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Low-Dose Atomoxetine May Be Effective as ADHD Maintenance Treatment in Children

  • Authors: News Author: Laurie Barclay, MD
    CME Author:
    Désirée Lie, MD, MSEd
  • CME Released: 12/19/2006; Reviewed and Renewed: 12/19/2007
  • Valid for credit through: 12/19/2008
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Target Audience and Goal Statement

This article is intended for primary care clinicians, psychiatrists, and other specialists who care for children with ADHD.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  • Compare the effect on ADHD relapse rate of same- and low-dose atomoxetine after acute-phase treatment.
  • Compare the adverse effects of same and low-dose atomoxetine during maintenance treatment of ADHD.


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  • Laurie Barclay, MD

    Laurie Barclay, MD is a freelance reviewer and writer for Medscape.


    Disclosure: Laurie Barclay, MD has disclosed no relevant financial relationships.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor of Family Medicine; Director, Division of Faculty Development, University of California, Irvine School of Medicine, Irvine, California


    Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

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Low-Dose Atomoxetine May Be Effective as ADHD Maintenance Treatment in Children

Authors: News Author: Laurie Barclay, MD CME Author: Désirée Lie, MD, MSEdFaculty and Disclosures

CME Released: 12/19/2006; Reviewed and Renewed: 12/19/2007

Valid for credit through: 12/19/2008


December 19, 2006 — In children aged 6 to 16 years, low-dose atomoxetine therapy was effective as maintenance treatment of attention deficit hyperactivity disorder (ADHD), according to the results of a study reported in the December issue of Pediatrics.

"Data from acute studies of atomoxetine in patients with attention-deficit/hyperactivity disorder suggest that a dose of 1.2 mg/kg per day is required to attain a maximal symptom response," write Jeffrey H. Newcorn, MD, from Mount Sinai Medical Center in New York City, and colleagues. "However, lower doses could be effective during maintenance treatment, which would reduce drug exposure and potential problems related to tolerability during chronic treatment."

In this double-blind study, patients aged 6 to 16 years who had a robust response to an initial acute trial of atomoxetine were randomized to continue treatment for up to 8 months with either the dose to which they had responded acutely (1.2–1.8 mg/kg per day; n = 116; same-dose group) or a lower dose (0.5 mg/kg per day; n = 113; low-dose group). The main end point was relapse, defined as an ADHD Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score returned to 90% of the original baseline value (before acute treatment) for 2 consecutive visits. A secondary end point was mean change in ADHD Rating Scale total score.

At randomization, symptom severity was low and similar in both groups; at study end, relapse rates and mean change in ADHD Rating Scale total score were also similar in both groups. However, the low-dose group had more reports of affective lability, and the same-dose group had more reports of increases in heart rate (than when atomoxetine was started). Increases in weight during the study were greater in the low-dose group than in the same-dose group.

"For patients who experience a robust response to atomoxetine, it may be possible to retain the response during maintenance treatment with a reduced dose of atomoxetine," the authors write. "Tolerability did not seem to be markedly different between patients in the 2 groups."

Study limitations include inadequate power to detect a difference between groups as small as the one observed and absence of a placebo group.

"These data suggest that during long-term treatment, it may be possible to treat responders to atomoxetine with a lower dose than is required to achieve acute response," the authors conclude. "This may be an important strategy for those patients who respond very well to atomoxetine but continue to experience troublesome adverse effects that do not abate over the course of treatment."

Eli Lilly and Company supported this study and employs 4 of its authors. Two other authors have disclosed a financial relationship with Eli Lilly, McNeil, Shire, Novartis, Cephalon, Organon, AstraZeneca, and/or Pfizer.

Clinical Context

Acute studies of atomoxetine for patients with ADHD have suggested a maximal response at a dose of 1.2 mg/kg per day, and placebo-controlled studies suggest that treatment should be continued to prevent symptom relapse and return after the acute phase. However, dose response during maintenance has not been studied and there are concerns about symptom control and adverse effects over the long term, according to the authors of the current study.

This is a continuation study comparing rates of relapse and adverse effects in children, aged 6 to 16 years, at 20 US sites who responded to acute-phase treatment with atomoxetine and who then continued, for up to 8 months, to take either same- or low-dose atomoxetine.

Study Highlights

  • Study participants were 516 acute-phase children, aged 6 to 16 years, who met the DSM IV criteria for any subtype of ADHD, determined by history and semistructured interview.
  • Symptom severity had to be at least 1.5 standard deviations above age and sex norms.
  • Excluded were patients with bipolar disorder, psychosis, seizures, pervasive developmental disorder, other comorbid psychiatric conditions, or who were on contraindicated medications.
  • Among this acute-phase group, responders to atomoxetine were defined as those who showed at least a 40% reduction in ADHD Rating Scale total score after 6 weeks of treatment with a maximum of 1.8 mg/kg per day of atomoxetine.
  • Among the responders, 116 were randomized to continue atomoxetine at a mean of 1.43 mg/kg per day (same-dose group) and 113 to atomoxetine 0.5 mg/kg per day (low-dose group) for up to 8 months.
  • The same-dose group continued treatment at the same dose they received during acute-phase treatment for the duration of the study.
  • Randomization was double-blinded.
  • The ADHD Rating Scale is an 18-item validated scale to determine ADHD severity that was used as the primary outcome for the continuation study.
  • Primary outcome was the change in mean ADHD Rating Scale score between study start and end.
  • Secondary outcomes were the Clinical Global Impressions-ADHD Severity and the Child Health Questionnaire.
  • At baseline and study end, weight, physical signs, genotyping, drug screen, and serum biochemistry were determined.
  • Mean age was 10.5 years, 70% were male, 62% had combined ADHD subtypes of hyperactive/impulsive and inattentive, and 60% had previous stimulant exposure.
  • At study start, both groups had similar low symptom severity after acute treatment (ADHD Rating Scale score was 15.1 for the same-dose group and 14.0 for low-dose group).
  • There were no differences in relapse rates for the 2 groups at end point (2.6% for the same-dose group and 2.7% for the low-dose group).
  • The proportion of patients who did not relapse but who no longer met response criteria was not significantly different in the 2 groups (17.4% for the same-dose group and 22.9% for the low-dose group).
  • No differences were observed in the inattentive and hyperactivity/impulsivity subscales of the Clinical Global Impressions-ADHD Severity scores or in the mean change in Clinical Global Impressions psychosocial summary score.
  • The low-dose group had a significantly lower score (ie, worsening) on the role emotion/behavior subscale than the same-dose group (-1.13 for the low-dose vs +5.75 for the same-dose group; P = .017).
  • Affective lability was higher in the low-dose group (4.5%) than in the same-dose group (0%) ( P = .027).
  • Increases in heart rate were higher in the same-dose group than in the low-dose group.
  • Increases in weight were greater for the low-dose group than in the same-dose group.

Pearls for Practice

  • In ADHD patients who respond to acute-phase treatment with atomoxetine, continuation for 8 months at a low dose is not associated with a higher relapse rate.
  • In atomoxetine responders, continuation for 8 months of a low dose of atomoxetine is associated with higher affective lability, worsening role emotional/behavior scores, more weight gain, and fewer reports of increases in heart rate than continuation of the same dose.

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