13C Measurement of GABA Synthesis in Depression

描述(申请人提供)：几行证据表明氨基酸神经递质系统异常有助于抑郁症的神经生物学。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变化。最值得注意的是，抑郁症患者似乎有广泛的GABA降低，研究一致地表明，抑郁症患者的血浆和脑脊液GABA浓度低于非抑郁症对照组。最近，磁共振波谱也显示抑郁症患者枕叶皮质中的GABA浓度显著降低。这些降低的GABA浓度似乎存在于一大群抑郁症受试者中，这表明它可能是识别具有共同病理生理特征的抑郁症患者的一个有用的标记。此外，降低的GABA浓度似乎在ECT或抗抑郁药物治疗后恢复正常，这表明可能与治疗方式的抗抑郁效果有关。其他证据表明，谷氨酸能功能改变也与情绪障碍的发病机制和病理生理学有关。与这一假设一致，最近在抑郁受试者中发现皮质谷氨酸浓度升高，而那些表现出GABA浓度降低的受试者也是如此。这项研究的主要目的是获得更多关于抑郁症患者枕叶皮质氨基酸神经递质浓度异常的潜在神经生物学机制的信息。我们计划通过使用1H-MRS和13C-MRS来测量未用药的抑郁症患者和健康对照组的氨基酸浓度、GABA合成率和谷氨酸/谷氨酰胺循环，以实现这一目标。此外，我们将继续研究皮质GABA浓度与抑郁症的不同临床亚型和GAD65基因等位基因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.