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Ketamine: anesthetic, psychotomimetic, antidepressant, or anthelmintic?

Molecular Psychiatry volume 27, pages 3116–3118 (2022)Cite this article

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During the late 1960s and early 1970s, several drugs, such as PCP and (R,S)-ketamine, were used by young people for recreation as PCP and (R,S)-ketamine reportedly produce dissociative (i.e., euphoria, floating sensation) and schizophrenia-like symptoms (i.e., positive symptoms, negative symptoms, cognitive impairment) in healthy subjects (Fig. 1) [2, 3]. Furthermore, it is reported that (R,S)-ketamine-induced cognitive impairment could be recovered following abstinence from (R,S)-ketamine. In contrast, (R,S)-ketamine is reported to cause depressive symptoms such as anhedonia in healthy subjects. Interestingly, (R,S)-ketamine is reported to improve cognitive impairment in patients with major depressive disorder (MDD) [4]. In 1983, (R,S)-ketamine was identified to be an antagonist at N-methyl-D-aspartate receptor (NMDAR) in the brain. Clinical findings using PCP and (R,S)-ketamine strongly suggest a crucial role of NMDAR in the pathogenesis of schizophrenia [3]. The NMDAR hypothesis in schizophrenia has been supported by a number of researchers. Ketamine-induced physiological and behavioral changes in rodents, non-human primates, and humans have been widely used as a pharmacological model of schizophrenia. However, there are currently no approved drugs based on the NMDAR hypothesis.

Importantly, certain drug abusers took ketamine for its rapid-acting antidepressant effect [2]. Therefore, (R,S)-ketamine has been recognized as potentially exerting rapid-acting antidepressant effects in subjects with substance abuse [2]. In 2000, Dr. Berman and his colleagues (Yale University, USA) reported a double-blind, placebo-controlled study of intravenous (R,S)-ketamine (0.5 mg/kg) infusion in patients with MDD (Fig. 1) [5]. In 2006, Dr. Zarate and his colleagues (National Institute of Mental Health, USA) demonstrated rapid-acting and sustained antidepressant effects of (R,S)-ketamine in treatment-resistant patients with MDD (Fig. 1) [6]. Subsequently, the robust antidepressant actions of (R,S)-ketamine in treatment-resistant patients with MDD or bipolar disorder have been replicated by several groups worldwide. Therefore, the discovery of the robust antidepressant effect of (R,S)-ketamine is serendipity in the research and treatment of mood disorders. Off-label (R,S)-ketamine has been widely used in the treatment of severe depression.

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Fig. 1

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Acknowledgements

The author would like to thank Professor Edward F. Domino who encouraged my arketamine project from 2014. The author would like to thank our collaborators who are listed as the co-authors of our papers in the reference list. This study was supported by the grant from Japan Society for the Promotion of Science (to K.H., 21H02846, 21H00184, 21H05612).

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

    Kenji Hashimoto

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KH is the sole author that conceived, drafted and approved the final version of this work.

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Correspondence to Kenji Hashimoto.

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Competing interests

Dr. Hashimoto 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. Dr. Hashimoto also declares that he has received research support and consultant from Dainippon Sumitomo, Otsuka, Taisho, Murakami Farm, and Perception Neuroscience.

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This comment is dedicated to the memory of Professor Edward F. Domino who passed away on November 3, 2021.

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Hashimoto, K. Ketamine: anesthetic, psychotomimetic, antidepressant, or anthelmintic?. Mol Psychiatry 27, 3116–3118 (2022). https://doi.org/10.1038/s41380-022-01587-7

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