Researchers have reported a stimulatory effect of carbohydrate-rich intake on platelet-poor plasma (PPP) serotonin (5-HT) levels in healthy human subjects. Dietary manipulation may serve as a safer and less invasive means than pharmacologic challenge to provoke serotonergic responsivity in studies of schizophrenia. In the present study, we used the carbohydrate-rich meal test as an indicator of 5-HT activity in 12 patients with chronic schizophrenia maintained for at least 6 months on clozapine. PPP 5-HT levels were measured at baseline and at 1, 2 and 3 h after administration of the test. Findings were compared with those in schizophrenic patients treated with classic antipsychotic agents for the same duration. The maximal PPP 5-HT response was reached 120 min after meal administration in the clozapine-treated group and 60 min after in the classic antipsychotic-treated group (P<0.05 vs baseline for both). The 5-HT level (as percentage of baseline) at 60 min was significantly lower in the clozapine-treated group (P<0.02), as were individual PPP 5-HT peak values (P<0.05). The individual time to reach the peak response was similar in the two groups. Our results indicate that in patients with chronic schizophrenia 5-HT responsivity to the natural challenge of carbohydrate-rich meals is lower in those treated with clozapine than in those given classic antipsychotic agents. Values in both groups were lower than those in an appropriate historical comparative group of healthy subjects. We suggest that both clozapine and classic antipsychotic agents suppress serotonergic system sensitivity, but to a different degree. Copyright 2001 John Wiley & Sons, Ltd.