Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis

Abstract

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.

Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis

“…This issue could be addressed by conducting a prospective study, with ascertainment of subjects in the clinical high risk phase. However, this would require a large number of samples, as the prevalence of NMDAR antibodies in this population is similarly low [approximately 5% ( 21 )], and only a minority of subjects with clinical high risk will later develop psychosis ( 22 ).…”

The Relationship Between Grey Matter Volume and Clinical and Functional Outcomes in People at Clinical High Risk for Psychosis

“…Our findings suggest that in people at CHR for psychosis, relatively reduced right striatal volume is associated with a poor functional outcome. The absence of associations with either symptomatic remission or transition to psychosis, despite a relatively large sample size, raises the possibility that other neuroimaging measures 62–65 or peripheral blood markers, 66 , 67 might be better predictors of outcomes in CHR individuals, particularly when these are integrated in multi-modal models. 68 We plan to investigate this in further studies in the EU-GEI sample.…”

NMDAR autoantibodies in psychiatric disease - An immunopsychiatric continuum and potential predisposition for disease pathogenesis

“…NMDAR autoantibodies were tested to detect NMDAR antibodies even before the development of an acute psychosis in a medium-sized cohort of 254 patients presenting a high clinical risk for psychosis. However, the frequency of NMDAR antibodies did not differ significantly between patients carrying a high risk for psychosis and controls (8.3% vs. 5.2%) [ 37 ]. Nevertheless, small changes in psychopathology were observed between groups.…”