Psychotropic Agents: Part I: Antipsychotics and Antidepressants

746 Pages·1980·19.18 MB·English

by  J. Schmutz

Psychotropic Agents
Part I: Antipsychotics and
Antidepressants
Contributors
M. Ackenheil . G. Bartholini . H. J. Bein . W. F. M. van Bever· S. Bhanji
M. H. Bickel· U. Breyer-Pfaff· T. B. Cooper· A. Delini-Stula· R. Fog
Y. Givant . G. GogolAk . R. Hempel· R. Hess· T. M. Itil· W. Janke
P.AJ. Janssen· I. Jurna . M. Karobath . B. Kjellberg· N.S. Kline
H. Kreiskott· R. Kretzschmar· M. H. Lader· G. Langer· E. Lehr
F. Leuschner· K. G. Lloyd· N. Matussek· P. L. Mobley· I. MSZ)l1er Nielsen
B. Mliller-Oerlinghausen· I. Munkvad· W. Neumann· C. W. Picard
A. Randrup . J. Roubicek . J. Scheel-Kruger· E. Schi0rring . J. Schmutz
M. Schou· C. Soldatos· F. G. Sulman· F. Sulser· 1. Teschendorf
P. Thomann· F. 1. Zeelen
Editors
F. Hoffmeister· G. Stille
Springer-Verlag Berlin Heidelberg New York 1980
Professor Dr. F. HOFFMEISTER
Bayer AG, Institut fUr Pharmakologie, Aprather Weg 18a, D-5600 Wuppertal1
Professor Dr. G. STILLE
Institut fUr Arzneimittel des Bundesgesundheitsamtes,
StauffenbergstraBe 13, D-1000 Berlin 30
With 82 Figures
ISBN-13: 978-3-642-67540-9 e-ISBN-13: 978-3-642-67538-6
DOl: 10.1007/978-3-642-67538-6
Library of Congress Cataloging in Publication Data. Main entry under title: Antipsychotics and antidepressants.
(Handbook of experimental pharmacology; v. 55fI) (Psychotropic agents; pt. 1) Includes bibliographies and indexes.
I. Tranquilizing drugs - Physiological effect. 2. Antidepressants - Physiological effects. I. Ackenheil, M. II. Stille, GUnther,
1923-. III. Hoffmeister, Friedrich. IV. Series. V. Series: Handbook of experimental pharmacology; v. 55/1. QP905.H3
vol. 55/1, pt. 1 [RM333] 615'.1s [615'.7882] 80-12230.
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© by Springer-Verlag Berlin Heidelberg 1980
Softcover reprint of the hardcover 1st edition 1980
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
Handbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 55/1
Editorial Board
G.V. R. Born, Cambridge . A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi . E. G. Erdos· V. Erspamer . U. S. von Euler· W. S. Feldberg
G. B. Koelle· O. Krayer· M. Rocha e Silva· J. R. Vane· P. G. Waser
Preface
The volumes on "psychotropic substances" in the Handbook of Experimental Phar
macology series clearly show that the classical concept of this discipline has become
too narrow in recent years.
For instance, what substances are psychotropic is determined not by the criteria
of the animal trial, i.e. by experimental pharmacology, but by their action on the psy
che, which in the final analysis is only accessible to us in man. Psychotropic substances
force experimental pharmacology (and thus also this Handbook) outside its tradition
allimits, which have essentially depended on animal studies.
The antipsychotics and antidepressants were not discovered in animal ex
periments, but by chance (or more precisely, by clinical empiricism). Experienced psy
chiatrists trained in the observation of patients recognised the efficacy of drugs, the
beneficial effect of which nobody had dreamed of before: DELAY and DENICKER in the
case of chlorpormazine, KLINE in the case of the monoamine oxidase inhibitors and
KUHN in the case of imipramine. It was only after these discoveries that the pharma
cologists developed experimental models of the psychoses in animal experiments.
However, even today we still do not know with certainty which of the effects shown
in animals is relevant for the clinical effect despite the vast abundance of individual
investigations. For many years, this uncertainty led to the testing of antipsychotics
(e.g. of the neuroleptic type) in models which actually produced the undesired effects.
