MICA: Targeting neuro-inflammation in Schizophrenia

精神分裂症是一种慢性致残精神疾病，每100人中就有1人患有精神分裂症。它是职业成年人疾病负担的十大原因之一，患者通常过早死亡20年。精神分裂症的经济负担非常沉重：据估计，英国每年要花费118亿英镑，整个欧洲每年大约要花费1000亿欧元。在过去的60年里，抗精神病药物一直是精神分裂症的基石和一线治疗方法。然而，在四分之三的患者中，它们是无效的或不能耐受的，即使在有效的情况下，它们对阴性和认知症状的疗效有限，并且不能改善疾病。鉴于现有治疗方法的这些局限性，对精神分裂症的替代更好的治疗方法，特别是那些可能改变疾病的治疗方法，迫切需要和巨大的潜力。在精神分裂症患者中可以看到许多大脑变化，但最近的证据表明，炎症系统的变化可能是导致这种疾病的关键因素。多种证据表明，精神分裂症患者的炎症程度有所增加，不仅在血液中，而且在大脑中，一种叫做小胶质细胞的细胞过度活跃。小胶质细胞是大脑中主要的免疫细胞。使用一种称为正电子发射断层扫描（PET）的神经成像技术，可以测量活体人类的小胶质细胞激活。通过PET成像，我们的研究小组和其他研究人员发现精神分裂症患者的小胶质细胞活性增加，我们也发现在精神分裂症的早期阶段，在抗精神病药物治疗之前。此外，更大的小胶质细胞过度活动与更严重的症状有关。综合这些证据，特别是与精神分裂症早期症状严重程度和升高的关联，暗示了小胶质细胞在精神分裂症病理生理中的激活，并表明靶向小胶质细胞可能是一种新的治疗方法。然而，目前尚不清楚激活的小胶质细胞是否在精神分裂症的症状和其他大脑变化中起主要作用，或者小胶质细胞的变化是否是次要现象。关键的测试是逆转小胶质细胞的激活，并确定对症状和大脑测量的影响。为了达到这个目的，我们的目标是使用一种名为natalizumab的药物，专门针对小胶质细胞。在之前的工作中，我们已经证明natalizumab可以减少多发性硬化症患者的小胶质细胞过度活动，多发性硬化症是一种以神经炎症强烈增加为特征的疾病。这表明natalizumab进入大脑，可能对精神分裂症有潜在的影响。在本提案中，我们计划测试两个关键的知识缺口。首先是小胶质细胞过度活跃是否与精神分裂症中出现的其他大脑变化有关。另一个是是否有可能减少精神分裂症患者的小胶质细胞过度活动，以及这是否会改善症状。为此，我们将使用脑部扫描来测量小胶质细胞以及已知在精神分裂症中发生改变的大脑结构和功能的其他方面。然后，我们将给精神分裂症患者服用natalizumab或安慰剂3个月，以便：i)通过PET成像评估，检查natalizumab治疗是否会导致神经炎症的减少；Ii)与安慰剂相比，神经炎症的减轻是否与精神分裂症症状严重程度的减轻有关。这项研究将为精神分裂症的小胶质细胞潜在的特异性靶向提供第一个证据，为这种疾病的新药开发提供一个合理的平台，并提高我们对疾病的神经生物学的理解。

Schizophrenia affects 1 in 100 people and is a chronic and disabling psychiatric illness. It is amongst the top ten causes of disease burden in working adults, and patients typically die 20 years prematurely. Schizophrenia has a very high economic burden: it costs the UK an estimated £11.8 billion per year and across Europe approximately 100 billion Euros each year.Antipsychotic drugs have been the cornerstone and first-line treatment for schizophrenia over the last 60 years. However, they are ineffective or not tolerated in three-quarters of patients and, even where they are effective they have limited efficacy for the negative and cognitive symptoms, and are not disease modifying.Given these limitations of existing treatments, there is an urgent need and huge potential for alternative, better treatments for schizophrenia, particularly those that may be disease modifying.A number of brain changes are seen in schizophrenia but recent evidence suggests a key role for alterations in the inflammatory system that could underlie the illness. Multiple lines of evidence have shown that there is an increase in inflammation in schizophrenia, not only in the blood but also in the brain where cells called microglia show overactivity. Microglia are the main immune cells in the brain. It is possible to measure microglia activation in living humans using a neuroimaging technique called Positron Emission Tomography (PET).Using PET imaging our research group and others have shown an increase in microglia activity in schizophrenia patients and we have also shown this in the early phase of schizophrenia, prior to antipsychotic treatment. Furthermore, greater microglia overactivity was linked to more severe symptoms.Taken together this evidence, particularly the association with symptom severity and the elevation in the early phase of schizophrenia, implicates microglial activation in the pathophysiology of schizophrenia, and indicates that targeting microglia could be a new approach to treatment. However, it is still unknown if activated microglia play a primary role in the symptoms and other brain changes seen in schizophrenia or whether microglia changes are a secondary phenomenon. The key test is to reverse microglial activation and determine the effect on symptoms and brain measures.To achieve this purpose we aim to use a drug called natalizumab that specifically targets microglia. In prior work we have shown that natalizumab reduces microglia overactivity in patients with multiple sclerosis, a disorder characterized by a strong increase in neuro-inflammation. This shows that natalizumab gets into the brain and could potentially have an effect in schizophrenia. In this proposal we plan to test two critical gaps in knowledge. The first is whether microglia overactivity is related to other brain changes seen in schizophrenia. The other is whether it is possible to reduce microglia overactivity in schizophrenia and if this will improve symptoms. To do this we will use brain scans to measure microglia and other aspects of brain structure and function known to be altered in schizophrenia. We will then give the patients with schizophrenia natalizumab or placebo for a period of 3 months in order to: i) examine if treatment with natalizumab will lead to a reduction in neuro-inflammation, as assessed via PET imaging; ii) if reduction in neuro-inflammation is associated with a reduction in schizophrenic symptom severity when compared to placebo.This study will provide the first evidence of the potential specific targeting of microglia in schizophrenia, providing a rational platform for the development of new drugs for this disorder as well as improving our understanding on the neurobiology of illness.