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

ImportanceStandard repetitive transcranial magnetic stimulation protocols are difficult to integrate into inpatient psychiatric care because they require daily treatment over several weeks. Accelerated intermittent theta-burst stimulation (iTBS) may offer a feasible augmentation strategy for hospitalized patients with treatment-resistant depression (TRD). ObjectiveTo determine whether connectivity-guided accelerated iTBS improves depressive symptoms beyond routine multimodal inpatient care in hospitalized patients with TRD. Design, Setting, and ParticipantsThis randomized, double-blind, sham-controlled clinical trial was conducted in the inpatient unit of the Department of Psychiatry, University of Oldenburg, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany. Patients aged 18 to 65 years with unipolar TRD were recruited between May 2021 and August 2024. InterventionsParticipants received active or sham iTBS targeting an individualized left dorsolateral prefrontal cortex site showing strongest functional anticorrelation with the subgenual anterior cingulate cortex using resting-state functional MRI. Treatment was delivered as 3 daily sessions over 10 weekdays (30 sessions; 54 000 pulses total) as augmentation to routine multimodal inpatient care. Main Outcomes and MeasuresPrimary and secondary outcomes were changes in Montgomery-[A]sberg Depression Rating Scale (MADRS) scores assessed weekly and Beck Depression Inventory-II (BDI-II) scores assessed daily during the 2-week stimulation phase. Exploratory outcomes included response and remission rates. ResultsOf 57 randomized participants, 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 psychiatric comorbidity in 82% of participants. Active iTBS was associated with steeper MADRS improvement than sham (-3.54 points/week; 95% CI, -5.53 to -1.55; false discovery rate- adjusted P<.001), corresponding to model-estimated reductions of 12.06 versus 4.98 points (Cohen dD=D-0.89). BDI-II trajectories similarly favored active treatment, although with a smaller effect size (-0.23 points/day; 95% CI, -0.41 to -0.05; false discovery rate-adjusted P=.02; Cohen dD=D-0.22). MADRS response rates were higher with active iTBS (42.3% vs 13.0%), whereas remission rates were numerically but not significantly greater (26.9% vs 12.5%). No serious adverse events occurred. Conclusions and RelevanceAccelerated 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 clinical implementation. Trial RegistrationClinicalTrials.gov Identifier: NCT04832750.