I have been fortunate to work in stimulating environments that have afforded me substantial opportunities to engage in research training throughout my graduate (M.D., Ph.D.) and residency training. In July, I will continue my training an additional year with the Daniel X. Freedman Clinical Neuroscience Fellowship at Yale University. However, without support from a K08 award, I would be required to assume substantial clinical responsibilities in order to support my salary when I join the Yale faculty in July, 1999. I have designed this K08 award to enable me to pursue a comprehensive five-year research-training Plan. This plan will provide me with the background and skills necessary to become an independent investigator-using novel magnetic resonance spectroscopy (MRS) techniques. I would like to apply these techniques to the study of GABA and glutamate neurotransmission related to the pathophysiology and treatment of affective disorders. Over the past two years I have developed basic skills in-proton-MRS (1H-MRS). We have produced exciting preliminary data describing reductions in cortical GABA associated with depression, and elevation of cortical GABA levels following electroconvulsive therapy (ECT). I propose to continue these investigations with two aims. 1) To fully characterize both GABAergic and glutamatergic systems in affective disorder disease states. (Years 1-3) and 2) To use pharmacological probes along with [13C]-MRS to examine possible pathophysiological mechanisms related to amino acid neurotransmitter regulation in depression. In order to advance the use of MRS applications in the study of affective disorders, I have identified several key areas where I will require additional training including: 1) nuclear magnetic resonance, 2)1 neurochemistry, kinetic modeling, and related neuroimaging technologies, 3) clinical and basic neuropharmacology applicable to affective disorders research; and 4) clinical trials methodologies. I believe my background in the basic sciences will enable me to complete the rigorous training plan outlined in this application. This training along with continued practical application of the technology under the co-mentorship of Drs. Rothman and Krystal should thoroughly prepare me for a career as an independent investigator using MRS technology to study brain neurochemistry. This novel line investigation will open previously inaccessible areas of research, with a broad range of future applications.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZRG1-BDCN-6 (01))
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Goldschmidts, Walter L
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Yale University
Schools of Medicine
New Haven
United States
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Sanacora, Gerard; Fenton, Lisa R; Fasula, Madonna K et al. (2006) Cortical gamma-aminobutyric acid concentrations in depressed patients receiving cognitive behavioral therapy. Biol Psychiatry 59:284-6
Gueorguieva, R V; Sanacora, G (2006) Joint analysis of repeatedly observed continuous and ordinal measures of disease severity. Stat Med 25:1307-22
Sanacora, Gerard; Gueorguieva, Ralitza; Epperson, C Neill et al. (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705-13
Sanacora, Gerard; Berman, Robert M; Cappiello, Angela et al. (2004) Addition of the alpha2-antagonist yohimbine to fluoxetine: effects on rate of antidepressant response. Neuropsychopharmacology 29:1166-71
Sanacora, G; Mason, G F; Krystal, J H (2000) Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Crit Rev Neurobiol 14:23-45