MICA: Targeting neuro-inflammation in Schizophrenia

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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.