title: Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine.
abstract: The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence suggests that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by anα-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that (R)-ketamine exerted longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.).
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fukumoto
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.).
authors.forename: Hidetoh
authors.initials: H
authors.lastname: Toki
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.).
authors.forename: Michihiko
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashihayata
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.).
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Yamaguchi
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan (K.F., H.T., M.I., T.H., J.Y., S.C.); and Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (K.H.) s-chaki@so.taisho.co.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D019417:Hindlimb Suspension / Q000379:methods / Q000523:psychology; D007649:Ketamine / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine