The Lancet, August 20 1977 pp398-399

Letters to the Editor

ANTIPSYCHOTIC EFFECT OF OPIATE AGONISTS

Sir, —The involvement of dopamine (D.A.) in the tonic inhibition of prolactin secretion and the action of antipsychotic medications at D.A. receptors have led to the suggestion that antipsychotic drugs can be identified by their stimulation of prolactin secretion,^1-3 and the prolactin-stimulation model does seem to predict antipsychotic efficacy^{4, 5} and clinical potency.⁶ Our data suggest an antipsychotic efficacy for opiate agonists represented by the drug methadone, based on its effects on serum- prolactin.

Methadone was administered orally in a dose of 40mg to seven male volunteers from the methadone maintenance programme, while seven controls received coloured water (placebo). Each experimental session comprised 16h with the subject at rest in bed at 8am after an overnight fast for the placement of an indwelling venous catheter in the forearm. Hourly blood-sampling began at 9 am and continued until midnight. Methadone and inactive placebo were given at time zero (11am). All samples were placed on ice and centrifuged within an hour; and the serum was frozen at -20ºC until prolactin assay in duplicate by radioimmunoassay.⁷

Methadone produced a significant rise (p<0.01), analysis of variance) in serum-prolactin from a mean of 12.3 ng/ml ± 1.1 to 22.6 ng/ml ± 4.0 60 min after drug administration. Prolactin concentrations increased to a peak of 25.3 ng/ml ± 3.5 at 120 min and were significantly raised up to the 4 h sample when the value was 22.7 ng/ml ± 3.6. Concentrations returned to baseline in the 9, 10, 11, and 12 h samples. All volunteers receiving methadone had sustained increases in serum-prolactin. These data suggest that methadone interferes with the postsynaptic action od D.A. and may have antipsychotic efficacy in man. Like the potent antipsychotic medication, haloperidol, methadone, and other opiate agonists are potent inhibitors of the enzyme D.A.-stimulated adenylate cyclase,^{9, 10} produce a dose related increase in D.A. metabolites,⁹ and produc??????????psy reversed by the central D.A.-receptor-stimulating ????????apomorphine.¹¹ Methadone and other opiate agonists may increase serum- prolactin by stimulating endogenous opioid peptide receptors, which in turn inhibit D.A. impulse flow or release. Studies with morphine¹² and endogenous opioid peptides^{13- 15} have shown that stimulation of opiate –receptor sites causes an increase in serum-prolactin possibly by decreasing D.A. activity in the median eminence.¹⁵ These data support speculations,¹⁶ behavioural studies,^{17, 18} anecdotal reports from the era before antipsychotic medication era,¹⁹and our clinical experience in methadone maintenance programs that opiate agonists may be antipsychotic in man. If methadone and other opiate agonists are not antipsychotic in man, then inhibition?????D.A. impulse flow or release as assessed in vivo by increases in serum-prolactin may not be a viable model for the relevant antipsychotic locus of action of the neuroleptics.

(????? question marks are where my copy of text is unreadable. The person who gave me these copies will hopefully be able to enlighten me and I will make the change if and when I am sure of what it says. – Rose.)

M. S. Gold
R. K. Donabedian
M. Dillard, Jr.
F. W. Slobetz
C. E. Riordan
H. D. Kleber

Departments of Psychiatry,
Medicine, and Laboratory Medicine
Yale University School of Medicine
New Haven, Connecticut 06510, U.S.A.

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3. Sachar, E. J., Gruen, P. H., Altman, N., Halpern, F. S., Frantz, A. G. in Hormones, Behaviour, and Psychopathology, edited by E. J. Sachar; p.161. New York, 1976
4. Meltzer, H. Y., Piyakalmala, S., Schyve, P., Fang, V. S. Psychopharmacology, 1977, 51, 185
5. Langer, G., Ahn, H. S., Perel, J. M., Maleman, M. H., Sachar, D.J. Lancet, 1977,I,493
6. Langer, G., Sachar, E. J., Gruen, P. H., Halpern, F. S. Nature,1977, 266, 639
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8. Snyder, S. H., Banerjee, S. P., Yamamura, H. I., Greenberg, D. Science,1974, 184, 1243.