Rich-club connections dynamics are associated with long-term outcomes in major depressive disorder

Major depressive disorder (MDD) is a highly recurrent psychiatric illness, yet its neurobiological trajectory across acute, remission, and relapse phases remains unclear. Identifying stage-specific network alterations associated with long-term outcomes may help inform future personalized treatment strategies.

In a longitudinal diffusion MRI study, 95 first-episode MDD patients and 40 healthy controls underwent structural connectome analysis. Graph-theoretical methods were used to characterize rich-club organization and related network properties across disease stages. Associations with clinical symptoms, cognitive function, and relapse risk were systematically evaluated.

Rich-club organization was preserved across all groups; however, distinct stage-specific alterations emerged. Acute and relapse phases showed pronounced reductions in rich-club connections strength and density, reflecting impaired hub-to-hub integration. By contrast, remission was characterized by a relative enhancement of rich-club connection strength, exceeding levels observed in healthy controls. Importantly, greater rich-club strength during remission was associated with a lower risk of subsequent relapse and positively correlated with cognitive performance.

Rich-club connections in MDD follow a dynamic trajectory from disruption to relative reorganization. While acute and relapse phases are marked by network vulnerability, network reconfiguration during remission is associated with functional recovery and a lower risk of relapse. These findings suggest that rich-club connections may represent a neuroimaging-derived correlate of disease course and relapse vulnerability, and highlight hub connectivity as a potential target for future mechanistic and interventional investigations in MDD.