Comparative effectiveness and safety of esketamine versus injectable racemic ketamine and oral antidepressants for major depressive disorder: A population-based target trial emulation.
Ching-hua Julie Lee, Yunzhe Qian, Weiqun Yu, Cristina Cusin, Kevin Sheng-kai Ma
Journal of affective disorders August 1, 2026 Peer reviewed DOI: 10.1016/j.jad.2026.121487 via PubMed
Summary
Esketamine was associated with higher risks of suicidal ideation, generalized anxiety disorder, insomnia, and cardiac arrest compared to injectable R,S-ketamine. However, when compared to patients with treatment-resistant depression on oral antidepressants, esketamine showed lower risks for suicidal ideation and attempts but a higher risk of cardiac arrest. In total, 4505 esketamine users were evaluated against 197,694 injectable R,S-ketamine users and 887,220 oral antidepressant users.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 192,419 |
| Population | U.S. adults with major depressive disorder |
| Key finding | Esketamine initiators had higher risks of adverse outcomes compared to injectable R,S-ketamine but lower risks compared to oral antidepressants. |
Abstract
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). 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. 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). 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.