Association of Esketamine use with mortality and clinical outcomes in patients with cancer-related depression: A target trial emulation.

Abstract

Although esketamine shows efficacy for treatment-resistant depression, its potential effectiveness in cancer-related depression (CRD) has not been well-established. We therefore evaluated the real-world effectiveness and safety of esketamine in CRD using a target trial emulation framework based on anonymized electronic health records from the TriNetX network. Adults aged 18-74 years with CRD who initiated esketamine or oral antidepressant monotherapy between March 5, 2019, and December 31, 2024, were included. The primary outcome was all-cause mortality; secondary outcomes encompassed emergency room (ER) visits, intensive care unit (ICU) visits, hospitalizations, suicide-related events, palliative care, several physical complications, and psychiatric outcomes. Outcomes were assessed at two years after the index event and summarized across three follow-up windows, using Kaplan-Meier estimations and Cox proportional hazards models. After propensity score matching, 1751 patients per group were included. Compared with the oral-antidepressant-only group, esketamine initiation was associated with significantly lower risks of 2-year all-cause mortality (hazard ratio [HR] 0.737, 95% confidence interval [CI] 0.614-0.886), ER visits (HR 0.574, 95% CI 0.501-0.657), ICU visits (HR 0.538, 95% CI 0.423-0.683), and psychotherapy utilization (HR 0.267, 95% CI 0.171-0.418). The esketamine group also showed a lower risk of ischemic stroke (HR 0.394, 95% CI 0.223-0.698), and subgroup analyses indicated that these observed associations were more pronounced in older patients. Overall, esketamine was associated with lower mortality and generally comparable safety outcomes in CRD, supporting its role as a potential therapeutic option for managing CRD.

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