POSTGRAD. MED. J. (i963), 39, 26

BIOCHEMISTRY OF SCHIZOPHRENIAJ. R. SMYTHIES, M.D., M.R.C.P., D.P.M.

Department of Psychological Medicine, University of Edinburgh

Specific HypothesesTHE last ten years have witnessed an enormousincrease in the amount of work carried out in thisfield and, after many years of disappointment, atlong last some positive findings are beginning toemerge. It is too early to make the claim that anydefinite cause of the illness is known but evidenceis now to hand that suggests quite strongly thetype of biochemical abnormality that may be in-volved. Progress in research depends to a greatextent on the formulation of adequate hypothesesthat can be tested experimentally. The recentprogress in schizophrenia research has dependedpartly on the development of such. hypotheses andpartly on ad hoc observations both on the meta-bolism of schizophrenic patients and on the modeof action of psychotomimetic drugs.

The First Specific HypothesisOne key to understanding the biochemical basis

of schizophrenia may lie in the chemical formulaof the psychotomimetic drugs. These are com-pounds that can induce in normal people many ofthe signs and symptoms of an acute schizophrenicillness without causing any delirium or clouding ofconsciousness. The first such drug to be dis-covered was mescaline in i886. This is a closerelative of adrenaline being 3,4,5-trimethoxy-phenylethylamine (Fig. i). This chemical re-lationship formed the basis of the first specificbiochemical theory of schizophrenia published in1952 by Osmond and Smythies. This theorypostulated that schizophrenia might be caused bya derangement of adrenaline metabolism wherebythe phenolic hydroxyl groups of the latter would bemethylated to form dimethoxyphenylethanolamine(Fig. 2) which is a close relative of mescaline. Thebiochemical detail in this hypothesis was suppliedby Harley-Mason. These mescaline-like products(' M-substance') would then affect the brain andinduce the psychosis. The link between stressand schizophrenia, which has been clinicallydemonstrated, would thus be explained, for thebiochemical fault would lie in the physiologicalmechanisms actiyated by stress and thus thebiochemical malfunction might only becomemanifest if the stress mechanisms became operativeor overloaded.

CH130 CH2CH2 NH2 HO : CHOHCH2NH.CH3

CH30 HO

CH30

FIG. i.-Mescaline and adrenaline.

HO CH.OH.CH2.NH.CH3 CH3 CH OH CH2NH.CH3

HO //CH3

FIG. 2.-Adrenaline and dimethoxyphenylethanolamine.

Recently a fair amount of evidence has ac-cumulated bearing on this hypothesis.

(i) It was demonstrated (Axelrod and Tomchick,1958; Armstrong, McMillan and Shaw, I957)that the normal method of metabolizing adrenalinein the human is by methylating one of the phenolichydroxyl groups to give metanephrine (Fig. 3)which in turn is deaminated to give VMA.

(ii) It was shown by Harley-Mason, Laird andSmythies (I958) that a minor metabolite ofmescaline in the human is 3-methoxy-4,5-dihydroxyphenylethylamine (Fig. 3). Thus themetabolites of mescaline and adrenaline are evenmore alike than their parent substances and onecan see how mescaline could act by some inter-ference between its own metabolism and that ofadrenaline.

(iii) Anxiety-prone individuals, who possess ahigh level of tone in their sympathetic nervoussystems, tend to react more severely to mescalinethan do less anxiety-prone individuals and theirsymptoms are much more akin to those seen inactual schizophrenia. Thus a condition of stimula-tion of the sympathetic system seems to facilitatethe psychotic process. Furthermore the symptom-free relatives of schizophrenic patients react in amuch more psychotic (paranoid) manner to LSDthan do normal controls.

(iv) Friedhoff and Van Winkle (I962) haveclaimed to have isolated dimethoxyphenylethyl-

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January I963 SMYTHIES: Biochemistry of Schizophrenia 27

HO CH.OH.CH2NHCH3 CH30O CH.OH.CH2.NH.CH3

HO HO

CH30 CH2.CH2.NH2 CH30tCH2CH2NH2

CH3 0 HO

CH30 HO

FIG. 3.-(Upper) Metabolism of adrenaline to meta-nephrine. (Lower) Metabolism of mescaline (aminor pathway in humans).

