Immuno-metabolic dysfunction in Psychosis and the use of Imaging

Abstract

Numerous avenues of enquiry suggest a potential causal relationship between immune dysfunction and oxidative stress and schizophrenia. Non-resolving elevation of interleukin 6 (IL-6/IL6r) has been implicated, related to development of psychosis, present before the initiation of medication. Chronic inflammation is also a key driver of metabolic dysfunction, common in schizophrenia. Mechanistically, IL6/IL6r and related low molecular weight proteins have the ability to cross the blood-brain barrier and increase its permeability, drawing in further local inflammatory actors including nitric oxide and chemokines. Activated microglia may lead to grey matter volume (GMV) loss through excessive dendritic pruning and/or impaired surveillance and clearance of dysfunctional or pathological synapses. Thus, the immune system may be related to structural brain change via complex effects on neuronal development, micro and astrocytic function and synaptic pruning and explain increased grey matter volume loss seen in mental illness. However, whilst aberrant immune profiles may be relevant, current evidence is actually mixed, with uncertain evidence of progressive GMV loss in schizophrenia groups as a whole, PET microglial activity and relevance of peripheral measured of inflammation.  A clear characterisation of a brain signature related to chronic low-level inflammation in schizophrenia, with evidence of related phenotypic profile will help advance our ability to target precision medicines. This presentation will outline recent evidence from the Psychosis Immune Mechanism Stratified Medicine Study (PIMS) focused on the phenotypic and neuro-anatomical profile of immune active psychosis from genomic, early and later stage populations using large samples and multimodal data driven approaches.

Bio

Rachel is Professor of Psychiatry in the Department of Psychiatry, University of Oxford and Director of the Oxford Health Biomedical Research Centre. She trained in Medicine at the Royal Free Hospital, University of London and completed Psychiatry training in Birmingham. Her PhD investigated longitudinal outcomes of depression and suicidality in first episode psychosis. Her clinical work is in the Birmingham Early Intervention Service. Her research focuses on the identification of novel treatments for early stages of schizophrenia, and she leads the Psychosis Immune Mechanism Stratified Medicine Study (PIMS), a collaborative multi-stage project investigating inflammatory mechanisms and phenotypic profile of psychosis. Her translational research includes NIHR funded Early Psychosis Informatics into Care (EPICare) registry. She is chief investigator and co-investigator on a number of RCTs for repurposed and targeted treatments. Rachel is Chair of the NIHR Mental Health Translational Research Collaboration and Honorary General Secretary of the British Association for Psychopharmacology.