Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia

Abstract

Evidence for symptomatic convergence of schizophrenia and N-methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. Objectives: To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap with and distinction from those in NMDA-R encephalitis. Design: Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and ␣-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined. Participants: Two hundred thirty matched healthy controls were compared with patients (unmedicated for at least 6 weeks) with schizophrenia (n=121), MD (n=70), or BLPD (n=38). Main Outcome Measures: The primary outcome was the overall number of seropositive cases for NMDA-R and AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. Results: Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classified as having catatonic or disorganized schizophrenia were reclassified as having misdiagnosed NMDA-R encephalitis (presence of specific serum and cerebrospinal fluid IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone). None of the patients or controls had antibodies against AMPA-R. Conclusions: Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypes in schizophrenia and MD is different from that with NMDA-R encephalitis. The latter disorder should be considered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.

Comparisons between Psychiatric Symptoms of Patients with Anti-NMDAR Encephalitis and New-Onset Psychiatric Patients

“…Highlighting the connection between NMDAR hypofunction and schizophrenia, Kantrowitz et al [16] described NMDAR dysfunction as the “final common pathway” for the mechanisms underlying the pathogenesis of schizophrenia and associated it with both positive and negative symptoms. Interestingly, the overlap between NMDAR encephalitis and schizophrenia regarding NMDAR hypofunction and psychotic symptoms has led researchers to question whether autoantibodies against NMDAR are part of the pathogenesis of schizophrenia [17,18,19]. To date, there have been several studies examining the presence of anti-NMDAR antibodies in patients with schizophrenia, but the results are variable.…”

“…Some researchers have described NMDAR dysfunction as the “final common pathway” for the mechanisms underlying the pathogenesis of schizophrenia and have associated it with both positive and negative symptoms [16]. Very interestingly, a few studies have reported that antibodies against NMDAR were also found in patients with schizophrenia [17,18,19]. Thus, some researchers have proposed that anti-NMDAR encephalitis and schizophrenia could be on the same spectrum and have a common underlying mechanism [6].…”

Effects of schizophrenic blood serum on astrocytes in human fetal brain organotypic culture: a morphometric study

“…Что касается воз-можного присутствия аутоантител в СК пациентов, то для интерпретации результатов настоящего исследования представляют интерес данные литературы [15,16] о нали-чии в крови больных шизофренией антител к мускарино-вым ацетилхолиновым рецепторам астроцитов, которые способны взаимодействовать с культивируемыми астро-цитами, действуя как агонисты соответствующих рецеп-торов и супрессоры продукции цАМФ. Было также уста-новлено [17,18], что в СК больных шизофренией присут-ствуют аутоантитела к ряду ключевых белков мозга, дис-функция которых характерна для шизофрении, включая рецепторы дофамина и NMDA-рецепторы глутамата, экс-прессируемые в том числе и астроцитами [17,18]. Так, установлена связь [37] между наличием антител к NMDA-рецепторам и психотическими симптомами.…”

“…[14]. При этом в крови больных шизофренией обнаружены противомозговые антитела, в частности к астроцитарным мускариновым рецепторам [15,16], глутаматным NMDA-рецепторам [17,18]. С дру-гой стороны, дисфункция астроцитов может быть суще-ственным звеном патогенеза шизофрении, так как имеет прямое отношение к нарушениям энергетического, глута-матного и кинуренинового метаболизма в мозге пациен-тов [19][20][21].…”

Immunology of Schizophrenia

“…A predominant type 2 immune response inhibits the enzyme indoleamine 2,3-dioxygenase, resulting in an increased production of kynurenic acid in schizophrenia and in NMDA receptor antagonism [46,48]. The recent findings of NMDA receptor antibodies in about 10% of acute diseased schizophrenia patients (unmedicated) is especially interesting in this regard [49,50]. …”