Development, disease and degeneration in schizophrenia: a unitary pathophysiological model
Development, disease and degeneration in schizophrenia: a unitary pathophysiological model
复制标题
DOI：
10.1016/s0022-3956(99)00033-3
复制
发表时间：
1999-11-01
影响因子：
4.8
通讯作者：
Keshavan, MS
中科院分区：
文献类型：
--
作者：
Keshavan, MS
近年来，人们提出了几种精神分裂症的病理生理学模型，即早期和晚期脑神经发育模型和病后神经退行性模型，理论家们经常认为这些解释是相互排斥的。我们认为，所有这些机制可能在大脑发育过程中和疾病早期过程中连续的关键“脆弱性窗口”期间相互作用累积，从而导致疾病的临床表现。早期脑损伤可能导致选择性神经网络发育不良，从而导致许多患者出现病前认知和社会心理功能障碍。青春期精神病的发作可能与突触的过度消除有关，其次与阶段性多巴胺能过度活动有关。疾病发作后，这些与持续未经治疗的精神病相关的神经化学变化可能会导致进一步的神经退行性过程。强直性谷氨酸能神经传递的减少和阶段性谷氨酸能过量可能会诱发这些过程，并且可能具有相当大的解释力。这一假说与精神分裂症的核心特征一致，例如病前表现、青少年发病、疾病早期的功能衰退、认知障碍、多巴胺的作用以及基因和环境在病理生理学中的作用。这种“三击”模型扩展了其他研究人员的类似综合概念，并生成与未来精神分裂症病理生理学和治疗研究相关的可测试预测。 (C) 1999 Elsevier Science Ltd. 保留所有权利。
In recent years, several pathophysiological models of schizophrenia, i.e. the early and late brain neurodevelopmental and post-illness onset neurodegenerative models, have been proposed and theorists have often argued as if these explanations are mutually exclusive. We propose that all these mechanisms may interact cumulatively during successive critical 'windows of vulnerability' during brain development and during the early course of the illness to lead to the clinical manifestations of the illness. Early brain insults may lead to dysplasia of selective neural networks that account for the premorbid cognitive and psychosocial dysfunction seen in many;patients. The onset of psychosis in adolescence may be related to an excessive elimination of synapses and secondarily, phasic dopaminergic overactivity. Following illness onset, these neurochemical alterations in relation to continuing untreated psychosis may lead to further neurodegenerative processes. A reduction in tonic glutamatergic neurotransmission and a phasic glutamatergic excess can potentially predispose to these processes and may have considerable explanatory power. This hypothesis is consistent with central characteristics of schizophrenia such as premorbid manifestations, adolescent onset, functional decline early in this illness, cognitive impairments, the role of dopamine and the role of genes and environment in pathophysiology. This 'three hit' model extends similar integrative conceptualization by other investigators and generates testable predictions of relevance to future pathophysiology and treatment research in schizophrenia. (C) 1999 Elsevier Science Ltd. All rights reserved.