ORIGINAL ARTICLE

Predictors of the Onset of Schizophrenia in US Military Personnel Natalya S. Weber, MD, MPH,* Rakel A. Larsen, MS,*† Robert H. Yolken, MD,‡ David N. Cowan, PhD, MPH,*† Michael R. Boivin, MD, MPH,* and David W. Niebuhr, MD, MPH, MS*§ Abstract: Alterations in immune response may be an important component in the etiopathogenesis of schizophrenia and bipolar disorder. We examined the associations of pentraxin-3 (PTX3) with the onset of schizophrenia or bipolar disorder. We tested preonset serum specimens from 160 US military service members who were later diagnosed with schizophrenia or bipolar disorder and 160 matched controls without psychiatric disorders. Lower serum levels of PTX3 were predictive of schizophrenia but not of bipolar disorder. Subjects with below-median PTX3 levels had a 3.0 odds ratio (confidence interval, 1.6–5.7) for schizophrenia onset in the multivariable logistic regression model controlling for demographic and military variables. The test for trends was significant (p = 0.002), with the likelihood increasing as the levels of PTX3 decreased. Crude and adjusted categorized levels were not predictive of bipolar disorder. A lower level of inflammatory response indicated by PTX3 might be implicated in developing schizophrenia. Key Words: Psychosis, bipolar, immune response, pentraxin-3, biomarker (J Nerv Ment Dis 2015;203: 319–324)

S

chizophrenia and bipolar disorder are severe and pervasive psychiatric disorders with unclear etiology and pathogenesis and variable clinical presentations and outcomes. Their etiology is complex and involves both genetic and environmental components, which are very challenging to disentangle (Arnedo et al., 2015; Maki et al., 2005; O'Donovan et al., 2003; Rutten and Mill, 2009; Tandon et al., 2008). Numerous studies have reported associations between schizophrenia/ bipolar disorder and the alteration of the immune system in general (Beumer et al., 2012b; Bilbo and Schwarz, 2009; Boyajyan et al., 2008; Gibney and Drexhage, 2013; Goldstein et al., 2009; Leboyer et al., 2012; Monji et al., 2009; Radulescu, 2009; Singh et al., 2009, 2011; Singh and Chaudhuri, 2014) and inflammatory processes in particular (Brietzke et al., 2009; Goldstein et al., 2009; Hamdani et al., 2012; Miller et al., 2009; Rapaport and Lohr, 1994; Sirota et al., 2005). Multiple findings suggest that the activation of the immune system and prolonged neuroinflammation are implicated in the etiopathogenesis and symptomatology of schizophrenia and bipolar disorder (Barbosa et al., 2014; Beumer et al., 2012b; Brito-Melo et al., 2012; Doorduin et al., 2009; Drexhage et al., 2011, 2010; Weigelt et al., 2011). Chronic inflammation may harm the cerebral microvascular system and impair blood circulation in the brain. Norepinephrine and similar hormones could activate the inflammatory component of the immune system and trigger the expression of genes that cause chronic, low-grade inflammation. Whereas a number of studies found an increase in C-reactive protein (CRP), a marker of general inflammation, to be associated with schizophrenia and bipolar disorder (Beumer et al., 2012a; Dickerson et al., 2013; Miller et al., 2014; Wium-Andersen et al.,

*Preventive Medicine Branch, Walter Reed Army Institute of Research, Silver Spring, MD; †ManTech Health, Herndon, VA; ‡Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore; and §Division of Epidemiology and Biostatistics, Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, MD. Send reprint requests to Natalya S. Weber, MD, MPH, Preventive Medicine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0022-3018/15/20305–0319 DOI: 10.1097/NMD.0000000000000285

