A systematic, quantitative review of blood autoantibodies in schizophrenia

Department of Psychiatry, Georgia Regents University, Augusta, GA, United States.
Schizophrenia Research (Impact Factor: 3.92). 08/2013; 150(1). DOI: 10.1016/j.schres.2013.07.029
Source: PubMed


Schizophrenia is associated with immune system dysfunction, including an increased prevalence of autoimmune disorders and autoantibodies. We performed a systematic, quantitative review of self-reacting blood antibodies in patients with schizophrenia.
We identified articles by searching PubMed, PsychInfo, and ISI, and the reference lists of identified studies.
Eighty-one of 111 studies identified met the inclusion criteria. There was a significant increased prevalence of positive titers for 20 different autoantibodies in patients with schizophrenia compared to controls. The prevalence of positive anti-cardiolipin IgG and NMDA receptor titers was also significantly increased in subjects with first-episode psychosis versus controls (p<0.01). Absolute titers for anti-cardiolipin IgG and IgM, and nerve growth factor were significantly increased in patients with schizophrenia compared to controls (p<0.02 for each).
Schizophrenia is associated with an increased prevalence of multiple autoantibodies, although there is marked study heterogeneity, and correlations between autoantibodies and clinical features are inconsistent. This area merits more research evaluation, especially controlling for potential confounding factors such as clinical status, age, genetic background, psychotropic medications, BMI, and smoking.

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    • "One of the argument in favor of an autoimmune hypothesis of psychosis has been the circumstantial evidence of high serum levels of self reacting antibodies in patient's sera. Findings of various systemic and organ-specific autoantibodies have already been reported in major depression, bipolar disorders and schizophrenia (Padmos et al., 2004; Jones et al., 2005; Laske et al., 2008; Ezeoke et al., 2013; Margari et al., 2013), but the screening of patients for autoantibodies known to be present in other autoimmune conditions has not validated any particular hypothesis (Sidhom et al., 2012; Pathmanandavel et al., 2013). Autoantibodies with cross reactivity against brain antigens have been described in the sera and cerebrospinal fluid of patients with schizophrenia, but consistency in the findings has not been high and the correlation with disease "
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    ABSTRACT: In recent years, an inflammatory autoimmune process, autoantibodies mediated, has been porposed as having a role in the development of different psychiatric disorders. The aim of this study was to assay organ-specific and non organ-specific circulating autoantibodies in schizophrenia, mood disorders and healthy controls; among organ-specific autoantibodies we focused on different fluorescence patterns of anti-brain autoantibodies against rat and monkey's sections of hippocampus, hypothalamus and cerebellum. Serum samples from 50 acutelly ill patients (30 schizophrenia and 20 mood disorders) and from 20 healthy controls were collected. Autoantibodies were assayed by indirect immunofluorescence, enzyme linked immunosorbent assay and chemiluminescence immunoassay. We found a significant difference for circulating autoantibodies to hypothalamus, hippocampus and cerebellum and for anti-nuclear autoantibodies in both schizophrenia and mood disorders when compared to the control group. Referring to the two groups of patients only, circulating antibodies anti-hypothalamus were found significant higher in mood disorders rather than in schizophrenia, with specific regard to nuclear and cytoplasmic staining of the neurons. These data suggest an aspecific diffuse brain involvement of anti-brain autoantibodies in acute phases of schizophrenia and mood disorders. The greater involvement of the hypothalamus in mood disorders highlights the close relationship between autoimmunity, hypothalamic-pituitary-adrenal axis and affective disorders.
    Full-text · Article · Nov 2015
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    • "Both genetic and environmental risk factors have been proposed, but the precise etiology of ADHD is still largely unknown. Autoantibodies affecting the central nervous system have been suggested to play a role in neuropsychiatric disorders including autism, schizophrenia and limbic encephalitis (Margari et al., 2013; Moscato et al., 2010; Braunschweig and Van de Water, 2012; Ezeoke et al., 2013; Leypoldt et al., 2015). For a review see Najjar et al. (2013). "
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    ABSTRACT: A high seroprevalence of Yo antibodies targeting cerebellar Purkinje cells was recently reported in children with attention deficit/hyperactivity disorder (ADHD). We investigated the presence of 8 paraneoplastic neurological syndrome (PNS)-associated antibodies including anti-Yo in 169 adult ADHD patients. No associations between ADHD and serum Yo antibodies or other antibodies associated with PNS were found. However, 10 out of 48 ADHD patient sera analyzed by immunofluorescence presented antibodies targeting cerebellar Purkinje cells. This reactivity probably represents the presence of low levels of antibodies against multiple cellular hitherto unknown antigens with little to no clinical significance.
    Full-text · Article · Sep 2015 · Journal of Neuroimmunology
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    • "Although NMDAR antibodies have been linked to psychiatric sequelae secondary to autoimmune diseases, and both NMDAR dysfunction (Olney and Farber, 1995; Jentsch and Roth, 1999) and comorbid autoimmune disease (Eaton et al., 2010; Benros et al., 2013; Benros et al., 2014a; Benros et al., 2014b) have been consistently linked to primary psychiatric disorders, the relationship between NMDAR antibodies and primary psychiatric disorders is less clear. Over the last 4 years, several studies have yielded mixed findings concerning this relationship (Ezeoke et al., 2013; Pollak et al., 2013). There are no systematic reviews to date evaluating the relationship between NMDAR antibodies and bipolar or major depressive disorders, or addressing the effects of covariates such as NMDAR-subunit/immunoglobulin-class combinations assessed versus identified, timing of serum acquisition, disease state severity, medication status, or assay methods, including the dilution cut-off points used to define seropositivity. "
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    ABSTRACT: BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts, but these findings have not been systematically assessed in aggregate or in relation to methodological covariates. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for studies in any language that provided data on NMDAR antibody seropositivity or absolute serum titers in schizophrenia or schizoaffective, bipolar, or major depressive disorders. We used a random effects model to pool estimates across studies. RESULTS: Nine studies met the eligibility criteria. Five studies (3387 participants) provided data on NMDAR antibody seropositivity in psychiatric versus control groups based on high-specificity seropositivity thresholds (cell-based assays [CBAs]: 1:320 dilution, 1:200 dilution, visual score>1; enzyme-linked immunosorbent assay [ELISA]: 90(th) percentile of control titers). Meta-analysis showed significantly higher odds of NMDAR antibody seropositivity among those with schizophrenia or schizoaffective, bipolar, or major depressive disorders compared with healthy controls (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.04-9.27; P=.043; I(2)=68%). Four studies (3194 participants) provided outcome data for these groups based on low-specificity seropositivity thresholds (CBAs 1:10 dilution; ELISA: 75(th) percentile of control titers). Meta-analysis showed greater heterogeneity and no significant between-group difference (OR, 2.31; 95% CI, 0.55-9.73; P=.25; I(2)=90%). Seropositive participants in psychiatric groups had various combinations of IgG, IgM, and IgA class antibodies against NR1, NR1/NR2B, and NR2A/NR2B subunits. Subgroup analysis revealed significantly higher odds of seropositivity among all participants based on 1:10 versus 1:320 dilution seropositivity thresholds (OR, 4.56; 95% CI, 2.41-8.62; P<.001; I(2)=0%; studies=2, n=2920), but no apparent difference between first-episode and chronic schizophrenia or schizoaffective disorder (OR, 1.15; 95% CI, 0.19-7.24; P=.88, I(2)=43%, studies=2, n=1108). Average NR2A/NR2B antibody titers determined by ELISA were significantly higher among participants with first-episode schizophrenia (P<.0001) and acute mania (P<.01) compared with healthy controls. Levels decreased by 58% at 8weeks in first-episode schizophrenia, and by about 13% at 4days in acute mania. CONCLUSIONS: Individuals with schizophrenia or schizoaffective, bipolar, or major depressive disorders are collectively about three times more likely to have elevated NMDAR antibody titers compared with healthy controls based on high-specificity, but not low-specificity, seropositivity thresholds, though considerable methodological and statistical heterogeneity exists. Evidence concerning the effect of disease state and time of serum acquisition is varied and consistent, respectively. Adequately powered longitudinal studies employing standardized assay methods and seropositivity threshold definitions, and quantifying NMDAR antibodies in both sera and cerebrospinal fluid are needed to further elucidate the clinical and pathophysiological implications of this association. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved. KEYWORDS: Antibodies; Bipolar disorder; Immunoglobulin; Major depressive disorder; Meta-analysis; N-methyl-d-aspartate receptor; Psychoimmunology; Schizoaffective disorder; Schizophrenia; Systematic review
    Full-text · Article · May 2014 · Schizophrenia Research
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