Amines and Schizophrenia

278 Pages·1967·15.47 MB·English

AMINES A ND
SCHIZOPHRENIA
Edited by
HAROLD E. HIMWICH
Gajesburg State Research Hospital, Galesburg, 111. (U.S.A.)
SEYMOUR S. KETY
National Institutes of Health, Bethesda, Md. (U.S.A.)
JOHN R. SMYTHIES
University of Edinburgh (Scotland)
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First edition 1967
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LIST OF CONTRIBUTORS
BALDESSARINI, R. J., Section on Medicine, Laboratory of Clinical Science,
National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland 20014.
BERLET, H. H., Thudichum Psychiatric Research Laboratory, Galesburg
State Research Hospital, Galesburg, Illinois.
BOURDILLON, R. E., Royal Southern Hospital, Caryl Street, Liverpool 8,
England.
BRUNE, G. G., Neurologische Universitatsklinik, Hamburg-Eppendorf,
Hamburg 20, Martinistr. 52, Germany.
COLE, J. O., Chief, Psychopharmacology Service Center, National Institute
of Mental Health, National Institutes of Health, Bethesda, Mary-
land.
DURELL, J., Chief, Section on Psychiatry, Laboratory of Clinical Science,
National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland.
EFRON, D. H., Head, Pharmacology Program, Psychopharmacology Service
Center, National Institute of Mental Health, National Institutes of
Health, Bethesda, Maryland.
FORREST, A. D., Consultant Psychiatrist, Andrew Duncan Clinic, Royal
Edinburgh Hospital, Morningside Terrace, Edinburgh, Scotland.
FRIEDHOFF, A. J., Co-Director of Center for the Study of Acute Psychotic
Disorders, Department of Psychiatry and Neurology, New York
University School of Medicine, 550 First Avenue, New York 16,
New York.
HIMWICH, H. E., Director, Research Division, Galesburg State Research
Hospital, Galesburg, Illinois.
HIMWICH, W. A., Thudichum Psychiatric Research Laboratory, Galesburg
State Research Hospital, Galesburg, Illinois.
HOLMSTEDT, B., Professor, Department of Toxicology, Karolinska Institutet,
Stockholm 60, Sweden.
HORWITT, M. K., Director, L. B. Mendel Research Laboratory, Elgin State
Hospital, Elgin, Illinois.
JENNER, F. A., Physician in Charge, Medical Research Council Unit for
Research on the Chemical Pathology of Mental Disorders, Hollymoor
Hospital, Birmingham, England.
KETY, S. S., Chief, Laboratory of Clinical Science, National Institute of
Mental Health, National Institutes of Health, Bethesda, Maryland.
vii
viii LIST OF CONTRIBUTORS
KUEHL, F. A., Jr., Assistant Director, Bio-organic Chemistry, Merck Sharp
Dohme Research Laboratories, Rahway, New Jersey.
LASTER, L., Chief, Gastroenterology Unit, National Institute of Arthritis and
Metabolic Diseases, National Institutes of Health, Bethesda, Maryland.
LEBEDEV, B., Professor of Psychiatry and Director of Bechterev State Institute
for Psychoneurological Research, Leningrad, U.S.S.R.
LEONARD, F., Program Head, Chemistry, Psychopharmacology Service
Center, National Institute of Mental Health, National Institutes of
Health, Bethesda, Maryland.
MANDELL, A., Assistant Professor, Department of Psychiatry, University of
California School of Medicine, Center for Health Sciences, Los Angeles,
California.
MUDD, S. H., Laboratory of General and Comparative Biochemistry,
National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland.
PERRY, T. L., Associate Professor, Department of Pharmacology, The
University of British Columbia, Faculty of Medicine, Vancouver 8,
Canada.
PSCHEIDT, G. R., Thudichum Psychiatric Research Laboratory, Galesburg
State Research Hospital, Galesburg, Illinois.
RICHTER, D., Medical Research Council Laboratories, Woodmansterne Road,
Carshalton, Surrey, England.
RIDGES, A. P., Department of Medicine, University of Liverpool, Ashton
Street, Liverpool, England.
SCHILDKRAUT, J. J., Laboratory of Clinical Science, National Institute of
Mental Health, National Institutes of Health, Bethesda, Maryland.
SMYTHIES, J. R., Senior Lecturer, Department of Psychological Medicine,
University of Edinburgh, Edinburgh 8, Scotland.
SNYDER, S. H., Laboratory of Clinical Science, National Institute of Mental
Health, National Institutes of Health, Bethesda, Maryland.
