M-CPP PET Scanning of Alcoholism:Effects of Sertraline

描述（由申请人提供）： 大量的临床前和临床工作证明了5-羟色胺系统与酒精中毒有关。 最近发表的两项成功的血清素药物临床试验为该领域带来了重大希望。 一项研究证明了SSRI舍曲林在晚发性（A型）酗酒者中的显着效果，而另一项研究则证明了5-HT 3拮抗剂昂丹司琼在早发性酗酒者中的疗效。 在酒精中毒中没有其他治疗反应的预测因子。 神经影像学，特别是正电子发射断层扫描（PET），提供了一个强大的工具，以确定特定的大脑区域，可能是基础或与酗酒有关。神经内分泌，生理，主观和最近[18 F]氟脱氧葡萄糖（FDG）PET扫描反应的广谱5-羟色胺激动剂m-CPP都被用来检查5-羟色胺系统的酒精中毒，并已被用于预测临床反应的5-羟色胺药物在其他精神疾病。 FDG PET扫描最近也开始为我们提供对抑郁症和其他疾病的局部药物治疗反应的理解，但在酒精中毒中还没有这样做。 我们提出了一个临床试验的酒精中毒，增加了预测血清素神经成像和神经内分泌探针的研究，并在研究结束时进行后续成像扫描。 我们将选取100名近期戒酒的酗酒者，处方200毫克舍曲林，每周进行认知行为心理治疗，并随访12周。 我们将在试验前完成退出时进行m-CPP FDG PET扫描和安慰剂FDG PET扫描，并在试验完成时进行FDG PET扫描。 我们的目标是：首先，研究酗酒者组中由5-羟色胺探针m-CPP诱导的FDG-PET扫描相对于安慰剂FDG-PET扫描测量的局部脑代谢的变化，并将它们与健康对照组进行比较;其次，将m-CPP诱导的脑代谢变化与酗酒者组中舍曲林治疗试验中12周期间的临床反应相关联;最后，评估舍曲林对安慰剂FDG-PET扫描的局部代谢变化的影响，并将脑代谢变化与治疗结果相关联。 我们假设将有一组对舍曲林有反应的临床应答者和无应答者，并且在试验前对m-CPP激发的肾上腺素能反应的程度、大脑区域代谢、激素、生理或主观将预测试验中对舍曲林的治疗应答。 我们还假设治疗反应性舍曲林组的FDG-PET扫描正常化。 这项研究应该有助于确定一组治疗反应舍曲林，检查是否可以使用神经影像学和神经内分泌技术预测治疗反应，并确定哪些大脑区域涉及基线和治疗反应。

DESCRIPTION (provided by applicant): A significant body of preclinical and clinical work demonstrates the involvement of the serotonin system in alcoholism. Recent publication of two successful clinical trials of serotonin medications holds significant promise for the field. One study demonstrated a significant effect of the SSRI sertraline in late-onset (type A) alcoholics, while the other demonstrated efficacy of the 5-HT3-antagonist ondansetron in early-onset alcoholics. No other predictors of treatment response have been developed in alcoholism. Neuroimaging, particularly positron emission tomography (PET) scanning, offers a powerful tool to identify specific brain regions that may underlie or be associated with alcoholism. Neuroendocrine, physiological, subjective and recently [18 F] fluoro-deoxy-glucose (FDG) PET scanning responses to the broad spectrum serotonin agonist m-CPP have all been used to examine the serotonin system in alcoholism, and have previously been used to predict the clinical response to serotonin medications in other psychiatric disorders. FDG PET scanning has also recently begun to offer us an understanding of the regional pharmacotherapeutic treatment response to a serotonergic medication in depression, and in other disorders, but has yet to do so in alcoholism. We propose a clinical trial of a serotonergic medication in alcoholism, with the addition of a predictive serotonin neuroimaging and neuroendocrine probe before the study, and a follow up imaging scan at the end of the study. We will take 100 recently abstinent alcoholics, prescribe 200mg of sertraline together with weekly cognitive behavioral psychotherapy, and follow them for a 12-week period. We will perform an m-CPP FDG PET scan and a placebo FDG PET scan on completion of withdrawal prior to the trial, and an FDG PET scan on completion of the trial. Our aims are: firstly, to study changes in regional cerebral metabolism measured by FDG-PET scan induced by serotonin probe m-CPP relative to placebo FDG-PET scans in a group of alcoholics, and compare them with a group of healthy controls; secondly, to correlate the m-CPP induced changes in brain metabolism with the clinical response in a treatment trial of sertraline in the group of alcoholics over a 12-week period; and lastly, to assess the effect of sertraline on changes in placebo FDG- PET scans' regional metabolism, and to correlate changes in brain metabolism with treatment outcome. We hypothesize there will be group of clinical responders and non-responders in response to sertraline, and that the degree of serotonergic response, cerebral regional metabolic, hormonal, physiological or subjective, to the m-CPP challenge prior to the trial will predict the treatment response to sertraline in the trial. We would also hypothesize normalization of the FDG-PET scans in the treatment responsive sertraline group. This study should help identify a group of treatment responders to sertraline, examine whether that treatment response can be predicted using neuroimaging and neuroendocrine techniques, and identify what brain regions are implicated at baseline and in response to treatment.