In a recent issue of Nature, Zanos et al. (
1) 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 (
- Zanos P.
- Moaddel R.
- Morris P.J.
- Georgiou P.
- Fischell J.
- Elmer G.I.
- et al.
NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
Nature. 2016; 533: 481-486
2) and consequently NMDAR-dependent synaptic plasticity (
- 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.
Br J Pharmacol. 1983; 79: 565-575
- Collingridge G.L.
- Kehl S.J.
- McLennan H.
Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.
J Physiol. 1983; 334: 33-46
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- NMDAR inhibition-independent antidepressant actions of ketamine metabolites.Nature. 2016; 533: 481-486
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate.Br J Pharmacol. 1983; 79: 565-575
- Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.J Physiol. 1983; 334: 33-46
- Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study.Biol Psychiatry. 2016; 80: 424-431
- Effects of memantine and MK-801 on NMDA-induced currents in cultured neurons and on synaptic transmission and LTP in area CA1 of rat hippocampal slices.Br J Pharmacol. 1996; 117: 689-697
- An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.J Clin Psychopharmacol. 2008; 28: 631-637
- Ketamine and phencyclidine: The good, the bad and the unexpected.Br J Pharmacol. 2015; 172: 4254-4276
- Relationship of ketamine’s plasma metabolites with response, diagnosis, and side effects in major depression.Biol Psychiatry. 2012; 72: 331-338
- Long-term depression in the CNS.Nat Rev Neurosci. 2010; 11: 459-473
- Reconsolidation of memory after its reactivation.Behav Brain Res. 1997; 84: 241-246
Published online: September 28, 2016
Accepted: June 23, 2016
Received in revised form: June 23, 2016
Received: June 21, 2016
© 2016 Published by Elsevier Inc. All rights reserved.
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- Reply to: Antidepressant Actions of Ketamine Versus HydroxynorketamineBiological PsychiatryVol. 81Issue 8
- PreviewWe 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).
- What’s the Buzz About Hydroxynorketamine? Is It the History, the Story, the Debate, or the Promise?Biological PsychiatryVol. 81Issue 8
- PreviewThe 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).