Sustained effectiveness and safety of esketamine for major depressive disorder: a target trial simulation of real-world data.
Ting-Hui Liu, Hong-Shiang Shen, Jheng-Yan Wu, Po-Yu Huang, Yu-Ju Shih, Chih-Cheng Lai
Translational Psychiatry April 10, 2026 DOI: 10.1038/s41398-026-04032-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Target-trial simulation (observational cohort using propensity-score matching) Peer reviewed |
|---|---|
| Sample size | 6,766 |
| Population | Adults aged 18 years or older with major depressive disorder who received esketamine or a conventional antidepressant during an inpatient episode |
| Interventions | Esketamine conventional antidepressant |
| Duration | Follow-up up to 2 years, with outcomes assessed at days 1-14, days 15-365, and days 15-730 |
| Topics | Depression Ketamine Esketamine |
| Keywords | Humans Antidepressive agents Treatment outcome Suicide Adult Middle aged Female |
| Citations | 1 |
| Key findings | Esketamine use was associated with lower suicide-related events, lower all-cause mortality, and less recurrent major depressive disorder at two years compared with conventional antidepressants, without increased major adverse cardiovascular events beyond the first 14 days. The authors report that the composite suicide-related outcome was primarily driven by reductions in suicidal ideation, and that differences in suicide attempts and intentional self-harm could not be determined because of low event counts. |
Abstract
This study aimed to evaluate the long-term effectiveness and safety of esketamine in adults with Major depressive disorder (MDD), focusing on suicide-related events, all-cause mortality, and major adverse cardiovascular events (MACEs). This target-trial simulation used the TriNetX Global Collaborative Network. Adults (≥ 18 years) with MDD who received either esketamine or a conventional antidepressant during an inpatient episode were included. After propensity-score matching for demographic and clinical variables, matched pairs were analyzed followed up to 2 years. The primary outcome was a composite of suicide-related events. Hazard ratios (HRs) with 95% CIs were estimated across acute (days 1-14), intermediate (days 15-365), and long-term (days 15-730) periods. After 1:1 matching, 3383 pairs were analyzed. Esketamine use was associated with lower suicide-related events at days 1-14 (0.77% vs 3.78%; HR, 0.19; 95% CI, 0.12-0.29; P < 0.001), days 15-365 (2.13% vs 2.63%; HR, 0.63; 95% CI, 0.46-0.86; P = 0.003), and days 15-730 (2.66% vs 2.78%; HR, 0.74; 95% CI, 0.55-0.99; P = 0.04). Mortality was lower (6.03% vs 7.63%; HR, 0.61; 95% CI, 0.51-0.73; P < 0.001), as was recurrent MDD at 2 years (3.46% vs 4.67%; HR, 0.76; 95% CI, 0.59-0.98; P = 0.04). MACEs were lower during days 1-14 (2.10% vs 4.97%; HR, 0.39; 95% CI, 0.30-0.51; P < 0.001) and not significantly different thereafter. In conclusion, esketamine treatment was associated with sustained reductions in suicidal ideation and all-cause mortality without increased MACEs risk. The composite suicide-related outcome was primarily driven by reductions in suicidal ideation; differences in suicide attempt and intentional self-harm could not be determined due to low event counts.
Comparable studies
Other non-randomized and open-label trials on esketamine for depression, most cited first.