Efficacy and safety of mixed amphetamine salts extended release (adderall XR) in the management of oppositional defiant disorder with or without comorbid attention-deficit/hyperactivity disorder in school-aged children and adolescents: A 4-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled, forced-dose-escalation study

Background: Oppositional defiant disorder (ODD)is associated with a high degree of impairment in social skills, family interaction, and academic functioning. Comorbid ODD is reportedly present in 40% to 70% of children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Objective: The goal of this study was to assess theefficacy and safety of mixed amphetamine salts extended release (MAS XR) for the treatment of ODD in children and adolescents aged 6 to 17 years. Methods: This was a 4-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled, forced-dose-escalation study. Patients were randomized to receive active treatment with MAS XR 10, 20, 30, or 40 mg/d or placebo. The primary efficacy end point was the ODD subscale of the Swanson, Nolan, and Pelham-IV (SNAP-IV) parent rating. Primary safety measures included adverse events recorded at each visit and for 30 days after study drug discontinuation, and changes in vital signs, 12-lead electrocardiographic (ECG) findings, laboratory tests and physical examinations, and body weight. A post hoc efficacy reanalysis was completed based on the results for the per-protocol population. For this analysis, patients were divided into high and low baseline severity categories according to the dichotomized baseline ODD parent or teacher score or dichotomized baseline ADHD parent or teacher score (high defined as scores at the median or greater and low defined as scores less than the median). Results: A total of 308 children and adolescents (age range, 6-17 years; 213 males, 95 females) were randomized to receive active treatment with MAS XR 10 mg/d (n = 60) 20 mg/d (n = 58), 30 mg/d (n = 69), or 40 mg/d (n = 61) or placebo (n = 60). Of the 308 study patients, 244 (79.2%) had comorbid ADHD. A significant change from baseline in the ODD symptoms measured with the SNAP-IV parent rating subscale was found for the MAS XR 30-mg/d (-0.52; P < 0.001) and 40-mg/d (-0.56; P = 0.002) groups in the per-protocol analysis and for the MAS XR 30-mg/d group in the intent-to-treat analysis (-0.42; P < 0.005). Throughout the study, MAS XR was well tolerated in these children and adolescents with ODD, and most adverse events were mild to moderate in intensity. The most frequently reported adverse events occurring in MAS XR-treated patients were anorexia/decreased appetite (25.3%), insomnia (19.5%), headache (18.5%), and abdominal pain (10.7%). Statistically, but not clinically, significant decreases in body weight were seen with MAS XR (range, -1.1 to -3.5 lb; P < 0.001 vs placebo). Changes in laboratory values, ECG measurements, and physical and other vital signs were also not clinically significant. The post hoc reanalysis was based on the per-protocol population (n = 229). An assessment of the high baseline symptom severity subgroups showed a good response to MAS XR treatment for the SNAP-IV parent and teacher rating scales (both, P < 0.05). Conclusion: This study found that higher doses ofMAS XR (30 and 40 mg) were effective and well tolerated in the management of ODD in these schoolaged children and adolescents in the presence or absence of ADHD.