2014), others did not confirm this finding (Khandaker et al., 2014; Singh and Chaudhuri, 2014; Stojanovic et al., 2014). Such differential results could be attributed to the heterogeneity of these disorders (Dickerson et al., 2007; Singh and Chaudhuri, 2014). Both CRP and pentraxin-3 (PTX3) belong to the pentraxin superfamily. PTX3 is, and behaves like, an acute-phase protein with blood levels below 2 ng/ml in normal conditions and rapid increases in a few hours reaching 200 to 800 ng/ml in correlation with the severity of the inflammatory or infectious condition (Baruah et al., 2006; Muller et al., 2001). PTX3 is rapidly produced and released by both somatic and immune cell types in response to primary inflammatory signals and serves as a marker of primary local activation of innate immunity and inflammation (Fazzini et al., 2001; Inforzato et al., 2012; Latini et al., 2004). Compared with the short pentraxin CRP, long PTX3 has been suggested as a more direct indicator of tissue involvement by inflammatory and infectious processes (Muller et al., 2001). PTX3 serves as a prototype of soluble pattern recognition molecules that recognize pathogen-associated molecular patterns. In coordination with the cellular arm, PTX3 is involved in the initiation of the immune response (Inforzato et al., 2012). In this study, we used PTX3 as a marker of inflammation and explored its relationship with the subsequent onset of schizophrenia or bipolar disorder.

METHODS Data Collection We used a subset of study subjects (80 subjects with schizophrenia, 80 subjects with bipolar disorder, each with his/her matched control) of the Military New Onset Psychosis Project (MNOPP), a large nested case-control study of the US military service members who developed schizophrenia (N = 855) and 1165 matched controls or bipolar disorder (N = 1118) and 2236 matched controls and received medical discharges from the military between 1992 and 2005. MNOPP examines potential associations of selected preonset biomarkers with schizophrenia and bipolar disorder among military personnel using existing data and specimens collected and stored for routine health care and surveillance (Niebuhr et al., 2011, 2008). Data from essentially all medical care received by military active component service members, including care in civilian facilities that is paid for by the military, is captured by the military health care system and is very well documented. The US military routinely collects serum for human immunodeficiency virus testing at entry into the service and approximately every 2 years thereafter. In addition, serum is obtained before and after deployments. Excess serum remaining from each specimen is stored at the Department of Defense Serum Repository (DoDSR) and is authorized to be used for surveillance and selected research programs. The DoDSR is maintained by the Armed Forces Health Surveillance Center (AFHSC) (http://afhsc.mil/), which also maintains a variety of administrative and medical data on service members. The availability of preillness serum specimens combined with data from prediagnosis medical encounters afforded us unique opportunities to evaluate potentially predictive biomarkers. The MNOPP cases were selected from the data provided by the US Army Physical Disability Agency, the Secretary of the Navy Council of Review Boards, and the Air Force Personnel Center/USAir

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Force Physical Disability Division. The medical and demographic data from 1989 to 2006 (released in 2007) were provided by the Defense Medical Surveillance System, AFHSC, Silver Spring, MD. Serum specimens from 1988 to 2006 (released in 2007) were retrieved from the DoDSR, AFHSC, Silver Spring, MD. Those 18 years or older who were on active duty at the time of their schizophrenia or bipolar disorder diagnosis and who had at least one serum sample of 0.5 ml or greater in the DoDSR obtained before diagnosis were selected as potential MNOPP cases. For the schizophrenia study, the time of disease onset was estimated as the earliest date of either the first hospitalization with psychiatric disorder, International Classification of Disease 9th Revision (ICD-9-CM) codes (290–319) in any diagnostic position, or the date when the medical or physical evaluation board was initiated. Because hospitalizations are much less prevalent among service members with bipolar disorder compared with those with schizophrenia, the onset of bipolar disorder was estimated as the first hospitalization or outpatient encounter with a primary psychiatric diagnosis ICD-9-CM code. Control subjects, who were older than 18 years with no inpatient or outpatient psychiatric disorder diagnoses, were selected from the active duty US military service population. All MNOPP control subjects were matched to their case subjects on sex, race, branch of military service, date of birth (±12 months), military entrance ±12 months), and serum specimen collection time (±90 days). Multiple matched (±90 days) serum specimens, stored at −30°F, were obtained for the MNOPP from the DoDSR. The details of the MNOPP, the diagnostic process leading to medical discharge from military service and the validity of the psychiatric diagnosis have been provided elsewhere (Millikan et al., 2007; Niebuhr et al., 2011). For this study, we have randomly (without replacement) selected a sample of 160 MNOPP subjects who later were diagnosed with schizophrenia or bipolar disorder. Their individually matched (1:1) controls were also pulled from the MNOPP study data, reaching a total of 320 subjects in the sample. The subjects' first available serum specimens were identified from the existing pool of sera previously retrieved from the DoDSR for the MNOPP and tested. This study was approved by the Walter Reed Army Institute of Research Institutional Review Board and the institutional review board of the Johns Hopkins School of Medicine.

