title: Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.
abstract: OBJECTIVE
  The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied.
  
  
  METHODS
  The subjects were 49 Japanese patients with major depressive disorder receiving FLV 200 mg/day for 6 weeks. Depressive symptoms and side effects were evaluated by the Montgomery Asberg Depression Rating Scale (MADRS), and the UKU Side Effect Rating Scale, respectively. The Css of FLV and FLA were measured by HPLC, and the CYP2D6 genotyping was performed by PCR methods.
  
  
  RESULTS
  The Css of FLV and FLV+FLA showed significant negative correlations with the final MADRS score. The Css of FLV, FLA and FLV+FLA were significantly higher in the responders (final MADRS score < or =10) than in non-responders. The proportion of responders was significantly higher in the patients with the Css of FLV, FLA and FLV+FLA above 150, 55 and 180 ng/ml, respectively. In the multiple regression, the Css of FLV+FLA showed a significant negative correlation with the final MADRS score. In the logistic regression, the Css of FLA had a significant effect on the differentiation of responders from non-responders. The incidence of side effects was low, and the development of nausea, the most frequent one, was not dependent on any Css. The number of mutated CYP2D6 alleles causing absent or decreased enzyme activity was not related to the therapeutic response or development of nausea.
  
  
  CONCLUSIONS
  The present study suggests that there is a therapeutic threshold for the Css of FLV and probably also for the Css of FLA, and the Css of FLV+FLA above 180 ng/ml best predicts a good therapeutic response.
authors.affiliation: Department of Neuropsychiatry, Yamagata University School of Medicine, 990-9585 Yamagata, Japan.
authors.forename: Gisa
authors.initials: G
authors.lastname: Gerstenberg
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoshima
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukasawa
authors.forename: Keizo
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Higuchi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murata
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimoyama
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shimizu
authors.forename: Koichi
authors.initials: K
authors.lastname: Otani
mesh_terms: D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood*; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016666:Fluvoxamine / Q000031:analogs & derivatives / Q000097:blood* / Q000627:therapeutic use*; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000627:therapeutic use*; D012907:Smoking; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids; D018687:Antidepressive Agents, Second-Generation; D019389:Cytochrome P-450 CYP2D6; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors; C477448:fluvoxamino acid