136 rebound of rapid eye-movement (R.E.M.) sleep following as normals do. Other reports of possibly abnormal biochemistry in schizophrenic patients have been made but remain to be substantiated.

show

Mental Health

a

R.E.M.

deprivation

HYPOTHESES

RECENT PROGRESS IN SCHIZOPHRENIA RESEARCH

J. R. SMYTHIES Department of Psychiatry, University of Alabama Medical Center, Birmingham, Alabama 35294, U.S.A. IN previous reviewsl2 it was stated although very little was known of the nature of the putative biochemical lesion in schizophrenia, at least some workable hypotheses were available and directing promising research. In the past few years further developments have taken place which will be the subject of this review. I will first review the data and then discuss the hypotheses generated by these data. The methionine effect.-This was discovered in 1961 by and his co-workers and has been confirmed by other groups.4-9 The finding is that about 40% of chronic schizophrenics react to 20 g/day of L-methionine with an acute psychotic reaction. The other 60% do not react in this way. Methionine (250 mg/kg) given to mice and rats10 produces a behavioural reaction in conditioned avoidance tests (BovetGatti) similar to that produced by lysergic acid diethylamide (L.S.D.). This methionine effect in rodents can be blocked by

Kety

serine. Platelet

monoamineoxidase (M.A.O. ).—This has been reported to be significantly lower than normal in both schizophrenics and manic depressives by several investigators12-15 but this could not be confirmed by others.16-18 Schildkraut et al.19 have suggested that only a subgroup of patients, in which paranoid symptoms and delusions are prominent, have low blood-M.A.o. In monozygotic twins discordant for schizophrenia, the same low level of M.A.O. activity is found in both. Thus a low level of M.A.O. activity may be necessary but not a sufficient condition for certain psychotic conditions to de-

velop. Histamine resistance.-This has been reported by several workers.20-24 If histamine is injected intradermally a weal appears. This weal is smaller than normal in many schizophrenic patients but enlarges to normal following clinical remission. However, these studies have been criticised on the grounds that concomitant drug therapy was not properly controlled in most studies. Certain drugs--e.g., amphetamines and M.A.O. inhibitors, tend to worsen schizophrenics’ condition and others-e.g., phenothiazines and butyrophenones-improve it. The former potentiate brain catecholamine, particularly dopamine, function and the latter block catecholamine, particularly dopamine, receptors. Certain other drugs--e.g., d-L.S.D., mescaline, and dimethyltryptamine (D.M.T.), can induce acute schizophreniform reactions ("bad trips") in some people. These drugs act on the brain serotonin (5-hydroxytryptamine [5-H.T.]) receptor.

D,L-&rgr;-chlorophenylalnine (fenclonine), which blocks 5-H.T. synthesis, can induce psychotic reactions in carcinoid patients. Reports have appeared that the hallucinogens D.M.T. and O-methylbufotenine (5-methoxy-N,N-dimethyltryptamine) (O.M.B.) occur in human body fluids as trace metabolites25 but it seems that schizophrenics do not contain more than normal (see below). Saavedra and Axelrod26 have shown that brain contains both the precursor and the enzymes required to produce D.M.T. from tryptamine. Gillin et al. 25 have shown that schizophrenics fail to)

The

Transmethylation Hypothesis This was put forward in 1952 by Osmond, Smythies, and Harley-Mason.27 It is based on the fact that the psychotomimetic drug mescaline is an 0-methylated derivative of dopamine, so that it is possible that schizophrenia might be related to an aberration of transmitter metabolism with the production in the body of compounds like mescaline. Other candidates for the possible endogenous psychotoxin are similarly methylated derivatives of 5-H.T. such as D.M.T. and 5-methoxy-N, N-dimethyltryptamine (o.M.B.). The precursor, tryptamine, and the enzymes required to produce D.M.T. are present in the brain, which can actually synthesise D.M.T. in vitro from added tryptamine.28 In the past few years D.M.T. has been detected in low concentrations in human bodyfluids by gas chromatography and mass spectrometry (G.C.-M.S.),29 but evidence still has to be presented that schizophrenics are significantly different from normals with respect to concentration, turnover, or sensitivity to D.M.T. One explanation of the methionine’ effect described above is that this aminoacid is the

