title: What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities.
abstract: OBJECTIVE
  Abundant clinical data now confirm that ketamine produces a remarkable rapid-onset antidepressant effect - hours or days - in contrast to the delayed onset (typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life-saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self-limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid-onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery.
  
  
  METHODS
  A search was conducted on published literature (e.g. PubMed) and Internet sources to identify information relevant to ketamine's rapid-acting antidepressant action and, specifically, to the possible mechanism(s) of this action. Key search words included 'ketamine', 'antidepressant', 'mechanism of action', 'depression' and 'rapid acting', either individually or in combination. Information was sought that would include less well-known, as well as well-known, basic pharmacologic properties of ketamine and that identified and evaluated the several hypotheses about ketamine's mechanism of antidepressant action.
  
  
  RESULTS
  Whether the mechanistic explanation for ketamine's rapid-onset antidepressant action is related to its well-known antagonism of the NMDA (N-Methyl-d-aspartate) subtype of glutamate receptor or to something else has not yet been fully elucidated. The evidence from pharmacologic, medicinal chemistry, animal model and drug-discovery sources reveals a wide variety of postulated mechanisms.
  
  
  CONCLUSIONS
  The surprising discovery of ketamine's rapid-onset antidepressant effect is a game-changer for the understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies of depression proposed, suggests exciting new drug-discovery targets.
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Strasburger
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Bhimani
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Kaabe
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Krysiak
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Nanchanatt
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Nguyen
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Pough
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Prince
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Ramsey
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Savsani
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Scandlen
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cavaretta
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.|University of Arizona College of Pharmacy, Tucson, AZ, USA.
authors.forename: R B
authors.identifier: http://orcid.org/0000-0002-1456-4451
authors.initials: RB
authors.lastname: Raffa
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D003863:Depression / Q000188:drug therapy; D004565:Electroconvulsive Therapy; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D007737:Kynurenine / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D007649:Ketamine
keywords: NMDA receptor; ketamine; major depressive disorder; mechanism of action; rapid-onset antidepressant