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

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.