CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD

J Am Acad Child Adolesc Psychiatry. 2007 Feb;46(2):242-51. doi: 10.1097/01.chi.0000246056.83791.b6.


Background: Atomoxetine, a selective norepinephrine reuptake inhibitor effective in the treatment of attention-deficit/hyperactivity disorder (ADHD), is metabolized through the cytochrome P-450 2D6 (CYP2D6) enzyme pathway, which is genetically polymorphic in humans. Variations in plasma atomoxetine exposures can occur because of genetic variation or as a consequence of coadministration with drugs that inhibit CYP2D6.

Method: We examined the effects of CYP2D6 on the efficacy, safety, and tolerability of atomoxetine in children and adolescents using pooled data from atomoxetine clinical trials.

Results: At endpoint, poor metabolizers had markedly greater reductions in mean symptom severity scores compared with extensive metabolizers (p < .05). Poor metabolizers had greater increases in heart rate and diastolic blood pressure (p < .001) and smaller increases in weight (p < .05) than extensive metabolizers. Several adverse events, including decreased appetite and tremor, were more frequent in poor metabolizers (p < .05).

Conclusions: These results suggest that CYP2D6 poor metabolizers taking atomoxetine in doses up to 1.8 mg/kg/day are likely to have greater efficacy, greater increases in cardiovascular tone, and some differences in tolerability compared with CYP2D6 extensive metabolizers taking similar doses.

Trial registration: NCT00190684.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenergic Uptake Inhibitors / administration & dosage
  • Adrenergic Uptake Inhibitors / pharmacokinetics*
  • Adrenergic Uptake Inhibitors / therapeutic use*
  • Atomoxetine Hydrochloride
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / enzymology
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Biotransformation / genetics
  • Child
  • Cytochrome P-450 CYP2D6 / genetics*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Genotype
  • Humans
  • Male
  • Meta-Analysis as Topic
  • Polymorphism, Genetic / genetics*
  • Propylamines / adverse effects
  • Propylamines / pharmacokinetics*
  • Propylamines / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


  • Adrenergic Uptake Inhibitors
  • Propylamines
  • Atomoxetine Hydrochloride
  • Cytochrome P-450 CYP2D6

Associated data