OBJECTIVE: Some but not all second-generation antipsychotics can induce considerable weight gain and metabolic syndrome. Although the exact biochemical mechanisms for these adverse effects are unclear, appetite-regulating neuropeptides of the central nervous system are thought to be implicated in this process. The hypothalamic mediator Agouti-related protein (AGRP) is inhibited by leptin and was shown to increase food intake. The aim of the present study was to investigate the trajectory of AGRP levels during antipsychotic-induced weight gain. METHODS: As part of a controlled prospective clinical study, we determined indicators of body fat mass, plasma AGRP, and leptin levels in 16 patients with schizophrenia treated with ziprasidone and 21 patients with schizophrenia treated with olanzapine. Measurements by enzyme-linked immunosorbent assay were obtained before treatment (T0), after 4 weeks (T1), and after 3 months (T2) of treatment. RESULTS: Whereas body mass index and leptin levels increased in patients treated with olanzapine compared to patients treated with ziprasidone, plasma AGRP levels did not differ among the treatment groups and did not change over time. Associations between AGRP and fat mass as well as appetite were disrupted in the olanzapine-treated patients but not in the ziprasidone group. CONCLUSION: Future studies are needed to test whether the lack of a decrease in AGRP levels during weight gain in patients treated with olanzapine could perpetuate adverse metabolic long-term effects.