Phase 2 Trial: iTBS Extends Ketamine Response in TRD Patients

iTBS Shows Promise in Prolonging Ketamine's Effects in Treatment-Resistant Depression

A randomized, double-blind, sham-controlled Phase 2 trial published on November 4, 2026, provides preliminary evidence that intermittent theta-burst stimulation (iTBS) following ketamine infusions can sustain antidepressant effects in adults with treatment-resistant depression (TRD). The study, registered under OpenAlex ID W7225295108, enrolled 45 participants who had responded to two low-dose ketamine infusions (0.5 mg/kg). Thirty-eight were randomized to receive either five days of accelerated iTBS or sham stimulation, with 37 completing the 49-day follow-up period.

Results from the intention-to-treat analysis demonstrated a statistically significant overall reduction in depressive symptoms, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), in the active iTBS group compared to sham (P = 0.020). Exploratory analyses also suggested higher remission rates at Days 15 and 29 for the active iTBS group, though maintenance of response did not achieve statistical significance (log-rank P = 0.063).

Mechanistic Insights: Brain Network Changes Detected by fMRI

Functional MRI (fMRI) analyses in a subset of 15 participants indicated that the combination of ketamine and iTBS may induce differential changes in large-scale brain networks, specifically in thalamocortical and corticostriatal connectivity. These findings align with emerging hypotheses that both ketamine and neuromodulation therapies exert antidepressant effects by modulating brain circuit function rather than targeting isolated neurotransmitter systems.

Notably, the study's design—enriching the sample for ketamine responders before randomization—offers a non-obvious insight: future protocols may benefit from pre-selecting individuals who show acute ketamine response, potentially increasing the power to detect sustained effects of adjunctive interventions like iTBS.

Clinical and Research Implications: Toward Durable TRD Protocols

The rapid but transient antidepressant effects of ketamine have limited its clinical utility for TRD, prompting significant interest in strategies to extend its benefits. This trial provides early evidence that iTBS, a form of repetitive transcranial magnetic stimulation (rTMS) delivering brief, high-frequency bursts, may help maintain symptom relief in this challenging population.

• For researchers: The trial highlights the value of combining pharmacological and neuromodulatory approaches and underscores the need for larger, multi-site studies to confirm efficacy and clarify mechanisms.
• For clinicians: The findings may inform future protocols for sustaining remission in TRD, though current evidence remains preliminary and not practice-changing.
• For policymakers and payers: The study signals a potential shift toward combination treatment paradigms, which may affect reimbursement models and clinical guidelines if validated in larger trials.

Importantly, this trial's enriched design and use of neuroimaging endpoints may set a precedent for future studies aiming to personalize and optimize TRD care.

Risks, Limitations, and Unknowns

The evidence for iTBS extending ketamine’s antidepressant effects in TRD remains preliminary, with several caveats. The trial’s sample size was modest (n=38 randomized, n=37 completed), and some endpoints—such as sustained response maintenance—did not reach statistical significance. Exploratory fMRI findings, while intriguing, were based on a small subset and should be interpreted cautiously.

Potential risks include the unknown long-term safety of repeated ketamine and iTBS exposure, especially in vulnerable populations. Adverse events were not detailed in the preliminary report, and the durability of combined treatment effects beyond 49 days remains untested. Additionally, the enriched responder design may limit generalizability to all TRD patients, as non-responders to ketamine were excluded from randomization.

Looking Forward: Next Steps for Combination Therapies in TRD

Future research should focus on larger, adequately powered trials to replicate and extend these findings, ideally with diverse patient populations and longer follow-up periods. Mechanistic studies using advanced neuroimaging and biomarker endpoints may clarify which individuals are most likely to benefit from combined ketamine-iTBS protocols.

For the field, this trial marks a step toward integrated, circuit-targeted interventions for TRD. However, clinical adoption will require robust evidence of efficacy, safety, and cost-effectiveness. Stakeholders should monitor forthcoming data and regulatory developments as combination strategies move through the translational pipeline.

By Dr. Alex Lin, MD, PhD. Reviewed by Dr. Sarah K. Patel, MD, November 2026. Research based on primary trial publication and OpenAlex registry record.