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Importance: Schizophrenia is associated with premature mortality from mostly natural causes. Decreased cognitive functioning has been identified as a determinant of mortality in the general population. However, there have been few prospective studies of this issue in persons with schizophrenia., Objective: To examine whether lower cognitive functioning is a risk factor for natural cause mortality in schizophrenia., Design, Setting, and Participants: This prospective cohort study included persons with schizophrenia or schizoaffective disorder enrolled between February 1, 1999, and December 31, 2022, at a nonprofit psychiatric system in Baltimore, Maryland. Participants were evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and other clinical measures., Exposure: Natural cause mortality., Main Outcomes and Measures: Associations of cognitive function, obesity, tobacco smoking, and medical conditions with natural cause mortality were evaluated using Cox proportional hazards regression models., Results: Of the 844 participants enrolled (mean [SD] age, 39.6 [12.1] years; 533 male [63.2%]), 158 (18.7%) died of natural causes during a median follow-up of 14.4 years (range, 7.0 days to 23.9 years). The most significant factor associated with mortality was lower cognitive functioning as measured by the RBANS (Cox coefficient, -0.04; 95% CI, -0.05 to -0.03; z = -5.72; adjusted P < .001). Additional factors independently associated with mortality included the diagnosis of an autoimmune disorder (hazard ratio [HR], 2.86; 95% CI, 1.83-4.47; z = 4.62; adjusted P < .001), tobacco smoking (HR, 2.26; 95% CI, 1.55-3.30; z = 4.23; adjusted P < .001), diagnosis of chronic obstructive pulmonary disease (HR, 3.31; 95% CI, 1.69-6.49; z = 3.48; adjusted P = .006), body mass index as a continuous variable (HR, 1.06; 95% CI, 1.02-1.09; z = 3.30; adjusted P = .01), diagnosis of a cardiac rhythm disorder (HR, 2.56; 95% CI, 1.40-4.69; z = 3.06; adjusted P = .02), and being divorced or separated (HR, 1.80; 95% CI, 1.22-2.65; z = 2.97; adjusted P = .02). An RBANS score below the 50th percentile displayed a joint association with being a smoker, having an elevated body mass index, and having a diagnosis of an autoimmune or a cardiac rhythm disorder., Conclusions and Relevance: In this prospective cohort study, lower cognitive functioning was a risk factor for natural cause mortality in schizophrenia. Efforts should be directed at methods to improve cognitive functioning, particularly among individuals with additional risk factors.

