Psychosis Immune Mechanism Stratified Medicine Study (PIMS)

Low-grade inflammation, particularly that related to the pro-inflammatory cytokine interleukin 6 (IL-6) pathway, could be causally linked to psychosis, and offers innovative treatment targets. Elevated circulating IL-6 and related protein levels are present prior to psychosis onset and may be seen more often in patients with specific types of symptoms - cognitive difficulties such as working memory and difficulty processing information and negative symptoms such as poor motivation, diminished pleasure, reduced facial expression, reduced speech and social isolation. There is also evidence that inflammation may be related to mood symptoms such as depression, which are common in psychosis. However, recent drug trials of anti-inflammatory agents in psychosis have yielded mixed results, potentially because these were given to groups of patients with psychosis regardless of whether there was evidence of current inflammation. It is unlikely anti-inflammatory treatment could be helpful for patients who do not have increased inflammation.

The PIMS project will focus on the IL-6 pathway, and immune markers up (interleukin 1 beta (IL-1B) and tumour necrosis factor (TNF-a) and downstream (C-reactive protein) of IL-6, as potential new therapeutic target for schizophrenia using a number of approaches.

First, we will use Mendelian randomization analysis of existing large genomic data to test whether IL-6 and related immune markers are causally linked with psychosis. We will then use existing data from large clinical and epidemiological samples and machine learning approaches to identify illness stage and symptom dimension most closely linked with inflammation, and the relevance of peripheral blood levels of markers of inflammation to brain structure: identifying the biotype of immune-related psychosis.

This work will inform a randomised double blind experimental medicine study, giving psychosis patients with evidence of inflammation one dose of Tocilizumab. Tocilizumab is an anti-inflammatory medication used in Rheumatoid arthritis that blocks IL-6 signalling. We will see if this has any effect on psychotic symptoms especially cognition. We will test whether IL-6 blockade has effect and on circulating inflammatory markers and brain measures of oxidative stress using magnetic resonance spectroscopy implicated in psychosis.

We will carry out experiments on immune cells collected from patients before and after tocilizumab; this could identify cellular source of low-grade inflammation seen in psychosis. We will create modelled brain cells from specific blood cells (monocytes) to test whether they act differently from healthy people in different test conditions.

Finally, we will use results to refine established animal models of schizophrenia to understand the biology of the immune target and inflammation-related psychosis.

The PIMS study group comprises experts in psychosis, immuno-psychiatry, epidemiology, neuroscience, bioinformatics, genomics, and pharmacology with established track record in their fields and experience of collaborating and/or leading large projects. We will work with our Industry Advisory Board to take findings forward with the ultimate aim of developing new stratified medicine treatments for psychosis patients with active inflammation.

Dopamine receptor blockade remains the sole mechanism of action of antipsychotic drugs since they were discovered over 60 years ago. Despite adequate treatment, psychotic symptoms often persist and poor social and occupational functioning may show little benefit. Low-grade activation of the innate immune system is of increasing interest as a non-dopamine mechanism of pathogenesis and new treatment target. Increased circulating IL-6 and C-reactive protein (CRP) concentrations are present prior to psychosis onset; are related to negative and cognitive symptoms; and may persist in treatment-resistant illness. Although, clinical trials of anti-inflammatory agents in psychosis have yielded mixed results, this may reflect a failure to stratify or select patients who show signs of immune activation. However, the optimal methodology that would identify such a group of patients is not yet clear. The PIMS project will focus on the IL-6/IL-6R pathway and immune markers up and downstream of IL-6 (e.g. IL-1B, TNF-a, CRP) as potential therapeutic targets for schizophrenia. We will use (i) Mendelian randomization to test causality of association of these biomarkers with schizophrenia; and (ii) clinical and epidemiological samples to identify illness stage and symptom dimensions most closely linked with inflammation. This work will inform a randomised experimental medicine study of IL-6 inhibition in selected patients, and test whether they show evidence of a symptomatic, cognitive or a neuroimaging response to a single dose of the anti IL-6 monoclonal antibody, toclizumab, versus placebo over the ensuing month of immune suppression, where we will also carry out deep immuno-phenotyping including functional assays and develop microglia from patients' monocytes to understand the brain relevance of peripheral inflammation. We will use results to refine established murine models to further understand the biology of IL-6 and related immune targets, and to identify new druggable targets.

The need for new, effective treatment for psychotic illnesses is readily apparent. Over one third of patients presenting with first episode psychosis do not respond to current dopaminergic treatments and functional outcomes are poor. Present treatments cause considerable side effect burden and are prescribed without any consideration of stage of illness nor personalised approach.

The PIMS study will be the most comprehensive and in depth investigation of innate inflammatory mediators in psychosis to date, utilising a number of innovative scientific methods. We will be the first to investigate IL-6 and related immune proteins are causality linked with psychosis, and to identify the stage of illness and symptom profile most closely linked with inflammation. These will inform a clinical trial. Our experimental medicine study will be the first conducted within an immune selected patient group. Pre-clinical related studies (in human tissue with deep immunophenotyping) will add significant discovery of druggable targets. This would have clear outputs for industry and academic collaborations aiming to develop this potential to new interventions and larger scale targeted trials.

Our impact will have key relevance to future studies investigating treatment of poor outcome and unmet need in psychotic disorder and will be particularly relevant to basic science, neuroscience, pharmacology, psychiatry and psychology.

The major beneficiaries of our study are future patients living with psychotic illnesses such as schizophrenia, and researchers aiming to improve the treatment of psychosis. Successful completion of this proposal will provide significant insight into the neurobiological changes that occur in psychosis and how these relate to inflammation. In turn this will help answer key questions about the future direction and potential of the innate immune system as a target area for new treatments.

Research outputs will include the development of pilot data and consolidation of focus for a number a future grant applications including the Developmental Pathway Funding Scheme. WP1&2 will enable the targeting of future trials by specific stage and clinical presentation with the highest chance of effect. In addition, big data will combine outputs from 1 and 2 to allow further fine-grained exploration of the immune phenotype/genotype. WP 3 will potentially lead to a full trial of IL6 immunotherapy and future application for development of other targets as developed deep immunophenotyping.

Our approach is in complete concordance with the strategies recommended by the MRC's review of mental health research, specifically calling to "strengthen our knowledge of cellular and molecular neurological mechanisms and the function of the brain and how this relates to mental health and disease". Furthermore, the study is in line with the MRC Translational Research Strategy to support "the development of new and improved systems and theories for health research", which emphasises the need to "bring discoveries in science closer and faster to the clinic".

PIMS will result in a group of expertise across discipline working together with a focus on a novel area of drug development: focussing on immune dysfunction in schizophrenia. We have within our consortium the main researchers and academics active in this field in the UK. PIMS will establish the UK as the leading centre for drug discovery, development and application and validation targeting the immune system in schizophrenia.