PROSTAGLANDINS AND SCHIZOPHRENIA

1031

Thus, although disturbed prostaglandin activity may occur,

SCHIZOPHRENIA AND NEUROACTIVE PEPTIDES FROM FOOD

SiR,-Dr Horrobin’s (March 10, p. 529) heuristic "reconciliation", via prostaglandin deficiency, of various concepts of the

"biological defect" in schizophrenia included an inaccurate version of my 1966 proposal that cereal grains and probably some other foods play a genetically determined causal role in schizophrenia.’ I have elsewhere reviewed evidence that polypeptides developed during digestion of cereal grains are the effector agents,2 and the endorphin-like (exorphin) activity of some has been reported. 1,4 Horrobin uses the misleading phrases "hypersensitivity to wheat proteins" and "wheat sensitivity" to indicate this concept-terms which connote "allergy", an implication not justified by facts. They further distort the concept by restricting it to wheat. My hypothesis,’ schematically presented, was: genotype for schizophrenia + (cereals x Pc x time) phenotype, where Pc pathogenicity factor (wheat highest, millets and sorghums lowest?). It was based, not on anecdotal evidence, as Horrobin implies, but on three findings: =

(1) A high positive correlation between changes in first admissions for schizophrenia and changes in consumption of wheat (r = 0-91, p<0’01) and of wheat plus rye (multiple regression, r = 0-96, r<001). (2) Food consumption and epidemiological data suggesting the morbid risk for schizophrenia was greatest where wheat (and rye) were eaten in large amounts, somewhat less in rice-eaters, and still less where maize or millets and sorghum were the staple grains. (3) Clinical observations suggesting that gluten enteropathy (coeliac disease) and schizophrenia may be genetically related-a proposition which deserves formal testing by careful family studies of proven codiacs.

This argument prompted US5,6 and others’ to see if wheat gluten would reverse the beneficial effects of a diet totally free of all cereal grains and milk. It did. The effect of glutens from all cereal grains deserves testing. This conclusion is reinforced by the work of Klee et al. 3,4 who have, as a result of our studies, sought and found naloxone-reversible endorphin-like (exorphin) activity in peptic digests of milk casein and of corn and barley gluten as well as highly potent peptides from wheat gluten. Horrobin postulates that food-derived opioids produce schizophrenic behaviour by interfering with prostaglandin activity, and Klee et al.4 suggest that exorphins "provide a plausible biochemical mechanism" for the effect of diet in schizophrenia. Despite this possibility and suggestive evidence that endorphin-like substances may be involved in the pathogenesis of schizophrenia, I propose that the neuroactivity of other (non-exorphin) food-derived peptides also be investigated. For example, episodes of stereotyped head swinging or foot patting and patterned seizures were produced in rats 1-17 h after intraventricular injection of a polypeptide fraction from wheat gluten.9 These effects and long latent periods are quite unlike those occurring after a similar injection of endorphins or metenkephalin 10 and suggest the possibility of nonendorphin-like neuroactive substances in our gluten peptide fraction.

suggest2

that the basic

biological

genetic impairment (e.g.,

Departments of Molecular Biology and Behavioral Sciences, Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pennsylvania 19129, U.S A.

F. C. DOHAN

PROSTAGLANDINS AND SCHIZOPHRENIA

SiR,-In my hypothesis (March 10, p. 529) I proposed that schizophrenia is related to a specific defect in 1-series prostaglandins (P.G.s) with normal or near-normal production of the 2-series, leading to a severe imbalance between the two groups of compounds. Paracetamol (acetaminophen) inhibits formation of both series and therefore cannot be used to test the hypothesis. Dr Watt’s statement (March 24, p. 668) that his failure’ to observe either worsening or improvement of schizophrenia with paracetamol is evidence against my hypothesis is invalid. Moreover, there is a major methodological objection to that study.’ Patients were given 1 g of paracetamol 6-hourly. The concentration of paracetamol required to inhibit brain P.G. synthesis by 50o/c is 20 ug/ml in the mouse and 14 ug/ml in the rabbit. 2.3 In normal human volunteers the mean peak concentration of the drug in plasma after 1.8 g of paracetamol was 2 V-g/m1.4 It is therefore highly improbable that 1 g 6-hourly would have inhibited brain P.G. synthesis by more than 5%. Watt also states that I had previously supported the idea that schizophrenia was related to an excess of P.G.s. The excess P.G. proposal was Feldberg’s:5 I merely pointed out that some of the biological actions of P.G.E1 follow a "bell-shaped" dose-response curve and that some patients with excess p.G.EI production might be expected to display some schizoid features.6 Dr Checkley and Dr Slade (March 31, p. 730) cite Kay and Roth’s paper’ and conclude that blindness is common in elderly schizophrenics. However, that study referred not to ordinary schizophrenics who had grown old, but to a very unusual group of patients with what has been called "late paraphrenia". In none of the 99 patients did the illness begin before 55 and in only 1 was the first hospital admission before 60. The female/male ratio was 10/1, and there was little evidence of an increased risk of schizophrenia in first-degree relatives. 7 were reported to have severe visual impairment which Kay and Roth stated was normal for the age-group. Their paper is not relevant to the question whether blindness partly protects against the disease usually thought of when the word schizophrenia is used. From their considerable experience at two major London teaching institutions Checkley and Slade then produce a single case of a schizophrenia-like psychosis in a patient with retinitis pigmentosa, a disease commonly associated with organic brain damage. I did better, for I that I had found one apparently authentic case of blindness in a genuine schizophrenic. The observations of Checkley and Slade seem to reinforce the view that blind schizophrenics are rare. I also suggest that those blind people who do exhibit schizophrenic features may sometimes have a

