Journal of affective disordersFeb 25, 2026

Comparing the benefits and risks of esketamine, injectable ketamine, and oral antidepressants for major depression in a large population study

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Esketamine was associated with a mixed profile: worse signals than injectable R,S-ketamine, but fewer suicidal and anxiety outcomes than oral antidepressants alongside higher cardiac arrest risk.

Evidence

A population-based target trial emulation of U.S. adults with MDD from 2018 to 2024 compared 4,505 esketamine initiators with 197,694 injectable R,S-ketamine initiators and 887,220 oral-antidepressant patients using propensity-score matching.

Caveat

Because treatment assignment came from observational records, residual confounding could explain some contrasts, and head-to-head clinical trials are still needed.

Simplified

OBJECTIVE: This study evaluated the long-term comparative effectiveness and safety of esketamine versus injectable ketamine and esketamine versus oral antidepressants for major depressive disorder (MDD).

METHODS: This emulated target trial utilized observational data from a cohort of U.S. adults with MDD between 2018 and 2024. Patients were categorized into those receiving esketamine, injectable R,S-ketamine, and those with treatment-resistant depression (TRD) prescribed at least two classes of oral antidepressants. Esketamine initiators were matched to injectable R,S-ketamine initiators and to patients receiving oral antidepressants using propensity scores based on clinical and demographic factors. Outcomes included suicidal ideation or attempt, neuropsychiatric, and cardiovascular outcomes. Cox proportional hazards regression was used to estimate the risk of outcomes.

RESULTS: A total of 4505 esketamine initiators, 197,694 injectable R,S-ketamine initiators, and 887,220 patients receiving oral antidepressant were included. After propensity score matching, compared with injectable R,S-ketamine initiators, esketamine initiators were associated with higher risks of suicidal ideation (HR = 1.24, 95% CI = 1.06-1.46), generalized anxiety disorder (HR = 1.55, 95% CI = 1.37-1.74), insomnia (HR = 1.25, 95% CI = 1.07-1.46), and cardiac arrest (HR = 1.57, 95% CI = 1.21-2.20). Compared with patients with TRD receiving oral antidepressants, esketamine initiators were associated with lower risks of suicidal ideation (HR = 0.89, 95% CI = 0.83-0.96), suicide attempt (HR = 0.71, 95% CI = 0.56-0.90), and generalized anxiety disorder (HR = 0.82, 95% CI = 0.74-0.91), but a higher risk of cardiac arrest (HR = 2.09, 95% CI = 1.50-2.91).

CONCLUSION: Injectable R,S-ketamine demonstrated a more favorable safety and effectiveness profile than esketamine, whereas esketamine was associated with greater effectiveness but a higher risk of cardiac arrest compared with oral antidepressants. Head-to-head clinical trials are needed to validate these findings.