Safiye Zeynep TATLI, Deniz CEYLAN, Vesile Senturk CANKORUR
Klinik Psikiyatri Dergisi - 2026;29(2):129-145
Esketamine is a glutamatergic treatment option for major depressive disorder, particularly treatment-resistant depression, because of its rapid antidepressant effects. However, the expanding meta-analytic literature is characterized by methodological heterogeneity and partial overlap of primary trials, which complicates the clinical interpretation of efficacy and safety findings. A higher-level synthesis is therefore needed to contextualize the existing evidence. We conducted an umbrella review of published meta-analyses evaluating the efficacy and/or safety of esketamine in adults with MDD. PubMed/MEDLINE and Scopus were searched for meta-analyses published between December 2020 and December 2025. Given overlap of primary trials and heterogeneity in outcome definitions, findings were synthesized qualitatively. Outcomes included depressive symptom severity, response and remission rates, suicidality-related outcomes, relapse and maintenance effects, and safety and tolerability. Twenty-nine meta-analyses were included. Esketamine was associated with reductions in depressive symptom severity compared with placebo, with effects most pronounced at very early post-administration time points (hours to days). Reported effect sizes were generally small to moderate. Response and remission rates were higher in the acute phase, particularly at early assessments. Outcomes related to suicidal ideation were examined in a limited number of meta-analyses and were largely confined to acute post-dose evaluations. Relapse prevention and maintenance effects were reported in few meta-analyses and were mainly based on similar continuation-phase trials. Esketamine was associated with higher rates of non-serious adverse events, most commonly dissociation, dizziness, sedation, and gastrointestinal symptoms, while serious adverse events and all-cause discontinuation were not consistently increased. At the meta-analytic level, intranasal esketamine is associated with a rapid-onset antidepressant effect of modest magnitude that appears time-sensitive. Current evidence suggests that esketamine may be considered as an adjunctive option for early symptomatic relief in selected patients. However, evidence regarding long-term effectiveness, relapse prevention, and effects on suicidal ideation remains limited. Further independently funded studies with long-term outcomes are needed to better define its clinical role.
