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

Thomas A. Pollak*, Matthew J. Kempton, Conrad Iyegbe, Angela Vincent, Sarosh R. Irani, Ester Coutinho, David A. Menassa, Leslie Jacobson, Lieuwe de Haan, Stephan Ruhrmann, Gabriele Sachs, Anita Riecher-Roessler, Marie-Odile Krebs, Paul Amminger, Birte Glenthoj, Neus Barrantes-Vidal, Jim van Os, Bart P. F. Rutten, Rodrigo A. Bressan, Mark van der GaagRobert Yolken, Matthew Hotopf, Lucia Valmaggia, James Stone, Anthony S. David, Philip McGuire, Maria Calem, Stefania Tognin, Gemma Modinos, Eva Velthorst, Tamar C. Kraan, Daniella S. van Dam, Nadine Burger, Barnaby Nelson, Patrick McGorry, Christos Pantelis, Athena Politis, Joanne Goodall, Stefan Borgwardt, Sarah Ittig, Erich Studerus, Renata Smieskova, Philippe A. Delespaul, EUGEI High-Risk Study Group

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)


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.

Original languageEnglish
Pages (from-to)2590-2604
Number of pages15
JournalMolecular Psychiatry
Issue number6
Early online date19 Oct 2020
Publication statusPublished - Jun 2021



Cite this