Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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 α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined.


METHODS
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).


METHODS
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.
Department of Psychiatry, University of Magdeburg, Magdeburg, Germany. johann.steiner@med.ovgu.de
Johann
J
Steiner
Martin
M
Walter
Wenzel
W
Glanz
Zoltán
Z
Sarnyai
Hans-Gert
HG
Bernstein
Stefan
S
Vielhaber
Andrea
A
Kästner
Martin
M
Skalej
Wolfgang
W
Jordan
Kolja
K
Schiltz
Christine
C
Klingbeil
Klaus-Peter
KP
Wandinger
Bernhard
B
Bogerts
Winfried
W
Stoecker
D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D001883:Borderline Personality Disorder / Q000175:diagnosis / Q000276:immunology; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000276:immunology; D004660:Encephalitis / Q000175:diagnosis / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007136:Immunoglobulins / Q000097:blood; D008297:Male; D008875:Middle Aged; D018091:Receptors, AMPA / Q000276:immunology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D012559:Schizophrenia / Q000175:diagnosis / Q000276:immunology; D012680:Sensitivity and Specificity
D001323:Autoantibodies; D007074:Immunoglobulin G; D007136:Immunoglobulins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C580825:NR1A protein, human; C121001:NR2B NMDA receptor; C104722:glutamate receptor ionotropic, AMPA 2