Prospective, Naturalistic, Pilot Study of Open-Label Atomoxetine Treatment in Preschool Children with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective: The aim of this study was to report preliminary data regarding effectiveness and tolerability of atomoxetine in 3-to 5-year-old preschool children with attention-deficit=hyperactivity disorder (ADHD). Methods: Nine boys and 3 girls (mean age ¼ 5.0 AE 0.72 years) diagnosed with ADHD were treated with atomoxetine in an open-label pilot study. Atomoxetine was gradually titrated to a maximum dose of 1.8 mg=kg per day.Results: There was a significant effect of time from baseline to end point on the parent-rated hyperactivity= impulsivity Swanson Nolan and Pelham (SNAP-IV-HI) subscale ratings (F[9, 11] ¼ 6.32, p < 0.0001). The mean difference between the baseline and end-point parent SNAP-IV-HI scores was 10.2 AE 7.3 ( p ¼ 0.0005). The rate of positive response (defined as at least a 30% reduction in the end-point parent SNAP-IV-HI scores and a Clinical Global Impressions-Improvement [CGI-I] rating of Much Improved or Very Much Improved) was 75%. The Children's Global Assessment Scale scores improved significantly over time [F(9, 11) ¼ 6.24 p < 0.001]. The mean end-point daily dose of atomoxetine was 1.59 AE 0.3 mg=kg. A high proportion (66.7%) of the preschoolers experienced side effects with atomoxetine. Side effects of defiance, tantrums, aggression, and irritability were most disconcerting to parents, and gastrointestinal complaints were the most commonly reported adverse effects. One child was terminated from the study due to ''chest ache.'' There were no changes in weight, height, or cardiovascular measures.Conclusion: This open-label pilot study provides preliminary evidence of effectiveness and tolerability of atomoxetine for treating ADHD in preschool children, although double-blind, randomized, placebo-controlled studies are needed to confirm this.

Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder

“…In all three studies, atomoxetine was titrated to a maximum of 1.8 mg/kg per day. The external data involved in these analyses included data from children 5 years of age with ADHD from the 8 week, double-blind, placebo-controlled study (mean final dose was 1.4 mg/kg) that enrolled children 5 and 6 years of age (Kratochvil et al 2011); data from children 5 years of age with ADHD from an open-label study (mean final dose was 1.25 mg/kg) that enrolled children 5 and 6 years of age (Kratochvil et al 2007); and data from children 4 and 5 years of age with ADHD from an open-label study (mean final dose was 1.59 -0.3 mg/kg) that enrolled children 3-5 years of age (Ghuman et al 2009). …”

“…In the Kratochvil et al 2011 study, patients had comorbidities that included oppositional defiant disorder, enuresis, separation anxiety, phobia, tics, and other comorbidities (Kratochvil et al 2011). In the Ghuman et al study, the comorbidities included oppositional defiant disorder, communication disorders, elimination disorders, anxiety disorders, conduct disorder, adjustment disorder, reactive attachment disorder, and pica (Ghuman et al 2009). …”

“…A number of medications were also grounds for exclusion, including primarily medications with psychoactive effects that could confound efficacy analyses (e.g., antidepressants or antipsychotics) and medications that could have unwanted pharmacodynamic or other interactions with atomoxetine, such as additive sympathomimetic effects. In the external studies, some of the exclusion criteria included concurrent treatment with medications that have central nervous system effects; current treatment with atomoxetine or failure to respond to a previous trial of atomoxetine; and current diagnosis of adjustment disorder, autism, psychosis, bipolar disorder, suicidality, or hepatic disease (Kratochvil et al 2007;Ghuman et al 2009;Kratochvil et al 2011).…”

“…In the open-label study conducted by Ghuman et al (2009), AEs (or ''side effects'') were reported at each visit via the parentcompleted Side Effects Rating Scale (SERS), which addressed potential atomoxetine-specific AEs (Greenhill et al 2003). Events from the Ghuman study were not mapped to MedDRA preferred terms because of complications and uncertainties related to the use of the SERS; specifically, many side effects on the questionnaire were groups of events that precluded mapping to a single MedDRA preferred term.…”

“…Events from the Ghuman study were not mapped to MedDRA preferred terms because of complications and uncertainties related to the use of the SERS; specifically, many side effects on the questionnaire were groups of events that precluded mapping to a single MedDRA preferred term. Additionally, it was not considered appropriate to integrate the AE data from the Ghuman et al study into the External Overall Dataset because of the differences in AE reporting methods (solicited) (Ghuman et al 2009) compared with the two external studies (spontaneous) conducted by Kratochvil et al (2007Kratochvil et al ( , 2011. The Lilly studies collected TEAEs via spontaneous reporting.…”