PROJECT SUMMARY Children with Down syndrome (DS) have a 3-5 times greater prevalence of Attention Deficit Hyperactivity Disorder (ADHD) than typically developing children. Despite this higher risk of ADHD, rates of stimulant medication treatment are disproportionately low in children with DS+ADHD even though stimulants are the most efficacious ADHD treatment and are recommended by consensus guidelines for use in children with intellectual disability (ID) and comorbid ADHD. Possible reasons for under-utilization of stimulant treatment in DS+ADHD include: 1) diagnostic uncertainty regarding how to accurately diagnose ADHD in children with DS, making providers prone to “diagnostic overshadowing” (i.e., attributing ADHD to the ID); 2) there is not a single clinical trial examining the safety and efficacy of stimulant medication in children with DS+ADHD; and 3) concerns about cardiac safety, given the high incidence of congenital heart disease or defects (CHD) in the DS population. We propose a pilot study to define the clinical features of DS+ADHD thereby enabling more accurate diagnosis and a pilot clinical trial to inform sample size estimates for a larger clinical trial. We propose to perform the first randomized clinical trial of stimulant medication in children with DS+ADHD to provide evidence regarding the short and long-term safety and efficacy of stimulant use in children with DS+ADHD, both with and without CHD. One hundred (100) children with DS+ADHD and 70 children with DS and no ADHD (DS-ADHD), all aged 6-12 and matched on age, gender, and IQ, will participate. All 170 children enrolled in the study will complete a comprehensive assessment battery evaluating ADHD diagnostic criteria as well as behavioral, cognitive, academic, and functional impairments. The 100 children in the DS+ADHD group will also complete a multi-phased randomized, double-blind clinical trial with crossover to placebo and long-term follow- up to assess the short- and long-term efficacy and safety of stimulant medications for treating ADHD symptoms and impairment in children with DS. Study aims will focus on 1) Identifying behavioral, cognitive, academic, and functional impairments that differentiate children with DS+ADHD from children with DS-ADHD; 2) Informing sample size of larger clinical trial; 3) Assessing the short- and long-term safety of stimulant treatment in children with DS+ADHD with a specific focus on cardiac safety; 4) Determining the short- and long-term efficacy of stimulant treatment at remediating cognitive, behavioral, and functional impairments in children with DS+ADHD; and 5) Exploring moderators (e.g., IQ, ADHD subtype, executive functioning, comorbid internalizing disorders, CHD) of stimulant response and side effects. Results from this study will provide much needed diagnostic and treatment data that will directly impact the outcomes of the approximately 45,000 children with DS+ADHD nationwide.

PROJECT NARRATIVE Though children with Down syndrome (DS) are at increased risk for having a comorbid diagnosis of Attention- Deficit / Hyperactivity Disorder (ADHD), ADHD is often under-recognized in children with DS due to “diagnostic overshadowing” by the primary intellectual disability. Even when ADHD is diagnosed in children with DS, ADHD is often under-treated due to a lack of data to support the efficacy and safety of stimulant medication in children with DS+ADHD, especially among the 50% of children with DS who have congenital heart defects for whom there could be increased cardiac risk. This study is the first clinical trial of stimulant medication in children with DS+ADHD and will determine the short- and long-term efficacy and safety of these medications in children with DS+ADHD and has the potential to significantly improve the functional status, behavior, and quality of life of children with DS+ADHD.