Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.
Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.
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朝着抑郁症的谷氨酸假说：情绪障碍神经心理药理的新兴前沿。
DOI：
10.1016/j.neuropharm.2011.07.036
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发表时间：
2012-01
影响因子：
4.7
通讯作者：
Popoli, Maurizio
中科院分区：
文献类型：
--
作者：
Sanacora, Gerard;Treccani, Giulia;Popoli, Maurizio
在单胺假说首次提出半个世纪后，令人信服的证据表明，一系列大脑区域和回路的长期变化调解了复杂的认知情绪行为，代表了情绪/焦虑障碍的生物学基础。大量临床研究表明，病理生理学与主要谷氨酸系统功能障碍、调节谷氨酸清除和代谢机制的功能障碍以及调节认知-情绪行为的许多脑区域的细胞结构/形态不适应变化有关。同时，来自动物模型的大量数据表明，不同类型的环境应激增强了边缘/皮质区域谷氨酸的释放/传递，并产生强大的结构效应，诱导树突重塑，突触减少，可能还有与抑郁症患者相似的体积减少。由于这些区域和回路中的绝大多数神经元和突触使用谷氨酸作为神经递质，因此认为谷氨酸在某种程度上与情绪/焦虑障碍“有关”是有限的；相反，我们应该认识到谷氨酸系统是精神病理学的主要媒介，并且可能也是抗抑郁药物治疗作用的最终共同途径。从抑郁症的单胺假说到以谷氨酸为中心的神经可塑性假说的范式转变，可能代表了工作假说的重大进步，推动了新药和疗法的研究。重要的是，尽管有多种以单胺为基础的作用机制的药物可供使用，但仍有很大比例的患者未能实现抑郁症状的持续缓解。对治疗难治性抑郁症的改进药物疗法的需求尚未得到满足，这意味着开发具有谷氨酸传递和相关途径等新作用机制的新化合物有很大的空间。
Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way ‘involved’ in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
11
作者：
Bessa, J. M.;Ferreira, D.;Sousa, N.
通讯作者：
Sousa, N.
影响因子：
56.9
作者：
BECHARA, A;TRANEL, D;DAMASIO, AR
通讯作者：
DAMASIO, AR
影响因子：
3.3
作者：
BAKER, KG;HALLIDAY, GM;TORK, I
通讯作者：
TORK, I
影响因子：
3.4
作者：
Bechtholt-Gompf, Anita J.;Smith, Karen L.;Oenguer, Dost
通讯作者：
Oenguer, Dost