ADVERSE EFFECTS OF ESKETAMINE IN TREATMENT RESISTANT DEPRESSION: A COMPREHENSIVE LITERATURE REVIEW (2020-2025)

Background: Esketamine nasal spray represents the first FDA approved treatment with a novel mechanism of action for treatment resistant depression (TRD) in decades. While its efficacy has been well established, a thorough understanding of the adverse effect profile remains essential for informed clinical decision making and optimal patient safety. We therefore undertook this systematic review to characterize the safety profile of esketamine in treatment resistant depression. Aim: This review examines esketamine's adverse effect profile, focusing on common effects, cardiovascular safety, urological considerations, cognitive outcomes, abuse liability, special populations, and serious adverse events. Materials and Methods: We performed a comprehensive literature search across multiple databases including PubMed, Cochrane Library, Web of Science, Embase, Google Scholar, and MEDLINE for studies published 2020-2025. Results: Common adverse effects like dissociation and sedation resolved within two hours. Blood pressure elevations normalized within 1.5 hours without intervention. Pre approval concerns were not confirmed: no bladder cystitis occurred despite years of exposure, cognitive function remained stable or improved, and misuse was rare (less than 0.01%). Serious adverse events were infrequent (less than 0.2% of sessions), occurring mainly during initial treatments. Mortality rates matched background rates in treatment resistant depression. Elderly patients showed similar tolerability but needed closer cardiovascular monitoring. Conclusion: Under proper clinical supervision, esketamine shows an acceptable safety profile. Most adverse effects are temporary and mild to moderate. Long term studies extending up to 6.5 years found no evidence of organ damage, cognitive decline, or meaningful abuse problems. For patients who have failed multiple treatments, esketamine provides an important alternative with manageable safety concerns.