Sunil Khushalani

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.

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.

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.

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.

Effect of Probiotic Supplementation on Schizophrenia Symptoms and Association With Gastrointestinal Functioning: A Randomized, Placebo-Controlled Trial

OBJECTIVE A range of immune system abnormalities have been associated with schizophrenia. Probiotic compounds modulate the immune response and offer a potential treatment strategy for schizophrenia. Probiotic compounds have also been observed to improve gastrointestinal dysfunction, which is a common problem in individuals with schizophrenia. We performed a randomized, double-blind, placebo-controlled trial to examine whether probiotic supplementation can reduce symptom severity in patients with schizophrenia receiving antipsychotic treatment and also whether probiotics are associated with bowel functioning. METHODS Outpatients with schizophrenia (N = 65) meeting DSM-IV criteria and with at least moderately severe psychotic symptoms were enrolled in the study from December 2010-August 2012. Following a 2-week placebo run-in period, patients were randomly assigned to 14 weeks of double-blind adjunctive probiotic (combined Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or placebo therapy. Psychiatric symptoms were assessed biweekly with the Positive and Negative Syndrome Scale (PANSS), and patients were queried weekly about their gastrointestinal functioning. RESULTS Repeated-measures analysis of variance showed no significant differences in the PANSS total score between probiotic and placebo supplementation (F = 1.28, P = .25). However, patients in the probiotic group were less likely to develop severe bowel difficulty over the course of the trial (hazard ratio = 0.23; 95% CI, 0.09-0.61, P = .003). CONCLUSIONS Probiotic supplementation may help prevent a common somatic symptom associated with schizophrenia. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01242371.

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.

A double-blind trial of adjunctive allopurinol for schizophrenia

OBJECTIVE To investigate if adjunctive allopurinol reduces symptoms in schizophrenia outpatients with persistent symptoms despite adequate pharmacotherapy. METHOD N=59 schizophrenia outpatients were randomly assigned to receive adjunctive allopurinol 300 mg bid or identical-looking placebo for 8 weeks after a 2-week placebo run-in. Symptoms were assessed biweekly. RESULTS A total of n=51 patients completed the trial. Including all n=59 randomized patients, a total of 4 of 31 in the allopurinol group and 0 of 28 in the placebo group had at least a 20% reduction in total PANSS score at the final study visit (chi-square=3.88, p=.049). Among the n=51 completers, individuals in the allopurinol group rated themselves as more improved than did those in the placebo group (z=-2.24, p=.025). The allopurinol medication was well tolerated and there were not any adverse events attributed to the study medication. CONCLUSIONS Allopurinol may be an effective adjunctive medication for some patients with persistent schizophrenia.

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.