This paper provides a review of safety and efficacy data as well as of pharmacological characteristics of
atomoxetine, a new
drug treatment for the
Attention Deficit/Hyperactivity Disorder (
ADHD). To date, the only pharmacological treatment available in France for children and adolescents diagnosed with
ADHD is
methylphenidate, a psychostimulant
drug. However, the clinical response to
methylphenidate may be absent or insufficient in about 20-30%
drug-treated children while the occurrence of adverse effects with
methylphenidate (sleep disturbances, loss of appetite,
tics increase...) may sometimes require a
dose reduction or even the discontinuation of the treatment.
Atomoxetine is an alternative candidate
drug for the treatment of
ADHD. The
drug has been developed with respect to the actual standards of investigation of drugs intended to a -pediatric use.
Atomoxetine has been recently licensed in the USA for the treatment of
ADHD.
Atomoxetine is a potent inhibitor of the
norepinephrine transporter that shows only mini-mal affinity for other
neurotransmitter systems. Although pharmacokinetics of
atomoxetine is influenced by the polymorphism of the
CYP2D6 metabolic pathway, safety and -tolerability data reported during clinical trials did not show any difference in poor versus extensive metabolizers. In addition,
atomoxetine does not inhibit nor induce the
CYP2D6 enzymatic function. The major metabolite of
atomoxetine is
4-hydroxyatomoxetine, a pharmacologically active metabolic found in very low plasma concentrations in pediatric patients, suggesting that it plays only a minor role in the
norepinephrine reuptake inhibition. Preliminary studies were aimed to assess the effective dose range of
atomoxetine and to evaluate its safety and efficacy on the reduction of
ADHD symptoms in adults and children diagnosed with
ADHD. Main data on the child and adolescent population were obtained in four double-blind, randomized, placebo-controlled trials: two identical pivotal trials, a multiple dose study, a once-daily dose study. The first two pivotal trials were carried out in
ADHD children aged 7-13 years, treated with
atomoxetine vs placebo for a duration of 9 weeks. Patients presenting comorbidities (ie
conduct disorder, -anxiety, depression) as well as a history of previous treatment with
methylphenidate were also eligible to participate. The primary outcome was the reduction of the score on the
ADHD rating scale,
ADHD-RS ; secondary criteria included the responder's rate (patients with an
ADHD-RS score reduction of 25% or above), the Clinical Global Impression Scale and the Conners Parent Rating Scale. With a mean dose of 1.5 mg/kg/day,
atomoxetine showed a significant reduction of mean
ADHD-RS scores at endpoint (ANOVA, p<0.001) (table II). Yet, the clinical significance of both studies is limited since efficacy was scored only in a social/familial setting and not in classroom conditions. In addition, intermediate results from baseline to endpoint were not presented in the publication. The multiple dose trial showed a significant reduction of the symptom score at the 1.2 and 1.8 mg/kg/day doses. The objective of the last study was to assess the efficacy of a single daily dose of
atomoxetine versus placebo during a 6 week-treatment. Patients were evaluated by parents, investigators, as well as by teachers. The superiority of
atomoxetine was demonstrated as compared to the placebo and the effect size of the daily dosing was similar to that reported with multiple doses. Preliminary data on
ADHD patients presenting comorbidities showed that
atomoxetine alone signi-ficantly reduced the symptom scores of anxiety and depression and similarly to
atomoxetine associated with
fluoxetine. In
ADHD children with the
oppositional defiant disorder, oppositional symptoms were reduced in the group receiving
atomoxetine 1.8 mg/kg/day. Preliminary results in children with
ADHD and chronic
tics or
Tourette syndrome showed a significant reduction of
ADHD symptoms and a tendency to the decrease of
tics. Tolerance and safety data pooled from the child and adolescent trials were acceptable. Study discontinuations due to adverse events in the four registration studies were only 2.8%. The most frequent adverse effects reported were gastrointestinal symptoms and decreased appetite.
Weight loss reported early in clinical studies tended to stabilize during the open-label extension phases lasting up to 9 months. A retrospective comparison showed that the adverse event profile of poor metabolizers was similar to that of extensive metabolizers. In summary, data presented suggest that
atomoxetine is a safe and effective
drug for the treatment of
ADHD in children and adolescents. Further studies are expected to accurately define the place of
atomoxetine in the treatment strategy of
ADHD, a chronic and invalidating disorder affecting 3 to 7% of school-aged children.