BLOOD FLOW CHANGES AND ANTIPSYCHOTIC DRUG ACTION

说明(摘自申请者的摘要)：抗精神病药物可减少精神病，引起运动效应，并有其他各种作用。除了对受体群体的作用外，这些影响的大脑底物还知之甚少。研究人员建议使用PET和15OH2在非药物精神分裂症患者中确定抗精神病药物对局部脑血流量(RCBF)影响的动态时间进程，作为对人脑药物作用的直接药效学评估。RCBF测量将跨越药代动力学时间进程。研究人员建议表征两种不同的抗精神病药物，传统的抗精神病药物氟哌啶醇和新型抗精神病药物奥氮平急性和6天给药后rCBF变化的动态时间过程。还将评估急性和亚急性抗精神病药物治疗后rCBF变化预测后续治疗反应的能力。根据他们的初步发现，研究人员假设，选定区域由药物引起的急性和亚急性rCBF变化将预测阳性症状(前扣带回和内侧额叶皮质)、阴性症状(额叶中叶和顶下皮质)和运动副作用(基底节)的治疗反应。建议的亚急性给药方案将接近两种抗精神病药物的药代动力学稳态。该提案的另一个目的是比较氟哌啶醇和奥氮平在急性和亚急性(稳态)抗精神病药物注射的扫描过程中引起的rCBF变化。研究人员提出，基底节的激活模式将最好地区分这两种抗精神病药物。这些研究有望提供抗精神病药物活性的rCBF相关性。这些信息将允许开发与药物作用机制相关的假说，以及潜在的药物作用替代标记物。

DESCRIPTION (adapted from applicant's abstract): Antipsychotic drugs reduce psychosis, induce motor effects, and have miscellaneous other actions. The brain substrates of these effects, beyond actions on receptor populations are poorly understood. The investigator proposes to determine the dynamic time course of the effects of antipsychotics on regional cerebral blood flow (rCBF) using PET and 15OH2 in drug-free schizophrenia patients as a direct pharmacodynamic assessment of drug action in the human brain. rCBF measurements would span the pharmacokinetic time course. The investigator proposes to characterize the dynamic time course of rCBF alterations following the acute and six days of administration of two different antipsychotic drugs, the traditional antipsychotic haloperidol and the newer antipsychotic olanzapine. The ability of the changes in rCBF following acute and subacute antipsychotic administration to predict subsequent treatment response would also be evaluated. Based on their preliminary findings, the investigators hypothesize that acute and subacute drug-induced rCBF changes in selected regions will predict treatment response for positive symptoms (anterior cingulate and medial frontal cortex), for negative symptoms (middle frontal cortex and inferior parietal cortex), and motor side effects (basal ganglia). The proposed subacute drug administration regimen would approximate a pharmacokinetic steady state for both antipsychotics. An additional aim of the proposal is to compare the rCBF changes induced by haloperidol versus olanzapine during the scanning sessions obtained with acute and subacute (steady state) antipsychotic administration. The investigator proposes that the pattern of activation in the basal ganglia will best discriminate the two antipsychotic agents. These studies will hopefully provide rCBF correlates of antipsychotic activity. This information will allow the development of hypotheses related to drug mechanism of action, as well as potential surrogate markers of drug action.