THE KETAMINE PARADOX: WHY THE WEAKER ENANTIOMER MAY PROVE THE STRONGER ANTIDEPRESSANT
H. Zubeen, S. Tushar, S. Rutuja
Zenodo (CERN European Organization for Nuclear Research) May 8, 2026 preprint DOI: 10.5281/zenodo.20080785 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review |
|---|---|
| Interventions | Ketamine Esketamine Arketamine |
| Topics | Esketamine Ketamine |
| Key findings | Argues that NMDA receptor affinity is an incomplete framework for predicting antidepressant potency, citing preclinical evidence that arketamine, despite weaker NMDA binding, produces stronger and more durable antidepressant effects with fewer adverse effects than esketamine, which is FDA-approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation. |
Abstract
Ketamine — a dissociative anaesthetic and uncompetitive NMDA receptor antagonist — represents the most significant advance in depression pharmacology in half a century. As a racemic mixture of (S)-ketamine (esketamine) and (R)-ketamine (arketamine), it harbours a central paradox: the enantiomer with weaker NMDA binding appears, in preclinical models, to produce stronger and more durable antidepressant effects with fewer adverse effects. Esketamine has received FDA approval for treatment-resistant depression (TRD) and major depressive disorder with acute suicidal ideation, yet arketamine — despite being pharmacologically inferior on the receptor affinity metric used to justify esketamine — consistently outperforms it in animal models. This review examines the mechanistic, clinical, and critical dimensions of this paradox, arguing that NMDA affinity is an incomplete framework for predicting antidepressant potency and that the field has perhaps been measuring the wrong thing.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |