CHECKPOINT: Finding immune & metabolic pathways to SMI
Lead Research Organisation:
University of Cambridge
Department Name: Department of Psychiatry
Abstract
What? CHECKPOINT will be a national and international hub of scientists and people with lived experience (PWLE) working openly and transparently together. We will unlock the unprecedented opportunity provided by big data and advanced computational analysis to find causal pathways that connect physical and mental health. This will accelerate development of personalised treatments that work by targeting the immune and metabolic causes of severe mental illness (SMI) in those patients most likely to benefit.
Why? There is growing evidence through research that people with SMI can also have unusual changes in their immune system, like inflammation, and have increased risk of metabolic disorders, like obesity, due to unusual fat and sugar metabolism in the body. These links between physical and mental health indicate a new opportunity to understand, treat and prevent SMI and make significant advances on a science-based approach for precision psychiatry. The fundamental challenge now is to discover how immune and metabolic factors can actually cause SMI. If we can find these causal links, from the body through the brain to the mind, we can develop new drug treatments for SMI that work by targeting the immune or metabolic systems. We can use blood tests, brain scans and other biomarkers to identify which patients will benefit from personalised treatment. We can advise patients more precisely about which lifestyle adjustments, such as eating a different diet or being more active, are most likely to be beneficial for their mental health.
How? CHECKPOINT will address these key challenges by bringing together a diverse group of investigators with inter-disciplinary scientific expertise, and PWLE, based at 5 centres of excellence in the UK and Europe. The team will use large amounts of existing data, from genetic studies of SMI and other sources, in three main ways.
The first way is called target triangulation. We will use genetic analysis to screen a large number of molecules and cells in the immune and metabolic systems that could be targeted for treatment. We expect to find a small proportion of screened targets will have a causal role in disorders like schizophrenia, or across a range of SMI disorders. Targets that pass preliminary screening will be prioritized for deeper analysis of genetic, clinical and longitudinal follow-up data, to find the top few immune or metabolic targets for SMI by triangulating multiple convergent lines of evidence for causality.
The second way is called biomarker innovation. We will analyse blood immune cells collected from patients with psychosis and starting treatment with anti-psychotic drugs. We will also analyse brain MRI scans, and design video games to measure thinking and behaviour in young people. We will identify which of these potential biomarkers could be used to identify the patients with SMI most likely to respond to treatments targeting the immune or metabolic systems.
The third way is called therapeutic personalisation. We will find which new drugs or already-licensed medications are most likely to be effective in treating the immune or metabolic causes of SMI. Scientists and PWLE will also co-produce two projects: (i) to develop better tools for predicting adverse physical health co-occurring with mental health, especially due to anti-psychotic drug treatment; and (ii) to build evidence from health data and interviews with patients about which lifestyle interventions are most likely to be effective and accessible for people with SMI.
Why? There is growing evidence through research that people with SMI can also have unusual changes in their immune system, like inflammation, and have increased risk of metabolic disorders, like obesity, due to unusual fat and sugar metabolism in the body. These links between physical and mental health indicate a new opportunity to understand, treat and prevent SMI and make significant advances on a science-based approach for precision psychiatry. The fundamental challenge now is to discover how immune and metabolic factors can actually cause SMI. If we can find these causal links, from the body through the brain to the mind, we can develop new drug treatments for SMI that work by targeting the immune or metabolic systems. We can use blood tests, brain scans and other biomarkers to identify which patients will benefit from personalised treatment. We can advise patients more precisely about which lifestyle adjustments, such as eating a different diet or being more active, are most likely to be beneficial for their mental health.
How? CHECKPOINT will address these key challenges by bringing together a diverse group of investigators with inter-disciplinary scientific expertise, and PWLE, based at 5 centres of excellence in the UK and Europe. The team will use large amounts of existing data, from genetic studies of SMI and other sources, in three main ways.
