Ketamine and Esketamine in the Treatment of Treatment-Resistant Major Depressive Disorder

Abstract

Treatment-resistant major depressive disorder represents a significant challenge in contemporary psychiatry, as a substantial proportion of patients fail to respond adequately to conventional antidepressants, remaining with persistent symptoms, functional impairment, and an increased risk of suicide. In this context, ketamine and esketamine have emerged as innovative therapeutic alternatives due to their rapid onset of action and glutamatergic mechanism of action. The present study aimed to review the main scientific evidence regarding the efficacy, safety, mechanisms of action, and clinical applicability of ketamine and esketamine in the treatment of treatment-resistant major depressive disorder. This study consists of a systematic literature review conducted according to the PRISMA 2020 guidelines. Searches were performed in the PubMed/MEDLINE, Scopus, Web of Science, Embase, and Virtual Health Library (VHL) databases. A total of 61 studies were initially identified, of which 13 met the eligibility criteria and were included in the qualitative analysis. The analyzed studies demonstrated that ketamine and esketamine rapidly reduce depressive symptoms and suicidal ideation while improving functional outcomes and quality of life. In addition, racemic ketamine showed higher response and remission rates than esketamine in some studies, although both therapies demonstrated satisfactory efficacy and safety when administered in specialized clinical settings. It is concluded that ketamine and esketamine represent important therapeutic advances for patients with treatment-resistant major depressive disorder by providing rapid antidepressant effects and significant clinical benefits. However, studies with longer follow-up periods are still needed to clarify long-term safety, maintenance of therapeutic response, and the standardization of treatment protocols.