Intermittent theta burst stimulation to extend early ketamine response in treatment‐resistant depression: A preliminary enriched randomized, double‐blind, sham‐controlled trial
Tung‐Ping Su, Mao‐Hsuan Huang, Wan‐Chen Chang, Wen‐Han Chang, Pei‐Chi Tu, Wei‐Shan Huang, Wei‐Chung Mao, Mu‐Hong ChenBackground
Ketamine produces rapid antidepressant effects in treatment‐resistant depression (TRD), but these benefits diminish within days. Whether intermittent theta‐burst stimulation (iTBS) can sustain ketamine response and whether such effects are associated with changes in large‐scale brain networks are unclear.
Methods
Adults with TRD who exhibited an antidepressant response to two low‐dose ketamine infusions (0.5 mg/kg) were randomized to 5 days of accelerated iTBS or sham stimulation. The primary outcome was the change in Montgomery‐Åsberg Depression Rating Scale (MADRS) scores across the Phase 2 period through Day 49. Resting‐state functional MRI was obtained at baseline and after the stimulation course to examine thalamocortical and corticostriatal connectivity.
Results
Among 45 enrolled participants, 5 did not complete ketamine induction and 2 withdrew before randomization. Thirty‐eight were randomized to active iTBS ( n = 19) or sham iTBS ( n = 19), and 37 completed follow‐up through Day 49 (non‐completion rate, 17.8%). In the intention‐to‐treat analysis, the Phase 2 mixed‐effects model showed a significant overall group effect favoring active iTBS ( P = 0.020), without a significant group × time interaction. Exploratory remission rates were higher with active iTBS at Days 15 and 29. Response maintenance favored active iTBS but did not reach statistical significance (log‐rank P = 0.063). Exploratory fMRI analyses in 15 participants suggested differential group‐by‐time changes in thalamocortical and corticostriatal connectivity.
Conclusion
In this enriched trial, ketamine infusion followed by iTBS was associated with lower overall depressive symptom severity during the randomized follow‐up period through Day 49 among early ketamine responders. Exploratory fMRI analyses suggested treatment‐related network changes.