Antibodies to Surface Dopamine-2 Receptor and N-Methyl-D-Aspartate Receptor in the First Episode of Acute Psychosis in Children

  • Karrnan Pathmanandavel
    Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead
    Search for articles by this author
  • Jean Starling
    The Walker Unit, Concord Centre for Mental Health, Concord West, Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, Australia.
    Search for articles by this author
  • Vera Merheb
    Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead
    Search for articles by this author
  • Sudarshini Ramanathan
    Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead
    Search for articles by this author
  • Nese Sinmaz
    Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead
    Search for articles by this author
  • Russell C. Dale
    Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead
    Search for articles by this author
  • Fabienne Brilot
    Address correspondence to Fabienne Brilot, Ph.D., Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney, Locked Bag 4001, Westmead Sydney, NSW 2145, Australia
    Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead
    Search for articles by this author



      The dopamine and glutamate hypotheses are well known in psychosis. Recently, the detection of autoantibodies against proteins expressed on the surface of cells in the central nervous system has raised the possibility that specific immune-mediated mechanisms may define a biological subgroup within psychosis, although no cohort of a first episode of psychosis in children has been investigated.


      Serum taken during the acute presentation of 43 children with first episode of psychosis and serum from 43 pediatric control subjects was assessed for the presence of immunoglobulin (Ig)G, IgM, or IgA antibodies to dopamine-2 receptor (D2R) and NR1 subunit of the N-methyl-D-aspartate receptor using a flow cytometry live cell-based assay and immunolabeling of murine primary neurons.


      Using a cutoff of three SD above the control mean, serum antibodies to D2R or NR1 were detected in 8 of 43 psychotic patients but not detected in any of 43 control subjects (p < .001). Positive immunoglobulin binding to D2R was found in 3 of 43 psychosis patients (3 IgG, 1 IgM, 0 IgA) and to N-methyl-D-aspartate receptor in 6 of 43 patients (5 IgG, 1 IgM, 1 IgA). Specificity of antibody was confirmed by immunoaffinity purification and immunoabsorption. Significant differences in antibody binding to live, fixed, and fixed and permeabilized neurons were observed, confirming that only live cells can define surface epitope immunolabeling.


      This is the first report of serum antibodies to surface D2R and NR1 in pediatric patients with isolated psychosis, which supports the hypothesis that a subgroup of patients may be immune-mediated.


      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


        • Beaulieu J.M.
        • Gainetdinov R.R.
        The physiology, signaling, and pharmacology of dopamine receptors.
        Pharmacol Rev. 2011; 63: 182-217
        • Guillin O.
        • Abi-Dargham A.
        • Laruelle M.
        Neurobiology of dopamine in schizophrenia.
        Int Rev Neurobiol. 2007; 78: 1-39
        • Creese I.
        • Burt D.R.
        • Snyder S.H.
        Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.
        Science. 1976; 192: 481-483
        • Seeman P.
        • Lee T.
        • Chau-Wong M.
        • Wong K.
        Antipsychotic drug doses and neuroleptic/dopamine receptors.
        Nature. 1976; 261: 717-719
        • Horacek J.
        • Bubenikova-Valesova V.
        • Kopecek M.
        • Palenicek T.
        • Dockery C.
        • Mohr P.
        • Höschl C.
        Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia.
        CNS Drugs. 2006; 20: 389-409
        • Miyamoto S.
        • Duncan G.E.
        • Marx C.E.
        • Lieberman J.A.
        Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs.
        Mol Psychiatry. 2005; 10: 79-104
        • Coyle J.T.
        Glutamate and schizophrenia: Beyond the dopamine hypothesis.
        Cell Mol Neurobiol. 2006; 26: 365-384
        • Tamminga C.A.
        • Holcomb H.H.
        Phenotype of schizophrenia: A review and formulation.
        Mol Psychiatry. 2005; 10: 27-39
        • van Os J.
        • Kapur S.
        Lancet. 2009; 374: 635-645
        • Coutinho E.
        • Harrison P.
        • Vincent A.
        Do neuronal autoantibodies cause psychosis? A neuroimmunological perspective.
        Biol Psychiatry. 2014; 75: 269-275
        • Rothermundt M.
        • Arolt V.
        • Bayer T.A.
        Review of immunological and immunopathological findings in schizophrenia.
        Brain Behav Immun. 2001; 15: 319-339
        • Lancaster E.
        • Dalmau J.
        Neuronal autoantigens--pathogenesis, associated disorders and antibody testing.
        Nat Rev Neurol. 2012; 8: 380-390
        • Zuliani L.
        • Graus F.
        • Giometto B.
        • Bien C.
        • Vincent A.
        Central nervous system neuronal surface antibody associated syndromes: Review and guidelines for recognition.
        J Neurol Neurosurg Psychiatry. 2012; 83: 638-645
        • 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
        • Hughes E.G.
        • Peng X.
        • Gleichman A.J.
        • Lai M.
        • Zhou L.
        • Tsou R.
        • et al.
        Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.
        J Neurosci. 2010; 30: 5866-5875
        • 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
        • Lai M.
        • Hughes E.G.
        • Peng X.
        • Zhou L.
        • Gleichman A.J.
        • Shu H.
        • et al.
        AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
        Ann Neurol. 2009; 65: 424-434
        • Lancaster E.
        • Lai M.
        • Peng X.
        • Hughes E.
        • Constantinescu R.
        • Raizer J.
        • et al.
        Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: Case series and characterisation of the antigen.
        Lancet Neurol. 2010; 9: 67-76
        • Ben-Pazi H.
        • Stoner J.A.
        • Cunningham M.W.
        Dopamine receptor autoantibodies correlate with symptoms in Sydenham’s chorea.
        PLoS One. 2013; 8: e73516
        • Brimberg L.
        • Benhar I.
        • Mascaro-Blanco A.
        • Alvarez K.
        • Lotan D.
        • Winter C.
        • et al.
        Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: A novel rat model of Sydenham chorea and related neuropsychiatric disorders.
        Neuropsychopharmacology. 2012; 37: 2076-2087
        • Dale R.C.
        • Merheb V.
        • Pillai S.
        • Wang D.
        • Cantrill L.
        • Murphy T.K.
        • et al.
        Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders.
        Brain. 2012; 135: 3453-3468
        • 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
        • Tsutsui K.
        • Kanbayashi T.
        • Tanaka K.
        • Boku S.
        • Ito W.
        • Tokunaga J.
        • et al.
        Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features.
        BMC Psychiatry. 2012; 12: 37
        • Steiner J.
        • Walter M.
        • Glanz W.
        • Sarnyai Z.
        • Bernstein H.G.
        • Vielhaber S.
        • et al.
        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; 70: 271-278
        • Dale R.C.
        • Tantsis E.
        • Merheb V.
        • Kumaran R.-Y.A.
        • Sinmaz N.
        • Pathmanandavel K.
        • et al.
        Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
        Neurol Neuroimmunol Neuroinflammation. 2014; 1: e12
        • Amatoury M.
        • Merheb V.
        • Langer J.
        • Wang X.M.
        • Dale R.C.
        • Brilot F.
        High-throughput flow cytometry cell-based assay to detect antibodies to N-methyl-D-aspartate receptor or dopamine-2 receptor in human serum.
        J Vis Exp. 2013; 81: e50935
        • Brilot F.
        • Dale R.C.
        • Selter R.C.
        • Grummel V.
        • Kalluri S.R.
        • Aslam M.
        • et al.
        Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease.
        Ann Neurol. 2009; 66: 833-842
        • Brilot F.
        • Merheb V.
        • Ding A.
        • Murphy T.
        • Dale R.C.
        Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome.
        Neurology. 2011; 76: 1508-1513
        • Mohammad S.S.
        • Ramanathan S.
        • Brilot F.
        • Dale R.C.
        Autoantibody-associated movement disorders.
        Neuropediatrics. 2013; 44: 336-345
        • Fath T.
        • Ke Y.D.
        • Gunning P.
        • Gotz J.
        • Ittner L.M.
        Primary support cultures of hippocampal and substantia nigra neurons.
        Nat Protoc. 2009; 4: 78-85
        • 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
        • Dalmau J.
        • Gleichman A.J.
        • Hughes E.G.
        • Rossi J.E.
        • Peng X.
        • Lai M.
        • et al.
        Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies.
        Lancet Neurol. 2008; 7: 1091-1098
        • 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 [published online ahead of print September 3].
        Mol Psychiatry. 2013; (doi:10.1038/mp.2013.110)
        • Deakin J.
        • Lennox B.R.
        • Zandi M.S.
        Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis.
        Biol Psychiatry. 2014; 75: 284-291
        • 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. 2013; 44: 2475-2487
        • Vincent A.
        • Bien C.G.
        • Irani S.R.
        • Waters P.
        Autoantibodies associated with diseases of the CNS: New developments and future challenges.
        Lancet Neurol. 2011; 10: 759-772
        • Haussleiter I.S.
        • Emons B.
        • Schaub M.
        • Borowski K.
        • Brune M.
        • Wandinger K.P.
        • Juckel G.
        Investigation of antibodies against synaptic proteins in a cross-sectional cohort of psychotic patients.
        Schizophr Res. 2012; 140: 258-259
        • Masdeu J.C.
        • Gonzalez-Pinto A.
        • Matute C.
        • Ruiz De Azua S.
        • Palomino A.
        • De Leon J.
        • et al.
        Serum IgG antibodies against the NR1 subunit of the NMDA receptor not detected in schizophrenia.
        Am J Psychiatry. 2012; 169: 1120-1121
        • 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
        • Avrameas S.
        • Selmi C.
        Natural autoantibodies in the physiology and pathophysiology of the immune system.
        J Autoimmun. 2013; 41: 46-49
        • Duarte-Rey C.
        • Bogdanos D.P.
        • Leung P.S.
        • Anaya J.M.
        • Gershwin M.E.
        IgM predominance in autoimmune disease: Genetics and gender.
        Autoimmun Rev. 2012; 11: A404-A412
        • Mestecky J.
        • Raska M.
        • Julian B.A.
        • Gharavi A.G.
        • Renfrow M.B.
        • Moldoveanu Z.
        • et al.
        IgA nephropathy: Molecular mechanisms of the disease.
        Annu Rev Pathol. 2013; 8: 217-240
        • Gresa-Arribas N.
        • Titulaer M.J.
        • Torrents A.
        • Aguilar E.
        • McCracken L.
        • Leypoldt F.
        • et al.
        Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: A retrospective study.
        Lancet Neurol. 2014; 13: 167-177
        • Bien C.G.
        • Vincent A.
        • Barnett M.H.
        • Becker A.J.
        • Blumcke I.
        • Graus F.
        • et al.
        Immunopathology of autoantibody-associated encephalitides: Clues for pathogenesis.
        Brain. 2012; 135: 1622-1638
        • Cox C.J.
        • Sharma M.
        • Leckman J.F.
        • Zuccolo J.
        • Zuccolo A.
        • Kovoor A.
        • et al.
        Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: Implications in human disease.
        J Immunol. 2013; 191: 5524-5541
        • Titulaer M.J.
        • McCracken L.
        • Gabilondo I.
        • Armangue T.
        • Glaser C.
        • Iizuka T.
        • et al.
        Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study.
        Lancet Neurol. 2013; 12: 157-165
        • Kayser M.S.
        • Titulaer M.J.
        • Gresa-Arribas N.
        • Dalmau J.
        Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-D-aspartate receptor encephalitis.
        JAMA Neurol. 2013; 70: 1133-1139
        • Najjar S.
        • Pearlman D.
        • Zagzag D.
        • Golfinos J.
        • Devinsky O.
        Glutamic acid decarboxylase autoantibody syndrome presenting as schizophrenia.
        Neurologist. 2012; 18: 88-91
        • Hacohen Y.
        • Absoud M.
        • Woodhall M.
        • Cummins C.
        • De Goede C.G.
        • Hemingway C.
        • et al.
        Autoantibody biomarkers in childhood-acquired demyelinating syndromes: Results from a national surveillance cohort.
        J Neurol Neurosurg Psychiatry. 2014; 85: 456-461
        • Hacohen Y.
        • Wright S.
        • Waters P.
        • Agrawal S.
        • Carr L.
        • Cross H.
        • et al.
        Paediatric autoimmune encephalopathies: Clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens.
        J Neurol Neurosurg Psychiatry. 2013; 84: 748-755
        • Kruer M.C.
        • Hoeftberger R.
        • Lim K.Y.
        • Coryell J.C.
        • Svoboda M.D.
        • Woltjer R.L.
        • Dalmau J.
        Aggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizures: The first pediatric case of gamma-aminobutyric acid type B receptor autoimmunity.
        JAMA Neurol. 2014; 71: 620-623
        • Suleiman J.
        • Brenner T.
        • Gill D.
        • Brilot F.
        • Antony J.
        • Vincent A.
        • et al.
        VGKC antibodies in pediatric encephalitis presenting with status epilepticus.
        Neurology. 2011; 76: 1252-1255
        • Armangue T.
        • Titulaer M.J.
        • Malaga I.
        • Bataller L.
        • Gabilondo I.
        • Graus F.
        • et al.
        Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.
        J Pediatr. 2013; 162: 850-856
        • Boronat A.
        • Gelfand J.M.
        • Gresa-Arribas N.
        • Jeong H.Y.
        • Walsh M.
        • Roberts K.
        • et al.
        Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels.
        Ann Neurol. 2013; 73: 120-128
        • Hacohen Y.
        • Deiva K.
        • Pettingill P.
        • Waters P.
        • Siddiqui A.
        • Chretien P.
        • et al.
        N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse.
        Mov Disord. 2014; 29: 90-96
        • Mohammad S.S.
        • Sinclair K.
        • Pillai S.
        • Merheb V.
        • Aumann T.D.
        • Gill D.
        • et al.
        Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-methyl-D-aspartate receptor or dopamine-2 receptor.
        Mov Disord. 2013; 29: 117-122

      Linked Article

      • Fact or Fiction? Examining a Role for N-Methyl-D-Aspartate Receptor Autoantibodies in Psychiatric Illness
        Biological PsychiatryVol. 77Issue 6
        • Preview
          There is a pressing need in psychiatry to establish biologically based disease subtypes, which might allow for more specific diagnosis and effective intervention. An active area of investigation in this realm has been autoimmunity and mental illness. The discovery and characterization of anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis has led the resurgent effort into understanding whether specific autoantibody syndromes might define a subset of patients with psychiatric diagnoses or symptoms, such as schizophrenia or psychosis.
        • Full-Text
        • PDF