Schizophrenia, "Just the Facts" 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse.
Schizophrenia, "Just the Facts" 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse.
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DOI：
10.1016/j.schres.2011.01.011
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发表时间：
2011-04
影响因子：
4.5
通讯作者：
Tandon, Rajiv
中科院分区：
文献类型：
--
作者：
Keshavan, Matcheri S.;Nasrallah, Henry A.;Tandon, Rajiv
目前将精神分裂症作为一种单一疾病的概念远远不能令人满意，需要重新概念化。我们的“事实”系列中的前五篇论文回顾了迄今为止对精神分裂症的了解，有限数量的关键事实似乎很突出。精神分裂症的特征在于持续的认知缺陷、通常在青年时开始的阳性和阴性症状、实质性遗传性以及脑结构、功能和神经化学改变，包括多巴胺能失调。人们提出了几种病理生理学模型，对这种疾病有不同的解释，就像传说中的六个印度盲人摸索大象的不同部位，得出了不同的结论。然而，积累知识整合成统一的结构精神分裂症发病机制的几个现存的模型，我们讨论一个例子，涉及神经发育不平衡的兴奋/抑制神经系统导致神经可塑性受损。这种不平衡可能接近临床表现，可能是由各种遗传、表观遗传和环境原因以及炎症和氧化应激等病理生理过程引起的。这种努力“连接点”（和可视化的大象）仍然是有限的精神分裂症的大量临床，病理和病因学的异质性和模糊的边界与其他几种精神疾病，导致重叠的综合征的“模糊聚类”，从而减少了内容，判别和预测有效性的单一结构的这种疾病。未来的道路涉及几个关键方向：a）选择越来越多来自转化神经科学的有效表型定义; B）通过跨诊断维度和精神病理学分期方法解决临床异质性; c）通过阐明“扩展的”中间表型和病理生理过程的独立家族来解决病理生理异质性（例如，改变的兴奋/抑制、显著性或执行电路、氧化应激系统），其贯穿结构、功能、神经化学和分子领域; d）、通过绘制基因组和环境因素及其与综合征和特定病理生理学的相互作用来解决病因异质性签名; e）将因果因素与后果和补偿现象分开; f）制定或重新制定可以被反驳/测试的假设，也许在小鼠或其他实验模型中。这些步骤可能会导致精神分裂症的当前实体被有效地解构和重新配置为表型重叠，但病因独特和经验可测试的组成实体（类似于精神发育迟滞，癫痫或癌症综合征）。老鼠可能是拯救被困大象的方法！
The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our “facts” series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to “connect the dots” (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a “fuzzy cluster” of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of “extended” intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant!
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DOI：
10.1002/bs.3830010402
发表时间：
1956-01-01
期刊：
BEHAVIORAL SCIENCE
影响因子：
--
作者：
BATESON, G;JACKSON, DD;WEAKLAND, J
通讯作者：
WEAKLAND, J
影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
DOI：
10.1016/j.ijdevneu.2008.07.013
发表时间：
2008-11-01
影响因子：
1.8
作者：
Arthi, K.;Tamilarasi, A.
通讯作者：
Tamilarasi, A.
影响因子：
4.5
作者：
DeLisi, LE
通讯作者：
DeLisi, LE
影响因子：
4.8
作者：
Bearden, Carrie E.;van Erp, Theo G. M.;Cannon, Tyrone D.
通讯作者：
Cannon, Tyrone D.