A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder.
OBJECTIVE
This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD).


METHODS
Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes.


RESULTS
Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p = .01), with a suggested trend for catechol-O-methyltransferase (COMT) (p = .04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p = .008), DRD4 exon 3 VNTR (p = .006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p = .02). Irritability was predicted by COMT (p = .02). Vegetative symptoms were predicted by 5HTTLPR (p = .003). No significant effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25).


CONCLUSIONS
This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects.
Semel Institute for Neuroscience & Human Behavior and David Geffen School of Medicine, University of California, Los Angeles, USA. jmcgough@mednet.ucla.edu
James J
JJ
McGough
James T
JT
McCracken
Sandra K
SK
Loo
Marc
M
Manganiello
Michael C
MC
Leung
Jeremy R
JR
Tietjens
Thao
T
Trinh
Shilpa
S
Baweja
Robert
R
Suddath
Susan L
SL
Smalley
Gerhard
G
Hellemann
Catherine A
CA
Sugar
D000124:Achievement; D000293:Adolescent; D001143:Arousal / Q000235:genetics; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D018592:Cross-Over Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D007438:Introns / Q000235:genetics; D007508:Irritable Mood; D008297:Male; D008433:Mathematics; D008774:Methylphenidate / Q000627:therapeutic use*; D018598:Minisatellite Repeats / Q000235:genetics; D010597:Pharmacogenetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D050638:Receptors, Dopamine D4 / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics; D016896:Treatment Outcome
D000697:Central Nervous System Stimulants; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; C494208:SNAP25 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D050825:Synaptosomal-Associated Protein 25; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D002394:Catechol O-Methyltransferase