Table Of ContentCatecholamine (probably noradrenaline) nerve terminals in frontal cortex specimen ob-
tained from a schizophrenic patient post mortem. Smear preparation incubated in 10~
5
alpha-methylnoradrenaline. Only varicosities are seen. Magnification x75. Photograph
by Lars Olsen (pp. 199-203).
CATECHOLAMINES
A ND
SCHIZOPHRENIA
Edited by
STEVEN W. MATTHYSSE, PH.D.
and
SEYMOUR S. KETY, M.D.
Harvard University School of Medicine
and
Massachusetts General Hospital, Boston
P E R G A M ON PRESS
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Copyright © 1975 Pergamon Press Ltd.
All Rights Reserved. No part of this publication may be
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publishers
First edition 1975
Library of Congress Catalog Card No. 75-4093
THE PROCEEDINGS OF A SYMPOSIUM ON CATECHOLAMINES
AND THEIR ENZYMES IN THE NEUROPATHOLOGY OF
SCHIZOPHRENIA, IN STRASBOURG, FRANCE, MAY 18-21,
1973, AND PUBLISHED ORIGINALLY AS VOLUME 11,
JOURNAL OF PSYCHIATRIC RESEARCH, 1975.
Printed in Great Britain by A. Wheaton & Co., Exeter
ISBN 008 018242 9
ACKNOWLEDGEMENTS
THE EDITORS wish to acknowledge with gratitude the financial support of the Schizophrenia
Research Program of the Committee on Benevolences of the Supreme Council of the Scot-
tish Rite Freemasonry. We are also grateful to Professors Paul Mandel and Guy Vincendon
for arranging the symposium in Strasbourg, to the Centre de Neurochimie for providing the
conference facilities, and to Mary Slayter and Gladys Wilson for their invaluable editorial
assistance.
PROLOGUE
SEYMOUR S. KETY
SCHIZOPHRENIA, although it is not a major cause of death like cancer or heart disease,
nevertheless ranks with these as one of the most serious national health problems in every
country in the world. This is because of the number of people affected, its long duration—
with onset early in life and often persisting for years, the loss of human potential and the
sheer public cost.
The magnitude of the problem of schizophrenia is matched by our ignorance about it.
We do not know its etiology or pathogenesis, how to diagnose it objectively or how to
prevent it effectively. For all of these, we have many more hypotheses than conclusive
information and little agreement. The one therapeutic modality having value which is
generally recognized—pharmacotherapy with the phenothiazine and butyrophenone
drugs—is associated with serious side effects which increased knowledge of their mechanism
of action could help to prevent.
The need for answers in the face of ignorance has resulted in widely promulgated, ill-
founded treatment fads and conceptual dogmas. A hypothesis that schizophrenia may
be a genetically determined deficiency disease is used to justify a widely advertised cam-
paign of treatment with a potpourri of vitamins in high dosage in the face of repeated
failures to show their efficacy under controlled conditions. The lack of objective diagnostic
criteria has permitted the concept of schizophrenia to be so broadened and abused as to
include a wide variety of social deviance, eventually permitting the entire concept to be
dismissed as a myth.
The effect of both of these movements which appear to be increasing in popularity
in many countries is to diminish the thrust for sober, unsensational research on the problem
and does disservice to the schizophrenic patients who nevertheless continue to occupy one
quarter of all hospital beds, to the many more in the community who can realize only a
faction of their intellectual and social potential, and to their families.
The size of the problem speaks for considerably augmented research efforts to solve it,
for the elaboration and consolidation of knowledge we already have and the search for
answers to questions we can ask now, in addition to the undiminished acquisition of fun-
damental knowledge.
The diminution of public interest in research, both fundamental and clinical, on mental
illness and the tendency to deny its existence is especially serious now because the time has
never been more propitious for a serious attack on this multi-faceted problem, using in-
formation, techniques and concepts that have only recently emerged from fundamental
studies of the brain and behaviour.
Those of us who have had a long-standing interest in research on schizophrenia have
seen remarkable changes in the field over the past decade and a half. Before that time, it
was difficult to suggest what areas of basic research could yield relevant results or upon
what foundation to begin to build a superstructure. In the absence of these, there were in-
stead bold hypotheses attempting to bridge the wide gap all at once—and few, if indeed any,
have stood the test of time.
Fortunately, during that period there has been a burgeoning effort in fundamental
research throughout the many disciplines on which psychiatry depends. There has resulted
xi
xii PROLOGUE
considerable knowledge at the psychological, physiological, neurochemical and phar-
macological levels about aspects of behaviour which appear to represent the cardinal
features of schizophrenia, or which are disturbed in that syndrome: arousal, attention,
reward, motivation, exploration or withdrawal, appetitive and aversive behaviours, stereo-
typy, mood and other affective states. New anatomical pathways have been discovered
and some, already known, like the limbic system, have been richly explored. The chemistry,
physiology and pharmacology of the synapse has become a central focus of neurobiology.
New tools have been developed or applied to the central nervous system—histofluorescence,
immunofluorescence, electron microscopy, cell culture, biochemical, mathematical and
population genetics. In the field of schizophrenia itself, new evidence has been acquired
demonstrating the importance of genetic factors and heuristic hypotheses for their mode of
transmission are being examined. Controlled studies are being undertaken of intrafamilial
and other environmental influences. New and effective drugs have been included in the
treatment of schizophrenia and much has been learned about their mechanism of action.
In the current pharmacological and biochemical approaches to schizophrenia, one sees
for the first time the emergence of parsimonious and plausible hypotheses regarding the
nature of the biological substrate on which schizophrenia develops. Heretofore, biochemical
hypotheses of schizophrenia have tended to focus on one segment of the disorder, halluci-
nations, but a more useful biological hypotheses would offer the basis of understanding
not only the hallucinations, but also the more cardinal and general features, such as thought
disorder, anhedonia, affective-cognitive slippage and autism. If there is a biochemical
substrate for schizophrenia, we should also find it associated with what is genetically
transmitted, and we should expect to begin to account for some of the characteristics of
the vulnerable and subclinical states. Certain psychological features of schizophrenia
have recently been epitomized: heightened arousal, decreased habituation, neophobia,
failure to discriminate figure from ground, inappropriate affect and attributions of signifi-
cance.
The adrenergic system of the brain has many properties that suggest its involvement in
schizophrenic illness. It has its origin in a relatively small number of neurons concentrated
in the brain stem, and, by means of axons with a tendency to branch extravagantly, it per-
meates every other region of the brain, presumably exerting some modulation on a wide
variety of higher nervous functions. Although inconclusive, there is considerable evidence
suggesting that this adrenergic system is involved in behavioural states such as arousal
and attention, exploration, pleasure and reward, motivation and even learning.
Considerable evidence has been adduced that the psychosis induced by amphetamines
represents an exaggerated activity of dopaminergic synapses in the brain. The interesting
and compelling convergence of the phenothiazines and butyrophenones on dopamine
receptors emphasizes the importance of studies on the dopamine pathways in the brain,
especially those less well known that the nigrostriatal tracts, as reasonable candidates for
the site of action of the antipsychotic drugs and one of the plausible biological substrates
for schizophrenia.
It is these remarkable convergences, often unexpected and unpredicted, from the results
of many areas of basic research upon some of the features of schizophrenia, which has
created considerable ferment throughout the world and a feeling on the part of some
scientists that a number of rational approaches to the psychobiological substrates of that
disorder is now possible.
PROLOGUE xiii
This conference began with the thought of Steven Matthysse that the Third International
Symposium on Catecholamines provided an unusual opportunity to bring together many
of the experts throughout the world on the catecholamine system to present their findings
and discuss the implications which their research may have for a greater understanding of
the biological mechanisms involved in schizophrenia. It is our hope that this conference
will review the evidence which implicates the catecholamines, will underscore the missing
links, the controversial findings and the weak points in the evidence in order to stimulate
research that will lead to a more definitive understanding of the role catecholamines may
play.
The Benevolent Foundation of Scottish Rite Freemasonry which has for forty years
supported research projects at basic and clinical levels that may contribute to an understand-
ing of schizophrenia, has generously agreed to support this conference, and Professors
Mandel and Vincendon who were already deeply involved in the arrangements for the
Third Catecholamine Symposium, kindly agreed to make the arrangements for this one.
We are grateful to all of these and to the participants who were willing to devote an addi-
tional two days to discuss this important social problem. It is not often that the problem
of mental illness has had such dedicated scientific competence lavishly showered upon it,
and the result can only be salutary.
EPILOGUE
STEVEN MATTHYSSE
IN PLANNING a conference on "Catecholamines and their Enzymes in the Neuropathology
of Schizophrenia" we were confident that, regarding the first part of our title—"Catechola-
mines and their Enzymes"—a substantial document could not fail to be generated, since
we were fortunate enough to have assembled the world's most critical and productive
investigators in the field; and the results have more than fulfilled our expectations. In the
second part—"the Neuropathology of Schizophrenia"—we knew we were on ground where
angels fear to tread, schizophrenia having been aptly described by Fred Plum as "the
graveyard of neuropathologists." The experimental results are strong in themselves, but
it is not so easy to build from them a sturdy foundation for understanding this baffling
illness.
