BACKGROUND: Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Glucoregulatory abnormalities have also been associated with the use of antipsychotic medications themselves. While antipsychotics may increase adiposity, which can decrease insulin sensitivity, disease- and medication-related differences in glucose regulation might also occur independent of differences in adiposity. METHODS: Modified oral glucose tolerance tests were performed in schizophrenic patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical antipsychotics, and untreated healthy control subjects (n = 31), excluding subjects with diabetes and matching groups for adiposity and age. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load. RESULTS: Significant time x treatment group interactions were detected for plasma glucose (F(12,222) = 4.89, P<.001) and insulin (F(12,171) = 2.10, P =.02) levels, with significant effects of treatment group on plasma glucose level at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at all time points, in comparison with patients receiving typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75 minutes after load, again in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose level were detected when comparing risperidone-treated vs typical antipsychotic-treated patients and when comparing typical antipsychotic-treated patients vs untreated control subjects. CONCLUSION: Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.