Sex differences in symptom-specific brain abnormalities across disease stages in depression

The incidence and clinical manifestations of major depressive disorder (MDD) differ between sexes. This implies distinct neuropathological mechanisms. This study aimed to investigate sex-specific brain patterns in MDD by stratifying patients according to both sex and disease course.

We recruited 1170 participants (811 MDD patients and 359 healthy controls) who underwent T1-weighted and resting-state functional magnetic resonance imaging. We explored duration-stage-related, sex-specific differences in gray matter (GM), amplitude of low-frequency fluctuation (ALFF), and structural-functional coupling. We also used the structural covariance network (SCN) to assess morphological connectivity reorganization. Finally, we explored the relationship between key brain measures derived from the preceding multimodal analyses and clinical features.

GM abnormalities in both sexes were observed first appeared in areas supporting sensorimotor and interoceptive functions, and later extended to areas involved in cognitive and emotional processing. Critically, we found distinct sex-specific epicentres of pathology. In male patients, the right postcentral gyrus (PoCG) exhibited early GM atrophy and decreased betweenness centrality within the SCN. In female patients, the left inferior temporal gyrus (ITG) showed early GM atrophy, increased degree centrality within the SCN, reduced ALFF values, and a two-stage evolution of structural-functional coupling with a transition lasting 3 years. Clinically, GM volumes of the right PoCG in male patients were negatively associated with insomnia-early, genital symptoms, and weight loss, while in female patients, GM volumes of the left ITG were negatively associated with depressed mood, work and interest, and psychic anxiety.

This study shows a sex-specific neuropathological origin in MDD, with the left ITG serving as the core pathological area in females and the right PoCG in males. These conclusions not only advance our insight into the sex-dependent mechanisms underlying MDD but also provide a stage-informed framework for individualized interventions, suggesting that the early years of the disease may be a critical period for structure-targeted therapies.