Clinical overview of NMDA-R antagonists and clinical practice

Adv Pharmacol. 2020;89:103-129. doi: 10.1016/bs.apha.2020.04.004. Epub 2020 Jun 1.


Depression represents one of the most common and debilitating mental illnesses in the world today. Despite this pressing issue, the majority treatments for depression give patients therapeutic response only approximately half of the time, with many not responding at all. In part, this stagnation has been due to the dominance of the monoamine hypothesis that guides the current approach to understanding and treating depression. While therapies that increase levels of monoamines have been useful, clearly a more complete understanding of the neural circuits and treatments is needed to better help patients. Recent work that exploits the glutamatergic system within the brain has demonstrated a functional role for glutamate in combatting depression. While more research is required to understand the specific glutamatergic pathophysiological mechanisms within depression, emerging clinical work has already demonstrated promising results. Current treatments that target the glutamatergic system, especially NMDA receptor antagonists have already shown efficacy in several clinical trials. In this chapter we briefly introduce a mechanistic basis for a role of glutamate in the pathophysiology of depression. We further review basic and translational studies that describes potential mechanisms and roles for glutamate. A discussion of the first promising NMDA receptor antagonist for depression, ketamine, follows afterward. The development of NMDA receptor antagonists for treatment of depression is chronicled, from initial studies up through the recent FDA approval of intranasal esketamine as well as other newer compounds that have shown recent promise in clinical trials.

Keywords: Glutamate; Ketamine; Major depressive disorder; Monoamine hypothesis; NMDA receptor antagonists; Treatment-resistant depression.

Publication types

  • Review

MeSH terms

  • Antidepressive Agents / pharmacology
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / physiopathology
  • Glutamic Acid / therapeutic use
  • Humans
  • Ketamine / therapeutic use
  • Practice Patterns, Physicians'*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Antidepressive Agents
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Ketamine