Intermittent Theta-Burst Stimulation for Depressive Symptoms in Parkinson Disease: A Randomized Clinical Trial.
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IMPORTANCE: Depressive symptoms in patients with Parkinson disease (PD) are common and burdensome. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) targeting the left dorsolateral prefrontal cortex (DLPFC-L) is effective but time intensive, limiting practicality. OBJECTIVE: To evaluate the antidepressant efficacy and neurofunctional effects of the ultra-brief intermittent theta-burst stimulation (iTBS) protocol for patients with PD depression (PD-D) compared with active HF-rTMS and sham stimulation. DESIGN, SETTING, AND PARTICIPANTS: This triple-arm, randomized, sham-controlled single-center clinical trial was conducted at Xinhua Hospital, Shanghai Jiao Tong University School of Medicine in China from August 1, 2024, to January 31, 2025. Patients with PD aged 50 to 80 years with 24-item Hamilton Depression Rating Scale (HAMD-24) scores of 8 to 20 were randomized 1:1:1 to iTBS, HF-rTMS, or sham iTBS. Outcomes were assessed at baseline, week 1, week 2, and week 6. Data analysis was finalized in February 2026. INTERVENTIONS: Ten daily sessions over 2 weeks: active iTBS (3 minutes and 20 seconds), active HF-rTMS (20 minutes), or sham iTBS. MAIN OUTCOMES AND MEASURES: The primary outcome was the HAMD-24 score at week 2. Secondary outcomes included anxiety (measured by the 14-item Hamilton Anxiety Rating Scale [HAMA-14]), motor symptoms (measured by the Movement Disorder Society-Unified Parkinson Disease Rating Scale), quality of life (measured by the 8-item Parkinson's Disease Questionnaire [PDQ-8]), and prefrontal hemodynamics (measured using functional near-infrared spectroscopy). Primary analysis followed the principle of intention to treat. RESULTS: Of 54 randomized participants (mean [SD] age, 70.1 [5.3] years; 29 men [53.7%]), 50 (92.6%) completed the trial. Linear mixed-effects models revealed a significant group × time interaction for the HAMD-24 (F6,145 = 4.84; P < .001). At week 2, both active interventions were superior to sham (HAMD-24 score mean difference: iTBS, -4.97 [95% CI, -7.71 to -2.23]; P < .001; and HF-rTMS, -5.73 [95% CI, -8.95 to -2.51]; P < .001). Effects persisted at week 6 (HAMD-24 score mean difference: iTBS vs sham, -6.05 [95% CI, -9.26 to -2.83]; P < .001; and HF-rTMS vs sham, -5.57 [95% CI, -9.36 to -1.78]; P = .002), with no between-group differences. Both interventions improved PDQ-8 scores at week 2 (mean difference: iTBS vs sham, -2.33 [95% CI, -3.33 to -1.33]; P < .001; and HF-rTMS vs sham, -2.43 [95% CI, -4.60 to -0.26]; P = .02). iTBS also alleviated anxiety (mean difference: HAMA-14 score vs sham, -4.04 [95% CI, -7.73 to -0.35; P = .03). Active stimulations increased DLPFC-L activation (estimated adjusted difference: iTBS vs sham, 151.18 [95% CI, 51.24-251.11]; P = .004; and HF-rTMS vs sham, 173.26 [95% CI, 71.92-274.60]; P = .001) and reduced time in low-efficiency connectivity states (iTBS: median change, -0.12 [IQR, -0.29 to 0.02]; false discovery rate-corrected P = .045; and HF-rTMS: -0.12 [IQR, -0.32 to 0]; false discovery rate-corrected P = .02). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of patients with PD-D, the ultra-brief iTBS achieved antidepressant efficacy comparable with that of standard HF-rTMS while markedly reducing treatment time, supporting its use as a pragmatic therapy for PD-D. This study suggests the promise of symptom-stratified neuromodulation for personalized treatment protocols. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2100044421.