13C Measurement of GABA Synthesis in Depression

描述（由申请人提供）：一些证据表明氨基酸神经递质系统异常与抑郁症的神经生物学有关。在人类中，有明确的证据表明，抑郁症患者的氨基酸神经递质功能发生了改变。最值得注意的是，抑郁症患者似乎有广泛的GABA减少，研究一致表明，与非抑郁症患者相比，抑郁症患者的血浆和脑脊液GABA浓度较低。最近，磁共振波谱也显示抑郁症患者枕叶皮层GABA浓度显著降低。这些降低的GABA浓度似乎存在于抑郁症受试者的一个大亚组中，这表明它可能是识别具有共同病理生理的抑郁症个体亚型的有用标记。此外，在ECT或抗抑郁药物治疗后，减少的GABA浓度似乎恢复正常，这表明可能与治疗方式的抗抑郁作用有关。其他证据表明，谷氨酸功能的改变也与情绪障碍的发病机制和病理生理有关。与这一假设相一致的是，最近在同一组抑郁受试者中发现了皮质谷氨酸浓度升高和GABA浓度降低。本研究的主要目的是获得有关抑郁症受试者枕皮质氨基酸神经递质浓度异常的潜在神经生物学机制的额外信息。我们计划通过1H-MRS和13C-MRS来获得无药抑郁症患者和健康对照受试者的氨基酸浓度、GABA合成速率和谷氨酸/谷氨酰胺循环的测量。此外，我们将继续研究皮质GABA浓度与各种临床抑郁症亚型和GAD65基因等位变异之间的潜在关联。

DESCRIPTION (provided by applicant): 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.