Psychiatry · Medical Literature
Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial.
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.
Clinical relevance
In adults with major depressive disorder and active suicidal ideation, does the addition of a 16-week course of cognitive behavioral therapy (CBT) to esketamine improve suicidal ideation and prevent depressive relapse compared with esketamine plus treatment as usual (TAU)? __SNAPSHOT__ {"studyDesign":"Rater-blinded, randomized controlled trial (1:1 allocation); feasibility trial with efficacy secondary outcomes (CBT-ENDURE; NCT04760652)","setting":"Multi-site; inpatient psychiatric units and outpatient interventional psychiatry services, United States (Yale School of Medicine and affiliated centers); enrollment March 2021 – May 2025","sampleSize":"n=93 randomized (57 inpatients; 36 outpatients); target enrollment was 100 participants","population":"Treatment-seeking adults meeting DSM-5 criteria for major depressive disorder with active suicidal ideation (MDSI); included both inpatients hospitalized for acute suicidal ideation or suicide attempt and outpatients with significantly elevated suicidal ideation referred to an interventional psychiatry service; prior esketamine/ketamine non-responders and those currently enrolled in formal CBT programs were excluded","intervention":"Esketamine nasal spray (starting dose 84 mg) followed by a 16-week course of CBT combining traditional one-on-one therapy sessions with a computer-assisted program for psychoeducation and skills acquisition","comparator":"Esketamine nasal spray (starting dose 84 mg) plus treatment as usual (TAU) alone","primaryOutcome":"Feasibility, defined as achieving ≥80% of targeted enrollment (n=100) and ≥70% retention through the study endpoint","followUp":"18 weeks (primary efficacy assessment at Week 18; additional assessment at Week 26 per protocol)","fundingSource":"Government (National Institute of Mental Health, R01MH125205; National Center for Advancing Translational Science CTSA grant UL1 TR001863; Health Resources and Services Administration); Yale University. Note: Lead author reported receiving contract research funding from Janssen Pharmaceuticals, Sage Therapeutics, and Oui Therapeutics for other trials, and consulting fees from Janssen and Sage."}
Key findings
The trial met its primary feasibility endpoint: 93 of a targeted 100 participants were enrolled (93% of target, satisfying the ≥80% recruitment threshold) and the study completion rate was 72%, satisfying the ≥70% retention criterion. For the key secondary outcome of suicidal ideation change from baseline through Week 18, multiple measures favored the CBT plus esketamine group over the TAU plus esketamine group. On the Beck Scale for Suicidal Ideation (BSSI), the CBT group demonstrated a statistically significant greater reduction (mean difference −1.91, 95% CI −3.57 to −0.24; P=0.025). The Clinician Global Impression – Severity scale (CGI-S) also favored CBT (mean difference −0.33; full 95% CI not reported in the abstract). The MADRS total score likewise favored the CBT group (specific effect size and CI not reported in the abstract beyond directional favorability). However, no statistically significant difference between groups was observed on the Columbia-Suicide Severity Rating Scale (C-SSRS), the MADRS suicidal ideation subscale item, or in the rate of suicide-related events. NNT for preventing a suicide-related event: not calculable from available data. Adverse event data beyond suicide-related events were not reported in the abstract.
Practice implications
CBT-ENDURE establishes that enrolling high-risk patients with MDSI — a population historically excluded from clinical trials — into a randomized controlled trial combining esketamine with structured CBT is feasible in both inpatient and outpatient settings. The trial also provides preliminary evidence that adjunctive CBT may reduce suicidal ideation more than esketamine plus TAU, based on statistically significant improvement on the BSSI and CGI-S. However, the most widely used and validated measure of suicidal ideation severity, the Columbia-Suicide Severity Rating Scale (C-SSRS), did not show a significant between-group difference, nor did the MADRS suicidal ideation item or rates of suicide-related clinical events. This inconsistency across validated instruments is an important limitation and tempers confidence in the efficacy signal. The trial was powered for feasibility, not efficacy; therefore, the secondary efficacy results should be interpreted as hypothesis-generating and not confirmatory. Findings apply to treatment-seeking adults with MDD and active suicidal ideation who have not previously failed esketamine or ketamine, and who are not already engaged in formal CBT. Subgroups such as adolescents, elderly patients, those with psychotic features, bipolar depression, or primary substance use disorders were not adequately represented based on the reported enrollment context. Because only the abstract was available for this summary, additional outcome data, subgroup analyses, adverse event profiles, and mechanistic findings from the full publication may meaningfully alter interpretation. Practice should not change based on this trial alone; a larger, adequately powered, confirmatory RCT is needed. __LIMITATIONS__ Trial was powered for feasibility, not efficacy; secondary efficacy findings are exploratory and underpowered for definitive conclusions.,Enrollment fell short of the 100-participant target (93 enrolled), though the pre-specified feasibility threshold was met.,Inconsistent efficacy signal across suicidal ideation instruments: C-SSRS, MADRS-SI item, and suicide-related event rates did not differ significantly between groups, while BSSI and CGI-S did — raising concerns about which instruments are most sensitive and appropriate in this population.,Rater-blinding (not full double-blinding): patients and clinicians delivering CBT were not blinded, introducing substantial performance and detection bias.,Heterogeneous sample combining inpatients (n=57) and outpatients (n=36) with potentially different baseline severity, risk trajectories, and access to TAU, which may have diluted or confounded treatment effects.,TAU was not standardized or described in detail in the abstract, limiting understanding of the true comparator condition.,Generalizability is limited to treatment-seeking adults at academic medical centers with access to esketamine administration infrastructure; results may not apply to community or resource-limited settings.,The 16-week CBT course was delivered using a hybrid model (in-person plus computer-assisted); the relative contribution of each component is unknown.,No data on long-term outcomes beyond Week 26 are reported.,Lead investigator has financial relationships with Janssen Pharmaceuticals, the manufacturer of esketamine (Spravato), though the trial itself was government-funded; potential for investigator-level conflict of interest warrants acknowledgment.,Only the abstract was available for this analysis; full safety data, attrition patterns, and subgroup results are not yet assessable. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ CBT-ENDURE demonstrates that randomizing high-risk adults with major depression and suicidal ideation to esketamine plus CBT is feasible in real-world inpatient and outpatient settings. Adjunctive CBT produced statistically significant greater reductions in suicidal ideation on some — but not all — validated instruments compared to esketamine plus TAU, and did not significantly reduce suicide-related events; these secondary findings should be considered preliminary and hypothesis-generating. A larger, adequately powered confirmatory trial is needed before this combination can be broadly recommended as a standard-of-care relapse prevention strategy.