SPAIDE, J. K., Thudichum Psychiatric Research Laboratory, Galesburg State
Research Hospital, Galesburg, Illinois.
SPRINCE, H., Chief Research Biochemist, Veterans Administration Hospital,
Coatesville, Pennsylvania.
STRAUGHAN, D. W., Department of Psychiatry, University of Edinburgh,
Edinburgh, Scotland.
SZARA, S., Chief, Section on Psychopharmacology, Clinical Neuropharma-
cology Research Center, CI, IR, NIMH, William A. White Building,
Saint Elizabeth's Hospital, Washington 20, D.C.
WAISMAN, H. A., Professor of Pediatrics, University of Wisconsin Medical
Center, Madison, Wisconsin.
PREFACE
THIS Preface, as usual, is written after all the rest of this volume had been
put together, and in retrospect certain events in the achievement of this
production are outstanding. In the first place, the project is the brainchild of
John Smythies, who drew into it first Seymour Kety and then Harold Himwich,
so that the final product reflects the combined endeavours of three different
laboratories, all, however, deeply involved in the problem of schizophrenia.
The wherewithal to make this project possible came from Grant No. MH 10999-
01 and we are happy to acknowledge our gratitude to the National Institutes of
Health. In all the many transactions involved in attaining the necessary funds,
the procedures were greatly facilitated by the understanding cooperation and
know-how of Dr. Daniel Efron, who also contributed significantly to the
scientific discussions following presentation of papers. The encouragement
and good offices of Dr. Thomas T. Tourlentes, Superintendent of the Gales-
burg State Research Hospital, in obtaining our grant, and the administrative
cooperation of Miss Florence O. Johnson, Assistant Superintendent of the
hospital, were invaluable.
This project was made possible by the good will and cooperation from many
other sources. Perhaps first among them we should thank Mrs. Helena Lemp
who made available at low costs the services, built up over a matter of years
by the Federation of American Societies for Experimental Biology, in the
recording of the discussions following the papers. The reader will see that
they added significantly to the information contained within this volume. We
found the management of the Dennis Hotel to be reasonable and helpful
and we are happy to acknowledge this cooperation. In the management of
the actual meetings, Dr. Williamina A. Himwich helped unobtrusively in
many ways, and for one thing made it possible for Harold Himwich to act as
Chairman during the second day of the meeting, undisturbed by exigencies
associated with administrative detail. Seymour Kety not only was the Chairman
on the first day of the meeting, but the reader will find a brilliant Summary
and a heuristic hypothesis from his pen. The keynoter of the meeting was
John Smythies who very ably set the groundwork for the discussions to follow
in the Introduction. Without the cooperative efforts of all these individuals
and others as well, this contribution could not have taken place, nor could we
have had the informative and stimulating presentations and discussions
enjoyed by the participants. We would like to believe that much of the exhilarat-
ing feeling which comes from the viewing of new vistas will be shared by the
readers of this volume.
ix
INTRODUCTION
J. R. SMYTHIES
Department of Psychological Medicine, University of Edinburgh, Scotland
THE AIMS of this present Symposium are to survey and discuss the possible
biochemical basis of schizophrenia, with particular regard to the role that
certain amines may play. The last ten years has witnessed a quantity of work
in this field and I think it is fair to say that modest progress has been made.
By this I do not mean that we can yet say with conviction what are the bio-
chemical bases of schizophrenia, manic-depressive psychosis and kindred
diseases. But we do have at last some interesting data and working hypotheses
in this field and this enables us to give a reasonable account of what could be
the biochemical mechanisms involved. These hypotheses account for the
known phenomena and can be tested by experiment. Much of this Symposium
will be concerned with attempts so to test these hypotheses. It may be helpful
at this point to distinguish between: (1) demonstrated facts, (2) working
hypotheses, and (3) experimental data still sub judice.
(1) The demonstrated facts I would take to be as follows:
(i) Three important amines—norepinephrine, serotonin and dopa-
mine—occur in the brain, together with the enzymes for their syntheses
and breakdown. Furthermore, the first two occur particularly in those
parts of the brain concerned with emotion and the higher control of
learning, motivation and behaviour (Smythies, 1965) that so manifestly
are at fault in the psychoses. These amines presumably play an import-
ant role in neuronal function.
(ii) There is a group of drugs that produces psychoses in man.
