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What Are the Causes for Discrepancies of Antidepressant Actions of (2R,6R)-Hydroxynorketamine?

  • Kenji Hashimoto
    Correspondence
    Address correspondence to Kenji Hashimoto, Ph.D., Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan.
    Affiliations
    Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Inohana, Chiba, Japan
    Search for articles by this author
  • Yukihiko Shirayama
    Affiliations
    Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Inohana, Chiba, Japan

    Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan
    Search for articles by this author
Published:December 27, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.12.007
      The N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine is an attractive compound capable of inducing rapid and sustained antidepressant effects in treatment-resistant patients with major depression and bipolar depression. However, the precise molecular mechanisms underlying its antidepressant actions are currently unknown. Zanos et al. (
      • Zanos P.
      • Moaddel R.
      • Morris P.J.
      • Georgiou P.
      • Fischell J.
      • Elmer G.I.
      • et al.
      NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
      ) reported that the metabolism of (R,S)-ketamine (inhibitory constant [Ki] = 799 nM for NMDAR) to (2R,6R)-hydroxynorketamine (HNK; Ki >10,000 nM for NMDAR) was essential for (R,S)-ketamine-mediated antidepressant activity. However, there is now an increasing debate about the antidepressant actions of (2R,6R)-HNK in rodents (
      • Abdallah C.G.
      What’s the buzz about hydroxynorketamine? Is it the history, the story, the debate, or the promise?.
      ).
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