Neuro-Psychopharmacology. Proceedings of the 11th Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Vienna, July 9–14, 1978

676 Pages·1979·49.165 MB·English

by  B. Saletu, P. Berner and L. Hollister (Eds.)

NEURO-PSYCHOPHARMACOLOGY
Proceedings of the 11th Congress of the Collegium
Internationale Neuro-Psychopharmacologicum
Vienna, July 9-14, 1978
Editors:
B. SALETU P. BERNER
Vienna, Austria Vienna, Austria
L. HOLLISTER
PaloAllo, USA
PERGAMON PRESS
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Copyright ©1979 Collegium Internationale
Neuro-Psychopharmacologicum
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First edition 1979
British Library Cataloguing in Publication Data
Collegium Internationale Neuro-
Psychopharmacologicum. Congress, lllh,
Vienna, 1978
Neuro-psychopharmacology.
1. Neuropsychopharmacology
I. Title II. Saletu, B 111. Berner, P
IV. Hollister, Leo L
615'.78 RM315 79-40552
ISBN 0-08-023089-X
in order to make this volume available as economically
and as rapidly as possible the authors' typescripts have
been reproduced in their original forms. This method
unfortunately has its typographical limitations but it is
hoped that they in no way distract the reader.
Printed and bound in Great Britain by
William Clowes (Beccles) Limited, Beccles and London
C. I. N. P. COMMITTEES
EXECUTIVE COMMITTEE
President L. HOLLISTER, Palo Alto, U.S.A.
Past President P. DENIKER, Paris, France
President-Elect A. CARLSSON, Göteborg, Sweden
Vice-Presidents M. LADER, London, England
H. VAN PRAGG, Utrecht, The Netherlands
Secretary J. ANGST, Zurich, Switzerland
Treasurer P. JANSSEN, Beerse, Belgium
COUNCILLORS E. COSTA, Washington, U.S.A.
S. GARATTINI, Milan, Italy
A. HERZ, Munich, Germany
O. RAFAELSEN, Copenhagen, Denmark
P. SIMON, Paris, France
F. SULSER, Nashville, U.S.A.
Z. VOTAVA, Strbske Plese, Chechoslovakia
NOMINATING COMMITTEE
Chairman H. HIPPIUS, Munich, Germany
MEMBERSHIP COMMITTEE
Chairman M. HAMILTON, Leeds, England
Members D. GINESTET, Paris, France
N. MATUSSEK, Munich, Germany
PUBLICATION COMMITTEE
Chairman C. STEFANIS, Athens, Greece
Members J. BOISSIER, Paris, France
E. CUENCA, Cadiz, Spain
A. LEEDS, Rockville, U.S.A.
M. SANDLER, London, England
FINANCE COMMITTEE
Chairman M. LADER, London, England
Members J. ANGST, Zurich, Switzerland
A. CARLSSON, Göteborg, Sweden
P. DENIKER, Paris, France
S. GARATTINI, Milan, Italy
H. HIPPIUS, Munich, Germany
L. HOLLISTER, Palo Alto, U.S.A.
H. LEHMANN, Montreal, Canada
XI
llthC. I. N. P. CONGRESS COMMITTEES
SCIENTIFIC PROGRAM COMMITTEE
Chairman P. BERNER
Members R. BATTEGAY, Basle, Switzerland
B. DA VIES, Victoria, Australia
J. ELKES, Baltimore, U.S.A.
S. GERSHON, New York, U.S.A.
J. GLOWINSKI, Paris, France
L. GRAM, Copenhagen, Denmark
M. KAROBATH, Vienna, Austria
G. LANGER, Vienna, Austria
C. RADOUCO-THOMAS, Quebec, Canada
B. SALETU, Vienna, Austria
T. SILVERSTONE, London, England
ORGANIZING COMMITTEE
Chairman B. SALETU
Members P. BERNER, Vienna, Austria
W. BIRKMAYER, Vienna, Austria
G. HARRER, Salzburg, Austria
G. HOFFMANN, Linz, Austria
O. HORNYKIEWICZ, Vienna, Austria
H. KONZETT, Innsbruck, Austria
O. KRAUPP, Vienna, Austria
K. KRYSPIN-EXNER, Innsbruck, Austria
H. LECHNER, Graz, Austria
F. LEMBECK, Graz, Austria
Ch. STTUMPF, Vienna, Austria
H. VESELY, Vienna, Austria
A. VILLENEUVE, Quebec, Canada
LADIES COMMITTEE
M. SALETU
C. BERNER
M. CHRISTIAN
R. CSERVENKA
A. LAHNSTEINER
M. KAROBATH
xii
ACKNOWLEDGEMENTS
The C. I. N. P. wishes to thank the following pharmaceutical companies
for their valuable contributions:
Abbott Laboratories, Chicago, 111., U.S.A.
