The N-methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies.
Yihao Jiang, Yiyan Dong, Hailan Hu
Philosophical transactions of the Royal Society of London. Series B, Biological sciences July 29, 2024 DOI: 10.1098/rstb.2023.0225 via PubMed
Summary
AI-generated from the abstractKetamine, an NMDAR antagonist, has superior antidepressant efficacy compared to traditional monoamine-targeting drugs, acting faster and more potently. While substantial evidence supports an NMDAR-antagonism-based hypothesis for its mechanisms, controversial results from other NMDAR inhibitors have led to alternative arguments. This article reviews the historical development of the NMDAR-centered hypothesis, classifies NMDAR inhibitors by their mechanisms, and evaluates preclinical and clinical evidence of their antidepressant effects. It critically analyzes debates over ketamine's NMDAR-dependent and independent actions, aiming to clarify molecular targets to guide future depression treatments.
Study at a glance
| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine |
| Keywords | Nmdar hypothesis Nmdar inhibitors Antidepressant efficacy Depression treatment Ketamine therapy |
| Key finding | Ketamine's antidepressant mechanisms involve both NMDAR-dependent and independent actions, with ongoing debate from clinical results of other NMDAR inhibitors. |
Abstract
Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.