Approximately 40%-80% of children and adolescents with autism spectrum disorder (ASD) exhibit clinically significant anxiety symptoms. These symptoms are associated with increased social deficits, depression, irritability, and stereotyped and self-injurious behaviors. Children and adolescents with anxiety also frequently avoid potentially stressful situations, thereby missing opportunities to learn important new skills. Despite the significant consequences of anxiety symptoms, several critical treatment-relevant issues remain unresolved. First, there is a lack of clarity about how to differentiate ASD and anxiety symptoms. Second, little is known about how anxiety manifests in those with ASD and intellectual disability (ID). Third, the neural substrates of anxiety in ASD are poorly understood. The overarching goal of this project is to investigate these open issues in order to make interventions more precise, more personalized, and more likely to promote positive outcomes -- an objective consistent with the National Institutes of Health (NIH), the Roadmap, Precision Medicine, and Research Domain Criteria Project (RDoC) Initiatives and the Interagency Autism Coordinating Committee (IACC) Strategic Plan, Chapter 4.

While there is no doubt that anxiety is a very serious issue for those with ASD, what to do about this problem is less clear. The search for empirically-validated treatments has begun with multiple small trials providing promising evidence that selective serotonin reuptake inhibitors (SSRIs) and cognitive behavior therapy (CBT) might reduce anxiety in those with ASD. However, this work is in its early stages. There is a great need for large, rigorously designed trials that validate the effectiveness of both medication and CBT, as well as functional neuroimaging studies that identify neural predictors of treatment efficacy and markers of therapy-induced change. Such work holds the potential to help answer the questions posed above and to assist the field in developing more personalized treatments. In Project 1 of the Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder, we will conduct a study in children with ASD and clinically significant anxiety ages 8-14 to compare efficacy of these different treatment types.

The overall aims of the study are to better characterize the sub-group of children and preadolescents with ASD that exhibit clinically significant anxiety and fears through a 16-week randomized comparative treatment trial of Behavioral Intervention for Anxiety in Children with Autism (BIACA), sertraline, and placebo in youth with ASD, IQ\>50, and clinically significant anxiety as assessed by a PARS score that is greater than or equal to 8. Clinician-administered gold standard assays will be used of traditional DSM (Pediatric Anxiety Rating Scale \[PARS\] and the Anxiety Disorders Interview Schedule-IV \[ADIS-IV\]), and nontraditional ASD related anxiety symptoms (Autism Spectrum Addendum to the ADIS \[ASDD\]), as well as parent reports of potentially overlapping symptoms that complicate the ASD anxiety phenotype. Additionally fMRI will be used to investigate neural predictors of treatment efficacy, markers of treatment induced change, and signatures of anxiety sub-types.