Glutamate Probes in Adolescent Depression

DESCRIPTION (provided by applicant): This proposal is for a K23 Mentored Patient-Oriented Research Career Development Award to complete training and research experience needed to prepare the candidate for a successful career as an independent investigator. The candidate's long-term goal is a career in academic child and adolescent psychiatry focused on research that improves the care of patients with depression. This will be accomplished through increased understanding of its pathophysiology. Depression is a significant and common illness during childhood, a major public health problem, and a leading causes of disability worldwide. Recent basic science and clinical research in adults with depression suggests that glutamate, the brain's primary excitatory neurotransmitter plays a role in the neurochemical basis of depression. There is little information about the functioning of glutamate in adolescents with depression. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive brain imaging technique that measures the concentrations of brain chemicals such as glutamate. Intracortical facilitation (ICF) is a transcranial magnetic stimulation (TMS) neurophysiological test which measures the functioning of glutamate. The candidate proposes to use 1H-MRS and ICF in a cross-sectional study of glutamate concentrations and functioning in adolescent depression [with three groups] of subjects (depressed subjects who have not yet taken an antidepressant medication, subjects who had depression that responded to an antidepressant, and healthy controls). [Depressed subjects will have these two measures repeated after eight weeks of standard clinical treatment with fluoxetine. This will test the hypotheses that cortical glutamate concentrations are decreased while glutamate functioning is increased in adolescents with depression and that successful treatment with fluoxetine normalizes these differences.] This innovative approach will advance understanding of glutamate neurotransmission in adolescent depression, inform the development of new biomarkers, and assist with the identification of treatment targets. This project is tailored to inform subsequent longitudinal studies of depressed adolescents for federal R01 grant applications. The candidate has prior experience with ICF measures but would benefit from additional training in 1H-MRS methodology and TMS neurophysiology paradigms. The candidate and mentoring team propose a career development plan focused on 1H-MRS neuroimaging, TMS neurophysiology studies, clinical and translational research methodologies, [neurodevelopment,] and the neurobiology of disease research. This rigorous plan includes intensive mentoring, courses through the Mayo Clinic Graduate School, and international seminars. Well defined benchmarks regarding publications and grant submissions will ensure substantial productivity during the award period and a successful transition to an independent academic researcher in child and adolescent psychiatry.