Cell- and Single Molecule-Based Methods to Detect Anti-N-Methyl-D-Aspartate Receptor Autoantibodies in Patients With First-Episode Psychosis From the OPTiMiSE Project


      Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating autoantibodies against glutamatergic NMDAR in psychotic disorders remains controversial, with detection prevalence rates and immunoglobulin classes varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of patients with first-episode psychosis using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating autoantibodies against glutamatergic NMDAR in approximately 5% of patients with first-episode psychosis. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need for new sensitive methods to detect the presence of low-titer autoantibodies against glutamatergic NMDAR in seropositive patients who cannot be clinically identified from seronegative ones.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Crisp S.J.
        • Kullmann D.M.
        • Vincent A.
        Autoimmune synaptopathies.
        Nat Rev Neurosci. 2016; 17: 103-117
        • Dalmau J.
        • Lancaster E.
        • Martinez-Hernandez E.
        • Rosenfeld M.R.
        • Balice-Gordon R.
        Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.
        Lancet Neurol. 2011; 10: 63-74
        • Dalmau J.
        • Geis C.
        • Graus F.
        Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system.
        Physiol Rev. 2017; 97: 839-887
        • Pollak T.A.
        • Beck K.
        • Irani S.R.
        • Howes O.D.
        • David A.S.
        • McGuire P.K.
        Autoantibodies to central nervous system neuronal surface antigens: Psychiatric symptoms and psychopharmacological implications.
        Psychopharmacology (Berl). 2016; 233: 1605-1621
        • de Witte L.D.
        • Hoffmann C.
        • van Mierlo H.C.
        • Titulaer M.J.
        • Kahn R.S.
        • Martinez-Martinez P.
        • et al.
        Absence of N-methyl-D-aspartate receptor IgG autoantibodies in schizophrenia: The importance of cross-validation studies.
        JAMA Psychiatry. 2015; 72: 731-733
        • Haussleiter I.S.
        • Emons B.
        • Schaub M.
        • Borowski K.
        • Brune M.
        • Wandinger K.P.
        • et al.
        Investigation of antibodies against synaptic proteins in a cross-sectional cohort of psychotic patients.
        Schizophr Res. 2012; 140: 258-259
        • Masopust J.
        • Andrys C.
        • Bazant J.
        • Vysata O.
        • Kuca K.
        • Valis M.
        Anti-NMDA receptor antibodies in patients with a first episode of schizophrenia.
        Neuropsychiatr Dis Treat. 2015; 11: 619-623
        • Rhoads J.
        • Guirgis H.
        • McKnight C.
        • Duchemin A.M.
        Lack of anti-NMDA receptor autoantibodies in the serum of subjects with schizophrenia.
        Schizophr Res. 2011; 129: 213-214
        • Sinmaz N.
        • Amatoury M.
        • Merheb V.
        • Ramanathan S.
        • Dale R.C.
        • Brilot F.
        Autoantibodies in movement and psychiatric disorders: Updated concepts in detection methods, pathogenicity, and CNS entry.
        Ann N Y Acad Sci. 2015; 1351: 22-38
        • Mikasova L.
        • De Rossi P.
        • Bouchet D.
        • Georges F.
        • Rogemond V.
        • Didelot A.
        • et al.
        Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis.
        Brain. 2012; 135: 1606-1621
        • Irani S.R.
        • Alexander S.
        • Waters P.
        • Kleopa K.A.
        • Pettingill P.
        • Zuliani L.
        • et al.
        Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia.
        Brain. 2010; 133: 2734-2748
        • Hansen H.C.
        • Klingbeil C.
        • Dalmau J.
        • Li W.
        • Weissbrich B.
        • Wandinger K.P.
        Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis.
        JAMA Neurol. 2013; 70: 117-119
        • Manto M.U.
        • Laute M.A.
        • Aguera M.
        • Rogemond V.
        • Pandolfo M.
        • Honnorat J.
        Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases.
        Ann Neurol. 2007; 61: 544-551
        • Groc L.
        • Choquet D.
        • Stephenson F.A.
        • Verrier D.
        • Manzoni O.J.
        • Chavis P.
        NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin.
        J Neurosci. 2007; 27: 10165-10175
        • Groc L.
        • Choquet D.
        Measurement and characteristics of neurotransmitter receptor surface trafficking [review].
        Mol Membr Biol. 2008; 25: 344-352
        • Levi S.
        • Triller A.
        Neurotransmitter dynamics.
        in: Kittler J.T. Moss S.J. The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. CRC Press/Taylor & Francis, Boca Raton, FL2006
        • Pathmanandavel K.
        • Starling J.
        • Merheb V.
        • Ramanathan S.
        • Sinmaz N.
        • Dale R.C.
        • et al.
        Antibodies to surface dopamine-2 receptor and N-methyl-D-aspartate receptor in the first episode of acute psychosis in children.
        Biol Psychiatry. 2015; 77: 537-547
        • Ladepeche L.
        • Dupuis J.P.
        • Bouchet D.
        • Doudnikoff E.
        • Yang L.
        • Campagne Y.
        • et al.
        Single-molecule imaging of the functional crosstalk between surface NMDA and dopamine D1 receptors.
        Proc Natl Acad Sci U S A. 2013; 110: 18005-18010
        • Lennox B.R.
        • Palmer-Cooper E.C.
        • Pollak T.
        • Hainsworth J.
        • Marks J.
        • Jacobson L.
        • et al.
        Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: A case-control study.
        Lancet Psychiatry. 2017; 4: 42-48
        • Zandi M.S.
        • Irani S.R.
        • Lang B.
        • Waters P.
        • Jones P.B.
        • McKenna P.
        • et al.
        Disease-relevant autoantibodies in first episode schizophrenia.
        J Neurol. 2011; 258: 686-688
        • Castillo-Gómez E.
        • Oliveira B.
        • Tapken D.
        • Bertrand S.
        • Klein-Schmidt C.
        • Pan H.
        • et al.
        All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class.
        Mol Psychiatry. 2016; ([published online ahead of print Aug 9])
        • Dahm L.
        • Ott C.
        • Steiner J.
        • Stepniak B.
        • Teegen B.
        • Saschenbrecker S.
        • et al.
        Seroprevalence of autoantibodies against brain antigens in health and disease.
        Ann Neurol. 2014; 76: 82-94
        • Hammer C.
        • Stepniak B.
        • Schneider A.
        • Papiol S.
        • Tantra M.
        • Begemann M.
        • et al.
        Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.
        Mol Psychiatry. 2014; 19: 1143-1149
        • Endres D.
        • Perlov E.
        • Baumgartner A.
        • Hottenrott T.
        • Dersch R.
        • Stich O.
        • et al.
        Immunological findings in psychotic syndromes: A tertiary care hospital’s CSF sample of 180 patients.
        Front Hum Neurosci. 2015; 9: 476
        • Busse S.
        • Busse M.
        • Brix B.
        • Probst C.
        • Genz A.
        • Bogerts B.
        • et al.
        Seroprevalence of N-methyl-D-aspartate glutamate receptor (NMDA-R) autoantibodies in aging subjects without neuropsychiatric disorders and in dementia patients.
        Eur Arch Psychiatry Clin Neurosci. 2014; 264: 545-550
        • Pollak T.A.
        • McCormack R.
        • Peakman M.
        • Nicholson T.R.
        • David A.S.
        Prevalence of anti-N-methyl-D-aspartate (NMDA) antibodies in patients with schizophrenia and related psychoses: A systematic review and meta-analysis.
        Psychol Med. 2014; 44: 2475-2487