Pharmacogenetics of methylphenidate response in preschoolers with ADHD.
Pharmacogenetics of methylphenidate response in preschoolers with ADHD.
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DOI：
10.1097/01.chi.0000235083.40285.08
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发表时间：
2006-11
影响因子：
13.3
通讯作者：
J. McGough;J. McCracken;J. Swanson;M. Riddle;S. Kollins;L. Greenhill;H. Abikoff;M. Davies;Shirley Z Chuang;T. Wigal;S. Wigal;K. Posner;Anne M. Skrobala;Elizabeth A. Kastelic;J. Ghuman;C. Cunningham;Sharon Shigawa;R. Moyzis;B. Vitiello
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文献类型：
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作者：
J. McGough;J. McCracken;J. Swanson;M. Riddle;S. Kollins;L. Greenhill;H. Abikoff;M. Davies;Shirley Z Chuang;T. Wigal;S. Wigal;K. Posner;Anne M. Skrobala;Elizabeth A. Kastelic;J. Ghuman;C. Cunningham;Sharon Shigawa;R. Moyzis;B. Vitiello
目的：探讨哌甲酯治疗学龄前儿童注意力缺陷多动障碍（ADHD）症状减轻和副作用的遗传调节因子。方法在一项双盲、安慰剂对照、交叉哌甲酯滴定试验中，从81名受试者中分离DNA。家长和教师完成了ADHD症状量表和副作用评级，每周随机给予五种条件，包括立即释放哌甲酯1.25，2.5，5.0，7.5 mg和安慰剂，每天三次。候选基因假设影响兴奋剂的效果或ADHD的个体风险进行基因分型。结果：虽然初步分析没有显示出显著的遗传效应，但二次分析揭示了症状反应与多巴胺受体（DRD4）启动子（p=.05）和突触体相关蛋白25（SNAP25）等位基因T1065G（p=.03）和T1069C（p=.05）的变异之间的关联。SNAP 25变异体也与抽搐（p= 0.02）、颊舌运动（p= 0.01）和易怒（p= 0.04）相关。DRD4变异也与挑拣有关（p=.03）。增加剂量可预测DRD 4变异体的易怒（p=.05）和社交退缩（p=.03）。对多巴胺转运蛋白（DAT 1）无显著影响。结论：新出现的证据表明，从遗传学研究中了解ADHD药物反应和副作用的个体变异性的潜力，尽管在这些发现被证明具有临床实用性之前还需要进行更多的研究。
OBJECTIVE The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHOD DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers completed ADHD symptom scales and side effect ratings for each of five randomly administered weekly conditions that included immediate-release methylphenidate 1.25, 2.5, 5.0, 7.5 mg and placebo given three times daily. Candidate genes hypothesized to influence stimulant effects or individual risks for ADHD were genotyped. RESULTS Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter (p=.05) and synaptosomal-associated protein 25 (SNAP25) allelesT1065G (p=.03) andT1069C (p=.05). SNAP25 variants were also associated with tics (p=.02), buccal-lingual movements (p=.01), and irritability (p=04). DRD4 variants were also associated with picking (p=.03). Increasing dose predicted irritability (p=.05) and social withdrawal (p=.03) with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1). CONCLUSIONS Emerging evidence suggests the potential for understanding the individual variability of response to and side effects of ADHD medications from the study of genetics, although additional research is required before these findings are proven to have clinical utility.