@article{ee8b64ef3a7840e6aebe09197a27c507,
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.",
keywords = "autism spectrum disorders, dopamine, genetics, hyperactivity, methylphenidate",
author = "McCracken, {J. T.} and Badashova, {K. K.} and Posey, {D. J.} and Aman, {M. G.} and L. Scahill and E. Tierney and Arnold, {L. E.} and B. Vitiello and F. Whelan and Chuang, {S. Z.} and M. Davies and B. Shah and McDougle, {C. J.} and Nurmi, {E. L.}",
note = "Funding Information: The RUPP Autism Network comprises the following investigators listed by role and study site: Ohio State University: principal investigator Michael G Aman, PhD, co-investigators L Eugene Arnold, MEd, MD, Yaser Ramadan, MD, Andrea Witwer, MA, Ronald Lindsay, MD and Patricia Nash, MD; University of California at Los Angeles: principal investigator James T McCracken, MD, co-investigators Bhavik Shah, MD, James McGough, MD, Pegeen Cronin, PhD, Lisa Lee, BA; Indiana University: principal investigator Christopher J McDougle, MD, co-investigators David Posey, MD, Naomi Swiezy, PhD, Arlene Kohn, BA; Yale University: principal investigator Lawrence Scahill, MSN, PhD, co-investigators Andres Martin, MD, Kathleen Koenig, MSN, Fred Volkmar, MD, Deirdre Carroll, MSN, Allison Lancor, BS; Kennedy Krieger Institute: principal investigator Elaine Tierney, MD, co-investigators Jaswinder Ghuman, MD, Nilda Gonzalez, MD, Marco Grados, MD; National Institute of Mental Health: principal investigator Benedetto Vitiello, MD, co-investigator Louise Ritz, MBA; statisticians: Shirley Z Chuang, MS, Mark Davies, MPH, of Columbia University; data management: James Robinson, MEd, Don McMahon, MS, Nathan Kline Institute. Research supported by NIMH contracts N01 MH-70070 (principal investigator: Dr McCracken), N01 MH-70009 (principal investigator: Dr Scahill), N01 MH-70001 (principal investigator: Dr McDougle), and N01 MH 80011 (principal investigator: Dr Aman); by NIH Division of Research Resources General Clinical Research Center grants M01 RR-00750 (to Indiana University), M01 RR-00052 (to John Hopkins University), M01 RR-00034 (to Ohio University) and M01 RR-06022 (to Yale University); by NIMH grants MH-01805 (to Dr McCracken) NIMH grants MH094613 and T32MH073517 (Dr Nurmi) and MH-68627 (to Dr Posey); and by funding from the Korczak Foundation (to Dr Scahill). The opinions and assertions contained in this report are the private views of the authors and are not to be construed as official or as reflecting the views of the National Institute of Mental Health, the National Institutes of Health, or the Department of Health and Human Services. Funding Information: Dr Aman has received consulting fees from Bristol-Myers Squibb, BioMarin, Roche and Supernus. Dr Aman also reports research support from Bristol-Myers Squibb and Johnson and Johnson. Dr Arnold has received research funding from Curemark, Shire and Lilly, and has consulted on advisory boards for AstraZeneca, Biomarin, Novartis, Noven, Seaside Therapeutics and Shire. Dr McCracken reports receiving consulting fees from BioMarin, Novartis and PharmaNet; he also reports research support from Bristol-Myers Squibb, Roche and Seaside Therapeutics. Dr McDougle reports having received consultant fees from Bristol-Myers Squibb, Hoffman-LaRoche and Forest Research Institute; he has also received research support and is on the speakers{\textquoteright} bureau of Bristol-Myers Squibb. Dr Scahill reports receiving consultant fees from Brackett, Pfizer, Hoffman, BioMarin; he has also received research support from Pfizer, Shire and Hoffman. The remaining authors declare no conflict of interest.",
year = "2014",
month = jun,
doi = "10.1038/tpj.2013.23",
language = "English (US)",
volume = "14",
pages = "295--302",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "3",
}