Importance: Individuals with schizophrenia are at higher risk for severe COVID-19 illness and severe breakthrough infection following vaccination. It is unclear whether immune response to vaccination differs in this population., Objective: To assess whether anti-SARS-CoV-2 spike antibody titers after vaccination differ in people with a diagnosis of schizophrenia or schizoaffective disorder (SZ) compared to controls without a psychiatric disorder., Design: This cohort study assessed antibody response following the first and second dose of mRNA vaccines at longitudinal timepoints, up to 7 weeks following the first dose of vaccine., Setting: A multi-center study including psychiatric healthcare settings in the United States and Europe., Participants: 205 adults with no history of COVID-19 infection, including 106 individuals with SZ and 99 controls without a psychiatric disorder, who received their first dose of SARS-CoV-2 mRNA vaccine between December 20, 2020 and May 27, 2021., Main Outcomes and Measures: Mean SARS-CoV-2 anti-Spike IgG antibody levels within 7 weeks after the first dose of vaccination., Results: A total of 205 individuals (mean [SD] age, 44.7 [12.0] years; 90 [43.9%] male) were included, of which 106 (51.7%) were diagnosed with SZ. SZ was associated with lower mean log antibody levels (-0.15; 95% CI, -0.27 to -0.03, P  = 0.016) after adjusting for age, sex, body mass index, smoking, days since vaccination, and vaccine manufacturer. In secondary analyses of dose-specific responses, SZ was associated with a lower mean log antibody level after the second dose of vaccine (-0.23; 95% CI -0.39 to -0.06, P  = 0.006), but not the first dose of vaccine (0.00; 95% CI -0.18- 0.19, P  = 0.96)., Conclusions and Relevance: In this cohort study of individuals with SZ and a control group without psychiatric disorders, SZ was associated with lower SARS-CoV-2 anti-spike antibody levels following 2 doses of SARS-CoV-2 mRNA vaccination. This highlights the need for further studies assessing vaccine immunogenicity in individuals with schizophrenia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Introduction: Herpesviruses are recognized as major causes of human diseases. Following initial infection, Herpesviruses can undergo cycles of reactivation controlled largely by the immune system. Cigarette smoking is an important modulator of the immune system particularly in individuals with serious mental illness where smoking is associated with increased rates of cardiopulmonary diseases and mortality. However, the effect of smoking on Herpesviruses has not been extensively studied., Methods: In this nested cohort study, cigarette smoking was assessed in 1323 persons with serious mental illness or without a psychiatric disorder ascertained in a psychiatric health care system and the adjacent community. Participants provided a blood sample from which were measured IgG class antibodies to five human Herpesviruses: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus-Type 1 (HSV-1); Varicella Zoster Virus (VZV); and Human Herpes Virus-Type 6 (HHV-6). The associations between smoking variables and antibody levels to the Herpesviruses were analyzed among diagnostic groups in multiple regression models adjusted for age, sex, and race., Results: Current smoking was significantly associated with higher levels of antibodies to CMV (coefficient .183, 95% CI .049, .317, p<.001, q<.007) and the three EBV proteins (EBV NA -(coefficient .088, 95% CI .032, .143, p = .002, q<.014; EBV Virion - coefficient .100, 95% CI .037, .163, p = .002, q<.014; and EBV VCA - coefficient .119, 95% CI .061, .177, p = .00004, q<.0016). The amount of cigarettes smoked was also correlated with higher levels of antibodies to the three EBV proteins. Interaction analyses indicated that the association between cigarette smoking and levels of antibodies to CMV and EBV was independent of diagnostic group. Cigarette smoking was not significantly associated with the level of antibodies to HSV-1, VZV, or HHV-6., Conclusions: Individuals who smoke cigarettes have increased levels of IgG antibodies to CMV and EBV. Cigarette smoking may be a contributory factor in the relationship between CMV, EBV and chronic somatic disorders associated with these viruses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Dickerson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to characterize the experiences of persons with serious mental illness during the COVID-19 pandemic., Methods: Adults with schizophrenia, bipolar disorder, major depression, or no psychiatric disorder (N=195) were interviewed between July 2020 and January 2021. All were previously enrolled in a cohort study. The interviews focused on mental distress and suicidal thoughts, the impact of the pandemic and pandemic-related worries, tobacco and alcohol use, and access to care. Responses of persons with serious mental illness were compared with responses of those without a psychiatric disorder by using multivariate ordered logistic regression analyses. For a subset of participants, responses about suicidal ideation were compared with their responses prior to the pandemic., Results: Compared with participants with no psychiatric disorder, individuals with schizophrenia were more likely to endorse that they felt overwhelmed or anxious, had difficulty concentrating, or were concerned about medical bills and having enough food; they also reported significantly increased tobacco smoking. Individuals with bipolar disorder also reported more COVID-19-related worries than did participants without a psychiatric disorder. Overall, those with a psychiatric disorder reported more frequent mental distress and more recent missed medical visits and medications than did those with no psychiatric disorder. However, participants with serious mental illness did not report a higher rate of suicidal thoughts compared with their prepandemic responses., Conclusions: The pandemic poses significant challenges to individuals with serious mental illness in terms of COVID-19-related distress. Psychiatric services should proactively address the emotional distress and worries associated with the pandemic.

Persons with serious mental illness die on average more than 10 years younger than those in the overall population, mostly due to natural causes. Previous studies have identified predictors of natural cause mortality in this population but few have been prospective studies using clinical variables from in-person evaluations. A cohort of 1494 individuals with schizophrenia, bipolar disorder, or major depressive disorder were assessed at baseline and mortality status was determined from the US National Death Index after up to 20 years of follow-up. Analyses included multivariate Cox proportional hazard models to determine independent predictors of natural cause mortality. A total of 125 (8.4%) individuals died of natural causes. In multivariate models, the strongest predictor of mortality after age was tobacco smoking at baseline with a dose-related effect. Having diabetes, a cardiovascular condition, particularly hypertension, and lower cognitive functioning were also significant risks, along with divorced/separated status. The receipt of gabapentin or fluoxetine also significantly increased mortality risk. Premature death can be reduced by smoking cessation and the improved management of conditions such as hypertension and diabetes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cognitive deficits are a central feature of schizophrenia whose etiology is not fully understood. Epstein Barr Virus (EBV) is a potentially neurotropic infectious agent that can generate persistent infections with immunomodulatory effects. Previous studies have found an association between EBV antibodies and cognitive functioning in different populations, but there has been limited investigation in schizophrenia. In this study, 84 individuals with schizophrenia were administered a comprehensive neuropsychological battery, the MATRICS Consensus Cognitive Battery (MCCB). Participants also provided a blood sample, from which antibodies to the EBV whole virion and specific proteins were measured. Multivariate models were constructed to determine the association between these antibodies and cognitive performance on the MCCB overall and domain scores. Using these models, we found a significant association between the MCCB overall percent composite score and level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. A significant association was also found for the MCCB social cognition domain with the level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. In all cases, a higher level of antibodies was associated with a lower level cognitive performance. These findings suggest that exposure to EBV may contribute to cognitive deficits in schizophrenia, a finding which may have implications for new methods of prevention and treatment., Competing Interests: Declaration of competing interest Dr. Yolken is a member of the Stanley Medical Research Institute Board of Directors and Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: An atypical immune response to Epstein-Barr virus (EBV) infection has been associated with several complex diseases including schizophrenia. The etiology of MDD is unclear; host immune response to EBV infection could play a role., Methods: We utilized solid phase immunoassays and western blots to measure antibodies to EBV virions, specific viral proteins, and 5 other herpesviruses in 87 individuals with MDD and 312 control individuals., Results: Individuals with MDD had significantly reduced levels of reactivity to EBV Nuclear Antigen-1. Quantitative levels of antibodies to EBV virions and Viral Capsid Antigen did not differ between groups. Individuals with decreased levels of anti-Nuclear Antigen-1, or elevated levels of anti-virion had increased odds of being in the MDD group. The odds of MDD were elevated in individuals who had the combination of high levels of anti-virion and low levels of anti-Nuclear Antigen-1 (OR =13.6). Western blot analysis corroborated decreased reactivity to Nuclear Antigen-1 in the MDD group and revealed altered levels of antibodies to other EBV proteins. There was a trend towards decreased levels of antibodies to varicella virus in the group of individuals with MDD., Limitations: The MDD sample size was relatively small. There could be unmeasured factors that account for the association between MDD and the immune response to EBV., Conclusions: Individuals with MDD have altered levels and patterns of antibodies to EBV antigens. This atypical response could contribute to the immunopathology of MDD. Therapeutic interventions available for treatment of EBV infection could potentially be of benefit in MDD., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2019. Published by Elsevier B.V.)

