Andrea Origoni

Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the Repeatable Battery for the Assessment of Neuropsychological Status

Cognitive dysfunction is an important feature of schizophrenia and bipolar disorder. There is uncertainty about the relative magnitude of cognitive deficits in these disorders. We evaluated a total of 446 individuals: 229 with schizophrenia, 117 with bipolar disorder, and 100 controls without a history of psychiatric disorder. All participants were administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a cognitive screening battery that evaluated immediate verbal memory, visuospatial/constructional abilities, attention, language, and delayed memory. A comparison of the three groups showed significant differences on the RBANS total score and all of the measured domains. In all of the comparisons, the schizophrenia group obtained the lowest scores, followed by the bipolar disorder group, and then the individuals without psychiatric disorder. In an analysis of covariance of RBANS total scores with the patient samples, the difference between schizophrenia and bipolar disorder remained significant after controlling for a range of demographic and clinical variables. Both schizophrenia and bipolar disorder are associated with significant cognitive impairments, but those in schizophrenia are more severe. Cognitive deficits may be an appropriate target of treatment interventions in these disorders.

C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia

OBJECTIVES We investigated the association between serum levels of C-reactive protein (CRP), a marker of inflammation, and the severity of psychopathology and cognitive impairment in schizophrenia. METHODS We measured the levels of CRP in N=413 individuals with schizophrenia. Symptom severity was evaluated with the Positive and Negative Syndrome Scale (PANSS) and cognitive functioning with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS The individuals with CRP >or=5.0 mg/microl had significantly lower RBANS cognitive scores than those with CRP <5.0 mg/microl (F=8.07, p<.005). However the CRP groups did not differ in the severity of positive, negative, or general PANSS symptoms (all p>.2). CONCLUSIONS Elevated serum levels of C-reactive protein in schizophrenia are associated with the severity of cognitive impairment but not of psychiatric symptoms. The long term consequences of elevated levels of CRP require further investigation.

Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder.

OBJECTIVES We investigated the association between serum levels of C-reactive protein (CRP), a marker of inflammation, and the severity of psychopathology in outpatients with bipolar disorder. We also compared the levels of CRP in the bipolar disorder individuals with those of a non-psychiatric control group. METHODS We measured the level of CRP in N=122 outpatients with bipolar disorder and N=165 control individuals and evaluated the symptom severity of the bipolar disorder patients with the Young Mania Rating Scale (YMRS) and the Hamilton Depression Scale (Ham-D). RESULTS Within the bipolar disorder sample, CRP was significantly associated with the YMRS score (r=.306, p<.006), age of onset, gender, and race. CRP was not significantly associated with the Ham-D score or other clinical or demographic variables. In a multivariate analysis of covariance, CRP was the only independent predictor of YMRS score (F=11.7, p=.0009). The CRP levels of the n=41 individuals with YMRS >6 were significantly greater than the levels of the n=81 individuals with YMRS <or=6 (F=7.94, <.006). The CRP levels of the group with YMRS >6 were also significantly greater than the levels of the control group (p=.033) while the CRP levels of the group with YMRS <or=6 did not differ from that of controls (p>.05). CONCLUSIONS Our results suggest that outpatients with bipolar disorder with mania symptoms have increased levels of CRP as compared to those without mania symptoms and compared to individuals without psychiatric disorders. The long-term consequences of CRP in bipolar disorder should be the subject of future studies.

Cigarette Smoking Among Persons With Schizophrenia or Bipolar Disorder in Routine Clinical Settings, 1999–2011

