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Abstract

Atypical antipsychotics (APs) are considered the frontline treatment for individuals with schizophrenia, autism spectrum disorder, and a range of other mental health challenges. Risperidone is the most prescribed AP to children and adolescents, with high rates of off-label prescription. However, these drugs have serious metabolic consequences. Often, chronic treatment results in weight gain, insulin intolerance, and dyslipidemia, all of which have lasting impacts in adulthood. Despite the prevalence of childhood prescription, few studies have examined the effect in a model of young mice. Therefore, we aimed to elucidate the effects of chronic risperidone treatment on weight gain and indices of glucose and lipid metabolism in adolescent mice. We hypothesized that risperidone treatment in adolescent mice would result in weight gain and uncover a metabolic effect in both sexes. At 4 weeks of age male and female C57BL/6J mice were divided into either control or risperidone groups. Mice were given either a 45% high fat diet or a 45% high fat diet + 50 mg/kg of risperidone. Each group was kept on their respective diets for 6 weeks. Here, we show that chronic risperidone treatment in young mice leads to weight gain and increased adiposity in a sex-dependent manner, independent of changes in food intake. Risperidone treatment in both sexes resulted in improvements in insulin action, and improvements in glucose tolerance in male mice. Overall, our investigation demonstrates the sexually dimorphic effect of risperidone treatment on weight gain in adolescent mice and – in stark contrast to clinical data – leads to improved glucose homeostasis.