H3 QCH2.CH2. NH2CH30

CH30

CH30(CH2.CH2.N (CH3)2CH30Q

CH30FIG. 4.-(Upper) Dimeth-

oxyphenylethylamine.(Lower) N.N.-dimethyl-mescaline.

amine (Fig. 4) from the urine of iS to I9 schizo-phrenics and not from any of 14 normal controls.Confirmation of this work is awaited with interestas if it is confirmed it would constitute partial veri-fication of the Osmond-Smythies hypothesis.

(v) However, against the hypothesis is the factthat tests of overall metabolism in schizophrenia(Resnick, Wolfe, Freeman and Elmadjian, I958;Cohen, Holland and Goldenberg, I959; La Brosse,Mann and Kety, I96I) have failed to show anydifferences between the metabolism of adrenaline inthe case of schizophrenic patients and normalcontrols. Schizophrenics excrete the same meta-bolites in the same proportions as do normalpeople; they show the same rate of utilization ofinjected adrenaline; nor do they apparently excreteany abnormal metabolites of adrenaline. Themetabolism of dopamine, as measured by injectingits precursor DOPA, is also normal (Lenz, I962).Nor do schizophrenics react in any qualitativelyabnormal manner to injected adrenaline: theyshow in fact less reaction than do normal people(Pollin, Cardon and Kety, I96I; Pollin and

Goldin, I96I). However, it is known that inmany cases the body deals quite differently withsubstances injected than with substances pro-duced at the normal site of action of the agent andfurthermore adrenaline crosses the blood-brainbarrier in only a few localized places. So thesenegative results do not necessarily carry any greatweight.

(vi) Some indirect evidence was produced byCosta (I960) who reported that there is a closequantitative correlation between the hallucinogenicpowers of a drug and its capacity of potentiatingthe action of adrenaline on various pharmaco-logical preparations.

(vii) The evidence concerning the generalimportance of excess methylation will be reviewedbelow.

The Second Specific HypothesisThis was formulated independently by Gaddum

and by Woolley and Shaw in I954. This hypo-thesis is based on the fact that the most powerfulhallucinogen known-lysergic acid diethylamide(LSD)-(Fig. 5) has powerful anti-serotonin

H\NO.H HHNOCC21H1

NCH2 NH2 N

HO

\ N'R2 NH

RIFIG. 5.-Lysergic acid diethylamine (shown as com-

pounded of serotonin and nicotinamide).

properties when tested on smooth muscle. Thisled to the suggestion that psychosis may be linkedwith abnormalities of serotonin (5-HT) (Fig. 6, I)in the brain. We now know, however, that therecannot be any direct link between peripheral anti-5-HT action and psychosis because (i) closerelatives of LSD such as brom-LSD and MBL 6iare as (or more) powerful anti-5-HT agents, cancross the blood-brain barrier and yet are psychia-trically quite inert. (ii) Furthermore, no consistentmajor abnormalities of 5-HT metabolism havebeen found in schizophrenics (Rodnight, I96I).A few cases have been reported to show variousquantitative abnormalities but the details requireconfirmation. (iii) However, 5-HT clearly mustplay some important role in brain function as bothit and its correlated enzymes are found in the brainand in particular in those parts of the brain thatare concerned with the control of emotion and

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28 POSTGRADUATE MEDICAL JOURNAL January I963

HOc 7CH2CH2NH2 HO7 CH2.CH2N(CH3)2

HIH

N 2-CH2 N(CH3)2 NCH2 CH2.N(CH3)2

H mH izOH

CH2.CH2 N(CH312 CH30 CH2 CH2 N(CH3)2

N <NH 7 H E

FIG. 6.-I. Serotonin. II. Bufotenin. III. DMT.IV. 6-hydroxy-DMT, a metabolite of III. V.psilocyn. VI. 0-methylated derivative of bufotenin.

