Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters

Atypical antipsychotic drugs (AAPDs) such as olanzapine have a serious side effect profile including weight gain and metabolic dysfunction, and a number of studies have suggested a role for gender in the susceptibility to these effects. In recent times, the gut microbiota has been recognised as a major contributor to the regulation of body weight and metabolism. Thus, we investigated the effects of olanzapine on body weight, behaviour, gut microbiota and inflammatory and metabolic markers in both male and female rats. Male and female rats received olanzapine (2 or 4 mg/kg/day) or vehicle for 3 weeks. Body weight, food and water intake were monitored daily. The faecal microbial content was assessed by 454 pyrosequencing. Plasma cytokines (tumour necrosis alpha, interleukin 8 (IL-8), interleuin-6 and interleukin 1-beta (IL-1 beta)) as well as expression of genes including sterol-regulatory element binding protein-1c and CD68 were analysed. Olanzapine induced significant body weight gain in the female rats only. Only female rats treated with olanzapine (2 mg/kg) had elevated plasma levels of IL-8 and IL-1 beta, while both males and females had olanzapine-induced increases in adiposity and evidence of macrophage infiltration into adipose tissue. Furthermore, an altered microbiota profile was observed following olanzapine treatment in both genders. This study furthers the theory that gender may impact on the nature of, and susceptibility to, certain side effects of antipsychotics. In addition, we demonstrate, what is to our knowledge the first time, an altered microbiota associated with chronic olanzapine treatment.