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N-Methyl-D-Aspartate Receptor Autoantibodies in Psychiatric Illness
Author's Accepted Manuscript
N-methyl D-Aspartate receptor autoantibodies in psychiatric illness Michael S. Zandi PhD, Belinda Lennox DM, Angela Vincent FRS
www.sobp.org/journal
PII: DOI: Reference:
S0006-3223(15)00472-2 http://dx.doi.org/10.1016/j.biopsych.2015.03.034 BPS12575
To appear in:
Biological Psychiatry
Cite this article as: Michael S. Zandi PhD, Belinda Lennox DM, Angela Vincent FRS, N-methyl D-Aspartate receptor autoantibodies in psychiatric illness, Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2015.03.034 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Correspondence: N-methyl D-Aspartate receptor autoantibodies in psychiatric illness Michael S. Zandi PhD, Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge Belinda Lennox DM, Department of Psychiatry, University of Oxford Angela Vincent FRS, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford.
Address for correspondence Dr Michael Zandi Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge CB2 0QQ [email protected]
Dear Editor, We would like to respond to the comments made in a recent editorial (1) on Pathmanandavel et al (2). We agree the technique for detection of NMDAR autoantibodies is critical and that CSF is a useful material for identifying patients with classical “antiNMDAR” encephalitis. However, the cell-based assays that Kayser refers to can be done either with live cells or with permeabilised/fixed human embryonic kidney cells expressing the NMDAR subunits (NR1 with or without NR2B). We favour live cells because they only detect antibodies binding to extracellular epitopes, which are clinically relevant, and we seldom have problems with non-specific binding of serum which is much more common with fixed cells as used by many laboratories (3,4). This led to another point raised by Kayser referring to the low binding score that one of three sera from the first psychosis study (5) and the possibility that it, and by implication a third of such results, might be clinically irrelevant, and he cites our further study in support of this (6), which was focused on 56 cases in a tertiary neurology setting. 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) or above (7). Moreover, 9 of the 18 patients, mainly with a disease course refractory to regular psychiatric treatment, received immunotherapies and 8 improved clinically. Whilst not definitive RCT evidence, this provides an indication that the NMDAR antibodies measured by a live-cell assay are relevant in some patients with a purely psychiatric phenotype. The disease relevance of serum NMDAR antibodies has been called into question, but it has not been easy to acquire CSF from patients who are not neurologically ill (as in Masdeu et al (8)). The field needs 1. comparisons of antibody tests using samples defined, independent of NMDAR-Ab detection, in order to inform the most sensitive and specific methods, and 2. randomised controlled treatment trials for the patients at the borderland of psychiatry and neurology with serum and CSF sampling both for evidence of inflammation and for antibody tests. Our studies have been supported by the NIHR Biomedical Research Centres in Cambridge and Oxford. AV and the University of Oxford hold patents and receive royalties from Athena Diagnostics and Euroimmun AG. The other report no biomedical financial interests or potential conflicts of interest.
References 1. Kayser MS. Fact or fiction? Examining a role for N-methyl-d-aspartate receptor autoantibodies in psychiatric illness. Biological Psychiatry. 2015 Mar 15;77(6):506507. 2. Pathmanandavel K, Starling J, Merheb V, Ramanathan S, Sinmaz N, Dale RC, et al. Antibodies to surface dopamine-2 receptor and N-methyl-D-aspartate receptor in the first episode of acute psychosis in children. Biological Psychiatry. 2014.
3. Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Annals of neurology. 2014 Jul;76(1):82-94. 4. Lancaster E, Leypoldt F, Titulaer MJ, Honnorat J, Waters PJ, Reindl M, et al. IgG antibodies to the NMDA receptor are distinct from IgA and IgM responses. Annals of neurology. 2014 Jul 22. 5. Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, et al. Disease-relevant autoantibodies in first episode schizophrenia. Journal of Neurology. 2011 Apr;258(4):686-688. 6. Zandi MS, Paterson RW, Ellul MA, Jacobson L, Al-Diwani A, Jones JL, et al. Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes. Journal of neurology, neurosurgery, and psychiatry. 2014a Sep 22. 7. Zandi MS, Deakin JB, 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. Schizophrenia Research. 2014b Dec;160(1-3):193-195. 8. Masdeu JC, 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 Oct;169(10):1120-1121.
