Division of Mental Health & Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan.
Pharmacogenomics. 2010 Apr;11(4):537-46. doi: 10.2217/pgs.09.168.
The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response.
MATERIALS & METHODS: A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers.
The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p < 0.05). The allele frequencies in CYP3A418 and CYP2C1917 were too low to permit further subgroup analyses.
Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.
抗抑郁药依地普仑（S-CIT）由细胞色素 P450（CYP）酶 CYP2D6、2C19 和 3A4 代谢。本研究评估了 CYP2D6、2C19 和 3A4 遗传多态性对 S-CIT 血浆浓度和患者治疗反应的影响。
共招募 100 例诊断为重度抑郁症的患者入组本研究，采用汉密尔顿抑郁量表评估其抑郁症状。根据 CYP2D6 的4、5 和10、CYP2C19 的2、3 和17 以及 CYP3A4 的*18 的功能及其在亚洲人群中的等位基因频率，选择这些基因的遗传多态性。采用 SNPstream 基因分型系统、PCR 和直接测序方法分析多态性。采用 HPLC 分析 S-CIT 及其代谢物 S-去甲基西酞普兰和 S-二去甲基西酞普兰的稳态血清浓度。根据这些多态性等位基因组合的半定量基因剂量（SGD）和基因剂量（GD）模型，将 CYP2D6 分为中效代谢者（0.5、1 和 1.5 SGD）和高效代谢者，而 CYP2C19 分为弱代谢者（0 GD）和高效代谢者（1 和 2 GD）。
在 8 周治疗期间，中效 CYP2D6 代谢（0.5 SGD）患者组中，重度抑郁症缓解的患者频率显著更高（p=0.0001）。此外，在第 2、4 和 8 周时，CYP2C19 弱代谢者的 S-CIT 血清水平显著高于高效代谢者（p<0.05）。CYP3A418 和 CYP2C1917 的等位基因频率过低，无法进行进一步的亚组分析。
我们的结果表明，CYP2C19 的遗传多态性可能影响 S-CIT 血清浓度，基于基因剂量分析，特定的 CYP2D6 多态性可能预测患者的治疗结果。