OBJECTIVE This study examined the prevalence of cigarette smoking and the quantity of cigarettes consumed by individuals with schizophrenia or bipolar disorder and by those with no psychiatric disorder in the period 1999-2011. METHODS A total of 991 individuals with schizophrenia, bipolar disorder, or no psychiatric illness provided information about their cigarette smoking at recruitment into a research study for which they were selected without regard to their smoking status. Differences among groups and trends over time among new enrollees were examined with multivariate models. Regression analyses were used to compare smoking between the schizophrenia and bipolar disorder groups. RESULTS There were marked differences in the prevalence of smoking and in the quantity of cigarettes consumed among the diagnostic groups. Overall, 64% of individuals with schizophrenia, 44% with bipolar disorder, and 19% without psychiatric illness reported that they were current smokers. These group differences remained fairly constant over the observation period, and there were no statistically significant time trends in smoking or cigarette consumption after adjustment for demographic covariates. Within the psychiatric illness groups, smoking and cigarette consumption were significantly associated with less education, a history of substance abuse, longer illness duration, Caucasian race, and schizophrenia diagnosis but not with psychiatric symptom severity. CONCLUSIONS The prevalence of smoking has remained alarmingly high among individuals with schizophrenia and bipolar disorder in routine psychiatric settings. Concerted efforts are urgently needed to promote smoking cessation in these groups.

Markers of Gluten Sensitivity and Celiac Disease in Recent-Onset Psychosis and Multi-Episode Schizophrenia

BACKGROUND Increased immune sensitivity to gluten has been reported in schizophrenia. However, studies are inconsistent about this association. METHODS The sample of 471 individuals included 129 with recent-onset psychosis, 191 with multi-episode schizophrenia, and 151 controls. Immunoglobulin (Ig)G and IgA antibodies to gliadin and to tissue transglutaminase, and IgG antibodies to deamidated gliadin were measured. Quantitative levels of antibodies in the psychiatric groups were compared with controls. All participants were categorized as to whether their levels of antibodies met standardized cutoffs for celiac disease. HLA DQ2 and HLA DQ8 alleles were detected by real-time polymerase chain reaction. RESULTS Individuals with recent-onset psychosis had increased levels of IgG (odds ratio [OR] 5.50; 95% confidence interval [CI] 2.65-11.42) and IgA (OR 2.75; 95% CI 1.31-5.75) antibodies to gliadin compared with control subjects. Individuals with multi-episode schizophrenia also had significantly increased levels of IgG antibodies to gliadin (OR 6.19; 95% CI 2.70-14.16). IgG antibodies to deamidated gliadin and IgA antibodies to tissue transglutaminase were not elevated in either psychiatric group, and fewer than 1% of individuals in each of the groups had levels of these antibodies predictive of celiac disease. There were no significant differences in the distribution of the HLA DQ2/8 alleles among the groups. CONCLUSIONS Individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

Gastrointestinal inflammation and associated immune activation in schizophrenia

Immune factors are implicated in normal brain development and in brain disorder pathogenesis. Pathogen infection and food antigen penetration across gastrointestinal barriers are means by which environmental factors might affect immune-related neurodevelopment. Here, we test if gastrointestinal inflammation is associated with schizophrenia and therefore, might contribute to bloodstream entry of potentially neurotropic milk and gluten exorphins and/or immune activation by food antigens. IgG antibodies to Saccharomyces cerevisiae (ASCA, a marker of intestinal inflammation), bovine milk casein, wheat-derived gluten, and 6 infectious agents were assayed. Cohort 1 included 193 with non-recent onset schizophrenia, 67 with recent onset schizophrenia and 207 non-psychiatric controls. Cohort 2 included 103 with first episode schizophrenia, 40 of whom were antipsychotic-naïve. ASCA markers were significantly elevated and correlated with food antigen antibodies in recent onset and non-recent onset schizophrenia compared to controls (p≤0.00001-0.004) and in unmedicated individuals with first episode schizophrenia compared to those receiving antipsychotics (p≤0.05-0.01). Elevated ASCA levels were especially evident in non-recent onset females (p≤0.009), recent onset males (p≤0.01) and in antipsychotic-naïve males (p≤0.03). Anti-food antigen antibodies were correlated to antibodies against Toxoplasma gondii, an intestinally-infectious pathogen, particularly in males with recent onset schizophrenia (p≤0.002). In conclusion, gastrointestinal inflammation is a relevant pathology in schizophrenia, appears to occur in the absence of but may be modified by antipsychotics, and may link food antigen sensitivity and microbial infection as sources of immune activation in mental illness.

