Abstract
(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice. To prevent the metabolism of (R)-ketamine to (2 R,6 R)-HNK, mice were pretreated with cytochrome P450 (CYP) inhibitors. The concentrations of (R)-ketamine, (R)-norketamine, and (2 R,6 R)-HNK in plasma, brain, and cerebrospinal fluid (CSF) samples were determined using enantioselective liquid chromatography-tandem mass spectrometry. The concentrations of (R)-norketamine and (2 R,6 R)-HNK in plasma, brain, and CSF samples after administration of (R)-norketamine (10 mg/kg) and (2 R,6 R)-HNK (10 mg/kg), respectively, were higher than those generated after administration of (R)-ketamine (10 mg/kg). Nonetheless, while (R)-ketamine attenuated, neither (R)-norketamine nor (2 R,6 R)-HNK significantly altered immobility times of LPS-treated mice. Treatment with CYP inhibitors prior to administration of (R)-ketamine increased the plasma levels of (R)-ketamine, while generation of (2 R,6 R)-HNK was almost completely blocked. (R)-Ketamine exerted the antidepressant effects at a lower dose in the presence of CYP inhibitors than in their absence, which is consistent with exposure levels of (R)-ketamine but not (2 R,6 R)-HNK. These results indicate that metabolism to (2 R,6 R)-HNK is not necessary for the antidepressant effects of (R)-ketamine and that unmetabolized (R)-ketamine itself may be responsible for its antidepressant actions.
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Acknowledgements
We thank Drs. Takashi Hashihayata, Dai Nozawa, and Masahiro Abe of Taisho Pharmaceutical Co., Ltd. for providing authentic standards for (R)-ketamine and (2 R,6 R)-HNK. We also thank Dr. Rodney W. Stevens of Taisho Pharmaceutical Co., Ltd. for proofreading the manuscript.
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C.Y. was supported by a Research Fellowship of the Japan Society for the Promotion of Science. K.H. is an inventor named on a filed patent application for “The use of R-ketamine in the treatment of psychiatric diseases” by Chiba University. K.H. has received research support from Dainippon Sumitomo, Mochida, Otsuka, and Taisho. J.Y., H.T., H.K., A.M.Y., and S.C. are employees of Taisho Pharmaceutical Co., Ltd. Y.Q. declares no biomedical financial interests or potential conflicts of interest.
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Yamaguchi, Ji., Toki, H., Qu, Y. et al. (2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice. Neuropsychopharmacol 43, 1900–1907 (2018). https://doi.org/10.1038/s41386-018-0084-y
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DOI: https://doi.org/10.1038/s41386-018-0084-y
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