NMDAR inhibition-independent antidepressant actions of ketamine metabolites

  • Nature volume 533, pages 481486 (26 May 2016)
  • doi:10.1038/nature17998
  • Download Citation


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.

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Change history

  • Corrected online 13 May 2016

    The competing financial interests statement did not display correctly online when this paper was first published; this has been corrected and the statement is now available.


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We thank A. Keller for his assistance with the qEEG experiments, M. K. Lobo for assistance with the social defeat experiments, B. Alkondon for the rat hippocampal slice preparation and biocytin processing, V. Meadows and S. Krimmel for assistance with behavioural experiments and manuscript review, E. Pereira for critical comments on the manuscript and figures, D. Luckenbaugh for assistance with statistical analysis, and C. Moore for the small molecule X-ray crystallography. Research was supported by NIMH grants MH099345 and MH107615 to T.D.G. and MH086828 to S.M.T., and the NIA (R.M., I.W.W.), NIMH (C.A.Z.), and NCATS (C.J.T.) NIH intramural research programs. Receptor binding profiles and Ki determinations were supported by the NIMH Psychoactive Drug Screening Program, Contract HHSN-271-2008-025C, to B. L. Roth in conjunction with J. Driscoll. Initial synthesis of the ketamine metabolites used in this study was supported by NIA Contract HHSN271201000008I to I.W.W.

Author information

Author notes

    • Irving W. Wainer

    Present address: Mitchell Woods Pharmaceuticals, Shelton, Connecticut 06484, USA.


  1. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Panos Zanos
    • , Polymnia Georgiou
    • , Greg I. Elmer
    • , Heather J. Pribut
    • , Scott M. Thompson
    •  & Todd D. Gould
  2. Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA

    • Ruin Moaddel
    • , Nagendra S. Singh
    • , Katina S. S. Dossou
    •  & Irving W. Wainer
  3. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA

    • Patrick J. Morris
    • , Yuhong Fang
    •  & Craig J. Thomas
  4. Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Jonathan Fischell
    •  & Scott M. Thompson
  5. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Greg I. Elmer
    • , Edson X. Albuquerque
    •  & Todd D. Gould
  6. Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA

    • Greg I. Elmer
    •  & Cheryl L. Mayo
  7. Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Manickavasagom Alkondon
    •  & Edson X. Albuquerque
  8. Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Peixiong Yuan
    •  & Carlos A. Zarate Jr
  9. 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

    • Xi-Ping Huang
  10. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Edson X. Albuquerque
  11. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • Todd D. Gould


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P.Z., R.M., P.J.M., I.W.W., C.J.T., C.A.Z. and T.D.G. were responsible for the overall experimental design. P.J.M., Y.F. and C.J.T. synthesised the ketamine metabolites and deuterated ketamine derivatives, and provided mass spectrometer confirmations. Bioanalytical quantitation of ketamine and metabolites were performed by R.M., N.S.S. and K.S.S.D.. P.Z., P.G. and H.J.P. conducted and analysed the results of the behavioural and qEEG experiments. X.-P.H. supervised and analysed the results of the binding experiments. P.Y. performed the western blot experiments. E.X.A., M.A., J.F. and S.M.T. helped design and analyse the electrophysiology experiments, which were conducted by M.A., J.F. and S.M.T. G.I.E. and C.L.M. conducted and analysed the results of the i.v. self-administration. P.Z. and T.D.G. outlined and wrote the paper, which was reviewed by all authors.

Competing interests

The authors declare competing financial interests: I.W.W., R.M., and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. They have assigned their rights in the patent to the U.S. government but will share a percentage of any royalties that may be received by the government. I.W.W., C.A.Z., R.M., T.G., P.Z., C.T., and P.M. are listed as co-inventors on a patent application for the use of (2R, 6R)-hydroxynorketamine and (2S, 6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders. I.W.W., C.A.Z., R.M., C.T., and P.M. have assigned their rights in this patent to the U.S. government but will share a percentage of any royalties that may be received by the government. T.G. and P.Z. have assigned their rights in this patent to the University of Maryland but will share a percentage of any royalties that may be received by the University of Maryland.

Corresponding author

Correspondence to Todd D. Gould.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains (1) Supplementary Table 1, which includes the details for the number of animals and the results of the statistical analyses in each experiment; (2) Supplementary Figure 1, with the complete blot images for Figure 4 and Extended Data Figure 8; (3) the Supplementary Methods for the synthesis of (2R,6R)-HNK, (2S,6S)-HNK, and D-Ket, in addition to the analytical data that supports the synthetic steps and the X-ray crystallographic data that confirms the absolute and relative conformation for (2S,6S)-HNK and (2R,6R)-HNK.


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