title: Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1.
abstract: Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites' levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.|Organization for Research Initiatives and Development, Doshisha University, Kyoto 610-0394, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Gastroenterology, Gifu Municipal Hospital, Gifu 500-8513, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tomita
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.|Labratory of Nano-bio Probe, Quantitative Biology Center (QBic), RIKEN, Osaka 565-0874, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tashiro
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Kanitta
authors.initials: K
authors.lastname: Watcharanurak
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.|Department of Nursing School of Health Sciences, Gifu University of Medical Science, Gifu 501-3892, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Mitani
authors.affiliation: Department of Medical Science and Technology, Faculty of Health Sciences, Hiroshima International University, Hiroshima, 739-2695, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Fujigaki
authors.affiliation: Department of Medical Sciences Innovation, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan.
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijyo University, Aichi 468-8503, Japan.|Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.affiliation: Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan.|Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Aichi 470-1192, Japan.|Aino University, Osaka 567-0012, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Neuropsychopharmacology &Toxicology Program, College of Pharmacy, Kangwon National University, Gangwon 200-701, Republic of Korea.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.|Department of Medical Sciences Innovation, Fujita Health University Graduate School of Health Sciences, Aichi 470-1192, Japan.|Japanese Drug Organization of Appropriate Use and Research, Aichi 468-0069, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003863:Depression / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology*; D004790:Enzyme Induction; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy / Q000523:psychology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000172:deficiency; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000235:genetics; D007737:Kynurenine / Q000097:blood; D008297:Male; D055442:Metabolome; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012701:Serotonin / Q000378:metabolism; D013550:Swimming; D014364:Tryptophan / Q000097:blood
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D012701:Serotonin; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan