The relation of cytochrome P450 2D6 (CYP2D6) activity to metabolism, response and adverse effects of atomoxetine was determined by CYP2D6 genotyping in 10 out of 100 children treated for attention deficit hyperactivity disorder at Amphia Hospital, Breda, The Netherlands. Eight of 10 patients genotyped showed compromised CYP2D6 activity, and 2 had normal activity. Enzyme activity is expressed as 4 phenotypes: ultrarapid (high), extensive (70-80% have normal activity), intermediate (10-40% have lower), and poor (5-10% have no activity). A semiquantitative gene dose based on allele activity is defined as 0 for poor metabolizer, 0.5, 1, and 1.5 intermediate, 2 extensive, and >2 ultrarapid metabolizer. Four of 8 patients with compromised CYP2D6 activity (gene doses of 0.5 and 1.0) stopped atomoxetine treatment because of initial adverse effects (gastrointestinal, sleeping, malaise, and mood disorders). In 4 other patients (CYP2D6 gene doses of 1.0 and 1.5) atomoxetine doses were reduced after genotyping, leading to better tolerability and efficacy. A patient with only compromised CYP2C19 activity (a minor pathway in atomoxetine metabolism) responded better after a change in dose time to morning instead of evening. Cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping before atomoxetine treatment requires consideration. [1]

COMMENT. Cytochrome P450 2D6 genotyping before starting atomoxetine treatment may be of benefit in avoidance of overdose or ineffectiveness and premature withdrawal. Atomoxetine is a selective norepinephrine reuptake inhibitor, approved in 2002 for the treatment of ADHD. The recommended daily dose is 1.2 mg/kg, ranging from 0.5 mg/kg initial dose to a maximum of 1.8 mg/kg. Unlike the dosage of stimulant medication that is not based closely on body weight, the initial recommended dose of atomoxetine is commonly calculated by weight. The results of the Netherlands study might indicate the need to begin treatment with atomoxetine using the smallest test dose (10 mg daily), with gradual increments based more on early response or side effects than body weight. The cost to a patient of cytochrome P450 2D6 genotyping is quoted by one laboratory at >$700; that of CYP450 C19 is slightly greater. The cost-benefit ratio of initial enzyme testing of cytochrome P450 2D6 versus close monitoring of response to carefully graded doses of atomoxetine would require further study. Failed treatment with recommended dose schedules of atomoxetine or early occurrence of side effects should alert clinicians to a probable underlying abnormal cytochrome enzyme activity.