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Clinical Responses to Atomoxetine in Attention-Deficit/Hyperactivity Disorder: The Integrated Data Exploratory Analysis (IDEA) Study

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Abstract

Objectives

Clinical experience suggests that some (but not all) patients with attention-deficit/hyperactivity disorder (ADHD) are highly responsive to the nonstimulant atomoxetine. We conducted a retrospective analysis of randomized controlled trials (RCTs) to identify potential baseline (moderator) and on-treatment (mediator) predictors of responses.

Method

Data from 6 U.S. RCTs among patients aged 6 to 18 years were pooled (N = 1,069; subjects treated with atomoxetine, n = 618). Subjects were categorized as much improved (≥40% decrease in ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored total score), minimally improved (25%-<40% decline), or nonresponders (<25% decrease). Logistic regression, analyses of variance, and repeated-measures analyses were used to explore associations between baseline and on-treatment variables, achieving a much improved response at trial endpoint (6–9 weeks).

Results

Forty-seven percent of patients showed a much improved clinical response, and 40% did not respond. Only 13% of the patients had a minimal response. No baseline characteristics predicted achieving a much improved clinical response; the only predictor of achieving this response was being at least minimally improved by treatment week 4 (sensitivity = 81%, specificity = 72%, positive predictive value = 75%, and negative predictive value = 79%).

Conclusions

Clinical response to atomoxetine was bimodal, with most subjects being either responders who were much improved or nonresponders. There were no demographic or clinical predictors of response. However, subjects who ultimately achieved a much improved response were likely to be at least minimal responders by week 4. The recommendation to consider either augmenting or switching treatment in patients who do not achieve at least this level of response to atomoxetine by 4 weeks offers a method for limiting the extended duration of titration to subjects who are most likely to benefit further, while minimizing the duration of exposure in those less likely to achieve an excellent response.

Section snippets

Analysis Framework

Integrated data exploratory analysis was a retrospective analysis of pooled data from the acute phases (6–9 weeks) of the six industry-sponsored U.S. randomized, double-blind, placebo-controlled trials of pediatric outpatients with ADHD (Table 1).2, 6, 7, 8, 23 These studies examined the effect of atomoxetine on symptom reduction as measured by the ADHD Rating Scale (ADHD-RS)24 total score as the primary outcome measure. The study designs, inclusion and exclusion criteria, and assessments in

Distribution of Responders and Nonresponders

A total of 60% of all patients had evidence of at least minimal clinical response to atomoxetine as indicated by a 25% or greater decline from baseline in the ADHD-RS total score. Of these, 78% (47% of all of the patients) had a 40% or greater decrease in the ADHD-RS total score. In contrast, 40% of the patients were nonresponders (i.e., <25% decrease in ADHD-RS total score). Only a relatively small proportion (13%) had a minimal response (i.e., 25%–<40% decrease in the ADHD-RS total score);

Discussion

The IDEA study found that the probability of responding to atomoxetine is relatively bimodal, with 47% of patients showing a much improved response, 13% showing minimal response, and 40% being nonresponders. This finding substantiates the clinical observation that there is considerable variability in patient response. However, this study failed to identify any demographic or clinical factors that were associated with these divergent profiles of response.

One factor that was found to be

References (36)

  • J Biederman et al.

    Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data

    Psychopharmacology (Berl)

    (2007)
  • DK Kelsey et al.

    Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial

    Pediatrics

    (2004)
  • CJ Kratochvil et al.

    A pilot study of atomoxetine in young children with attention-deficit/hyperactivity disorder

    J Child Adolesc Psychopharmacol

    (2007)
  • D Michelson et al.

    Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study

    Pediatrics

    (2001)
  • D Michelson et al.

    Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study

    Am J Psychiatry

    (2002)
  • T Spencer et al.

    Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder

    J Clin Psychiatry

    (2002)
  • MA Stein et al.

    A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder

    Pediatrics

    (2003)
  • SP Hinshaw

    Moderators and mediators of treatment outcome for youth with ADHD: understanding for whom and how interventions work

    J Pediatr Psychol

    (2007)
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    Funding for this research was provided by Eli Lilly and Company.

    The authors thank Stephen W. Gutkin of Rete Biomedical Communications for assistance in manuscript preparation.

    Clinical trials registration information—Evaluation of Continuous Symptom Treatment of ADHD: A Placebo-Controlled Double-Blind Assessment of Morning-Dosed or Evening-Dosed Strattera. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00486122. Results of the other studies analyzed in the Integrated Data Exploratory Analysis study are posted at www.clinicalstudyresults.org, ID numbers 5670, 7972, 2746, 1585, 1586, and 3468, and www.lillytrials.com.

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