Laboratory Analysis The samples from each case-control group were analyzed on the same microplate, increasing the validity of within-group comparisons. Serum PTX3 levels were measured in the Stanley Neurovirology Laboratory, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, using a commercially available enzymelinked immunoassay kit acquired from Immuno-Biological Laboratories Inc (IBL-America), Minneapolis, Minnesota. Results were presented in nanograms per milliliter after extrapolation to a standard curve.

Statistical Analyses The mean differences and standard deviations were calculated and the paired-difference t-test was performed for the overall schizophrenia and bipolar disorder study samples and stratified by sex, age, race, and time between serum collection and diagnosis. The schizophrenia and bipolar disorder study PTX3 levels were each found to be normally distributed after one pair with an outlier was removed from each sample. We also categorized PTX3 into low and high levels split at the distribution medians separately calculated for the schizophrenia and bipolar disorder samples, as well as into quartiles. The chi-square test, Cochran-Armitage test for trend, and multivariable logistic regression models were used to estimate the risk of schizophrenia/bipolar disorder expressed as an odds ratio (OR) comparing higher versus lower PTX3 levels and quartiles 1 through 3 versus quartile 4. To estimate a linear 320

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increase in the risk of developing schizophrenia or bipolar disorder, we analyzed the PTX3 level as a continuous variable and calculated the OR per standard deviation of PTX3 change employing multivariable logistic regression. ORs are presented with 95% confidence intervals (CIs). Level of significance was set at 0.05. We controlled for possible confounding effects of demographic and service-related characteristics by using individual case-control matching in our study design. Some of our statistical approaches required individually matched pairs of case and control subjects to be analyzed as frequency matched groups. All covariates (sex, race, military branch, age at diagnosis, years of service, and time between serum collection and diagnosis) were included in multivariable modeling to decrease the possibility of residual confounding. All data manipulations and testing were performed using Statistical Analysis System (SAS) 9.3.

RESULTS We tested a total of 320 first-available-after-accession serum specimens from US military service members who later were diagnosed with schizophrenia (n = 80) or bipolar disorder (n = 80) and their 160 individually matched controls. The schizophrenia and bipolar disorder subset samples were representative of the respective MNOPP study populations from which the samples were drawn. The distributions of demographic and service-related characteristics are presented in Table 1. Study case subjects were individually matched to their controls on all the characteristics in the table and therefore have the same distribution of their controls. Both samples contain predominantly young men serving in the Army with a length of service mostly fewer than 5 years before discharge. The sex, race, and branch of service distributions were more balanced in the bipolar disorder subset compared with the schizophrenia study subset. Most of the serum samples were collected over a year before diagnosis. Controls had similar distributions owing to individual matching and are therefore not displayed in the table. Mean and standard deviations of PTX3 levels for subjects with schizophrenia versus their matched controls are presented with their corresponding p values in Table 2. For the bipolar disorder study, none of the results were significant (Fig. 1). We found that PTX3 levels among subjects with schizophrenia were significantly lower (t = −3.12, p = 0.003) than the levels among their paired controls, with a mean difference of 0.29 ng/ml. Among all subgroups compared, the mean was lower among subjects with schizophrenia than controls. Among men (t = −2.80, p = 0.007), whites (t = −2.46, p = 0.019), 21- to 30-year-olds (21–25-year-olds, t = −2.22, p = 0.033; 26–30-year-olds, t = −3.03, p = 0.008), and subjects whose serum was collected within 1 year of diagnosis (t = −1.80, p = 0.040), the differences were statistically significant. On the bivariate analysis, a level of PTX3 below the median (0.6 ng/ml) was associated with an OR of 3.0 (CI, 1.6–5.7) and did not change in the multivariable logistic regression model controlling for all the covariates presented in Table 1. When the lowest (≤0.3 ng/ml) and highest (>3.5 ng/ml) quartiles were compared (Fig. 1), the OR for schizophrenia was 3.0 (CI, 1.2–7.5) in bivariate and 2.9 (CI, 1.1–7.7) in multivariable analyses. The Cochran-Armitage test for trend was significant (p = 0.002). Every standard deviation decrease in PTX3 level in a multivariable regression model controlling for sex, race, military branch, age at diagnosis, years of service, and time between serum collection and diagnosis was associated with a corresponding 2.2 times (p = 0.002) elevation in schizophrenia risk. None of the quartiles of PTX3 were associated with bipolar disorder (Fig. 1).

