8.1 CSF PATHOLOGY INCLUDING BLOOD-BRAIN BARRIER DYSFUNCTION IN PSYCHOSIS AND THE POTENTIAL EFFICACY OF ANTI-INFLAMMATORY TREATMENTS – FROM REGISTER STUDIES TO META-ANALYSIS

Abstract

Utilizing the nationwide Danish registers, we have shown dose-response associations between infections and general medical diseases involving inflammatory processes, such as autoimmune diseases, with the development of psychosis. In people with autoimmune diseases, infections further increased the risk, potentially due to affecting the Blood-Brain Barrier, making the brain more vulnerable to the potential detrimental effects of the autoantibodies. Hence, particularly the group of autoimmune diseases with suspected presence of brain-reactive antibodies had a further increased risk of psychosis if experiencing severe infections. The results are based on data from 1) nationwide register studies on all individuals living in Denmark after 1969, 2) a Danish population-based sample of over 80.000 individuals born after 1981 with GWAS analyses and linked to the nationwide registers, 3) systematic reviews and meta-analysis on all CSF studies conducted on psychosis and on all placebo controlled RCT’s investigating anti-inflammatory treatment response of psychosis. Conducting the first systematic review of all available studies on cerebrospinal fluid (CSF) immune alterations, we showed that the CSF/serum albumin ratio was increased in schizophrenia, compared to healthy controls, indicating Blood-Brain Barrier dysfunction. Moreover, total CSF protein and the IgG ratio was increased in schizophrenia, whereas the IgG Albumin ratio was decreased. In the CSF of people with schizophrenia there were increased levels of Interleukin-6 and IL-8 levels, compared to healthy controls. The levels of IL-6 were particularly increased during acute psychotic episodes. In the two studies investigating how often the analyzes of CSF resulted in re-diagnosis, CSF dependent re-diagnosis occurred in 3.2–6% of cases. Moreover, results from register information on specific CSF infections and associations with psychosis and mental disorders in general will be presented, including the effect on measures of cognition. Furthermore, immunogenetic and genetic findings regarding genes related to the Blood-Brain Barrier and the impact of environmental exposures on the associations with psychosis and mental disorders in general from a population-based cohort of over 80.000 Danish individuals will be presented at the session. Lastly, results on the efficacy of anti-inflammatory treatment in addition to antipsychotics will be presented based on an updated meta-analysis of all trials conducted, including associations with the ability to pass the Blood-Brain Barrier of the anti-inflammatory medication. In conclusion, current findings suggest that psychotic disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not yet allow any firm conclusion due to the lack of unbiased CSF studies and high sensitive imaging studies of the Blood-Brain Barrier during psychotic episodes. High-quality longitudinal CSF studies are indeed lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with signs of CSF inflammation.