PMID- 30215218
OWN - NLM
STAT- MEDLINE
DCOM- 20181231
LR  - 20181231
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Linking)
VI  - 235
IP  - 11
DP  - 2018 Nov
TI  - Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine 
      in a chronic social defeat stress model.
PG  - 3177-3185
LID - 10.1007/s00213-018-5017-2 [doi]
AB  - 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)-d(1)-hydroxynorketamine [(2R,6R)-d(1)-HNK], a final metabolite of 
      (R)-d(2)-ketamine, in the plasma and brain after administration of 
      (R)-d(2)-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)-d(2)-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.
FAU - Zhang, Kai
AU  - Zhang K
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, 260-8670, Japan.
AD  - Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China.
FAU - Toki, Hidetoh
AU  - Toki H
AD  - Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
FAU - Fujita, Yuko
AU  - Fujita Y
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, 260-8670, Japan.
FAU - Ma, Min
AU  - Ma M
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, 260-8670, Japan.
FAU - Chang, Lijia
AU  - Chang L
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, 260-8670, Japan.
FAU - Qu, Youge
AU  - Qu Y
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, 260-8670, Japan.
FAU - Harada, Shingo
AU  - Harada S
AD  - Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
FAU - Nemoto, Tetsuhiro
AU  - Nemoto T
AD  - Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
FAU - Mizuno-Yasuhira, Akiko
AU  - Mizuno-Yasuhira A
AD  - Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
FAU - Yamaguchi, Jun-Ichi
AU  - Yamaguchi JI
AD  - Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
FAU - Chaki, Shigeyuki
AU  - Chaki S
AD  - Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
FAU - Hashimoto, Kenji
AU  - Hashimoto K
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
LA  - eng
GR  - JP18dm0107119/Japan Agency for Medical Research and Development/
PT  - Journal Article
DEP - 20180913
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Antidepressive Agents)
RN  - 690G0D6V8H (Ketamine)
RN  - AR09D82C7G (Deuterium)
RN  - XQY6JVF94X (norketamine)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*administration & dosage/chemistry/metabolism/pharmacology
MH  - Brain/drug effects/metabolism
MH  - Chronic Disease
MH  - Depression/drug therapy/metabolism/psychology
MH  - Deuterium/*administration & dosage/chemistry/metabolism
MH  - *Disease Models, Animal
MH  - Ketamine/*administration & dosage/*analogs & derivatives/chemistry/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Stress, Psychological/*drug therapy/metabolism/psychology
MH  - Treatment Outcome
OTO - NOTNLM
OT  - (2R,6R)-hydroxynorketamine
OT  - (R)-ketamine
OT  - Deuterium isotope effect
OT  - Metabolism
EDAT- 2018/09/15 06:00
MHDA- 2019/01/01 06:00
CRDT- 2018/09/15 06:00
PHST- 2018/07/18 00:00 [received]
PHST- 2018/08/29 00:00 [accepted]
PHST- 2018/09/15 06:00 [pubmed]
PHST- 2019/01/01 06:00 [medline]
PHST- 2018/09/15 06:00 [entrez]
AID - 10.1007/s00213-018-5017-2 [pii]
AID - 10.1007/s00213-018-5017-2 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2018 Nov;235(11):3177-3185. doi: 
      10.1007/s00213-018-5017-2. Epub 2018 Sep 13.