The development of impaired glucose tolerance induced by antipsychotics (APs) is of concern as a serious adverse effect of psychiatric drug therapy. However, the mechanism by which APs cause dysfunction of the glucose-insulin response is not fully understood. Recent studies have shown that patients treated with APs for schizophrenia were more likely to exhibit impaired glucose tolerance after a glucose load compared with healthy control subjects, even if fasting glucose levels were within the reference range. To explain these findings, we hypothesized that insulin secretion is increased in schizophrenic patients treated with AP, even those normal fasting glucose (NFG) levels. Therefore, oral glucose tolerance tests were conducted in 159 Japanese inpatients with AP-treated schizophrenia and in 90 healthy subjects without schizophrenia. Plasma glucose and serum insulin concentrations were measured before (0 minute) and at 30, 60, 90, and 120 minutes after the oral glucose load. Although insulin levels at 0 minute were similar in both groups of subjects, insulin levels were significantly higher in the patients treated with AP at all times after the glucose load than in the healthy subjects. In analyses of NFG subjects, insulin levels were significantly higher in the patients treated with AP compared with the healthy subjects at all times after glucose loading. Overall, we found that insulin secretion in response to a glucose load was significantly higher in the patients treated with AP, irrespective of NFG. These results suggest that APs affect the glucose-insulin response, which may lead to subclinical insulin resistance before the onset of overt glucose intolerance.