MICA: Targeting neuro-inflammation in Schizophrenia

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.

Schizophrenia affects about 1 in 100 people and is a leading cause of disability in adults. Current drug treatments, antipsychotics, are not effective or poorly tolerated in ~three-quarters of patients. Moreover, they essentially use the same dopamine receptor blocking mechanism. Therefore, there is an urgent need to identify alternative molecular targets to develop new treatment for this disorder.

Recent studies have shown that microglia activation plays a role in schizophrenia. Activated microglia express high levels of TSPO. Studies using TSPO PET tracers, such as [11C]-PK11195, have shown increased binding in patients with schizophrenia with large effect sizes (from 0.9 to 1.8), and increases are also seen in the prodromal phase of schizophrenia. Greater TSPO binding was positively correlated with greater symptom severity. However, it is still unknown if activated microglia play a primary role in the symptoms and brain changes seen in schizophrenia or whether changes are of secondary relevance. The key test is to reverse microglial activation and determine the effect on symptoms.

To achieve this purpose we will use natalizumab, a monoclonal antibody that specifically targets microglia. We have shown that this antibody reduces microglia activity in multiple sclerosis patients. In our study we will use [11C]-PK11195 PET imaging in conjunction with brain imaging, peripheral and central inflammatory markers and clinical assessment, in order to achieve the following objectives: 1) to assess if treatment with natalizumab will lead to a reduction in microglia activity when compared to placebo; 2) to determine if a reduction in microglial activity is associated with a reduction in schizophrenic symptom severity; 3) to determine if changes in microglial activity are directly associated with changes in pro-inflammatory cytokines; 4) to determine if changes in microglial activity are directly associated with structural brain changes.

Novelty:

We believe this study will be the first use of a monoclonal antibody targeting microglia in schizophrenia, and in psychiatry in general.
We also believe it will be the first study to obtain simultaneous PET-MR measures of microglial function and MR markers of glutamate and free water fraction. A key advantage of simultaneous acquisition of these data over conventional acquisition on different scanners at different times is that we will be able to determine their relationship at the same time. This is important for measures that may vary over time and will be of potential broad relevance for future studies.

The findings from our proposed research will be of potential importance to:

The pharmaceutical industry:
A number of leading UK pharmaceutical and biotech companies (eg Astra-Zeneca, GSK) are developing anti-inflammatory treatments for CNS disorders. The knowledge gathered with our study will inform this drug development, as it will provide information about the disease biology and in particular the role of microglia in the pathophysiology of schizophrenia. Our study will potentially provide a mechanistic proof of concept and imaging biomarkers to support the progression of drugs in development into clinical trials.

Academics and clinicians in the schizophrenia field:
An important impact from our studies will be an improved understanding of the mechanisms underlying the neurobiology of schizophrenia. So far, the majority of studies in the neurobiology of schizophrenia have focused on neurotransmitters, specifically dopamine and glutamate. Only recently, with the advances in brain PET and the synthesis of new ligands that target directly microglia, has there been a chance to study neuroinflammation in the living brain. Our study has the potential to provide a key test of the role of microglia and other aspects of inflammation in schizophrenia.

Academics and clinicians across psychiatry, neurology and related fields:
Our study will determine the relationship between MR measures of water diffusion and microglial activation. These findings have the potential to inform the understanding of these MR measures, in particular the degree to which they reflect microglial and other inflammatory changes, with potential applications across CNS disorders.

To patients, carers and society in general:
The cost of schizophrenia and related disorders across Europe has been estimated at ~100 billion Euros/ year and a significant portion of this cost is related to lack of efficacy of current antipsychotic medication. This study will provide a proof of concept of the value of reducing microglial activation and other aspects of inflammation. It will inform the development of new drugs that could improve the treatment of schizophrenia, reducing the health and economic burden to patients, carers and society.