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Brain-relevant antibodies in first-episode psychosis: a matched case–control study

Published online by Cambridge University Press:  18 September 2017

Fiona Gaughran ,
John Lally ,
Katherine Beck ,
Ruaidhri McCormack ,
Poonam Gardner-Sood ,
Ester Coutinho ,
Leslie Jacobson ,
Bethan Lang ,
Ricardo Sainz-Fuertes  and
Evangelos Papanastasiou
...Show all authors
Fiona Gaughran
Affiliation:
National Psychosis Service, South London and Maudsley NHS Foundation Trust The Collaboration for Leadership in Applied Health Research and Care (CLAHRC), South London Psychosis Research Team, London, UK Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
John Lally*
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland Department of Psychiatry, School of Medicine and Medical Sciences, University College Dublin, and St Vincent's University Hospital, Dublin, Ireland
Katherine Beck
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Ruaidhri McCormack
Affiliation:
Addenbrooke's Hospital, Cambridge, UK
Poonam Gardner-Sood
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Ester Coutinho
Affiliation:
Nuffield Department of Clinical Neurosciences, Oxford University Hospitals, University of Oxford, Oxford, UK
Leslie Jacobson
Affiliation:
Nuffield Department of Clinical Neurosciences, Oxford University Hospitals, University of Oxford, Oxford, UK
Bethan Lang
Affiliation:
Nuffield Department of Clinical Neurosciences, Oxford University Hospitals, University of Oxford, Oxford, UK
Ricardo Sainz-Fuertes
Affiliation:
Basic and Clinical Neuroscience at the Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London, UK
Evangelos Papanastasiou
Affiliation:
Cognition Schizophrenia and Imaging Laboratory (CSI Lab), Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK
Marta Di Forti
Affiliation:
SGDP, Institute of Psychiatry, Psychology and Neuroscience, King's College London, and South London and Maudsley NHS Foundation Trust, London, UK
Tim Nicholson
Affiliation:
Section of Cognitive Neuropsychiatry, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Angela Vincent
Affiliation:
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
Robin M. Murray
Affiliation:
National Psychosis Service, South London and Maudsley NHS Foundation Trust Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
*
Author for correspondence: Dr John Lally, E-mail: [email protected]
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Abstract

Background

There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP).

Methods

Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case–control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded.

Results

VGKC-complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls.

Conclusions

This case–control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context.

Keywords

AntibodiesFEPfirst-episode psychosisNMDAschizophreniaVGKC-complex
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 8 , June 2018 , pp. 1257 - 1263
Copyright
Copyright © Cambridge University Press 2017 

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Footnotes

†

These authors contributed equally to the paper and are joint first authors.

‡

These authors contributed equally to the paper and should be acknowledged as joint last authors.

