Pharmacogenetics of methylphenidate response in preschoolers with ADHD.
OBJECTIVE
The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD).


METHODS
DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers completed ADHD symptom scales and side effect ratings for each of five randomly administered weekly conditions that included immediate-release methylphenidate 1.25, 2.5, 5.0, 7.5 mg and placebo given three times daily. Candidate genes hypothesized to influence stimulant effects or individual risks for ADHD were genotyped.


RESULTS
Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter (p=.05) and synaptosomal-associated protein 25 (SNAP25) allelesT1065G (p=.03) andT1069C (p=.05). SNAP25 variants were also associated with tics (p=.02), buccal-lingual movements (p=.01), and irritability (p=04). DRD4 variants were also associated with picking (p=.03). Increasing dose predicted irritability (p=.05) and social withdrawal (p=.03) with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1).


CONCLUSIONS
Emerging evidence suggests the potential for understanding the individual variability of response to and side effects of ADHD medications from the study of genetics, although additional research is required before these findings are proven to have clinical utility.
McGOUGH
James
J
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.. Electronic address: jmcgough@mednet.ucla.edu.
McCRACKEN
James
J
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Swanson
James
J
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Riddle
Mark
M
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Kollins
Scott
S
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Greenhill
Laurence
L
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Abikoff
Howard
H
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Davies
Mark
M
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Chuang
Shirley
S
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Wigal
Tim
T
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Wigal
Sharon
S
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Posner
Kelly
K
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Skrobala
Anne
A
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Kastelic
Elizabeth
E
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Ghuman
Jaswinder
J
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Cunningham
Charles
C
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Shigawa
Sharon
S
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Moyzis
Robert
R
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
Vitiello
Benedetto
B
Drs. McGough and McCracken and Ms. Shigawa are with the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the University of California, Irvine; Drs. Greenhill and Posner, Mr. Davies (retired), Ms. Chuang, and Ms. Skrobala are with New York State Psychiatric Institute, Columbia University, New York; Drs. Riddle and Kastelic are with Johns Hopkins University, Baltimore; Dr. Kollins is with Duke University Medical Center, Durham, NC; Dr. Abikoff is with the New York University Child Study Center, New York; Dr. Ghuman is with the University of Arizona, Tucson; Dr. Cunningham is with the McMaster University, Hamilton, Ontario, Canada; Dr. Moyzis is with the University of California, Irvine; and Dr. Vitiello is with the National Institute of Mental Health, Bethesda, MD.
D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000627:therapeutic use*; D002675:Child, Preschool; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007508:Irritable Mood / Q000187:drug effects; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects / Q000627:therapeutic use*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012934:Social Isolation; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics; D020323:Tics / Q000139:chemically induced
D000697:Central Nervous System Stimulants; D050825:Synaptosomal-Associated Protein 25; D050638:Receptors, Dopamine D4; D008774:Methylphenidate