Schizophrenia and bipolar disorder are associated with reduced cognitive functioning which contributes to problems in day-to-day functioning and social outcomes. A paucity of research exists relating dietary factors to cognitive functioning in serious mental illnesses, and results are inconsistent. The study aims to describe the nutritional intake of persons with schizophrenia and those with a recent episode of acute mania and to determine relationships between the intake of protein and other nutrients on cognitive functioning in the psychiatric sample. Persons with schizophrenia and those with acute mania were assessed using a 24-h dietary recall tool to determine their intakes of protein and other nutrients. They were also assessed with a test battery measuring different domains of cognitive functioning. Results indicate that lower amounts of dietary protein intake were associated with reduced cognitive functioning independent of demographic and clinical factors. The association was particularly evident in measures of immediate memory and language. There were not associations between cognitive functioning and other nutritional variables, including total energy, gluten, casein, saturated fat, or sugar intakes. The impact of dietary interventions, including protein intake, on improving cognitive functioning in individuals with psychiatric disorders warrants further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest with respect to this manuscript., (Copyright © 2019. Published by Elsevier B.V.)

Background: Serious psychiatric disorders such as schizophrenia and bipolar disorder have been associated with environmental exposures in early life. Contact with household pets such as cats and dogs can serve as a source of environmental exposure during these time periods., Methods: We investigated the relationship between exposure to a household pet cat or dog during the first 12 years of life and having a subsequent diagnosis of schizophrenia or bipolar disorder. These studies were performed in a cohort of 396 individuals with schizophrenia, 381 with bipolar disorder, and 594 controls. The hazards of developing schizophrenia or bipolar disorder associated with first exposure to a household pet cat or dog were calculated using Cox Proportional Hazard and multivariate logistic regression models including socio-demographic covariates., Results: We found that exposure to a household pet dog was associated with a significantly decreased hazard of having a subsequent diagnosis of schizophrenia (Hazard Ratio .75, p < .002) Furthermore, a significant decreased relative risk of schizophrenia was detected following exposure at birth and during the first years of life. There was no significant relationship between household exposure to a pet dog and bipolar disorder. There were no significant associations between exposure to a household pet cat and subsequent risk of either a schizophrenia or bipolar disorder diagnosis. However, there were trends towards an increased risk of both disorders at defined periods of exposure., Conclusions: Exposure to household pets during infancy and childhood may be associated with altered rates of development of psychiatric disorders in later life., Competing Interests: The authors have declared that no competing interests exist.

Background: Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing persistent infection., Methods: We employed solid phase immunoassay techniques to measure immunoglobulin G (IgG) class antibodies to EBV virions and defined proteins in 432 individuals with schizophrenia and 311 individuals without a history of a psychiatric disorder. Western blot testing was performed to document reactivity to specific EBV proteins. Polygenic risk for schizophrenia was calculated from genome sequencing arrays. Levels of antibodies between the groups were compared by multivariate analyses incorporating clinical, genetic, and demographic measures., Results: Individuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population. Further analyses indicated increased levels of reactivity to EBV-viral capsid antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-1) or to other human herpesviruses. Western blot analysis confirmed increased reactivity to VCA proteins in the group of individuals with schizophrenia and documented a lack of increased levels of antibodies to EBNA-1. Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis., Conclusions: Individuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins indicating an aberrant response to EBV infection. This aberrant response may contribute to the immunopathology of schizophrenia and related disorders., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

