Abstract There is increasing evidence for the role of the microbiome in various mental health disorders. Moreover, there has been a growing understanding of the importance of the microbiome in mediating both the efficacy and side effects of various medications, including psychotropics. In this issue, Tomizawa and colleagues report on the effect of psychotropic drugs on the gut microbiome of 40 patients with depression and/or anxiety disorders. In their longitudinal cohort, the authors find that antipsychotics, but not anxiolytics, decrease microbiome alpha diversity. They further find that antipsychotics dosage was negatively correlated with alpha diversity in these patients. The health consequences of these microbiome alterations remain to be fully understood. In this commentary, we will discuss such findings through the lens of several recent studies on the microbiota-gut-brain axis. We also use the paper as a backdrop to discuss directionality and, by extension, causality in relation to microbiota-gut-brain-brain signaling.