The Ketamine Paradox: Why the Weaker Enantiomer May Prove the Stronger Antidepressant

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.