Patients treated with second-generation ('atypical') antipsychotics (SGA) frequently experience severe weight gain that leads to obesity and obesity-related disorders, interferes with medication compliance, and necessitates discontinuation of treatment. Along with the weight gain, patients often report significant increases in appetite and persistent insatiability. The role of appetite dysregulation in antipsychotic-induced weight gain, as well as the biological mechanisms underlying these coincident phenomena in patients treated with psychotropic medications are unknown. Short-term (3 months) treatment with the SGA, olanzapine, increases body weight, % body fat, and fasting levels of the appetite-stimulating hormone, ghrelin. These changes may occur via olanzapine's interaction with hypothalamic networks that regulate food intake. In non-patient samples, fasting ghrelin concentration is typically less in obese vs. non-obese individuals. Therefore, the concomitant increase in fasting ghrelin and body weight in patients secondary to antipsychotic treatment seems counterintuitive and warrants further investigation. Daily fluctuations in one's experiences of hunger and satiety are also closely regulated by the appetite- suppressing neuropeptide YY (PYY), which tends to be diminished in obesity. No studies have examined the effects of psychotropic medication use on PYY, nor postprandial ghrelin or PYY responses in patients treated with weight-increasing medications. Critical gaps include studies that assess changes in appetitive hormones over a typical course of antipsychotic treatment, that include fasting and postprandial hormone measurements, and that relate changes in biological and psychological appetitive constructs with weight and weight-related outcomes. This study is novel in its prospective evaluation of changes in ghrelin and PYY responses using a controlled feeding paradigm in drug-naTve patients with psychosis treated with two SGA that have high weight-gain liability (olanzapine and risperidone). Outcomes will be compared to those measured in patients treated with two SGA with low weight gain liability (ziprasidone and aripiprazole). The study will also examine the relation of treatment-induced changes in appetitive hormones with changes in subjective ratings of appetite and cravings, and with changes in body composition. Findings will address critical mechanistic questions regarding appetite dysregulation as it pertains to the pervasive clinical challenge of psychotropic medication-induced weight gain, obesity, and diabetes. Ultimately, information gained from this study may be instrumental in reducing obesity and obesity-related morbidities in patients with severe mental illness.
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