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...