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 Peer reviewed DOI: 10.1016/j.jad.2026.122106 via PubMed
Summary
Esketamine users with major depressive disorder (MDD) showed higher risks of comorbid substance use disorders (SUD) compared to those treated with antidepressants or repetitive transcranial magnetic stimulation (rTMS). Specifically, the highest relative risks were for hallucinogen (RR 2.41), opioid (RR 2.26), and stimulant (RR 2.17) use versus the antidepressant group. Additionally, within the esketamine cohort, having comorbid SUD was linked to increased risks for self-harm, suicide attempts, emergency visits, hospitalization, and mortality.
Study at a glance
| Design | retrospective cohort study |
|---|---|
| Sample size | 30,670 |
| Population | adults aged ≥18 years with major depressive disorder |
| Key finding | Esketamine users had higher risks of comorbid substance use disorders and associated negative clinical outcomes compared to matched patients receiving other treatments. |
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.