BLOOD FLOW CHANGES AND ANTIPSYCHOTIC DRUG ACTION

描述（改编自申请人摘要）：抗精神病药物减轻精神病，诱导运动效应，并具有其他杂项作用。这些影响的脑底物，除了对受体群体的作用外，人们知之甚少。研究者提出利用PET和15OH2测定抗精神病药物对无药精神分裂症患者局部脑血流量（rCBF）影响的动态时间过程，作为药物作用在人脑中的直接药效学评估。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的抗精神病药物（传统的氟哌啶醇和较新的抗精神病药物奥氮平）急性和6天后rCBF改变的动态时间过程。急性和亚急性抗精神病药物给药后rCBF变化预测后续治疗反应的能力也将被评估。基于他们的初步发现，研究人员假设，急性和亚急性药物诱导的rCBF在选定区域的变化将预测阳性症状（前扣带皮层和内侧额叶皮层）、阴性症状（额叶皮层中部和下顶叶皮层）和运动副作用（基底神经节）的治疗反应。提议的亚急性给药方案将近似于两种抗精神病药物的药代动力学稳定状态。该提案的另一个目的是比较氟哌啶醇与奥氮平在急性和亚急性（稳定状态）抗精神病药物治疗期间扫描过程中引起的rCBF变化。研究者提出，基底神经节的激活模式将最好地区分两种抗精神病药物。这些研究有望提供rCBF与抗精神病活性的相关性。这些信息将允许发展与药物作用机制有关的假设，以及药物作用的潜在替代标记物。

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.