These reactions are somewhat similar, allowing for the many different
environmental and situational parameters necessarily involved, to
certain schizophrenic syndromes. These drugs include such agents as
mescaline, dimethyltryptamine, psilocyn and LSD.
(iii) The agents in group (ii) are all either N-methyl or O-methyl
derivatives of the neurohumours listed in (i). O-methylation is a normal
route of metabolism in the body for catecholamines and Axelrod has
discovered in mammalian tissues an N-methylating enzyme (capable
of turning tryptamine into dimethyltryptamine).
1
2 J. R. SMYTHIES
(2) The three main hypotheses in this field, arising naturally from these
established facts, are as follows:
(i) The hypothesis put forward in 1952 by Harley-Mason, Osmond
and Smythies, based on the chemical relationship between mescaline
and norepinephrine, suggested that schizophrenia may be associated
with an abnormality of O-methylation of norepinephrine with the
production in the body of some psychotoxic metabolite such as
dimethoxyphenylethanolamine.
(ii) The hypothesis put forward by Gaddum and by Woolley and
Shaw in 1954, based on the pharmacological antagonism between
LSD and serotonin, that schizophrenia may be associated with some
abnormality of serotonin metabolism. This was next developed by
Szara and his co-workers, who discovered the psychotomimetic
properties of the N-methyl derivatives of tryptamine and its analogs.
This suggested that there might be an abnormal N-methylating process
in schizophrenia with the production in the body of psychotoxic
metabolites such as dimethyltryptamine. Irvine and Page combined
these hypotheses to suggest that a compound like serotonin can be
both N-methylated and O-methylated to yield a compound like 5-
methoxy-N :N-dimethyltryptamine—which they proceeded to demon-
strate was a very potent disrupter of conditioned avoidance behaviour
in the rat.
(iii) The third hypothesis derives naturally from these first two by a
change of emphasis from psychotoxic compounds to an aberrant
biochemical process and was first put on the map by Kety and his co-
workers. The basic biochemical mechanism at fault in schizophrenia
may be transmethylation (for a variety of possible causes). This
disorder of methylation by itself might lead to functional changes in
neurones incompatible with their normal function and on the behavioral
level with the production of a psychosis. This fault might also lead to
the production of abnormally methylated compounds of the types
already described which would aggravate the situation by adding their
own psychotoxic effects to the neuronal function already disordered
by the abnormal transmethylating mechanism.1
These three hypotheses can be called for convenience:
(i) the catechol amine hypothesis;
(ii) the tryptamine hypothesis, and, at a more profound level of generaliza-
tion;
(iii) the transmethylation hypothesis.
1 Smythies, J. R. (1965) The Neurological Foundations of Psychiatry, Oxford, Blackwell,
1965.
INTRODUCTION 3
(3) An important topic for discussion at this meeting therefore must consist
of the experimental data that have been put forward in attempts to confirm,
refute, or generally test, these hypotheses. This data consist of the following:
(i) The experiments I have already referred to by Pollin, Cardon and
Kety who showed that feeding the methyl-donor methionine to schizo-
phrenics made their symptoms worse. This work has been confirmed by
Brune and Himwich, and by Sprince's group. These findings have been
further developed by Brune and Himwich. Methione has other functions
besides being a methyl-donor and one of these other functions might have
been responsible for exacerbating the schizophrenic symptoms. Brune
and Himwich therefore fed another methyl-donor of a different chemical
family—betaine. This also made schizophrenic symptoms worse.
Therefore, the transmethylation hypothesis received support.
(ii) The reports by Friedhoff and Van Winkle that it is possible to
isolate a metabolite predicted by theory (i) from schizophrenic urine—
namely dimethoxyphenylethylamine (the di-O-methyl derivative of
dopamine rather than norepinephrine). This is not apparently a
normal metabolite. This report has been entirely confirmed by three
groups (two of which are represented at this meeting) and partially
confirmed by Takesada et al It has been denied by Perry's group which
is also represented at this meeting.
(iii) The experiments from Himwich's laboratory showing that certain
amines particularly tryptamine are excreted in excess during a psychotic
attack, and the levels returning to normal in the individual with clinical
remission.
(iv) The reports that the plasma of schizophrenic patients is more
toxic than the plasma of normal individuals (as measured by a variety
of biological test mechanisms—particularly learned behaviour in rats
as measured by the group led by Jack Bergen at the Worcester Founda-
tion). This toxic agent may be a small molecule (perhaps an abnormal
biogenic amine) linked to plasma protein.
Some of the papers to be presented at this Symposium will discuss these
facts, these hypotheses and this experimental data directly—and we are most
fortunate to have most of the people who have been active in this field present.
Other papers will be concerned with biochemical data basic to these formula-
tions. It therefore gives me much pleasure to hand over to our Chairman for
today's proceedings, Dr. Seymour Kety.
STRUCTURE-ACTIVITY RELATIONSHIPS
OF MESCALINE
J. R. SMYTHIES and E. A. SYKES
Department of Psychological Medicine, University of Edinburgh, Scotland
IT IS generally agreed that mescaline produces a state of psychosis that
has certain similarities to some aspects of the schizophrenic syndrome. It
would therefore be of some theoretical interest for biological psychiatry to
know on what biochemical system mescaline exerts its effects. One way of
studying this is by the structure-activity relationships (SAR) method. We
have explored the effect of various analogs of mescaline on animal behaviour.
In our early work we used the Winter and Flataker test; latterly we have
employed the conditioned-avoidance response (CAR).
Our first task was to determine the effects of mescaline itself on the CAR
as the base-line for our subsequent studies. The literature at that date was
somewhat confusing. Cook and Weidley (1957) using a pole-jump escape
technique had failed to block the CAR in rats with dosages up to 100 mg/kg.
Chorover (1960), however, using a shuttle box extinguished the CAR with a
dosage of 25 mg/kg.
In our experiments we have used a shuttle box with a buzzer as the condi-
tioned stimulus (CS) and shock as the unconditioned stimulus (UCS). The
buzzer-shock interval was 5 sec and the rat had to learn to cross from one
compartment of the box to the other within these 5 sec to avoid the shock.
Normally this was quickly learned and the rat would cross with a regular
buzzer-cross reaction time (RT) of some 4 sec. This leaves scope for detecting
both an increase in RT (as produced by CPZ) or a decrease in RT (as produced
typically by amphetamine). Each 2-hr experimental period consisted of seven
runs of twenty trials each. The trials were randomly spaced and occupied 8
min, and were followed by 5 min time-out. We recorded the number of
shocks received and the RT. The injection (of drug or saline) was given between
the second and third runs. The first two runs in any experiment were discarded
as the animals took some minutes to adapt to the experimental situation (and
hence a few shocks were delivered before the CR and RT became stabilized).
A series of saline controls was followed by a drug run and then another saline
control. The results are expressed in D-S scores, i.e. as the difference between
the drug score and the mean of the preceding and following saline scores for
each "run" of twenty trials. The statistical significance of the results was
assessed by Wilcoxon's non-parametric ranking method for paired replicates.
5
6 J. R. SMYTHIES AND E. A. SYKES
RESULTS
Mescaline has a biphasic effect on CAR performance. Different animals
show widely different degrees of susceptibility to the drug. At 25 mg/kg the
drug first inhibits the CAR (increased RT and shocks). This is followed by a
decrease in RT (Fig. 1). Some animals are more sensitive than others, and
Fig. 2 shows the reaction of the most sensitive (n = 4), and Fig. 3 that of the
least sensitive (n = 4). At 12-5 mg/kg the inhibitory phase is less marked or
absent and the excitatory phase is more marked. At these dosage levels there
were no signs of ataxia or "toxic" effects of the drug. This was confirmed by
M-S MESCALINE 25 MG/KG
-•SHOCKS
* * *P<OOOI
* * P<OOI
•* P<005
0-2
BLOCKS OF 20 TRIALS PER SESSION
FIG. 1. The effect of mescaline 25 mg/kg on shocks and reaction time (RT:
expressed in mm of kymograph paper; 1 mm = 2-5 sec).
the Rushton-Steinberg test for ataxia which showed no ataxia at 25 mg/kg.
At 50 mg/kg, however, signs of paralysis of the hind legs appeared, so it seems
that 25 mg/kg should normally be the maximum dose.
One first analog was trimethoxyphenylalanine (Fig. 4) which we supposed
might cross the blood-brain barrier more easily than mescaline. However, it
proved almost completely inactive even in a dosage of 100 mg/kg. This may be
correlated with the report (Blaschko, 1965) that this substance is not a sub-
strate for decarboxylase.
We then investigated two compounds: 3-4,dimethoxyphenylethylamine
(d.m.p.e.) and N,N-dimethylmescaline (Fig. 4). The former was chosen
because of its current interest as a possible abnormal metabolite in schizo-
phrenia. Figures 5-7 show its effect on the CAR at 25, 50 and 100 mg/kg.