McCracken James T, Aman Michael G, McDougle Christopher J, Tierney Elaine, Shiraga Sharon, Whelan Fiona, Arnold L Eugene, Posey David, Ritz Louise, Vitiello Benedetto, Scahill Lawrence
Research Units on Pediatric Psychopharmacology Autism Network, University of California at Los Angeles, Los Angeles, CA 90024-1759, USA.
J Child Adolesc Psychopharmacol. 2010 Feb;20(1):1-5. doi: 10.1089/cap.2009.0059.
Guanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , a drug transporter at the blood-brain barrier, are associated with variability in the efficacy of guanfacine in children with PDD and hyperactivity.
Children with PDD who participated in an 8-week open-label trial of guanfacine were genotyped for the C3435T single-nucleotide polymorphism (SNP) variant of the MDR1 gene, a variant reported to alter function of the transporter. The decrease from baseline to 8 weeks in parent-rated Aberrant Behavior Checklist (ABC) hyperactivity and Swanson, Nolan, and Pelham (SNAP) scores were analyzed by MDR1 genotype. Response was compared between subjects homozygous for the minor allele T of the C34535T MDR1 variant (T/T) versus other genotypes (C/T and C/C).
Disruptive behavior decreased during guanfacine treatment as assessed by several end points in the 25 enrolled children (23 boys and 2 girls). Genotype data were available from 22 children. Subjects with either C/T or C/C (n = 16) genotypes showed a three-fold greater improvement than T/T MDR1 C3435T genotype (n = 6) (mean decrease of 15.1 +/- 12.6, or 50.7% from baseline, versus 4.5 +/- 5.1, or 15.6% from baseline) in parent-rated ABC Hyperactivity scores over 8 weeks (p = 0.03). Parent-rated ADHD SNAP scores also differed by genotype (p = 0.05).
Gene variants in MDR1 may influence guanfacine response on hyperactive-impulsive behaviors via altered membrane transport. If replicated in larger samples, additional studies would be important to clarify the mechanisms underlying this effect and to determine its clinical significance. 2.
已证实胍法辛可减少注意力缺陷多动障碍（ADHD）儿童的多动行为，对于广泛性发育障碍（PDD）合并多动的儿童可能也有此作用。本探索性研究的目的是检验编码多药耐药蛋白（MDR1或ABCB1）（一种血脑屏障处的药物转运体）的基因变异是否与胍法辛治疗PDD合并多动儿童的疗效差异相关。
参与胍法辛8周开放标签试验的PDD儿童接受了MDR1基因C3435T单核苷酸多态性（SNP）变异的基因分型，该变异据报道会改变转运体的功能。根据MDR1基因型分析从基线到8周家长评定的异常行为检查表（ABC）多动评分和斯旺森、诺兰和佩勒姆（SNAP）评分的下降情况。比较了C34535T MDR1变异的次要等位基因T纯合子（T/T）受试者与其他基因型（C/T和C/C）受试者的反应。
根据25名入组儿童（23名男孩和2名女孩）的几个终点指标评估，胍法辛治疗期间破坏性行为减少。22名儿童有基因型数据。C/T或C/C基因型（n = 16）的受试者在8周内家长评定的ABC多动评分方面比T/T MDR1 C3435T基因型（n = 6）有大三倍的改善（平均下降15.1±12.6，即较基线下降50.7%，而T/T基因型为4.5±5.1，即较基线下降15.6%）（p = 0.03）。家长评定的ADHD SNAP评分也因基因型而异（p = 0.05）。
MDR1基因变异可能通过改变膜转运影响胍法辛对多动冲动行为的反应。如果在更大样本中得到重复，进一步研究对于阐明这种效应的潜在机制以及确定其临床意义将很重要。 2.
