title: Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression.
abstract: Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.
authors.affiliation: Psychiatrische Dienste Aargau AG, Klinik Königsfelden, Brugg, Switzerland.
authors.forename: Eveline
authors.initials: E
authors.lastname: Jaquenoud Sirot
authors.forename: Sabine
authors.initials: S
authors.lastname: Harenberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Vandel
authors.forename: Carlos A Mendonça
authors.initials: CA
authors.lastname: Lima
authors.forename: Patrick
authors.initials: P
authors.lastname: Perrenoud
authors.forename: Klaus
authors.initials: K
authors.lastname: Kemmerling
authors.forename: Daniele F
authors.initials: DF
authors.lastname: Zullino
authors.forename: Henriette
authors.initials: H
authors.lastname: Hilleret
authors.forename: Séverine
authors.initials: S
authors.lastname: Crettol
authors.forename: Michèle
authors.initials: M
authors.lastname: Jonzier-Perey
authors.forename: Kerry Powell
authors.initials: KP
authors.lastname: Golay
authors.forename: Muriel
authors.initials: M
authors.lastname: Brocard
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
authors.forename: Pierre
authors.initials: P
authors.lastname: Baumann
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D000078785:Mirtazapine; D010597:Pharmacogenetics; D011569:Psychiatric Status Rating Scales; D012737:Sex Factors; D012907:Smoking / Q000378:metabolism; D013237:Stereoisomerism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6