title: Dopamine transporter genotype influences the physiological response to medication in ADHD.
abstract: 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.
authors.affiliation: Division of Neurology Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. d.gilbert@cchmc.org
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gilbert
authors.forename: Zhewu
authors.initials: Z
authors.lastname: Wang
authors.forename: Floyd R
authors.initials: FR
authors.lastname: Sallee
authors.forename: Keith R
authors.initials: KR
authors.lastname: Ridel
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merhar
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Tara D
authors.initials: TD
authors.lastname: Lipps
authors.forename: Colin
authors.initials: C
authors.lastname: White
authors.forename: Nevert
authors.initials: N
authors.lastname: Badreldin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wassermann
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D000697:Central Nervous System Stimulants; D002648:Child; D018592:Cross-Over Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use; D009044:Motor Cortex / Q000187:drug effects* / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects; D010597:Pharmacogenetics; D010641:Phenotype; D011437:Propylamines / Q000627:therapeutic use; D005879:Tourette Syndrome / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride