Selecting Best Neuroleptic Treatment for Veterans with Schizophrenia

描述（由申请人提供）： 拟议的研究的主要目标是开始将基础和临床研究转化为创新的临床评估和治疗方法。功能性脑成像以及动物2-脱氧葡萄糖研究表明，抗精神病药物对纹状体活动具有强大的影响。本项目是我们和其他人的一系列研究的后续研究，这些研究发现，通过18-F-2-脱氧葡萄糖正电子发射断层扫描（FDG-PET）评估纹状体的相对代谢率较低，可预测抗精神病药物的反应。我们将在基线（第0天）和为期4周的利培酮治疗试验结束时，在大样本未用药的精神分裂症患者（n=64;加上额外的16例患者，以允许20%的损耗）中获得fMRI和感觉运动门控（惊吓的被动和主动注意前脉冲抑制（PPI））。使用功能磁共振成像，该项目将扩展早期的FDG-PET研究，该研究显示低背尾状核活动预测抗精神病药物反应。我们还将获得健康对照组（n=32;加上3个损耗）的fMRI和PPI测量值，作为比较反应亚组与治疗无反应亚组相比，利培酮治疗后尾状核和PPI活性是否更正常化的基准。 我们的试点数据表明，PPI措施是一个潜在的代理尾状核功能，并可能最终作为有用的中间治疗预测。我们也有新的试点数据表明，低尾状核活动测量功能磁共振成像和穷人PPI显示出一种趋势，预测更好的反应，4周利培酮试验精神分裂症患者。我们预计该项目将需要四年时间：启动三个月，患者和健康对照组采集39个月，数据分析和撰写科学手稿6个月。该项目将在James J. Peters VA医疗中心进行，涉及从三个中心招募的患者：James J. Peters和纽约港VA医疗中心以及西奈山医院（J. J. Peters VAMC附属机构）。大约三分之二的患者样本将在J. J. Peters VAMC招募、诊断和治疗。三分之一的患者样本将从NY Harbor VAMC招募，来自Mount Sinai的患者将仅用于脱落目的。将从James J. Peters VAMC招募健康对照。功能磁共振成像和心理生理学测试将在西奈山为所有研究参与者进行，那里有最先进的头部专用3 T磁共振成像扫描仪和认知心理生理学实验室。 这项研究的主要目的是开始鉴定潜在的生物标志物，用于预测精神分裂症患者抗精神病药物治疗的反应。目前，还没有生物学标记来帮助精神科医生确定哪种抗精神病药物将在给定患者中产生最佳反应。相反，为特定患者选择抗精神病药物涉及复杂的试错过程。证明尾状核和感觉运动门控措施作为预测精神分裂症患者治疗反应的生物标志物的有用性，可以将生态有效的工具从实验室带到床边。

DESCRIPTION (provided by applicant): The proposed research has the primary goal of beginning to translate basic and clinical research into innovative clinical assessment and therapeutics. Functional brain imaging, as well as, animal 2-deoxyglucose studies have demonstrated that antipsychotic drugs have robust effects on striatal activity. This project is a follow-up to a series of studies of ours and others that have found low relative metabolic rates in the striatum as assessed by 18-F-2-deoxyglucose positron emission tomography (FDG-PET) to predict antipsychotic response. We will acquire fMRI and sensorimotor gating (passive- and active-attention prepulse inhibition (PPI) of startle) in a large sample of unmedicated schizophrenia patients (n=64; plus an additional 16 patients to allow for 20% attrition) at baseline (Day 0) and at the end of a 4-week risperidone treatment trial. Using fMRI, this project will extend earlier FDG-PET studies which showed low dorsal caudate activity predicts antipsychotic response. We will also obtain fMRI and PPI measures in a healthy-control group (n=32; plus 3 for attrition) as a benchmark for comparing whether caudate and PPI activity is more normalized with risperidone treatment in the responder subgroup compared with the treatment non-responder subgroup. Our pilot data suggest that PPI measures are a potential proxy for caudate function and may eventually serve as useful intermediary treatment predictors. We also have new pilot data indicating that low caudate activity measured with fMRI and poor PPI show a trend for predicting better response to a 4-week risperidone trial in schizophrenia patients. We anticipate that this project will take four years: three months for startup, 39 months for patient and healthy control comparison group acquisition, and 6 months for data analysis and writing scientific manuscripts. The project will be conducted at the James J. Peters VA Medical Center and involve patients recruited from three sites: the James J. Peters and New York Harbor VA Medical Centers, and Mount Sinai Hospital (J.J. Peters VAMC affiliate). Approximately two-thirds of the patient sample will be recruited, diagnosed and treated at the J.J. Peters VAMC. One-third of the patient sample will be recruited from the NY Harbor VAMC and patients from Mount Sinai will be recruited for attrition purposes only. Healthy controls will be recruited from the James J. Peters VAMC. The fMRI and psychophysiological testing sessions will take place at Mount Sinai for all study participants where a state-of-the-art head-dedicated 3T MRI scanner and the Cognitive Psychophysiology Laboratory are located. The primary objective of the proposed research is to begin to identify potential biomarkers for predicting antipsychotic treatment response in patients with schizophrenia. Currently, there is no biological marker to assist psychiatrists in determining which antipsychotic medication will give the optimal response in a given patient. Instead, the selection of an antipsychotic medication for a particular patient involves a complex trial- and-error process. Demonstration of the usefulness of caudate and sensorimotor gating measures as biomarkers for predicting treatment response in schizophrenia patients could bring ecologically-valid tools from bench to bedside.