Prevalence of anti-N-methyl-d-aspartate (NMDA) receptor antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a 'purely' psychotic illness without overt neurological symptoms. We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis. Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69-9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94-2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used. A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.