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[Atomoxetine: a new treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents]

D Purper-Ouakil, P Fourneret, M Wohl, J-P Rénéric
L'Encéphale 2005, 31 (3): 337-48
16142049
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.

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