autonomic responses in general. Disorders of5-HT tnetabolism are clearly linked with the stateof the emotions. The sedative agent reserpineproduces its effects on mood by depleting thebrain stores of serotonin and reserpine commonlyinduces in humans a state of clinical depression.Furthermore, the potent anti-depressant drugimipramine facilitates the transport of 5-HTacross cell membranes and sensitizes tissues tothe action of 5-HT. (iv) It has also been shownthat LSD has important effects on brain 5-HT.It raises the levels of 5-HIT in the brain by 40%and induces a large increase in the rate of turnover(to 350%) (Sankar, Gold, Phipps and Sankar,I96I). This effect is not shared by its non-psychotomimetic relatives i-LSD and brom-LSD(Freedman, I96I). LSD and 5-HT have complexinteractions in the brain. In some regions theyare antagonistic, in others they are also antagonisticbut reverse their roles, in yet others they actsynergistically.

Brodie (1958) has put forward the hypothesisthat LSD jacts by depressing the central para-sympathetic by competing with 5-HT at its activesites (owing to the ' built in ' indole structure ofLSD) and also by activating the central sympa-thetic. Certainly most hallucinogens are powerfulstimulants of the central sympathetic systemalthough not all powerful central sympatheticstimulants are hallucinogenic. This attractivehypothesis still remains to be proved. But clearly5-HT is of great importance to psychiatry.Present trends seem to link it closer with de-pression than with schizophrenia but it may alsoplay some important role in the latter.

The Third Specific HypothesisA third hypothesis has recently been put forward

by McIsaac (I96I). He notes the close chemicalsimilarity between the hallucinogenic drug harmine

CH2 30'3 -'CH2 CH3(0 Y( H2

1-H20HH H

N'CHHH30

FIG. 7.-(Upper) Melatonin and io-methoxyharmalan.(Lower) Harmine.

and the pineal hormone melatonin (Fig. 7).Melatonin is synthesized in the pineal gland andthence is distributed to the rest of the brain. Itsfunction in humans is not understood. Its closerelative io-methoxy harmalan is a potent 5-HTantagonist and i mg. of it completely disorganizeslearned behaviour in the rat. Thus a disorder ofmelatonin metabolism could be associated withcertain cases of psychosis.

The Fourth Specific HypothesisThe previous three hypotheses have been based

on the possible production in the body of sometoxic agent or on the disorder of some naturallyoccurring compound. The fourth hypothesis pos-tulates a more wide-spread and general disorder ofa particular biochemical mechanism that mayproduce a variety of abnormal substances. Thismechanism is methylation (Smythies, I963).The evidence for this is as follows: (i) We notedearlier that mescaline can be regarded as a deriva-tive of adrenaline when the phenolic hydroxylgroups of the latter are methylated (and one added).This is 0-methylation. (ii) Then a series of otherhallucinogens were discovered which are deriva-tives of tryptamine in which the methyl groups areattached to the nitrogen atom (N-methylatlon).Tryptamine itself so treated gives N.N.-dimethyl-tryptamine (DMT) (Fig. 6, III), a potent hallu-cinogen which also causes violent disturbances ofthe autonomic nervous system. Its effects last forabout one hour. N.N.-diethyltryptamine (DET)acts in a similar manner only the effects last forabout three hours. The active agents may be their6-hydroxylated metabolites (Fig. 6, IV). (iii)Then psilocybin was discovered. This is a phos-phoric acid ester of psilocyn which is 4-hydroxy-N.N.-dimethyltryptamine (Fig. 6, V). Both thesecompounds are hallucinogenic with effects similarto those produced by DET. (iv) Bufotenin (Fig.6, II) is N.N.-dimethyl serotonin. It has power-ful effects on the autonomic system and somerather ill-defined hallucinogenic activity. SoN-methylation of important physiological sub-stances can produce potent hallucinogenic sub-

