BLOOD FLOW CHANGES AND ANTIPSYCHOTIC DRUG ACTION

描述（改编自申请人摘要）：抗精神病药物减少精神病，诱导运动效应，并有其他各种作用。除了对受体群体的作用外，这些作用的大脑底物还知之甚少。研究者建议使用PET和15OH2在无药物的精神分裂症患者中确定抗精神病药物对局部脑血流量（rCBF）影响的动态时程，作为药物在人脑中作用的直接药效学评估。rCBF测量将跨越药代动力学时间过程。研究者建议描述两种不同抗精神病药物（传统抗精神病药物氟哌啶醇和新型抗精神病药物奥氮平）急性给药和6天给药后rCBF变化的动态时程。还将评估急性和亚急性抗精神病药给药后rCBF变化预测后续治疗反应的能力。基于他们的初步研究结果，研究人员假设选定区域的急性和亚急性药物诱导的rCBF变化将预测阳性症状（前扣带回和内侧额叶皮层），阴性症状（中额叶皮层和下顶叶皮层）和运动副作用（基底神经节）的治疗反应。拟定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急性和亚急性（稳态）抗精神病药给药扫描期间氟哌啶醇与奥氮平诱导的rCBF变化。研究者认为，基底神经节的激活模式将最好地区分两种抗精神病药物。这些研究将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设，以及药物作用的潜在替代标志物。

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.