Ketamine and Esketamine in Obsessive–Compulsive Disorder: A Scoping Review of Clinical and Mechanistic Evidence

Background/Objective: A substantial proportion of patients with obsessive–compulsive disorder (OCD) does not respond adequately to first-line treatments such as selective serotonin reuptake inhibitors and cognitive-behavioral therapy. OCD has traditionally been conceptualized as a serotonergic disorder. However, emerging evidence suggests that glutamatergic dysfunction plays an important role. Ketamine and esketamine are NMDA receptor antagonists with rapid antidepressant effects and have therefore attracted interest as potential treatments for OCD. This scoping review aims to map and synthesize the existing preclinical and clinical evidence regarding the therapeutic potential of ketamine and esketamine in OCD. Methods: A scoping review methodology based on the Arksey and O’Malley framework and Joanna Briggs Institute guidance was applied. Searches were conducted in PubMed, Scopus, and Web of Science. Studies that examined ketamine or esketamine in OCD populations or relevant experimental models were included. Results: Twenty-one studies met the inclusion criteria, of which five were preclinical studies and sixteen were clinical investigations. Preclinical evidence suggests that ketamine and esketamine improve compulsive-like behaviors. Clinical studies suggest that ketamine can produce rapid reductions in obsessive symptoms, though results remain inconsistent. Most trials evaluated single administrations, while limited evidence suggests that repeated dosing strategies may provide greater clinical benefit. Conclusions: Ketamine and esketamine show promise as rapid acting interventions for OCD, particularly in treatment refractory cases. However, current evidence remains preliminary and heterogeneous. Future research should prioritize adequately powered randomized trials and investigation of repeated administration protocols with longer follow-up periods to determine efficacy and optimal clinical implementation.