1MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
J Psychopharmacol. 2014 Feb;28(2):133-41. doi: 10.1177/0269881113512041. Epub 2013 Nov 20.
Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration.
In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped.
Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline:nortrip-tyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response.
While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.
抗抑郁药的反应在患者之间存在差异,这可能是由于细胞色素 P450 酶将抗抑郁药代谢为无活性化合物的速度不同所致。药物代谢率受编码这些酶的基因中的常见变异影响。然而,CYP450 基因型或抗抑郁药血清浓度是否可以预测治疗结果仍不清楚。
在 GENDEP(一项使用依地普仑或去甲替林治疗的抑郁患者的药物遗传学研究)中,在治疗 8 周后测量了抗抑郁药及其主要代谢物的血清浓度,并对 CYP2D6 和 CYP2C19 的变体进行了基因分型。
在服用依地普仑的患者(n=223)中,CYP2C19 基因型与依地普仑血清浓度和去甲西酞普兰:西酞普兰比值显著相关。对于服用去甲替林的患者(n=161),CYP2D6 基因型与去甲替林和 10-羟基去甲替林血清浓度以及 10-羟基去甲替林:去甲替林比值显著相关。赋予更高酶活性的 CYP450 基因型与较低的药物血清浓度和较高的代谢物:药物比值相关。尽管如此,CYP450 基因型或抗抑郁药血清浓度与治疗反应之间没有发现显著关联。
虽然 CYP450 基因型与依地普仑和去甲替林的血清浓度之间存在显著关系,但基因型不能预测这两种药物治疗反应的差异。此外,抗抑郁药血清浓度的差异与治疗反应的可变性无关。