Crystal Vaughan

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.

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.

Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder

BACKGROUND Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder. METHODS We measured the levels of high sensitivity CRP in serum samples from 107 individuals with bipolar disorder. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Trail Making Test Part A and WAIS Information and Letter Number Sequencing. We estimated the odds of RBANS scores <=70 for participants whose CRP levels were above the 75th and the 90th percentile of the level of non-psychiatric controls. We also examined the association between cognitive scores and CRP levels. Covariates included demographic factors, mood symptom severity, cigarette smoking status, and body mass index. RESULTS There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile (OR=4.32, p=.018) and the 75th percentile (OR=3.07, p=.04)) of the control group. There was an inverse relationship between CRP levels and performance on RBANS total (t=-2.48, p=.015); RBANS immediate memory (t=-2.16, p=.033); RBANS attention (t=-2.18, p=.032); RBANS language (t=-2.13, p=.036); Trail Making A (t=-2.39, p=.019). LIMITATIONS Factors which we did not measure such as diet, allergen exposure, and underlying autoimmune disorders may contribute to CRP levels. CONCLUSIONS Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.

Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia

OBJECTIVES We investigated the effect of elevated levels of C-reactive protein (CRP) and exposure to Herpes simplex virus type 1 (HSV-1) on the severity of cognitive impairment in individuals with schizophrenia. METHODS We measured the levels of CRP and of antibodies to HSV-1 in serum samples from 588 individuals with schizophrenia by enzyme immunoassay tests. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and psychiatric symptoms with the Positive and Negative Syndrome Scale (PANSS). The effects of HSV1 and CRP on cognitive functioning were analyzed with linear and logistic regression analyses adjusting for demographic and clinical variables. RESULTS The individuals with elevated CRP levels and HSV-1 seropositivity had lower RBANS cognitive scores. The strongest effect was found in individuals who had both serological evidence of HSV-1 exposure and elevated levels of CRP. These individuals had odds of 2.35 to have an RBANS Total score<=60 as compared to individuals who were HSV-1 seronegative and who did not have elevated levels of CRP (p=.002). The risks of decreased cognitive functioning associated with HSV-1 exposure and elevated levels of CRP were independent and additive. There was no effect of HSV-1 exposure and CRP levels on the severity of symptoms as measured by the PANSS (all p>.5). CONCLUSIONS Elevated levels of CRP and exposure to HSV-1 are associated with the severity of cognitive impairment in schizophrenia. These findings indicate that infection and inflammation may play a major role in the cognitive deficits associated with schizophrenia.

Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder

Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.

Markers of gluten sensitivity in acute mania: A longitudinal study

Increased levels of antibodies to gliadin, which is derived from the wheat protein gluten, have been reported in schizophrenia and bipolar disorder in cross-sectional studies. We examined longitudinally the levels of antibody reactivity to gliadin in acute mania. The sample included 60 individuals assessed during a hospital stay for acute mania, 39 at a 6-month follow-up, and a sample of 143 non-psychiatric controls. Antibodies to gliadin were measured by enzyme immunoassay. The relationship of the antibodies to the clinical course of mania was analyzed by the use of regression models. Individuals with mania had significantly increased levels of IgG antibodies to gliadin, but not other markers of celiac disease, at baseline compared with controls in multivariate analyses. However, these levels were not significantly different from those of controls at the six month follow-up. Among the individuals with mania, elevated levels at follow-up were significantly associated with re-hospitalization in the 6-month follow-up period. The monitoring and control of gluten sensitivity may have significant effects on the management of individuals hospitalized with acute mania.

Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia

Immune system factors including complement pathway activation are increasingly linked to the etiology and pathophysiology of schizophrenia. Complement protein, C1q, binds to and helps to clear immune complexes composed of immunoglobulins coupled to antigens. The antigenic stimuli for C1q activation in schizophrenia are not known. Food sensitivities characterized by elevated IgG antibodies to bovine milk caseins and wheat glutens have been reported in individuals with schizophrenia. Here, we examined the extent to which these food products might comprise the antigen component of complement C1q immune complexes in individuals with recent onset schizophrenia (n=38), non-recent onset schizophrenia (n=61) and non-psychiatric controls (n=63). C1q seropositivity was significantly associated with both schizophrenia groups (recent onset, odds ratio (OR)=8.02, p≤0.008; non-recent onset, OR=3.15, p≤0.03) compared to controls (logistic regression models corrected for age, sex, race and smoking status). Casein- and/or gluten-IgG binding to C1q was significantly elevated in the non-recent onset group compared to controls (OR=4.36, p≤0.01). Significant amounts of C1q-casein/gluten-related immune complexes and C1q correlations with a marker for gastrointestinal inflammation in non-recent onset schizophrenia suggests a heightened rate of food antigens in the systemic circulation, perhaps via a disease-associated altered intestinal permeability. In individuals who are in the early stages of disease onset, C1q activation may reflect the formation of immune complexes with non-casein- or non-gluten-related antigens, the presence of C1q autoantibodies, and/or a dissociated state of immune complex components. In conclusion, complement activation may be a useful biomarker to diagnose schizophrenia early during the course of the disease. Future prospective studies should evaluate the impacts of casein- and gluten-free diets on C1q activation in schizophrenia.

Antibodies to the glutamate receptor in mania

Dickerson F, Stallings C, Vaughan C, Origoni A, Khushalani S, Yolken R. Antibodies to the glutamate receptor in mania. Bipolar Disord 2012: 14: 547–553.