This is an application for a K23 Mentored Patient-Oriented Research Career Development Award (CDA) entitled Neural and Behavioral Response to Memantine in Adolescents with Autism. The candidate has a background in the clinical management of autism spectrum disorders (ASDs) and related psychopathology and training in clinical trial methodology and is currently the Director of the Autism Spectrum Disorders Clinical and Research Program in Pediatric Psychopharmacology at Massachusetts General Hospital (MGH) and an Assistant Professor of Psychiatry at Harvard Medical School (HMS). In pursuit of investigating the neural correlates and scope of psychopharmacologic treatment for ASDs and related psychopathology, the candidate has designed and conducted clinical trials and multi-modal neuroimaging studies in ASDs. In the process he has learned the fundamentals of multi-modal neuroimaging and its potential as a vehicle for translational research in autism. Based on promising preliminary findings from a study of memantine for the treatment of core features of autism, as well as collaborative multimodal neuroimaging studies investigating the spectroscopic and functional neural correlates of autism, the candidate has developed the current proposal to conduct a clinical trial of memantine in individuals with ASDs that includes spectroscopic and functional neuroimaging as outcome measures. The proposed CDA will enable the candidate to gain experience and training in multi-modal neuroimaging techniques as an investigative tool for evaluating treatment-related neural changes in ASDs. The candidate's career goal is to become an independent clinician-researcher with a knowledge base in multi-modal neuroimaging, neurochemistry, and psychopharmacologic treatment of ASDs and related psychopathology. Through the proposed research, interactions with mentors and consultants, and didactic coursework, the candidate seeks to gain expertise in the following complementary areas: 1) advanced clinical trial methodology and biostatistics; 2) neuroimaging techniques and their applications to clinical psychiatric research; 3) principles of neurochemistry; and 4) the responsible conduct of research. The long-term goal is to become an independent investigator in the area of multi-modal neuroimaging and psychopharmacological treatment research in ASDs. The candidate's immediate goal is to implement a large randomized controlled trial of a medication for ASDs while gaining experience and knowledge in those areas that are integral to clinical research. Exposure to the multi-disciplinary research community at MGH, as well as access to a large clinical population with ASDs and availability of facilities and resources to conduct research at MGH, provides the candidate with the ideal environment in which to carry out this work. Memantine is a glutamatergic agent that has shown promise in improving cognitive and behavioral functioning in a number of neuropsychiatric disorders. Guided by the preliminary findings of the promising role of memantine for the treatment of core features of autism, the candidate proposes to examine the effects of memantine on the behavioral and neural correlates of ASDs in 40 adolescents. The primary aim is to test the hypotheses that memantine monotherapy will be safe, well tolerated, and efficacious for improving social interaction in adolescents with ASDs by conducting a 12-week randomized controlled trial followed by a 12-week open-label extension phase for treatment responders. Brain glutamatergic hyperactivity has been hypothesized to contribute to the pathophysiology of ASDs. The candidate presents preliminary findings from a proton magnetic resonance spectroscopic (1HMRS) study of the glutamatergic system in autism, which showed a significant increase in glutamate in the anterior cingulate cortex (ACC) region with no change in the bilateral medial temporal lobes (MTL) regions among adolescent males with high-functioning (HF) autistic disorder. Additionally, preliminary data presented from a functional MRI (fMRI) study in HF-ASD subjects revealed altered functional connectivity of ACC and MTL structures (amygdala & hippocampus), with regions of the brain that are implicated in autism. Guided by these preliminary findings from spectroscopic and functional neuroimaging studies, the secondary aim of the proposed project is to test the hypothesis that memantine treatment is associated with a decrease in glutamate concentration in the ACC and a change towards normalization in functional connectivity of ACC and MTL consistent with clinical improvement in social interaction. In order to measure changes in brain neurometabolites and functional connectivity, ASD participants will undergo multimodal imaging before and after short-term treatment with memantine. Lastly, the candidate aims to explore neural biomarkers of response to short- and long-term memantine monotherapy by identifying neural correlates of ASDs by comparing the multimodal neuroimaging findings of subjects with ASDs (N=40) with those of matched healthy controls (N=20). The proposed project aims to expand available treatments for the core features of ASDs and illuminate the neural mechanisms of change underlying improvements in social functioning. The CDA will provide the candidate with an invaluable opportunity to gain knowledge, skills, and training required in the area of translationa clinical research in autism including mentorship, didactics, and the development of a fruitful ASDs research program.
This proposal extends our investigation by conducting a controlled trial to study the clinical efficacy and tolerability of memantine monotherapy for the treatment of social impairment in adolescents with ASDs. We will also examine the effects of memantine therapy on neural functioning by measuring the changes in brain neurometabolites and functional connectivity on magnetic resonance imaging acquired pre- and post-memantine treatment. Studying the neural correlates of ASDs in the context of treatment intervention will offer information on the moderating and mediating role of neural markers underlying variability of therapeutic response, help identify biomarkers of treatment response, and elucidate the mechanism of action of the therapeutic agents.
