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Ketamine in neuropsychiatric disorders: an update

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Abstract

The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of—or further research with—subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.

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Fig. 1: Current hypothesized mechanisms of ketamine.

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Acknowledgements

The authors thank the 7SE research unit and staff for their support.

Funding

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857). Additional funding was provided by a NARSAD Young Investigator Award to BK. The NIMH and NARSAD had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The work was completed as part of the authors’ official duties as Government employees. The views expressed do not necessarily reflect the views of the NIH, the Department of Health and Human Services, or the United States Government.

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Authors and Affiliations

  1. Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Jenessa N. Johnston, Bashkim Kadriu, Christoph Kraus, Ioline D. Henter & Carlos A. Zarate Jr

  2. Translational and Experimental Medicine, Neuroscience at Jazz Pharmaceuticals, San Diego, CA, USA

    Bashkim Kadriu

  3. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria

    Christoph Kraus

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  1. Jenessa N. Johnston
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  5. Carlos A. Zarate Jr
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All authors contributed equally to the conceptualization of the manuscript, literature search, generation of the figure and table, writing, and revision of this manuscript. All authors approved the final version of the paper.

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Correspondence to Jenessa N. Johnston.

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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; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated 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 post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. BK is now a full-time employee and shareholder of Jazz Pharmaceuticals. All other authors have no conflict of interest to disclose, financial or otherwise.

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Johnston, J.N., Kadriu, B., Kraus, C. et al. Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacol. 49, 23–40 (2024). https://doi.org/10.1038/s41386-023-01632-1

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