For example, if one uses "catatonia" as selection criterion in animals, one will repeat
edly develop antipsychotics with potentially strong extrapyramidal side effects.
Clozapine opened up a new dimension: this is an antipsychotic without significant
extrapyramidal side effects. For other reasons, the hopes aroused by this preparation
have unfortunately not been fulfilled.
Although an abundance of preparations is available for treatment of psychoses to
day, advances appear to be stagnating. The first volume of "psychotropic substances"
reflects the present situation. The material gathered conveys an impression of the
great activity in this field in recent years. However, it also shows that we have made
hardly any real progress in fundamental knowledge in the last 20 years. Cooperation
between different disciplines in the field of psychoactive agents is exemplary, as is also
illustrated by the present volume. Research into the neuropharmacology, neurophys
iology and neurochemistry of these preparations shows that they are not actually psy
choactive agents, but in fact neuropharmacologically active agents. Their neuronal ef
fects are reflected in psychic manifestations. The only real psychoactive drug is the
placebo: it acts directly on the psyche.
As is legitimate for psychoactive agents, the clinicians, psychologists and be
havioral researchers also have their say in this volume. It is clearly shown that to a
VI Preface
greater extent than in other areas, in this field of drug research the observation of
patients and test subjects constitutes the basis for new hypotheses which can only be
tested secondarily in animals. The question may be asked as to why one needs the ani
mal trial at all. However, it hardly likely to be disputed that brain function is more
accessible both for the neurophysiologist and for the neurochemist in animals than
in patients, in whom many investigations cannot be performed for ethical reasons.
The path to knowledge is thus different from that in other groups of drugs.
With the large number of disciplines involved, overlapping standpoints cannot be
avoided. Indeed, it is perhaps desirable to find a certain phenomenon interpreted by
pharmacologists, and then by neurophysiologists, or even by behavioral researchers.
It is to be hoped that we have succeeded in reviewing research in the field of antip
sychotics with an appropriate selection of authors and choice of topics. We also were
concerned to do justice to the personal experience of the individual researchers. We
hope that the volume will provide a bridge leading from the past into the future of
psychosis pharmacotherapy.
Berlin, August 1980 G. STILLE
List of Contributors
Dr. M. ACKENHEIL, Nervenklinik der UniversiHit Munchen, Psychiatrische Klinik
und Poliklinik, NuBbaumstraBe 7, D-8000 Munchen 2
Professor Dr. G. BARTHOLINI, Research and Development Department, Synthelabo
L.E.R.S., 58 Rue de la Glaciere, F-75013 Paris
Professor Dr. H.J. BEIN, MeisenstraBe 11, CH-4104 Oberwil
Dr. W.F.M. VAN BEVER, Janssen Pharmaceutica Research Laboratories,
B-2340 Beerse
Dr. S. BHANJI, Postgraduate Medical Institute, University of Exeter, Barrack Road,
GB-Exeter, EX2 5 DW
Professor Dr. M. H. BICKEL, Pharmakologisches Institut, UniversiHit Bern, Fried
buhlstraBe 49, CH-3000 Bern
Professor Dr. Dr. U. BREYER-PFAFF, Institut fUr Toxikologie der Universitat,