methyl

groups in

source for all reactions via its deri-

transmethylation S-adenosylmethionine. Thus, feeding large amounts of methionine may increase transmethylation

vative

reactions. Recent work in this department30 3has been directed towards measuring levels of D.M.T. and O.M.B. in the cerebrospinal fluid (c.s.F.) of schizophrenics and normal controls. The proteins were removed from the fluids, which were then extracted to obtain basic compounds and reacted with heptafluorobutyrylimidazole to obtain highly fluorescent derivatives as described elsewhere.32 The amounts of derivatives were measured on a gas chromatograph with electron capture. Representative records were spiked with the pure standard compound for O.M.B., D.M.T., tryptamine, and N-methyltryptamine (limit of sensitivity D.M.T. 1 pg/ml, O.M.B. 5 pg/ml). In 2 c.s.F. specimens the results were confirmed for D.M.T. by mass spectometry (carried out by Dr Lou Mandell) and in 1 for D.M.T., o.M.B., and tryptamine by the L.K.B. Instrument Company. c.s.F. from 34 schizophrenic and 17 normal controls was tested. The latter were from genitourinary surgery patients, kindly made available by Dr Guenter Corssen. The results showed that D.M.T., O.M.B., and tryptamine are present in human c.s.F. (D.M.T. at approximately 1-0 ng/ml) but there was no increased incidence in

schizophrenics as compared with normal controls. In fact, the trend was in the other direction: D.M.T. was positive in 10 out of 34 schizophrenics compared with 7 out of 17 controls; O.M.B. was positive ie. 11 out of 34 schizophrenics compared with 13 out of 17 controls; but tryptamine was positive in 20 out of 34 schizophrenics compared with 3 out of 17 controls. This finding is compatible with the findings of Brune and Himwich33 that acute schizophrenics have increased tryptamine levels in urine. Identification by G.C. that a substance is present is not absolutely certain, but this study at least provides evidence that schizophrenics do not have higher c.s.F.

137 levels of hallucinogenic N-methylated tryptamines than do controls. Christian3’ found evidence that D.M.T. may be a normal transmitter in the brain. It is found specifically in the vesicle fraction, is taken up into vesicles; and stimulates adenylate cyclase activity when bound tc synaptosomes. In insect, it has been shown to depolarise cells in salivary glands.3Beaton et at. 36 found that shock stress in rats causes a marked rise in brain D.M.T. levels particularly in the vesicular fraction. Thus D.M.T. may be related to stress rather than any specific neuropsychiatric disease. Our human c.s.F. data showed a number of other peaks on the chromatogram. The nature of these and their possible relation to schizophrenia are presently under investigation. These findings in c.s.F. confirm those of Angrist and Mandel in blood37 using G.c.-M.s. D.M.T. was found (limit of sensitivity 0.5ng/ml) in blood but there was no significant dif ference between schizophrenics and normals. The One-carbon-cycle Hypothesis. When methionine loses its methyl group it become’

homocysteine which then combines with serine tc cystathionine. This is part of the one-carbon Beaton" has shown that the behaviour disrupting cycle. become

