Psychosis Immune Mechanism Stratified Medicine Study (PIMS)

低度炎症，特别是与促炎细胞因子白细胞介素6（IL-6）通路相关的炎症，可能与精神病有因果关系，并提供了创新的治疗靶点。在精神病发作之前，循环IL-6和相关蛋白水平升高，并且可能在具有特定类型症状的患者中更常见-认知困难，如工作记忆和信息处理困难，以及阴性症状，如动机不良，快乐减少，面部表情减少，言语减少和社会孤立。还有证据表明，炎症可能与精神病中常见的抑郁症等情绪症状有关。然而，最近的精神病抗炎药药物试验产生了混合的结果，可能是因为这些药物被给予精神病患者群体，而不管是否有当前炎症的证据。PIMS项目将重点关注IL-6通路，以及IL-6上游（白细胞介素1 β（IL-1B）和肿瘤坏死因子（TNF-α））和下游（C反应蛋白）的免疫标志物，作为精神分裂症潜在的新治疗靶点。首先，我们将使用孟德尔随机化分析现有的大型基因组数据，以测试是否IL-6和相关的免疫标记物与精神病的因果关系。然后，我们将使用来自大型临床和流行病学样本的现有数据以及机器学习方法来识别与炎症最密切相关的疾病阶段和症状维度，以及炎症标志物的外周血水平与大脑结构的相关性：识别免疫相关精神病的生物型。这项工作将为一项随机双盲实验医学研究提供信息，给有炎症证据的精神病患者一剂托珠单抗。Tocilizumab是一种用于风湿性关节炎的抗炎药物，可阻断IL-6信号传导。我们将看到这是否对精神病症状特别是认知有任何影响。我们将测试IL-6阻断是否对循环炎症标志物和使用与精神病有关的磁共振波谱的氧化应激的脑测量有影响。我们将对托珠单抗治疗前后从患者身上收集的免疫细胞进行实验;这可以识别精神病中观察到的低度炎症的细胞来源。我们将从特定的血细胞（单核细胞）中创建模型脑细胞，以测试它们在不同的测试条件下是否与健康人有不同的行为。最后，我们将利用结果来完善已建立的精神分裂症动物模型，以了解免疫靶点和炎症相关精神病的生物学。PIMS研究小组由精神病，免疫精神病学，流行病学，神经科学，生物信息学，基因组学和药理学方面的专家组成，他们在各自领域有良好的记录，并有合作和/或领导大型项目的经验。我们将与我们的行业咨询委员会合作，推进研究结果，最终目标是为患有活动性炎症的精神病患者开发新的分层药物治疗。

Low-grade inflammation, particularly that related to the pro-inflammatory cytokine interleukin 6 (IL-6) pathway, could be causally linked to psychosis, and offers innovative treatment targets. Elevated circulating IL-6 and related protein levels are present prior to psychosis onset and may be seen more often in patients with specific types of symptoms - cognitive difficulties such as working memory and difficulty processing information and negative symptoms such as poor motivation, diminished pleasure, reduced facial expression, reduced speech and social isolation. There is also evidence that inflammation may be related to mood symptoms such as depression, which are common in psychosis. However, recent drug trials of anti-inflammatory agents in psychosis have yielded mixed results, potentially because these were given to groups of patients with psychosis regardless of whether there was evidence of current inflammation. It is unlikely anti-inflammatory treatment could be helpful for patients who do not have increased inflammation.The PIMS project will focus on the IL-6 pathway, and immune markers up (interleukin 1 beta (IL-1B) and tumour necrosis factor (TNF-a) and downstream (C-reactive protein) of IL-6, as potential new therapeutic target for schizophrenia using a number of approaches. First, we will use Mendelian randomization analysis of existing large genomic data to test whether IL-6 and related immune markers are causally linked with psychosis. We will then use existing data from large clinical and epidemiological samples and machine learning approaches to identify illness stage and symptom dimension most closely linked with inflammation, and the relevance of peripheral blood levels of markers of inflammation to brain structure: identifying the biotype of immune-related psychosis. This work will inform a randomised double blind experimental medicine study, giving psychosis patients with evidence of inflammation one dose of Tocilizumab. Tocilizumab is an anti-inflammatory medication used in Rheumatoid arthritis that blocks IL-6 signalling. We will see if this has any effect on psychotic symptoms especially cognition. We will test whether IL-6 blockade has effect and on circulating inflammatory markers and brain measures of oxidative stress using magnetic resonance spectroscopy implicated in psychosis. We will carry out experiments on immune cells collected from patients before and after tocilizumab; this could identify cellular source of low-grade inflammation seen in psychosis. We will create modelled brain cells from specific blood cells (monocytes) to test whether they act differently from healthy people in different test conditions.Finally, we will use results to refine established animal models of schizophrenia to understand the biology of the immune target and inflammation-related psychosis. The PIMS study group comprises experts in psychosis, immuno-psychiatry, epidemiology, neuroscience, bioinformatics, genomics, and pharmacology with established track record in their fields and experience of collaborating and/or leading large projects. We will work with our Industry Advisory Board to take findings forward with the ultimate aim of developing new stratified medicine treatments for psychosis patients with active inflammation.