Hippocampal Dentate Gyrus Plasticity and Its Association With Dimensional Clinical Improvement Across Four Depression Treatment Interventions

OBJECTIVE: The hippocampal dentate gyrus (DG) has been proposed as a key site of neuroplasticity underlying antidepressant effects. This study examined longitudinal effects of four standard depression treatment interventions on DG volume and their relationships with dimensional clinical and cognitive outcomes. METHODS: This prospective multisite nonrandomized study involved 450 participants: 181 healthy individuals and 269 patients with major depressive disorder who received cognitive-behavioral therapy (CBT, N=106), pharmacotherapy (N=83), repetitive transcranial magnetic stimulation (rTMS, N=39), or electroconvulsive therapy (ECT, N=41). Clinical assessments and structural MRI were obtained at baseline, after a course of treatment (16 weeks for CBT and pharmacotherapy; 6 weeks for rTMS and ECT), and 6 months later. DG volume was set as the primary outcome. Linear mixed-effects models were used to assess treatment effects on DG volume, its long-term trajectories, and its associations with changes in dimensional symptom scores and cognitive function. RESULTS: Across all patients, treatment was associated with a significant increase in DG volume, which was mainly driven by a robust significant increase in the ECT group. Change in DG volume was significantly correlated specifically with improvement in the core depressive symptom dimension, with no associations observed for anxiety, somatic, or insomnia dimensions or any cognitive domains. Long-term analyses revealed a nonlinear increase-decrease DG trajectory that parallelled changes in core depressive symptoms. CONCLUSIONS: The results suggest that MRI-detectable DG plasticity is not a shared mechanism of depression treatment interventions but may reflect working mechanisms unique to ECT.