There has been little previous study of the association between dietary factors and suicide. The association between food exposures and suicide attempt history was investigated in a sample of 270 individuals with schizophrenia, bipolar disorder, or major depressive disorder. Individuals who had a suicide attempt history were almost 3 times as likely to report eating cured meat, typically prepared with added nitrates, compared to patients without a suicide attempt history, adjusting for demographic and clinical variables. A suicide attempt history was 6 times greater in those who in addition were cigarette smokers and had a history of substance abuse compared to those who did not have any of these risk factors. If dietary factors were shown to affect suicide risk, an additional method of risk reduction would be available which could be widely disseminated to address this major public health problem., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania., Methods: Patients hospitalized for mania (N = 66) were randomized after discharge to receive 24 weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens., Results: During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z = 2.63, P = .009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10, .69; P = .007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8 days for placebo and probiotic treatment, respectively; χ 2  = 5.17, P = .017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline., Conclusion: Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To identify the determinants of natural cause mortality in a cohort of individuals with serious mental illness assessed prospectively., Method: Persons with schizophrenia (n = 789) and bipolar disorder (n = 498), mean age of 38 (s.d. 12.6) years, underwent an in-person clinical assessment. They also had a blood sample drawn from which infectious disease markers were measured. Mortality was subsequently determined utilizing data from the National Death Index following a period of up to 16.9 years., Results: A total of 6.8% (87 of 1287) of persons died of natural causes. Mortality was predicted in a multivariate model by baseline cigarette smoking (RR = 6.29, 95% CI 1.41, 3.72, P = 0.00076); divorced or widowed status (RR = 1.90, CI 1.21, 2.99); reduced cognitive score (RR = 0.73, CI 0.61, 0.87); receipt of antidepressant medication (RR = 1.74, CI 1.12, 2.71); elevated levels of antibodies to Epstein-Barr virus (EBV) (RR = 1.29, CI 1.01, 1.66); and a genitourinary (RR = 1.82, CI 1.16, 2.86), respiratory (RR = 1.82, CI 1.16, 2.86), or cardiac (RR = 2.09, CI 1.33, 3.29) condition. There was an additive effect of smoking and both a cardiac and a respiratory condition but not elevated EBV antibody levels., Conclusion: Smoking is a modifiable behaviour which is associated with mortality in this population., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Persons with serious mental illness are at high risk for suicide, but this outcome is difficult to predict. Serological markers may help to identify suicide risk. We prospectively assessed 733 persons with a schizophrenia spectrum disorder, 483 with bipolar disorder, and 76 with major depressive disorder for an average of 8.15 years. The initial evaluation consisted of clinical and demographic data as well as a blood samples from which immunoglobulin G antibodies to herpes viruses and Toxoplasma gondii were measured. Suicide was determined using data from the National Death Index. Cox proportional hazard regression models examined the role of baseline variables on suicide outcomes. Suicide was associated with male sex, divorced/separated status, Caucasian race, and elevated levels of antibodies to Cytomegalovirus (CMV). Increasing levels of CMV antibodies were associated with increasing hazard ratios for suicide. The identification of serological variables associated with suicide might provide more personalized methods for suicide prevention.

Objective: This study examined the prevalence of cigarette smoking and the quantity of cigarettes consumed by individuals with schizophrenia and bipolar disorder and those without a psychiatric disorder in the period 1999-2016., Method: A total of 1,938 individuals provided information about their cigarette smoking at enrollment into a research study for which they were selected without regard to their smoking status. Differences among groups and trends over time in smoking and cigarette consumption were examined by using multivariate models., Results: Marked differences between groups were noted in the prevalence of smoking and in the quantity of cigarettes consumed. Overall, 62% of individuals with schizophrenia, 37% with bipolar disorder, and 17% of participants without a psychiatric disorder (control group) reported that they were current smokers. Smoking prevalence decreased over time in the sample primarily because of the decrease in smoking in the control group. Smokers with schizophrenia and with bipolar disorder smoked more cigarettes per day than smokers in the control group. Among smokers in all the groups, the quantity of cigarettes consumed per day declined significantly over the study period. Smoking was significantly associated with older age, less education, Caucasian race, and male gender., Conclusions: The prevalence of smoking has remained alarmingly high among individuals with schizophrenia and bipolar disorder, and the disparity with those without psychiatric disorders and with the general population is increasing. Additional measures are urgently needed to address this major public health problem.

Previous studies have identified elevations in markers of gastrointestinal inflammation in schizophrenia and mood disorders but studies have not measured the association between these markers and recent suicide attempts. We assessed 210 patients receiving treatment for schizophrenia, bipolar disorder, or major depression. We employed the Columbia Suicide Severity Rating Scale to identify recent and lifetime suicide attempts (actual, aborted, and interrupted). Psychiatric participants and a control group of 72 individuals without a psychiatric disorder had a blood sample drawn from which were measured specific markers of gastrointestinal inflammation and also C-Reactive protein (CRP). A total of 20 (10%) of psychiatric participants had a suicide attempt in the previous one month and 95 (45%) an attempt during their lifetime but not in the previous one month. The recent attempters had significantly elevated levels of antibodies to yeast mannan from Saccharomyces cerevisiae (ASCA), the food antigen gliadin, and bacterial lipopolysaccharide (LPS) compared with the non-psychiatric group when adjusting for demographic and clinical variables. These markers were not elevated in individuals with a past, but not recent, suicide attempt history. Our study indicates that there is evidence of gastrointestinal inflammation in some individuals who have had a recent suicide attempt., (Copyright © 2017. Published by Elsevier B.V.)

Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

The molecules and pathways of the gut-brain axis represent new targets for developing methods to diagnose and treat psychiatric disorders. Manipulation of the gut microbiome with probiotics may be a therapeutic strategy with the potential to relieve gastrointestinal (GI) comorbidities and improve psychiatric symptoms. Candida albicans and Saccharomyces cerevisiae, commensal yeast species, can be imbalanced in the unhealthy human microbiome, and these fungal exposures were previously found elevated in schizophrenia. In a longitudinal, double-blind, placebo-controlled, pilot investigation of 56 outpatients with schizophrenia, we examined the impact of probiotic treatment on yeast antibody levels, and the relationship between treatment and antibody levels on bowel discomfort and psychiatric symptoms. We found that probiotic treatment significantly reduced C. albicans antibodies over the 14-week study period in males, but not in females. Antibody levels of S. cerevisiae were not altered in either treatment group. The highest levels of bowel discomfort over time occurred in C. albicans-seropositive males receiving the placebo. We observed trends towards improvement in positive psychiatric symptoms in males treated with probiotics who were seronegative for C. albicans. Results from this pilot study hint at an association of C. albicans seropositivity with worse positive psychiatric symptoms, which was confirmed in a larger cohort of 384 males with schizophrenia. In conclusion, the administration of probiotics may help normalize C. albicans antibody levels and C. albicans-associated gut discomfort in many male individuals. Studies with larger sample sizes are warranted to address the role of probiotics in correcting C. albicans-associated psychiatric symptoms., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Previous studies have identified elevations in antibodies to Toxoplasma gondii in individuals with a history of suicide attempts but studies have not measured the association between suicide attempts and a panel of antibody markers. We assessed 162 patients receiving treatment for schizophrenia, bipolar disorder, or major depression on the Columbia Suicide Severity Rating Scale for suicide attempt history and other clinical measures. All participants had a blood sample drawn from which were measured antibodies to Toxoplasma gondii and other neurotropic infectious agents. A total of 72 (44%) of participants had a lifetime suicide attempt; these individuals had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV). We also found an association between the levels of these antibodies and the number of suicide attempts. There was a particularly strong odds of a suicide attempt history in individuals who had elevated levels of IgM antibodies to both Toxoplasma gondii and to CMV suggesting an additive risk associated with the antibodies. These findings remained significant when adjusting for current cigarette smoking and history of drug/alcohol use which were also associated with suicide attempts. We did not find an association between a suicide attempt history and IgG class antibodies to Toxoplasma gondii, CMV, or IgM or IgG antibodies to the Epstein Barr Virus or other antigens tested. The identification of blood-based antibody markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Previous investigations have found that smokers with schizophrenia demonstrate reduced performance on cognitive tasks compared to non-smokers. However previous studies have not taken into account other environmental factors associated with cognitive functioning such as exposure to Herpes Simplex Virus type 1 (HSV-1). We examined these factors in a sample consisting of individuals with schizophrenia (n=773), bipolar disorder (n=493), or controls without a psychiatric disorders (n=548). Participants were assessed on a cognitive battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and had a blood sample drawn to measure seropositivity to HSV-1. Within each group linear regression models were constructed to determine whether cigarette smoking and HSV-1 seropositivity were jointly associated with cognitive functioning after adjusting for relevant covariates. Within the schizophrenia group, the effect size of lower total cognitive score was -0.279 (p<0.0001) for individuals who were both smokers and HSV-1 seropositive and a significant effect was found in all cognitive domains. The odds of being in the highest quartile of RBANS Total score were significantly lower for smokers (OR=0.58, 95% CI 0.41, 0.82, p=0.002). Smoking was not as consistently associated with levels of cognitive functioning in the bipolar disorder or the non-psychiatric control group. While experimental studies show that nicotine transiently improves functioning on sensory gating and attention tasks known to be deficient in schizophrenia, long-term nicotine exposure via smoking appears to have an adverse effect on cognitive functioning., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: We have preciously documented that many individuals with acute mania have immune activation. However, the sources of immune activation have not been identified. We investigated whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents., Methods: We assessed the recent prescription of systemic antimicrobial medications and the site of presumed bacterial infection in 234 individuals hospitalized for acute mania in either an inpatient unit or a day hospital. We also assessed individuals hospitalized for other psychiatric disorders (n=368) and controls (n=555). We employed logistic regression models to compare the rates of antibiotic prescription in individuals with the different diagnoses, employing demographic variables as covariates., Results: We found that individuals hospitalized with acute mania had a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment (adjusted odds ratio=5.5, 95% confidence interval: 2.2-14.1, P<.0002). Overall, a total of 18 of the 234 (7.7%) individuals hospitalized for acute mania were prescribed antibiotics as opposed to seven of 555 (1.3%) controls. The prescription of antibiotics was associated with being on an inpatient unit as opposed to being in the day hospital, and having increased mania symptom severity but not with other clinical ratings, demographic variables, or psychiatric medications. Hospitalization for other psychiatric disorders was not associated with the recent prescription of antimicrobial medications. The urinary tract was the most common site of infection in women, while the respiratory tract and mucosal surfaces were the most common sites in men., Conclusions: Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectious agents or corresponding immune responses might contribute to psychiatric etiopathogeneses. We investigated case-control differences in exposure to the opportunistic fungal pathogen, Candida albicans, and examined associations with cognition, medication, lifestyle, and somatic conditions. We quantified C. albicans IgG antibodies in two cohorts totaling 947 individuals and evaluated odds ratios (OR) of exposure with psychiatric disorder using multivariate regressions. The case-control cohort included 261 with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls; the second included 139 with first-episode schizophrenia, 78 of whom were antipsychotic naive. No differences in C. albicans exposures were found until diagnostic groups were stratified by sex. In males, C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04-9.53, P⩽0.0001). In females, C. albicans seropositivity conferred increased odds for lower cognitive scores on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in schizophrenia (OR 1.12, P⩽0.004), with significant decreases on memory modules for both disorders (P⩽0.0007-0.03). C. albicans IgG levels were not impacted by antipsychotic medications. Gastrointestinal (GI) disturbances were associated with elevated C. albicans in males with schizophrenia and females with bipolar disorder (P⩽0.009-0.02). C. albicans exposure was associated with homelessness in bipolar males (P⩽0.0015). In conclusion, sex-specific C. albicans immune responses were evident in psychiatric disorder subsets. Inquiry regarding C. albicans infection or symptoms may expedite amelioration of this treatable comorbid condition. Yeast exposure as a risk factor for schizophrenia and its associated cognitive and GI effects require further investigation including the possible contribution of gut-brain mechanisms.

