Atomoxetine was generally well tolerated and resulted in reduced core ADHD symptoms in a study of 101 5- and 6-year-old children in a randomized, placebo-controlled trial, but those reductions did not necessarily translate to overall clinical and functional improvement.
After 8 weeks, mean total scores on the ADHD-IV Rating Scale were reduced significantly more in the treatment vs. placebo groups, based on both parent reports (–13.2 vs. –5.8 points) and teacher reports (–12.5 vs. –5.0 points). However, the difference between the treatment and placebo groups in regard to the number of patients who were much or very much improved, based on Clinical Global Impressions–Improvement (CGI-I) scale scores after adjustment for age and study center, did not differ significantly, with 40% vs. 22% of treatment and placebo patients, respectively, being much or very much improved, Dr. Christopher J. Kratochvil of the University of Nebraska, Omaha, and his colleagues reported online in Pediatrics.
Furthermore, 62% of 44 participants in the treatment group and 77% of 49 in the placebo group remained moderately, markedly, or severely ill at the completion of the study, based on the Clinical Global Impressions–Severity (CGI-S) scale, the investigators said (Pediatrics 2011 March 21 [doi:10.1542/peds.2010-0825]).
Study participants were children aged 5 and 6 years (mean, 6.1 years) who met the criteria for any subtype of ADHD based on the DISC (Diagnostic Interview Schedule for Children), a clinical interview, and review by a clinical consensus conference of the three academic research sites participating in the trial. Most of the children (68%) were male, and most (86%) were white.
The study drug was initiated at 0.5 mg/kg per day, with flexible titration to 0.8, 1.2, 1.4, and a maximum of 1.8 mg/kg per day (average, 1.4 mg/kg per day) at four weekly and one biweekly visit, based on response, tolerability and a pharmacotherapist’s clinical judgment. At each visit, a pharmacotherapist provided psychoeducation about ADHD and behavioral-management strategies to the parents.
Treatment was generally well tolerated. Those in the treatment group were significantly more likely to experience decreased appetite, gastrointestinal upset, and sedation. However, those effects were mild or moderate in severity.
The findings provide useful information because – despite limited data – practitioners commonly treat ADHD in preschoolers with stimulant and nonstimulant agents, including atomoxetine, the investigators said.
Based on findings from a prior study showing that effect sizes with another treatment (immediate-release methylphenidate) varied in preschool- and school-age children, investigators in the current study thought that it was important to determine whether such variations in efficacy and tolerability also exist for atomoxetine, they said. Several studies have provided evidence of safety and efficacy for children aged 6 years and older, but Dr. Kratochvil and his colleagues wrote that their study was first to provide randomized, controlled data on use of the drug in children as young as age 5 years.
The findings of the current study suggest that efficacy and tolerability of atomoxetine for 5- and 6-year-old children seem similar to that seen in older children. However, even with doses averaging at the maximum approved dose of 1.4 mg/kg per day combined with a psychoeducational intervention, only 40% of treated subjects were rated as "much" or "very much" improved at study end, they said.
Also, although the change in ADHD Rating Scale scores was statistically significantly improved, the mean final total score was still more than 1 standard deviation above norms.
"Thus, although effective, clinically significant symptoms remained for the majority of children treated with atomoxetine," they said, concluding that future research should include longer treatment and follow-up to help elucidate whether treatment benefits increase or are sustained over time, and to assess for long-term adverse effects.
The study is well designed, and provides useful information about the safety and efficacy of atomoxetine in young children, but the interpretation of the findings is ultimately limited by the size of the sample and the relatively brief duration of treatment, agreed Dr. David Fassler of the department of psychiatry at the University of Vermont, Burlington.
"In reality, most young children with ADHD are treated over an extended period of time," he said in an interview. "Accordingly, I would concur with the authors’ recommendation that future research should include longer treatment studies, as well as trials [in which atomoxetine is compared with] the stimulant medications typically used in the treatment of ADHD."
Dr. Kratochvil disclosed that he received grant support from Eli Lilly, McNeil, Shire, Abbott, Somerset, and Cephalon, and was a consultant for Eli Lilly, AstraZeneca, Abbott, Theravance, and Pfizer. He is the editor of the Brown University Child and Adolescent Psychopharmacology Update, receives royalties from a book with Oxford, is a member of the REACH Institute Primary Pediatric Psychopharmacology Steering Committee and the board of directors of the American Professional Society for ADHD and Related Disorders, and receives study drugs for a National Institute of Mental Health–funded study from Eli Lilly and Abbott. The study was supported by a National Institute of Mental Health grant, and contracts between Eli Lilly and Duke University Medical Center and Columbia University/New York State Psychiatric Institute. The study drug was provided by Eli Lilly. Dr. Fassler said that he had no conflicts of interest to disclose.