Experimental Therapeutics and Pathophysiology Branch, Division of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Int J Neuropsychopharmacol. 2012 Sep;15(8):1063-72. doi: 10.1017/S1461145711001593. Epub 2011 Nov 1.
Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.
氨基酸递质系统功能障碍在重度抑郁症（MDD）的病理生理学中起着重要作用。我们使用质子磁共振波谱（¹H-MRS）来研究氨基酸递质在前额叶皮质中的水平是否可以预测 MDD 患者对单次静脉注射 N-甲基-D-天冬氨酸（NMDA）拮抗剂氯胺酮的抗抑郁反应。14 名未服用药物的 MDD 患者在接受单次静脉注射氯胺酮（0.5mg/kg）前 1-3 天接受扫描。我们测量了腹内侧前额叶皮质（VM-PFC）和背内侧/背外侧额前皮质（DM/DA-PFC）中的γ-氨基丁酸（GABA）、谷氨酸和 Glx/谷氨酸比（谷氨酰胺的替代标志物）。进行相关性分析，以确定治疗前 GABA、谷氨酸或 Glx/谷氨酸比是否可以预测氯胺酮给药后 230 分钟时抑郁和焦虑症状的变化。治疗前 GABA 或谷氨酸与两个感兴趣区域（ROI）中抑郁症状的改善均无相关性（p>0.1）；DM/DA-PFC 中的 Glx/谷氨酸比与抑郁症状的改善呈负相关[r s（11）=-0.57，p<0.05]。VM-PFC 中的治疗前谷氨酸水平与焦虑症状的改善呈正相关[r s（11）=0.57，p<0.05]。这些发现表明，较低的 Glx/谷氨酸比与对氯胺酮治疗的反应改善之间存在关联。因为谷氨酰胺主要存在于神经胶质细胞中，所以在这项研究中观察到的 Glx/谷氨酸比降低可能反映了 MDD 患者死后研究中同一区域神经胶质细胞的减少，并表明这种神经病理学结构的存在可能与氯胺酮对抑郁症的抗反应性相关。
