Efficacy of tDCS-primed iTBS in major depressive disorder: A randomized, sham-controlled trial with exploratory resting motor threshold analyses.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a promising treatment for major depressive disorder (MDD), yet inter-individual variability remains a challenge. Cathodal transcranial direct current stimulation (tDCS) is hypothesized to "prime" the cortex via homeostatic metaplasticity, potentially enhancing the efficacy of subsequent iTBS. METHODS: We conducted a randomized, double-blind, sham-controlled trial with 76 patients with MDD. Participants received 20 daily sessions of either active cathodal tDCS (1 mA, 10 min) or sham tDCS, followed 15 min later by iTBS to the left dorsolateral prefrontal cortex. Primary outcomes were depression severity (HAMD-17 and MADRS). Resting motor threshold (RMT) changes were examined in exploratory analyses of their associations with clinical and neurocognitive outcomes. RESULTS: Both groups demonstrated robust antidepressant effects with high response rates (>70%). However, active tDCS priming did not yield superior depression reduction compared to sham (p > 0.05). In exploratory within-group analyses, greater acute RMT change was nominally associated with subsequent self-reported neurocognitive improvement in the active tDCS group (r = -0.385, P = 0.033, uncorrected). However, the treatment-group × RMT-change interaction was not statistically significant (F(1, 188) = 2.746; p = 0.099). CONCLUSIONS: Cathodal tDCS priming failed to augment iTBS antidepressant efficacy in this medication-free, non-treatment-resistant cohort, possibly attributable to a ceiling effect, suboptimal tDCS parameters, or timing configuration. Exploratory analyses suggest a preliminary association between acute physiological responsiveness to tDCS and subsequent neurocognitive improvement, warranting replication in adequately powered confirmatory studies.