Foremost among the areas of agreement is the fact that phenothiazine and butyrophenone
tranquilizers block dopamine receptors (see articles by Carlsson, Anden, Fuxe, Ungerstedt,
Sedvall and Crow). To be sure, that is not their only action, and we cannot yet safely con-
clude that dopamine blockade is the key to the therapeutic efficacy of these drugs in schizo-
phrenia, but there is no doubt that dopamine blockade is a prominent effect of antipsy-
chotic drugs, and it occurs at clinically relevant in vivo doses and at reasonable in vitro
concentrations. There is also agreement from the studies of Angrist and others that am-
phetamine and related drugs are capable of causing psychoses which have a striking resem-
blance to paranoid schizophrenia. It is not yet clear whether the amphetamine effect can
be ascribed to dopamine, since this drug also affects norepinephrine synapses; but it is highly
probable that it acts through the catecholamine system.
To go from a catecholamine hypothesis of neuroleptic and psychotomimetic drug action
to a theory of the etiology of schizophrenia requires a logical step which can be made in a
number of ways. The most obvious formulation is that too much dopamine is released
at central synapses. This hypothesis might have two versions, one postulating a generalized
abnormality analogous to an "inborn error of metabolism," the other confined to aparticu-
lar dopamine tract (e.g. limbic or cortical). Other formulations must also be considered.
Dopamine receptors may be hypersensitive and react excessively to a normal quantity of
released dopamine; an antagonistic system (perhaps cholinergic, as Davis has suggested
on the basis of the antagonism between physostigmine and methylphenidate) may be
underactive; a system which is under tonic dopaminergic inhibition may be defective, dis-
inhibition by blockade of the dopamine input restoring it to normal activity; the conversion
of dopamine to noradrenaline may be impaired, causing a relative dopaminergic excess
and noradrenergic deficiency; or there may be a defect in adaptive regulation in the dopa-
mine system, as Mandell has proposed. Thus there are not one but several "catecholamine
hypotheses" of schizophrenia.
That unresolved questions should remain concerning the role of catecholamines in
schizophrenia is to be expected, since the hypothesis is but a few years old. Indeed it is
remarkable that, under the determining influence of these ideas, investigation of dopamine
transmission has rapidly become a central theme in neuropharmacology. The unresolved
questions can, I believe, be grouped in five categories.
(1) Correlations between the clinical efficacy and potency of neuroleptic drugs, and their
actions on the dopamine system, are favourable for the most part, but there are discrepancies,
XV
xvi EPILOGUE
some of which have been accounted for but others remain unresolved. Thioridazine is
approximately equipotent with chlorpromazine clinically, but has much weaker effects
on stereotypy, turning in animals with unilateral nigrostriatal lesions (Crow), and dopamine
metabolism (Matthysse). It also has a lower incidence of extrapyramidal side effects in
man. On the other hand, Sedvall reports that thioridazine does elevate cerebrospinal
fluid homovanillic acid. The new drug clozapine also appears to be lower in extrapyramidal
activity than its clinical potency would predict (Anden and Fuxe). Snyder has obtained
convincing evidence that these two drugs have much stronger anticholinergic properties
than the other neuroleptics, which may neutralize their nigrostriatal effects. Thiethylperazine
presents the converse dilemma: a drug with marked extrapyramidal and dopamine blocking
properties which is not considered to be antipsychotic. Less work has been done with this
paradox and at the moment it is not known whether it can be resolved.
Effects of antipsychotic drugs on the dopamine-sensitive adenylate cyclase system devel-
oped in Greengard's laboratory generally show encouraging correlations with clinical
efficacy and potency similar to the in vivo preparations. Here, too, there is an unresolved
question concerning relative potency: haloperidol and chloromazine, which are equi-
potent on the cyclase system, have more than an order of magnitude difference in their
clinical potencies (see discussion by Iversen). In this case the in vivo systems approximate
clinical potency more closely and the discrepancy may be related to transport phenomena;
but at the present time it is not accounted for.
The dopaminergic system of the brain appears more complex than was at first recognized.
In addition to the nigrostriatal and mesolimbic pathways, dopamine terminals in the cortex
have been revealed by refined histofluorescence techniques (Hokfelt) and by the biochemical
effects of lesions (Glowinski). There is also evidence for presynaptic in addition to post-
synaptic dopamine receptors (Carlsson). It may be that discrepancies in the correlation
between clinical and pharmacological potency can be resolved by considering the effects
of drugs on separate components of the dopamine system. Anden has already obtained
evidence that regional differences may account for the lack of extrapyramidal activity of
clozapine.
