Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder

• Published in: The pharmacogenomics journal Vol. 17; no. 1; pp. 98 - 104
• Main Authors: Pagerols, M, Richarte, V, Sánchez-Mora, C, Garcia-Martínez, I, Corrales, M, Corominas, M, Cormand, B, Casas, M, Ribasés, M, Ramos-Quiroga, J A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2017; Nature Publishing Group
• Subjects: 45/22; 45/23; 45/77; 631/208/205; Adolescent; Attention Deficit Disorder with Hyperactivity - diagnosis; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention deficit hyperactivity disorder; Biomedical and Life Sciences; Biomedicine; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - therapeutic use; Chi-Square Distribution; Child; Child, Preschool; Dopamine beta-Hydroxylase - genetics; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine D3 receptors; Dopamine receptors; Dopamine Uptake Inhibitors - adverse effects; Dopamine Uptake Inhibitors - therapeutic use; Drug therapy; Female; Gene Expression; Gene Frequency; Gene-Environment Interaction; Haplotypes; Human Genetics; Humans; Hyperactivity; Methylphenidate; Methylphenidate - adverse effects; Methylphenidate - therapeutic use; Odds Ratio; Oncology; original-article; Pharmacogenetics; Pharmacogenomic Variants; Pharmacotherapy; Phenotype; Polymorphism, Single Nucleotide; Pregnancy; Prenatal experience; Prenatal Exposure Delayed Effects; Psychopharmacology; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D3 - genetics; Risk Factors; Single-nucleotide polymorphism; Smoking; Smoking - adverse effects; Treatment Outcome; Tyrosine 3-Monooxygenase - genetics
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2015.89

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.