Esketamine-ECT Combination in Adolescent Depression: Interim Trial Insights

Esketamine Plus ECT Shows Rapid Impact on Suicidal Ideation in Adolescents

Interim results from a randomized, double-blind, controlled trial published on October 21, 2026 (OpenAlex W7223103183) indicate that adjunctive subanesthetic-dose esketamine (0.25 mg/kg) administered during electroconvulsive therapy (ECT) significantly accelerates the reduction of suicidal ideation in adolescents aged 13-17 with major depressive disorder (MDD). The study enrolled 113 participants, randomized to receive either esketamine plus propofol or saline plus propofol during ECT sessions. The primary outcome—change in suicidal ideation measured by the Beck Scale for Suicide Ideation—showed a strong group × time effect (F = 95.27, P < 0.001), with the esketamine group experiencing a more rapid decline.

Response rates were notably higher in the esketamine group (76.8%) compared to controls (57.9%), with an adjusted odds ratio of 2.49 (95% CI: 1.08-5.75). However, remission rates between groups were similar at this interim stage. Early reductions in depressive symptoms were also observed, as measured by the 24-item Hamilton Depression Rating Scale and other standardized instruments.

Mechanistic Rationale and Clinical Context

Esketamine, the S-enantiomer of ketamine, is an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid-acting antidepressant and anti-suicidal properties. ECT remains a standard intervention for severe, treatment-resistant depression and acute suicidality, but its onset of action can be delayed. Combining subanesthetic-dose esketamine with ECT aims to leverage esketamine’s rapid effects while maintaining ECT’s robust efficacy, potentially bridging the critical period before ECT’s full benefits emerge.

This trial is among the first to systematically evaluate this combination in adolescents—a population for whom both ECT and esketamine are typically reserved for severe, refractory cases due to safety and ethical considerations. Notably, the addition of esketamine did not increase short-term cognitive impairment, as measured by the Montreal Cognitive Assessment, and was associated with fewer reports of injection pain (10.7% vs 33.3%).

Implications for Clinical Practice and Research Policy

The trial’s findings may influence future clinical protocols for managing acute suicidality in adolescent depression, especially where rapid reduction in suicidal ideation is a priority. If confirmed in final analyses and replicated, adjunctive esketamine could be integrated into ECT regimens, potentially reducing risk during the high-vulnerability period early in treatment.

• Regulatory Considerations: Esketamine is currently approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression and depressive symptoms in adults with acute suicidal ideation, but not for pediatric populations or in combination with ECT. These interim results may prompt regulatory agencies to consider expanded indications or off-label guidance, pending long-term safety data.
• Trial Design and Reporting: The study’s randomized, double-blind, controlled design and use of intention-to-treat analysis strengthen its validity. However, as an interim report, it does not address long-term outcomes or rare adverse events, which are critical for policy decisions.
• Health System Impact: The combination approach could affect resource allocation, training, and consent processes in psychiatric care settings. Implementation would require careful coordination between anesthesiology, psychiatry, and pediatric care teams.

Risks, Limitations, and Remaining Unknowns

Despite promising early results, key risks and uncertainties remain. The trial’s interim nature means long-term cognitive, psychiatric, and functional outcomes are unknown. Esketamine’s dissociative and abuse potential, although mitigated at subanesthetic doses and in controlled settings, warrants ongoing monitoring, particularly in adolescents. Additionally, the similar remission rates between groups suggest that while esketamine may accelerate initial improvement, its impact on sustained recovery is unclear.

One non-obvious challenge is the potential for differential effects based on individual neurodevelopmental trajectories—adolescents’ brains are uniquely sensitive to both pharmacologic and electrical interventions, and subtle cognitive or emotional impacts may only emerge over time. This underscores the importance of extended follow-up and neuropsychological assessment in future reports.

Future Directions and Regulatory Outlook

Final results from this trial, including long-term follow-up, will be critical for informing clinical guidelines and regulatory decisions. Additional phase 3 trials, ideally with diverse populations and multi-site collaboration, will be needed to confirm efficacy and safety. Policymakers and professional societies may begin to draft provisional guidance for off-label use in severe cases, but broad adoption will depend on further evidence and consensus regarding risk-benefit profiles.

For researchers, this study highlights the value of innovative, mechanism-driven combination therapies in psychiatry and the need for rigorous, age-specific safety monitoring. For clinicians and families, it offers cautious hope for more rapid relief in life-threatening depressive episodes, balanced by the imperative for careful, individualized decision-making.

How we research: This article was written by Dr. Alex M. Greene, MD, MSc (psychiatry and clinical trials), and reviewed by Dr. Priya N. Shah, PhD (neuropharmacology), on 2026-10-22. Sources include the original trial registry and publication, as well as FDA and clinical guidelines as cited above.