Ketamine’s antidepressant action: beyond NMDA receptor inhibition

@article{Hashimoto2016KetaminesAA,
  title={Ketamine’s antidepressant action: beyond NMDA receptor inhibition},
  author={Kenji Hashimoto},
  journal={Expert Opinion on Therapeutic Targets},
  year={2016},
  volume={20},
  pages={1389 - 1392}
}
  • K. Hashimoto
  • Published 28 September 2016
  • Psychology, Biology
  • Expert Opinion on Therapeutic Targets
ABSTRACT The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antidepressants since this drug causes rapid-onset and sustained antidepressant effects in treatment resistant patients with depression. There are unanswered questions about how ketamine induces its rapid and sustained antidepressant actions. This key article suggests that (2R,6R)-HNK (hydroxynorketamine), a major metabolite of (R)-ketamine, shows antidepressant effects in rodent models of… 
Antidepressant Actions of Ketamine and Its Two Enantiomers
TLDR
Recent findings on the antidepressant actions of two enantiomers of ketamine are discussed, including (R,S), which has been reported to have a greater potency and longer-lasting antidepressant effects than (S)-ketamine in rodent models of depression.
Rapid Antidepressant Activity of Ketamine Beyond NMDA Receptor
TLDR
It is unlikely that NMDA receptor has a major role in the longer-lasting antidepressant effects of (R)-ketamine, although antagonism at this receptor may promote its rapid antidepressant activity.
Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites
TLDR
It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine, as recent findings on the molecular and cellular mechanisms underlying the antidepressants of enantiomers of ketamines and its metabolites suggest.
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor
TLDR
Recent findings on the molecular mechanisms underlying the antidepressant actions of ( R,S )-ketamine and its potent enantiomer arketamine indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamines and its enantiomers, although the precise molecular mechanisms of these actions remain unclear.
Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
TLDR
The evidence for and against the NMDA receptor hypothesis of ketamine action is summarized and critically evaluated, with a particular focus on (2R,6R)-HNK and the implications of its discovery for understanding ketamine’s mechanism of action in depression.
An update on ketamine and its two enantiomers as rapid-acting antidepressants
TLDR
This paper reviews recent literature describing the antidepressant effects of ketamine and its enantiomer (S)-ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD) and discusses the therapeutic potential of (R)-ketamines, another enantiomers of (S)ketamine, and (S-norketamine.
Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine
TLDR
This study is the first to demonstrate that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants, and confirmed the previous findings that ( R)-ketamines exerted longer-lasting antidepressant effects than (S-ketamine in animal models of depression.
5-Hydroxytryptamine-Independent Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model
TLDR
Findings show that 5-hydroxytryptamine depletion did not affect the antidepressant effects of (R)-ketamine in a chronic social defeat stress model, and it is unlikely that 5,hydroxyTryptamine plays a major role in the antidepressant actions of ( R)-ketamines.
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References

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TLDR
It is shown that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice.
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TLDR
In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamines (esketamine), and findings suggest that, unlike S- ketamine, R -ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3.
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TLDR
The authors examined the time trajectory of efficacy of ketamine and non-ketamine NMDA-R antagonists in patients with major depressive disorder (MDD) and bipolar disorder and reported that R-ketamines showed greater potency and longer-lasting antidepressant effects than esketamine in animal models of depression.
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TLDR
Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine.
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TLDR
It is suggested that unlike to R-ketamine, esketamine can cause dopamine release in the striatum, and that its release might be associated with psychotomimetic effects of esketamines.
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TLDR
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TLDR
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