Shifts in the brain sex continuum in major depressive disorder: Evidence for a persistent neurobiological marker.

BACKGROUND

Major depressive disorder (MDD) heterogeneity impedes the discovery of robust neurobiological markers. This study investigated the brain sex continuum (BSC) score, which is a system-level functional architecture marker reflecting psychological androgyny (Zhang et al., 2021), as a persistent neurobiological alteration and replicable diagnostic marker in MDD and its association with symptoms and treatment.

METHODS

Resting-state functional connectivity (rsFC) was analyzed in two independent longitudinal cohorts of unmedicated MDD patients (Xiangya Hospital, XYH: n = 173 and Peking University, PKU: n = 79) and healthy controls (n = 238 and 89, respectively). We confirmed the applicability of the BSC score in current samples. Group differences, effects of 8-week antidepressant treatment, and associations with depressive symptoms (17-item Hamilton depression rating scale, HAMD-17) were evaluated.

RESULTS

No single individual rsFC consistently differentiated MDD patients from controls across both cohorts. However, BSC scores were reproducibly elevated in unmedicated MDD patients versus controls (PKU: Odds Ratio,OR=7.69,95%CI,0.08to34.45, and XYH: OR=2.39,95%CI,0.99to5.81), indicating a shift toward the extreme male end of the continuum. This BSC shift was primarily driven by elevated alterations in between-network connectivity, particularly in female patients. Crucially, this shift persisted post-treatment in both cohorts and substantially improved diagnostic accuracy. Strikingly, BSC scores showed no significant association with baseline HAMD or symptom changes post-treatment.

CONCLUSIONS

The BSC represents a persistent neurobiological marker in MDD that is dissociated from clinical symptom expression. This uncoupling reveals a core neuropathology distinct from symptom-based diagnostic frameworks, advancing biomarker development for heterogeneous depression.