Weight-gain is a common side effect associated with taking anti-psychotic therapies, and unfortunately the mechanism of action by which this specifically occurs is poorly understood. Risperidone is a commonly-prescribed second generation antipsychotic that is known to induce significant weight gain in patients taking the drug, and addressing this side effect represents a high unmet medical need. Up to this point it has been thought that there is a myriad of underlying causes to risperidone-induced weight gain. Recent evidence has suggested that alterations in the gut microbiome composition of patients who are taking SGAs could be implicated in loss of healthy metabolism leading to weight gain. Researchers from the University of Iowa sought to expand upon this theory by examining whether or not shifts in the microbiome brought on by risperidone treatment in mice are linked to metabolic dysfunction and subsequent weight gain.
The researchers treated wild-type C57 mice with risperidone and the animals displayed significant weight gain after 6 weeks as compared to controls. The gut microbiomes of these animals were then sequenced by analyzing fecal matter and microbiota composition was significantly different in risperidone mice as compared to the control group (e.g. increases in relative abundances of Firmicutes and decreases of relative abundances of Bacteriodetes). Next, a technique known as bomb calorimetry determined that the weight gains in risperidone-treated mice were due to suppressed energy expenditure. The researchers conducted a final unique experiment to further associate the microbiome’s role in risperidone-induced weight gain. Risperidone-naïve mice received fecal transplants from overweight mice that had received risperidone. The naïve mice who had received the transplant form risperidone mice demonstrated reductions in non-aerobic resting metabolic rate and energy expenditure as well as weight gain. The researchers also conducted fecal phage transplants, as the bacteriophageome could also play a role in energy expenditure. After having received transplant from risperidone-treated mice, naïve mice demonstrated a marked reduction in energy expenditure coupled with weight gain.
Together, the results from this study support risperidone’s role in altering composition of the gut microbiome which can be mechanistically linked to reductions in energy expenditure. The implications from this study are significant as second generation anti-psychotics represent some patients’ only viable treatment option for schizophrenia or psychosis. Targeting cognitive maladies such as psychosis is challenging as drug interactions must be specific while avoiding non-specific targets. Addressing this common weight-gain side effect by focusing on the microbiome could encourage the development of ancillary therapies to maximize treatment benefit for patients through reduction of undesired side-effects.