BACKGROUND: Treatment with olanzapine (atypical antipsychotic drug) is frequently associated with various metabolic anomalies, including obesity, dyslipidemia, and diabetes mellitus. Recent data suggest that olanzapine orally disintegrating tablets (ODT), which dissolve instantaneously in the mouth, might cause less weight gain than olanzapine standard oral tablets (OST). DESIGN AND METHODS: Ten healthy men received olanzapine ODT (10 mg o.d., 8 days), olanzapine OST (10 mg o.d., 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, blood samples were taken for measurement of pancreatic polypeptide, peptide YY, glucagon-like peptide-1, total glucagon, total ghrelin, and cholecystokinin (CCK) concentrations. RESULTS: With the exception of pre- and postprandial concentration of ghrelin at dinner and preprandial CCK concentrations at breakfast, which were all slightly increased (respectively P=0.048, P=0.034 and P=0.042), olanzapine did not affect gut hormone concentrations. Thus, olanzapine ODT and OST had similar effects on gut hormone secretion. CONCLUSION: Short-term treatment with olanzapine does not have major impact on the plasma concentration of gut hormones we measured in healthy men. Moreover, despite pharmacological difference, gut hormone concentrations are similar during treatment with olanzapine ODT and OST. The capacity of olanzapine to induce weight gain and diabetes is unlikely to be caused by modulation of the secretion of gut hormones measured here. We cannot exclude the possibility that olanzapine's impact on other gut hormones, to impair insulin sensitivity and stimulate weight gain, exists.