Glutamate, brain connectivity and duration of untreated psychosis

描述（由申请人提供）：精神分裂症疾病的前驱期和早期阶段与社交和智力能力显著下降有关，慢性疾病的下降更为温和。荟萃分析一致地确定了未治疗精神病（DUP）的持续时间较长、出现阳性症状和治疗之间的持续时间较长以及较差的长期结果之间的关系。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。过量的谷氨酸能改变大脑的连通性，这可能解释了为什么DUP时间较长的人临床结果更差。我们建议使用多模式神经成像技术对67名首次发作的精神病患者进行利培酮（一种常用的抗精神病药物）治疗前后16周的研究。我们将测量(1)谷氨酸和(2)大脑结构和功能连通性的指标，并测试谷氨酸能异常在首发患者中存在的假设，以及更长时间的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。我们之前的联合磁共振光谱（1H-MRS）、弥散张量成像（DTI）和静息状态功能磁共振（fMRI）研究在了解未服药的精神分裂症患者谷氨酸系统和大脑连接的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的相关性紊乱，这表明谷氨酸/谷氨酰胺周期异常。虽然抗精神病药物似乎可以调节谷氨酸，但代谢物之间相关性的紊乱并没有随着治疗而恢复。此外，我们发现未接受药物治疗的精神分裂症患者的结构和功能连接异常预测了患者随后对治疗的反应。据我们所知，还没有其他研究小组使用互补的神经成像技术进行研究，以获得首发精神病中谷氨酸能功能和大脑连通性的广泛特征，以及它们在治疗中的变化。拟议的研究结果可能提示DUP与不良治疗反应相关的机制，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.