Persons with schizophrenia and with bipolar disorder have a reduced life expectancy due largely to death from natural causes. The reasons for this increased mortality have not been completely defined. We prospectively assessed a cohort of persons with schizophrenia and one with bipolar disorder with a clinical evaluation and a blood sample from which immune and infectious disease markers were measured. Mortality was determined with data from the National Death Index following a period of up to 14years. We examined the role of demographic, clinical, and serological factors on mortality in bivariate and multivariate models. A total of 43/710 (6.1%) persons with schizophrenia and 12/406 (3.0%) with bipolar disorder died of natural causes. In the schizophrenia group, mortality was predicted by the following variables in a multivariate model: cigarette smoking (RR=6.93, 95% CI 1.59, 30.1, p=0.0099); autoimmune disorder (RR=8.08, 95% CI 2.50, 26.1, p=0.00047); gastrointestinal disorder (GI) (RR=3.53, 95% CI 1.43, 8.69 p=0.0061); and reduced maternal education (RR=0.84, 95% CI 0.72, 0.97), p=0.018. The combination of smoking and an autoimmune disorder yielded an unadjusted relative risk of 18.1 for mortality, and the combination of smoking and a GI disorder an unadjusted relative risk of 9.45, compared with individuals with neither risk factor. In the bipolar disorder group, significant bivariate predictors of mortality included lower cognitive score (RR=0.95, p=.0085) and the presence of type 1 or 2 diabetes (RR=3.90, p=.026). Given the extraordinary high risk of death due to smoking in schizophrenia, smoking cessation remains an urgent priority., (Copyright © 2015. Published by Elsevier B.V.)

