NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Polymnia Georgiou, Jonathan Fischell, Greg I. Elmer, Manickavasagom Alkondon, Peixiong Yuan, Heather J. Pribut, Nagendra S. Singh, Katina S. S. Dossou, Yuhong Fang, Xi-Ping Huang, Cheryl L. Mayo, Irving W. Wainer, Edson X. Albuquerque, Scott M. Thompson, Craig J. Thomas, Carlos A. Zarate and Todd D. Gould ()
Additional contact information
Panos Zanos: University of Maryland School of Medicine
Ruin Moaddel: Biomedical Research Center, National Institute on Aging, National Institutes of Health
Patrick J. Morris: National Center for Advancing Translational Sciences, National Institutes of Health
Polymnia Georgiou: University of Maryland School of Medicine
Jonathan Fischell: University of Maryland School of Medicine
Greg I. Elmer: University of Maryland School of Medicine
Manickavasagom Alkondon: University of Maryland School of Medicine
Peixiong Yuan: Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
Heather J. Pribut: University of Maryland School of Medicine
Nagendra S. Singh: Biomedical Research Center, National Institute on Aging, National Institutes of Health
Katina S. S. Dossou: Biomedical Research Center, National Institute on Aging, National Institutes of Health
Yuhong Fang: National Center for Advancing Translational Sciences, National Institutes of Health
Xi-Ping Huang: NIMH Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Cheryl L. Mayo: Maryland Psychiatric Research Center, University of Maryland School of Medicine
Irving W. Wainer: Biomedical Research Center, National Institute on Aging, National Institutes of Health
Edson X. Albuquerque: University of Maryland School of Medicine
Scott M. Thompson: University of Maryland School of Medicine
Craig J. Thomas: National Center for Advancing Translational Sciences, National Institutes of Health
Carlos A. Zarate: Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
Todd D. Gould: University of Maryland School of Medicine

Nature, 2016, vol. 533, issue 7604, 481-486

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature17998

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