The Impact of Intranasal Esketamine on Treatment-Resistant Depression: A Systematic Review

Introduction: Treatment-resistant depression (TRD) is a major public health and societal challenge, associated with persistent symptoms, functional impairment, and increased healthcare and economic burden. Intranasal esketamine has emerged as a rapid-acting adjunctive therapy with a distinct glutamatergic mechanism of action. This systematic review summarizes current evidence on its effectiveness and implementation-relevant outcomes in TRD. Methods: A systematic literature review was conducted in accordance with PRISMA 2020. PubMed/MEDLINE and EMBASE were searched for English-language systematic reviews and meta-analyses published between 2010 and 2026 using database-specific but equivalent Boolean strategies combining intranasal esketamine terms with TRD terms. Titles/abstracts were screened and eligible records underwent full-text assessment. Five studies were included in qualitative synthesis. The last search was conducted on 5 March 2026. Results: Meta-analytic evidence from randomized trials reported greater symptom improvement with intranasal esketamine versus control (MADRS SMD = −3.88; 95% CI −5.71 to −2.05) and higher response rates (RR = 1.99; 95% CI 1.28–3.10), alongside improvements in disability (SDS SMD = −3.01) and patient-reported symptoms (PHQ-9 SMD = −2.32). Adverse events were more frequent, including dizziness (RR = 3.55) and nausea (RR = 3.88). Real-world data showed substantial symptom reduction (Hedges’ g = −1.98) and higher remission likelihood at three months (OR = 5.1), with high overall adverse-event prevalence (82%) and dissociation commonly reported (49%). Conclusions: Intranasal esketamine shows clinically relevant benefits in TRD with convergent trial and real-world signals, but requires supervised delivery and sustained follow-up. Further research should clarify long-term outcomes, clinical meaningfulness, and health-system cost-effectiveness.