Relationship between atomoxetine plasma concentration, treatment response and tolerability in attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder

Philip Hazell 0 1 2 3 4 5 6 7 Katja Becker 0 1 2 3 4 5 6 7 Eija A. Nikkanen 0 1 2 3 4 5 6 7 Paula T. Trzepacz 0 1 2 3 4 5 6 7 Yoko Tanaka 0 1 2 3 4 5 6 7 Linda Tabas 0 1 2 3 4 5 6 7 Deborah N. D'Souza 0 1 2 3 4 5 6 7 Jennifer Witcher 0 1 2 3 4 5 6 7 Amanda Long 0 1 2 3 4 5 6 7 George Ponsler 0 1 2 3 4 5 6 7 Ralf W. Dittmann 0 1 2 3 4 5 6 7 0 K. Becker Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty, Philipps-University of Marburg , Marburg, Germany 1 K. Becker Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health , Mannheim, Germany 2 P. Hazell Discipline of Psychological Medicine, Concord Clinical School, University of Sydney , Sydney, Australia 3 R. W. Dittmann Department of Child and Adolescent Psychosomatics, University of Hamburg , Hamburg, Germany 4 R. W. Dittmann Eli Lilly Endowed Chair for Pediatric Psychopharmacology, Central Institute of Mental Health, University of Heidelberg , Mannheim, Germany 5 P. T. Trzepacz (&) Y. Tanaka L. Tabas D. N. D'Souza J. Witcher A. Long G. Ponsler Lilly Research Laboratories, Lilly Corporate Center , Indianapolis, IN 46285, USA 6 E. A. Nikkanen Folkhalsans Habiliteringsavdelning, Folkhalsan Raseborg Ltd., Meltola, Finland 7 E. A. Nikkanen Department of Pediatrics, Helsinki University Central Hospital, Peijas Hospital , Vantaa, Finland The purpose of this study was to examine whether atomoxetine plasma concentration predicts attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) response. This post-hoc analysis assessed the relationship between atomoxetine plasma concentration and ADHD and ODD symptoms in patients (with ADHD and comorbid ODD) aged 6-12 years. Patients were randomly assigned to atomoxetine 1.2 mg/kg/day (n = 156) or placebo (n = 70) for 8 weeks (Study Period II). At the end of 8 weeks, ODD non-remitters (score [9 on the SNAP-IV ODD subscale and CGI-I [ 2) with atomoxetine plasma concentration \800 ng/ml at 2 weeks were re-randomized to either atomoxetine 1.2 mg/kg/day or 2.4 mg/kg/day for an additional 4 weeks (Study Period III). ODD remitters and non-remitters with plasma atomoxetine C800 ng/ml remained on 1.2 mg/kg/day atomoxetine for 4 weeks. - Attention-Deficit/Hyperactivity Disorder (ADHD) is among the most common neuropsychiatric disorders in childhood and adolescence. The prevalence rates of ADHD in the general population of 612-year olds range from 4 to 12% (Brown et al. 2001). Up to 65% of children with ADHD may have one or more comorbid conditions (Goldman et al. 1998). Oppositional defiant disorder (ODD) commonly co-occurs with ADHD, and this comorbid group often experiences severe functional impairment (Gadow and Nolan 2002; Drabick et al. 2004). Children with ADHD comorbid with ODD tend to have more severe ADHD symptoms, and family distress, and peer problems when compared with children with ADHD alone (Kuhne et al. 1997). Atomoxetine, a potent and selective norepinephrine reuptake inhibitor, is used for the treatment of ADHD in children, adolescents and adults. A recent study that examined atomoxetine in pediatric patients aged 612 years demonstrated that in patients with ADHD and ODD, treatment with atomoxetine resulted in a significant improvement in ADHD symptoms and global clinical functioning (Bangs et al. 2008). The bioavailability and clearance of atomoxetine is influenced by the activity of the polymorphically expressed enzyme cytochrome P450 2D6 (CYP2D6) (Sauer et al. 2005). The plasma half-life of atomoxetine ranges from 5.2 h [extensive metabolizers (EM)] to 21.6 h (poor metabolizers [PM]), depending on the CYP2D6 phenotype. In CYP2D6 EM, atomoxetine clearance can be reduced by selective CYP2D6 inhibitors (Sauer et al. 2005). When taking atomoxetine doses up to 1.8 mg/kg, CYP2D6 PM are likely to show greater efficacy, an increase in cardiovascular tone, and are somewhat more likely to experience adverse events than EM (Michelson et al. 2007). Since atomoxetine is a relatively new medication, whether particular plasma concentrations might predict level of clinical response is of interest. In this report, we describe a secondary analysis of a previously published study (Bangs et al. 2008) that assessed the efficacy of atomoxetine in treating symptoms of ODD in children with ADHD and comorbid ODD. The objective of this report is to examine whether atomoxetine plasma concentration predicts symptom response in those patients with ADHD and comorbid ODD, including whether increasing dose is associated with improving response for those who have not fully responded to the usual recommended atomoxetine daily dose. Materials and methods The details for the methods used in this international multicenter clinical study are described in a previous publication (Bangs et al. 2008). Patients were aged 612 years and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for ADHD (hyperactive/impulsive, inattentive, or combined type) and comorbid ODD as determined by clinician assessment, structured clinical interview [Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged ChildrenPresent and Lifetime Version (K-SADS-PL)] (Kaufman et al. 1997), ADHD rating scale, Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV), (Swanson et al. 2001) score above age and gender norms, Clinical Global Impressions-Severity (CGI-S) (Guy 1976; National Institute of Mental Health 1985) score C4, and SNAP-IV ODD scores of C15. Patients with a history of bipolar I or II disorder, psychosis, or pervasive developmental disorder were excluded, as were those with a current diagnosis of major depressive disorder, post-traumatic stress disorder, patients with a Childrens Depression Rating Scale-Revised (CDRS-R) (Poznanski et al. 1996) total raw score [40, serious suicidal risk, history of any seizure disorder (other than febrile seizures), history of alcohol or other drug abuse within the past three months, current cardiovascular disease or other disorders that could be aggravated by increased blood pressure or heart rate, or those who were likely to need psychotropic medications other than atomoxetine during study participation. Additional exclusion criteria details are described in Bangs et al. (2008). Efficacy measures included the investigator-rated SNAP-IV ODD as well as SNAP-IV ADHD-combined subscales. The SNAP-IV ODD subscale and the SNAP-IV ADHD combined subscale scores were used to measure changes in symptoms of ODD and ADHD. For the analyses reported here, the SNAP-IV ADHD combined subscale scores (total 18 items including both inattention and impulsivity/hyperactivity subscales) and the SNAP-IV ODD subscale scores (total eight items) were evaluated. The CGI-Improvement (CGI-I) scale is a single-item, clinician rating of the total improvement (or worsening) of the patients symptoms since the beginning of treatment. The CGI-I, as use (...truncated)