reported

1

Dohan, F. C. Acta psychiat. scand. 1966, 42, 125. Dohan, F. C. in The Biological Basis of Schizophrenia (edited by G. Hemmings and W A. Hemmings); p. 167. Lancaster, 1978. 3. Klee, W. A., Zioudrou, C., Streaty, R. A. in Endorphins in Mental Health Research (edited by E. Usdin, W. E. Bunney, and N. S. Kline); p. 209. London,1979. 4 Zioudrou, C., Streaty, R. A., Klee, W. A. J.biol. Chem. 1979, 252, 2446. 5 Dohan, F. C., Grasberger, J. C., Lowell, H. T., Johnston, H. T., Arbegast, 2

A. W. Br. J. Psychiat. 1969, 115, 595. Dohan, F.C , Grasberger, J. C. Am. J. Psychiat. 1973, 130, 685. Singh, M M,Kay,S. R.Science, 1976, 191, 401. 8 Terenius, L., Wahlstrom, A. in Centrally Acting Peptides (edited by J. Hughes, p. 161 Baltimore, 1978. 9 Dohan, F. C, Levitt, D. R., Kushnir, L. D. Pavlov. J. biol. Sci. 1978, 13, 6 7

73 10 Bloom, F.,

defect in schizophrenia is via defective enzymes or, receptors) of the gut and other barrier systems which eases the passage of food-derived neuroactive polypeptides from gut lumen to brain cells. I

Segal, D., Ling, N., Guillemin, R.Science, 1976, 194, 630.

1. Falloon, I., Watt, D C, Lubbe, K , Macdonald, A., Shepherd, M. Psychol. Med. 1978, 8, 495 2 Willis, A. L., Davison, P., Ramwell, P. W., Brocklehurst, W E , Smith, B. in Prostaglandins in Cellular Biology (edited by P. W. Ramwell and B. B. Pharriss), p. 227. New York, 1972. 3. Flower, R. J., Vane, J R. Nature, 1972, 240, 410. 4 Prescott, L., F Clin Pharmac Ther. 1969, 10, 383 5 Feldberg, W., Psychol Med 1976 6, 359. 6. Horrobin, D F., Ally, A. L., Karmali, R. A., Karmazyn, M., Manku, M. S., Morgan,R O ibid 1978, 8, 43 7. Kay, D W K., Roth, M. J. ment. Sci. 1961, 107, 649.

1032 for both the visual and mental impairment. deficiency, which affects both brain and retinal function, might be one example of such a cause and could be involved in the problems of the elderly living alone, many of whom are likely to be on a zinc-deficient diet.

Gordin et awl. and Flasse and Beckers,"found the T.R.H.-stimulation test to be the most reliable. The high frequency of hypothyroidism in our series is partly explained by the fact that most of our patients lived in an endemic goitre area: " 11 of them had antithyroid microsomal antibodies.

common cause

Zinc

Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada

J. P. LOUVET

DAVID F. HORROBIN Department of Endocrinology, Centre Hospitalier Regional Purpan, 31052 Toulouse, France

