title: Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism.
abstract: The molecular mechanisms underlying major depressive disorder remain poorly understood, and current antidepressant treatments have many shortcomings. The recent discovery that a single intravenous infusion of ketamine at a subanesthetic dose had robust, rapid and sustained antidepressant effects in individuals with treatment-resistant depression inspired tremendous interest in investigating the molecular mechanisms mediating ketamine's clinical efficacy as well as increased efforts to identify new targets for antidepressant action. We review the clinical utility of ketamine and recent insights into its mechanism of action as an antidepressant, including the roles ofN-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor upregulation, activation of downstream synaptogenic signalling pathways and the production of an active ketamine metabolite, hydroxynorketamine. Emerging knowledge of the molecular mechanisms underlying both ketamine's positive therapeutic and detrimental side effects will aid the development of a new generation of much-needed superior antidepressant agents.
authors.affiliation: From the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada (Aleksandrova, Wang); and the Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada (Aleksandrova, Phillips).
authors.forename: Lily R
authors.initials: LR
authors.lastname: Aleksandrova
authors.affiliation: From the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada (Aleksandrova, Wang); and the Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada (Aleksandrova, Phillips).
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
authors.affiliation: From the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada (Aleksandrova, Wang); and the Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada (Aleksandrova, Phillips).
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy*; D006801:Humans; D007649:Ketamine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D008959:Models, Neurological; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine