Haaf Moritz, Leicht Gregor, Curic Stjepan, Mulert Christoph
Psychiatry Neuroimaging Branch (PNB), Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Psychiatry and Psychotherapy, UKGM, Justus-Liebig University Giessen, Giessen, Germany.
Curr Pharm Biotechnol. 2018;19(4):293-307. doi: 10.2174/1389201019666180620112528.
The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals.
We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria.
In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents.
This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia- like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.
诸如氯胺酮等 N - 甲基 - D - 天冬氨酸谷氨酸受体（NMDAR）拮抗剂可短暂诱发精神分裂症样的阳性、阴性和认知症状，这一观察结果导致了精神分裂症药理学模型从多巴胺能功能障碍向谷氨酸能功能障碍的范式转变。NMDAR 功能低下可直接因兴奋 - 抑制（E/I）失衡解释许多精神分裂症症状，也能解释多巴胺能功能障碍本身。然而，迄今为止，尚无靶向 NMDAR 的新药获批。在寻找可能的生物标志物过程中，有趣的是，氯胺酮在健康参与者中诱发的精神病理变化伴随着脑电图（EEG）、脑磁图（MEG）和功能磁共振成像（fMRI）信号的改变。
我们系统检索了 PubMed/Medline 和 Web of Knowledge 数据库（2006 年 1 月至 2017 年 7 月），以识别有关氯胺酮精神分裂症模型的人体 EEG/MEG 和 fMRI 研究。检索策略共识别出 209 条引文，其中 46 篇文章符合指定的纳入标准。
在 EEG/MEG 研究中，氯胺酮诱发了事件相关电位的变化，如 P300 电位和失配负波，类似于在精神分裂症患者中观察到的改变。在 fMRI 研究中，不同脑区观察到激活改变，最显著的是在前扣带回皮质和边缘结构以及与任务相关的脑区。这些改变伴随着功能连接的变化，表明潜在脑网络的平衡发生了转变。药物治疗在不同程度上确实改变了氯胺酮在 EEG/MEG 和 fMRI 研究中诱发的变化。
本综述强调了氯胺酮模型在精神分裂症药物研发中的潜在适用性，因为它提供了评估药物对精神分裂症样症状的影响以及寻找相关神经生理学和神经影像学生物标志物的可能性。
