Inflammation and cognition in severe mental illness: patterns of covariation and subgroups.

A potential relationship between dysregulation of immune/inflammatory pathways and cognitive impairment has been suggested in severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, multivariate relationships between peripheral inflammatory/immune-related markers and cognitive domains are unclear, and many studies do not account for inter-individual variance in both cognitive functioning and inflammatory/immune status. This study aimed to investigate covariance patterns between inflammatory/immune-related markers and cognitive domains and further elucidate heterogeneity in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 289, HC = 770). We applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive domains 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 defined daily dose (DDD) of antipsychotics (SMI cohort). Our findings suggest a link between cognitive impairment and innate immune dysregulation in a subset of individuals with severe mental illness.

Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy.

BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity  was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

Tobacco smoking related to childhood trauma mediated by cognitive control and impulsiveness in severe mental disorders.

BACKGROUND: People with severe mental disorders (SMDs) show an increased prevalence of tobacco smoking compared to the general population. Tobacco smoking and other adult adverse health behaviors have been associated with traumatic experiences in childhood. In the present study we investigated the relationship between childhood trauma and tobacco smoking in people with SMDs, including the possible mediating role of cognitive- and personality characteristics, i.e. cognitive control, impulsiveness, affective lability and self-esteem. METHODS: Enrolled in the study were 871 participants with schizophrenia (SCZ, N = 484) and bipolar (BD, N = 387) spectrum disorders. We assessed tobacco smoking behavior (yes/no and amount), and history of childhood trauma with the Childhood Trauma Questionnaire. Data on cognitive control, impulsiveness, affective lability, and self-esteem were available in subsamples. We performed linear and logistic regressions, and conducted mediation analyses in PROCESS. All analyses were as standard adjusted for age, sex, and diagnostic group. RESULTS: Experience of one or more subtypes of childhood trauma was significantly associated with smoking tobacco in SMDs (p = 0.002). There were no significant associations between childhood trauma and amount of tobacco smoking. Cognitive control and impulsiveness were significant mediators between childhood trauma and tobacco smoking. CONCLUSIONS: These findings indicate the experience of childhood trauma as a predisposing factor for tobacco smoking in SMDs. Cognitive control and impulsiveness were suggested as mediating mechanisms, indicating the importance of considering inhibition related self-regulatory aspects in efforts to improve health behavior in individuals with SMDs and childhood trauma.

Limited association between infections, autoimmune disease and genetic risk and immune activation in severe mental disorders.

BACKGROUND: Low-grade inflammation may be part of the underlying mechanism of schizophrenia and bipolar disorder. We investigated if genetic susceptibility, infections or autoimmunity could explain the immune activation. METHODS: Seven immune markers were selected based on indicated associations to severe mental disorders (IL-1Ra, sIL-2R, IL-18, sgp130, sTNFR-1, APRIL, ICAM-1) and measured in plasma of patients with schizophrenia (SCZ, N = 732) and bipolar spectrum disorders (BD, N = 460) and healthy controls (HC, N = 938). Information on rate of infections and autoimmune diseases were obtained from Norwegian national health registries for a twelve-year period. Polygenic risk scores (PRS) of SCZ and BD were calculated from genome-wide association studies. Analysis of covariance were used to test effects of infection rate, autoimmune disease and PRS on differences in immune markers between patients and HC. RESULTS: Infection rate differed between all groups (BD > HC > SCZ, all p < 0.001) whereas autoimmune disease was more frequent in BD compared to SCZ (p = 0.004) and HC (p = 0.003). sIL-2R was positively associated with autoimmune disease (p = 0.001) and negatively associated with PRS of SCZ (p = 0.006) across SCZ and HC; however, associations represented only small changes in the difference of sIL-2R levels between SCZ and HC. CONCLUSION: There were few significant associations between rate of infections, autoimmune disease or PRS and altered immune markers in SCZ and BD, and the detected associations represented only small changes in the immune aberrations. The findings suggest that most of the low-grade inflammation in SCZ and BD is explained by other factors than the underlying PRS, autoimmunity and infection rates.

Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis.

Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra (P = 0.01) and IL-18 (P = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 (P = 0.02) and PRS of anxiety and IL-18 (P = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R (P = 0.02) and PRS of educational attainment and sIL-2R (P = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P = 0.02) and sTNFR-1 (IE, P = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

Interleukin-18 signaling system links to agitation in severe mental disorders.

OBJECTIVE: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. METHODS: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. RESULTS: Agitation was positively associated with IL-18BP (ß = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (ß = 0.06, t = 1.27, p = 0.20), IL-18 (ß = 0.05, t = 1.25, p = 0.21), IL-18R1 (ß = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. CONCLUSION: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.