Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial.
Samuel T Wilkinson, Brandon M Kitay, Matthew Macaluso, Mia C Santucci, Kristina Kumpf, Cindy Voghell, Lauren Astorino, Rachel Hershenberg, Valeria Martinez-kaigi, Tiffany Nowell, Michael E Thase, Gerard Sanacora, T Greg Rhee
The Journal of clinical psychiatry May 4, 2026 Peer reviewed DOI: 10.4088/jcp.25m16285 via PubMed
Summary
The study evaluated the feasibility and efficacy of combining cognitive behavioral therapy (CBT) with esketamine in patients with major depression and suicidal ideation. A total of 93 participants were randomized to receive either CBT with esketamine or esketamine with treatment as usual. The results showed that the CBT group had a greater reduction in suicidal ideation compared to the treatment as usual group, with a Beck Scale for Suicidal Ideation mean difference of -1.91.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 93 |
| Population | patients with major depressive disorder and suicidal ideation |
| Key finding | The combination of CBT with esketamine was more effective in reducing suicidal ideation compared to esketamine plus treatment as usual. |
Abstract
Background: Suicide is a public health crisis in the US, with limited evidence demonstrating efficacy of treatments for high-risk patients due in part to their exclusion from most clinical trials. This clinical trial evaluates the feasibility and efficacy of adjunctive cognitive behavioral therapy (CBT) with esketamine in patients with major depression and suicidal ideation (MDSI). Methods: Treatment-seeking patients (57 inpatients; 36 outpatients) with major depressive disorder (DSM-5 criteria) and suicidal ideation were randomized (1:1) to receive esketamine plus a 16-week course of CBT or esketamine plus treatment as usual (TAU) alone. The starting dose of esketamine was 84 mg in both groups. The primary outcome was feasibility, with a key secondary outcome being improvement in suicidal ideation. CBT consisted of traditional one-on-one therapy sessions and a computer-assisted program to facilitate psychoeducation and attainment of skills. Enrollment occurred between March 2021 and May 2025. Outcomes: Ninety-three subjects were randomized with a 72% study completion rate, demonstrating feasibility (primary outcome) by meeting recruitment goals of 80% of the targeted enrollment and 70% of retention through study end point. Change in suicidal ideation from baseline through week 18 (a key secondary outcome), based on the Beck Scale for Suicidal Ideation (BSSI), Clinician Global Improvement Scale for Suicide Severity (CGI-S), and Montgomery-Åsberg Depression Rating Scale (MADRS), favored the CBT group over the TAU group (BSSI mean difference of -1.91, 95% CI -3.57 to -0.24, P=.025; CGI-S mean difference of -0.33, 95% CI -0.58 to -0.08, P=.011; MADRS mean difference of -3.77, 95% CI -6.62 to -0.93, P=.009). No difference between groups was observed in the Columbia-Suicide Severity Rating Scale score, MADRS-SI score, or suicide-related events. Interpretation: This study demonstrates the feasibility and the effectiveness of combining CBT with esketamine to reduce SI and prevent relapse in patients with MDSI. Trial Registration: ClinicalTrials.gov identifier: NCT04760652.