Functional neuroimaging highlights sex as a critical variable in depression research

Major depressive disorder (MDD) is a prevalent psychiatric illness marked by notable changes in mood, behavior and cognition. Emerging evidence indicates that depression can differ by sex in terms of onset, symptoms and treatment response. While modern psychiatry acknowledges sex differences in epidemiology, we are yet to identify biomarkers that could guide sex-specific interventions. Recent discoveries in MDD research point towards alterations in functional brain network patterns. This Perspective highlights the rationale for using resting-state functional magnetic resonance imaging (rs-fMRI) to identify sex differences in MDD. We present preliminary evidence for sex-based differences in depression from the limited existing rs-fMRI literature. Although limited and heterogeneous in their design, the results point towards the need for larger research studies. Furthermore, in female individuals, hormonal fluctuations during specific life phases pose a substantial risk for the onset of depressive episodes. We advocate that future studies integrate sex as an essential factor in MDD research and utilize resting-state functional connectivity to identify sex-specific neural features and biomarkers. We finally recommend ways to incorporate menstrual and reproductive cycle data into depression research to develop better diagnostic tools and personalized treatment strategies. Major depressive disorder (MDD) exhibits sex-specific differences in onset, symptoms and treatment response, yet biomarkers for guiding sex-specific interventions remain unidentified. Here the authors propose the use of resting-state functional magnetic resonance imaging to uncover sex-based neural differences in MDD, advocating for larger studies to enhance diagnostic tools and personalized treatments.