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Atomoxetine

In this first Drug Watch -- a new feature of JW Pediatrics and Adolescent Medicine -- we review the use of a nonstimulant therapy for ADHD.

Background: Atomoxetine (Strattera) is the first nonstimulant medication approved by the FDA for the treatment of school-aged children and adolescents with attention-deficit/hyperactivity disorder (ADHD). In contrast to stimulant medications that primarily regulate dopamine in the brain (e.g., methylphenidate and amphetamine), atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter in the central nervous system. Atomoxetine increases both norepinephrine and dopamine levels, especially in the prefrontal cortex.

Clinical Trials: In a placebo-controlled study, Michelson and colleagues randomized 297 children and adolescents (71% male; age range, 8-18 years) with moderate-to-severe ADHD as defined by DSM-IV criteria to receive one of three doses of atomoxetine or placebo. Approximately two thirds of the subjects in the treatment groups had the combined type of ADHD, and one third had primarily inattentive ADHD. Oppositional defiant disorder was the only common coexisting disorder among these children (38%). Atomoxetine given twice daily on a weight-adjusted basis of 0.5 mg/kg/day, 1.2 mg/kg/day, or 1.8 mg/kg/day for an 8-week period significantly reduced core ADHD symptoms (hyperactivity, impulsivity, and inattentiveness). The 1.2-mg/kg/day and 1.8-mg/kg/day dosages produced significant behavior change compared with placebo, although the higher dose did not produce better results. Social and family functioning, as measured by the Child Health Questionnaire, was also better in the atomoxetine groups than in the placebo group. Another team of investigators found a treatment effect size (0.71) for core ADHD symptoms with once-daily dosing of atomoxetine that was similar to that reported in earlier trials of twice-daily dosing. Parent ratings documented a sustained effect late in the day with the once-daily regimen.

In a randomized, open-label trial, Kratochvil and colleagues compared atomoxetine with methylphenidate for 10 weeks in 228 children with ADHD. Parents and clinicians using the ADHD-IV Rating Scale found significant and similar improvements in inattention and hyperactive/impulsive symptom domains with both medications. Side effects were also similar.

Pharmacology: Atomoxetine is well absorbed after oral administration and is minimally affected by consumption of food. It is metabolized primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) pathway. Seven percent of whites and 2% of blacks are poor metabolizers of drugs metabolized by CYP2D6. Although poor metabolizers of atomoxetine have higher plasma drug levels, the pattern of dose response is similar in poor metabolizers and extensive (rapid) metabolizers. CYP2D6 inhibitors (e.g., paroxetine and fluoxetine) may increase atomoxetine plasma levels, and caution should be used when they are co-administered. The action of albuterol on the cardiovascular system may be potentiated when used with atomoxetine. Atomoxetine is contraindicated in patients who have taken MAO inhibitors within 15 days and in those with narrow-angle glaucoma; the drug should be used with caution in patients with hypertension, hypotension, tachycardia, cardiovascular or cerebrovascular disease, or urinary retention.

Side Effects: The side effects of atomoxetine and stimulants are similar, including stomachache, headache, and appetite suppression (without a significant effect on growth). Motor and verbal tics associated with atomoxetine have not been reported.

Dosing: The recommended dosage for initial atomoxetine treatment is 0.5 mg/kg/day. After 3 to 5 days, the dosage may be increased to 1.2 to 1.4 mg/kg/day. Better effects have not been shown at higher doses. If daytime sedation occurs, atomoxetine may be given at bedtime or in divided dosages twice daily. Strattera capsules are available in strengths of 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg.

Comment: Atomoxetine may be useful for treating children and adolescents who do not respond to stimulant medication and those who have intolerable side effects from stimulants. Atomoxetine may be an alternative for stimulant-treated youth who cannot sustain attention for evening homework or who have severe late-afternoon or evening hyperactivity/impulsivity when the stimulant effect wears off. Some parents and adolescents request nonstimulant treatment; in such instances, atomoxetine may be the initial medication.

— Martin T. Stein, MD

Published in Journal Watch Pediatrics and Adolescent Medicine January 16, 2004

Citation(s):

Michelson D et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled, dose-response study. Pediatrics 2001 Nov; 108:E83.

Michelson D et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: A randomized, placebo-controlled study. Am J Psychiatry 2002 Nov; 159:1896-901.

• Medline abstract (Free)

Kratochvil CJ et al. Atomoxetine and methylphenidate treatment in children with ADHD: A prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 2002 Jul; 41:776-84.

• Medline abstract (Free)

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