action of 250 mg/kg methionine in rodents may be completely blocked by feeding an equal amount of serine, Sleep disruption induced by methionine can also be blocked by serine.38 This suggests that excess amounts oj homocysteine may be involved in the psychotoxic effects of methionine. Freeman et at. 39 have reported the cas( of a 16-year-old girl diagnosed as schizophrenic who hac a specific defect in one of the enzymes of the one carbon cycle-51, 101-methylenetetrahydrofolate re ductase. She was cured by doses of folic acid whic: corrected the metabolic disorder produced by the defect, The Tryptophan-uptake Hypothesis A third mechanism by which excess methionine could disrupt brain function underlying behaviour is by its competitive blockade of tryptophan uptake into the brain. Large doses of methionine lower brain 5-H.T. b) this mechanism as it has been shown that the levels oj brain 5-H.T. are a direct function of brain tryptophar levels which in turn are a direct function of blood (and dietary) tryptophan.4O Beaton41 has shown that glucose. succinate, and glycine, in addition to serine, will blod the sleep-disrupting effect of methionine in rats. The only common factor between glucose, glycine, and serine is that they all cause insulin release, and insulin raises brain 5-H.T. by blocking the uptake of the competing (large neutral) aminoacids on the tryptophan uptake mechanism, without blocking the uptake of tryptophan itself. Possibly the disruptive effect of methionine on behaviour is a complex function of these three mechanisms

raising brain 5-H.T. levels. The effectiveness of this would partly depend on the original cause of the defective 5-H.T. function (defective synthesis, defective transport of tryptophan (T.R.P.), blockade of 5-H.T. receptors by endogenous agents such as D.M.T., faulty compartmentalisation, decreased receptor sensitivity, &c.). However, the clinical effect of measures designed to augment central 5-H.T. function should certainly be studied in schizophrenia. An effective way of raising brain 5-H.T. is by Trp40 loading augmented by giving an M.A.o. inhibitor. This treatment was actually tested in a study reported in a paper published in 1958.44 7 chronic schizophrenics were given Trp 20 mg/kg plus iproniazid 20 mg. After a delay of 10-21 days, the following behavioural changes resulted an increase in energy level and motor activity and improvement in the ability to accept interpersonal relationships, and they displayed more affect. In addition, their voluntary intake of protein and tryptophan increased." This effect was confirmed by Kety’s group.39 This clearly suggests an improvement in the clinical condition of these patients and not a deterioration.43 5-hydroxyindoles (5-H.I.)—including mainly 5-H.T. with some 5-hydroxyindoleacetic acid (5-H.I.A.A.) levels in whole blood were reduced in 83% of retarded patients with hyperkinetic and aggressive behaviour. Raising of 5-H.I. levels by various drugs was associated with a reduction or disappearance of the hyperkinetic syndrome. Patients who remained hyperkinetic failed to show an increase in the blood-5-H.I. levels. This may reflect similar changes in brain 5-H.T. levels. L-Trp in rats reduces spontaneous locomotor activity,46 an effect prevented by D-Trp. The main metabolic pathways concerned are shown in fig. 1. Three pathways diverge from brain Trp--the major via kynurenine to nicotinamide and N-methylnicotinamide (excreted), a second to 5-H.T. and 5-H.I.A.A. (excreted), and possibly a third to D.M.T. Brain 5-H.T. is under direct control by dietary Trp (since the enzyme limiting the rate of 5-H.T. synthesis, Trp 5-hydroxylase, is not saturated with Trp). Other factors raising brain 5-H.T. are 43 (1) food deprivation; (2) immobilisation; (3) salicylates, which displace Trp from its plasma-albumin

conjoined. The A

5-H.T./Dopamine Imbalance Hypothesis

new hypothesis has been put forward independently by Smythies42 and Green and Grahame-Smith.43 This suggests that some cases of schizophrenia may be associ-

ated with

an imbalance between the brain dopamine sys(overactive) and 5-H.T. systems (underactive). Thus schizophrenia would be, in part, a similar kind of disorder to Parkinson’s disease, where the relative imbal-

tems

ance

of cerebral neurotransmitter function lies between

acetylcholine (overactive) and dopamine (underactive) Thus some cases of schizophrenia might be treated by

Fig.

