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Antidepressant Actions of Ketamine Versus Hydroxynorketamine

Published:September 28, 2016DOI:https://doi.org/10.1016/j.biopsych.2016.06.029
      In a recent issue of Nature, 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.
      ) show that metabolites of ketamine have rapid antidepressant-like actions in mice and that these are independent of the N-methyl-D-aspartate receptor (NMDAR). They report that a racemic mixture of R- and S-ketamine is metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), and that this metabolism is essential for the sustained antidepressant action of ketamine. They also show that (2R,6R)-HNK is the enantiomer of HNK that exerts behavioral, electroencephalographic, and cellular antidepressant-like effects in mice. Significantly, the effects of (2R,6R)-HNK are independent of NMDARs but somehow involve the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. These findings challenge the widely held view that the rapid and sustained antidepressant actions of single ketamine administration are caused by its ability to inhibit the NMDAR (
      • Anis N.A.
      • Berry S.C.
      • Burton N.R.
      • Lodge D.
      The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate.
      ) and consequently NMDAR-dependent synaptic plasticity (
      • Collingridge G.L.
      • Kehl S.J.
      • McLennan H.
      Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.
      ).
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      Linked Article

      • Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine
        Biological PsychiatryVol. 81Issue 8
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          We recently published a report in Nature describing the antidepressant actions of (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which are metabolites of S- and R-ketamine, respectively (1). In humans, S- and R-ketamine are rapidly metabolized and cleared, with more sustained levels of HNKs (2). We provided evidence that the metabolic breakdown of (R,S)-ketamine is essential for its antidepressant effects in mice, and that (2S,6S)- and (2R,6R)-HNK independently exert antidepressant actions that do not require N-methyl-D-aspartate receptor (NMDAR) inhibition (1).
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      • What’s the Buzz About Hydroxynorketamine? Is It the History, the Story, the Debate, or the Promise?
        Biological PsychiatryVol. 81Issue 8
        • Preview
          The History: Early in the 1990s, a set of animal studies presented N-methyl-D-aspartate receptor (NMDAR) modulation as a common pathway to traditional antidepressants (1). Later in the 1990s, a group of Yale University scientists set out to demonstrate the role of NMDAR modulation in clinical depression using subanesthetic doses of the NMDAR antagonist ketamine. Surprisingly, they discovered that a single ketamine infusion exerted rapid acting antidepressant (RAAD) effects that were sustained for 3 days, well beyond the short half-life of the ketamine compound (2).
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