Real-world comparison of intranasal racemic ketamine and esketamine in treatment-resistant depression: A retrospective observational study.
Jan Sarlon, Deanne Thomi, Annette B Brühl, Timur Liwinski, Undine E. Lang
Journal of Affective Disorders January 21, 2026 DOI: 10.1016/j.jad.2026.121208 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Retrospective observational study emulating a randomized trial using the target trial framework Peer reviewed |
|---|---|
| Sample size | 76 |
| Population | Adults with treatment-resistant depression |
| Interventions | Intranasal esketamine Intranasal racemic ketamine |
| Duration | Four-week induction phase (eight sessions) |
| Topics | Depression Esketamine Ketamine |
| Keywords | Intranasal racemic ketamine Non-inferiority |
| Citations | 1 |
| Key findings | Intranasal racemic ketamine was non-inferior to esketamine in reducing MADRS scores but failed non-inferiority for remission rates, which were higher with esketamine. |
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.
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.