Atomoxetine Therapy and CYP2D6 Genotype

Atomoxetine (brand name Strattera) is a non-stimulant drug used in the treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective noradrenaline reuptake inhibitor (SNRI) and is approved for children aged 6 and older, adolescents, and adults. Atomoxetine is part of a treatment plan for ADHD that may include other measures such as psychological, educational, and social support. Because atomoxetine is not a stimulant or a controlled substance it may be used in individuals with tics or other side effects associated with stimulants, and in individuals who have a substance abuse problem (or have a family member with a substance abuse problem). The most common side effects associated with atomoxetine therapy include weight loss, abdominal pain, headache, dizziness, fatigue, and irritability. In addition, atomoxetine has a boxed warning on the increased risk of suicidal ideation in children and adolescents treated with atomoxetine. The CYP2D6 enzyme is involved in the metabolism of atomoxetine (and a quarter of all prescribed drugs). Individuals who lack CYP2D6 activity (“poor metabolizers”) will have increased levels of atomoxetine and an increased risk of side effects compared with CYP2D6 normal metabolizers. Approximately 7% of Caucasians are CYP2D6 poor metabolizers. The drug label states that for known CYP2D6 poor metabolizers, the initial dose should only be increased to the usual target dose if symptoms fail to improve after 4 weeks and the initial dose is well tolerated (1). Atomoxetine dosing should be adjusted for individuals who are CYP2D6 poor metabolizers, individuals who are taking a strong CYP2D6 inhibitor (e.g., paroxetine, fluoxetine, and quinidine), and individuals with moderate or severe hepatic impairment. However, different authorities have different dosing recommendations. The Royal Dutch Association for the Advancement of Pharmacy (KNMP) Dutch Pharmacogenetics Working Group (DPWG) provides dosing recommendations for poor, intermediate and ultrarapid metabolizers. For poor metabolizers, DPWG recommends starting with the standard initial dose and to consult a care provider if side effects occur. If the medicine is effective, but side effects occur, DPWG recommends reducing the dose and monitoring efficacy (2). The Clinical Pharmacogenetics Implementation Consortium (CPIC) also provide recommendations for different CYP2D6 metabolizer phenotypes. For CYP2D6 poor metabolizers, CPIC recommends that if no clinical response is observed after 2 weeks of atomoxetine therapy, then a plasma concentration exposure check be used with an individual’s CYP2D6 genotype to help clinicians guide dose selection and titration (3).