The Role of Peripheral Inflammation in Clinical Outcome and Brain Imaging Abnormalities in Psychosis: A Systematic Review

Abstract

Promising research investigating the association between inflammatory biomarkers and response to antipsychotic and/or adjunctive therapy, observed by improvement in psychiatric assessment, is emerging. Increased inflammation has been suggested to contribute to higher severity of symptoms/treatment resistance through the effects that this has on brain structure and function. The present systematic review aims to clarify the potential role of peripheral inflammatory markers as predictors of clinical outcomes and their association with neuroimaging markers in patients with psychosis. Systematic searches of the literature using the databases PsychInfo, OVID Medline, and Embase were conducted to collate studies investigating the association of inflammatory biomarkers with clinical outcome in patients with psychotic disorders and studies examining the relationships between inflammatory biomarkers and neuroimaging data. Seventeen studies on predictors of clinical outcome and 14 on associations between neuroimaging data and inflammatory biomarkers in psychosis were identified, and risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). The main inflammatory markers associated with clinical outcome in psychosis were interleukin (IL)-6, IL-10, and C-reactive protein (CRP). High levels of CRP and IL-6 were associated with worse clinical outcome and deterioration of symptoms over time; in contrast, increased levels of IL-10 were associated with greater symptoms improvement. Smaller hippocampal volume and reduced cortical thickness were the main neuroimaging markers associated with increased peripheral inflammation. The heterogeneity across the studies (i.e., treatments strategies, duration) suggests that potential prediction power of inflammatory biomarkers could partially depend on the methodologies, supported by the overall NOS ratings of the studies. Future studies may need to consider whether a combination of these inflammatory and neuroimaging markers could further improve our ability of predicting clinical outcome in patients with psychosis.

Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis

“…Extending this approach using the UK Biobank population, we found that genetically predicted levels of IL-6 were associated with reduced grey matter primarily in the middle temporal gyrus, a region whose gene expression profile is enriched for IL-6 pathway proteins and for neuropsychiatric disorder ontologies. 14 Moreover, clinical studies report correlations between IL-6 levels and structural brain changes in individuals with schizophrenia, 15 with reduced grey matter volume being exaggerated in patients with psychosis and elevated inflammatory cytokines. 16 Though this causal evidence strongly implicates IL-6, only an intervention study in patients can test the causal hypothesis.…”

Anti-inflammatory medications for the treatment of mental disorders: A scoping review

“…IL-6 decreased with antidepressant treatment whilst treatment failure was associated with persistently high TNFα ( Strawbridge et al, 2015 ). Cytokine inhibitors used in the treatment of chronic inflammatory disorders improved depressive symptoms as a secondary outcome measure, irrespective of the improvement in the primary physical illness ( Kappelmann et al, 2018 ).Elevated levels of proinflammatory cytokines such as IL-6, IL-8, TNFα and INF-ɣ ( Miller et al, 2011 ; Frydecka et al, 2018 ; Mondelli et al, 2015 ) and reduced levels of anti-inflammatory cytokines such as IL-10 ( Frydecka et al, 2018 ) have also been demonstrated in psychotic disorders and correlated with symptom severity as well as a poor response to antipsychotics ( Mondelli et al, 2015 ; Enache et al, 2021 ; Kose et al, 2021 ).…”

Inflammatory Biomarkers as Predictors of Mortality and Persistent Symptoms at Follow-up in Patients with Severe COVID-19

“…This aligns with findings of systemic low-grade inflammation in several mental disorders including depressive and anxiety disorders in the literature . (20)(21)(22)(23) And this has implications for treatment and treatment outcomes in a variety of mental disorders . (24,25) Persistent neuropsychiatric symptoms are commonly reported in those with Long-COVID.…”

“…Gender, age, and admission oxygen saturations (as per the 4C score) were included without evaluation. These variables have been proven to be associated with severe COVID-19 disease (20)(21)(22).…”