Clinical Summary: Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial
Patients hospitalized or recently discharged with major depression and suicidal ideation remain at high relapse and suicide risk after the standard 4-week esketamine course ends. This trial asks the practical next-step question: whether adding a structured 16-week CBT course can sustain gains and improve longer-term outcomes in a population that most psychiatric trials have historically excluded.
Key Findings
- Adjunctive CBT improved self-reported suicidal ideation at week 18: least squares mean change in BSSI was −6.01 for the CBT group versus −4.10 for the TAU-only group (mean difference of −1.91, 95% CI, −3.57 to −0.24, P=.025).
- Adjunctive CBT improved overall depressive symptoms at week 18: least squares mean change in composite MADRS score was −11.29 for CBT versus −7.52 for TAU only (mean difference of −3.77, 95% CI −6.62 to −0.93, P= .009).
- Clinician-rated suicide severity also favored CBT at week 18: CGI improvement changed by −1.00 with CBT versus −0.63 with TAU-only (mean difference −0.37, 95% CI −0.68 to −0.05, P=.023), and CGI severity changed by −0.81 versus −0.49 (group difference of −0.33, 95% CI −0.58 to −0.08, P=.011).
- Not all suicidality measures separated groups: the MADRS SI item changed by −1.37 with CBT versus −0.98 with TAU-only (mean difference of −0.39, 95% CI −0.84 to 0.06, P=.088), and the C-SSRS ideation score changed by −0.80 versus −0.93 (group difference 0.13, 95% CI −0.39 to 0.65, P=.623).
- The trial met its feasibility target in this high-risk sample: 84/93 (90.3%) were retained through week 4, 72/93 (77.4%) through week 18, and 69/93 (74.2%) through week 26; among those randomized to CBT, the overall completion rate of all CBT sessions was 80.7% and completion of the 9 computer-assisted CBT modules was 76.7%.
For patients with major depression and suicidal ideation receiving intranasal esketamine, adding a structured 16-week CBT course improved longer-term suicidal ideation and depressive symptom outcomes versus esketamine with treatment as usual alone. This combination was feasible to deliver and retain even in a severely ill sample that included many inpatients.
Practice Implications
- When using esketamine for MDSI, plan beyond the 4-week index course; adding structured CBT is a practical relapse-prevention strategy supported by better week-18 BSSI, composite MADRS, and CGI outcomes.
- Do not rely on a single suicidality measure to track benefit. In this trial, BSSI and CGI measures detected between-group differences, whereas the MADRS SI item and C-SSRS ideation subscale did not.
- Expect that high-risk patients can engage in psychotherapy during and after acute esketamine treatment: CBT session completion was 80.7%, and computer-assisted module completion was 76.7%.
- Maintain close follow-up after hospitalization or emergency-level presentations. Most suicide-related serious adverse events were psychiatric in nature (19/24, 79.2%), and most psychiatric SAEs occurred in patients who were inpatients at enrollment (14/18, 77.8%).
