In a placebo-controlled single-crossover study, seven patients with treatment-resistant chronic paranoid schizophrenia who received methadone plus neuroleptic showed significant improvement. Methadone may be a useful adjunctive treatment in a subpopulation of patients with chronic paranoid schizophrenia.
(Am J Psychiatry 142:1106-1107, 1985)

Increasing attention has been directed in recent years toward the role of exogenous and endogenous opioids in schizophrenia. Case reports of patients who "self-medicate" with opiates (1), observations in methadone maintenance programs (2), and clinical (3) and neuroendocrine (4) studies suggest the hypothesis that methadone may exert an antipsychotic effect.

In this pilot study the efficacy of methadone as an adjunct to neuroleptic treatment was tested with severely impaired chronic schizophrenic patients who had not responded to conventional treatments.

METHOD

Seven patients (four men, three women) with chronic paranoid schizophrenia who were hospitalized on an inpatient psychiatric service participated in the study. Diagnosis was established through assessment of the patients by two psychiatrists using the Research Diagnostic Criteria. Informed, written consent was obtained in each case. The patients’ mean length of illness was 11.6 years (range, 3-26 years). Their mean age was 30.0 years (range, 18-50 years). The mean number of previous hospitalizations was 6.3 (range, 1-12).

These patients were resistant to neuroleptics, since they had remained severely psychotic (mean ± SD global Brief Psychiatric Rating Scale score, 69.3 ± 6.7) while receiving neuroleptic treatment continuously for the previous 6 to 32 months. Mean neuroleptic dose during the 2 months before the study was 2600 mg/day of chlorpromazine equivalents (range, 800-4800).

In this 3-week single-crossover study either methadone or placebo (sodium bicarbonate tablets) was added by random assignment to the fixed dose of neuroleptic that the patient had been receiving for at least 2 months before entering the study. The raters and subjects were blind to the identity of the study medication. The maximum daily dose of methadone was achieved by adding 5 mg every third or fourth day over 2 weeks; the methadone or placebo dose was held constant during the third study week. The maximum daily dose of methadone was lowered from 40 to 25 mg after one subject complained of nausea and sedation from the higher dose.

The Brief Psychiatric Rating Scale (BPRS) was administered weekly by two psychiatrists for four patients and by one psychiatrist for three patients. The patients who had a maximum reduction in BPRS score greater than 33% of the baseline score while receiving methadone plus neuroleptic and were rated as "much improved" or "very much improved" on the Clinical Global Impressions (CGI) Scale by both the treating and research psychiatrists could continue to take methadone plus neuroleptic after discharge. Patients initially given placebo plus neuroleptic who did not show such improvement were subsequently offered an open trial of methadone plus neuroleptic.

Since it was unclear to what extent withdrawal from methadone would influence the behavioural rating, the three patients who received methadone first were not crossed over to placebo. Patients who showed no improvement or did not elect to continue taking methadone were gradually withdrawn from methadone during the fourth study week. Vital signs were checked before each dose of the study drug, and the subjects were interviewed daily.

RESULTS

TABLE 1. Behavioural Ratings of Chronic Paranoid Schizophrenic Patients Taking Neuroleptics in Crossover Study of Adjunctive Treatment with Methadone and Placebo ^a