A. H. Robins, Richmond Va., U.S.A.
Burrough Wellcome Co., Research Triangle Park, N.C., U.S.A.
Chemie Linz AG, Linz, Austria
Chemiewerke Homburg, Frankfurt, Germany
Chemische Fabrik von Heyden, Munich, Germany
CIBA-GEIGY Corp., Summit, N.J., U.S.A.
CILAG-Chemie G. m. b. H„ Vienna, Austria
CILAG-Chemie AG, Schaffhausen, Switzerland
COMESA KG, Vienna, Austria
Cyanamid of Canada Ltd., Montreal, Canada
E. Merck, Darmstadt, Germany
F. Angelini A. C. R. A. F., Rome, Italy
Gist-Brocades NV, Delft, The Netherlands
Hoechst Austria AG, Vienna, Austria
Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J., U.S.A.
Hoffmann-La Roche Ltd., Quebec, Canada
Hoffmann-La Roche Inc., Nutley, N.J., U.S.A.
Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany
Hoffmann-La Roche & Co. AG, Basle, Switzerland
ICI-Pharma, Heidelberg, Germany
Lederle Laboratories, Pearl River, N.Y., U.S.A.
LEO Aktiebolaget, Helsingborg, Finland
McNeil Laboratories, Fort Washington, Pa., U.S.A.
Merck Sharp & Dohme Research Laboratories, West Point, Pa., U.S.A.
Merrell-National Laboratories, Cincinnati, Ohio, U.S.A.
Organon International BV, Oss, The Netherlands
Paul Martini Stiftung, Frankfurt, Germany
Philips-Duphar B.V., Amsterdam, The Netherlands
Sandoz Inc., East Hanover, N.J., U.S.A.
Sandoz Ltd., Basle, Switzerland
Solco Basel AG, Birsfelden, Switzerland
Smith Kline & French Laboratories, Philadelphia, Pa., U.S.A.
The Upjohn Company, Kalamazoo, Mich., U.S.A.
Troponwerke G. m. b. H. & Co. KG, Cologne, Germany
Warner-Lambert/Parke-Davis, Ann Arbor, Mich., U.S.A.
Wellcome Research Laboratories, England
Vienna Tourist Board, Vienna, Austria
xiii
Presidential Address
LEO E. HOLUSTER
Professor of Medicine, Psychiatry and Pharmacology, Stanford University
School of Medicine and Veterans Administration Hospital,
Palo Alto, CA. 94304, U.S.A.
Dr. Saletu, Dean Kraupp, Professor Berner, Esteemed Colleagues:
Welcome to the Eleventh Congress of the Collegium Internationale Neuropsycho-
pharmacologicum. We anticipate a week in which our brains will be filled with
new information, in which our stomachs will be filled with good food, and in
which our spirits will be lightened by the gemutlichkeit that no visitor to
Vienna can escape.
The enormous job of putting together a meeting such as this has undoubtedly
involved more persons than I could possibly name. We owe especial thanks to
Professor Peter Berner for arranging the excellent scientific program that awaits
us and to Dr. Berndt Saletu for making the innumerable arrangements that were
necessary to accommodate us physically. Such a vast undertaking is not expected
to run perfectly so that if any of you have encountered difficulties along the
way, please understand the complexity of the organization of such a Congress. We
also wish to thank our numerous supporting members (all of whom have been recog­
nized on the program, I hope) without whose support this Congress would have
truly been impossible.
Approximately twenty-five years ago, the modern era of neuropsychopharmacology
began with the successful treatment of schizophrenia with chlorpromazine. The
immediate past-President of the C.I.N.P., Professor Pierre Deniker, was a partici­
pant in this epoch-making event, which led, among many other things, to the forma­
tion of the C.I.N.P. twenty years ago. Few of us would have guessed then how well
this new, multidisciplinary field would fare over the succeeding years. Our field
has attracted the interest of clinicians and basic scientists from many special­
ties and many disciplines. Meetings such as this foster the communication between
such diverse groups necessary for the integration of knowledge that will allow us
better to understand and better to treat disorders of the central nervous system,
whether manifested by psychiatric, neurologic, endocrine or other disorders.
