Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model.
Kai Zhang, Hidetoh Toki, Yuko Fujita, Min Ma, Lijia Chang, Youge Qu, Shingo Harada, Tetsuhiro Nemoto, Akiko Mizuno‐Yasuhira, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Kenji Hashimoto
Psychopharmacology November 2018 DOI: 10.1007/s00213-018-5017-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacokinetic and behavioral study in mice Peer reviewed |
|---|---|
| Population | Mice, including a chronic social defeat stress model |
| Interventions | (R)-ketamine (R)-d2-ketamine |
| Dose | 10 mg/kg |
| Duration | Antidepressant effects assessed up to 7 days after administration |
| Topics | Ketamine Esketamine |
| Keywords | 2r,6r-hydroxynorketamine Deuterium isotope effect Metabolism |
| Key points | Deuterium substitution at the C6 position of (R)-ketamine slowed production of the metabolite (2R,6R)-HNK in mouse plasma and brain, but did not alter the rapid and long-lasting (7-day) antidepressant effects of (R)-ketamine in the chronic social defeat stress model. The authors argue it is therefore unlikely that (2R,6R)-HNK is essential for the antidepressant effects of (R)-ketamine. |
Abstract
(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. We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model. 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. 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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 17
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
and 12 more in the library
Cites 29
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- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 24 more in the library