Confirmatory Double-Blind Placebo-Controlled Efficacy Trial of a Gluten-Free Diet in a Subgroup of Persons with Schizophrenia Who Have High Levels of IgG Anti-Gliadin Antibodies

摘要 在过去的十年里，广泛的研究表明，大约三分之一的精神分裂症患者 有较高水平的抗醇溶蛋白抗体的Ig G类型(AGA Ig G)。这个对面筋敏感的群体可能 代表了一种尚未被认识到的病因。在过去，从饮食中去除面筋被证明可以 在戏剧性的病例报告和小型临床试验中减少或消除精神分裂症症状，但不是 始终如一。直到20世纪90年代的S，筛查IgA的能力才得到很好的发展，以至于没有一个人 在之前的无麸质饮食试验中，有2/3的人对精神分裂症患者进行了AGA免疫球蛋白筛查 这些研究的参与者不太可能从无麸质饮食(GFD)中受益。我们有 完成了两项临床试验(一项开放标签，一项随机双盲安慰剂对照)，证明 具有这种AGA免疫球蛋白表型精神分裂症患者从GFD中受益，而且在 阴性症状与AGA免疫球蛋白水平的变化有关。我们还表明，AGA抗体与 外周(即细胞因子)和中枢(即磁共振波谱(MRS)神经成像) 炎症指标。本申请提出了一种验证性双盲随机安慰剂- GFD对精神分裂症或分裂情感性患者住院期间疗效的对照试验 AGA-Ig G阳性的疾病。我们将筛查约600-800人的图表诊断 精神分裂症AGA抗体水平高，招募50名符合资格标准的患者进入住院单元 控制无面筋饮食(每天少于15毫克面筋)，为期五周。每天，试验组 将收到一份含有米粉的奶昔(25克)，对照组收到一份相同的蛋白质奶昔，其中包括 面筋面粉(25克)。我们将测试将目标参与(AGA-IgG)连接到的潜在作用机制 外周免疫激活指标(肿瘤坏死因子-α和白介素I-β)和肠道通透性改变引起的症状 (zonlin和ASCA)，以及与神经炎症相关的神经成像技术(MRS测量 肌醇和总胆碱)。 我们的验证性研究将有足够的力量来确定GFD的效用，或可信地 证明它是无效的。如果GFD如我们假设的那样有效，这将增加一种新的治疗方法 半个多世纪以来第一次用于精神分裂症的医疗模式。此外，这项研究还表明 面筋撤除效应的作用机制和致病途径。如果这种疗法是有效的，它 将通过帮助定义醇溶蛋白敏感型疾病来彻底改变精神分裂症的个性化药物 表型，并通过刺激开发其他药物的治疗，以阻断吸收 面筋。阴性结果将重新引导人们对这一病因途径的兴趣，以了解和治疗 精神分裂症的病理生理学，并预防精神分裂症患者的非生产性Gfds。

Summary In the past decade extensive research has shown that about one in three persons with schizophrenia have high levels of anti-gliadin antibodies of the IgG type (AGA IgG). This gluten sensitive group could represent an as-yet-unrecognized etiology. In the past, removing gluten from the diet has been shown to diminish or eliminate schizophrenia symptoms in dramatic case reports and small clinical trials, but not consistently. The ability to screen for AGA IgG was not well developed until the 1990's, so that not a single one of the previous gluten-free diet trials screened schizophrenia patients for AGA IgG, meaning that 2/3 of the participants in these studies would have been unlikely to benefit from the gluten-free diet (GFD). We have completed 2 clinical trials (one open label, one randomized double blind placebo controlled) demonstrating that people with schizophrenia having this AGA IgG phenotype benefit from a GFD and that strong improvement in negative symptoms is linked to changes in levels of AGA IgG. We have also shown that AGA IgG is linked to both peripheral (i.e. cytokines) and central (i.e., magnetic resonance spectroscopy (MRS) neuroimaging) measures of inflammation. This application proposes a confirmatory double-blind randomized placebo- controlled trial of the effects of a GFD in an inpatient setting in people with schizophrenia or schizoaffective disorder who are positive to AGA IgG. We will screen about 600-800 persons with chart diagnosis of schizophrenia for high levels of AGA IgG, recruiting 50 who meet eligibility criteria into an inpatient unit with controlled gluten free diet (less than 15 mg of gluten per day) for five weeks. Each day the experimental group will receive a shake containing rice flour (25 gram), and the control group an identical protein shake containing gluten flour (25 gram). We will test potential mechanisms of action linking the target engagement (AGA IgG) to symptoms via alteration in peripheral measures of immune activation (TNF-α and IL-Iβ) and gut permeability (zonulin and ASCA), as well as neuroimaging techniques related to neuroinflammation (MRS measures of myoinositol and total choline). Our confirmatory study will be adequately powered to establish the utility of the GFD, or to credibly demonstrate that it is not effective. If the GFD is effective, as we hypothesize, this would add a new treatment modality for schizophrenia for the first time in over half a century. In addition, the study would suggest mechanisms of action and etiologic pathways for the effects of gluten withdrawal. If this treatment is effective, it would revolutionize personalized medicine in schizophrenia by helping to define the gliadin-sensitive illness phenotype and by stimulating development of additional treatments of medications which block absorption of gluten. Negative results would redirect interest from this etiologic pathway for understanding and treatment of schizophrenia pathophysiology, and forestall unproductive GFDs in persons with schizophrenia.