Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial.
Samuel T. Wilkinson, Brandon Kitay, Matthew Macaluso, Mia C Santucci, Kristina T. Kumpf, Cindy Voghell, Lauren Astorino, Rachel Hershenberg, Valeria Martinez-Kaigi, Tiffany Nowell, Michael E. Thase, Gerard Sanacora, Taeho Greg Rhee
The Journal of Clinical Psychiatry May 4, 2026 DOI: 10.4088/jcp.25m16285 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 93 |
| Population | Patients with major depressive disorder and suicidal ideation |
| Interventions | Esketamine Cognitive behavioral therapy |
| Dose | 84 mg |
| Duration | 16-week intervention, 18-week assessment |
| Topics | Depression Esketamine |
| Registration | NCT04760652 |
| Key findings | Adding CBT to esketamine led to greater reductions in suicidal ideation than esketamine alone, as measured by three clinician-rated scales. |
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.
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.