Clinical effectiveness, pharmacokinetics and pharmacogenetics of mirtazapine in depression

Introduction: The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Method: In- and out-patients with major depressive episode (17-item Hamilton Depression Rating Scale, HAMD, total scores ≥18 points and Mini-Mental State Examination scores ≥24) received MIR for 8 weeks (30mg/day on days 1–14 and 30–45mg/day on days 15–56). A total of 45 patients (mean age 51 years; range 19–79) were included. Results: MIR treatment resulted in a significant (p<0.0001, Wilcoxon test) improvement in mean HAMD total score at the end of the study. The analysis of the enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in non-hydrolyzed and hydrolyzed plasma samples on days 14 and 56 showed a clear influence of gender and age on these parameters. Moreover, non-smokers had higher MIR plasma levels than smokers: S-MIR: 9.40±3.85 vs. 6.15±5.50 (p=0.005); R-MIR: 24.4±6.54 vs. 18.5±4.06 (p=0.003). Only in non-smokers, plasma levels of S-MIR and metabolites were associated with the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n=8), S-OH-MIR concentrations were higher than in the other patients (n=37), and the reduction of the HAMD scores was significantly more pronounced in the CYP2B6 *6/*6 genotyped patients at the end of the study. Conclusions: High CYP1A2 activity seen in smokers can mask the influence of the CYP2D6 genotype. The role of CYP2B6 for the metabolism and effectiveness of MIR should be further investigated.