No evidence for predictors of response to atomoxetine treatment of attention-deficit/hyperactivity disorder symptoms in children and adolescents with autism spectrum disorder

[Author Affiliation]Myriam Harfterkamp. 1 Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.Dennis van der Meer. 1 Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.Gigi van der Loo-Neus. 2 Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands.Jan K. Buitelaar. 2 Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands. 3 Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.Ruud B. Minderaa. 1 Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.Pieter J. Hoekstra. 1 Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.Funding: This study was funded by Eli Lilly and company.Address correspondence to: Myriam Harfterkamp, MD, Child and Adolescent Psychiatry Center, Department of Psychiatry, University Medical Center Groningen, Hanzeplein 1, Groningen 9717 ER, The Netherlands, E-mail: m.a.harfterkamp@umcg.nlTo The Editor:Attention-deficit/hyperactivity disorder (ADHD) symptoms are frequently observed in children and adolescents with an autism spectrum disorder (ASD); ∼30-80% of patients with ASD meet criteria for ADHD (Rommelse et al. 2010). The presence of ADHD in children and adolescents with ASD is a serious clinical problem; patients with such a dual diagnosis have more severe overall impairment, which frequently complicates these patients' therapeutic management (Gadow et al. 2006; Holtmann et al. 2007). Although a combination of these diagnoses was precluded by the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), the fifth edition (DSM-V) has now made it possible to classify both disorders at the same time (American Psychiatric Association 2000, 2013).Several small-scale, mostly open-label studies (Jou et al. 2005; Arnold et al. 2006; Posey et al. 2006; Troost et all. 2006; Charnsil 2011; Zeiner et al. 2011; Fernandez-Jaen et al. 2013) have suggested that atomoxetine, a noradrenergic reuptake inhibitor, might be a promising treatment for ADHD symptoms in children and adolescents with ASD. We have confirmed these preliminary findings in a double-blind placebo-controlled trial followed by an open-label extension period in children and adolescents with ASD and concomitant ADHD symptoms, and have demonstrated superior efficacy of atomoxetine compared with placebo, as rated by the investigator-administered ADHD-Rating Scale (ADHD-RS), with good tolerability (Harfterkamp et al. 2012). We also showed that continued treatment with atomoxetine up to a total treatment length of 28 weeks led to further improvement of ADHD symptoms in children with ASD, and to a decrease of adverse events (Harfterkamp et al. 2013).However, these group findings do not necessarily predict treatment response for an individual patient. From a clinical perspective it is worthwhile to know which patients with ASD and ADHD are most likely to have a good response to atomoxetine. A meta-analysis and a meta-regression analysis have evaluated the efficacy and safety of atomoxetine in children and adolescents with ADHD (without ASD) across nine randomized placebo-controlled trials (in total 1150 patients on atomoxetine) (Cheng et al. 2007). These analyses suggested that atomoxetine is more effective in patients with higher baseline ADHD symptom count, whereas male gender, presence of comorbid oppositional defiant disorder (ODD), and ADHD hyperactive/impulsive type were associated with somewhat smaller symptom reductions.However, another large-scale (in total 618 patients treated with atomoxetine) pooled analysis of six industry-sponsored United States randomized, double-blind, placebo-controlled atomoxetine trials ruled out baseline ADHD symptom count, male sex, ADHD type, race, previous stimulant use, presence of comorbid ODD, age, and CYP2D6 genotype status as predictors of achieving a much improved clinical response (Newcorn et al. …