M-CPP PET Scanning of Alcoholism:Effects of Sertraline

描述（由申请人提供）：大量临床前和临床工作证明血清素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。一项研究表明，SSRI类药物舍曲林对晚发型（a型）酗酒者有显著效果，而另一项研究表明，5- ht3拮抗剂昂丹司琼对早发型酗酒者有效。酒精中毒治疗反应的其他预测因素尚未发现。神经成像，特别是正电子发射断层扫描（PET）扫描，提供了一种强有力的工具来识别可能导致或与酒精中毒有关的特定大脑区域。神经内分泌、生理、主观以及最近[18 F]氟脱氧葡萄糖（FDG） PET扫描对广谱5 -羟色胺激动剂m-CPP的反应都已被用于检查酒精中毒患者的5 -羟色胺系统，并已被用于预测其他精神疾病患者对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中5 -羟色胺能药物的区域药物治疗反应的理解，但尚未在酒精中毒中做到这一点。我们建议对酒精中毒患者进行5 -羟色胺能药物的临床试验，并在研究前进行预测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随访成像扫描。我们将选取100名最近戒酒的酗酒者，给他们开200毫克的舍曲林和每周的认知行为心理治疗，并对他们进行为期12周的随访。我们将在试验前完成停药时进行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5 -羟色胺探针m-CPP诱导FDG-PET扫描相对于安慰剂FDG-PET扫描在一组酗酒者中的区域脑代谢变化，并与健康对照组进行比较；其次，将m-CPP诱导的脑代谢变化与一项为期12周的舍曲林治疗试验中酗酒者的临床反应联系起来；最后，评估舍曲林对安慰剂FDG- PET扫描区域代谢变化的影响，并将脑代谢变化与治疗结果联系起来。我们假设对舍曲林有临床反应和无反应，并且试验前对m-CPP挑战的血清素能反应、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。我们还假设在治疗反应性舍曲林组中FDG-PET扫描正常化。这项研究将有助于确定一组对舍曲林有治疗反应的患者，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，并确定在基线和治疗反应中涉及的大脑区域。

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.