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stances. (v) Furthermore, if the phenolic hydroxylgroup in some of these compounds is also methy-lated (0-methylation) (Fig. 6, VI) this increasestheir capacity to disrupt learned behaviour in therat. (vi) These findings have gained much insignificance by Axelrod's discovery (I96I) of anN-methylating enzyme in rabbit lung that willactually convert serotonin to bufotenin andtryptamine to DMT. Thus the metabolic mecha-nism has been demonstrated in mammalian tissuethat will convert important bodily chemicals intopsychotomimetic agents. (vii) The hypothesisthat excess methylation could play some part in theetiology of schizophrenia could be tested byfeeding schizophrenics with methyl donors-thatis with chemical compounds that act as donors ofmethyl groups in methylation processes. Methio-nine is just such a compound and a discovery ofmajor importance was made by Pollin and others(I96I). They fed a variety of aminoacids toschizophrenic patients under cover of a monoamineoxidase inhibitor (to prevent the breakdown ofamines derived from these amino acids). Theyfound that methionine, and methionine alone,caused in four of nine patients an exacerbationof their symptoms. Their hallucinations, de-lusions and anxiety were increased and thethought disorder was exacerbated. These findingshave been confirmed by Brune and Himwich(I962). Methionine has a number of properties,however, besides its action as a methyl donor.So Brune and Himwich investigated the effects ofanother (chemically unrelated) methyl donor-betaine. They found this to act just as methioninehad done. Thus the hypothesis has survived twotests. (viii) Fischer, Lagravere, Vazquez andDi Stefano (I96I) reported the isolation ofbufotenin itself from schizophrenic urine in 25 of26 cases. This was confirmed by Brune andHimwich (I962) but Rodnight (I96I) was unable tofind any in spite of a careful search using a sensitivemethod. In any case bufotenin could hardly bethe toxic agent of schizophrenia, because peoplewith this illness do not show the marked autonomicresponses characteristic of bufotenin poisoning.But its presence in the urine, if real, may be anindication of the basic disorder of methylationprocesses that may constitute the metabolic basisof schizophrenia.

Thus, to summarize this section it has beenshown that methylation of serotonin, tryptamineand derivatives of tryptamine and of adrenalinein either the N or the 0 position can producepowerful hallucinogenic substances. An enzymecapable of doing some of these reactions in vivohas been isolated. Feeding schizophrenics withmethyl donors of two different chemical species(methionine and betaine; under MAOI cover)

produces in many cases an exacerbation of theirsymptoms. Lastly the methylated compoundsbufotenin and 3,4-dimethoxyphenylethylaminehave been isolated, so it has been claimed, fromschizophrenic urine. All these findings supportthe working hypothesis that a disorder of methyla-tion processes is in some way causally connectedwith the schizophrenic illnesses. One difficultyhere is that schizophrenia is a genetically de-termined condition and most if not all othergenetically determined conditions are due to thelack of some enzyme, whereas here we seem toneed to postulate an extra enzyme (an N- or 0-methyl transferase) (Ashcroft, I962). However,it is possible that some enzyme that normally keepsmethylation within limits is lacking. There is onecurious paradox. The general rule for thesecompounds seems to be that an increase inmethylation is correlated with increased psycho-tomimetic activity. However, ifwe N.N.-dimethy-late mescaline itself the resultant compound(Fig. 4), according to Luduefia (1935), appears tohave lost its psychotomimetic activity. But, asthis is based on only a single experiment, this needsconfirmation.

Further experiments suggest themselves.Methionine, betaine and other methyl donorsshould be given together with a methyl acceptorsuch as glycocyamine. The hypothesis wouldpredict that this would abolish their toxic effect onschizophrenics. Secondly, using radioactive tracertechniques a minute study should be made ofmethylation processes in schizophrenia. Thenthe presence or absence of bufotenin and di-methoxyphenylethylamine in schizophrenic urineneeds settling.

