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Time will tell. Reply to “Comments to pharmacological and behavioral divergence of ketamine enantiomers by Jordi Bonaventura et al.” by Chen et al.

Molecular Psychiatry volume 27, pages 1863–1865 (2022)Cite this article

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We thank Chen et al. for their commentary [1] on our study [2] which focused on the pharmacological pleiotropy of (R,S)-ketamine’s enantiomers, and in particular, their interactions with opioid receptors and their performance in preclinical assays predictive of human abuse liability. Based on our experimental findings, and prior work, we made three main conclusions: (i) the clinical effects of racemic ketamine ((R,S)-ketamine) should not be attributed exclusively to NMDA receptor (NMDAR) antagonism but may also involve mu (MOR) and kappa (KOR) opioid receptors, (ii) the abuse liability profile of (R,S)-ketamine is likely due to (S)-ketamine’s pharmacological effects, and (iii) if (R)-ketamine is effective at treating depression, it should be preferred over (S)-ketamine, because of its lower preclinical abuse liability profile. In their commentary, Chen et al. [1] state that these conclusions are not justified. We address their criticisms below.

(R,S)-ketamine binds to and activates MORs and KORs [2, 3] and its efficacy has been associated with endogenous opioid activity [4]. Yet, in their commentary [1], Chen et al. claim that (R,S)-ketamine’s and (S)-ketamine’s antidepressant effects are exclusively due to NMDAR antagonism. This interpretation, however, is not supported by recent findings [3]. For example, Williams et al. [5] showed that the preferential MOR antagonist naltrexone decreased (R,S)-ketamine’s antidepressant but not its dissociative effects. This finding suggests that (R,S)-ketamine’s antidepressant effects are mediated by MORs, do not require NMDAR antagonism, and that NMDAR-dependent dissociative effects are not required for (R,S)-ketamine’s antidepressant effects.

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Authors and Affiliations

  1. Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, Catalonia, Spain

    Jordi Bonaventura

  2. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA

    Jordi Bonaventura, Sherry Lam, Meghan Carlton, Matthew Boehm, Juan L. Gomez, Oscar Solís & Michael Michaelides

  3. Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, MD, USA

    Marta Sánchez-Soto & David R. Sibley

  4. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD, USA

    Patrick J. Morris & Craig J. Thomas

  5. Neurobiology of Relapse Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA

    Ida Fredriksson & Yavin Shaham

  6. Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    Carlos A. Zarate Jr.

  7. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael Michaelides

Authors
  1. Jordi Bonaventura
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Contributions

JB, YS, CJZ, and MM wrote the paper with input from all coauthors. All authors critically reviewed the content and approved the final version before submission. This work was supported by the NIDA Intramural Research Program (ZIA000069), and by Grants RYC-2019-027371-I (JB) and PID2020-117989RA-I00 (JB) funded by MCIN/AEI /10.13039/501100011033 and by “ESF Investing in your future”. .

Corresponding authors

Correspondence to Jordi Bonaventura or Michael Michaelides.

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Competing interests

CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereo-isomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. PJM and CJT are coinventors on patents regarding the use and methods of production for (2R,6R)-hydroxynorketamine. They have assigned their patent rights to the US government but will share a percentage of any royalties that may be received by the government. MM has received research funding from AstraZeneca, Redpin Therapeutics, and Attune Neurosciences. All other authors declare no competing interests.

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Bonaventura, J., Lam, S., Carlton, M. et al. Time will tell. Reply to “Comments to pharmacological and behavioral divergence of ketamine enantiomers by Jordi Bonaventura et al.” by Chen et al.. Mol Psychiatry 27, 1863–1865 (2022). https://doi.org/10.1038/s41380-022-01480-3

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