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Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model

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Abstract

Rationale

(R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown.

Methods

We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model.

Results

Pharmacokinetic studies showed that levels of (2R,6R)-d1-hydroxynorketamine [(2R,6R)-d1-HNK], a final metabolite of (R)-d2-ketamine, in the plasma and brain after administration of (R)-d2-ketamine (10 mg/kg) were lower than those of (2R,6R)-HNK from (R)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2R,6R)-HNK. In contrast, levels of (R)-ketamine and its metabolite (R)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (R)-ketamine (10 mg/kg) and (R)-d2-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (R)-ketamine.

Conclusions

The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (R)-ketamine to (2R,6R)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (R)-ketamine in a CSDS model. Therefore, it is unlikely that (2R,6R)-HNK is essential for antidepressant effects of (R)-ketamine.

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Funding

This study was supported by AMED (to K.H., JP18dm0107119).

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Authors and Affiliations

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

    Kai Zhang, Yuko Fujita, Min Ma, Lijia Chang, Youge Qu & Kenji Hashimoto

  2. Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China

    Kai Zhang

  3. Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan

    Hidetoh Toki, Akiko Mizuno-Yasuhira, Jun-ichi Yamaguchi & Shigeyuki Chaki

  4. Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

    Shingo Harada & Tetsuhiro Nemoto

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  1. Kai Zhang
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  2. Hidetoh Toki
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  3. Yuko Fujita
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  4. Min Ma
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  11. Shigeyuki Chaki
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  12. Kenji Hashimoto
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Corresponding author

Correspondence to Kenji Hashimoto.

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Conflict of interest

Dr. Hashimoto is an inventor on a filed patent application on “The use of (R)-ketamine in the treatment of psychiatric diseases” by Chiba University. Dr. Hashimoto has received research support from Dainippon-Sumitomo, Otsuka, and Taisho. Drs. Toki, Mizuno-Yasuhira, Yamaguchi, and Chaki are employee of Taisho Pharmaceutical Co., Ltd., Japan. Other authors declare no conflict of interest.

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Zhang, K., Toki, H., Fujita, Y. et al. Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model. Psychopharmacology 235, 3177–3185 (2018). https://doi.org/10.1007/s00213-018-5017-2

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  • DOI: https://doi.org/10.1007/s00213-018-5017-2

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