Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients

• Published in: Psychopharmacologia Vol. 167; no. 4; pp. 443 - 448
• Main Authors: Gerstenberg, Gisa, Aoshima, Toshiaki, Fukasawa, Takashi, Yoshida, Keizo, Takahashi, Hitoshi, Higuchi, Hisashi, Murata, Yoshiko, Shimoyama, Ritsuko, Ohkubo, Tadashi, Shimizu, Tetsuo, Otani, Koichi
• Format: Journal Article
• Language: English
• Published: Berlin Springer Science and Business Media LLC 01.06.2003; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Amino Acids; Amino Acids - blood; Antidepressive Agents, Second-Generation; Antidepressive Agents, Second-Generation - blood; Antidepressive Agents, Second-Generation - therapeutic use; Biological and medical sciences; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Depressive Disorder, Major; Depressive Disorder, Major - blood; Depressive Disorder, Major - drug therapy; Dose-Response Relationship, Drug; Female; Fluvoxamine; Fluvoxamine - analogs & derivatives; Fluvoxamine - blood; Fluvoxamine - therapeutic use; Humans; Japan; Male; Medical sciences; Middle Aged; Neuropharmacology; Pharmacology. Drug treatments; Psychiatric Status Rating Scales; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Selective Serotonin Reuptake Inhibitors; Serotonin Uptake Inhibitors - blood; Serotonin Uptake Inhibitors - therapeutic use; Smoking; Treatment Outcome; Japan; Mood disorder; Human; Pharmacokinetic pharmacodynamic relationship; Serotonin; Enzyme; Isozyme; Metabolite; Psychotropic; Fluvoxamino acid; Cytochrome P450; Oral administration; Depression; Reuptake inhibitor; Clinical effects; Japanese; Chemotherapy; Treatment; Activity concentration relation; Steady-state plasma concentration; CYP2D6; Concentration metabolism relation; Antidepressant agent; Pharmacokinetics; Fluvoxamine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-003-1430-1

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. 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. 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. 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.