Intermittent Theta-Burst Stimulation and Depressive Symptoms in Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Intermittent theta-burst stimulation (iTBS) is an established treatment for major depressive disorder (MDD), but sham-controlled evidence for once-daily protocols remains limited. Objective: To determine whether 10 sessions of once-daily iTBS is superior to sham iTBS for adults with MDD. Design, Setting, and Participants: This randomized clinical trial was conducted at an outpatient psychiatric clinic in North Norway between January 1, 2022, and June 30, 2025, among 73 patients with MDD, aged 22 to 65 years, with a Montogomery-Åsberg Depression Rating Scale (MADRS) score of 20 or more, regardless of treatment refractoriness level. Statistical analyses were completed in October 2025. Intervention: Participants were randomized to 10 weekday sessions of once-daily iTBS (600 pulses at 120% of the resting motor threshold) or sham stimulation delivered with a validated sham coil to the left dorsolateral prefrontal cortex. A 4-week follow-up evaluated sustained effects. Main Outcomes and Measures: Main outcomes were between-group differences in depression scores on day 10, measured with the clinician-rated MADRS and the Beck Depression Inventory-II (BDI-II). Secondary outcomes included MADRS scores on day 5, MADRS and BDI-II scores at follow-up, and response and remission rates on day 10. Repeated depression measures were analyzed using linear mixed-effects models in a modified intention-to-treat sample. Adverse events were assessed daily and compared between groups. Results: Seventy-three participants (mean [SD] age, 36.1 [10.6] years, 40 female [54.8%]) completed the study: 41 were randomized to active iTBS and 32 to sham. iTBS was superior to sham on day 10 for MADRS scores (mean difference, 3.57 [95% CI, 0.79-6.35]; Hedges g = 0.61; P = .01), but not for BDI-II scores (mean difference, 3.05 [95% CI, -2.72 to 8.82]; P = .30). iTBS was also superior to sham on day 5 for MADRS scores (mean difference, 2.89 [95% CI, 0.13-5.64]; Hedges g = 0.50; P = .04) but not significant at follow-up due to improvement in the sham group. Treatments were well tolerated, with mild and transient adverse events. Conclusions and Relevance: In this randomized clinical trial of adults with MDD, a fixed 10-session schedule of once-daily iTBS resulted in greater reductions in clinician-rated depressive symptoms than sham during the treatment phase. The group difference was not sustained at the 4-week follow-up. These findings highlight the importance of treatment duration and extended follow-up in interpreting clinical response. Trial Registration: ClinicalTrials.gov Identifier: NCT05516095.