M. GOUARRE A. M. SALANDINI CL. BOULARD

HYPOTHYROIDISM AND ANOVULATION it is well known that thyroid dysfunction induce menstrual disorders and anovulationl-3 this cause of sterility is often neglected now that human gonadotrophins and clomiphene are available. Over the past three years, 68 patients, aged twenty to thirtynine, sought advice about infertility, there being no apparent cause for the sterility except anovulation. Gonadotrophin and clomiphene had been tried without success. 37 had symptoms that suggested mild hypothyroidism (sensitivity to cold, dry skin, tiredness, weak hair), associated in 30 cases with a slight thyroid enlargement. We assessed the thyroid function of these patients and in 10 young fertile women with normal thyroid function (controls). Serum-total-T4 was measured by a competitive protein binding method (’Tetrasorb’ 125I-T4 diagnostic kit, Abbott). Serum T3 and thyroid-stimulating hormone (T.S.H.) were determined by radioimmunoassay on unextracted serum.4,5 The thyrotrophin-releasing hormone (T.R.H.) stimulation test was carried out by giving 200 ug of synthetic T.R.H. as an intravenous bolus. Blood-samples were taken before the injection and 25, 60, and 120 min afterwards. Hypothyroidism was confirmed by low T4 and T levels and/or high basal T.s.H. serum concentrations in 15 out of the 37 patients. The other 22 patients had normal T4, T3, and basal T.S.H. values. In several cases the T.R.H. stimulation test fell within the normal range, but there was a significantly exaggerated T.S.H. response in the group as a whole and in 11 patients the T.s.H. values at all times were more than the mean+2 S.D. for the controls. All 37 patients were given desiccated thyroid extract. In all cases correction of menstrual abnormalities and biphasic basal body temperature occurred, and of these 37 patients in whom sterility was considered to be due to hypothyroidism, 20 became pregnant after replacement therapy. These results reaffirm a role for hypothyroidism in anovulation. However, mild hypothyroidism is sometimes difficult to detect.’,’ We, like

SERUM-IMMUNOREACTIVE-TRYPSIN CONCENTRATIONS IN CYSTIC FIBROSIS

SIR,-Although

can

SIR,-We have read with great interest the paper by Dr Crossley and her colleagues (March 3, p. 472) on the use of immunoreactive trypsin (I.R.T.) measurements in neonates with cystic fibrosis (c.F.). Our own work has been directed towards using i.R.T. measurements more as diagnostic test for than as a screen. We measured i.R.T. concentrations (using kits provided by Hoechst, U.K.) in 32 patients (age range 2-35 years) with established C.F. and in 16 parents (heterozygotes) of patients with c.F. 29 patients (91%) and 6 parents (38%) had abnormal trypsin concentrations. Unlike Crossley et al., who reported above normal I.R.T. concentrations in all C.F. neonates, we found that in only 3 out of the 29 patients with abnormal I.R.T. was the concentration supranormal; I.R.T. concentrations were very low in the remaining 26 (82%) patients. The figure of 82% patients with low trypsins corresponds with that of 85% of c.F. patients with pancreatic malabsorption. Our data suggest that low I.R.T. concentrations are an excellent index of diminished pancreatic reserve in c.F. and that serum-i.R.T. concentration would be a useful diagnostic test. Furthermore I.R.T. may provide a way of detecting heterozygotes, although the pick-up rate is not high. The fact that c.F. patients at birth invariably have very high I.R.T. concentrations which fall with age and the progress of the disease, allied with the fact that heterozygotes have high concentrations, supports the previous suggestion that an uncontrolled hypersecretion of zymogen granules is the basic cellular defect in c.F. Serum-i.R.T. concentration measurements should provide newer insights into the pathophysiology, diagnosis, and genetics of cystic fibrosis.

C.F.

Metabolic Unit,

Royal Free Hospital, London NW3 2QG

P. DANDONA

Cardiothoracic Institute, 1. Tyler, E. T. Fertil. Steril. 1953, 4, 218. 2. Buxton, C. L., Herrmann, W. L. J. Am. med. Ass. 1955, 155, 1035. 3. Neves-e-Castro, M., Calhaz-Jorge, C., Correia, S., Leitao, A., Reis-Valle, A., in Ovulation in Human (edited by P. G. Crosignani and D. R. Mishell);

p. 301. London, 1976. 4.

Dutau, G., Bayard, F., Bennet, P., Rochiccioli, P. Archs. fr. Pédiat. 1974,

31, 861. 5. Odell, W. D., Wilher, J. F., Paul,

W.

E. J.

clin. Endocr. Metab. 1965,

Brompton Hospital, London SW3

of Chemical

Department Royal Free Hospital Brompton Hospital

Pathology,

M. HODSON J. BELL L. RAMDIAL J.C.

J.

TEN C. BAT BATTEN

23,

47. 6. Bastenie, P.

A., Neuf, P., Bonnyns, M., Vanhaelst, L., Chailly, M. Lancet, 1967, ii, 488. 7. Fowler, P.B.S., Swale, J., Andrews, H. ibid. 1970, ii, 488. 8. Evered, D. C., Ormston, B. J., Smith, P. A., Hall, R., Bird, T. Br. med. J 1973, i, 657.

9.

Gordin, A., Heinonen,

O.

P., Saarinen, P., Lamberg, B-A. Lancet, 1972,i,

551. 10. Flasse, C., Beckers, C. Ann. Endocr. 1974, 35, 195. 11. Koutras, D. E. in The Thyroid (edited by S. C. Werner, and S. H. p. 409. New York, 1971.

HORMONAL RESULTS

Ingbar.