The cimetidine-induced increase in prolactin secretion in schizophrenia: effect of clozapine

There is considerable interest in the role of serotonin (5-HT) in the pathophysiology of schizophrenia and in the mechanism of action of clozapine, an atypical antipsychotic agent and a potent dopamine (DA), 5-HT2/5-HT1C and histamine (H) antagonist. Cimetidine, an H2 antagonist, produces robust, transient increase in plasma prolactin (PRL) levels in man following intravenous administration. This effect has been attributed, in part, to indirect central serotonergic mechanisms involving 5-HT2 receptors in the hypothalamus, but the evidence is inconclusive. This study investigated the effects of cimetidine on plasma PRL levels in unmedicated schizophrenic patients versus normal controls and the effect of chronic treatment with clozapine on the cimetidine-induced PRL response. The PRL response to cimetidine was significantly blunted in male but not female schizophrenic patients. The PRL response in male schizophrenic patients was inversely related to psychopathology. Chronic treatment with clozapine completely suppressed the plasma PRL response following cimetidine. These data are consistent with the hypothesis of an abnormality of serotonergic activity, including downregulation of 5-HT2 receptors, in male but not female schizophrenic patients. The role of antagonism of 5-HT2 receptors in the action of clozapine is discussed.