Accelerated Theta-Burst Stimulation for Treatment-Resistant Depression: A Randomized Clinical Trial.

Intermittent theta-burst stimulation (iTBS) is an established treatment for treatment-resistant depression (TRD). Sessions conducted more than once daily (ie, accelerated TBS [aTBS]) may enhance antidepressant effects. However, evidence is limited to small trials, and protocols are time-consuming and can require neuroimaging-based targeting. To evaluate the efficacy and safety of a pragmatic aTBS protocol for TRD. This triple-blinded, sham-controlled randomized clinical trial was conducted at a single center in São Paulo, Brazil, from July 2022 to June 2024, with a subsequent open-label phase. Patients aged 18 to 65 years with major depression, experiencing a TRD episode, and with a Hamilton Depression Rating Scale, 17-item (HDRS-17) score of 17 or higher were eligible for inclusion. Exclusion criteria were other psychiatric disorders (except anxiety), neurological conditions, and TBS contraindications. Participants received 45 active or sham stimulation sessions over 15 weekdays, with 3 iTBS sessions (1200 pulses each) per day, spaced 30 minutes apart and targeting the left dorsolateral prefrontal cortex using a craniometric approach. In the open-label phase, additional aTBS sessions were offered to achieve a response (≥50% HDRS-17 score improvement) if needed. The primary outcome was change in HDRS-17 score at week 5. Of 431 volunteers screened, 100 participants were enrolled and randomized to either sham or active aTBS. Mean (SD) participant age was 41.7 (8.8) years, and 84 participants (84%) were female. A total of 89 patients completed the study. In the intention-to-treat analysis, the mean change in HDRS-17 scores from baseline to the study end point was 5.57 (95% CI, 3.99-7.16) in the sham group and 9.68 (95% CI, 8.11-11.25) in the active group, corresponding to 31.87% and 54.7% score reductions, respectively, and a medium-to-large effect size (Cohen d, 0.65; 95% CI, 0.29-1.00; P < .001). Response and remission rates were also higher in the active group. Both interventions were well tolerated, but scalp pain was more frequent in the active group than the sham group (17.4% vs 4.4%). During the open-label phase, approximately 75% of patients received additional sessions. In this triple-blinded, sham-controlled randomized clinical trial, a pragmatic aTBS protocol using only 3 iTBS sessions per day and a nonexpensive, non-neuronavigated approach was found to be safe and effective for TRD. ClinicalTrials.gov Identifier: NCT05388539.