N-methyl D-Aspartate receptor autoantibodies in psychiatric illness Michael S. Zandi PhD, Belinda Lennox DM, Angela Vincent FRS
www.sobp.org/journal
PII: DOI: Reference:
S0006-3223(15)00472-2 http://dx.doi.org/10.1016/j.biopsych.2015.03.034 BPS12575
To appear in:
Biological Psychiatry
Cite this article as: Michael S. Zandi PhD, Belinda Lennox DM, Angela Vincent FRS, N-methyl D-Aspartate receptor autoantibodies in psychiatric illness, Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2015.03.034 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Correspondence: N-methyl D-Aspartate receptor autoantibodies in psychiatric illness Michael S. Zandi PhD, Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge Belinda Lennox DM, Department of Psychiatry, University of Oxford Angela Vincent FRS, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford.
Address for correspondence Dr Michael Zandi Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge CB2 0QQ [email protected]
Dear Editor, We would like to respond to the comments made in a recent editorial (1) on Pathmanandavel et al (2). We agree the technique for detection of NMDAR autoantibodies is critical and that CSF is a useful material for identifying patients with classical “antiNMDAR” encephalitis. However, the cell-based assays that Kayser refers to can be done either with live cells or with permeabilised/fixed human embryonic kidney cells expressing the NMDAR subunits (NR1 with or without NR2B). We favour live cells because they only detect antibodies binding to extracellular epitopes, which are clinically relevant, and we seldom have problems with non-specific binding of serum which is much more common with fixed cells as used by many laboratories (3,4). This led to another point raised by Kayser referring to the low binding score that one of three sera from the first psychosis study (5) and the possibility that it, and by implication a third of such results, might be clinically irrelevant, and he cites our further study in support of this (6), which was focused on 56 cases in a tertiary neurology setting. 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) or above (7). Moreover, 9 of the 18 patients, mainly with a disease course refractory to regular psychiatric treatment, received immunotherapies and 8 improved clinically. Whilst not definitive RCT evidence, this provides an indication that the NMDAR antibodies measured by a live-cell assay are relevant in some patients with a purely psychiatric phenotype. The disease relevance of serum NMDAR antibodies has been called into question, but it has not been easy to acquire CSF from patients who are not neurologically ill (as in Masdeu et al (8)). The field needs 1. comparisons of antibody tests using samples defined, independent of NMDAR-Ab detection, in order to inform the most sensitive and specific methods, and 2. randomised controlled treatment trials for the patients at the borderland of psychiatry and neurology with serum and CSF sampling both for evidence of inflammation and for antibody tests. Our studies have been supported by the NIHR Biomedical Research Centres in Cambridge and Oxford. AV and the University of Oxford hold patents and receive royalties from Athena Diagnostics and Euroimmun AG. The other report no biomedical financial interests or potential conflicts of interest.
References 1. Kayser MS. Fact or fiction? Examining a role for N-methyl-d-aspartate receptor autoantibodies in psychiatric illness. Biological Psychiatry. 2015 Mar 15;77(6):506507. 2. Pathmanandavel K, Starling J, Merheb V, Ramanathan S, Sinmaz N, Dale RC, et al. Antibodies to surface dopamine-2 receptor and N-methyl-D-aspartate receptor in the first episode of acute psychosis in children. Biological Psychiatry. 2014.
3. Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Annals of neurology. 2014 Jul;76(1):82-94. 4. Lancaster E, Leypoldt F, Titulaer MJ, Honnorat J, Waters PJ, Reindl M, et al. IgG antibodies to the NMDA receptor are distinct from IgA and IgM responses. Annals of neurology. 2014 Jul 22. 5. Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, et al. Disease-relevant autoantibodies in first episode schizophrenia. Journal of Neurology. 2011 Apr;258(4):686-688. 6. Zandi MS, Paterson RW, Ellul MA, Jacobson L, Al-Diwani A, Jones JL, et al. Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes. Journal of neurology, neurosurgery, and psychiatry. 2014a Sep 22. 7. Zandi MS, Deakin JB, 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. Schizophrenia Research. 2014b Dec;160(1-3):193-195. 8. Masdeu JC, 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 Oct;169(10):1120-1121.