Biomaterial Database

Pharmacogenetics of methylphenidate response in preschoolers with ADHD. 2006

James McGOUGH, and James McCRACKEN, and James Swanson, and Mark Riddle, and Scott Kollins, and Laurence Greenhill, and Howard Abikoff, and Mark Davies, and Shirley Chuang, and Tim Wigal, and Sharon Wigal, and Kelly Posner, and Anne Skrobala, and Elizabeth Kastelic, and Jaswinder Ghuman, and Charles Cunningham, and Sharon Shigawa, and Robert Moyzis, and Benedetto Vitiello

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.

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.

UI	MeSH Term	Description	Entries
D007508	Irritable Mood	Abnormal or excessive excitability with easily triggered anger, annoyance, or impatience.	Mood, Irritable,Irritable Moods,Moods, Irritable
D008297	Male		Males
D008774	Methylphenidate	A central nervous system stimulant used most commonly in the treatment of ATTENTION DEFICIT DISORDER in children and for NARCOLEPSY. Its mechanisms appear to be similar to those of DEXTROAMPHETAMINE. The d-isomer of this drug is referred to as DEXMETHYLPHENIDATE HYDROCHLORIDE.	Centedrin,Concerta,Daytrana,Equasym,Metadate,Methylin,Methylphenidate Hydrochloride,Phenidylate,Ritalin,Ritalin-SR,Ritaline,Tsentedrin,Hydrochloride, Methylphenidate,Ritalin SR
D010597	Pharmacogenetics	A branch of genetics which deals with the genetic variability in individual responses to drugs and drug metabolism (BIOTRANSFORMATION).	Pharmacogenomics
D002675	Child, Preschool	A child between the ages of 2 and 5.	Children, Preschool,Preschool Child,Preschool Children
D004311	Double-Blind Method	A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment.	Double-Masked Study,Double-Blind Study,Double-Masked Method,Double Blind Method,Double Blind Study,Double Masked Method,Double Masked Study,Double-Blind Methods,Double-Blind Studies,Double-Masked Methods,Double-Masked Studies,Method, Double-Blind,Method, Double-Masked,Methods, Double-Blind,Methods, Double-Masked,Studies, Double-Blind,Studies, Double-Masked,Study, Double-Blind,Study, Double-Masked
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000697	Central Nervous System Stimulants	A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here.	Analeptic,Analeptic Agent,Analeptic Drug,Analeptics,CNS Stimulant,CNS Stimulants,Central Nervous System Stimulant,Central Stimulant,Analeptic Agents,Analeptic Drugs,Central Stimulants,Agent, Analeptic,Agents, Analeptic,Drug, Analeptic,Drugs, Analeptic,Stimulant, CNS,Stimulant, Central,Stimulants, CNS,Stimulants, Central
D001289	Attention Deficit Disorder with Hyperactivity	A behavior disorder originating in childhood in which the essential features are signs of developmentally inappropriate inattention, impulsivity, and hyperactivity. Although most individuals have symptoms of both inattention and hyperactivity-impulsivity, one or the other pattern may be predominant. The disorder is more frequent in males than females. Onset is in childhood. Symptoms often attenuate during late adolescence although a minority experience the full complement of symptoms into mid-adulthood. (From DSM-V)	ADHD,Attention Deficit Disorder,Attention Deficit Hyperactivity Disorder,Brain Dysfunction, Minimal,Hyperkinetic Syndrome,Minimal Brain Dysfunction,ADDH,Attention Deficit Disorders with Hyperactivity,Attention Deficit Hyperactivity Disorders,Attention Deficit-Hyperactivity Disorder,Attention Deficit Disorders,Attention Deficit-Hyperactivity Disorders,Deficit Disorder, Attention,Deficit Disorders, Attention,Deficit-Hyperactivity Disorder, Attention,Deficit-Hyperactivity Disorders, Attention,Disorder, Attention Deficit,Disorder, Attention Deficit-Hyperactivity,Disorders, Attention Deficit,Disorders, Attention Deficit-Hyperactivity,Dysfunction, Minimal Brain,Syndromes, Hyperkinetic