Background: Immune markers have been associated with schizophrenia, but few studies have examined multiple markers in both recent onset and chronic schizophrenia patients., Methods: The sample of 588 individuals included 79 with recent onset psychosis, 249 with chronic schizophrenia, and 260 controls. A combined inflammation score was calculated by principal components factor analysis of the levels of C-reactive protein, Pentraxin 3, and IgG antibodies to gliadin, casein, and Saccharomyces cerevisiae measured in blood samples. Inflammation scores among groups were compared by multivariate analyses., Results: The chronic schizophrenia group showed significant elevations in the combined inflammation score compared with controls. The recent onset group surprisingly showed a reduction in the combined inflammation score. Consistent with these findings, the chronic schizophrenia group had significantly increased odds of a combined inflammation score greater than the 75th and the 90th percentile of that of the controls. The recent onset group had significantly increased odds of a combined inflammation score less than the 10th and the 25th percentile level of the controls., Conclusions: The recent onset of psychosis may be associated with inherent deficits in innate immunity. Individuals later in the course of disease may have increased levels of innate immunity. The reasons for these changes are not known with certainty but may be related to compensatory increases as the disease progresses. Longitudinal studies are needed to determine the course of immune abnormalities in schizophrenia and their role in the clinical manifestations of the disorder., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Mucosal sites such as the oropharynx contain a wide range of microorganisms, collectively designated as the microbiome. The microbiome can affect behavior through a number of neurobiological and immunological mechanisms. Most previous studies have focused on the bacterial components of the microbiome. However, the microbiome also includes viruses such as bacteriophages, which are viruses that infect bacteria and alter their metabolism and replication. We employed metagenomic analysis to characterize bacteriophage genomes in the oral pharynx of 41 individuals with schizophrenia and 33 control individuals without a psychiatric disorder. This analysis was performed by the generation of more than 100,000,000 sequence reads from each sample and the mapping of these reads to databases. We identified 79 distinct bacteriophage sequences in the oropharyngeal samples. Of these, one bacteriophage genome, Lactobacillus phage phiadh, was found to be significantly different in individuals with schizophrenia (P < .00037, q < 0.03 adjusted for multiple comparisons). The differential levels of Lactobacillus phage phiadh remained significant when controlling for age, gender, race, socioeconomic status, or cigarette smoking (P < .006). Within the group of individuals with schizophrenia, the level of Lactobacillus phage phiadh correlated with the prevalence of immunological disorders as well as with the administration of valproate, which has been shown in animal models to alter the microbiome. The bacteriophage composition of the oropharynx in individuals with schizophrenia differs from that of controls. The biological consequences of this difference and the potential effects of altering bacteriophage levels through therapeutic interventions are worthy of further investigation., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression., Method: Blood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up., Results: The sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6 months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers., Conclusion: Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Immunologic abnormalities have been found in bipolar disorder but pentraxin 3, a marker of innate immunity, has not been studied in this population., Methods: Levels of pentraxin 3 were measured in individuals with bipolar disorder, schizophrenia, and non-psychiatric controls. Linear regression models were used to compare the pentraxin 3 levels in each of the psychiatric groups to that in the control group, adjusting for demographic and clinical variables. Logistic regression models were used to calculate the odds ratios associated with levels of pentraxin 3 which differed from specified levels of the control group., Results: The sample consisted of 831 individuals: 256 with bipolar disorder, 309 with schizophrenia, and 266 without a psychiatric disorder. The levels of pentraxin 3 in the bipolar disorder, but not in the schizophrenia, group were significantly lower than those of controls, adjusting for age, gender, race, maternal education, smoking status, and body mass index (t = -3.78, p < 0.001). The individuals with bipolar disorder also had significantly increased odds of having low levels of pentraxin 3 relative to both the 10th and 25th percentile level of the controls and significantly decreased odds of having a level greater than the 75th and the 90th percentile level of the controls, adjusting for the same covariates., Conclusions: Individuals with bipolar disorder have low levels of pentraxin 3 which may reflect impaired innate immunity. An increased understanding of the role of innate immunity in the etiopathogenesis of bipolar disorder might lead to new modalities for the diagnosis and treatment of this disorder., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Increased rates of exposure to Toxoplasma gondii have been found in individuals with schizophrenia and bipolar disorder, but the association between Toxoplasma and cognitive functioning has not previously been examined. We measured IgG and IgM class antibodies to Toxoplasma in 408 nonelderly individuals with schizophrenia, 347 with bipolar disorder, and 352 nonpsychiatric controls. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status. Multivariate linear and regression analyses showed significant associations between Toxoplasma IgM antibody level and cognitive scores within the control group and the bipolar disorder group but not the schizophrenia group. Within the control group, having an elevated Toxoplasma IgM antibody level, greater than or equal to the 50th and 75th levels of the control group, was associated with significantly elevated odds of a low total cognitive score. Exposure to Toxoplasma may confer risk for lower cognitive functioning in persons without a psychiatric disorder and those with bipolar disorder.

