NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Authors: Heather J Pribut
Edson X Albuquerque
Carlos A Zarate Jr
Greg I Elmer
Cheryl L Mayo
Craig J Thomas
Polymnia Georgiou
Panos Zanos
Jonathan Fischell
Ruin Moaddel
Manickavasagom Alkondon
Patrick J Morris
Katina S S Dossou
Xi-Ping Huang
Irving W Wainer
Nagendra S Singh
Todd D Gould
Peixiong Yuan
Yuhong Fang
Scott M Thompson
Journal: Nature (2016)
Discipline: Multidisciplinary
Keywords: Major depressive disorder; antidepressants; ketamine; NMDAR antagonist; (2R,6R)-HNK
Affiliations: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA., Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA., Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA., Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA., Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA., Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA., Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA., Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA., NIMH Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27516, USA., Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA., Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Abstract:  Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. 

Retracted: No

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