Ketamine and Esketamine in Treatment of Resistant Depression

Aims: This review aims to explore the efficacy, mechanisms, administration routes, and safety profiles of ketamine and esketamine in the treatment of treatment-resistant depression (TRD). Methods: A comprehensive review of recent studies on ketamine and esketamine’s therapeutic applications in TRD was conducted. Sources included randomized controlled trials, systematic reviews, and meta-analyses from PubMed and Google Scholar. Results: Ketamine demonstrated rapid antidepressant effects within hours of administration, with symptom relief lasting several days to weeks. Esketamine, developed as an intranasal spray, provided an alternative route, improving accessibility while delivering therapeutic benefits. Additionally, ketamine has shown rapid effects on suicidal ideation, making it a viable option for crisis management in TRD patients. Both ketamine and esketamine enhance neuroplasticityby antagonizing NMDA receptors, leading to increased glutamate release, which activates AMPA receptors and promotes synaptogenesis. Clinical studies have shown that ketamine induces an immediate surge in brain-derived neurotrophic factor (BDNF) and upregulates the mTOR pathway, essential for the formation and strengthening of synaptic connections in mood-regulating brain regions. Although treatment is effective in the short-term, the data on long-term safety is scarce. Conclusions: Ketamine and esketamine represent significant advancements in the treatment of TRD, offering rapid symptom relief and neuroplastic benefits not achieved with traditional antidepressants. Future studies are required to establish long-term safety profiles and optimize dosing regimens. Overall, ketamine-based therapies provide a promising alternative for patients unresponsive to conventional treatments.