We may well be proud of the many new drugs that have been developed during the
past quarter century that have ameliorated the course of these disorders for many
patients. Present antipsychotic drugs embrace perhaps 200 or more compounds
marketed throughout the world, involving a multiplicity of chemical structures.
The tricyclic antidepressants are less numerous, but in recent years the number
of chemical structures has been expanded to include new bicyclic and tetracyclic
1
2 Leo F. Hollister
structures. A new division of monoamine oxidase inhibitors may allow more
specific utilization of these drugs for treating depression and Parkinson's
disease. The benzodiazepines have advantages that have made most of the barbitu­
rates obsolete; indeed, their rapid proliferation may make this class of compounds
even more plentiful than was the case with barbiturates. Lithium has replaced
bromide as an ion therapy in psychiatry; its unique ability to modulate the course
of manic-depressive disorder being a far greater contribution to treatment than
anything offered by the bromide ion.
The drug-induced model of Parkinson's disease ultimately led to a completely new
approach to treating this disorder. Treatment directed at increasing dopaminergic
transmission, either with levodopa or with amantadine, has been added to the more
conventional approach of treating with drugs that reduce cholinergic activity.
Levodopa-induced dyskinesia and tardive dyskinesia from antipsychotic drugs both
may be partial models for Huntington's disease. These models have stimulated new
approaches to the treatment of this disorder, either by decreasing dopamine recep­
tor sensitivity or by increasing cholinergic activity. We were well advised to
use the compound term, neuropsychopharmacology, for describing our field and for
naming this college some two decades ago.
Progress in the basic sciences of neuropharmacology has been even more impressive
than it has been in the clinical applications. Twenty-five years ago, the only
established central nervous system neurotransmitter was acetylcholine. Soon after
the introduction of antipsychotic drugs, the so-called biogenic amines, serotonin,
norepinephrine and dopamine, became considered as putative neurotransmitters. The
mechanisms by which these biogenic amines are synthesized, transported, stored,
released, recaptured and metabolized have been rather well worked out. Their
selective distribution in the brain was delineated by simple yet elegant histo-
chemical techniques. The effects of drugs on these systems led to the formulation
both of the amine hypothesis of depression and the dopamine hypothesis of
schizophrenia. These hypotheses, among others, can be tested in various ways,
the first time that this essential aspect of the scientific method has been
applicable to study of the pathogenesis of psychiatric disorders. More recently,
attention has been focused on receptors for these neurotransmitters and the
changes that may occur in these receptors during treatment with psychotherapeutic
drugs.
One might say that the many advances in the basic sciences are overwhelming.
Scarcely do we begin to understand the possible function of one or two neuro­
transmitters before additional ones are discovered. We are still uncertain about
the role in the brain of some old neurotransmitters, such as histamine and
epinephrine, not to mention the many new biogenic amines found in the brain that
may have a role as neurotransmitters. Amino acids and peptides are present in
abundance in the brain, and like the biogenic amines, are selectively distributed.
The various endorphins are currently of greatest interest, as their action may
relate to that of a classic drug, morphine, that acts on the central nervous
system. Far less clear is why gastrointestinal hormones, such as gastrin and
somatostatin, should be in the brain, or for that matter, whether the various
releasing hormones may have functions other than mediating control of the
pituitary by the brain.
Proliferation of receptors continues. It is likely that more than one type of
receptor exists in the brain for most of the known neurotransmitters. Is it
likely that specific receptors may be found for the very many centrally-acting
drugs, such as seems to be the case for morphine, and that for each of these
receptors for different types of drugs we may also expect to find an endogenous
ligand? Does the finding of specific binding sites for benzodiazepines in the
brain mean that God works for Hofmann-La Roche? Or does it simply mean that Art
Presidential address 3
imitates Nature and that chlordiazepoxide is a weak imitator of Nature's own
antianxiety drug, which too often seems to be present in too low a quantity for
many of our patients?
Thus, it is the basic sciences, as usual, that raise more questions than they
answer. And here is where one of the major current problems lies. We must con­
tinue to try to make sense of old discoveries while adding confusion through new
discoveries. The structure and function of the brain gets ever more complex, the
more we know about it. Yet somewhere, there must be a synthesis that reduces the
complexity. A biology that can code all the genetic information with four
nucleotides, or make all the necessary proteins with a mere 20 amino acids,
certainly does not require the anticipation of making receptors for every
centrally acting drug that has been invented to date as well as those still to
be invented. This problem is a never-ending one and is the reason that, for the
true scientist, work never ceases to be a fascinating challenge.
