DTI-ALPS index mediates the relationship between childhood trauma and antidepressant response in major depressive...

Impaired glymphatic function may mediate the impact of childhood trauma on antidepressant response, but this relationship remains unclear. This study examined whether glymphatic function mediates the association between childhood trauma and antidepressant response in major depressive disorder (MDD).

We included 104 MDD patients receiving selective serotonin reuptake inhibitors and 85 healthy controls (HCs). Glymphatic function was assessed using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) method. Childhood trauma was measured with the Childhood Trauma Questionnaire (CTQ), and antidepressant response was evaluated based on the percentage change in 17-item Hamilton Depression Rating Scale (HAMD-17) score from baseline to week 8 (ΔHAMD-17). Partial correlation, mediation, and support vector regression analyses were conducted to assess relationships among CTQ scores, DTI-ALPS indices, and ΔHAMD-17.

MDD patients showed higher CTQ scores and lower DTI-ALPS indices than HCs. Responders had lower CTQ scores than non-responders. CTQ scores, especially abuse subscales, were negatively correlated with ΔHAMD-17, while DTI-ALPS indices were positively correlated with ΔHAMD-17. The DTI-ALPS-L index was specifically associated with total and emotional abuse scores. CTQ scores could robustly predict ΔHAMD-17, with emotional abuse contributing most substantially. The DTI-ALPS-L index mediated the relationship between emotional abuse and ΔHAMD-17.

These findings emphasize the routine childhood trauma screening in MDD managements, to identify individuals at risk for poor antidepressant response and to guide early, targeted interventions. Additionally, the results offer novel insights into the neurobiological pathways linking childhood trauma to treatment response, laying the groundwork for future interventions aimed at restoring glymphatic function.