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. (
1
) 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 (
2
).To read this article in full you will need to make a payment
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References
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites.Nature. 2016; 533: 481-486
- What’s the buzz about hydroxynorketamine? Is it the history, the story, the debate, or the promise?.Biol Psychiatry. 2017; 81: e61-e63
- Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine–induced sustained antidepressant effects.Biol Psychiatry. 2017; ([published online ahead of print Oct 26])
- Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression.Eur Arch Psychiatry Clin Neurosci. 2017; 267: 177-182
- (R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine.Biol Psychiatry. 2017; 82: e43-e44
- Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: Comparison with (R)-ketamine.Int J Neuropsychopharmacol. 2018; 21: 84-88
- Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation.Int J Neuropsychopharmacol. 2014; 18: pyu077
- R-ketamine: A rapid-onset and sustained antidepressant without psychotomimetic side effects.Transl Psychiatry. 2015; 5: e632
- Regional differences in brain-derived neurotrophic factor levels and dendritic spine density confer resilience to inescapable stress.Int J Neuropsychopharmacol. 2015; 18: pyu121
- Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist.Eur Neuropsychopharmacol. 2015; 25: 2449-2458
Article info
Publication history
Published online: December 27, 2017
Accepted:
December 11,
2017
Received in revised form:
November 30,
2017
Received:
November 12,
2017
Identification
Copyright
© 2017 Society of Biological Psychiatry.
