MICA: Targeting neuro-inflammation in Schizophrenia

精神分裂症是一种慢性致残性精神疾病，每100人中就有1人受到影响。它是造成在职成年人疾病负担的十大原因之一，患者通常会过早死亡20年。精神分裂症有非常高的经济负担：据估计，英国每年花费118亿英镑，整个欧洲每年约花费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。然而，四分之三的患者对它们无效或无法耐受，即使它们有效，对阴性症状和认知症状的疗效也有限，而且不能改善疾病。鉴于现有治疗的这些局限性，精神分裂症迫切需要替代的、更好的治疗方法，特别是那些可能改善疾病的治疗方法。精神分裂症患者的大脑发生了一些变化，但最近的证据表明，炎症系统的变化在可能导致疾病的基础上发挥了关键作用。多条证据表明，精神分裂症患者的炎症增加，不仅在血液中，而且在大脑中，被称为小胶质细胞的细胞表现出过度活动。小胶质细胞是大脑中的主要免疫细胞。使用一种名为正电子发射断层扫描(PET)的神经成像技术，可以测量活人体内小胶质细胞的激活。使用PET成像，我们的研究小组和其他人已经显示，精神分裂症患者的小胶质细胞活动增加，我们也在抗精神病药物治疗之前的精神分裂症的早期阶段证明了这一点。综合这些证据，特别是与症状严重程度和精神分裂症早期升高的关系，小胶质细胞的激活与精神分裂症的病理生理有关，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脑变化中发挥了主要作用，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。为了实现这一目的，我们的目标是使用一种名为Natalizumab的药物，该药物专门针对小胶质细胞。在之前的工作中，我们已经表明，Natalizumab减少了多发性硬化症患者的小胶质细胞过度活动，这是一种以神经炎症的强烈增加为特征的疾病。这表明，那他珠单抗进入大脑，可能对精神分裂症有潜在的影响。在这项提案中，我们计划测试知识中的两个关键差距。第一个问题是小胶质细胞过度活动是否与精神分裂症的其他大脑变化有关。另一个问题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。为了做到这一点，我们将使用大脑扫描来测量小胶质细胞和已知精神分裂症患者大脑结构和功能的其他方面的变化。然后，我们将给予精神分裂症患者为期3个月的Natalizumab或安慰剂，以：i)通过PET成像评估，Natalizumab治疗是否会导致神经炎症的减轻；ii)与安慰剂相比，神经炎症的减轻是否与精神分裂症症状的严重程度降低相关。这项研究将提供精神分裂症中潜在的特定靶向小胶质细胞的第一个证据，为治疗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.