Pharmacogenetics of antidepressant medication intolerance
Pharmacogenetics of antidepressant medication intolerance
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DOI：
10.1176/appi.ajp.160.10.1830
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发表时间：
2003-10-01
影响因子：
17.7
通讯作者：
Schatzberg, AF
中科院分区：
文献类型：
--
作者：
Murphy, GM;Kremer, C;Schatzberg, AF
目的：作者试图确定抗抑郁药物不耐受的遗传标记。药物代谢酶如细胞色素P450 2D6 （CYP2D6）的遗传变异被认为是抗抑郁药不耐受（药代动力学效应）的基础。然而，编码5 -羟色胺受体的基因变异也可以解释抗抑郁药的副作用（药效学效应）。方法：一项为期8周的随机双盲药物遗传学研究比较了246例老年重度抑郁症患者广泛使用的抗抑郁药物帕罗西汀（一种选择性血清素再摄取抑制剂[SSRI]）和米氮平（非SSRI）。测定血清素2A （5-HT2A）位点（HTR2A） 102 T/C单核苷酸多态性（SNP）的基因型，该基因型先前与精神药物治疗结果相关。寡核苷酸微阵列被广泛用于表征CYP2D6基因的变异。临床结果包括治疗中断、不良事件、药物依从性和情绪变化。结果：生存分析显示，由于帕罗西汀引起的副作用而停药与HTR2A C/C基因型密切相关。C等位基因数量与停药概率呈显著的线性关系。帕罗西汀治疗的C/C基因型患者的副作用严重程度也更大。相比之下，HTR2A 102 T/C基因型对米氮平的副作用没有影响。CYP2D6基因型不能预测两种药物的治疗结果。结论：在确定帕罗西汀不耐受时，5-HT2A受体变异引起的患者之间的药效学差异似乎比药代动力学差异更重要。药物遗传标记物可能有助于预测抗抑郁治疗结果。
Objective: The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect).Method: An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT2A) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood.Results: Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication.Conclusions: Pharmacodynamic differences among patients due to variant 5-HT2A receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.