CBT After Esketamine in Major Depression and Suicidal Ideation

Key Takeaways

• The randomized comparison met feasibility criteria, reaching 80% of targeted enrollment and 70% retention through the study endpoint.
• Over 18 weeks, several clinician- and patient-rated measures favored the CBT group over treatment as usual alone.
• No between-group difference was reported for Columbia-Suicide Severity Rating Scale score, MADRS-SI score, or suicide-related events.

In adults with major depressive disorder and suicidal ideation, esketamine plus a 16-week CBT program met prespecified feasibility targets and was associated with improvement on several symptom measures compared with esketamine plus treatment as usual alone. The randomized comparison included treatment-seeking patients meeting DSM-5 criteria for major depressive disorder and reporting suicidal ideation. One group received adjunctive psychotherapy with esketamine, while the other received esketamine with usual care alone. The trial evaluated feasibility and symptom change through week 18.

The trial randomized 93 treatment-seeking patients 1:1, including 57 inpatients and 36 outpatients with DSM-5 major depressive disorder and suicidal ideation. Both groups began esketamine at 84 mg, and enrollment occurred from March 2021 through May 2025. Feasibility was the primary outcome, and improvement in suicidal ideation was a key secondary outcome. The study met its predefined feasibility criteria, achieving 80% of targeted enrollment and a 72% study completion rate that exceeded the retention threshold through the study endpoint. The design assessed whether the combined approach could be delivered and maintained over the planned treatment period.

From baseline to week 18, comparative results favored adjunctive CBT on several measures. Beck Scale for Suicidal Ideation scores showed a mean difference of -1.91, with a 95% CI from -3.57 to -0.24 and P=.025. Clinician Global Improvement Scale for Suicide Severity scores showed a mean difference of -0.33, with a 95% CI from -0.58 to -0.08 and P=.011. Montgomery-Åsberg Depression Rating Scale scores showed a mean difference of -3.77, with a 95% CI from -6.62 to -0.93 and P=.009. Across these measures, numerical improvements favored adjunctive CBT over treatment as usual alone.

CBT was delivered through traditional one-on-one sessions together with a computer-assisted program designed to support psychoeducation and skills attainment. No between-group difference was observed for Columbia-Suicide Severity Rating Scale score, MADRS-SI score, or suicide-related events. Investigators interpreted the findings as supporting the feasibility of combining CBT with esketamine and suggesting benefit on several suicidal ideation and depression measures in patients with major depressive disorder and suicidal ideation.