Is the reduction in suicidal ideation and deliberate self-harm during intranasal esketamine treatment independent of antidepressant response? A secondary, longitudinal analysis of a real-world TRD cohort with and without comorbid borderline personality disorder

In patients receiving routine esketamine treatment for depression, the reduction in suicidal thoughts over six months is not fully explained by concurrent improvement in depressive symptoms, suggesting a partly independent anti-suicidal effect. This pattern also holds for deliberate self-harm in the subgroup with comorbid borderline personality disorder, a population previously excluded from clinical trials. Early improvement in depression predicts later reduction in suicidal ideation, but a direct, non-mediated path remains. Change in trait impulsivity was explored as an alternative mediator of these effects.

Study at a glance

Abstract

In acute trials of intravenous and intranasal ketamine/esketamine, the rapid anti-suicidal effect appears to be at least partly independent of the overall antidepressant response. That question has, to our knowledge, never been examined in a real-world esketamine cohort followed for six months, nor in a sample enriched for comorbid borderline personality disorder (BPD), a population excluded from pivotal trials. The present secondary analysis asks whether the longitudinal reduction in suicidal ideation (and, secondarily, deliberate self-harm) observed during routine esketamine treatment is statistically accounted for by concurrent improvement in depressive symptoms, or whether a component persists independently of mood improvement. Primary — H1 (independence). The within-person reduction in suicidal ideation across T0–T4 remains statistically significant after adjustment for time-varying depressive severity (MADRS); i.e., the anti-suicidal change is not fully explained by concurrent improvement in depression. Secondary — H2 (lagged mediation). Early improvement in depression (ΔMADRS, T0→T2) is associated with subsequent reduction in suicidal ideation (T2→T4), but a direct (non-mediated) path remains. Secondary — H3 (self-harm, BPD subgroup). The reduction in deliberate self-harm episode frequency across T0–T4 in the BPD subgroup persists after adjustment for concurrent MADRS, and is only partially mediated by early depression improvement. Exploratory — H4. Change in trait impulsivity (BIS-11) functions as an alternative mediator of the change in suicidal ideation and/or self-harm.