Large-Scale Transcriptomics Studies Provide Insight Into Sex Differences in Depression

Major depressive disorder (MDD) is a leading cause of disability, affecting more than 300 million people worldwide. We first review the well-known sex difference in incidence of MDD, with women being twice as likely to be diagnosed as men, and briefly summarize how the impact of MDD varies between men and women, with sex differences in symptoms, severity, and antidepressant drug response. We then attempt to deconstruct the biological bases for MDD and discuss implications for sex differences research. Next, we review findings from human postmortem studies, both from selected candidate gene studies and from well-powered, unbiased transcriptomics studies, which suggest distinct, and possibly opposite, molecular changes in the brains of depressed men and women. We then discuss inherent challenges of research on the human postmortem brain and suggest paths forward that rely on thoughtful cohort design. Although studies indicate that circulating gonadal hormones might underlie the observed sex differences in MDD, we discuss how additional sex-specific factors, such as genetic sex and developmental exposure to gonadal hormones, may also contribute to altered vulnerability, and we highlight various nuances that we believe should be considered when determining mechanisms underlying observed sex differences. Altogether, this review highlights not only how various sex-specific factors might influence susceptibility or resilience to depression, but also how those sex-specific factors might result in divergent pathology in men and women.