A comprehensive review of the clinical progress of esketamine: From anesthesia to antidepressant therapy

Esketamine, the S-enantiomer of ketamine, has emerged as a rapid-acting antidepressant with unique mechanisms. This narrative review synthesizes current evidence on its clinical applications, safety, and regulatory status based on peer-reviewed literature published between January 2000 and March 2024, searched in PubMed, Web of Science, and the Cochrane Library. Esketamine exerts its effects primarily through noncompetitive antagonism of N-methyl-D-aspartate receptors, leading to rapid modulation of glutamatergic signaling and neuroplasticity. In anesthesia, it provides effective sedation with minimal respiratory depression. In psychiatry, intravenous and intranasal esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression, with response rates of 50% to 70% within 24 hours. However, long-term safety data remain limited, and concerns persist regarding dissociative symptoms, cognitive impairment, and abuse potential. Regulatory approvals vary: the Food and Drug Administration approved intranasal esketamine for treatment-resistant depression in 2019, while European and Asian countries have adopted differing restrictions. Esketamine represents a paradigm shift in depression treatment, but its use requires careful patient selection, monitoring, and risk management. Future research should focus on head-to-head comparisons with other rapid-acting interventions, long-term outcomes, and integration into stepped-care models.