Inflammation and brain function
Research type
Research Study
Full title
The role of inflammation in brain and cognitive function in mental disorders
IRAS ID
208083
Contact name
Oliver Howes
Contact email
Sponsor organisation
King's College London
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Research Summary:
Schizophrenia affects 1/100 people and is a chronic disabling psychiatric illness. It comprises positive (psychotic), negative and cognitive symptoms. Recently it has become clear that subcortical dopamine dysfunction underlies psychosis. However, this appears to be the final step in the pathophysiological process, and does not explain negative and cognitive symptoms. It is therefore critical to identify the up-stream disease mechanisms underlying the disorder to aid development of better treatments for schizophrenia.Converging lines of evidence suggest that neuro-inflammation occurs in schizophrenia, and specifically over-activity of brain-resident immune cells called microglia. Although this process may account for brain structural changes and imbalances in neurotransmitter concentrations inherent to the condition (specifically glutamate), as well as schizophrenia’s symptom profile, it must be noted that neuro-inflammation is seen in a number of other disorders and may occur secondary to other factors. Thus key gaps in our knowledge exist, specifically relating to whether activated microglia play a primary role in schizophrenia, or whether this is a secondary phenomenon of no pathophysiological significance. The key test is to reverse microglial activation and determine the effect on symptoms, as well as to determine the relationship between microglial activation and brain structural and glutamate measures. To achieve this, we propose use to use a drug called natalizumab that specifically targets microglia and reduces their activity in the brain.
Two arms to the study are proposed: a case-control arm and a nested longitudinal arm. The case-control design will determine the association between microglial activation and other measures in patients with schizophrenia relative to controls. However, this is not able to determine causal relationships. To determine this we will use natalizumab to assess the effect of reducing microglial activation on brain functional measures. This will be a longitudinal study in patients only.
Lay summary of study results:
We assessed the effects of 3-month treatment with natalizumab on a brain imaging marker of microglial activity in patients with first-episode psychosis, and whether this would improve symptoms of psychosis. We found evidence of increased microglial activity in the temporal lobe and total grey matter in patients with psychosis relative to a healthy control group. However, treating these patients with natalizumab did not normalise the signal for increased microglial activity. Furthermore, the effects of natalizumab on symptoms of psychosis were not superior to placebo. These findings indicate that microglia are overactive in cortical brain regions of patients with early schizophrenia, but natalizumab is not efficacious in addressing this potential pathology.REC name
London - West London & GTAC Research Ethics Committee
REC reference
17/LO/0002
Date of REC Opinion
14 Mar 2017
REC opinion
Further Information Favourable Opinion