Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance.
Dian-Jeng Li, Tien-Wei Hsu, Te-Chang Changchien, Yi-Ya Fang, Fu-Chi Yang, Hung-Yi Lin, Chih-Sung Liang
Journal of affective disorders November 1, 2026 DOI: 10.1016/j.jad.2026.122106 via PubMed
Summary
AI-generated from the abstractPatients with major depressive disorder who are prescribed esketamine have higher rates of comorbid substance use disorders compared to those treated with antidepressants or repetitive transcranial magnetic stimulation. Among esketamine users, those with a substance use disorder face greater risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality. The findings indicate a prescription bias toward patients with comorbid substance use disorders and highlight the need for careful monitoring and specialized care for this population.
Study at a glance
| Characteristics | Retrospective cohort study Peer reviewed |
|---|---|
| Sample size | 30,670 |
| Population | Adults aged 18 years or older with major depressive disorder in the TriNetX US Collaborative Network |
| Topics | Addiction Depression Esketamine |
| Keywords | Mortality Suicide attempt |
| Key finding | 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. |
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.