Differential associations between cytokine and complement proteins in the clinical high risk and first episode stages of psychosis: Blood based investigation across three international studies of psychosis: NEURAPRO, STEP and OPTiMiSE

Dysregulation of inflammatory mediators and complement cascade proteins has been implicated in psychosis. In the current study, we aimed to investigate the relationship between complement cascade proteins and inflammatory cytokines in blood from people at clinical high risk (CHR) for psychosis and at first episode of psychosis (FEP). Baseline blood samples from two cohorts of CHR participants [NEURAPRO (n = 153) and STEP (n = 146)], and one cohort of FEP patients [OPTiMiSE (n = 226)] were included. The blood levels of three Inflammatory markers including Interleukin (IL)-6, Tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) along with about 30 complement proteins were considered for the analyses. First, we evaluated the interrelationship between the inflammatory markers and then using regression models, we investigated their association with complement proteins. We detected positive associations among all three inflammatory markers IL-6, TNF-α, and CRP in CHR individuals, whereas in FEP positive association was observed only between IL-6 and TNF-α. Regression models showed strong positive associations for complement proteins C3, C4A, C4B, C5, CFB and CFI with all three inflammatory markers in both CHR cohorts. This indicates the presence of a complement related pro-inflammatory tone at risk of developing psychosis. In contrast, in the FEP cohort, complement proteins C1QA, C3, C5, FCN-2, and MASP2 showed an inverse association with TNF-α, and no association found with IL-6 or CRP. These results suggest a switch in the immune activity in the peripheral circulation of FEP compared to CHR. These novel findings propose that complement protein-targeted anti-inflammatory therapy could be effective at CHR state and hence could be used for early intervention in psychosis.