哌醋甲酯与阿托莫西汀交叉研究中多巴胺转运体和 CYP2D6 基因与注意缺陷/多动障碍治疗反应的关系。

IF 1.5 4区 医学 Q2 PEDIATRICS
Jeffrey R Bishop, Chuan Zhou, Andrea Gaedigk, Beth Krone, Rick Kittles, Edwin H Cook, Jeffrey H Newcorn, Mark A Stein
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引用次数: 0

摘要

背景:很少有生物或临床预测因素能指导注意力缺陷/多动障碍(ADHD)的药物选择和/或剂量。不断积累的数据表明,遗传因素可能会影响哌醋甲酯(兴奋剂)和阿托西汀(非兴奋剂)这两种常用处方药的临床相关药效学(如多巴胺转运体-SLC6A3,通常也称为 DAT1)或药代动力学(如药物代谢酶细胞色素 P450 2D6 CYP2D6)效应。这是首次对同时服用这两种药物的多动症青少年进行研究,探讨基因变异对治疗反应的临床意义。研究方法对199名参加双盲交叉研究的青少年进行了为期4周的DAT1和CYP2D6基因变异检测,以确定它们如何改变与ADHD症状变化之间的时间关系,该研究采用了阶梯滴定剂量优化方案。结果我们的研究结果表明,CYP2D6表型对两种药物的调节作用和ADHD总症状之间的时间反应关系存在趋势(阿托西汀[ATX]:p = 0.058;哌醋甲酯[MPH]:p = 0.044)。DAT1 3'非翻译区(UTR)串联重复序列(VNTR)基因型也有改变阿托西汀剂量与ADHD-RS总分关系的趋势(p = 0.029)。与 10/10 基因型相比,DAT1 9/10 重复基因型的参与者对 ATX 的剂量反应更快,而 9/9 基因型的参与者随着剂量的增加没有反应。无论基因型如何,CYP2D6代谢组的多动症症状和剂量在治疗4周后相似。结论大多数 CYP2D6 代谢正常或 DAT1 基因型为 10/10 或 9/10 的多动症患儿对这两种药物反应良好。虽然我们观察到CYP2D6和DAT1随着时间的推移对治疗反应有一些统计学意义上的影响,但我们的数据表明,用于临床目的的基因分型在指导ATX或MPH的治疗决策方面可能作用有限,因为在研究队列中,这两种药物在滴定到更大剂量3周后普遍有效。DAT1与ATX治疗的潜在关联是一项新发现,这与之前的报告一致,即9/9基因型的DAT1与低剂量和中等剂量治疗的低反应率有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

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来源期刊
CiteScore
3.60
自引率
5.30%
发文量
61
审稿时长
>12 weeks
期刊介绍: Journal of Child and Adolescent Psychopharmacology (JCAP) is the premier peer-reviewed journal covering the clinical aspects of treating this patient population with psychotropic medications including side effects and interactions, standard doses, and research on new and existing medications. The Journal includes information on related areas of medical sciences such as advances in developmental pharmacokinetics, developmental neuroscience, metabolism, nutrition, molecular genetics, and more. Journal of Child and Adolescent Psychopharmacology coverage includes: New drugs and treatment strategies including the use of psycho-stimulants, selective serotonin reuptake inhibitors, mood stabilizers, and atypical antipsychotics New developments in the diagnosis and treatment of ADHD, anxiety disorders, schizophrenia, autism spectrum disorders, bipolar disorder, eating disorders, along with other disorders Reports of common and rare Treatment Emergent Adverse Events (TEAEs) including: hyperprolactinemia, galactorrhea, weight gain/loss, metabolic syndrome, dyslipidemia, switching phenomena, sudden death, and the potential increase of suicide. Outcomes research.
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