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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 Chen

Psychiatry and Clinical Neurosciences November 4, 2026 DOI: 10.1111/pcn.70165 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled trial Double-blind Peer reviewed
Sample size 38
Population Adults with treatment-resistant depression who exhibited an antidepressant response to two low-dose ketamine infusions
Intervention Ketamine
Dose 0.5 mg/kg ketamine
Duration 5 days of accelerated iTBS or sham; follow-up through Day 49
Measures Montgomery-Åsberg Depression Rating Scale (MADRS), resting-state functional MRI
Topics Ketamine Depression Esketamine
Keywords Corticostriatal Neuromodulation Thalamocortical Transcranial magnetic stimulation
Key findings Adding five days of accelerated iTBS after ketamine induction was associated with lower overall depressive symptom severity through Day 49 compared with sham (significant overall group effect, P = 0.020), though the group-by-time interaction was not significant. Exploratory remission rates were higher with active iTBS at Days 15 and 29, and response maintenance favored active iTBS without reaching significance (log-rank P = 0.063). Exploratory fMRI analyses suggested treatment-related changes in thalamocortical and corticostriatal connectivity.

Abstract

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. 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. 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. 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.

Comparable studies

Other randomized controlled trials on ketamine for depression, most cited first.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

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