Empirical DiscoveriesCarbohydrate Metabolism

Several reports have appeared recently claimingto show that there are disorders in carbohydratemetabolism and in basic -energy metabolism inschizophrenia. (i) Firstly, schizophrenics seem toshow phosphorus retention. (ii) Frohman andhis co-workers in a series of papers have claimedthat schizophrenic plasma contains a factor withthe following properties: (a) it increases the rate ofturnover of ATP in red blood cells but renders thisrate of turnover incapable of the large increase thatis normally observed following the administrationof insulin; (b) it increases the amount of glucosepassing down the Meyerhof pathway of anaerobicglycolysis (which leads to the production of ATPand energy) in proportion to the amount passingdown the ribose pathway (whose function is largelysynthesis of nucleoproteins, etc.) but again thisproportion cannot be increased by insulin as it canin normals; (c) it causes an elevation of the lactate/

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pyruvate ratio produced by red cells suggestingsome inhibition of aerobic metabolism. Theylocalized this factor in the a-globulin fraction ofthe plasma. In a recent paper they report,however, that this factor appears in the blood ofschizophrenics only following physical exercise.This obscures somewhat its clinical significance.Further identification of this factor is awaited withinterest. Partial confirmation of these results hasbeen reported by Arnold and Hofmann (I962).They could not detect any differences in inter-mediate carbohydrate biochemistry betweenschizophrenics and controls in the resting state,i.e. before giving, in their case, not insulin butsuccinic acid. However, after giving succinic acidto the subjects (by intravenous injection) a cleardifference emerged. The specific activity andp32 uptake of ATP and triose-phosphate signi-ficantly increased in the normal group but did notdo so in the case of the schizophrenic group.Relatives of schizophrenics, who themselves hadhad no psychiatric disease, gave intermediatevalues. This is similar to the reaction observedby Frohman and his group following the injectionof insulin. The differences before giving insulin(or succinic acid) in the two groups may possiblybe explained by different exercise levels or diag-nostic criteria. However, it seems probable thatschizophrenics show a disturbance in intermediatecarbohydrate metabolism that is apparent onlyafter insulin or succinic acid is administered.(iii) Sacks (1959) has claimed that schizophrenicbrain is unable to oxidize its proper quota ofglucose and there is dilution, possibly at thepyruvate level, by intermediates derived fromlipid and/or protein metabolism. (iv) Thiscorrelates with reports that a factor in schizo-phrenic plasma (also localized to the a-globulinfraction) inhibits the uptake of glucose by ratdiaphragm and retina.

The Toxicity of Schizophrenic Body FluidsThere have been many reports in the literature

that schizophrenic body fluids are toxic to a largevariety of organisms ranging from fibroblasts tomonkeys. Recently more sophisticated and bettercontrolled tests have been applied. It has beenshown that schizophrenic plasma will disrupt thebehaviour of trained rats to a significantly greaterdegree than does normal plasma. Bergen,Pennell, Freeman, Hoagland and Smythies (I960)and Winter and Flataker (1958) used the rat rope-climbing test. The former group showed that thetoxic factor will diffuse across a semi-permeablemembrane. It must therefore be a small moleculeattached to protein and further tests showed thatthe globulin fraction was mainly involved. Bishop(I960) used instrumental-conditioned behaviour

with particularly good clinical control of hismaterial and showed that schizophrenic plasmaproduced a significant impairment (P<o.oi) ofnew learning but no impairment in the retentionof overlearning.

