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

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.

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

• State of the evidence: Esketamine for anxiety ↑Supports

  The reduction in suicidal ideation over six months remained statistically significant after adjusting for depressive severity, suggesting an anti-suicidal effect partly independent of mood improvement.

  Synthesized September 21, 2026

• State of the evidence: Ketamine for anxiety ↑Supports

  The within-person reduction in suicidal ideation over six months remained statistically significant after adjusting for time-varying depressive severity, indicating an anti-suicidal effect partly independent of mood improvement.

  Synthesized September 21, 2026

Comparable studies

Other observational and cohort studies on esketamine for anxiety, most cited first.