Real-world comparison of intranasal racemic ketamine and esketamine in treatment-resistant depression: A retrospective observational study.

Intranasal racemic ketamine is non-inferior to esketamine for reducing depression symptoms in adults with treatment-resistant depression, with comparable symptom improvement over four weeks. However, remission rates were higher with esketamine (38.7%) than with racemic ketamine (15.6%), and racemic ketamine failed to meet non-inferiority for remission. Safety profiles were similar, though racemic ketamine caused slightly more transient blood pressure elevations. Racemic ketamine may be a cost-effective alternative where esketamine access is limited, but higher remission with esketamine warrants further study.

Study at a glance

Abstract

Treatment-resistant depression (TRD) imposes major individual and societal burden, with few therapeutic options. Intranasal esketamine is approved but limited by cost and accessibility, prompting interest in alternatives. To assess non-inferiority of racemic ketamine versus esketamine in a real-world setting. We performed a single-centre, retrospective observational study emulating a randomized trial using the target trial framework. Adults with TRD received either intranasal esketamine or off-label racemic ketamine during an eight-session, four-week induction phase. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores; secondary outcome was remission (MADRS ≤12). Safety and tolerability were monitored. MADRS changes were analysed via repeated measures ANOVA; non-inferiority was predefined as <3-point between-group difference. Remission was assessed with odds ratios and Bayesian multilevel modelling, with non-inferiority defined as <50% difference in remission probability. Seventy-six patients were included (esketamine n = 31; ketamine n = 45). Both groups showed significant symptom improvement, with comparable MADRS reduction (-9.3 vs -10.0; p = 0.41), meeting the primary non-inferiority criterion. Remission rates were higher with esketamine (38.7%) than ketamine (15.6%; OR 0.29, 95% CI 0.10-0.86), failing non-inferiority, supported by a 98.6% posterior probability of esketamine's superiority. Safety profiles were similar, though ketamine showed slightly more transient blood pressure elevations. Intranasal racemic ketamine is non-inferior to esketamine in symptom reduction and may represent a cost-effective alternative where esketamine access is limited. Higher remission rates with esketamine warrant further prospective studies to clarify clinical significance and optimize racemic ketamine use, improving accessibility and affordability for TRD patients.