OBJECTIVES The atypical antipsychotic (AAP) class is often associated with metabolic disease, but the mechanistic underpinnings of this risk are not understood. Due to reports linking gut bacteria function to metabolic disease, we hypothesize that AAP treatment in adults results in gut dysbiosis potentiating metabolic criteria. This report describes recent findings linking AAP treatment with differences in gut microbiota communities in a human cohort with bipolar disorder (BD). METHODS In a cross-sectional design, we obtained 16S ribosomal sequences from 117 BD patients (49 AAP treated, 68 non-AAP treated). Analysis of molecular variance (AMOVA) was used to detect significant clustering of microbial communities between groups, and the inverse Simpson Diversity Index was used to calculate alpha diversity. Detection of differentially abundant operational taxonomic units (OTUs) between groups was performed using linear discriminant analysis effect size. RESULTS The AAP-treated cohort was significantly younger and had an increased body mass index compared with non-AAP-treated patients. Groups did not differ in other psychotropic medication use with the exception of higher use of benzodiazepines in the AAP cohort. We detected significant separation between microbiota communities of AAP-treated and nontreated patients (AMOVA; p=0.04). AAP-treated females showed significant decreased species diversity when compared with non-AAP-treated females (p=0.015). Males showed no significant diversity between treatment groups (p=0.8). Differentially abundant OTUs between treatment groups were OTU1, OTU25, and OTU32 that classified to Lachnospiraceae, Akkermansia, and Sutterella, respectively. CONCLUSIONS These data suggest that AAP treatment is associated with specific representation of gut bacterial families in AAP-treated patients. In addition, AAP treatment is associated with decreased species richness in female AAP-treated patients.