Hodge Public Lecture 2022

Can we target the immune system to develop new treatments for psychosis?

Professor Rachel Upthegrove, Professor of Psychiatry and Youth Mental Health, University of Birmingham, gave the Hodge Day Public Lecture 2022.

Postgraduate research student Elle Mawson, School of Medicine, provides a write-up of the event.

After a stimulating afternoon of speakers from Cardiff University and across the UK discussing their research into the role of inflammation and immune system function in psychiatric disease, Professor Rachel Upthegrove gave a public lecture on her research into the convergence of environmental and genetic risk factors, and how they may affect the functioning of the immune system to lead to disorders such as schizophrenia and bipolar disorder.

Environmental risk factors for psychiatric disease (such as deprivation, pollution, the impact of living in urban areas) are highly prevalent in cities like Birmingham. Professor Upthegrove discussed how this has influenced her research and highlighted the importance of understanding the mechanisms whereby these risk factors can lead to psychiatric disease and the imminent need for novel treatments for patients.

All current drug treatments for psychosis work via the same mode of action involving dopamine signalling between brain cells. Although these treatments are effective in many patients, they come with a significant burden of side effects, and around 30% of patients are non-responsive. They also tend to only rescue psychotic symptoms such as hallucinations and delusions and do little to treat the impairments in cognition and mood seen in many patients.

Many studies have investigated which genes are more common in patients with psychiatric diseases than in the general population and have found that many processes in the immune system appear to have gene variants that occur with increased frequency in patients compared to healthy individuals. Not all carriers of these risk genes will go on to develop schizophrenia or other psychiatric disorders, so the presence of environmental risk factors may explain how genetic risk manifests into disease in certain individuals.

Interleukin 6 (IL-6) is a molecule that plays a key role in the immune system and works to create a state of inflammation. Inflammation is an important process and key to a healthy body’s ability to fight against disease and recover from injury. A consistent inflammatory state can be damaging and affects the development and functioning of cells in the brain. IL-6 has been found to be elevated in individuals prior to the onset of psychosis, and the level of IL-6 at age 9 has been found to be a predictor of developing psychosis in later life.

C-reactive protein (CRP) is another molecule that is an indicator of an inflammatory state. Studies using large databases of information from the same individuals over many years have found that when children are stratified into consistently anxious and consistently non-anxious groups, the anxious children have a higher likelihood of developing psychosis at age 24, a finding which appears to be driven by the level of CRP in an individual. The idea that the environment may impact these relationships is supported by findings that the number of childhood trauma events is also related to the level of psychotic symptoms in patients with bipolar disorder.

Early data showed promising results from an antibiotic drug called minocycline which can work to reduce inflammation in the brain and protect brain cells. However, a larger drug trial found no evidence that minocycline improved symptoms in schizophrenia, nor did it affect the level of IL-6 in patients. However, emerging evidence has shown that adding anti-inflammatory drugs to the treatment regimen of patients may improve symptoms. To improve understanding of how best to develop novel treatments that target inflammatory mechanisms in psychiatric disease, Professor Upthegrove’s group are conducting the Psychosis Immune Mechanism Stratified Medicine Study (PIMS). The aim of the study is to validate whether IL-6 could be a therapeutic target but based on the principle of stratifying patients based on their level of inflammation, to specifically target those patients who are most likely to benefit from these types of treatments.

In the PIMS study, cutting edge genetic and machine learning techniques are used to understand which specific aspects of inflammation should be targeted for drug treatment and to understand whether there is a direct causal relationship between inflammation and brain function, as an alternative explanation may be that inflammation results as a consequence rather than a cause of disease.

Professor Upthegrove’s team have predicted that IL-6 levels would be associated with particular markers of disease such as reduced volume and thickness of brain tissue in brain areas known to be relevant to schizophrenia. Their early results seem to agree with this prediction and have found from genetic data that certain gene variants related to IL-6 are related to these changes in brain tissue thickness and volume. As the genes present in an individual are determined at conception, these results indicate that IL-6 may be causally related to brain structure and is perhaps an early predeterminant of developing psychiatric conditions such as schizophrenia.

Professor Upthegrove’s research group are also conducting the Targeted Experimental Medicine Study in Psychosis which is trialling a drug called Tocilizumab. Tocilizumab is currently licenced to treat rheumatoid arthritis and works by blocking the activity of IL-6. The study is in its very early stages, however research using lab-grown cells has shown promising results indicating the drug may be effective.

The importance of medical research being translatable in its ability to influence the way psychiatric disorders are treated in the clinic and the range of treatment options available to patients is often stressed. In concluding her lecture, Professor Upthegrove stressed the importance of this process working in reverse, in that the results seen from drug trials such as the minocycline study should work to adjust how we consider mechanisms of disease in earlier phases of research.

The lecture was highly engaging and informative and produced a lively question and answer session with many questions from the  audience which included, clinicians, students, pre-clinical researchers, and members of the public.