ALEX COMFORT

One theory of the action of antipsychotic drugs is that they are dopamine-blocking agents acting selectively on systems in the nucleus accumbens, ^1,2 an idea recently restated by Crow et al.³ It would be possible to test the hypothesis by examining the effects of a drug on the levels of homovanillic acid and 3,4-dihydroxyphenyl acetic acid (D.O.P.A.C) in the nucleus. Westerink and Korf⁴ found that antipsychotic drugs with few extra pyramidal side-effects tend to produce the largest increase in these metabolites, but Crow et al.⁵ point out that other drugs including morphine also produce increases although they "probably lack antipsychotic activity".

The elucidation of the mode of action of antipsychotic drugs continues, but the discussion of the subject focuses attention on a possibility which has been in the minds of drug-addiction experts for some time – that morphinoids may act as antipsychotics for some individuals whether through this chemical mechanism or in some other fashion. There do not appear ever to have been clinical trials of morphine or heroin in overt schizophrenia, for obvious reasons. On the other hand, a clinical impression remains, unsupported by any good figures, that among addicts there are some who would have become psychotic if not addicted, and who use morphinoids (heroin in particular) to hold at bay intolerable prepsychotic sensations, and that these are sharply exacerbated by withdrawal.

Morphine can claim to be regarded as the first specific antipsychotic to be subjected to experimentation.⁶ Early alienists, notably Young⁷ and Brandreth,⁸ used it both in affective and in other psychotic disorders with "wonderful good results." It fell into disfavour by the beginning of the 19th Century, but later workers revived its use.

The history of morphine as a 19th century antipsychotic has been traced in greater detail by Carlson and Simpson.¹⁰ It fell into disuse with the recognition of its additional properties, its widespread abuse as a painkiller by the general public, the high toxicity of laudanum administered to infants, and the sensationalisation of the "opium vice" by writers such as De Quincey. It is possible, however, to detect in the wide use of laudanum as a Victorian domestic remedy some of the features of modern drug abuse, including the existence of stable addicts. The Victorian anti-slavery campaigner, Wilberforce, and many other public figures, were lifelong consumers of laudanum. Wilberforce used it for trigeminal neurosis, but others seem to have received it on medical advice for palliate psychotic symptoms..

19th century psychiatry recognised affective disorder but not schizophrenia: a high proportion of the "insanity" which came within it purview was in fact organic psychosis, the leading cause of committal to an institution being neurosyphilis. We might be disinclined to use a hazardous drug for affective disorder when safe drugs are available. As to schizophrenic manifestations, whether the alienists who used morphine were dealing with conditions for which we would now prescribe standard antipsychotics is hard to assess. It is of course possible to argue that any euphoriant might alleviate the anxiety and fear which often characterise early schizophrenia; there are no doubt prepsychotics who abuse alcohol, but alcohol hardly qualifies as an antipsychotic agent on this score. Before experimenting with an addictive agent it might be more rational to see whether nalorphine, for example, exacerbates or lessens psychotic symptoms. Preliminary evidence suggests that it improves them. After the work of Wahlstron and Gunne, double-blind trials are said to be in hand at the Salk institute.¹¹ If, as seems to be the case, endorphins exacerbate psychotic symptoms, the action of morphine might be specific, and dependent on competitive blocking of sites. If this is so, addiction, provided it is stable, may amount to no more than assisted compliance in some patients. There are occasions when a mild degree of addiction to halperidol or thioridazine would be a consummation devoutly to be wished, and obviate the need for depot preparations.

Europeans accustomed to the legal prescription, for long periods of time, of stabilising and maintenance doses of heroin to registered addicts as an alternative to withdrawal, are also accustomed to the "balanced" addict, who bears striking resemblances in some cases to the "balanced psychotic whose behaviour and acceptance by society are maintained by antipsychotic medication.

It is possible to postulate a group of patients who would have become psychotic if they were not addicted; by no means all balanced addicts fall into this class. Cultures where heroin and morphine, with a number of other drugs, induce irrational reactions in legislators have no opportunity to demonstrate a suppression of irrationality in users. The combination of universal availability with high price and illegality make it a hopeless task to see whether addiction figures coincide with a detectable fall in admissions from other mental disorders. People can be both mad and addicted, and addiction may itself precipitate psychosis through social pathways in persons who are easily destabilised. Moreover, the image of the inevitably deteriorating addict is itself a self-fulfilling prophecy given the legal and illegal overtones of the drugs involved.

Further study of psychotogenesis and of the relation between morphinoids and endogenous neurotransmitters and neuromodulators will probably, in the end, clarify the biochemistry both of addiction and of schizophrenia. Meanwhile, it is virtually impossible, given the social and legal position, to devise an ethical test to see whether there is a group of psychotics for whom morphinoids are an effective antipsychotic maintenance therapy. Of course, the attitude generated by justified alarm at drug abuse increase may change in the direction of registration and control. Strong biochemical evidence that the action of morphinoids resembles that of non-addictive antipsychotics would, even if it were to be obtained, be too recondite to influence legislation (cost-effectiveness is more likely to do so). Nor, on British experience, is the controlled prescription of drugs as an alternative to gang-busters-style prohibition a trouble-free solution. But in the reevaluation of this difficult problem, the possibility, however remote, that there is a group of psychotics for whom morphinoids are therapeutic – and may even prove to be the only effective treatment – ought perhaps to be borne in mind. At least the biochemical findings may give some pointers for or against this possibility. It is interesting that many experienced workers seem to share a clinical impression that the possibility is real, but none seems to have devised a feasible means of confirming it.

REFERENCES

1. Anden, N. E. J. Pharm. Pharmac. 1972, 24, 905
2. Stevens, J. R. Archs. gen. Psychiat. 1973, 29, 177
3. Crow, T. J., Deakin, J. F. W., Johnstone, E. C., Longden, A. Lancet, 1976, ii, 563
4. Westerink, B. H. C., Korf, J. ibid. p. 749
5. Crow, T. J., Deakin, J. F. W., Johnstone, E. C., Longden, A. ibid. p 1027
6. Tourney, G. in Changing Patterns in Psychiatric Care (edited by T. Rothman); p. 20. New York, 1970
7. Young, G. Treatise on Opium founded on Practical considerations. Millar,, 1753
8. Brandreth, J. P. Medical Commentaries for Year 1791. Edinburgh, 1792.
9. Bucknill, J. D., Tuke, D. H. Manual of Psychological Medicine. Philadelphia, 1858.
10. Carlson, E. T., Simpson, M. M. Am. J. Psychiat. 1963, 120, 112
11. Science, 1977, 193, 1229

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