Ketamine: The final frontier or another depressing end?

Behav Brain Res. 2020 Apr 6:383:112508. doi: 10.1016/j.bbr.2020.112508. Epub 2020 Feb 1.


Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine's antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine's mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine's actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine's response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine's antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.

Keywords: Antidepressant mechanism; Depression; Ketamine; Major Depressive Disorder; NMDA; Non-NMDA mechanism; Rapid antidepressant; Spravato.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Humans
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Norepinephrine Plasma Membrane Transport Proteins / drug effects
  • Receptor, Muscarinic M1 / drug effects
  • Receptors, AMPA / drug effects
  • Receptors, Dopamine D2 / drug effects
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, kappa / drug effects
  • Receptors, Opioid, mu / drug effects
  • Receptors, Serotonin, 5-HT3 / drug effects
  • Receptors, sigma / drug effects
  • Serotonin Plasma Membrane Transport Proteins / drug effects


  • Antidepressive Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Excitatory Amino Acid Antagonists
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptor, Muscarinic M1
  • Receptors, AMPA
  • Receptors, Dopamine D2
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Receptors, Serotonin, 5-HT3
  • Receptors, sigma
  • Serotonin Plasma Membrane Transport Proteins
  • Esketamine
  • Ketamine