Gilbert Donald L, Wang Zhewu, Sallee Floyd R, Ridel Keith R, Merhar Stephanie, Zhang Jie, Lipps Tara D, White Colin, Badreldin Nevert, Wassermann Eric M
Division of Neurology Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Brain. 2006 Aug;129(Pt 8):2038-46. doi: 10.1093/brain/awl147. Epub 2006 Jun 7.
Attention deficit hyperactivity disorder (ADHD) is a complex, multifactorial disorder characterized by physical hyperactivity and behavioural disinhibition. Short interval cortical inhibition (SICI), measured in motor cortex with transcranial magnetic stimulation, is reduced in ADHD and correlates with symptom severity. However, ADHD medication-induced changes in SICI vary widely among normal individuals and have not been well studied in children with ADHD. Therefore, we undertook this study to measure and compare effects of two ADHD medications, methylphenidate (MPH), a psychostimulant, and atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, on SICI in children with ADHD. In addition, we wished to determine whether a genetic variation in the dopamine transporter (DAT1), a site of action of MPH, could influence the effects of MPH or ATX on SICI. We performed a randomized, double-blind, single-dose, crossover study comparing 0.5 mg/kg MPH with 1.0 mg/kg ATX in 16 children with ADHD, aged 8-17. Seven were homozygotes and 9 heterozygotes for the DAT1 variable number of tandem repeats 10-repeat allele. Medication and genotype effects on SICI were estimated with repeated measures, mixed model regression. We found that MPH and ATX had similar effects on SICI. However, medication effects differed significantly by DAT1 genotype [F(2,13) = 13.04, P = 0.0008]. Both MPH and ATX increased SICI in heterozygotes but not in 10-repeat homozygotes. In conclusion, MPH and ATX have similar effects on SICI in children with ADHD. A genetic variation in DAT1, previously linked to ADHD risk and MPH behavioural responses, influences the neurophysiological effects of both MPH and ATX.
注意缺陷多动障碍（ADHD）是一种复杂的多因素疾病，其特征为身体多动和行为抑制障碍。通过经颅磁刺激在运动皮层测量的短间隔皮层抑制（SICI）在ADHD患者中降低，且与症状严重程度相关。然而，ADHD药物引起的SICI变化在正常个体中差异很大，在ADHD儿童中尚未得到充分研究。因此，我们进行了这项研究，以测量和比较两种ADHD药物，即精神兴奋剂哌甲酯（MPH）和选择性去甲肾上腺素再摄取抑制剂托莫西汀（ATX）对ADHD儿童SICI的影响。此外，我们希望确定多巴胺转运体（DAT1）的基因变异，即MPH的作用位点，是否会影响MPH或ATX对SICI的作用。我们进行了一项随机、双盲、单剂量、交叉研究，比较了16名8至17岁ADHD儿童中0.5mg/kg的MPH与1.0mg/kg的ATX。7名是DAT1可变串联重复序列10重复等位基因的纯合子，9名是杂合子。通过重复测量、混合模型回归估计药物和基因型对SICI的影响。我们发现MPH和ATX对SICI有相似的影响。然而，药物作用因DAT1基因型而有显著差异[F(2,13) = 13.04，P = 0.0008]。MPH和ATX均使杂合子的SICI增加，但在10重复纯合子中未增加。总之，MPH和ATX对ADHD儿童的SICI有相似的影响。先前与ADHD风险和MPH行为反应相关的DAT1基因变异会影响MPH和ATX的神经生理作用。
