No effect of transcranial direct current stimulation on brain age during cognitive behavioral therapy for major depressive disorder: secondary results from a randomized, double-blind, sham-controlled trial.

Major depressive disorder (MDD) has previously been associated with accelerated brain ageing, a feature reported to remain unchanged after antidepressant pharmacotherapy. We conducted a secondary analysis of a randomized trial augmenting cognitive behavioral therapy (CBT), a long-established first-line treatment for depression, with active or sham transcranial direct current stimulation (tDCS), a newer neuromodulatory approach that has received FDA approval for MDD in at-home device format. We calculated the brain-predicted age difference (brain-PAD = predicted brain age - chronological age) in 38 unmedicated patients with MDD before and after treatment, using a model trained on anatomical MRI scans from N = 3377 healthy controls. Linear mixed-effects models tested change in brain-PAD and predicted brain age, adjusting for age and sex. The randomized comparison showed no evidence that active tDCS produced differential change in brain-PAD relative to sham (β = 0.85 years, 95% CI [-0.83, 2.53], p = .308, BF10 = 0.22). Contrary to our hypothesis, in the combined treated cohort (CBT ± tDCS), average change in brain-PAD was negligible (β = 0.01 years, 95% CI [-0.82, 0.84], p = .985, BF10 = 0.13), despite symptomatic improvement on the HAM-D. Baseline brain-PAD also did not differ among MDD patients, healthy controls, and first-degree relatives after adjustment for age and sex (F(2,93) = 1.31, p = .276, BF10 = 0.04). These findings suggest that short-term depression improvement and adjunctive tDCS were not accompanied by detectable changes in MRI-derived brain age or brain-PAD. However, our relatively young patients, small sample size, wide confidence intervals, limited local calibration, and unmeasured candidate moderators of the brain age constrain definitive conclusions. Larger, longer, and biologically stratified trials are needed to determine whether brain age biomarkers are modifiable and useful tools in clinical practice.