1—Relevant parts of TRP and

The four

pathways from Trp

to

tyrosine (TYR) metabolic pathways. D.M.T., I.A.A., 5-H.T., and R3 (nico-

shown. Cross-hatched part is the common uptake mechanism for the "large neutral" aminoacids including Trp, methionine (ME T , valine ,VAL , leucine (LEU). PHE=phenylalamne. B=site of action of methionine. A=trvptophan pyrrolase—site of action rucotinamide adenine dmucleotide .NAD. and allopur-inol ’blockade".

tinamide)

are

138

binding sites; (4) ingestion of carbohydrates (via insulin release; (5) the dietary reduction of large neutral aminoacids competing with Trp for uptake; (6) lowering cortisol levels (decreased stress) via a modulation of the activity of Trp pyrrolase; (7) feeding large amounts of nicotinamide44 via the inhibition of Trp pyrrolase by nicotinamide adenine nucleotide; and(8) allopurinol4l by inhibiting Trp pyrrolase. Nicotinamide also produces sedation in mice49 and an increase in R.E.M. sleep.50 Evidence that the dopamine system is only overactive relative to another system is provided by the finding that homovanillic acid, the major metabolite of dopamine, is not elevated in schizophrenic C.S.F.51-53 Moreover, prolactin levels in schizophrenics are normal. 54 Prolactin release is inhibited by dopamine and excessive central dopamine activity might be expected to lead to lowered blood prolactin levels. of 5-H.T. levels in blood from schizophrenics given conflicting results. Two studies in chronic schizophrenia report low levels55 56 two studies found lower levels in chronic than acute cases, 57 58 and one more recent study59 found high levels in unmedicated chronic schizophrenics and normal levels in medicated chronic schizophrenics. A further study of the blood of autistic children found high levels.60 Possibly there are two types of schizophrenics-those with low 5-H.T. levels and those with high. Furthermore, the levels in platelets may not accurately reflect brain levels. Moreover, turnover may be more important than levels. In other cases an underreactive -f-aminobutyric acid (G.A.B.A.) system (e.g., the inhibitory input into the substantia nigra) may be involved. More work in this area is necessary. Direct

kynurenine pathways is faulty. Excess methionine may act on this system by promoting the indole pathway to indoleacetic acid (I.A.A.) instead of the kynurenine pathway.64 Brune and Himwich33 reported that urinary tryptamine and I.A.A. increase during active psychotic episodes and decrease afterwards. Heyman65 found that schizophrenics show a decreased excretion of N-methylnictotinamide but an increase in N-methyl-2-pyridone-5-carboxamide. Further work in this

area

is

neces-

sary.

Wyatt et a1.66 found that 5-hydroxytryptophan (5-H.T.P.) plus a peripheral decarboxylase inhibitor produced a mild to moderate improvement in 6 out of 7 chronic undifferentiated schizophrenic patients. In 4 chronic paranoid patients, 1 improved but 2 became worse. The results were interpreted as possibly being due to raised brain 5-H.T. levels.

measurements

OTHER RECENT FINDINGS

have

Defective Tryptophan Metabolism Hypothesis The relevant metabolic system is shown in fig. 2. Reports of abnormalities in this pathway have appeared from time to time. Lozovskii61 found that Trp loading in schizophrenics leads to an increase in N-methylnicoThe

tinamide excretion and in decrease in xanthurenic acid excretion compared to normals. Benassi et al." in a similar Trp loading experiment (100 mg/kg) found that

schizophrenics

kynurenine, kynurenic acid, and xanthurenic acid, but not more 3-hydroxyanthranilic acid, than controls. Payne et a1.63 reported findings that suggest that the normal control mechanism that regulates Trp metabolism via the indole or excrete

The overall blood-flow is normal in all cases. This regional distribution indicates that certain brain areas are overactive and others underactive in different cases. A THERAPEUTIC PROGRAMME FOR SCHIZOPHRENIA

more

Tro

8

Fig.

