Advertisement

N-Methyl-D-Aspartate Receptor Autoantibodies in Psychiatric Illness

      We would like to respond to the comments made in a recent editorial (
      • Kayser M.S.
      Fact or fiction? Examining a role for N-methyl-D-aspartate receptor autoantibodies in psychiatric illness.
      ) concerning the article by Pathmanandavel et al. (
      • 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.
      ). We agree the technique for detection of N-methyl-D-aspartate receptor (NMDAR) autoantibodies is critical and that cerebrospinal fluid is a useful material for identifying patients with classic “anti-NMDAR” encephalitis. However, the cell-based assays that Kayser (
      • Kayser M.S.
      Fact or fiction? Examining a role for N-methyl-D-aspartate receptor autoantibodies in psychiatric illness.
      ) refers to can be done either with live cells or with permeabilized/fixed human embryonic kidney cells expressing NMDAR subunits (NR1 with or without NR2B). We favor live cells because they detect only antibodies binding to extracellular epitopes, which are clinically relevant, and we seldom have problems with nonspecific binding of serum, which is much more common with fixed cells as used by many laboratories (
      • Dahm L.
      • Ott C.
      • Steiner J.
      • Stepniak B.
      • Teegen B.
      • Saschenbrecker S.
      • et al.
      Seroprevalence of autoantibodies against brain antigens in health and disease.
      ,
      • Lancaster E.
      • Leypoldt F.
      • Titulaer M.J.
      • Honnorat J.
      • Waters P.J.
      • Reindl M.
      • et al.
      Immunoglobulin G antibodies to the N-methyl-D-aspartate receptor are distinct from immunoglobulin A and immunoglobulin M responses.
      ). Another point raised by Kayser refers to the low binding score of one of three sera from the first psychosis study (
      • Zandi M.S.
      • Irani S.R.
      • Lang B.
      • Waters P.
      • Jones P.B.
      • McKenna P.
      • et al.
      Disease-relevant autoantibodies in first episode schizophrenia.
      ) and the possibility that it, and by implication one-third of such results, might be clinically irrelevant, and he cites our further study (
      • Zandi M.S.
      • Paterson R.W.
      • Ellul M.A.
      • Jacobson L.
      • Al-Diwani A.
      • Jones J.L.
      • et al.
      Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes.
      ), which was focused on 56 cases in a tertiary neurology setting, in support of this. Clinical relevance of the antibodies can be demonstrated through the coupling of antibody removal and clinical improvement. We recently reported 18 patients with psychosis and NMDAR autoantibodies, 17 with peak antibody levels of ≥1:5 (cell-based assay visual score) (
      • Zandi M.S.
      • Deakin J.B.
      • Morris K.
      • Buckley C.
      • Jacobson L.
      • Scoriels L.
      • et al.
      Immunotherapy for patients with acute psychosis and serum N-methyl D-aspartate receptor (NMDAR) antibodies: A description of a treated case series.
      ). Moreover, 9 of the 18 patients, mainly with a disease course refractory to regular psychiatric treatment, received immunotherapies, and 8 improved clinically. Although not definitive randomized controlled trial evidence, this study provides an indication that the NMDAR antibodies measured by a live cell assay are relevant in some patients with a purely psychiatric phenotype.
      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:

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

      References

        • Kayser M.S.
        Fact or fiction? Examining a role for N-methyl-D-aspartate receptor autoantibodies in psychiatric illness.
        Biol Psychiatry. 2015; 77: 506-507
        • 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
        • 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
        • Lancaster E.
        • Leypoldt F.
        • Titulaer M.J.
        • Honnorat J.
        • Waters P.J.
        • Reindl M.
        • et al.
        Immunoglobulin G antibodies to the N-methyl-D-aspartate receptor are distinct from immunoglobulin A and immunoglobulin M responses.
        Ann Neurol. 2015; 77: 183
        • 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
        • Zandi M.S.
        • Paterson R.W.
        • Ellul M.A.
        • Jacobson L.
        • Al-Diwani A.
        • Jones J.L.
        • et al.
        Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes.
        J Neurol Neurosurg Psychiatry. 2015; 86: 708-713
        • Zandi M.S.
        • Deakin J.B.
        • Morris K.
        • Buckley C.
        • Jacobson L.
        • Scoriels L.
        • et al.
        Immunotherapy for patients with acute psychosis and serum N-methyl D-aspartate receptor (NMDAR) antibodies: A description of a treated case series.
        Schizophr Res. 2014; 160: 193-195
        • 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

      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
      • Reply to: N-Methyl-D-Aspartate Receptor Autoantibodies in Psychiatric Illness
        Biological PsychiatryVol. 79Issue 9
        • Preview
          We appreciate the letter of Zandi et al. It raises important points related to the specificity of laboratory techniques used for N-methyl-D-aspartate receptor (NMDAR) antibody determination. However, Zandi et al. indicate they “seldom have problems with nonspecific binding of serum, which is more common with fixed cells as used in many laboratories.” In fact, their data show the opposite: In their own study, 23.2% of the patients had nonspecific binding of serum and were classified as “unlikely autoimmune encephalitis” (1).
        • Full-Text
        • PDF