COMT by DRD3 Epistatic Interaction in Modulating Behaviors in Children with ADHD: A Pharmaco-Dynamic Behavioral Approach

J Atten Disord. 2021 Oct;25(12):1720-1730. doi: 10.1177/1087054720934191. Epub 2020 Jun 20.


Objective: Examining the joint effect of two functional variants in two dopamine-related genes (DRD3 and COMT) on ADHD-relevant behaviors under three experimental conditions (EC).

Method: 362 children with ADHD were assessed by parents and teachers during a week of baseline evaluation, followed by 1 week of MPH and placebo, administered in a double-blind crossover design.

Results: Statistically significant 3-way (DRD3-by-COMT-by-EC; p = .004) and 2-way interactions (COMT by EC; p = .002) were observed on Conners'-Teachers scores. Children with the COMT Met/Met genotype had lower scores at baseline and on placebo compared to the other genotype groups. Furthermore, stratifying the children according to their COMT genotypes helped to detect statistically significant and biologically meaningful effects of DRD3 genotype.

Conclusions: These findings suggest that COMT and DRD3 genetic variants may together play a role in ADHD symptomatology and response to treatment through gene-gene interaction.

Keywords: ADHD; COMT; DRD3; epistasis; pharmaco-dynamic.

Publication types

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

MeSH terms

  • Attention Deficit Disorder with Hyperactivity* / drug therapy
  • Attention Deficit Disorder with Hyperactivity* / genetics
  • Catechol O-Methyltransferase / genetics
  • Central Nervous System Stimulants* / therapeutic use
  • Child
  • Cross-Over Studies
  • Genotype
  • Humans
  • Methylphenidate* / therapeutic use
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / therapeutic use


  • Central Nervous System Stimulants
  • DRD3 protein, human
  • Receptors, Dopamine D3
  • Methylphenidate
  • COMT protein, human
  • Catechol O-Methyltransferase