DISCUSSION In this study, we found that subjects with schizophrenia had significantly lower PTX3 levels before illness onset compared with matched controls. This difference was present for every subgroup comparison, © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015

TABLE 1. Description of Schizophrenia and Bipolar Disorder Study Subjectsa Subjects Subjects With With Bipolar Schizophrenia Disorder Characteristic Sex

Level

Female Male Race Black White Other 18–20 yrs Age categoriesb 21–25 yrs 26–30 yrs 31–35 yrs >35 yrs Branch of military Army Air Force Marines Navy ≤1 yrs Time in servicec >1–≤ 3 yrs >3–≤ 5 yrs >5–≤ 10 yrs >10 yrs Time from serum >3 yrs collection to diagnosis 2–3 yrs 1–2 yrs 0.5–1 yrs ≤0.5 yrs

n

%

n

%

12 68 32 40 8 17 35 17 7 4 64 7 0 9 21 28 13 11 7 30 18 17 7 8

15.0 85.0 40.0 50.0 10.0 21.3 43.7 21.3 8.7 5.0 80.0 8.7 0.0 11.3 26.3 35.0 16.3 13.7 8.7 37.5 22.5 21.3 8.7 10.0

31 49 13 59 8 18 32 19 6 5 40 18 3 19 15 30 9 15 11 41 13 20 5 1

39.0 61.0 16.3 73.7 10.0 22.5 40.0 23.7 7.5 6.3 50.0 22.5 3.7 23.8 18.7 37.5 11.3 18.7 13.8 51.2 16.2 25.0 6.3 1.3

a

Controls are individually matched to the case subjects and therefore have the same distribution of the case subjects presented characteristics. b At the time of case diagnosis. c Time in years to case diagnosis.

although not all differences were significant. To our knowledge, no previous studies have reported decreased levels of CRP or PTX3 associated with schizophrenia regardless of stage in the disease progression or subgroups of the explored populations (Dickerson et al., 2013; Miller et al., 2014; Singh and Chaudhuri, 2014; Wium-Andersen et al., 2014). Some studies have found elevations in CRP or PTX3 in schizophrenia (Beumer et al., 2012a; Dickerson et al., 2013; Miller et al., 2014; Wium-Andersen et al., 2014), whereas others have not reported any associations (Dickerson et al., 2014; Khandaker et al., 2014; Singh and Chaudhuri, 2014; Stojanovic et al., 2014). The underlying reason for our dissimilar findings in the schizophrenia subset is not clearly understood but could derive from the differences in study populations, stages of pathologic process before or after the disease onset, and PTX3 measurement techniques, to mention just a few. Wium-Andersen et al. (2014), for instance, found elevated plasma CRP levels to be associated with a 6- to 11-fold increase in risk of late- and very-late-onset schizophrenia in the general population, whereas we found lower PTX3 levels in healthy individuals to be associated with an increased risk of schizophrenia onset in young adulthood. Although no significant associations were detected in our bipolar disorder sample, Dickerson et al. (2014) found decreased levels of PTX3 in individuals diagnosed with bipolar disorder but not with schizophrenia in their large sample of psychiatric participants recruited