Singh and Kay67 have confirmed in a double-blind study Dohan’s claims68 that wheat gluten exacerbates schizophrenic symptomatology. Dohan’s hypothesis was based on epidemiological studies comparing the incidence of schizophrenia in locations with a high wheat dietary intake versus locations with a low dietary intake (e.g., wartime Sweden and U.S. vs. occupied countries; Western Europe in peace-time versus rice-eating countries). Singh and Kay maintained a population of schizophrenics on a gluten-free diet and showed that wheat flour but not soy flour, reversed the clinical amelioration produced by antischizophrenic drugs. Franzen and Ingvar69 have determined by xenon-133 studies that regional blood-flow is abnormal in chronic schizophrenics. Patients showing the symptoms of apathy, indifference, and autism have decreased cerebral flow in the frontal lobes, whereas patients showing cognitive disturbances show increased flows in post-central areas.

2-Part of the

kyneurenine pathway.

of schizophrenia conthe overactive brain dopamine, and other catecholamine systems. For this, receptor blockers such as phenothiazines, butyrophenones, and related drugs are used. Unfortunately, it has been found that an unacceptably large proportion of patients on long-term treatment with these drugs develop irreversible brain damage in the form of tardive dyskinesia. Thus new methods of treatment are urgently needed. We plan at this centre to attempt to develop a method based on augmenting brain 5-H.T. function. If certain cases of schizophrenia are associated with impaired 5-H.T. function then this may prove of therapeutic benefit. Of course, other cases may be associated with excessive 5-H.T. production. Furthermore, it may be possible to raise 5-H.T. production excessively with undesirable effects. However, a careful clinical trial along these lines is certainly warranted in the present state of our knowledge. The strategy is to try and find the equivalent in schizophrenia for levodopa treatment of Parkinson’s disease. Progress can be biochemically monitored by sequential estimations of blood-5-H.T., urinary 5-H.I.A.A., methylnicotinamide, and other Trp metaboThe

current

centrates

standard

solely

on

treatment

reducing

139 and O.M.B., and platelet M.A.o. The following dietary and medication strategies to raise brain 5-H.T. and lower brain dopamine can be tested in various combinations: (1) raise dietary Trp (+M.A.0. inhibitor); (2) lower dietary methionine and other large neutral aminoacids; (3) lower dietary tyrosine and phenylalanine; (4) feed glycine or serine; (5) feed nicotinamide in large doses; (6) feed co-factors of Trp pathways that must be promoted (Trp-3-H.T.) such as pyridoxine; (7) administer salicylates and/or allopurinol. Several of these have been tried already in isolation with varying results. However, effective treatment in certain cases may depend on finding the optimum combination. Schizophrenics may be divided into those with decreased, with normal, and possibly with excessive central 5-H.T. function. The first group may be further subdivided on the basis of the cause for their decreased 5-H.T. function (see above) and of what concomitant abnormalities there may be in other systems-e.g., dopamine and others. The group of schizophrenias may turn out to have a most complex series of abnormal pathobiochemistries. Other strategies would include the development of a good non-toxic inhibitor of indoleamine-Nmethyltransferase for which Mandel’° has developed a candidate and the development of a good G.A.B.A. agonist that can cross the blood-brain barrier. This derives from the observation’1 that the inhibitory input to the dopamine-containing neurones in the substantia nigra is gabergic. Hence dopaminergic activity could be reduced by activating an inhibitory input rather than by receptor blockade, which might prevent the development of tardive dyskinesia. Unfortunately, at present, no such agent is known. However, it has -recently been shown’2 that arecaidine and other constituents of betel nut are powerful inhibitors of G.A.B.A. uptake. These warrant testing in schizophrenia. The remarkable potential of modulating behaviour by control of dietary factors including aminoacids is instanced by a report by Little73 that feeding rats a low Trp diet abolishes the analgesic response to morphine. He concludes, "The results of these studies demonstrate that the quality of the diet consumed can influence greatly the behavioural and biochemical potency of

lites, skin histamine reaction, blood

D.M.T.

drugs." Requests for reprints should be addressed to J. R. S., Department Psychiatry, School of Medicine, University of Alabama Medical Center, University Station, Birmingham, Alabama 35294, U.S.A. of

