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

对具有高水平 IgG 抗麦醇溶蛋白抗体的精神分裂症患者亚组进行无麸质饮食的验证性双盲安慰剂对照疗效试验

• 批准号: 10001815
• 负责人: WILLIAM W EATON
• 金额: $ 21.2万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001815
• 关键词: Antibodies; Antigens; Area; Barley; Blood; Brain; Case Study; Celiac Disease; Cerebrospinal Fluid; Choline; Clinical; Clinical Trials; Control Groups; DSM-V; Development; Diagnosis; Diet; Diffusion Magnetic Resonance Imaging; Double-Blind Method; Eligibility Determination; Environment; Etiology; Flour; Functional disorder; Gliadin; Glutamate Receptor; Gluten; Immunoglobulin G; Impaired cognition; Inflammation; Inpatients; Intervention; Intestinal permeability; Link; Magnetic Resonance Spectroscopy; Measures; Mediating; Meta-Analysis; Modality; Neurobehavioral Manifestations; Neurologic; Outcome; Participant; Pathway interactions; Patient Recruitments; Patients; Peripheral; Permeability; Persons; Pharmaceutical Preparations; Phenotype; Placebos; Population; Prevention; Proteins; Randomized; Randomized Controlled Trials; Reporting; Research; Rice; Rye cereal; Saccharomyces cerevisiae; Schizoaffective Disorders; Schizophrenia; Series; Specificity; Subgroup; Symptoms; TNF gene; Techniques; Testing; Time; Water; Wheat; Withdrawal; Work; absorption; anti-IgG; blood-brain barrier permeabilization; confirmatory clinical trial; cytokine; efficacy trial; experimental group; extracellular; immune activation; immunoreaction; improved; interest; myoinositol; neuroimaging; neuroinflammation; open label; personalized medicine; randomized placebo controlled trial; receptor; recruit; symptomatic improvement; zonulin

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.

总结 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 具有高水平的IgG型抗麦胶蛋白抗体（阿加IgG）。这种麸质敏感的群体可以 代表了一种尚未被认识的病因在过去，从饮食中去除麸质已被证明， 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， 始终如一直到20世纪90年代，筛选阿加IgG的能力才得到很好的发展，因此没有一个人 的先前无麸质饮食试验筛选精神分裂症患者的阿加IgG，这意味着2/3的 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2项临床试验（一项开放标签，一项随机双盲安慰剂对照），证明 具有这种阿加IgG表型的精神分裂症患者受益于GFD， 阴性症状与阿加IgG水平的变化有关。我们还表明，阿加IgG与 外周（即细胞因子）和中枢（即，磁共振波谱（MRS）神经成像） 炎症的测量。本申请提出了一种验证性双盲随机安慰剂- GFD对精神分裂症或情感性精神分裂症患者住院治疗效果的对照试验 阿加IgG阳性者。我们将筛查约600-800人， 精神分裂症高水平的阿加IgG，招募50名符合资格标准的患者进入住院部， 控制无麸质饮食（每天少于15毫克麸质）五周。每天实验组 将接受含有米粉（25克）的奶昔，对照组接受相同的蛋白质奶昔， 面筋面粉（25克）。我们将测试将靶向接合（阿加IgG）与 通过外周免疫活化（TNF-α和IL-1 β）和肠道通透性指标的改变而出现症状 （zonulin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把握度来确定GFD的效用，或 证明它是无效的。如果GFD是有效的，正如我们假设的那样，这将增加一种新的治疗方法， 这是世纪以来首次出现精神分裂症的治疗方法。此外，该研究还表明， 面筋撤退的影响的作用机制和病因途径。如果治疗有效， 将通过帮助定义对麦胶蛋白敏感的疾病， 表型，并通过刺激开发其他治疗药物，阻止吸收 面筋。阴性结果将重新引导对该病因学途径的兴趣，以了解和治疗 精神分裂症病理生理学，并预防精神分裂症患者的非生产性GFD。