MICA: Targeting neuro-inflammation in Schizophrenia
Lead Research Organisation:
King's College London
Department Name: Psychosis Studies
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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.
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.
Publications
Onwordi E
(2018)
Trends in mortality in schizophrenia and their implications.
in Acta psychiatrica Scandinavica
McCutcheon R
(2018)
Amygdala reactivity in ethnic minorities and its relationship to the social environment: an fMRI study.
in Psychological medicine
Frank E
(2018)
Platform for systems medicine research and diagnostic applications in psychotic disorders-The METSY project.
in European psychiatry : the journal of the Association of European Psychiatrists
Modinos G
(2018)
Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Borgan F
(2019)
In Vivo Availability of Cannabinoid 1 Receptor Levels in Patients With First-Episode Psychosis.
in JAMA psychiatry
Borgan F
(2019)
The effects of cannabinoid 1 receptor compounds on memory: a meta-analysis and systematic review across species.
in Psychopharmacology
D'Ambrosio E
(2019)
The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function: A PET imaging study.
in Psychiatry research. Neuroimaging
Dahoun T
(2019)
The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study.
in Translational psychiatry
Petty A
(2019)
Enhanced Dopamine in Prodromal Schizophrenia (EDiPS): a new animal model of relevance to schizophrenia.
in NPJ schizophrenia
McCutcheon RA
(2019)
Mesolimbic Dopamine Function Is Related to Salience Network Connectivity: An Integrative Positron Emission Tomography and Magnetic Resonance Study.
in Biological psychiatry
Kaar SJ
(2019)
Making decisions about antipsychotics: a qualitative study of patient experience and the development of a decision aid.
in BMC psychiatry
Merritt K
(2019)
O5.6. REMISSION FROM ANTIPSYCHOTIC TREATMENT IN FIRST EPISODE PSYCHOSIS RELATED TO LONGITUDINAL CHANGES IN BRAIN GLUTAMATE LEVELS
in Schizophrenia Bulletin
Beck K
(2019)
Prevalence of treatment-resistant psychoses in the community: A naturalistic study.
in Journal of psychopharmacology (Oxford, England)
Jauhar S
(2019)
Understanding and Predicting Variability in Response to Treatment in Psychotic Disorders: In Vivo Findings.
in Clinical pharmacology and therapeutics
Kaar SJ
(2019)
Pre-frontal parvalbumin interneurons in schizophrenia: a meta-analysis of post-mortem studies.
in Journal of neural transmission (Vienna, Austria : 1996)
Merritt K
(2019)
Remission from antipsychotic treatment in first episode psychosis related to longitudinal changes in brain glutamate.
in NPJ schizophrenia
Bloomfield M
(2019)
41.2 THE EFFECTS OF DEVELOPMENTAL STRESS AND TRAUMA ON THE DOPAMINE SYSTEM
in Schizophrenia Bulletin
Dahoun T
(2019)
Disrupted-in-schizophrenia 1 functional polymorphisms and D2 /D3 receptor availability: A [11 C]-(+)-PHNO imaging study.
in Genes, brain, and behavior
Ashok AH
(2019)
Tobacco smoking and dopaminergic function in humans: a meta-analysis of molecular imaging studies.
in Psychopharmacology
Beck K
(2019)
Prevalence of serum N-methyl-d-aspartate receptor autoantibodies in refractory psychosis - ADDENDUM.
in The British journal of psychiatry : the journal of mental science
Bonoldi I
(2019)
Basic Self-Disturbances Related to Reduced Anterior Cingulate Volume in Subjects at Ultra-High Risk for Psychosis.
in Frontiers in psychiatry
Rogdaki M
(2019)
Glutamatergic function in a genetic high-risk group for psychosis: A proton magnetic resonance spectroscopy study in individuals with 22q11.2 deletion.
in European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Borgan FR
(2019)
Glutamate levels in the anterior cingulate cortex in un-medicated first episode psychosis: a proton magnetic resonance spectroscopy study.
in Scientific reports
Gaughran F
(2019)
Effect of lifestyle, medication and ethnicity on cardiometabolic risk in the year following the first episode of psychosis: prospective cohort study.
