The Contribution of Inflammatory Biomarkers in the Emergence of Negative Symptoms in Psychosis

Authors: Connor Dunleavy, Professor Sarah Aldred, Professor Rachel Upthegrove et al., 2022

What is Schizophrenia and Inflammation?

Schizophrenia is a highly debilitating mental illness, characterised by positive (e.g. hallucinations, delusions) and negative symptoms (e.g. avolition, social withdrawal, anhedonia). Schizophrenia is recognised as a neurodevelopmental disorder, however through the interaction of a genetic vulnerability and environmental stressors, a person may be more at risk for developing the illness. A First Episode of Psychosis (FEP) is a period where individuals may begin to experience some symptoms and disturbances in functioning.

Inflammation refers to the body’s process of healing itself by fighting toxins, infections, or injuries. Evidence suggests that negative symptoms in FEP may be linked to unusual inflammatory processes, more specifically, to immune cell dysfunction in the brain. Increased exposure to stress (environmental, psychological, or social) results in increased immune activation and dysfunctional proinflammatory cell signalling, as well as oxidative distress – both of which can result in brain tissue damage or neurodegeneration, which may contribute to schizophrenia pathology. However, evidence of a direct link between inflammation and negative symptoms specifically, has been mixed; possibly due to small sample sizes, heterogeneity of illness duration, or methodological variations in cytokine quantification

What Does Current Research Say About Schizophrenia and Inflammation?

Research shows that proinflammatory cytokines are elevated in FEP and Sz. In relation to specific symptoms however, One particular study has reported a positive correlation between negative symptoms and elevated inflammatory markers (plasma TNF-α) in a chronic Sz sample, however these findings were not replicated in a drug-naïve sample in this study. Despite this, other research conducted elsewhere has also found correlations between TNF-α and negative symptoms across clinically high-risk populations, first episode populations as well as within chronically medicated Sz cohort, highlighting a potential link between inflammation and negative symptoms.

What Are the Aims of this Review and What Data Was Collected?

This systematic review aims to provide a comprehensive overview of cytokine perturbations in people who have experienced a FEP, but who have not yet received antipsychotic medication, so that the relationship between inflammatory markers and negative symptoms can be examined. The researchers used academic search engines and specialist key words (e.g. “first episode psychosis”, “medication naïve”, “immune dysregulation”, “negative symptoms”) to identify studies conducted on humans between the years 1982-2021. A ‘three-phase’ exclusion process removed duplicates, posters, conference abstracts, papers not measuring proinflammatory cytokines or negative symptoms, papers doing in-vitro or genetic studies and lastly, animal studies. The total included in this review is N = 10. The data included provided information on 651 antipsychotic naïve FEP patients with a mean age of 25. From the same 10 studies, we obtained information from 521 health controls with a mean age of 26. Twenty-four different cytokines were assessed using venous blood samples via an inflammation quantification technique (e.g. ELISA). The following cytokines were assessed: TNF-α, IFN-γ, IL1β, IL-2, IL-6, IL-8, IL-12, IL-17, (proinflammatory), IL-4 and IL-10 (anti-inflammatory).

What Do the Results Tell Us?

Results suggest that four proinflammatory cytokines were significantly upregulated in the FEP population, when compared with controls. Specifically, significant effect sizes were reported for IFN-γ, IL-6, IL-12 and IL-17 in patients with FEP. Further analyses identified a significant positive association between IFN-γ and IL-6 and Body Mass Index in FEP populations, as well as another association with percentage male sex. Due to the lack of available data, a narrative review was conducted to a assess the relationship between cytokine concentration and severity of negative symptoms on an individual study level. Overall, significant correlations between the PANSS Negative sub-score and changes in inflammatory markers were reported seven times, in six different studies, with reference to six different cytokines.

These are: IL-6, IL-2, TNF-α, and IL1β, which are pro-inflammatory and correlated positively with the PANSS Negative sub-score. However, for IL-4 and IL-10 which are anti-inflammatory, IL-4 was positively correlated with PANSS Negative sub-score, whereas IL-10 was negatively correlated with negative symptoms. So overall findings are somewhat mixed.

Future Directions for Research:

The biggest issue facing inflammatory research in psychosis is that there is not an agreed upon panel of inflammatory biomarkers that are consistently researched – some papers will look at a large groups of commonly assessed cytokines, but another lab may investigate a less well characterised cytokine in isolation, making conclusions difficult to draw. We can tackle this by identifying a panel of biomarkers of interest that are important in psychosis and consistently reporting findings. This will enable a more in-depth analysis of cytokine perturbations in psychosis, and potential relationships with symptoms.

Another issue is the indirect nature of peripheral blood samples – this is blood collected from the veins, which is a good surrogate measure, but will not completely accurately reflect the composition of cytokines that affect the brain, compared to samples collected from cerebral spinal fluid (CSF). However, collecting CSF is more complex and invasive, which is why it is less used in research.

Another methodological issue is the lack of standardisation when analysing such data. For example, blood samples can be affected by the time it was taken (i.e., morning vs afternoon), fasting conditions, differences in storage, different analysis methodologies across different labs (i.e., ELISA vs multiplex), and the machines used for analyses (i.e., different configurations across different labs).

All these factors can contribute to the wildly variable findings in the literature. As such, a good step forward is to develop a standardised method for analysing peripheral blood samples in relation to inflammation and psychosis and publishing and disseminating findings in accordance with the principles of Open Science.

How can you help?

If you’re interested in getting involved with inflammation and psychosis research, reach out to Connor (cxd680@student.bham.ac.uk), the author of this paper who is running a 6 week exercise study for males aged 18-38, who have a diagnosis of a First Episode of Psychosis – you’ll get free coaching and free access to facilities at the University of Birmingham!

Twitter Socials: Primed Lab, Connor Dunleavy, Dr Rachel Upthegrove

Blog written by Melanie Lafanechere (Research Associate for PRIMED+)

Reference: Dunleavy C, Elsworthy RJ, Upthegrove R, Wood SJ, Aldred S. (2022). Inflammation in first-episode psychosis: The contribution of inflammatory biomarkers to the emergence of negative symptoms, a systematic review and meta-analysis. Acta Psychiatry Scand. 146(1), 6-20. DOI: 10.1111/acps.13416