Intermittent theta burst stimulation to extend early ketamine response in treatment‐resistant depression: A preliminary enriched randomized, double‐blind, sham‐controlled trial
Year: 2026
Type: article
Abstract: BACKGROUND: 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.
DOI: 10.1111/pcn.70165
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,240
OpenAlex ID: W7225295108