Elsevier

Biological Psychiatry

Volume 81, Issue 8, 15 April 2017, Pages e69-e71
Biological Psychiatry

Correspondence
Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine

https://doi.org/10.1016/j.biopsych.2016.08.039Get rights and content

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Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant Nos. MH107615 (to TDG) and MH086828 (to SMT), and the National Institute on Aging (RM, IWW), National Institute of Mental Health (CAZ), and National Center for Advancing Translational Sciences (CJT) National Institutes of Health intramural research programs.

TDG has received consulting fees from Janssen Pharmaceuticals and research funding from Janssen Pharmaceuticals and Roche Pharmaceuticals during the preceding 2 years. IWW, RM,

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      Thus, an activity-dependent BDNF release and downstream TrkB and mTOR signaling increased synaptic function in the mPFC, a cascade of events required for the rapid and long-lasting antidepressant effects of (2R,6R)-HNK. However, (2R,6R)-HNK's antidepressant-like activity and its contribution to the actions of (R,S)-ketamine is still a matter of debate (Abdallah, 2020; Chaki and Yamaguchi, 2018; Collingridge et al., 2017; Farmer et al., 2020; Riggs et al., 2020; Zanos et al., 2017). In particular, for Hashimoto's group, (2R,6R)-HNK does not exert rapid and sustained antidepressant-like effects in different mouse preclinical tests of antidepressant effectiveness (Yamaguchi et al., 2018; Yang et al., 2017).

    • Glutamatergic receptor and neuroplasticity in depression: Implications for ketamine and rapastinel as the rapid-acting antidepressants

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      Interestingly, (2R,6R)-HNK hasn't been shown to effectively inhibit NMDARs at relevant concentrations (10 mg/kg), suggesting that HNK's antidepressant effects without the involvement of NMDARs [86]. This hypothesis has inspired controversy, especially whether the dose and concentration of ketamine metabolite in vivo and in vitro of rodents are related to antidepressant effects in humans [90]. Additionally, (2R,6R)-HNK directly activates AMPA receptors and BDNF–tropomyosin receptor kinase B (TrkB) cascade by mGluR2 signaling without binding to NMDARs, which is different from ketamine's [91].

    • Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents

      2020, Journal of the Neurological Sciences
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      As a result, mood-related benefits of ketamine may be independent of NMDAR blockage. The HNK hypothesis has inspired debate [64,70–72], particularly whether the doses and concentrations of ketamine metabolites that produce in vivo and in vitro effects in rodents are relevant to antidepressant effects in humans [73]. A pilot clinical study did not show a relationship between (2S,6S; 2R,6R)-HNK and response to ketamine in MDD patients [74].

    • Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine

      2019, Neuropharmacology
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      Based on the purported role of ketamine's metabolite (2R,6R)-HNK in its antidepressant activity (Zanos et al., 2016), we have again applied established translational neuropharmacokinetics methodology (Doran et al., 2012) to estimate currently clinically relevant Cb,u of (2R,6R)-HNK and subsequently investigated both these and reported preclinically effective exposures in an AMPAR-centric fashion. First, our work uniquely addresses the highly debated (Abdallah, 2017; Collingridge et al., 2017; Suzuki et al., 2017; Zanos et al., 2017) uncertainty around clinically relevant central (2R,6R)-HNK exposures at ketamine's clinical antidepressant dose (Zarate et al., 2012). A combination of our in vitro analyses (Table 1) and published mouse (1.2–1.4) (Yamaguchi et al., 2018; Zanos et al., 2016) and rat (0.73) (Moaddel et al., 2015) Cb:Cp suggests (2R,6R)-HNK has a Cp,u-favoring asymmetry at the BBB in rats (Cb,u:Cp,u of 0.38).

    • Ketamine metabolites with antidepressant effects: Fast, economical, and eco-friendly enantioselective separation based on supercritical-fluid chromatography (SFC) and single quadrupole MS detection

      2017, Journal of Pharmaceutical and Biomedical Analysis
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      While some of these metabolites retain KET’s ability to inhibit NMDARs (e.g., NK), others are either inactive or exhibit affinity towards completely different targets such as activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) by one particular enantiomer of HNK (2R,6R-HNK) which was identified to be responsible for the sustained antidepressant effects after KET administration [10]. While its counter-enantiomer (2S,6S-HNK) was shown to be a selective inhibitor of the α7-nicotinic acetylcholine receptor [11–13]. Considering the aforementioned diverse pharmacological activity of the optical isomers of KET’s metabolites, there is a need for reliable analytical methods enabling the stereoselective quantification of these compounds.

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