in The British journal of psychiatry : the journal of mental science
Jauhar S
(2019)
Correction: Regulation of dopaminergic function: An [18F]-DOPA PET apomorphine challenge study in humans.
in Translational psychiatry
Bloomfield MA
(2019)
The effects of psychosocial stress on dopaminergic function and the acute stress response.
in eLife
Pillinger T
(2019)
Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study.
in Translational psychiatry
Ashok AH
(2019)
Reduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging.
in Nature communications
Dahoun T
(2019)
The association of psychosocial risk factors for mental health with a brain marker altered by inflammation: A translocator protein (TSPO) PET imaging study.
in Brain, behavior, and immunity
McCutcheon RA
(2020)
Treatment of First-Episode Schizophrenia in a Young Woman.
in JAMA psychiatry
Barešic A
(2020)
Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks.
in Molecular psychiatry
Erritzoe D
(2020)
Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
McCutcheon RA
(2020)
Dopamine and glutamate in schizophrenia: biology, symptoms and treatment.
in World psychiatry : official journal of the World Psychiatric Association (WPA)
Kaar SJ
(2020)
Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.
in Neuropharmacology
Onwordi EC
(2020)
Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.
in Nature communications
McCutcheon R
(2020)
Schizophrenia-An Overview
in JAMA Psychiatry
Mizuno Y
(2020)
Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Rogdaki M
(2020)
Magnitude and heterogeneity of brain structural abnormalities in 22q11.2 deletion syndrome: a meta-analysis.
in Molecular psychiatry
McCluskey SP
(2020)
Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development.
in European journal of nuclear medicine and molecular imaging
Barnes TR
(2020)
Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.
in Journal of psychopharmacology (Oxford, England)
Adams RA
(2020)
Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans: A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models.
in Cerebral cortex (New York, N.Y. : 1991)
Potkin SG
(2020)
The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research.
in NPJ schizophrenia
Brugger SP
(2020)
Heterogeneity of Striatal Dopamine Function in Schizophrenia: Meta-analysis of Variance.
in Biological psychiatry
Howes OD
(2020)
Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study.
in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Osimo EF
(2020)
Cardiac structure and function in schizophrenia: cardiac magnetic resonance imaging study.
in The British journal of psychiatry : the journal of mental science
Maslej MM
(2021)
Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials.
in JAMA psychiatry
Beck K
(2021)
N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.
in Translational psychiatry
Description | EU Marie Curie Fellowship- Alice Petty |
Amount | £224,781 (GBP) |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 11/2021 |
End | 11/2023 |
Description | EU Marie Curie Fellowship- Garzia Rutigliano |
Amount | £326,371 (GBP) |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 09/2021 |
End | 08/2023 |
Title | NODE PET |
Description | Database of PET and other imaging data and repository for data sharing and pooling |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Combined analyses resulting in new publications |
Description | Genetics of neuropsychiatric disorders- Cardiff Uni collaboration |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We contributed new methodological approaches |
Collaborator Contribution | Access to data and expertise |
Impact | New analyses |
Start Year | 2021 |
Description | New imaging approach to white matter imaging |
Organisation | Harvard University |
Country | United States |
Sector | Academic/University |
PI Contribution | Sharing data |
Collaborator Contribution | Helping with analysis |
Impact | nil yet |
Start Year | 2018 |
Description | iPSC neurons and microglia |
Organisation | Keio University |
Country | Japan |
Sector | Academic/University |
PI Contribution | Collaboration to develop and investigation iPSC derived from patients |
Collaborator Contribution | They are deriving the iPSC models and running experiments |
Impact | New materials |
Start Year | 2022 |
Description | Media interviews on our research (The Guardian full page article 2017) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The Guardian: full page article on our IRIS study- picked up and reported by many other news outlets |
Year(s) Of Engagement Activity | 2017 |
Description | Press interviews |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Media interviews leading to published articles eg in The Guardian |
Year(s) Of Engagement Activity | 2022,2023 |
Description | Radio and TV interviews on our research |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interviews on BBC and newspapers (including Radio 4: All in the mind: interview on our research with Claudia Hammond 2018: Radio 4: Future Proofing: interview on future of mental health with Leo Johnson) |
Year(s) Of Engagement Activity | 2018 |