From the viewpoint of the clinician, a major current problem is the development
of better drugs than those that we have. The treatment of schizophrenia has
improved immeasurably during the 20-year life span of the C.I.N.P., yet most
improvements in antipsychotic drugs have been largely technical. Many current
drugs are better than chlorpromazine, either due to more specific pharmacologic
actions or by having fewer unwanted pharmacological actions. Yet, so far as we
know, they still work in relatively similar ways. Our batteries of pharmacologic
screening tests are designed to find new chemicals that mimic the drugs we already
have rather than to discover distinctly new approaches to treatment. We must find
some way to get out from this circular trap.
Tardive dyskinesia associated with antipsychotic drug treatment is a problem that
continues to be troubling. We haven't made a great deal of practical progress
either in preventing its occurrence or in treating it effectively. Thus, this
complication has become a major consideration in the use of these drugs. As it
may occur in non-schizophrenic patients treated with relatively small doses of
antipsychotics, it now seems prudent to restrict their clinical use to patients
with definite psychotic disorders about which there would be no argument concern­
ing the propriety of their use. One might tend to be somewhat more conservative
about doses and duration of treatment. So many treatments have been reported to
Improve tardive dyskinesia that it may take some time before we know which ones
are practical. The Implications of tardive dyskinesia go beyond the neurological
disorder. If the mechanism of tardive dyskinesia ±s a compensatory dopaminergic
receptor supersensitivity, why should it not also occur in the mesolimbic system
as it does in the nigrostriatal system? Some evidence has accumulated that such
receptor supersensitivity does indeed occur in the mesolimbic system. What,
then, are the implications for the schizophrenic patient? Could it mean that the
patients develop tolerance/dependence to antipsychotic drugs in a way similar to
the patient in chronic pain treated with opiates? Are schizophrenic patients
destined to require ever higher doses of these drugs to maintain their improve­
ment and will discontinuation of antipsychotic drugs result in a worse situation
than was present when they started treatment? These questions are highly perti­
nent to our use of antipsychotic drugs and we must find the answers soon.
Treatment of major depressions with drugs has always been more controversial than
treatment of schizophrenia. While there now seems to be little doubt that tri-
cyclics, and to a lesser extent the monoamine oxidase inhibitors, are effective
in some patients, we still have problems in choosing the right drug for the right
patient. Much clinical evidence suggests that in the case of the tricyclics, spe­
cific antidepressant effects are limited to those types of depression termed
"endogenous," a category not always consistently defined and diagnosed. Within
the endogenous group, preliminary work suggests that one can make biochemical
I Leo F. Hollister
4
distinctions based on the involved neurotransmitter and select in advance the type
of tricyclic most suited for an individual patient. Should such biochemical typ­
ology of endogenous depression be confirmed, the clinical Implications would be
exciting. The failure of many patients to respond to antidepressant drugs, either
rapidly or completely enough to indicate that improvement is clearly drug-related,
indicates the serious limitations of presently available drugs in the overall
treatment of this syndrome. The application of pharmacokinetic principles to the
exploitation of these drugs is another technical aspect which may enhance somewhat
their yield of therapeutic successes. Nonetheless, we still do not have alterna­
tive approaches to the treatment of depression from those available twenty years
ago. Once again, we are in some kind of circular trap.
Our treatment of manic-depressive disorder has been vastly improved by lithium,
especially in the prevention of recurrences of mania or depression. Yet, it has
not appreciably changed in the past decade. We do not have hypotheses about the
mode of action of this simple material on both the manic and depressive phases of
this illness that are nearly as tenable as those for the mode of action of anti-
psychotic or antidepressant drugs. The great success of lithium may have stulti­
fied research into other methods of treatment for manic-depressive disorder.
Recent indications that longterm, or even sometimes short-term, treatment with
lithium may be associated with irreversible renal damage mandate that alternative
approaches to treatment of manic-depressive disorder be explored. We can never
be content with the status quo.
Some of our problems are ones of omission. We lack effective drugs for many
common psychiatric disorders. Senile brain disease, also known as Alzheimer's
disease, remains a puzzle. Despite the fact that an increasing proportion of
people in developed countries live long enough to become vulnerable to this
disorder, we know very little about its pathogenesis and have few, if any, drugs
of even limited value. Research into this disorder and into pharmacologic
approaches to its treatment needs much more effort than the present level. A
similar situation applies to mental subnormality. Although a few specific causes
have been unraveled during the past twenty-five years, the cause of the deficient
mental state remains unknown in the vast majority of afflicted persons. No
presently available pharmacological treatment has done more than curb associated
behavioral disturbances. Substance abuse is a major problem in many countries
and, if past history is any guide, it will remain so for a long while. We are
not sure why people smoke or why once started, the habit is so difficult to con­
trol. Possibly no other substance abuse is so life-threatening as smoking, yet
relatively little effort has gone into developing drug treatments. Alcohol abuse
has long been treated with aversive drugs, such as disulfiram, but little other
progress has been made. With this drug, also, the ravages on health are consid­
erable. One can hardly overemphasize the scourge of opiate addiction. Our major
pharmacologic approach to treatment has been to supplant one opiate drug for
another. Recently, effective, long-acting narcotic antagonists have become avail­
able as therapeutic agents. These are seemingly perfect drugs, in that their
effects are highly predictable. The paradox is that patients won't take them.
