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Atomoxetine for Hyperactivity in Autism Spectrum Disorders: Placebo-Controlled Crossover Pilot Trial

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ABSTRACT

Objective

To explore placebo-controlled efficacy and safety of atomoxetine (ATX) for attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorders (ASD).

Method

Children ages 5 to 15 with ASD and prominent ADHD symptoms were randomly assigned to order in a crossover of clinically titrated ATX and placebo, 6 weeks each, separated by 1-week washout. Slopes for each condition were compared by paired t test.

Results

In 2004-2005, 12 boys and 4 girls (7 with autistic disorder, 1 Asperger's, 8 pervasive developmental disorder not otherwise specified) all completed at least 3 weeks of each condition. On the primary outcome, the Hyperactivity subscale of the Aberrant Behavior Checklist, ATX was superior to placebo (p =.043, effect size d = 0.90). It was also superior on a 0 to 3 rating of nine DSM-IV ADHD hyperactive/impulsive symptoms (p =.005, d = 1.27), but missed significance on nine inattentive symptoms (p =.053, d= 0.89). Nine subjects responded to ATX, four to placebo (25% improvement on the Hyperactivity subscale plus Clinical Global Impressions-Improvement of 1-2. One was rehospitalized for recurrent violence on ATX. Adverse events were otherwise tolerable, with no tendency to stereotypy.

Conclusions

ATX appears safe and effective for treating hyperactivity in some children with autism spectrum disorders. The effect appears as large as in a multisite methylphenidate trial in the same population, with fewer intolerable side effects. Further study in autism spectrum disorders is indicated.

Section snippets

Subjects

Participants were children/adolescents ages 5 to 15 years with mental age ≥18 months who had an ASD and symptoms of ADHD. They met the first four of five DSM-IV criteria for ADHD: symptom count, impairment, chronicity, and pervasiveness across settings (the fifth criterion would technically rule out ADHD by the presence of PDD) and had to have a parent-rated symptom mean ≥1.5 on either the nine inattentive or the nine hyperactive-impulsive ADHD symptoms, rated 0 to 3. Exclusion criteria

RESULTS

Sixteen subjects (Table 1) were randomized. Three terminated early, one each after the third, fourth, and fifth weeks of the second condition (one on ATX, twoon placebo). The intent-to-treat analysis included all 16. The mean highest dose was 44.2 ± 21.9 mg/day (range 20-100mg) for ATX and 48.0 mg/day (range 20-100) for placebo; dose did not correlate significantly with either initial severity (p =.6) or degree of improvement (p =.7).

Table 2 shows the outcome means (SD) at baseline and week 6

DISCUSSION

The placebo-controlled effect sizes (d = 0.89-1.27) reported here for ADHD symptoms in the presence of ASD are as good as those reported (Michelson et al., 2002, Michelson et al., 2004, Sutton et al., 2004) for typically developing children (d= 0.6-1.0), and at least as good as those for MPH (d = 0.5-0.89 rated by parents, 0.35-0.48 rated by teachers) found in the multisite RUPP Autism Network (2005) study in the same population. Nevertheless, the response rate (57% and 43%, after subtracting

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    Disclosure: The authors receive research funding from Lilly, Shire, Janssen, and PediaMed and are on speakers' bureaus of and/or consult for Shire, Novartis, Janssen, Sigma Tau, and Forest Laboratories.

    This investigator-initiated study was supported by Eli Lilly and by the General Clinical Research Center at the Ohio State University, GrantM01-RR00034 from the National Center of Research Resources, NIH.

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