Task-guided accelerated cTBS simultaneously treats depression and social dysfunction in patients with major depressive disorder: a randomized clinical trial

Current antidepressant therapies predominately target symptom remission in major depressive disorder (MDD) but often overlook social dysfunction, which is a critical determinant of functional recovery. Individualized, accelerated continuous theta burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (R.DLPFC) may offer a potential therapeutic approach for concurrently improving clinical and psychosocial outcomes in MDD. In this randomized, double-blind, sham-controlled trial, 70 patients with MDD were randomly assigned to receive either active (n = 37) or sham (n = 33) accelerated cTBS for 2 weeks. The treatments targeted individualized R.DLPFC sites, which were identified by task-evoked brain activation during a social interactive task (Ultimatum Game, UG). Depressive and anxiety symptoms, general social functioning, UG-derived behavioral and computational modeling indices (e.g., learning rates), and effective connectivity in social processing networks were assessed pre- and post-treatment. Active accelerated cTBS significantly outperformed sham stimulation in reducing depressive and anxiety symptoms and improving general social functioning (all ps < 0.001). The active group also demonstrated enhanced cooperation behavior (p = 0.002) and increased learning rates (89% HDI: [0.01, 0.21]). And the active group exhibited increased effective connectivity from the right insula to the R.DLPFC and stable effective connectivity from the anterior cingulate cortex (ACC) to the left insula after treatment, which was different from the sham group (Pp > 0.95). No severe adverse events occurred. Individualized, accelerated cTBS targeting task-evoked activation in the R.DLPFC safely and effectively improves clinical symptoms and social dysfunction in MDD. Altered effective connectivity among the DLPFC, insula and ACC may provide mechanistic insights into its therapeutic effects. Trial Registration: chictr.org.cn; ChiCTR2300068273.