A Randomized Double-Blind Study of Atomoxetine Versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children With Autism Spectrum Disorder

doi:10.1016/j.jaac.2012.04.011

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 51, Issue 7, July 2012, Pages 733-741

This work was presented in part at the International Conference sponsored by the European Society for Child and Adolescent Psychiatry (ESCAP) in Budapest, Hungary, August 25, 2009.

https://doi.org/10.1016/j.jaac.2012.04.011 Get rights and content

Objective

The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established.

Method

In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or placebo for 8 weeks. The primary endpoint was the ADHD Rating Scale (ADHD-RS) score; secondary endpoints were the Clinical Global Impression of ADHD-Improvement (CGI-I) and the Conners Teacher Rating Scale-Revised: Short Form (CTRS-R:S) score.

Results

Baseline mean ADHD-RS scores for atomoxetine versus placebo were 40.7 and 38.6; after 8 weeks, mixed-effect model repeated-measure means were 31.6 (95% confidence interval 29.2–33.9) and 38.3 (36.0–40.6), respectively, with a difference in least square means of −6.7 (–10.0 to –3.4; p < .001). The CTRS-R:S Hyperactivity subscore also improved significantly for atomoxetine compared with placebo, but not the other CTRS-R:S subscores. However, there were not significantly more patients on atomoxetine (20.9%) who improved much, or very much according to the CGI-I, than on placebo (8.7%; p = 0.14). Adverse events (mostly nausea, decrease in appetite, fatigue, and early morning awakening) were reported in 81.3% of atomoxetine patients and 65.3% of placebo patients (p > .1). There were no serious adverse events.

Conclusions

Atomoxetine moderately improved ADHD symptoms in patients with ASD and was generally well tolerated. Adverse events in this study were similar to those in other studies with ADHD patients without ASD.

Clinical trial registration information—A Randomized Double-Blind Study of Atomoxetine Versus Placebo for ADHD Symptoms in Children with ASD; www.clinicaltrials.gov; NCT00380692.

Section snippets

Study Participants

Candidates for inclusion in the study were children and adolescents between 6 and 17 years with a clinical diagnosis of ASD and concomitant ADHD symptoms, who had been referred to one of nine participating Dutch child and adolescent psychiatry centers; six university centers (Amsterdam, Groningen, Leiden, Maastricht, Nijmegen, and Utrecht) and three nonuniversity centers (The Hague, Hoorn, and Oosterhout). Study candidates could also be recruited from other mental health institutions.

For

Flow of Participants

The CONSORT diagram (Figure 1) displays the flow of participants through the study. Three of the 97 randomized patients had erroneously been included in the study because of deviations from the inclusion and exclusion criteria. One child did not have an IQ of at least 60. This child had a nonverbal IQ above 60, but was not testable with regard to his verbal IQ. Two other children with a clinical diagnosis of ASD did not meet algorithm cut-off scores on the ADI-R. There were no further

Discussion

This is the first adequately powered placebo-controlled study examining the efficacy and safety of atomoxetine for symptoms of ADHD in children with ASD. Our findings indicate that atomoxetine is superior to placebo after a treatment period of 8 weeks and is generally well tolerated. There were no serious adverse events. Only one patient in the atomoxetine group discontinued because of a (nonserious) adverse event. Reported adverse events in this study population are already listed. With

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: This study was funded by Eli Lilly and Co.

: Disclosure: Dr. Harfterkamp has received travel funding from Eli Lilly and Co., and Eurocept. Dr. van de Loo-Neus has received honoraria for presenting or serving as a consultant for Eli Lilly and Co., UCB Pharma, and Eurocept. Drs. Escobar and Schacht are stakeholders of Eli Lilly and Co. Dr. Buitelaar has served as a consultant for, on the speakers' bureau for, and/or on the advisory boards for Janssen Cilag, Eli Lilly and Co., Bristol-Myer Squibb, Organon/Shering Plough, UCB, Shire, Medice, and Servier. Dr. Hoekstra has received funding through the Netherlands Organisation for Health Research and Development (ZonMw), the National Institute of Mental Health (NIMH), and the European Union Seventh Framework Programme, as well as honoraria for presentations from Boerhaave, Shire, and Eli Lilly and Co. Drs. Minderaa, van der Gaag, and Pamulapati report no biomedical financial interests or potential conflicts of interest.

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New researchA Randomized Double-Blind Study of Atomoxetine Versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children With Autism Spectrum Disorder

Objective

Method

Results

Conclusions

Section snippets

Study Participants

Flow of Participants

Discussion

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Biol Psychiatry

Attention deficit hyperactivity disorder symptoms in pervasive developmental disorders: association with autistic behavior domains and coexisting psychopathology

Psychopathology

ADHD symptom subtypes in children with pervasive developmental disorder

J Autism Dev Disord

PDD symptoms in ADHD, an independent familial trait?

J Abnorm Child Psychol

Issues in the management of patients with complex attention-deficit hyperactivity disorder symptoms

CNS Drugs

Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity

Arch Gen Psychiatry

Acute and long-term safety and tolerability of risperidone in children with autism

J Child Adolesc Psychopharmacol

Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders

Pediatrics

Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder

Pediatrics

Neuropsychological effects of risperidone in children with pervasive developmental disorders: a blinded discontinuation study

J Child Adolesc Psychopharmacol

Cognitive effects of risperidone in children with autism and irritable behavior

J Child Adolesc Psychopharmacol

Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective analysis of 80 cases

J Child Adolesc Psychopharmacol

New research
A Randomized Double-Blind Study of Atomoxetine Versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children With Autism Spectrum Disorder