Kelly Deanna L, Lee Christopher M, Roche Daniel J O, Talor Monica V, Clark Sarah, Eaton William W
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
medRxiv. 2025 Feb 25:2025.02.24.25322813. doi: 10.1101/2025.02.24.25322813.
Schizophrenia and related disorders (SRD) are characterized by positive and negative symptoms, such as anhedonia and avolition. There are no current FDA approved treatments for negative symptoms, which is a critical gap in our treatment of people with SRDs, since they are a major determinant of functional impairment. An emerging literature suggests that SRDs have a relationship with immune function and inflammation. Recently an SRD subgroup with high inflammation and elevated levels of anti-gliadin antibodies (AGA) of immunoglobulin G type (IgG) ha been characterized. Negative symptom improvement has been previously observed with gluten removal in this subgroup in two small clinical trials.
We conducted a 5-week confirmatory double-blind placebo-controlled trial of a gluten free diet (GFD) versus gluten-containing diet (GCD) for negative symptoms in people with SRD who have elevated AGA IgG (NCT03183609). Participants were between the ages of 18-64 years, had baseline negative symptoms and a diagnosis of schizophrenia or schizoaffective disorder. Those included were screened for an AGA IgG >20 U, no serologic evidence of celiac disease, and stable antipsychotic treatment and dose. All participants were inpatients, received a GFD and were randomized to 30 grams of gluten or rice flour daily delivered in protein shakes. The Clinical Assessment Interview for Negative Symptoms (CAINS) Motivation and Pleasure (MAP) scale was the primary outcome measure. We also examined the CAINS Expressivity (EXP) scale, the Scale for the Assessment of Negative Symptoms (SANS), the Brief Psychiatric Rating Scale (BPRS), the MATRICS Consensus Cognitive Battery (MCCB) and conducted regular side effect screening and laboratory measures for safety.
Between 2018 and 2024, we included 39 participants (N=21 GFD and N=18 GCD). There was a significant improvement over time in the CAINS MAP (treatment X time =30.1, =2.78, =0.045) in the GFD compared to GCD, but no significant change in the CAINS EXP, the SANS, BPRS or MCCB. The diet was well tolerated; the most frequently occurring side effects were constipation (38.1% GFD, 33.3% GCD), sedation (33.3% GFD, 50% GCD), dry mouth (33.3% GFD, 33.3% GCD), headache (33.3% GFD, 27.8% GCD), and insomnia (33.3% GFD, 27.8% GCD).
This is the first large scale double-blind randomized clinical trial in SRD with AGA IgG+. This replication of smaller studies suggests that negative symptoms, particularly anhedonia and avolition may be improved. However, we did not replicate our previous finding of cognitive improvement and COVID-19 likely impacted the extent of improvement in negative symptoms due to quarantines and lockdowns. More work is needed to determine the mechanism of action of gluten removal in this subgroup with hopes of developing new treatment targets for motivational deficits of this illness.
This project was funded by NIMH R01 R01MH113617 (DL Kelly PI).
精神分裂症及相关障碍（SRD）的特征为存在阳性和阴性症状，如快感缺乏和意志缺失。目前美国食品药品监督管理局（FDA）尚未批准用于治疗阴性症状的药物，这是我们治疗SRD患者时的一个关键缺口，因为阴性症状是功能障碍的主要决定因素。越来越多的文献表明，SRD与免疫功能和炎症有关。最近，已确定了一个炎症水平高且免疫球蛋白G型（IgG）抗麦醇溶蛋白抗体（AGA）水平升高的SRD亚组。此前在两项小型临床试验中观察到，该亚组患者去除麸质后阴性症状有所改善。
我们针对AGA IgG升高的SRD患者进行了一项为期5周的验证性双盲安慰剂对照试验，比较无麸质饮食（GFD）与含麸质饮食（GCD）对阴性症状的影响（NCT03183609）。参与者年龄在18至64岁之间，有基线阴性症状，且诊断为精神分裂症或分裂情感性障碍。入选者需筛查AGA IgG>20 U，无乳糜泻的血清学证据，且抗精神病药物治疗和剂量稳定。所有参与者均为住院患者，接受GFD，并随机分配至每日摄入30克麸质或米粉（以蛋白奶昔形式提供）的组中。阴性症状临床评估访谈（CAINS）动机与快感（MAP）量表是主要结局指标。我们还检查了CAINS表达（EXP）量表、阴性症状评估量表（SANS）、简明精神病评定量表（BPRS）、MATRICS共识认知成套测验（MCCB），并定期进行副作用筛查和实验室检查以确保安全。
在2018年至2024年期间，我们纳入了39名参与者（GFD组21名，GCD组18名）。与GCD组相比，GFD组的CAINS MAP随时间有显著改善（治疗×时间=30.1，F=2.78，P=0.045），但CAINS EXP、SANS、BPRS或MCCB无显著变化。该饮食耐受性良好；最常出现的副作用为便秘（GFD组38.1%，GCD组33.3%）、镇静（GFD组33.3%，GCD组50%）、口干（GFD组33.3%，GCD组33.3%）、头痛（GFD组33.3%，GCD组27.8%）和失眠（GFD组33.3%，GCD组27.8%）。
这是第一项针对AGA IgG阳性的SRD患者的大规模双盲随机临床试验。对较小规模研究的重复表明，阴性症状，尤其是快感缺乏和意志缺失可能会得到改善。然而，我们并未重复之前认知改善的发现，且由于隔离和封锁措施，新冠疫情可能影响了阴性症状的改善程度。需要开展更多工作来确定该亚组中去除麸质的作用机制，以期为该疾病的动机缺陷开发新的治疗靶点。
本项目由美国国立精神卫生研究所（NIMH）R01 R01MH113617资助（DL Kelly为首席研究员）。
