Atomoxetine in the Treatment of Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: A Randomized, Placebo-Controlled, Dose-Response Study

Abstract

ABSTRACT. Objective. Atomoxetine is an investigational, nonstimulant pharmacotherapy being studied as potential treatment for attention-deficit/hyperactivity disorder (ADHD). It is thought to act via blockade of the presynaptic norepinephrine transporter in the brain. We assessed the efficacy of 3 doses of atomoxetine compared with placebo in children and adolescents with ADHD.Methods. A total of 297 children and adolescents who were 8 to 18 years of age and had ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, were randomized to placebo or atomoxetine dosed on a weight-adjusted basis at 0.5 mg/kg/day, 1.2 mg/kg/day, or 1.8 mg/kg/day for an 8-week period. ADHD symptoms, affective symptoms, and social and family functioning were assessed using parent and investigator rating scales.Results. Approximately 71% of children enrolled were male, approximately 67% met criteria for mixed subtype (both inattentive and hyperactive/impulsive symptoms), and the only common psychiatric comorbidity was oppositional defiant disorder (approximately 38% of the sample). At baseline, symptom severity was rated as moderate to severe for most children. At endpoint, atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day were consistently associated with superior outcomes in ADHD symptoms compared with placebo and were not different from each other. The dose of 0.5 mg/kg/day was associated with intermediate efficacy between placebo and the 2 higher doses, suggesting a graded dose-response. Social and family functioning also were improved in the atomoxetine groups compared with placebo with statistically significant improvements in measures of children's ability to meet psychosocial role expectations and parental impact. Discontinuations as a result of adverse events were <5% for all groups.Conclusion. Among children and adolescents aged 8 to 18, atomoxetine was superior to placebo in reducing ADHD symptoms and in improving social and family functioning symptoms. Atomoxetine was associated with a graded dose-response, and 1.2 mg/kg/day seems to be as effective as 1.8 mg/kg/day and is likely to be the appropriate initial target dose for most patients. Treatment with atomoxetine was safe and well tolerated.

Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder

“…Atomoxetine is a development candidate for pharmacotherapy of ADHD and has been shown in early studies to be efficacious and well-tolerated for use in this disorder Michelson et al 2001). We propose that the atomoxetine-induced increase of DA EX and NE EX in the PFC, and presumably other cortical areas, enhances catecholaminergic neurotransmission in the cortex and this may be a mechanism of action of atomoxetine in the pharmacotherapy Figure 5.…”

“…In children and adolescents, atomoxetine had superior outcomes in reducing ADHD symptoms compared with placebo and had a graded dose response (Michelson et al 2001). Atomoxetine significantly reduced core symptoms of ADHD in an openlabel study in children .…”

“…Atomoxetine significantly reduced core symptoms of ADHD in an openlabel study in children . Overall, it was well tolerated in the child and adolescent age group (Michelson et al 2001;Spencer et al 2001). Atomoxetine has also been shown in a 6-week open label study to produce clinically significant improvement in the symptoms in patients with major depression (Chouinard et al 1984).…”

Randomized, Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents With Substance Use Disorder

“…The power calculations for designing the study were based on research in children and adolescents that suggested atomoxetine has an effect size of 0.7 for ADHD 27 and indicated that 35 subjects per group would provide 80% power to detect that effect size at a significance level of 0.05. At trial completion, the variability estimates from the final model indicated that the obtained sample size (35 per group) provided 80% power to detect a difference between groups in DSM-IV ADHD score of at least 9.9 as significant.…”

Evaluation of the Reinforcing Effects of Monoamine Reuptake Inhibitors Under a Concurrent Schedule of Food and I.V. Drug Delivery in Rhesus Monkeys

“…Atomoxetine is reported to be highly effective, yet produce few side effects and be devoid of abuse liability (Heil, 2002;Michelson et al, 2001Michelson et al, , 2002Spencer et al, 1998). Atomoxetine is a selective norepinephrine transporter inhibitor with a relatively low affinity for serotonin and dopamine uptake processes and with minimal affinity for other biological binding sites (Bymaster et al, 2002).…”