Use of the second-generation antipsychotic, risperidone, and secondary weight gain are associated with an altered gut microbiota in children.

S M Bahr,T L Burns,L M Teesch,C L Oltman,B D Butcher,C A Calarge,M A Azcarate-Peril,N Wooldridge,J R Kirby,B C Tyler

doi:10.1038/tp.2015.135

Abstract

The atypical antipsychotic risperidone (RSP) is often associated with weight gain and cardiometabolic side effects. The mechanisms for these adverse events are poorly understood and, undoubtedly, multifactorial in etiology. In light of growing evidence implicating the gut microbiome in the host's energy regulation and in xenobiotic metabolism, we hypothesized that RSP treatment would be associated with changes in the gut microbiome in children and adolescents. Thus, the impact of chronic (>12 months) and short-term use of RSP on the gut microbiome of pediatric psychiatrically ill male participants was examined in a cross-sectional and prospective (up to 10 months) design, respectively. Chronic treatment with RSP was associated with an increase in body mass index (BMI) and a significantly lower ratio of Bacteroidetes:Firmicutes as compared with antipsychotic-naïve psychiatric controls (ratio=0.15 vs 1.24, respectively; P<0.05). Furthermore, a longitudinal observation, beginning shortly after onset of RSP treatment, revealed a gradual decrease in the Bacteroidetes:Firmicutes ratio over the ensuing months of treatment, in association with BMI gain. Lastly, metagenomic analyses were performed based on extrapolation from 16S ribosomal RNA data using the software package, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Those data indicate that gut microbiota dominating the RSP-treated participants are enriched for pathways that have been implicated in weight gain, such as short-chain fatty acid production.

Highlights

Our results indicate that RSP use is associated with alteration of the gut microbiome that is enriched for metabolic pathways that might cause or exacerbate weight gain
We found a significant shift in Bacteroidetes and Firmicutes in participants exposed chronically to RSP (76 and 11%, respectively) when compared with psychiatric controls (51 and 41%, respectively)
The magnitude of these differences was most prominent in those participants who had gained significant weight

Summary

Introduction

Over the last two decades, the prescribing rate of secondgeneration antipsychotic medications (SGAs) to treat children has increased nearly eightfold, in light of evidence supporting their efficacy.[1,2,3] significant weight gain and associated cardiometabolic disturbances are common side effects, placing patients at an elevated risk for type 2 diabetes and cardiovascular disease.[1,4,5,6] Alarmingly, the life expectancy of patients with severe mental illness is 20–25 years shorter than that of the general population, primarily due to increased cardiovascular disease.[7,8,9]The mechanisms underlying SGA-induced weight gain are not well understood. Over the last two decades, the prescribing rate of secondgeneration antipsychotic medications (SGAs) to treat children has increased nearly eightfold, in light of evidence supporting their efficacy.[1,2,3] significant weight gain and associated cardiometabolic disturbances are common side effects, placing patients at an elevated risk for type 2 diabetes and cardiovascular disease.[1,4,5,6] Alarmingly, the life expectancy of patients with severe mental illness is 20–25 years shorter than that of the general population, primarily due to increased cardiovascular disease.[7,8,9]. The metabolic side effects are believed to be multifactorial in their etiology, including pharmacological, genetic, lifestyle and environmental contributors.[10,11,12] Recent evidence implicates the gut microbiome, which impacts various aspects of metabolism, including energy harvest and the development of obesity.[3,13,14,15,16,17] Davey et al have shown that acute olanzapine treatment in rats resulted in significant weight gain and cardiometabolic dysfunction in association with changes in the gut microbiota.[1,2,3] Importantly, mice lacking a microbiota do not gain as much weight compared with non-treated controls.[18]

Methods

Results

Conclusion