# The N-methyl-d-aspartate receptor hypothesis of ketamine’s antidepressant action: evidence and controversies

## TL;DR

This paper reviews evidence and debates about how ketamine's antidepressant effects work, focusing on its interaction with NMDA receptors.

## Contribution

The paper provides a critical analysis of the NMDAR hypothesis of ketamine's antidepressant action and evaluates alternative theories.

## Key findings

- Ketamine acts faster and more potently as an antidepressant compared to traditional monoamine-targeting drugs.
- Evidence supports the NMDAR antagonism hypothesis, but controversies remain due to mixed results from other NMDAR inhibitors.
- Understanding ketamine's mechanisms could guide the development of better depression treatments.

## 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’.