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216, 1110. 7. Antun, F., Burnett, G. B., Cooper, A. J., Daly, R. J., Smythies, J. R., Zealley, A. K. J. psychiat. Res. 1971, 18, 63. 8. Ananath, J., Ban, T. A., Lehmann, H. E., Bennet, J. Can. psychiat. Ass. J. 1970, 15, 15. 9. Park, L. C., Baldessarini, R. J., Kety, S. S. Archs gen. Psychiat. 1965, 12, 346. 10. Beaton, J. M., Smythies, J. R., Pegram, G. V., Bradley, R. J. Psychopharmacologia, 1974, 36, 101. 11. Beaton, J. M., Pegram, G. V., Bradley, R. J., Smythies, J. R. Behavioural Biol. 1974, 12, 249. 12. Murphy, D. L., Wyatt, R. J. Nature, 1972, 238, 225. 13. Wyatt, R. J., Belmaker, R., Murphy, D. in Modem Problems of Pharmacopsychiatry (edited by T. Ban, F. A. Freyhan, P. Pichot, and W. Pöldinger; vol. x. Basel, 1975. 14. Meltzer, H. Y., Stahl, S. M. Res. Commun. chem. Pathol. Pharmacol. 1974,

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Friedman, E., Shopsin, B., Sathanathan, G., Gershon, S. Am. J. Psychiat. 1974, 131, 1392. 17. Shaskan, E. G., Becker, R. E., Nature, 1975, 253, 695. 18. Bailey, A. R., Crow, T. J., Johnstone, E. C., et al. Br. J. clin. Pharmac. 1975, 2, 308. 19. Schildkraut, J. J., Herzog, J. M., Orsulak, P. J., Edelman, S. E., Shein, H. M., Frazier, S. H. Am. J. Psychiat. 1976, 133, 438. 20. Freeman, D. X., Redlich, F. D., Ingerscheiner, W. ibid. 1956, 112, 873. 21. Ermala, P., Autio, L. Acta psychiat. scand. 1951, 60, suppl. 1. 22. Weckowicz, T. E., Hall, R. J. nerv. ment. Dis. 1958, 126, 413. 23. Simpson, G. M., Kline, N. S. ibid. 1961, 133, 19. 24. Lucy, J. D., Archs Neurol. Psychiat. 1954, 71, 629. 25. Gillin, J. C., Kaplan, J., Stillman, R., Wyatt, R. J. Am. J. Psychiat. 1975, 133, 203. 26. Saavedra, J. M., Axelrod, J., Science, 1973, 173, 1365. 27. Osmond, H., Smythies, J., Harley-Mason, J. J. ment. Sci. 1952, 98, 309. 28. Saavedra, J. M., Axelrod, J. Science, 1971, 172, 1365. 29. Gillin, J. C., Kaplan, J., Stillman, R., Wyatt, J. D. Am. J. Psychiat. 1976, 133, 203. 30. Christian, S. T., Benington, F., Corbett, L., Morin, R. D., Smythies, J. R. 16.

6th Annual 1975.

Meeting of the

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City.

31. Corbett, L., Christian, S. T., Bradley, R. J., Smythies, J. R. Unpublished. 32. Christian, S. T., Benington, F., Morin, R. D., Corbet, L. Biochem. Med. 1975, 14, 191. 33. Brune, G. G., Himwich, H. E. Archs gen. Psychiat. 1962, 6, 324. 34. Christian, S. T., Harrison, R., Pagel, J. Ala. J. med. Sci. 1976, 13, 162. 35. Berndge, M. F., Prince, W. T. Br. J. Pharmac. 1974, 51, 269. 36. Beaton, J. M., Christian, S. T., Harnson, R. Unpublished. 37. Angrist, B., Mandel, L. Psychopharmacologia, (in the press). 38. Beaton, J. M., Smythies, J. R., Bradley, R. J. Biol. Psychiat. 1975, 10, 45. 39. Freeman, J. M., Finkelstein, J. D., Mudd, S. H. New Engl. J. Med. 1975,

