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

Pharmacogenomics J. 2017 Jan;17(1):98-104. doi: 10.1038/tpj.2015.89. Epub 2016 Jan 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Attention Deficit Disorder with Hyperactivity / diagnosis
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / therapeutic use*
  • Chi-Square Distribution
  • Child
  • Child, Preschool
  • Dopamine Uptake Inhibitors / adverse effects
  • Dopamine Uptake Inhibitors / therapeutic use*
  • Dopamine beta-Hydroxylase / genetics
  • Female
  • Gene Frequency
  • Gene-Environment Interaction
  • Haplotypes
  • Humans
  • Methylphenidate / adverse effects
  • Methylphenidate / therapeutic use*
  • Odds Ratio
  • Pharmacogenetics*
  • Pharmacogenomic Variants*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D3 / genetics
  • Risk Factors
  • Smoking / adverse effects
  • Treatment Outcome
  • Tyrosine 3-Monooxygenase / genetics


  • Central Nervous System Stimulants
  • DRD2 protein, human
  • DRD3 protein, human
  • Dopamine Uptake Inhibitors
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Methylphenidate
  • Tyrosine 3-Monooxygenase
  • Dopamine beta-Hydroxylase