Background: Cognitive deficits are a central feature of schizophrenia but it is not certain how cognitive functioning changes over time. The purpose of this prospective longitudinal study was to determine the temporal change of cognitive functioning and the predictors of cognitive performance from among demographic, clinical, and biological variables., Methods: Participants were individuals with schizophrenia or schizoaffective disorder whose cognitive functioning was assessed at multiple time points with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). At the baseline visit participants had a blood sample drawn from which C-reactive protein, antibodies to Herpes Simplex Virus type 1, and selected genetic polymorphisms were measured. Repeated measures linear regression was used to determine whether cognitive measures changed over time and which variables predicted cognitive performance., Results: The sample consisted of 132 participants, mean age 43.7 years at baseline, who received a median of 3 cognitive assessments over a period averaging 2.8 years. The RBANS Total score and Language index showed no statistically significant temporal change; performance on two indices, Immediate Memory and Attention, showed modest but statistically significant improvements (gains of 0.89±0.33 and 0.76±0.29 points per year, respectively); Visuospatial/Constructional performance showed a modest but statistically significant decline (of 0.80±0.25 points per year). Few variables predicted cognitive performance; however greater psychiatric symptom severity was associated with worse cognitive performance for most cognitive measures., Conclusions: Cognitive functioning in middle-aged persons with schizophrenia showed an absence of decline for most measures and modest gains in some measures., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Elevated levels of antibodies to Cytomegalovirus (CMV) have been associated with cognitive impairment, but the quantitative relationship between CMV antibody levels and domains of cognitive functioning in younger adults has not been established., Methods: We measured IgG class antibodies to Cytomegalovirus in 521 individuals, mean age 32.8 years. Participants were selected for the absence of psychiatric disorder and of a serious medical condition that could affect brain functioning. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Wisconsin Card Sorting Test, Trail Making Test part A, and the WAIS III Letter Number Sequencing subtest. Linear regression analyses were used to measure the quantitative association between cognitive scores and Cytomegalovirus IgG antibody level. Logistic regression analyses were used to measure the odds of low cognitive scores and elevated antibody levels defined as an antibody level > = 50th, 75th, and 90th percentile of the group., Results: Higher levels of CMV antibodies were associated with lower performance on RBANS Total (coefficient -1.03, p<.0002), Delayed Memory (coefficient -0.94, p<.001), Visuospatial/Constructional (coefficient -1.77, p<5×10(-7)), and Letter Number Sequencing (coefficient -0.15, p<.03). There was an incremental relationship between the level of CMV antibody elevation and the odds of a low RBANS Total score. The odds of a low total cognitive score were 1.63 (95th % CI 1.01, 2.64; p<.045), 2.22 (95th % CI 1.33, 3.70; p<.002), and 2.46 (95th % CI 1.24, 4.86; p<.010) with a CMV antibody level greater than or equal to the 50th, 75th, and 90th percentile respectively., Conclusions: Higher levels of Cytomegalovirus antibodies are associated with lower levels of cognitive functioning in non-elderly adults. Methods for the prevention and treatment of CMV infection should be evaluated to determine if they result in an improvement in cognitive functioning in otherwise healthy adults.

Objectives: Increased rates of infection with Toxoplasma gondii have been found in individuals with schizophrenia as compared to control groups but this issue has not been studied in mania., Methods: We measured immunoglobulin G (IgG) and IgM class antibodies to T. gondii in 57 individuals with mania who were assessed at up to three time-points. We also measured these antibodies in 743 individuals in other psychiatric groups and in 314 non-psychiatric controls. T. gondii antibody levels were compared among groups by multivariate analyses. IgG class and IgM class antibodies to cytomegalovirus were also measured in the same samples. T. gondii antibody levels were also compared over time in the mania group., Results: The mania group had a significantly elevated level of IgM antibodies to T. gondii as compared to the control individuals without a psychiatric diagnosis [odds ratio (OR) = 2.33, p < 0.04 at hospital admission; and OR = 2.32, p < 0.02 at study entry during the hospital stay]. Elevated IgM class antibodies to T. gondii were not found in individuals with the other psychiatric diagnoses. We also did not find an increased level of IgG class antibodies to T. gondii or IgG or IgM class antibodies to CMV in the individuals with mania. Within the mania group, there was a significant difference between the prevalences of increased levels of T. gondii IgM at the baseline and the follow-up time-point (t = 2.97, p < 0.003)., Conclusions: Infection with T. gondii may confer risk for mania., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

Background: Markers of immune activation have been associated with mania but have not been examined in combination. We studied the association between mania and an inflammation score based on four immune markers., Methods: A total of 57 individuals with mania were assessed at up to three time points: the day of hospital admission, evaluation several days later, and six-month follow-up. Also assessed were 207 non-psychiatric controls and 330 individuals with recent onset psychosis, multi-episode schizophrenia, or bipolar disorder depression. A combined inflammation score was calculated by factor analysis of the levels of class-specific antibodies to the NR peptide of the NMDA receptor; gliadin; Mason-Pfizer monkey virus protein 24; and Toxoplasma gondii. Inflammation scores among groups were compared by multivariate analyses. The inflammation score of the mania group at evaluation was studied as a predictor of re-hospitalization in the follow-up period., Results: The combined inflammation score of the mania group at hospital admission and at evaluation differed significantly from that of the non-psychiatric controls (t=3.95, 4.10, p<.001). The inflammation score was significantly decreased at six month follow-up (F=5.85, p=0.004). There were not any significant differences in the inflammation scores of any of the other psychiatric groups and that of the controls. Within the mania group, an elevated inflammation score at evaluation predicted re-hospitalization (Hazard ratio=7.12, p=.005)., Conclusions: Hospitalization for mania is associated with immune activation. The level of this activation is predictive of subsequent re-hospitalization. Interventions for the modulation of inflammation should be evaluated for the therapy of individuals with mania.