Abstract
Cognitive-behavioral therapy (CBT) is a primary treatment for depression. Although previous research has underscored the significant roles of white matter (WM) alterations and maladaptive parenting in depression risk, their associations with CBT response remain largely unknown. This longitudinal study investigated the interplay of WM integrity changes over time, treatment response, and parenting style in patients with depression. Diffusion-tensor-imaging and clinical data were assessed in n = 65 (55% female) patients with depression before and after 20 CBT sessions and n = 65 (68% female) healthy controls (HC) in a naturalistic design. Linear-mixed-effect models compared changes in fractional anisotropy (FA) between groups and tested associations between FA changes and symptom changes. It was investigated whether parenting style predicts depressive symptoms at follow-up and whether FA changes mediate this association. Patients showed differential FA changes over time in the corpus callosum and corona radiata compared to HC (p(tfce-FWE) = 0.008). Increases in FA in the corpus callosum, corona radiata and superior longitudinal fasciculus were linked to symptom improvement after CBT in patients (p(tfce-FWE) = 0.023). High parental care (p(FDR) = 0.010) and low maternal overprotection (p(FDR) = 0.001) predicted fewer depressive symptoms at follow-up. The association between maternal overprotection and depressive symptoms at follow-up was mediated by FA changes (p(FDR) = 0.044). Robustness checks-controlling for outliers, non-linear age effects, clinical characteristics, and patient subgroups-supported these results. Overall, patients with depression show changes in WM integrity following CBT, which are linked to treatment response. The results highlight the significance of early life adversities and related microstructural changes in the effectiveness of CBT for treating depression.