Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

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J Psychiatry Neurosci 2017;42(4):222-229

Lily R. Aleksandrova, MSc; Anthony G. Phillips, PhD; Yu Tian Wang, MD, PhD

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 of N-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.


Submitted Aug. 31, 2016; Revised Nov. 14, 2016; Accepted Nov. 20, 2016; Early-released Jan. 31, 2017

Affiliations: 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).

Competing interests: No financial interest or any direct conflict of interest exists. Y.T. Wang and A.G Phillips declare a patent related to glutamate receptor function (A Peptide that Specifically Blocks Regulated AMPA Receptor Endocytosis and Hippocampal CA1 Longterm Depression; Europe 04789721.0, and United States 13/066,700). A.G Phillips also declares a pending patent for the use of d-Govadine in treatment of cognitive deficits.

Contributors: All authors designed the study. L.R. Aleksandrova acquired and analyzed the data and wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.160175

Correspondence to: Y.T. Wang, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Rm F117 — 2211 Wesbrook Mall, Vancouver BC V6T 2B5; ytwang@interchange.ubc.ca