Several lines of evidence suggest amino acid neurotransmitter system abnormalities contribute to the neurobiology of depression. In humans, there is clear evidence of altered amino acid neurotransmitter function in depressed individuals. Most notably, depressed patients appear to have widespread GABA reductions, with studies consistently demonstrating lower plasma and CSF GABA concentrations in depressed subjects compared to non-depressed controls. More recently, magnetic resonance spectroscopy also demonstrated significantly decreased GABA concentrations in the occipital cortex of depressed patients. These reduced GABA concentrations appear to be present in a large subgroup of depressed subjects suggesting that it may be a useful marker in identifying a subtype of depressed individuals sharing a common pathophysiology. Furthermore, reduced GABA concentrations appear to normalize following ECT or antidepressant medications, suggesting a possible association to the antidepressant effects of the treatment modalities. Other evidence suggests that altered glutamatergic function is also associated with the pathogenesis and pathophysiology of mood disorders. Consistent with this hypothesis, elevated cortical glutamate concentrations were recently demonstrated in the same group of depressed subjects as those showing reduced GABA concentrations. The principal objective of this study is to gain additional information regarding the underlying neurobiological mechanism responsible for the abnormalities in amino acid neurotransmitter concentrations in the occipital cortex of depressed subjects. We plan to achieve this objective by using 1H-MRS and 13C-MRS to obtain measures of the amino acid concentrations, rates of GABA synthesis and glutamate/glutamine cycling in medication-free depressed patients and healthy comparison subjects. In addition, we will continue to investigate the potential association between cortical GABA concentrations and both the various clinical subtypes of depression and allelic variants of the GAD65 gene.
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