Can immune dysfunction cause psychosis?
Bringing the brain and the mind back together again
In the 1600’s French philosopher Rene Descartes proposed that the mind and the body were distinct: that thought could exist outside of the body, and the body could not think. This ‘Cartesian dualism’ has preoccupied philosophy ever since but has also had long-lasting and significant consequences for psychiatry. If physical matter is distinct from mental processes, then the physical brain is separated from the mind. This has, in part, perpetuated the development of research streams within mental health, neuroscience, psychiatry, and psychology in separated and distinct silos. The end result of this may be slower than the acceptable pace in developing new treatments for illnesses such as depression, anxiety and psychosis.
Yet our thoughts and behaviours are products of brain function, and this is influenced by development, environment and exposure.
The immense growth in neuroscience understanding over the past two decades has been matched only by that in immunology, the body system that controls, monitors and responds to environmental challenges. There is now the opportunity to bring the mind, environment and the brain back together again, and with this accelerate the development of better treatments.
On the 6th December, 2019, the Psychosis Immune Mechanism Stratified Medicine Study was launched.
This collaboration will join together immunologists, psychiatrists, data scientists, pharmacologists and young people with lived experience of psychosis in a joint effort to tackle key challenges in developing new immune-based treatments for psychosis.
The Universities of Birmingham, Cambridge, Manchester, Kings College, University College London and the University of Ireland Galway came together at the launch event, in Birmingham’s Institute for Mental Health.
What is psychosis?
Psychosis affects up to 3% of the population, usually starts in late adolescence and early adulthood. Common symptoms are hallucinations (hearing or seeing things that others cannot) delusions (false beliefs) and difficulty with memory, concentration, motivation and organisation of thoughts. Two thousand young people in England develop a psychosis for the first time (first episode psychosis) every year.
Current treatments include medication, talking therapies, family therapy and employment support. Evidence suggests that medication has an important role to play in treating psychosis, and in preventing it coming back, but the medications we have to use right now are not ideal. They all work in the same way, by blocking receptors for a neurochemical called dopamine and have significant side effects for a lot of people who take them. The current medications we have also do not work well enough in over 30% of people with psychosis.
PIMS and new treatments
We want to develop new treatments for psychosis that work in different ways, looking at targeting the immune system which may lead to better and personalised treatments.
PIMS is a 5-year program that will be the start of a number of avenues of investigation into the immune system in psychosis. We have a lot of work to do to test whether the immune system could be causally related to psychosis, where exactly in the immune system to target treatments and what difficulties in psychosis these treatments should be best used to treat.
We came together to celebrate the significant amount of funding RCUK has dedicated to this project, and to begin this work.
The launch afternoon began with input from Times Journalist and Author Sathnam Sanghera reading from “The Boy with The Topknot” highlighting the continued stigma of psychosis, the paucity of treatments and the need for significant investment in research.
This was followed by a discussion on the key aims and objectives of PIMS with The Birmingham Institute for Mental Health Youth Advisory Group. Experts Zaynab (@ZeZeJonesBoi) and Sarisha (@sarishagoodman) spoke powerfully about the need for new, and targeted treatments for psychosis with fewer side effects and a more preventative approach.
PIMS will focus on a small inflammatory protein called Interleukin 6 (IL-6) and its pathway in the immune system as a potential new therapeutic target for psychosis using a number of approaches. First, we will complete an analysis of existing large genetic data to find out whether IL-6 and related immune markers are causally linked with psychosis. We will then use a data science-driven approach with existing large clinical and epidemiological samples to identify what symptoms would be best to target any immune-based interventions at, and how early these interventions should be offered.
We will then complete a double-blind experimental medicine study, giving volunteers with psychosis a routinely used treatment for rheumatoid arthritis (Tocilizumab) or placebo to find out whether blocking IL-6 has effect and on circulating inflammatory markers and measures of oxidative stress (using brain imaging techniques such as magnetic resonance spectroscopy). Blood samples will be taken to allow deep immunophenotyping and modelled brain cells from specific blood cells (monocytes) to test whether they act differently from people without psychosis.
We hope that PIMS will be the catalyst for new investment and ongoing research into immune-based treatments for psychosis, building on this work and establishing a multidisciplinary consortium. It is a challenging program of work. On the 6th of December, we heard from Rachel Upthegrove (Lead Investigator for PIMS) who opened the afternoon outlining work done to date, the overarching aims of PIMS and key questions that will be addressed: can we establish causality? what symptoms should be targeted and when? Can data science help and would targeting peripheral immune markers improve brain health? Preliminary data suggest that these questions can be addressed with PIMS. Georgious Gkoutos outlined how a multi-omic AI can advance the pace and scale of discovery, as evidenced by his work with Health Data Research-UK pioneering work in cancer and other physical health disorders. Carmine Pariante gave an entertaining and engaging lessons-to-be-learned from his considerable experience in the immune investigation of depression, that the study team can learn from: these included don’t be afraid of controversy, expect some failures and build on what is already known. Golam Khandaker (Co-lead Investigator PIMS) detailed the clinical experimental medicine study that will begin in 18 months time, and how this will build on the current approach in depression and extend with deeper immunophenotyping. Nicholas Barnes showed the type of work that will be completed in PIMS, with data from more advanced Traumatic Brain Injury studies and pilot work developing blood cell models of microglia (brain active inflammatory cells). Charles Large (founder of Autifony) showed the exemplar of taking a potential idea to a validated target and on to full clinical trials with work from Bill Deakin, Jo Neill and Oli Howes on voltage potassium channel blockade. Yet the most important and powerful presentations were undoubtedly those bringing the stark reality of the limited treatment options for psychosis alive: @Sathnam, @ZeZeJonesBoi and @sarishagoodman with personal accounts of the stress psychosis can inflict on individuals and their families, and how the environment and childhood experiences are key. The environment, mind and neuroscience came together for this afternoon, the start of a strong and continued collaboration with a common goal: better, personalised treatments for psychosis!
NOTE FROM THE EDITORS: We are so pleased to have Professor Rachel Upthegrove write this interesting piece for InSPIre the Mind! Professor Upthegrove is Professor of Psychiatry and Youth Mental Health at the University of Birmingham and Consultant Psychiatrist in the Birmingham Early Interventions Services. Her research on mental health focuses on schizophrenia and co-morbid depression in the early stages of the illness, as well as inflammation-based models of psychosis. Once again, a massive thank you from us to her for this great insight into the PIMS Study and the need to develop novel treatments for psychosis!
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