Glutamate, brain connectivity and duration of untreated psychosis

描述(申请人提供)：精神分裂症疾病的前驱阶段和早期阶段与社交和智力能力的显著下降有关，慢性病的下降幅度较小。Meta分析一直认为，未经治疗的精神病(DUP)持续时间较长，出现阳性症状和治疗之间的持续时间与较差的长期结果之间存在关系。然而，这种现象的神经生物学及其对抗精神病药物反应的影响仍然知之甚少。谷氨酸能过量改变大脑连接可能为为什么DUP时间较长的人临床结果较差提供了解释。我们建议使用多模式神经成像技术对67名首发精神病患者进行利培酮治疗前后的研究，利培酮是一种常用的抗精神病药物。我们将测量(1)谷氨酸和(2)结构和功能脑连接的指数，并测试假设，即首发患者存在谷氨酸能异常，较长的DUP与更大的功能和结构连接异常相关，这为治疗反应差奠定了基础。我们以前的联合磁共振波谱(1H-MRS)、扩散张量成像(DTI)和静息状态功能磁共振(FMRI)研究在了解未用药的精神分裂症患者的谷氨酸系统和脑连接异常以及抗精神病药物对这些异常的调节方面取得了进展。我们已经确定了谷氨酸能功能障碍的两个指标，谷氨酸升高和N-乙酰天冬氨酸和谷氨酸之间已知相关性的紊乱，这提示谷氨酸/谷氨酰胺循环异常。虽然抗精神病药物似乎可以调节谷氨酸，但代谢物之间的相关性的紊乱并不能通过治疗恢复。此外，我们发现，未服药的精神分裂症患者的结构和功能连接异常都能预测患者随后对治疗的反应。据我们所知，没有其他小组进行了一项研究，使用互补的神经成像技术的组合，将允许产生谷氨酸能功能和大脑连接的广泛特征，在首发精神病及其治疗后的变化。拟议的研究结果可能提示DUP与治疗反应差有关的机制，这可能导致针对DUP的新干预措施。

DESCRIPTION (provided by applicant): The prodromal phase and the early stages of the schizophrenia illness are associated with significant decreases in social and intellectual abilitie, with more modest declines seen with chronic disease. Meta-analyses have consistently identified a relationship between the longer duration of untreated psychosis (DUP), the duration between the onset of positive symptoms and treatment, and worse long term outcomes. However, the neurobiology of this phenomenon and its implications for response to antipsychotic medications remain poorly understood. Glutamatergic excess altering brain connectivity might provide an explanation for why those with longer DUP have worse clinical outcomes. We propose to use multimodal neuroimaging to study 67 first episode psychosis subjects before and after sixteen weeks of treatment with risperidone, a commonly prescribed antipsychotic. We will measure indices of (1) glutamate and (2) structural and functional brain connectivity and test the hypotheses that glutamatergic abnormalities are present in first episode patients and that longer DUP is associated with greater functional and structural connectivity abnormalities that set the stage for poor response to treatment. Our previous combined MR spectroscopy (1H-MRS), diffusion tensor imaging (DTI), and resting state functional MR (fMRI) studies have made progress in the understanding of abnormalities in the glutamate system and brain connectivity in unmedicated patients with schizophrenia and modulation of these by antipsychotic medication. We have identified two indices of glutamatergic dysfunction, elevated glutamate and a disturbance in the known correlation between N-acetyl-aspartate and glutamate, which is suggestive of glutamate/glutamine cycle abnormalities. While antipsychotic medications appear to modulate glutamate, the disturbance in the correlation between metabolites is not restored with treatment. In addition, we found that both structural and functional connectivity abnormalities in unmedicated patients with schizophrenia predict patients' subsequent response to treatment. To our knowledge, no other group has performed a study that uses a combination of complementary neuroimaging techniques that will allow generating a broad characterization of glutamatergic function and brain connectivity in first episode psychosis and their change with treatment. The results of proposed studies could suggest a mechanism by which DUP is associated with poor treatment response which might lead to new interventions to target DUP.