This review and meta-analysis aimed to evaluate esketamine in managing major depressive disorder (MDD) / treatment resistant depression (TRD), preventing postpartum depression (PPD) and postoperative depression, including comparisons within and between administrations. Five databases (Pubmed, MEDLINE, Embase, Web of science and the Cochrane Library) were searched up to July 24, 2025. Randomized clinical trials investigating esketamine for depression, compared with control group were included. Efficacy outcomes included depression scales, remission rate, response rate and depression incidence rates. Safety outcomes included adverse events reported in more than two comparisons. Standardized mean differences (SMDs) and Relative risks (RRs) with their corresponding 95% confidential intervals (CIs) were estimated using fixed- or random-effects models. Administration regimes were ranked using surface under the cumulative ranking. Of 12,285 studies identified, 67 trials with 11,553 participants were included: 19 trials on MDD/TRD, 18 studies on PPD and 30 studies on postoperative depression. The overall pooled SMDs, compared with comparator, showed effective in treating and preventing depression (MDD -0.36, 95%CI -0.49, -0.24; PPD for postpartum 6 week -0.40, 95%CI -0.78, -0.02, and postoperative depression for postoperative 3 month -0.82, 95%CI -1.46, -0.18). Intravenous administration yields the greatest effect in treating MDD/TRD and preventing PPD, no matter of the measured outcome (scales scores, response rate of MDD/TRD or incidence rate of PPD or postoperative depression). Esketamine was associated with higher incidences of dizziness in both therapeutic and preventive effects. These findings highlight both short- and long-term efficacy of eskatemine in treating MDD/TRD, and preventing PPD and postoperative depression, with efficacy differing across administration routes.
