Incomplete network restoration may be associated with higher relapse risk in women with major depressive disorder

This study aimed to examine sex-specific alterations in structural brain network organization across different stages of major depressive disorder (MDD) and to explore whether stage-related network changes are associated with relapse risk in female patients.

Diffusion tensor imaging and graph-theoretical analyses were performed in 90 first-episode, drug-naïve patients with MDD (31 males, 59 females) and 50 matched healthy controls. Patients were followed for up to 12 months, with repeat imaging during remission and clinical assessment for relapse. Structural networks were reconstructed using deterministic tractography. Network measures included rich-club, feeder, and local connections. Group differences were assessed using general linear models with false discovery rate correction. Linear mixed-effects models were applied to account for within-subject dependence across disease stages. Associations with clinical outcomes were examined using partial correlation and receiver operating characteristic analyses.

Acute-phase rich-club disruption occurred in both sexes but was more severe in females (all P < 0.05). During remission, males showed robust compensatory recovery, exceeding control levels (P < 0.05), whereas females exhibited only partial restoration. Critically, reduced rich-club connections during remission were associated with 12-month relapse in females, a relationship absent in males (AUC = 0.836, P < 0.001). Mixed-effects models yielded convergent patterns across network measures (all P < 0.05).

These findings suggest different patterns of structural network change across disease stages in male and female patients with MDD. Rich-club connections may reflect aspects of structural network recovery and be associated with differences in relapse risk following remission across sexes.