One would like to think that problems created by drugs might be amenable to treat­
ment with drugs, but perhaps such reasoning is too naive. In any case, these
problems require our continued efforts.
Some of our current problems are in the social sphere. For a variety of reasons,
it is becoming increasingly difficult in many countries, most of all my own, to
do clinical research. No one would argue against proper ethical constraints to
protect human subjects, although what is proper is often difficult to define.
Superficially, it would seem reasonable to expect that before a drug were put
into man, testing in animals should be rather extensive. Yet, animal trials may
not be predictive, either in terms of therapeutic efficacy or of toxicity, of the
Presidential address 5
results to be ootained in man. We need to get drugs into man earlier than is
presently possible, for often a very limited human experience with a drug may
settle issues of whether or not the drug should be developed further. This issue
is even more critical when drugs or chemicals are used as probes for studying the
pathogenesis of disease states. Often none of these drugs or chemicals has any
potential commercial value, so the funds for extensive studies of animal toxicity
are not available. Without such preliminary studies, it may be impossible to use
the drug in man to test a particular hypothesis. The future of neuropsycho-
pharmacology's sister discipline, biological psychiatry, is heavily dependent
upon the resolution of this problem.
Finally, our right to treat patients with drugs is being challenged. Our success
with drug therapy in psychiatry has offended many who, for various reasons and
with various motivations, abhor the use of drugs. The possibility of adverse
effects from these drugs, especially tardive dyskinesia, has given impetus to
make mandatory the consent of patients or their protectors prior to any use of
drugs in psychiatric patients. In at least one state in the United States, such
a law has been passed. It remains to be seen whether it can be implemented
without serious disadvantage for those patients it presumably is meant to protect.
The implications of such laws are even more ominous: A different set of standards
is applied to the use of Psychotherapeutic drugs than to any other class of drugs.
Consent does not have to be obtained for the use of digoxin to treat patients with
congestive heart failure, even though the adverse consequences of digoxin are at
least as severe as those of antipsychocie drugs. For inexplicable reasons, the
civil liberties of psychiatric patients are deemed to be more important than those
of cardiac patients.
One may speculate that in today's climate it is easier to pervert the uses of
psychiatry than that of any other medical specialty. Egregious examples of the
misuse of psychiatry for political purposes are well documented. Drugs, which
in the lay person!s mind can easily be construed as means of controlling thoughts,
are a logical target of such fears. Our problem is that we are neglecting to
assure the public that Psychotherapeutic drugs are not used for nefarious pur­
poses. Drugs that remove the nagging hallucinations of schizophrenia, that dis­
perse the dark cloud of melancholy, that calm the frenzied activity of mania, or
that relieve the unknown apprehension of anxiety, are more properly liberating
agents than they are means of restraint. Our problem is to defend our right to
use these valuable agents that so many here have done so much to develop. If we
do not act soon, our hands may be tied before we know it, and our patients will
suffer.
Contrary to what you might suppose from my recital of this litany of problems for
our field, I am quite optimistic about its future. We have been fortunate in
attracting outstanding persons from many medical and scientific fields to this
common ground of neuropsychopharmacology. Our progress over this past quarter
century has been great. The fruits of our efforts are plainly visible. The
challenges of understanding the brain and how drugs work on it continue to
attract some of the best and brightest of our young colleagues. Present problems
are the challenges that will advance our science, but their solutions will engen­
der still more problems. The process is never-ending, but so is the search for
knowledge.
Now we shall adjourn to the scientific portion of our meeting. If this Eleventh
C.I.N.P. Congress is a success, you will become aware of even more problems than
those few that I have selected to call to your attention. At the same time, you
will be stimulated by contacts with your peers to attempt solutions for present
problems. In the long run, our patients will benefit, just as they have from the
efforts of neuropsychopharmacologists during the two decades that the C.I.N.P. has