Predictors of Schizophrenia

from Sheppard Pratt psychiatric programs and their controls ascertained from posted announcements at local health care facilities and universities in the same geographic area. This sample is strikingly different from ours demographically, psychosocially, and occupationally. Most importantly, whereas their study participants had a prolonged duration of psychiatric disorders and treatment for psychiatric and other much more highly prevalent comorbid diseases at the time of blood collection, our individuals were generally and psychiatrically healthy and their serum was collected before psychiatric diagnosis and antipsychotic treatment. Thus, it is possible to postulate that the decrease in PTX3 levels may vary between schizophrenia and bipolar disorder as a function of premorbid and morbid processes, respectively. Preonset PTX3 levels could be lower in a subgroup of those who were later diagnosed with schizophrenia but not bipolar disorder. After disease onset, PTX3 levels could decrease in those with bipolar disorder but be restored in those with schizophrenia as a result of antipsychotic treatment. Genetic, epigenetic, and environmental factors influencing PTX3 levels may no longer play a significant role after the onset of schizophrenia but become prominent in those with bipolar disorder. Alternatively, subgroups of individuals with either disorder could have lower levels of PTX3 after their onset, indicating immune dysregulation previously reported in the literature (Beumer et al., 2012b; Brito-Melo et al., 2012; Coelho et al., 2008; Doorduin et al., 2009; Drexhage et al., 2011, 2010). The decrease in PTX3 in those with schizophrenia could begin earlier, before or during a prodromal stage, because of comparatively more prolonged, profound, and quantitatively different immunological changes (Kunz et al., 2011). This dysregulation, however, could be later mitigated and PTX3 levels optimized by antipsychotic medications that are more frequently used in those with schizophrenia. Some antipsychotics, in fact, were reported to possess anti-inflammatory and immune-regulating properties (Basta-Kaim et al., 2012; De Souza et al., 2013; Hu et al., 2012; Zhang et al., 2014).

TABLE 2. PTX3 Levelsa in the Preonset Subjects With Schizophrenia Compared With Their Matched Controls Schizophrenia Subjects Mean

SD

Pentraxin All 0.61 0.48 By sex Males 0.60 0.49 Females 0.69 0.46 By race Black 0.59 0.45 White 0.60 0.49 Other 0.73 0.62 By age 18–20 yrs 0.55 0.34 21–25 yrs 0.71 0.57 26–30 yrs 0.37 0.30 31–35 yrs 0.86 0.56 >35 yrs 0.57 0.38 By serum collection to diagnosis time 3 yrs 0.62 0.53

Controls Mean

SD

p

0.90

0.69

0.003

0.89 0.97

0.72 0.56

0.007 0.172

0.78 0.90 1.28

0.57 0.71 0.92

0.107 0.019 0.364

0.75 1.04 0.81 0.95 0.43

0.43 0.84 0.44 0.86 0.50

0.268 0.033 0.008 0.847 0.668

0.94 0.89 0.90

0.72 0.72 0.66

0.040 0.118 0.083

a PTX3 levels measured in nanograms per milliliter after extrapolation to a standard curve and presented as mean for case and control groups of study subjects stratified by demographic and temporal characteristics.

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FIGURE 1. Adjusted* ORs† for schizophrenia or bipolar disorder onset, comparing the lower three quartiles of PTX3 levels with the upper fourth quartile.

PTX3 performs important functions in the intrinsic interplay of innate immunity and inflammation (Moalli et al., 2011). Pentraxins in general and PTX3 in particular are soluble pattern recognition receptors that play a dual role of protecting against extracellular microbes and autoimmunity (Baruah et al., 2006). The lack of either function could potentially contribute to the etiopathogenesis of schizophrenia. First, PTX3 has revealed a nonredundant role in resistance to selected pathogens (Moalli et al., 2011). As a component of innate immunity, PTX3 is in the first line of defense against pathogens as well as activation and orientation of the adaptive immune response. As a prototypic soluble pattern recognition molecule, PTX3 acts as the functional ancestor of antibodies (Inforzato et al., 2012; Moalli et al., 2011). Longlasting or temporal lack of PTX3 could potentially impact pathogen recognition, activation, and orientation of the adaptive immune response and/or antibody production. Impairment of any of these functions, particularly those where PTX3 plays its unique role, could lead to a vulnerability to the neurotropic pathogens associated with schizophrenia and bipolar disorder (Buka et al., 2001; Dickerson et al., 2010, 2003; Fox, 2010; Karlsson et al., 2001; Leweke et al., 2004; Lillehoj et al., 2000; Niebuhr et al., 2008; Tandon et al., 2008; Yolken, 2004; Yolken et al., 2001; Yolken and Torrey, 1995, 2008). Second, an autoimmune mechanism has been implicated in the etiopathogenesis of schizophrenia in a growing number of studies (Benros et al., 2012; Ezeoke et al., 2013; Margari et al., 2013; Severance et al., 2014; Strous and Shoenfeld, 2006). The lack of PTX3 could be a missing link that is associated with schizophrenia on the one hand and on the other potentially precluding the development of a properly functioning immune system or contributing to its derailment into a dysregulated state of autoimmune activation and damage. In general, a combination of genetic and environmental factors resulting in some immune dysregulation could be the most plausible speculation. Because only a subset of our study subjects with schizophrenia had significantly lower levels of PTX3, our results may suggest that immune dysregulation is more likely within a year of schizophrenia onset among men, whites, and 21- to 30-year-olds. This sex- and racespecific difference could be a result of inherent defects in the innate immunity pathway involved in the generation of PTX3 and disproportionally presented in those with young adult onset schizophrenia. Because schizophrenia is a pleiotropic and heterogenous disease with complex etiology (Arnedo et al., 2015), this difference may play a role in the etiopathogenesis of schizophrenia only in a specific subgroup. This study has notable strengths, including the follow-up of an initially disease-free population with subsequent complete and reliable case/control ascertainment (Millikan et al., 2007). Because of the large available control population, we were also successful in matching on a number of variables to control for potential confounding. Collecting serum specimens years before disease onset makes it likely that the cases were not prodromal and provides a reliable predisease assessment of the 322