Using a neurophysiological method devised bySmythies, Koella and Levy (I960), Bergen,Koella, Czicmann and Hoagland (I96I) showedthat intravenous injections of globulin fractionsfrom schizophrenic plasma produce the sameeffects on the optic evoked potential to light flashin the optic cortex of the unanesthetized rabbit(i.e. inhibition and decrease of variability) as dolarge doses of mescalin and LSD. German (I96I)placed schizophrenic serum directly on the ratcortex and recorded the potential evoked in thesomatosensory cortex by peripheral stimulation.This resulted in a significantly greater potentiationof the potential as compared with the effects ofnormal serum. This is similar to the resultproduced by small doses of mescaline and LSD.Geiger (I960) has studied the effect of schizo-phrenic serum on neurones grown in tissueculture. The effects she observed were clear cutand definite and were never seen if serum fromnormal people was used. (a) The glial motility(which 5-HT also effects) was increased; (b) theneural cytoplasm normally shows pumping andpulsatile movements. These were increased; (c)fine undulating membranes could be observed oncell surfaces and the transfer of material fromoligodendroglia to neurones became more evident;(d) after some tirhe the granules of liponucleo-protein became smaller and more diffuse and mightdisappear (LSD also does this). Wada andGibson (1959) injected extracts from schizophrenicand normal urine into the cerebrospinal fluid ofmonkeys and cats. The extracts from schizo-phrenic urine produced a variety of abnormalbehaviour patterns-e.g. states of rage and recur-rent stuporose and catatonic states that were notseen if extracts from normal urine were used.However, there is as yet no definite evidence thatthese ' toxic agents ' are specific for schizophreniaand indeed in some cases there is evidence thatthey may occur in any state of severe stress.

Tryptophane MetabolismPrice, Brown and Peters (I959) reported that

6 of i9 schizophrenics metabolized 1-tryptophaneabnormally. They excreted excessive amounts ofkynurenine and its relatives but less N-methyl-2-pyridone-carboxamide (NMPC) than did normalcontrols. Similar effects were found in cases ofporphyria and in other psychoses but the meta-bolism of tryptophane was normal in purelyneurological disorders. Benassi, Benassi, Allegriand Ballarin (I96I) were able to confirm these

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SMYTHIES: Biochemistry of Schizophrenia

results but Brown, White and Kennedy (I960)could confirm only the lesser excretion of NMPC.The significance of these findings should beclarified by further research.

Tryptamine MetabolismBrune and Himwich (I962) have reported that

schizophrenics excrete in the urine more tryp-tamine and indole-3-acetic acid when they are illthan they do during periods of clinical remission.Other workers have found smiliar results forcatechol amines and 5-HT.Neuraminic Acid

Bogoch, Dussik and Lever (I959) haveexamined a large number of schizophrenic patientsand have found that they have abnormally lowlevels of neuraminic acid (sialic acid) in thecerebrospinal fluid. Christoni and Zappoli (I960)have confirmed this result. Bogoch and his co-workers also measured levels of hexosamine andfound this to be low in schizophrenia as well as inmanic-depressive psychosis and organic braindamage. Methods for measuring neuraminicacid are not yet well established, however, and thiswork requires extension.

HistamineIt has now also been established that schizo-

phrenics react to histamine less than normalpeople do. Lucy (I954) showed this clinically inthe response of the whole patient and variousworkers have shown this since by measuring thewheals produced by intradermal injection ofhistamine. This correlates with the fact that theskin of schizophrenics contains fewer mast cellsthan normal.

Immunity and Allied ReactionsA recent discovery of the greatest interest has

been the schizophrenic and normal sera havedifferent immunological properties (Haddad andRabe, I96I). They sensitized guinea-pigs toschizophrenic serum and then completely de-sensitized them by repeated injections of normalserum. If schizophrenic serum was then injectedthe guinea-pigs showed anaphylactic reactions inevery case. Thus schizophrenic serum has oneor more antigens not present in normal serum.Fessel (I96I) has reported a variety of abnor-malities in the plasma proteins of schizophrenicpatients as shown by electrophoretic methods,particularly in the globulin fraction alreadyincriminated, it will be recalled, by the work ofFrohman and his co-workers (I960, a, b, c) onintermediate carbohydrate metabolism and Bergenand others (I960) on the toxic factor in plasma.

