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

  • Marianne L. Seney
    Correspondence
    Address correspondence to Marianne Seney, Ph.D.
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Jill Glausier
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Etienne Sibille
    Correspondence
    Etienne Sibille, Ph.D.
    Affiliations
    Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author

      Abstract

      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.

      Keywords

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