DRD4 exon 3 genotype and ADHD: Randomised pharmacodynamic investigation of treatment response to methylphenidate

World J Biol Psychiatry. 2019 Jul;20(6):486-495. doi: 10.1080/15622975.2017.1410221. Epub 2017 Dec 15.


Objectives: Dopamine plays an important role in modulating attention and motor behaviours, dimensions altered in attention deficit/hyperactivity disorder (ADHD). Numerous association studies have linked dopamine receptor 4 (DRD4) to increased risk of ADHD. This study investigated the effect of DRD4 exon 3 polymorphism on child behaviours in response to treatment with methylphenidate. Methods: A total of 374 children diagnosed with ADHD (ages 6-12 years) were evaluated under three experimental conditions: baseline, placebo and MPH (0.5 mg/kg/day). This was a 2-week prospective within-subject, placebo-controlled, crossover trial. The Conners' Global Index for parents and for teachers was used to evaluate the behaviours of the children. One-way repeated measures analysis of variance was used to test the effect of the interaction between DRD4 genotype and experimental conditions. Results: A significant interaction between DRD4 genotype and treatment was detected when the child's behaviour was evaluated by the parents (P = 0.035, effect size of 0.014), driven by a better treatment response in children homozygous for long 7-repeat allele. Conclusions: According to the parent assessment, children homozygous for the long 7-repeat allele were more responsive to experimental condition. This is the largest pharmacogenetic investigation of the effect of DRD4 exon 3 polymorphism in childhood ADHD. Trial Registration: clinicaltrials.gov, identifier NCT00483106.

Keywords: ADHD; DRD4 7-repeat; methylphenidate; pharmacogenetics; treatment response.

Publication types

  • Clinical Trial, Phase IV
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Central Nervous System Stimulants / pharmacology*
  • Child
  • Cross-Over Studies
  • Exons
  • Female
  • Genotype
  • Humans
  • Male
  • Methylphenidate / pharmacology*
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Prospective Studies
  • Psychiatric Status Rating Scales
  • Quebec
  • Receptors, Dopamine D4 / genetics*


  • Central Nervous System Stimulants
  • DRD4 protein, human
  • Receptors, Dopamine D4
  • Methylphenidate

Associated data

  • ClinicalTrials.gov/NCT00483106

Grant support