The N-methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences – July 29, 2024
Source: PubMed
Summary
Ketamine offers new hope for depression treatment, working within hours instead of weeks like traditional antidepressants. The drug's remarkable antidepressant efficacy stems from its interaction with brain receptors called NMDARs. While the NMDAR hypothesis explains ketamine's rapid effects, other NMDAR inhibitors haven't shown the same success, suggesting complex mechanisms behind its antidepressant properties.
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'.