Infection with Herpes Simplex Virus Type 1 Is Associated with Cognitive Deficits in Bipolar Disorder

BACKGROUND In a previous investigation, we found an association between reduced cognitive functioning and the prevalence of antibodies to herpes simplex virus type 1 in individuals with schizophrenia. The current study was undertaken to determine if this association also occurs in individuals with bipolar disorder. METHODS Cognitive functioning and serologic evidence of infection with potentially neurotropic herpesviruses were measured in 117 individuals with bipolar disorder and in 100 individuals without a history of psychiatric disorder. Cognitive functioning was evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status. For each patient, serologic evidence of infection was ascertained by the measurement of serum immunoglobulin G class antibodies with specificities for six potentially neurotropic human herpesviruses. The association between serologic evidence of herpesvirus infection and cognitive functioning was analyzed by univariate analyses, as well as multivariate analyses that included demographic and clinical factors associated with cognitive functioning. RESULTS Serologic evidence of infection with herpes simplex virus type 1 was an independent predictor of decreased cognitive functioning in the individuals with bipolar disorder (F = 20.5, p <.0001). Discriminant function analysis indicated that most of the difference in cognitive functioning between individuals who were antibody positive and antibody negative for herpes simplex virus type 1 could be attributed to immediate verbal memory (F = 12.07, p <.001). There was no significant association between cognitive functioning and the other human herpesviruses. No association between antibodies to herpesviruses and cognitive functioning was found in the control individuals without a history of psychiatric disorder. CONCLUSIONS Serologic evidence of herpes simplex virus type 1 infection is associated with cognitive impairment in individuals with bipolar disorder.

Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia

The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of low-grade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychotic-naïve first-episode schizophrenia, n=38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p<0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R(2)=0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R(2)=0.26-0.27, p<0.0001) and elevated in females compared to males (p<0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R(2)=0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R(2)=0.37, p<0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based monocyte activation, autoimmunity and metabolic dysfunction may also contribute to the observed marker profiles.

Outpatients with schizophrenia and bipolar I disorder: do they differ in their cognitive and social functioning?

The authors used a battery of cognitive and social functioning measures to evaluate stable outpatients with schizophrenia (n=74) and bipolar I disorder (n=26) who were receiving care at community and rehabilitation programs. The groups did not differ significantly on 36 of 41 measures. For most variables, comparisons between groups yielded effect sizes of <0.5. These results suggest that individuals with bipolar I disorder receiving community and rehabilitation services have many social and cognitive deficits that are as severe as those in schizophrenia.

C-reactive protein is elevated in schizophrenia.

BACKGROUND Increased levels of inflammatory markers have been reported in schizophrenia, but few studies have examined levels of high sensitivity C-reactive protein (CRP), a non-specific inflammatory marker. METHODS Levels of high sensitivity CRP were measured in individuals with schizophrenia, bipolar disorder, and non-psychiatric controls. Linear regression analyses were used to compare the CRP levels among the three groups adjusting for demographic and clinical variables. Logistic regression analyses were used to determine the odds ratios associated with elevated levels of CRP, defined as >=75th and 90th percentile in the controls. RESULTS The sample consisted of 715 individuals: 295 with schizophrenia, 192 with bipolar disorder, and 228 without a psychiatric disorder. The levels of CRP in the schizophrenia group, but not in the bipolar disorder group, were significantly increased compared to controls adjusting for age, gender, race, maternal education, smoking status, and Body Mass Index (BMI) (t=3.78, p=<.001). The individuals with schizophrenia had significantly increased odds of having elevated levels of CRP relative to both the 75th and 90th percentile levels of the controls adjusting for the same covariates (OR 1.79, 95% CI 1.14, 2.82; p=.012; OR 2.76, 95% CI 1.58, 4.83, p=<.001). In the multivariate linear and logistic regression analyses, levels of CRP were also associated with BMI and female gender. CONCLUSIONS Individuals with schizophrenia may be at risk for the adverse health consequences associated with elevated CRP in the overall population. Trials of interventions directed at lowering the level of CRP and other inflammatory markers are indicated.