Complement system biomarkers in first episode psychosis

Abstract

Several lines of evidence implicate immunological/inflammatory factors in development of schizophrenia. Complement is a key driver of inflammation, and complement dysregulation causes pathology in many diseases. Here we explored whether complement dysregulation occurred in first episode psychosis (FEP) and whether this provides a source of biomarkers. Eleven complement analytes (C1q, C3, C4, C5, factor B [FB], terminal complement complex [TCC], factor H [FH], FH-related proteins [FHR125], Properdin, C1 inhibitor [C1inh], soluble complement receptor 1 [CR1]) plus C-reactive protein (CRP) were measured in serum from 136 first episode psychosis (FEP) cases and 42 mentally healthy controls using established in-house or commercial ELISA. The relationship between caseness and variables (analytes measured, sex, age, ethnicity, tobacco/cannabis smoking) was tested by multivariate logistic regression. When measured individually, only TCC was significantly different between FEP and controls (p=0.01). Stepwise selection demonstrated interdependence between some variables and revealed other variables that significantly and independently contributed to distinguishing cases and controls. The final model included demographics (sex, ethnicity, age, tobacco smoking) and a subset of analytes (C3, C4, C5, TCC, C1inh, FHR125, CR1). A receiver operating curve analysis combining these variables yielded an area under the curve of 0.79 for differentiating FEP from controls. This model was confirmed by multiple replications using randomly selected sample subsets. The data suggest that complement dysregulation occurs in FEP, supporting an underlying immune/inflammatory component to the disorder. Classification of FEP cases according to biological variables rather than symptoms would help stratify cases to identify those that might most benefit from therapeutic modification of the inflammatory response.

Reference Intervals of Factor H and Factor H-Related Proteins in Healthy Children

“…In addition, recent developments in the determination of circulating FHR levels in adults have led to the discovery of new associations with disease. FHR-1 levels were shown to be increased during IgA nephropathy ( 31 , 32 ), although the authors report much higher levels than we and others have published ( 33 , 34 ). FHR-3 levels were shown to be elevated during sepsis ( 35 ) and in systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica ( 36 ).…”

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

“…One recent study found decreased Fig. 1 Plots the protein abundances derived from the mass spectrometry data for the significantly regulated proteins, VTN, C1RL, C8B, C8A, CFH, and C5 TCC complex (sC5b-9) plasma levels, a marker of terminal pathway activation in patients with first episode psychosis [55]. Another study showed increased alternative pathway activity in schizophrenia patients [56].…”

Is It Possible to Predict the Future in First-Episode Psychosis?

“…While meta-analyses initially suggested that antipsychotic medication might decrease pro-inflammatory activation ( 108 ), a later meta-analysis did not find a significant medication effect ( 110 ). Further signals of a change in immune response come from associations with markers of oxidative stress ( 112 ) and the activation of the complement system ( 113 ). While various markers of immune response have been found to correlate with clinical features, such as structural brain abnormalities, symptoms and cognitive deficits ( 114 – 116 ), less is known about their predictive value.…”