Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. Hashimoto K. Ketamine: anesthetic, psychotomimetic, antidepressant, or anthelmintic? Mol Psychiatry. 2022.

  2. Hashimoto K. Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochem Pharmacol. 2020;177:113935.

    Article  CAS  PubMed  Google Scholar 

  3. Wei Y, Chang L, Hashimoto K. Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor. Mol Psychiatry. 2022;27:559–73.

    Article  CAS  PubMed  Google Scholar 

  4. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016;533:481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yamaguchi JI, Toki H, Qu Y, Yang C, Koike H, Hashimoto K, et al. (2R,6R)-hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice. Neuropsychopharmacology 2018;43:1900–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shirayama Y, Hashimoto K. Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol 2018;21:84–8.

    Article  CAS  PubMed  Google Scholar 

  7. Bonaventura J, Gomez JL, Carlton ML, Lam S, Sanchez-Soto M, Morris PJ, et al. Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. Mol Psychiatry. 2022.

  8. Bonaventura J, Lam S, Carlton M, Boehm MA, Gomez JL, Solís O, et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021;26:6704–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nugent AC, Ballard ED, Gould TD, Park LT, Moaddel R, Brutsche NE, et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry. 2019;24:1040–52.

    Article  CAS  PubMed  Google Scholar 

  10. Viktorov M, Wilkinson MP, Elston VCE, Stone M, Robinson ESJ. A systematic review of studies investigating the acute effects of N-methyl-D-aspartate receptor antagonists on behavioral despair in normal animals suggests poor predictive validity. Brain Neurosci Adv. 2022;6:23982128221081645.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Reardon S. Depression researchers rethink popular mouse swim tests. Nature 2019;571:456–7.

    Article  CAS  PubMed  Google Scholar 

  12. Hashimoto K, Shirayama Y. What are the causes for discrepancies of antidepressant actions of (2R,6R)-hydroxynorketamine? Biol Psychiatry. 2018;84:e7–e8.

    Article  CAS  PubMed  Google Scholar 

  13. Ma L, Hashimoto K. The role of hippocampal KCNQ2 channel in antidepressant actions of ketamine. Neuron 2022;110:2201–3.

    Article  CAS  PubMed  Google Scholar 

  14. Farmer CA, Gilbert JR, Moaddel R, George J, Adeojo L, Lovett J, et al. Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression. Neuropsychopharmacology. 2020;45:1398–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Leal GC, Bandeira ID, Correia-Melo FS, Telles M, Mello RP, Vieira F, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatry Clin Neurosci. 2021;271:577–82.

    Article  PubMed  Google Scholar 

Download references


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

Author information

Authors and Affiliations



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

Corresponding author

Correspondence to Kenji Hashimoto.

Ethics declarations

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chang, L., Hashimoto, K. Comments to behavioral tests for antidepressant-like actions of (2R,6R)–hydroxynorketamine by Bonaventura et al.. Mol Psychiatry (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links