292, 492. 40. Wurtman, R. J., Fernstrom, J. D. Am. J. clin. Nutr. 1975, 28, 638. 41. Beaton, J. M., Smythies, J. R. Unpublished. 42. Smythies, J. R. Proc. Am. psychopath. Ass. (in the press). 43. Green, A. R., Grahame-Smith, D. G. Nature, 1976, 260, 487. 44. Lauer, J. W., Inskip, W. M., Bernshon, J., Zeller, E. A. Archs Neurol. Psychiat. 1958, 80, 122. 45. Greenberg, A. S., Coleman, M. Archs gen. Psychiat. 1976, 33, 331. 46. McCardle, K., Hirsh, K. Fedn. Proc. 1976, 35, 268. 47. Scherer, B., Kramer, W. Life Sci. 1972, 11, 189. 48. Fernando, J. C., Joseph, M. J., Curzon, G. Lancet, 1975, i, 1971. 49. Woolley, D. W. Science, 1958, 128, 1277. 50. Beaton, J. M., Pegram, G. V., Smythies, J. R., Bradley, R. J. Experientia, 1974, 30, 926. 51. Persson, T., Roos, B. E. Br. J. Psychiat. 1969, 115, 95. 52. Runon, R., Roos, B. E., Rakkolainen, V., Alanen, Y. J. psychosom. Res. 1971, 15, 375. 53. Bowen, M. B., Jr. Psychopharmacologia, 1973, 28, 309. 54. Meltzer, H. Y., Sachar, E. J., Frantz, A. G. Archs gen. Psychol. 1974, 31, 564. 55. Jus, A., Laskaowska, D., Zimmy, S. Ann. med. Psychol. 1958, 116, 898. 56. Halevy, A., Ross, R. H., Solomon, G. F. J. psychiat. Res. 1965, 3, 1. 57. Feldstein, A., Hoagland, H., Freeman, H. J. nerv. ment. Dis. 1959, 129, 62. 58. Todrick, A., Tait, A. C., Marshall, E. F. Br. J. Psychiat. 1960, 106, 884. 59. Garelis, E., Gillin, J. C., Wyatt, R. J., Neff, N. Am. J. Psychiat. 1975, 132, 184. 60. Robinson, D. S., Lovenberg, W., Keiser, H., Sjoerdsma, A. Biochem. Pharmac. 1968, 17, 109. 61. Lozovskii, D. V. Vop. med. Khim. 1962, 8, 616. 62. Bernassi, C. A., Allegri, G., Benassi, P., Rabassini, A. Clinica chim. acta. 1964, 9, 101. 63. Payne, I. R., Walsh, E. M., Whittenburg, E. J. R. Am. J. clin. Nutr. 1974,

27, 565. 64. Sprince, H., Parker, C. M., Jameson, D., Josephs, J. A., Jr Proc. Soc. exp. Biol. Med. 1965, 119, 942. Heyman, J. J. Trans. N. Y. Acad. Sci. 1963, 26, 354. Wyatt, R. J., Vaughan, T., Galanter, M., Kaplan, J., Green, 1972, 177, 1125. 67. Singh, M. M., Kay, S. R. ibid. 1976, 191, 401. 68. Dohan, F. C. Acta. psychiat. scand. 1966, 42, 125. 69. Franzen, G., Ingvar, D. H. J. psychiat. Res. 1975, 12, 199. 65. 66.

R. Science,

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70. 71. 72.

ADDENDUM

Bowers74 has found that lumbar c.s.F. levels of 5-H.I.A.A. are negatively correlated with prognostic variables in a group of schizophrenics. Acute cases had lower 5-H.I.A.A. levels than chronic cases. Shopsin’S has reported that Trp plus allopurinol is an effective treatment of depression.