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Comments to behavioral tests for antidepressant-like actions of (2R,6R)–hydroxynorketamine by Bonaventura et al.

Molecular Psychiatry volume 29, pages 3–4 (2024)Cite this article

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Rapid and sustained antidepressant actions of the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine in patients with depression are serendipitous discoveries for the treatment of depression [1]. However, non-ketamine NMDAR antagonists/modulators had no ketamine-like strong antidepressant effects in patients with depression. Importantly, increasing preclinical findings from several groups demonstrated that (R)-ketamine has greater potency and longer-lasting antidepressant-like effects in several rodent depression models than (S)-ketamine although the affinity of (R)-ketamine at NMDAR is lesser potent than that of (S)-ketamine. Collectively, NMDAR unlikely plays a key role in the actions of antidepressants on (R,S)-ketamine [1,2,3]. However, detailed molecular and cellular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its enantiomers remain unknown.

(R)-ketamine is metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine (HNK). (R)-norketamine is a major metabolite, whereas (2R,6R)-HNK is a minor metabolite [2, 3]. Zanos et al. reported that (2R,6R)-HNK is essential for antidepressant-like effects of (R,S)-ketamine in rodents [4]. In contrast, we reported that the (2R,6R)-HNK preparation from (R)-ketamine is not necessary for antidepressant-like effects of (R)-ketamine in rodents [2, 3]. A study using cytochrome P450 inhibitors demonstrated that preparation of (2R,6R)-HNK from (R)-ketamine is not necessary for the antidepressant-like effects of (R)-ketamine in inflammation-induced depression models, and that (R)-ketamine alone is responsible for its antidepressant-like effects [5]. Furthermore, a single injection of (R)-ketamine (20 mg/kg) caused antidepressant-like effects in learned helplessness rat models of depression, whereas (R)-norketamine (20 mg/kg) or (2R,6R)-HNK (20 and 40 mg/kg) did not show antidepressant-like effects in the same model [6]. These data suggest that (R)-ketamine alone, but not metabolites, has antidepressant-like effects in rodents with depression-like behaviors. Although several studies showed antidepressant-like effects of (2R,6R)-HNK in control mice and mice exposed to stress, they did not compare (2R,6R)-HNK and its parent compound (R)-ketamine in the same model.

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Acknowledgements

This study was supported by a grant from the Japan Society for the Promotion of Science (to KH, 21H02846 and to LC, 22K15743).

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  1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan

    Lijia Chang & Kenji Hashimoto

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  1. Lijia Chang
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LC and KH conceived, drafted, and approved the final version of this work.

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Correspondence to Kenji Hashimoto.

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Competing interests

KH is the inventor of filed patent applications on “The use of R-ketamine in the treatment of psychiatric diseases”, “(S)-norketamine and salt thereof as pharmaceutical”, “R-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, “R-ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder”, and “TGF-β1 in the treatment of depression” by the Chiba University. KH has also received speakers’ honoraria, consultant fee, or research support from Abbott, Boehringer Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Sumitomo-Pharma, Taisho, Otsuka, Murakami Farm, and Perception Neuroscience. LC declares no conflict of interest.

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Chang, L., Hashimoto, K. Comments to behavioral tests for antidepressant-like actions of (2R,6R)–hydroxynorketamine by Bonaventura et al.. Mol Psychiatry 29, 3–4 (2024). https://doi.org/10.1038/s41380-022-01766-6

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