WilhelmstraBe 56, D-7400 Tubingen
Dr. T. B. COOPER, Rockland Research Institute, Office of Mental Health, Orangeburg,
NY 10962/USA
Dr. A. DELINI-STULA, c/o Ciba-Geigy AG, Postfach, CH-4002 Basel
Dr. R. FOG, Centrallaboratoriet, Sct. Hans Mental Hospital, Dept. E,
DK-4000 Roskilde
Dr. Y. GIVANT, The Hebrew University of Jerusalem, Department of Applied
Pharmacology, Bioclimatology Unit, P.O.B. 12065, IL-Jerusalem 25432
Professor. Dr. G. GOGOLAK, Department of Neuropharmacology, Brain Research
Institute, University of Vienna, Wahringer Str. 13 a, A-1090 Wien
R. HEMPEL, Laboratorium fUr Pharmakologie und Toxikologie, Francoper Str. 66b,
D-2104 Hamburg 92
Professor Dr. R. HESS, Ciba-Geigy AG, Postfach, CH-4002 Basel
Professor Dr. T. M. ITIL, HZI Research Center, 150 White Plains Road, Tarrytown,
NY 10591/USA
Professor Dr. W. JANKE, Psychologisches Institut der Universitat Dusseldorf,
Lehrstuhl fUr Psychologie II, UniversitatsstraBe 1, D-4000 Dusseldorf
Dr. P. A. J. JANSSEN, Janssen Pharmaceutica Research Laboratories, B-2340 Beerse
VIII List of Contributors
Professor Dr. I. JURNA, Institut flir Pharmakologie und Toxikologie der UniversiHit
des Saarlandes, D-6650 Homburg
Doz. Dr. M. KAROBATH, Psychiatrische Universitatsklinik, Lazarettgasse 14,
A-1097 Wien
Dr. B. KJELLBERG, Centrallaboratoriet, Sct. Hans Mental Hospital, Dept. E,
DK-4000 Roskilde
Professor Dr. N. S. KLINE, Rockland Research Institute, Office of Mental Health,
Orangeburg, NY 10962jUSA
Dr. H. KREISKOTI, Knoll AG, BASF, Sparte Pharma, Biologische Forschung und
Entwicklung, Postfach 210805, D-6700 Ludwigshafen
Professor Dr. R. KRETZSCHMAR, Biologische Forschung und Entwicklung, Sparte
Pharma, BASF AG, D-6700 Ludwigshafen
Dr. M. H. LADER, Institute of Psychiatry, University of London, De Crespigny Park,
Denmark Hill, GB-London SE5 8AF
Dr. G. LANGER, Psychiatrische UniversiHitsklinik, Lazarettgasse 14, A-1097 Wien
Priv. Doz. Dr. E. LEHR, Pharmakologisches Laboratorium D der Firma C. H. Boeh
ringer Sohn, Postfach 200, D-6507 Inge1heim
Professor Dr. F. LEUSCHNER, Laboratorium flir Pharmakologie und Toxikologie,
Francoper StraBe 66b, D-2104 Hamburg 92
Dr. K.G. LLOYD, Synthelabo-L.E.R.S., 58 Rue de la Glacier-e, F-75013 Paris
Professor Dr. N. MATUSSEK, Psychiatrische Klinik und Poliklinik, NuBbaumstraBe 7,
D-8000 Miinchen 2
Dr. P.L. MOBLEY, Vanderbilt University School of Medicine, Tennessee Neuro
psychiatric Institute, 5101 Murfreesboro Road, Nashville, TN 37217jUSA
Dr. 1. M0LLER NIELSEN, Himmelbjergvej 125, Laven, DK-8600 Silkeborg
Professor Dr. B. MULLER-OERLINGHAUSEN, Psychiatrische und Neurologische Klinik
und Poliklinik, NuBbaumallee 36, D-1000 Berlin 19
Dr. 1. MUNKVAD, Centrallaboratoriet, Sct. Hans Mental Hospital, Dept. E,
DK-4000 Roskilde
W. NEUMANN, Laboratorium flir Pharmakologieund Toxikologie, Francoper Str. 66 b,
D-2104 Hamburg 92
Dr. C. W. PICARD, Wander Ltd., Forschungsinstitut, Postfach 2747, CH-3001 Bern
Dr. A. RANDRUP, Centrallaboratoriet, Sct. Hans Mental Hospital, Dept. E,
DK-4000 Roskilde
Professor Dr. J. ROUBICEK, HauptstraBe 34, CH-4102 Binningen-Basal
Dr. J. SCHEEL-KRUGER, Centrallaboratoriet, Sct. Hans Mental Hospital, Dept. E,
DK-4000 Roskilde
List of Contributors IX
Dr. E. SCHl0RRING, Centrallaboratoriet, Set. Hans Mental Hospital, Dept. E,
DK-4000 Roskilde
Dr. J. SCHMUTZ, Wander Ltd., Forschungsinstitut, Postfach 2747, CH-3001 Bern
Professor Dr. M. SCHOU, Psychopharmacology Research Unit, Aarhus University
Institute of Psychiatry, DK-8240 Risskov
Professor Dr. C. SOLDATOS, New York Medical College, Department of Psychiatry,
Division of Biological Psychiatry, 150 White Plains Road, Tarrytown,
NY 10591jUSA
Professor Dr. F. G. SULMAN, The Hebrew University of Jerusalem, Department of
Applied Pharmacology, Bioclimatology Unit, P.O.B. 12065, IL-Jerusalem 25432
Professor Dr. F. SULSER, Vanderbilt University, School of Medicine, Tennessee
Neuropsychiatric Institute, 1501 Murfreesboro Road, Nashville, TN 37217jUSA
Dr. J. TESCHENDORF, Biologische Forschung und Entwicklung, Sparte Pharma,
BASF AG, D-6700 Ludwigshafen
Dr. P. THOMANN, Ciba-Geigy Ltd., Postfach, CH-4002 Basel
Dr. F.J. ZEELEN, Organon Scientific Development Group, P.O. Box 20, NL-Oss
Contents
Antipsychotics: Chemistry (Structure and Effectiveness)
CHAPTER 1
Tricyclic Neuroleptics: Structure-Activity Relationships. J. SCHMUTZ and
C.W. PICARD
A. Criteria for Neuroleptic Activity . . . . . . . . . 3
B. Chemical Classification of the Tricyclic Neuroleptics 4
C. Molecular Conformation 4
D. Stereospecificity of Action . . 9
E. Nature of the Basic Side Chain 12
F. Aromatic Substitution 15
G. Nature of the Central Ring . . 18
H. Non-Cataleptogenic Neuroleptics 19
I. Conclusion 20
References 20
CHAPTER 2
Butyrophenones and Diphenylbutylpiperidines. P. A. J. JANSSEN and
W. F. M. VAN BEVER. With 3 Figures
A. Introduction 27
B. Structure-Activity Relationships 28
I. Chemistry . . . 28
II. Pharmacology .. 31
III. Clinical Aspects 35
1. Butyrophenones 35
2. Diphenylbutylpiperidines 36
C. Conclusion 37
References 37
CHAPTER 3
Centrally Acting Rauwolfia Alkaloids. H. J. BEIN
A. Introduction and History ............ . 43
B. Biologic Fate and Mechanisms of Action of Reserpine 44
XII Contents
C. Central Actions of Reserpine . . . . . . . . 46
I. Effect of Reserpine on Behavior . . . . . 46
II. Effect of Reserpine on the Motor System 48
III. Effects of Reserpine on Bioelectric Signals 50
D. Comparison with Other Neuroleptics . . . . 51
I. General Clinical Effects . . . . . . . . 51
II. Alleged Depression-Inducing Effect of Neuroleptics 52
References 52
CHAPTER 4
Behavioral Pharmacology of Antipsychotics. H. KREISKOTT
A. Introduction 59
B. Basic Aspects and Considerations in Regard to Investigations 59
C. Action of Antipsychotics on Spontaneous Behavior 61
I. Pattern of Action on Behavior 62
II. Locomotion ...... . 62
III. Immobilization . . . . . . 64
IV. Muscle Relaxation and Ptosis 65
V. Excitation Conditions 66
VI. Aggression 67
VII. Reproduction 69
VIII. Maternal Behavior 69
IX. Feeding Behavior . 69
X. Prey Catching 70
XI. Memory and Learning 70
D. Actions of Antipsychotics on Induced Behavioral Patterns 71
I. Stimulant-Induced Excitation Patterns 71
II. Tryptamine-Induced Convulsion 73
III. Withdrawal Syndrome 74
IV. Topical Brain Stimulation 74
V. Self-Stimulation 75
VI. Rotational Model . . . . 75
VII. Brain Lesions ..... 76
E. Side-Effects Following Acute and Chronic Administration and Tolerance
Phenomena 76
F. Conclusions 80
References 81
CHAPTER 5
Testing Antipsychotic Drug Effects with Operant Behavioral Techniques.
E.LEHR
A. General Advantages of Operant Procedures for the Demonstration of
Behavioral Drug Effects . . . . . . . . . . . . . . . . . . . . . . 89