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.