Connectivity-guided accelerated theta burst stimulation as augmentation for inpatient treatment-resistant depression: a randomized, double-blind, sham-controlled trial

This study examined whether connectivity-guided accelerated intermittent theta-burst stimulation (iTBS) improves depressive symptoms beyond routine multimodal inpatient care in hospitalized patients with treatment-resistant depression (TRD). In this randomized, double-blind, sham-controlled trial, patients with unipolar TRD received active or sham iTBS. Stimulation targeted an individualized left dorsolateral prefrontal cortex site showing most functional anticorrelation with the subgenual anterior cingulate cortex on resting-state functional MRI. Treatment was delivered as 3 daily sessions over 10 weekdays (30 sessions; 54,000 pulses) as an inpatient augmentation strategy. Primary and secondary outcomes were changes in Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II (BDI-II) scores during the 2-week stimulation phase. Exploratory endpoints included response and remission rates. Of the 57 randomized patients, 51 completed treatment (active, n=27; sham, n=24). The cohort exhibited moderate-to-severe treatment resistance (mean Maudsley Staging Method score, 10.9) and high psychiatric comorbidity. Active iTBS was associated with significantly steeper MADRS improvement than sham (-3.54 points/week; 95% CI, -5.53 to -1.55; PFDR=.02), corresponding to model-estimated reductions of 12.06 versus 4.98 points with a large effect size (d=-0.89). BDI-II trajectories similarly favored active treatment, though with a smaller effect (group-by-time estimate, -0.23 points/day; 95% CI, -0.41 to -0.05; PFDR=.04; d=-0.22). MADRS response rates were higher with active iTBS (42.3% vs 13.0%), while remission rates were numerically but not significantly higher (26.9% vs 12.5%). No serious adverse events occurred. In conclusion, connectivity-guided iTBS produced significant add-on antidepressant effects during acute inpatient treatment of TRD. Larger multicenter trials are needed to establish durability and optimize implementation.