Chronic administration of olanzapine induces metabolic and food intake alterations: A mouse model of the atypical antipsychotic-associated adverse effects

Rationale: Most of atypical antipsychotics (AAPs) are highly related to a major risk of metabolic drawbacks leading to dyslipidemia and obesity. Objective: To set up a mouse model of the AAP-associated weight gain in mice under the influence of chronic olanzapine regimen. Materials and methods: Female mice were housed in pairs and habituated to spontaneous feeding with a high-palatable diet (10% sucrose wet mash). Firstly, we orally administered olanzapine (0.75, 1.5 and 3 mg/kg), evaluating body weight and periuterine fat mass, as well as insulin, non-esterified fatty acids, triglycerides, and glucose levels. In a second experiment, we assessed the effect of olanzapine on energy expenditure through indirect calorimetry (IC). A third experiment was conducted to investigate the effects of olanzapine on a high fat-high sweet palatable diet (10% sucrose + 30% fat, HF-HS) in mice implanted with subcutaneous osmotic mini-pumps. Locomotor activity was also assessed. Results: In experiment 1, the highest dose of chronically administered olanzapine (3 mg/kg) induced significant weight gain accompanied by augmentation of periuterine fat depots, with no changes in locomotor activity. In experiment 2, chronic administration did not alter energy expenditure, whereas, decreased respiratory quotient (RQ). In experiment 3, subcutaneously infused olanzapine evidenced a dose and time-dependent increase of body weight and HF-HS diet consumed. Notably, serum analyses revealed a hyperinsulinemia together with increased levels of triglycerides and glucose. Conclusions: In this study, we describe in female mice metabolic alterations matching the metabolic syndrome, thus resembling the clinical situation of schizophrenic patients taking AAPs.