title: Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder.
abstract: Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder. However, a considerable interindividual variability exists in clinical outcome, which may reflect underlying genetic influences. We analyzed 57 single-nucleotide polymorphisms in 9 dopamine-related candidate genes (TH, DBH, COMT, DAT1 and DRD1-5) as potential predictors of MPH efficacy and tolerability, and we considered prenatal and perinatal risk factors as environmental hazards that may influence treatment effects in a gene-by-environment analysis. Our results provide evidence for the contribution of DRD3 (P=0.041; odds ratio (OR)=4.00), DBH (P=0.032; OR=2.85), TH (P=5.5e-03; OR=4.34) and prenatal smoking (P=1.7e-03; OR=5.10) to the clinical efficacy of MPH, with a higher risk for treatment failure in genetically susceptible subjects whose mother smoked during pregnancy. Adverse events after MPH treatment were significantly associated with variation in DBH (P=6.4e-03; OR=0.28) and DRD2 (P=0.047; OR=3.76). This study suggests that the dopaminergic system together with prenatal smoking exposure may moderate MPH treatment effects.
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pagerols
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Richarte
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Sánchez-Mora
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Garcia-Martínez
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Corrales
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Corominas
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Casas
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ribasés
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Ramos-Quiroga
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D006239:Haplotypes; D006801:Humans; D008774:Methylphenidate / Q000009:adverse effects / Q000627:therapeutic use*; D016017:Odds Ratio; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D000697:Central Nervous System Stimulants; C581293:DRD2 protein, human; C493593:DRD3 protein, human; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D008774:Methylphenidate; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase
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