Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial

Suicide is a major public-health problem, and most people who die by suicide have a treatable psychiatric disorder, commonly major depressive disorder. The authors describe limitations in existing treatments for patients at acute suicide risk: lithium may reduce long-term risk but is difficult to use acutely because of overdose concerns, while conventional antidepressants act slowly and may transiently worsen suicidal ideation in some younger patients. Ketamine and esketamine can reduce depressive symptoms and suicidal ideation rapidly, but the longer-term treatment strategy after the initial esketamine course remains uncertain. This uncertainty is particularly important because previous esketamine trials in major depression with suicidal ideation generally treated inpatients or emergency-department patients and did not provide maintenance esketamine beyond four weeks, despite the high risk of relapse and suicide after hospital discharge.

The key secondary outcome is relapse or worsening suicidal ideation among participants who show substantial improvement after two weeks of esketamine. Substantial benefit is defined as at least a 50% reduction in Beck Scale for Suicidal Ideation scores or a score of 5 or less. A modified intention-to-treat analysis includes participants who reach Week 3 and meet this response criterion. Time-to-event analyses using a log-rank test compare groups, with an event defined as restarting an acute esketamine course or urgently changing treatment because of worsening suicidal ideation, hospitalisation, suicide attempt or death, or an increase to at least 75% of baseline suicidal-ideation severity on two consecutive assessments. The planned sample provides approximately 80% power to detect a moderate-to-large effect on continuous outcomes, assuming 20% attrition, but the trial is not fully powered to detect between-group differences in suicide-related events. Mixed-effects models will examine cognitive outcomes over time, and exploratory analyses will assess whether cognitive changes, CBT engagement, and use of maintenance esketamine differ between groups.

The computer-assisted CBT component is presented as a potential implementation strength because it may standardise delivery, improve patients’ understanding of CBT principles, and help address the limited availability of adequately trained CBT practitioners in community settings. The choice of esketamine rather than racemic ketamine is based on its evidence from well-powered randomised trials and its regulatory indication for the population under study. The authors frame the trial as an attempt to determine whether CBT can help sustain the benefits of esketamine while potentially reducing reliance on burdensome, inconvenient, or costly repeated esketamine treatment.

The authors conclude that CBT-ENDURE may clarify longer-term treatment options for people with major depression and suicidal ideation who receive esketamine, particularly those beginning treatment during psychiatric hospitalisation, living far from treatment centres, or unable to continue frequent esketamine sessions. They state that evidence that CBT can improve longer-term outcomes or reduce the burden of maintenance esketamine would have important clinical implications.