This is a patient-oriented career development proposal designed to provide the candidate with advanced training, protected research time, and mentored research experience. Major depressive disorder is a serious and debilitating mental illness that affects over 15% of the population and leads to an increased risk of suicide. Yet, available treatments have limited efficacy and there are no FDA-approved rapid-acting antidepressants. The candidate's long-term career goal is to improve the treatment of neuropsychiatric disorders by using novel technologies to guide rational drug development. To continue his progress toward these goals, the candidate proposes: (1) a training plan to gain expertise in translational clinical investigations and in advanced MR methods with a focus on 13C magnetic resonance spectroscopy (13C-MRS). (2) A mentoring team with extensive expertise in drug development, neuroimaging, and neuroscience to provide the candidate with the resources and supervision needed to advance toward his research goals. (3) A sequence of supervised research projects that will establish and validate a pharmaco-imaging paradigm to study the mechanisms underlying the antidepressant and psychotomimetic effects of ketamine. Ketamine is an anesthetic agent, recently found to exert a rapid and potent antidepressant effect in severely depressed patients. However, its psychotomimetic effects, which may model core pathophysiological processes in schizophrenia, limit its widespread use in major depression. Mounting evidence indicates that a ketamine-induced surge in glutamate neurotransmission, particularly in the frontal cortex, plays a crucial role in the antidepressant and psychotomimetic effects of the drug. The proposed research projects take advantage of recent developments in frontal 13C-MRS - a method to measure glutamate/glutamine cycling noninvasively in vivo - to determine the effect of ketamine on glutamate neurotransmission cycling in a group of healthy volunteers (Aim 1 & 2), and in patients with Major Depressive Disorder (Aim 3). The research group hypothesize that subanesthetic doses of ketamine will induce a rapid increase in glutamate/glutamine cycling in the frontal cortex and that the ketamine-induced glutamate changes will correlate with the psychotomimetic effects of the drug. Moreover, the pilot data generated by Aim 3 studies will provide insight into the role of glutamate neurotransmission in the antidepressant effect of ketamine. These studies will provide key insight both into the mechanism of ketamine's rapid antidepressant effects in humans and the psychotomimetic effects that recapitulate core phenomenology of schizophrenia, thus contributing highly significant advances relevant to two devastating mental illnesses affecting millions of patients around the world.
Recent studies have highlighted the limitations of our current armamentarium of treatments for mood and psychotic disorders. Understanding of the mechanisms underlying the rapid-acting antidepressant and psychotomimetic effects of ketamine is critical to the development of novel antidepressant and antipsychotic medications. The proposed studies will use novel neurochemical imaging methods to help identify the mechanisms through which ketamine is capable of producing these effects and could provide information significantly critical to our understanding of the related pathophysiology and the development of new therapeutics.
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