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 DOI: 10.1016/j.jad.2026.121487 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Emulated target trial using observational data Peer reviewed |
|---|---|
| Sample size | 1,089,419 |
| Population | U.S. adults with major depressive disorder between 2018 and 2024 |
| Interventions | Esketamine Injectable R S-ketamine Oral antidepressants |
| Topics | Depression Esketamine Ketamine |
| Keywords | Outcomes Safety |
| Key findings | Esketamine was associated with higher risks of suicidal ideation, generalized anxiety disorder, insomnia, and cardiac arrest compared with injectable ketamine, but lower risks of suicidal ideation, suicide attempt, and generalized anxiety disorder compared with oral antidepressants, although with a higher risk of cardiac arrest. |
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.
Comparable studies
Other non-randomized and open-label trials on esketamine for depression, most cited first.
Citations in the library
Cites 20
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry 2018
- EFFECTS OF KETAMINE ON EXPLICIT AND IMPLICIT SUICIDAL COGNITION: A RANDOMIZED CONTROLLED TRIAL IN TREATMENT-RESISTANT DEPRESSION Depression and Anxiety March 25, 2014
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
and 15 more in the library