Changes in Neuroendocrine and Metabolic Hormones Induced by Atypical Antipsychotics in Normal-Weight Patients with Schizophrenia

Abstract

Context: Atypical antipsychotics (SGA) have the propensity to induce weight gain. Objective: The aim was to evaluateearly changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels. Design: We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study. Setting and Patients: Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University. Intervention: Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months. Results: At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals. Conclusions: Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis.