title: Dopamine transporter genotype and methylphenidate dose response in children with ADHD.
abstract: Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3'-untranslated region (3'-UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n=47), ages 5-16 years (mean=9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3'-UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.
authors.affiliation: Department of Psychiatry, The University of Chicago, Chicago, IL 60637, USA. mstein@yoda.bsd.uchicago.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Stein
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Waldman
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Sarampote
authors.forename: Karen E
authors.initials: KE
authors.lastname: Seymour
authors.forename: Adelaide S
authors.initials: AS
authors.lastname: Robb
authors.forename: Charles
authors.initials: C
authors.lastname: Conlon
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008774:Methylphenidate / Q000627:therapeutic use*; D018598:Minisatellite Repeats / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D010919:Placebos; D012016:Reference Values; D012737:Sex Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010919:Placebos; C493214:SLC6A3 protein, human; D008774:Methylphenidate