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examined inflammatory markers. It is of note that the levels of inflammatory markers we measured could not be attributed to antipsychotic medications or other epiphenomena related to the diagnosis and treatment of schizophrenia and bipolar disorder because they were measured before the earliest date of any psychiatric disorder. This study has several limitations. Because our population was composed mostly of young adults in the age range of 18 to 40 years who were medically and cognitively screened before entering military service, our findings may not be generalizable to other populations. Body mass index (BMI) and smoking status were not available and could not be controlled. Because of the military fitness standards, the range of BMI is much narrower in service members compared with the civilian population, which lessens the probability of its potential confounding effect. In addition, unlike CRP, PTX3 levels are not as affected by either BMI or smoking status. No genetic information was available on the subjects, so we could not interconnect various environmental and genetic factors. Our findings reinforce the notion that the etiology and pathogenesis of schizophrenia may involve nonspecific changes in immune system reactions, which are likely to be different for bipolar disorder. We plan to test PTX3 levels in our entire existing schizophrenia and bipolar disorder study populations and repeat these analyses when we obtain new, more recently discharged service members with schizophrenia or bipolar disorder (protocol in review). Future studies should focus on the potential gene-environment interaction, but such studies require access to genetic material, which may not be reliably obtained from serum specimens. These studies should also be longitudinal and allow for independent and interactive analysis of preonset serum infectious, inflammatory, and environmental biomarkers. ACKNOWLEDGMENTS The authors thank Walter Reed Army Institute of Research, Preventive Medicine Branch staff member Janice K. Gary, BS, for her work in careful review and administrative support in preparation of the manuscript, and the AFHSC personnel, particularly Dr Angelia A. Cost, for providing data, specimens, and help with methodological aspects of the study. This work was supported by the Stanley Medical Research Institute, Bethesda, MD (research grant 03-NV-005) and the Department of the Army. DISCLOSURES The views expressed are those of the authors and should not be construed to represent the positions of the Department of the Army or Department of Defense. 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 no conflicts of interest. REFERENCES Arnedo J, Svrakic DM, Del Val C, Romero-Zaliz R, Hernandez-Cuervo H, Molecular Genetics of Schizophrenia Consortium, Fanous AH, Pato MT, Pato CN, de Erausquin GA, Cloninger CR, Zwir I (2015) Uncovering the hidden risk architecture of the schizophrenias: Confirmation in three independent genome-wide association studies. Am J Psychiatry. 172:139–153. Barbosa IG, Machado-Vieira R, Soares JC, Teixeira AL (2014) The immunology of bipolar disorder. Neuroimmunomodulation. 21:117–122. Baruah P, Propato A, Dumitriu IE, Rovere-Querini P, Russo V, Fontana R, Accapezzato D, Peri G, Mantovani A, Barnaba V, Manfredi AA (2006) The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens. Blood. 107:151–158. Basta-Kaim A, Szczesny E, Leskiewicz M, Glombik K, Slusarczyk J, Budziszewska B, Regulska M, Kubera M, Nowak W, Wedzony K, Lason W (2012) Maternal

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Predictors of the Onset of Schizophrenia in US Military Personnel.

Alterations in immune response may be an important component in the etiopathogenesis of schizophrenia and bipolar disorder. We examined the associatio...
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