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June 1977

Inhibition of Dopamine Synthesis in Chronic SchizophreniaClinical Ineffectiveness of Metyrosine

Author Affiliations

From the Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, National Institute of Mental Health, St Elizabeths Hospital, Washington, DC (Drs Nasrallah, Donnelly, Bigelow, Potkin, Rauscher, Wyatt, and Gillin); the Department of Pharmacology, University of Rochester (NY) (Dr Rivera-Calimlim); and the Department of Pediatrics, University of Virginia, Charlottesville (Dr Rogol).

Arch Gen Psychiatry. 1977;34(6):649-655. doi:10.1001/archpsyc.1977.01770180035002

• According to the dopamine (DA) hypothesis of schizophrenia, there is a functional excess of dopaminergic activity within unspecified areas of the brain in schizophrenic patients. As a clinical test of this hypothesis, we administered metyrosine for three weeks to symptomatic chronic male schizophrenic patients who were maintained on suboptimal doses of neuroleptic agents. Metyrosine inhibits tyrosine hydroxylase, the ratelimiting enzymatic step in the synthesis of DA.

No clinical improvement was observed, using the National Institute of Mental Health Inpatient Behavioral Rating Scale or the Brief Psychiatric Rating Scale. Central inhibition of DA synthesis by metyrosine was suggested, however, by (1) the development of extrapyramidal side effects and (2) a significant increase in plasma prolactin concentrations. Plasma chlorpromazine concentrations remained unchanged during metyrosine treatment.

There was, nevertheless, a significant improvement on the scores of the Wechsler Adult Intelligence Scale Comprehension subtest, which measures judgment and common sense. This finding suggests that DA may be involved in the regulation of subtle psychological processes.

The results are discussed in light of the DA hypothesis of schizophrenia and previous reports suggesting that metyrosine potentiates the antipsychotic effect of neuroleptics in schizophrenia.