Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?
The American journal of psychiatry – March 01, 2025
Source: PubMed
Summary
Ketamine's rapid antidepressant effects may come from an unexpected source: its interaction with both brain opioid and NMDA receptors. While traditionally viewed as just an NMDA blocker, new evidence suggests ketamine's remarkable ability to lift severe depression stems from this dual-action mechanism. This synergistic effect explains why ketamine and esketamine work differently from conventional antidepressants, offering hope for treatment-resistant patients through innovative psychopharmacology approaches.
Abstract
Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders. Despite its complex pharmacology, ketamine is referred to as an N-methyl-d-aspartate (NMDA) receptor antagonist. In this review, the authors argue that ketamine's pharmacology should be redefined to include opioid receptors and the endogenous opioid system. They also highlight a potential mechanism of action of ketamine for depression that is attributed to bifunctional, synergistic interactions involving NMDA and opioid receptors.