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表明5-羟色胺系统参与了酒精中毒。最近发表的两项成功的5-羟色胺药物临床试验为该领域带来了巨大的希望。一项研究证明了SSRI舍曲林对迟发性(A型)酒精患者的显著效果，而另一项研究证明了5-HT3拮抗剂恩丹西酮对早发性酒精患者的疗效。目前还没有发现酒精中毒治疗反应的其他预测指标。神经成像，特别是正电子发射断层扫描(PET)，提供了一个强大的工具来识别特定的大脑区域，可能是酒精中毒的基础或与之相关。神经内分泌、生理、主观和最近的[18F]氟代脱氧葡萄糖(FDG)PET扫描对广谱5-羟色胺激动剂m-CPP的反应都被用来检查酒精中毒的5-羟色胺系统，并且以前被用来预测其他精神疾病对5-羟色胺药物的临床反应。FDG PET扫描最近也开始为我们提供对抑郁症和其他疾病患者对5-羟色胺能药物的局部药物治疗反应的了解，但在酒精中毒方面尚未做到这一点。我们建议对一种5-羟色胺能药物治疗酒精中毒进行临床试验，在研究之前增加一个预测性的5-羟色胺神经成像和神经内分泌探针，并在研究结束时进行后续的成像扫描。我们将接受100名最近戒酒的人，开出200毫克舍曲林，并每周进行认知行为心理治疗，并对他们进行为期12周的跟踪观察。我们将在试验前停药完成时进行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。我们的目的是：首先，研究一组酗酒者相对于安慰剂FDG-PET扫描所测得的m-CPP诱发的局部脑代谢改变，并与一组健康对照组进行比较；其次，研究m-CPP诱导的脑代谢改变与舍曲林治疗12周的临床疗效之间的相关性；最后，评估舍曲林对安慰剂FDG-PET扫描局部代谢改变的影响，以及脑代谢变化与治疗结果的相关性。我们假设将有一组临床应答者和无应答者对舍曲林做出反应，试验前对m-CPP挑战的5-羟色胺能反应、大脑区域代谢、激素、生理或主观反应的程度将预测试验中对舍曲林的治疗反应。我们还假设治疗反应舍曲林组的FDG-PET扫描正常化。这项研究应该有助于确定舍曲林的一组治疗反应者，检查是否可以使用神经成像和神经内分泌技术预测治疗反应，并确定基线和治疗反应涉及的大脑区域。

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.