Prefrontal Transcranial Pulse Stimulation for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Transcranial pulse stimulation is a novel noninvasive brain stimulation technique with preliminary evidence of antidepressant effects; however, its efficacy has not been tested in a double-blind, sham-controlled randomized clinical trial. Objective: To examine the antidepressant efficacy of transcranial pulse stimulation for major depressive disorder. Design, Setting, and Participants: This 2-arm, parallel-design, double-blind, sham-controlled randomized clinical trial was conducted between June 1, 2023, and October 31, 2025, at the Hong Kong Polytechnic University. Patients with major depressive disorder and a Hamilton Depression Rating Scale score of 14 or higher were convenience sampled and enrolled. Interventions: Participants were randomized 1:1 to receive 12 sessions (1000 pulses per session) of active or sham transcranial pulse stimulation targeting the left dorsolateral prefrontal cortex during 4 weeks. Main Outcomes and Measures: Change in Montgomery-Åsberg Depression Rating Scale score (range, 0 [no depression] to 60 [severe depression], with a change of at least 6 indicating minimal change and 12 or more indicating substantial change) after 12 treatment sessions. Results: This modified intention-to-treat analysis included 80 participants (mean [SD] age, 35.6 [11.7] years; mean [SD] years of education, 15.5 [3.3]; 53 females), with 74 completing treatment and 6 withdrawing (2 from sham due to adverse effects); 40 participants were randomized to the active group and 40 to the sham group. The active group demonstrated a statistically significantly greater reduction in Montgomery-Åsberg Depression Rating Scale scores than the sham group (mean difference, -4.19; 95% CI, -8.33 to -0.04; P = .048; Hedges g = 0.45). Resting-state functional magnetic resonance imaging analyses found that, compared with the sham stimulation, active stimulation significantly enhanced functional connectivity within the left dorsolateral prefrontal cortex (mean difference, 0.11; 95% CI, 0.03-0.19; P = .009); between the left dorsolateral prefrontal cortex and left orbitofrontal, superior medial prefrontal, and pregenual anterior cingulate cortices (mean difference, 0.11; 95% CI, 0.05-0.17; P < .001); and between the left dorsolateral prefrontal cortex and posterior cingulate cortex and bilateral precuneus and calcarine cortex (mean difference, 0.08; 95% CI, 0.01-0.16; P = .02). Conclusions and Relevance: In this randomized clinical trial of transcranial pulse stimulation, the treatment was safe, well tolerated, and associated with antidepressant effects and modulation of multiple depression-relevant brain circuits. These findings provide a rationale for future studies to optimize therapeutic efficacy by increasing the number of treatment sessions and refining targeting strategies. Trial Registration: ClinicalTrials.gov Identifier: NCT05551585.