title: Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.
abstract: Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Semel Institute for Neuroscience, Los Angeles, CA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: McCracken
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Semel Institute for Neuroscience, Los Angeles, CA, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Badashova
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Posey
authors.affiliation: Departments of Psychiatry and Psychology, The Nisonger Center UCEDD, Ohio State University, Columbus, OH, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Aman
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: L
authors.initials: L
authors.lastname: Scahill
authors.affiliation: Department of Psychiatry, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tierney
authors.affiliation: Departments of Psychiatry and Psychology, The Nisonger Center UCEDD, Ohio State University, Columbus, OH, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Arnold
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Vitiello
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Semel Institute for Neuroscience, Los Angeles, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Whelan
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Chuang
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Semel Institute for Neuroscience, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Shah
authors.affiliation: Department of Psychiatry, Lurie Autism Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: McDougle
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Semel Institute for Neuroscience, Los Angeles, CA, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Nurmi
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D015306:Biogenic Monoamines / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000150:complications / Q000235:genetics*; D006801:Humans; D008774:Methylphenidate / Q000627:therapeutic use*
chemical_list: D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D008774:Methylphenidate