.-L. NORDSTROM. With 1 Figure and 1 Table...... .... 94
Dopaminergic and Serotonergic Aspects
of Acute Extrapyramidal Syndromes
D.E. CASEY. With 1 Table ....................................... 101
Methods to Facilitate Early Exploratory Testing
of Novel Psychopharmacologic Agents in Humans
W.Z. POTTER and R.P. IRWIN. With 1 Figure and 2 Tables ............ 111
Neuroleptics and Diagnostic Heterogeneity
in Relation to Drug Evaluation
F.-A. WIESEL .................................................. 124
Residual and Negative Symptoms in Treatment with Neuroleptics
J .M. KANE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 131
Clinical Dosing of Neuroleptics
R.J. BALDESSARINI, B.M. COHEN, and M.H. TEICHER. With 3 Tables ... 138
Diagnostic Heterogeneity in Relation to Drug Evaluation:
Antidepressants
E.S. PAYKEL. With 2 Tables ...................................... 149
Dose-Effect Relationships for Tricyclic Antidepressants:
The Basis for Rational Clinical Testing of New Antidepressants
L.F. GRAM. With 2 Figures and 3 Tables ........................... 163
Dose-Effect and Concentration-Effect Relationships
with New Antidepressants
S.H. PRESKORN. With 1 Figure and 8 Tables ........................ 174
Therapeutic Potentials of Recently Introduced Antidepressants
P. VESTERGAARD, L.F. GRAM, P. KRAGH-S0RENSEN, P. BECH, N. REISBY,
T.G. BOLWIG, and the DANISH UNIVERSITY ANTIDEPRESSANT GROUP.
With 6 Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 190
Role of Genetic Polymorphism in Psychopharmacology - An Update
K. BR0SEN, S.H. SINDRUP, E. SKJELBO, K.K. NIELSEN, P. N0RREMARK,
and L.F. GRAM. With 2 Figures and 3 Tables ....................... 199
Psychotropic Drug Metabolism and Clinical Monitoring
A.E. BALANT-GORGIA and L.P. BALANT . . . . . . . . . . . . . . . . . . . . . . . . . . .. 212
Contents XI
Disposition of the Neuroleptics Perphenazine,
Zuclopenthixol, and Haloperidol Co segregates
with Polymorphic Debrisoquine Hydroxylation
L. BERTILSSON, M.L. DAHL, B. EKQVIST, and A. LLERENA.
With 5 Figures and 1 Table. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 230
Phenotypes for Psychotropic Drug Metabolism in the Elderly
B.G. POLLOCK and 1.M. PEREL. With 3 Figures ...................... 238
Analysis of 935 Haloperidol Concentration Measurements
Obtained During Routine Drug Monitoring of 134 Patients
M. GEx-FABRY, A.E. BALANT-GORGIA, and L.P. BALANT.
With 4 Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 246
Power Analysis for Correlation of Plasma Level and Clinical Data
1.M. DAVIS and Z. WANG. With 5 Tables ........................... 253
Subject Index ...................................... . . . . . . . . . . .. 265
List of Contributors
You will find the addresses at the beginning of the respective contribution.
Adham, N. 15 Kao, H.-T. 15
Aimi, J. 26 Kragh-S(Ilrensen, P. 190
Andrieux, M. 82 Lannfelt, L. 82
Aulakh, C.S. 52 Lesch, K.P. 52
Balant, L.P. 212,246 Llerena, A. 230
Balant-Gorgia, A.E. 212, 246 Macchi, M. 15
Baldessarini, RJ. 138 Martres, M.P. 82
Bech, P. 190 Meltzer, H.Y. 70
Bertilsson, L. 230 Morilak, D. 26
Besan~n, R 82 Murphy, D.L. 52
Bolwig, T.G. 190 Nielsen, K.K. 199
Bouthenet, M.L. 82 Nordstrom, A.-L. 94
Branchek, T. 15 Paykel, E.S. 149
Bnllsen, K. 199 Perel, J .M. 238
Casey, D.E. 101 Pilon, C. 82
Ciaranello, RD. 26 Pollock, B.G. 238
Cohen, B.M. 138 Potter, W.Z. 111
Dahl, M.L. 230 Preskom, S.H. 174
Dahl, S.G. 1 Reisby, N. 190
Danish University Andidepressant Roth, B.L. 26
Group 190 Schechter, L. 15
Davis, J .M. 253 Schlicker, E. 38
Dean, R 26 Schwartz, J.C. 82
Desai, R 26 Sindrup, S.H. 199
Edvardsen, 0. 1 Skjelbo, E. 199
Ekqvist, B. 230 Sokoloff, P. 82
Farde, L. 94 Souil, E. 82
Garlow, S. 26 Strosberg, A.D. 9
Gex-Fabry, M. 246 Sylte, I. 1
Giros, B. 82 Teicher, M.H. 138
Gothert, M. 38 Vestergaard, P. 190
Gram, L.F. 163, 190, 199 Wang, Z. 253
Hartig, P.R 15 Weinshank, R 15
Heller, M.R. 26 Wiesel, F.-A. 124
Irwin, R.P. 111 Zgombick, J. 15
Kane. J.M. 131
Molecular Modeling of Neurotransmitter Receptors
and Ligands
S.G. DAHL, 0. EDVARDSEN, and 1. SYLTE
1 Molecular Structure of Neurotransmitter Receptors
The cloning and sequencing of neurotransmitter receptor molecules has
provided new insight into their classification and functioning as well as
structural information which may be potentially useful in drug development.
X-ray crystallographic diffraction techniques are the most widely used
experimental methods for determining three-dimensional protein structures.
However, while the amino acid sequences are known for a continuously
increasing number of neurotransmitter receptors, there have been no
reports on the three-dimensional crystal structure of any such receptor.
In the absence of any detailed experimental three-dimensional receptor
structure, we have developed models of the dopamine Dz receptor (Dahl
et al. 1991), the serotonin 5-HT receptor (Sylte et aI., to be published),
1A
and the 5-HTz receptor (Edvardsen et al. 1992), based on their amino acid
sequence. The models were constructed by computer graphics and mole
cular modeling techniques, and used to examine the mechanisms of drug
and neurotransmitter interactions with these receptors.
The dopamine Dz receptor model was first presented in 1989 (Dahl
et al. 1989a,b), at a time when this was the only dopamine receptor which
had been cloned. When the Dl and D3 receptor sequences were published in
1990, confirming some of the hypotheses behind the Dz receptor modeling,
the paper describing the model (Dahl et al. 1991) was submitted for pub
lication. The Dz receptor model was based on the structural similarities
within the superfamily of G protein coupled neurotransmitter receptors. As
indicated in Fig. 1, the peptide chains of all these receptor molecules have
seven putative membrane-spanning domains, and the various dopamine,
serotonin, a-adrenergic, ~-adrenergic, and muscarinic acetylcholine receptors
have several conserved amino acid residues in the putative membrane
spanning domains. Site-directed mutagenesis experiments have suggested
that aspartic residues in and near transmembrane segments 2 and 3 are
required for ligand binding and signal transduction in dopamine Dz (Neve
et al. 1991), ~z-adrenergic (Strader et al. 1988, 1989b; Fraser et al. 1988),
Institute of Medical Biology, University of Troms0, 9037 Troms0, Norway