Inflammation and cognition in severe mental illness: Patterns of covariation and subgroups

Cognitive impairments are common in severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders, with substantial heterogeneity in both diagnostic categories. It has been suggested that dysregulation of immune and inflammatory pathways may contribute to cognitive impairment. This study aimed to investigate covariance patterns between cognitive domains and inflammatory/immune-related markers and further elucidate inter-individual variance in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 298, HC = 770). We applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive measures and inflammatory/immune markers. We found that poor verbal learning and psychomotor processing speed was associated with higher levels of interleukin-18 system cytokines and beta defensin 2, reflecting enhanced activation of innate immunity, a pattern augmented in SMI compared to HC. Applying hierarchical clustering on covariance patterns identified by the CCA revealed a high cognition – low immune dysregulation subgroup with predominantly HC (24% SZ, 45% BD, 74% HC) and a low cognition – high immune dysregulation subgroup predominantly consisting of SMI patients (76% SZ, 55% BD, 26% HC). These subgroups differed in IQ, years of education, age, CRP, BMI (all groups), level of functioning, symptoms and DDD of antipsychotics (SMI cohort). Our findings suggest a potential link between cognitive functioning and innate immune dysregulation.