Sustained effectiveness and safety of esketamine for major depressive disorder: a target trial simulation of real-world data

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.