Source: ter Laak MA, Temmink AH, Koeken A, et al. Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity. Pediatr Neurol. 2010; 43(3): 159– 162; doi: 10.1016/j.pediatrneurol.2010.04.004Investigators from the Netherlands performed a study to determine whether the genotypic pattern of cytochrome P450 pathway activity has a characteristic pattern associated with delayed response and adverse effects from atomoxetine in a series of children with attention deficit hyperactivity disorder (ADHD). Atomoxetine is a nonstimulant medication used to treat ADHD which is metabolized mainly through the cytochrome P450 2D6 (CYP2D6) enzyme pathway. Polymorphisms of this pathway are common in Caucasians and can result in a reduced ability to metabolize atomoxetine, leading to variability in efficacy and tolerability.Of 100 patients being treated with atomoxetine for ADHD, 10 took longer than 9 weeks to achieve therapeutic effects and experienced adverse effects attributable to the drug. These 10 patients underwent genotyping. Eight of the 10 patients showed compromised CYP2D6 activity, and 2 had normal activity. Four of eight patients with compromised CYP2D6 activity stopped atomoxetine treatment because of initial adverse effects (gastrointestinal, sleeping, malaise, and mood disorders). In four other patients atomoxetine doses were reduced after genotyping, leading to better tolerability and efficacy. A patient with normal CYP2D6 activity, but compromised CYP2C19 activity (a minor pathway in atomoxetine metabolism), responded better after a change in dose time to morning instead of evening. The cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping before atomoxetine treatment requires investigation. The authors conclude that prescribing physicians should consider genotyping prior to treatment with atomoxetine because of differences in CYP2D6 activity which impact clinical responses.Dr Millichap has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Atomoxetine HCl is a selective norepinephrine reuptake inhibitor, approved in 2002 for the treatment of ADHD in adults and children aged 6 years and older. Atomoxetine is used as an alternative to stimulant medication in children with ADHD complicated by tics or Tourette syndrome. It is also sometimes preferred in children with ADHD complicated by a tendency to seizures or sleep disorder.1Both inattentive and hyperactive/impulsive symptoms appear to be significantly reduced by atomoxetine, compared with placebo. Adverse events are infrequent, and include decreased appetite, somnolence, and fatigue.2–4 Suicidal ideation/behavior occurs in fewer than 1.6% and potentially significant hepatic changes in 2% of children treated with atomoxetine.3The recommended daily dose of atomoxetine is 1.2 mg/kg, ranging from a 0.5 mg/kg initial dose to a maximum of 1.8 mg/kg. Capsules are available in strengths as low as 10 mg for young children and as high as 80 and 100 mg for adults.The current study suggests that testing for cytochrome P450 2D6 genotyping before starting atomoxetine treatment may help avoid both overdosing and underdosing the medication. The cost:benefit ratio of initial enzyme testing of cytochrome P450 2D6 versus close monitoring of response to carefully graded doses of atomoxetine requires further study. A personal enquiry regarding the cost to a patient of cytochrome P450 2D6 genotyping is quoted by one laboratory at approximately $700; the cost of testing for CYP450 C19, a variant of lesser importance, is slightly greater. Failed treatment with recommended dose schedules of atomoxetine or early occurrence of side effects should alert clinicians to the possibility of underlying abnormal cytochrome enzyme activity.Assessing an individual child’s potential to metabolize a drug prior to prescribing it reflects the burgeoning in primary care of individualized medicine based on our enhanced understanding of biochemical genetics and new technologies. The methodologic challenges of cost versus benefit of such testing are daunting; among the factors to weigh are the costs of the therapy being considered, the costs of testing, and the cost and severity of the adverse consequences of treatment.In early September the United States Food and Drug Administration (FDA) approved the marketing of generic atomoxetine hydrochloride capsules in strengths of 10, 18, 25, 40, 60, and 100 mg. The annual sales of both branded and generics is estimated to be over US$ 530 million in the United States market according to The Economic Times of India.5