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Functional neuroimaging highlights sex as a critical variable in depression research

Nature Mental Health volume 3, pages 974–981 (2025)Cite this article

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Abstract

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.

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Fig. 1: Techniques for analyzing rs-fMRI data.
Fig. 2: Potential time windows for increased risk of depression onset in females.

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Author notes

  1. These authors contributed equally: Malvika Sridhar, Wiebke Struckmann.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Malvika Sridhar, Wiebke Struckmann, Noriah D. Johnson, Martin Tik, Cammie E. Rolle, Ian H. Kratter & Nolan R. Williams

  2. Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria

    Martin Tik

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Contributions

M.S.: conceptualization; writing—original draft, literature review and editing; visualization. W.S.: writing—original draft, literature review and editing. N.D.J.: writing—original draft, literature review. M.T.: writing—original draft, literature review. C.E.R.: writing—critique and editing. I.H.K.: conceptualization; writing—critique and editing. N.R.W.: supervision; writing—critique and editing.

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Correspondence to Nolan R. Williams.

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Sridhar, M., Struckmann, W., Johnson, N.D. et al. Functional neuroimaging highlights sex as a critical variable in depression research. Nat. Mental Health 3, 974–981 (2025). https://doi.org/10.1038/s44220-025-00477-5

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