(2) The antipsychotic actions of phenothiazines do not diminish after repeated dosage,
whereas tolerance does develop to many of their other pharmacological actions. If tolerance
develops to any pharmacological effect of the phenothiazines, it follows that the effect is
unlikely to be relevant to their antipsychotic action. At the present time it is notpossibleto
say definitely whether tolerance does or does not develop to the effect of phenothiazines on
dopaminergic transmission. According to Glowinski's data, tolerance does develop to the
effect on dopamine synthesis in an in vitro system. It would be most important to test for
tolerance in in vivo systems as well.
(3) The brilliant proposal of Snyder that the relative potencies of the stereoisomers of
amphetamine on the dopamine system are approximately equal, whereas the noradrenaline
system is affected much more by the dextro than by the levo form, does not seem to have
fared very well in the laboratory (see data presented by Baldessarini and review by Matthysse).
Most of this skepticism is based on the effects of amphetamine on catecholamine uptake,
whereas (as Fibiger and Carlsson point out) effects on release may be even more important.
Indeed, Fibiger has observed that self-stimulation in a dopaminergic site is affected approxi-
mately equally by the two stereoisomers, whereas a noradrenergic placement is much more
EPILOGUE xvii
sensitive to the dextro form. Clarification of this issue is important because Snyder's pro-
posal offers a method for tracing the psychotomimetic effect of amphetamine to one of the
two catecholamine systems, whereas at the present time it is not possible to decide whether
it is dopaminergic or noradrenergic.
(4) More accurate measurements of the relative clinical efficacy and potency of tran-
quilizing drugs are needed as a foundation for experimental psychopharmacology. Corre-
lations of clinical potency with effects on a test system cannot be more convincing than the
clinical observations on which they are based, and in many cases the data on therapeutic
efficacy are not adequate. Clinical practice is not uniform from one country to another, and
moreover a pharmaceutical house may abandon a possible antipsychotic drug because
preliminary trials suggest that it has no particular advantage over established drugs.
Thiethylperazine is a case in point; the actions of this drug are not in accord with the
"dopamine hypothesis" as discussed before, but actually there is little convincing evidence
that it is devoid of antipsychotic properties. All we really know is that it is not used for this
purpose. The analysis of relative potencies by Davis based on double-blind comparative
studies is a valuable step in this direction.
The qualitative, as well as quantitative effects of phenothiazines and related drugs also
need clarification. Although it is well established that neuroleptic drugs are not merely
sedatives, it is important to characterize which aspects of schizophrenia they improve and
which aspects are left largely unchanged. It is taken as axiomatic by many of the contributors
to this volume that investigating the mode of action of phenothiazines and related drugs
will contribute to our understanding of the pathogenesis of schizophrenia; but this assump-
tion is correct only to the extent that these drugs do indeed act on schizophrenia. Some of
the most characteristic disturbances in schizophrenia such as loosening of associations and
inadequate reality testing are improved, but the treated patient often remains unmotivated
and without purpose, and deficient in the capacity to experience pleasure. Conceivably
the disturbance in thinking is related to dopamine pathways but the lack of motivation has
some other cause, such as inadequate activity of the noradrenergic reward system (see dis-
cussion by Stein).
(5) It is natural to draw the conclusion, from the dopaminergic blocking effects of anti-
psychotic drugs, that schizophrenia is associated with hyperactivity of dopaminergic
neurons, although there are alternatives as discussed above. It is worth emphasizing that
the most direct reasoning would have led us astray both in Parkinson's disease and in
Huntington's chorea. In Parkinson's disease, as Vogt pointed out, the standard form of
treatment used to be drugs blocking acetylcholine transmission, but the assumption of a
primary cholinergic hyperactivity would have been wrong, since degeneration of dopamine
neurons was later demonstrated. Similarly in chorea, drugs blocking dopamine transmission
are the most effective known treatment, but degeneration of GABA neurons in the striatum,
rather than dopaminergic hyperactivity, appears to be implicated in the etiology (Iversen).
The evidence presented by Stein of a deficiency in cerebral dopamine-beta-hydroxylase in
schizophrenia does, indeed, suggest a primary disturbance in catecholaminergic pathways;
and it will be most important to replicate this observation. The decrease in platelet MAO
found by Murphy's group may prove very valuable as a genetic marker, although its im-
plications for pathogenesis would be clearer if it were associated with a change in cerebral
MAO. On the negative side, circulating DBH is not decreased in schizophrenia (Goldstein),
and no evidence of an alteration in dopamine metabolism has been revealed so far by studies
of cerebrospinal fluid metabolites.
