Psychiatrische Dienste Aargau AG, Klinik Königsfelden, Brugg, Switzerland.
J Clin Psychopharmacol. 2012 Oct;32(5):622-9. doi: 10.1097/JCP.0b013e3182664d98.
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.
遗传药理学检测和治疗药物监测可以显著改善抑郁症的药物治疗。本研究的目的是评估米氮平（MIR）的疗效与稳定状态血浆浓度及其在中重度抑郁症患者中的代谢物之间的关系，同时考虑其遗传药理学状态。住院和门诊患者（n = 45；平均年龄 51 岁；范围，19-79 岁）接受米氮平治疗 8 周（第 1-14 天每天 30mg，第 15-56 天每天 30-45mg）。研究结束时，MIR 治疗使汉密尔顿抑郁评定量表总分显著改善（P < 0.0001）。对于任何药代动力学参数，都没有证据表明血浆浓度与临床疗效之间存在显著关系。第 14 天和第 56 天血浆样本中 MIR 的对映异构体及其羟化（OH-MIR）和去甲基（DMIR）代谢物受到性别和年龄的影响。非吸烟者（n = 28）的 MIR 血浆水平高于吸烟者（n = 17）：MIR 的 S(+)-对映异构体为 9.4（SD，3.9）与 6.2（SD，5.5）ng/mL（P = 0.005）；MIR 的 R(-)-对映异构体为 24.4（SD，6.5）与 18.5（SD，4.1）ng/mL（P = 0.003）。只有在非吸烟者中，MIR 的 S(+)-对映异构体和代谢物的血浆水平取决于 CYP2D6 基因型。因此，吸烟者中所见的高 CYP1A2 活性似乎掩盖了 CYP2D6 基因型的影响。在携带 CYP2B6 *6/*6 基因型的患者（n = 8）中，S-OH-MIR 浓度高于其他患者（n = 37）。虽然尚不清楚 S-OH-MIR 是否与 MIR 的治疗效果相关，但在研究结束时，CYP2B6 *6/*6 基因型患者的汉密尔顿评分下降明显更为显著（P = 0.016）。CYP2B6 在 MIR 的代谢和疗效中的作用需要进一步研究。
