Peripheral immune biomarkers, brain imaging phenotypes and treatment response in major depressive disorder

Immune dysregulation is implicated in major depressive disorder (MDD), but its links to clinical features and in vivo brain phenotypes remain uncertain. We examined ten plasma biomarkers in 36 unmedicated MDD patients and 48 control participants using high-sensitivity immune profiling at baseline, alongside PET/MR imaging of brain serotonin transporter (SERT) binding and regional structural measures. Patients underwent three months of antidepressant treatment and were followed up with MR imaging. Glial fibrillary acidic protein (GFAP) was higher in MDD patients (β = 0.66, 95% CI 0.22 - 1.11), and interleukin-33 (IL-33) correlated with subcortical volumes across all participants (β = 0.22, 95% CI 0.07 - 0.38). No marker correlated with SERT binding or cortical thickness after correction, and neither SERT binding nor brain structural measures differed by diagnosis. In the longitudinal analysis, interleukin-13 (IL-13) was associated with greater antidepressant response during first-line treatment with escitalopram (β = 1.09, 95% CI 0.56 - 1.61). IL-15 and IL-13 showed nominal associations with hippocampal volume increase after treatment. These findings suggest astroglial involvement in MDD and that peripheral immune states relate to subcortical brain structure. IL-13 is a candidate prognostic marker of response to selective serotonin reuptake inhibitors. Its tentative association with longitudinal changes in hippocampal volume suggests that immune processes in MDD may be related to both the capacity for clinical improvement and brain structural plasticity during treatment.