Summary and DiscussionOne main finding of recent research has been the

demonstration of the close chemical relationshipbetween important constituents of the brain andhallucinogenic agents. Catecholamines and tryp-tamine derivatives such as 5-HT are found in thoseparts of the brain concerned with the highestcontrol of the autonomic nervous system. Simplechemical modification of these and similar com-pounds according to systematic principles (0-methylation and N-methylation) leads to the pro-duction of potent psychotomimetic agents suchas mescaline, DMT, psilocybin and (to someextent) bufotenin. Furthermore, most psycho-tomimetic agents seem to act as central stimulantsof the sympathetic nervous system and as peripheralsensitizing agents to the action of adrenaline.Brain HT may further be involved in psychosis as'is suggested by the observed correlation betweenthe ability of LSD and its analogues to causepsychosis and their power to raise levels and ratesof turnover of 5-HT in the brain.

Confirmation of the relation between excessmethylation and psychosis has been obtained byobserving that two methyl donors-methionineand betaine-both aggravate the symptoms ofschizophrenic subjects. It would be interestingto repeat these experiments in normal people.Further supportive evidence has been obtained inthe (as yet unconfirmed) reports that bufotenin anddimethoxyphenylethylamine have been isolatedby chromatographic methods from schizophrenicurine. Thus a number of different leads all crossat the same point and enable us to make the work-ing hypothesis that the most promising field tostudy in schizophrenia would be that of methyla-tion processes as applied to catecholamine andtryptamine derivatives. The way is now open fora considerable number of critical experiments totest this hypothesis and progress in this fieldshould be rapid.

Also of interest are the changes in intermediatecarbohydrate metabolism, tryptophane metabolismand neuraminic acid levels that have been reported.Further developments in these fields also can beexpected as well as attempts to correlate one fieldwith another. One could ask such questions as' would changes in methylation processes beexpected to affect intermediate carbohydratemetabolism and if so how '; and vice versa.Vigorous attempts are at present being made toisolate and identify the ' toxic factor ' in schizo-phrenic plasma. Its location in the globulinfraction offers the possibility of correlation withthe changes recently discovered in the immuno-logical properties of schizophrenic plasma.

But clearly priority in research at presentshould go to further testing that particular

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hypothesis that has already withstood the mostcritical tests. This is the hypothesis of excessmethylation. Priority should also go to basicstudies of the neurochemical and neuropharmaco-logical mode of action of the known chemical com-pounds that induce in man a state resemblingpsychosis.. This requires multidisciplinary re-search on a large scale. If only we can discoversome of the biochemical mechanisms that underliepsychosis then we can test the performance of thesemechanisms in schizophrenia. Furthermore, if weknow how mescaline, LSD, DMT, etc., act, wecould design anti-metabolites using rationalprinciples to block their action and we could thengive these drugs empirical trial in schizophrenia.

It is possible, for example, that in order to be apsychotomimetic agent a drug must both stimulatethe central sympathetic and sensitize tissues to theaction of the catecholamines. Any drug doingonly one or the other is ineffective. Drugs whichare effective in treating schizophrenia-such aschlorpromazine-certainly depress central sympa-thetic function and have anti-adrenaline properties.Amphetamine, on the other hand, is a powerfulstimulant of the central sympathetic system andcan induce in certain people a typical paranoidschizophrenic illness. Basic research of this kindleads eventually to therapeutic trials and theprogress from cause to therapy is, after all, theaim of medical research.

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ASHCROFT, G. (1962): Personal communication.AXELROD, J. (I96I): Enzymatic formation of Psychotomimetic Metabolites from Normally Occurring Compounds,

Science, 134, 343.- and ToMCHICK, R. (1958): Enzymatic 0-methylation of Epinephrine and Other Catechols,J7. biol. Chem., 233, 702.BENASSI, C. A., BENASSI, P., ALLEGRI, G., and BALLARIN, P. (I96I): Tryptophan Metabolism in Schizophrenic Patients,

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WOOLLEY, D. W., SHAW, E. (1954): A Biochemical and Pharmacological Suggestion About Certain Mental Disorders,Proc. nat. Acad. Sci. (Wash.), 40, 228.

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