The first way is called target triangulation. We will use genetic analysis to screen a large number of molecules and cells in the immune and metabolic systems that could be targeted for treatment. We expect to find a small proportion of screened targets will have a causal role in disorders like schizophrenia, or across a range of SMI disorders. Targets that pass preliminary screening will be prioritized for deeper analysis of genetic, clinical and longitudinal follow-up data, to find the top few immune or metabolic targets for SMI by triangulating multiple convergent lines of evidence for causality.
The second way is called biomarker innovation. We will analyse blood immune cells collected from patients with psychosis and starting treatment with anti-psychotic drugs. We will also analyse brain MRI scans, and design video games to measure thinking and behaviour in young people. We will identify which of these potential biomarkers could be used to identify the patients with SMI most likely to respond to treatments targeting the immune or metabolic systems.
The third way is called therapeutic personalisation. We will find which new drugs or already-licensed medications are most likely to be effective in treating the immune or metabolic causes of SMI. Scientists and PWLE will also co-produce two projects: (i) to develop better tools for predicting adverse physical health co-occurring with mental health, especially due to anti-psychotic drug treatment; and (ii) to build evidence from health data and interviews with patients about which lifestyle interventions are most likely to be effective and accessible for people with SMI.
Technical Summary
CHECKPOINT is a national and international hub of scientists and people with lived experience (PWLE) based at 5 UK and European sites. Together, we aim to unlock the unprecedented opportunity provided by big data and advanced computational analysis to advance understanding and treatment of severe mental illness.
Our key goal is to delineate causal pathways, from the body through the brain to the mind, by which immune and metabolic factors can cause SMI and which are therefore prioritised for therapeutic intervention. We will work towards this goal in 3 linked programs:
1) Target triangulation. We will use Mendelian randomization and other genetic analysis to screen a large number of molecules and cells in the immune and metabolic systems. A small subset of potential targets that pass preliminary screening will be prioritized for deeper analysis of genetic, clinical and longitudinal follow-up data, to ?nd the top few immune or metabolic targets for SMI by triangulating multiple convergent lines of evidence for causality.
2) Biomarker innovation. We will analyse blood immune cells collected from patients with psychosis and starting treatment with anti-psychotic drugs. We will also analyse brain MRI and PET scans, and behavioural data from gamified cognitive testing paradigms co-produced with young people. We will assess which of these biomarkers sit on causal pathways to SMI and could identify the patients most likely to respond to immune or metabolic interventions.
3) Therapeutic personalisation. We will use computational drug repurposing to predict which repurposable drugs are most likely to be e?ective in treating the immune or metabolic causes of SMI. We will co-produce two projects of immediate relevance to PWLE: (i) to develop tools for predicting adverse physical health co-occurring with mental health, e.g., due to anti-psychotic drug treatment; (ii) to build evidence about lifestyle interventions most likely to be e?ective and accessible for people with SMI.
Our key goal is to delineate causal pathways, from the body through the brain to the mind, by which immune and metabolic factors can cause SMI and which are therefore prioritised for therapeutic intervention. We will work towards this goal in 3 linked programs:
1) Target triangulation. We will use Mendelian randomization and other genetic analysis to screen a large number of molecules and cells in the immune and metabolic systems. A small subset of potential targets that pass preliminary screening will be prioritized for deeper analysis of genetic, clinical and longitudinal follow-up data, to ?nd the top few immune or metabolic targets for SMI by triangulating multiple convergent lines of evidence for causality.
2) Biomarker innovation. We will analyse blood immune cells collected from patients with psychosis and starting treatment with anti-psychotic drugs. We will also analyse brain MRI and PET scans, and behavioural data from gamified cognitive testing paradigms co-produced with young people. We will assess which of these biomarkers sit on causal pathways to SMI and could identify the patients most likely to respond to immune or metabolic interventions.
3) Therapeutic personalisation. We will use computational drug repurposing to predict which repurposable drugs are most likely to be e?ective in treating the immune or metabolic causes of SMI. We will co-produce two projects of immediate relevance to PWLE: (i) to develop tools for predicting adverse physical health co-occurring with mental health, e.g., due to anti-psychotic drug treatment; (ii) to build evidence about lifestyle interventions most likely to be e?ective and accessible for people with SMI.
