Anxiety in Youth with Autism Spectrum Disorder - PROJECT SUMMARY/ABSTRACT Anxiety is a common and impairing psychiatric comorbidity affecting up to 70% of youth with autism spectrum disorder (ASD) for which there are very limited evidence-based treatments. Gold-standard treatment approaches including selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) are often unsuitable, ineffective, or poorly tolerated in youth with ASD. No large scale, well-powered clinical trials of pharmacotherapy for anxiety in ASD have been published. Prior research on anxiety in ASD has key methodological limitations including the lack of high quality clinical endpoints, objective biomarkers, or known mechanisms underlying treatment response. Our long-term goal is to advance the evidence-based treatment for anxiety in youth with ASD by identifying underlying treatment mechanisms and conducting high quality clinical trials. The objectives of this proposal are to (1) identify autonomic nervous system (ANS) measures that can be obtained in youth with ASD which correlate with anxiety severity in the K99 phase (Aim 1) and (2) to conduct a randomized controlled trial of buspirone to preliminarily assess its efficacy (Aim 2) and whether ANS modulation is a target mechanism (Aim 3) in the R00 phase. This contribution is significant since youth with ASD commonly experience anxiety disorders and there are limited evidence-based treatments. The proposed research is innovative in that it will be the first ASD clinical trial to incorporate objective physiologic mechanisms, decreasing overreliance on subject self-/parent-report or clinician rating. Aims of the principal investigator’s K99 career development and training plan include (1) Obtain training and applied experience acquiring and interpreting autonomic nervous system (psychophysiology) data in youth with ASD, (2) Develop expertise in psychopharmacology clinical trials design and execution, (3) Develop familiarity with applied biostatistics relevant to intervention trials, and (4) Advance skills in manuscript preparation, grantsmanship, leadership, and responsible conduct of research. These goals will be achieved through a training plan comprised of mentorship, formal coursework, conferences, and manuscript/grant preparation. Knowledge gained via the training plan will be augmented by the applied research experience. Drs. Christopher McDougle, Kerry Ressler, Sabine Wilhelm, David Eddie, and Caitlin Ravichandran will serve as mentors on this award. Massachusetts General Hospital- Harvard Medical School provides an exceptional environment in which to conduct this training and research. By the end of the R00 period, the principal investigator will have a working methodology for obtaining ANS measures relevant to clinical trials in youth with ASD and anxiety, a preliminary estimate of the placebo effect and buspirone-placebo difference, and sample size needed to more fully test physiologic mechanisms. These will inform a multi-site R01 effectiveness trial of buspirone or other anti-anxiety medications. The principal investigator will also have the training and experience needed to successfully obtain R61/R33 funding to test novel agents that are either in active development or repurposed non-CNS agents for anxiety in this population.
