PIMS: Psychosis Immune Mechanism Stratified Medicine Study

On the 6th December 2019 the PIMS study was launched at an event at the University of Birmingham

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 about the key aims and objectives of PIMS from key collaborators in the study and Youth Advisory Group experts Zaynab Sohawon and Sarisha Goodman who spoke powerfully about the need for new, and targeted treatments for psychosis with fewer side effects and a more preventative approach.

Read the blog to discover more about the launch

Low-grade inflammation could be causally linked to psychosis, and offers innovative treatment targets. Elevated circulating IL-6 (glycoprotein produced by leucocytes for regulating immune responses and indicates inflammation) and related protein levels are present prior to psychosis onset and may be seen more often in patients with specific types of symptoms including; 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. 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.

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.

Principal Investigators:

Professor Rachel Upthegrove

Dr Golam Khandaker

University of Birmingham Collaborators:

• Professor Nicholas Barnes
• Professor George Gkoutos 
• Professor Stephen Wood
• Professor Rachel Upthegrove (PIMS PI)

University of Birmingham Early Career Researchers:

• Dr Sian Lowri Griffiths (Post-Doctoral Research Fellow, IMH and PIMS)
• Dr Andrey Barsky (Post-Doctoral Research Fellow CCB, and PIMS)
• Paris Lalousis (PhD Student)
• Alex Murray (PhD Student)

University of Cambridge Collaborators:

• Professor Ed Bullmore
• Dr Stephen Burgess
• Professor Peter Jones
• Dr Golam Khandaker (PIMS PI)
• Professor John Suckling

Kings College London Collaborators:

• Professor Carmine Pariante

University College London Collaborators:

• Professor Anthony David

NUI Gallway Collaborators:

• Professor Gary Donohoe