Antidepressant Actions of Ketamine: Potential Role of L-Type Calcium Channels

Chem Res Toxicol. 2021 May 17;34(5):1198-1207. doi: 10.1021/acs.chemrestox.0c00411. Epub 2021 Feb 10.


Recently, the United States Food and Drug Administration approved esketamine, the S-enantiomer of ketamine, as a fast-acting therapeutic drug for treatment-resistant depression. Although ketamine is known as an N-methyl-d-aspartate (NMDA) receptor antagonist, the underlying mechanisms of how it elicits an antidepressant effect, specifically at subanesthetic doses, are not clear and remain an advancing field of research interest. On the other hand, high-dose (more than the anesthetic dose) ketamine-induced neurotoxicity in animal models has been reported. There has been progress in understanding the potential pathways involved in ketamine-induced antidepressant effects, some of which include NMDA-receptor antagonism, modulation of voltage-gated calcium channels, and brain-derived neurotrophic factor (BDNF) signaling. Often these pathways have been shown to be linked. Voltage-gated L-type calcium channels have been shown to mediate the rapid-acting antidepressant effects of ketamine, especially involving induction of BDNF synthesis downstream, while BDNF deficiency decreases the expression of L-type calcium channels. This review focuses on the reported studies linking ketamine's rapid-acting antidepressant actions to L-type calcium channels with an objective to present a perspective on the importance of the modulation of intracellular calcium in mediating the effects of subanesthetic (antidepressant) versus high-dose ketamine (anesthetic and potential neurotoxicant), the latter having the ability to reduce intracellular calcium by blocking the calcium-permeable NMDA receptors, which is implicated in potential neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Brain-Derived Neurotrophic Factor / antagonists & inhibitors*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium Channels, L-Type / metabolism*
  • Humans
  • Ketamine / chemistry
  • Ketamine / pharmacology*
  • Molecular Structure


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Calcium Channels, L-Type
  • Ketamine
  • BDNF protein, human