Transdiagnostic dimensions of symptoms and experiences associated with immune proteins in the continuity of psychosis

Background There is limited evidence as to whether the immune protein profile is associated with a particular symptomatology pattern across the psychosis continuum. Methods We estimated two bifactor models of general and specific dimensions of psychotic experiences in unaffected siblings of patients (n = 52) and community controls (n = 200), and of psychotic symptoms in first-episode psychosis (FEP) patients (n = 110). We evaluated associations between these transdiagnostic dimensions and trait (TNF-α, IFN-γ), state (IL-6, IL-1β), and regulatory (TGF-β, IL-10, IL-4) cytokines. We explored whether schizophrenia genetic liability (schizophrenia polygenic risk score; SZ-PRS) modified the associations. Results High levels of trait marker IFN-γ were associated with the severity of general psychosis dimension in the unaffected siblings and community controls, expanding to the depressive dimension in siblings and to the manic dimension in FEP. High TNF-α levels were associated with more positive psychotic experiences in unaffected siblings and manic symptoms in FEP. Low levels of state markers IL-6 and IL-1β were observed in unaffected siblings presenting more depressive experiences. Still, high levels of IL-6 and IL-1β were associated with the severity of the depressive and negative symptom dimensions at FEP. The severity of transdiagnostic dimension scores across the three groups was associated with lower regulatory cytokines. Exploratory analysis suggested that a high SZ-PRS contributed mostly to associations with psychotic dimensions. Conclusions IFN-γ mapped onto the multidimensional expression of psychosis, reinforcing the trait concept. State markers IL-6 and IL-1β may fluctuate along the spectrum. Dysfunction in the regulatory arm may disinhibit the inflammatory system. Associations with psychotic dimensions may be more prone to SZ-PRS susceptibility.