11 February 2013. Some people with schizophrenia have elevated levels of antibodies to the N-methyl-D-aspartate (NMDA) glutamate receptor, according to a new study published online January 23 in JAMA Psychiatry. Led by Johann Steiner of Germany’s University of Magdeburg, the study, albeit small, also finds the antibodies in a smaller percentage of major depression cases but not in borderline personality disorder, and notes that the antibody profile of schizophrenia and major depression is distinct from that of NMDA receptor encephalitis, a syndrome whose symptoms overlap with schizophrenia. The results present the tantalizing possibility that a small subset of patients could be especially responsive to treatments that target the glutamate or immune systems, perhaps even early in the disorder.
A role for the immune system in the pathology of schizophrenia has recently been gaining momentum (see SRF related news story). Many schizophrenia candidate genes are immune related and located in the major histocompatibility complex region of chromosome 6p21.3-22.1 (see SRF related news story). In addition, increased inflammatory markers have been identified in blood as well as postmortem brain tissue (Potvin et al., 2008; Fillman et al. 2013).
Just how these immune alterations may lead to disturbances in neurotransmission is not yet clear. Antibodies directed against schizophrenia-relevant brain tissue epitopes such as the NMDA receptor provide an attractive link between the two hypotheses. Interestingly, autoimmunity to NMDA receptors produces NMDA-receptor encephalitis, a recently described inflammation of the brain that primarily affects women in early adulthood and produces a characteristic neuropsychiatric syndrome that shares many symptoms with schizophrenia (Dalmau et al., 2008). In many of the cases, the antibodies appear to have been generated in response to a tumor.
A few studies have examined NMDA receptor antibodies in schizophrenia, with mixed results—some have reported an absence of antibodies in the illness (Masdeu et al., 2012; Rhoads et al., 2011), while others have found elevated levels (Tsutsui et al., 2012; Zandi et al., 2011). However, none of the studies to date distinguished between various NMDA receptor epitopes or different antibody isotypes.
In the current study, the largest to date, Steiner and colleagues examined serum from subjects with acute schizophrenia (n = 121), major depression (n = 70), and borderline personality disorder (n = 38), as well as controls (n = 230), for the presence of different types of NMDA and AMPA receptor antibodies. Three different antibody isotypes were investigated: IgA, IgG, and IgM.
The researchers observed that 10 percent of the schizophrenia subjects (12 of 121) exhibited elevated NMDA receptor antibodies. However, two of the 12 subjects were subsequently found to meet the criteria for NMDA receptor encephalitis, and were reclassified post hoc, dropping the percentage of schizophrenia patients with antibodies to a still statistically significant 8 percent. In contrast, 3 percent of major depression (two of 70) and less than 1 percent of control (one of 230) subjects also demonstrated seropositivity. None of the borderline personality disorder patients exhibited measurable serum antibody titers, and no levels of AMPA receptor antibodies were detected in any of the subjects.
Previous reports of NMDA receptor encephalitis have demonstrated an immune profile that is restricted to elevated IgG antibodies against the NR1a subunit of the NMDA receptor, and consistent with these findings, the two patients in the current study who were initially diagnosed with schizophrenia but later reclassified as having NMDA receptor encephalitis exhibited a similar pattern (Dalmau et al., 2008). In contrast, a distinct and less specific immune profile was observed in schizophrenia and major depression, suggesting a potential way to distinguish them from the syndrome. IgG antibodies against NR1a/NR2b were observed in two schizophrenia cases, while the remainder exhibited IgA or IgM antibodies against NR1a. The two major depression subjects had IgA antibodies against NR1a/NR2b and NR1a, respectively, while the control subject had IgM antibodies against NR1a.
Although they note that larger sample sizes are needed to confirm their findings, the authors suggest that their study may be useful in validating NMDA antagonist-induced alterations in preclinical models of schizophrenia, and conclude that their identification of a subpopulation of patients with NMDA receptor antibodies “may open the door to personalized medicine and render patients susceptible to new specific glutamate-modulating, anti-inflammatory, or immuno-modulating therapies.”—Allison A. Curley.
Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, Kästner A, Skalej M, Jordan W, Schiltz K, Klingbeil C, Wandinger KP, Bogerts B, Stoecker W. 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. JAMA Psychiatry . 2013 Jan 23 ; :1-8. Abstract