Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance.

Abstract

Little is known about esketamine's effectiveness for patients with major depressive disorder (MDD) comorbid substance use disorders (SUD). We conducted a retrospective cohort study using the TriNetX US Collaborative Network, including adults aged ≥18 years with MDD. Three propensity-score-matched (1:1) cohorts were defined based on treatment: esketamine, antidepressant-only, and repetitive transcranial magnetic stimulation (rTMS). We calculated relative risks (RRs) to compare the prevalence of substance use disorder (SUD) across these groups. Among esketamine users, we employed Cox proportional hazards models to analyze clinical outcomes-including self-harm, suicide attempt, hospitalization, emergency visits, and mortality-comparing those with and without SUD from the first esketamine prescription. Esketamine users (n = 30,670) showed higher risks of comorbid SUD across all categories versus matched antidepressant and rTMS patients. Compared to the antidepressant group, the highest risks were for hallucinogen (RR 2.41, 95% CI 1.87-3.09), opioid (RR 2.26, 95% CI 2.14-2.37), and stimulant (RR 2.17, 95% CI 2.01-2.34). Elevated risks were also observed versus the rTMS group, with the highest for opioid (RR 3.70, 95% CI 3.14-4.35). Within the esketamine cohort, the presence of comorbid SUD was associated with higher risks for self-harm (HR 2.99, 95% CI 2.29-3.91), suicide attempt (HR 2.13, 95% CI 1.59-2.85), emergency visits (HR 1.78, 95% CI 1.70-1.85), hospitalization (HR 1.70, 95% CI 1.63-1.77), and mortality (HR 1.12, 95% CI 1.04-1.21). Esketamine prescription bias toward MDD patients with comorbid SUD underscores the need for enhanced monitoring and specialized care.

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: Ketamine for addiction ↓Opposes

  Esketamine users with comorbid substance use disorder had higher risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality compared with esketamine users without substance use disorder.

  Synthesized September 21, 2026

• State of the evidence: Esketamine ↓Opposes

  Esketamine users with comorbid substance use disorder had higher risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality compared to esketamine users without substance use disorder.

  Synthesized August 23, 2026

Comparable studies

Other observational and cohort studies on ketamine for addiction, most cited first.