References

Barry, H, Hardiman, O, Healy, DG, Keogan, M, Moroney, J, Molnar, PP, Cotter, DR, Murphy, KC (2011) Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. British Journal of Psychiatry 199, 508–509.CrossRefGoogle ScholarPubMed
Bebbington, P, Nayani, T (1995) The psychosis screening questionnaire. International Journal of Methods in Psychiatric Research 5, 11–19.Google Scholar
Beck, K, Lally, J, Shergill, SS, Bloomfield, MAP, MacCabe, JH, Gaughran, F, Howes, OD (2015) Prevalence of serum N-methyl-d-aspartate receptor autoantibodies in refractory psychosis. British Journal of Psychiatry 206, 164–165.CrossRefGoogle ScholarPubMed
Benros, ME, Eaton, WW, Mortensen, PB (2014) The epidemiologic evidence linking autoimmune diseases and psychosis. Biological Psychiatry 75, 300–306.CrossRefGoogle ScholarPubMed
Coutinho, E, Harrison, P, Vincent, A (2014) Do neuronal autoantibodies cause psychosis? A neuroimmunological perspective. Biological Psychiatry 75, 269–275.CrossRefGoogle ScholarPubMed
Dalmau, J, Gleichman, AJ, Hughes, EG, Rossi, JE, Peng, X, Lai, M, Dessain, SK, Rosenfeld, MR, Balice-Gordon, R, Lynch, DR (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurology 7, 1091–1098.CrossRefGoogle ScholarPubMed
de Witte, LD., Hoffmann, C., van Mierlo, HC, Titulaer, MJ, Kahn, RS, Martinez-Martinez, P (2015) Absence of N-methyl-D-aspartate receptor IgG autoantibodies in schizophrenia: the importance of cross-validation studies. JAMA Psychiatry 72, 731–733.CrossRefGoogle ScholarPubMed
Deakin, J, Lennox, BR, Zandi, MS (2014) Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis. Biological Psychiatry 75, 284–291.CrossRefGoogle Scholar
Eaton, WW, Byrne, M, Ewald, H, Mors, O, Chen, CY, Agerbo, E, Mortensen, PB (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. American Journal of Psychiatry 163, 521–528.CrossRefGoogle ScholarPubMed
Ezeoke, A, Mellor, A, Buckley, P, Miller, B (2013) A systematic, quantitative review of blood autoantibodies in schizophrenia. Schizophrenia Research 150, 245–251.CrossRefGoogle ScholarPubMed
Gresa-Arribas, N, Titulaer, MJ, Torrents, A, Aguilar, E, McCracken, L, Leypoldt, F, Gleichman, AJ, Balice-Gordon, R, Rosenfeld, MR, Lynch, D, Graus, F, Dalmau, J (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. The Lancet Neurology 13, 167–177.CrossRefGoogle ScholarPubMed
Hacohen, Y, Singh, R, Rossi, M, Lang, B, Hemingway, C, Lim, M, Vincent, A (2015) Clinical relevance of voltage-gated potassium channel-complex antibodies in children. Neurology 85, 967–975.CrossRefGoogle ScholarPubMed
Hammer, C, Stepniak, B, Schneider, A, Papiol, S, Tantra, M, Begemann, M, Siren, AL, Pardo, LA, Sperling, S, Mohd Jofrry, S, Gurvich, A, Jensen, N, Ostmeier, K, Luhder, F, Probst, C, Martens, H, Gillis, M, Saher, G, Assogna, F, Spalletta, G, Stocker, W, Schulz, TF, Nave, KA, Ehrenreich, H (2014) Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Molecular Psychiatry 19, 1143–1149.CrossRefGoogle ScholarPubMed
Haussleiter, IS, Emons, B, Schaub, M, Borowski, K, Brüne, M, Wandinger, K-P, Juckel, G (2012) Investigation of antibodies against synaptic proteins in a cross-sectional cohort of psychotic patients. Schizophrenia Research 140, 258–259.CrossRefGoogle Scholar
Irani, SR, Alexander, S, Waters, P, Kleopa, KA, Pettingill, P, Zuliani, L, Peles, E, Buckley, C, Lang, B, Vincent, A (2010a) 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 133, 2734–2748.CrossRefGoogle ScholarPubMed
Irani, SR, Bera, K, Waters, P, Zuliani, L, Maxwell, S, Zandi, MS, Friese, MA, Galea, I, Kullmann, DM, Beeson, D, Lang, B, Bien, CG, Vincent, A (2010b) N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133, 1655–1667.CrossRefGoogle Scholar
Irani, SR, Michell, AW, Lang, B, Pettingill, P, Waters, P, Johnson, MR, Schott, JM, Armstrong, RJ, S Zagami, A, Bleasel, A, Somerville, ER, Smith, SM, Vincent, A (2011) Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Annals of Neurology 69, 892–900.CrossRefGoogle ScholarPubMed
Kay, SR, Fiszbein, A, Opler, LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276.CrossRefGoogle ScholarPubMed
Kayser, MS, Titulaer, MJ, Gresa-Arribas, N, Dalmau, J (2013) Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurology 70, 1133–1139.CrossRefGoogle ScholarPubMed
Lang, B, Makuch, M, Moloney, T, Dettmann, I, Mindorf, S, Probst, C, Stoecker, W, Buckley, C, Newton, CR, Leite, MI, Maddison, P, Komorowski, L, Adcock, J, Vincent, A, Waters, P, Irani, SR (2017) Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. Journal of Neurology Neurosurgery & Psychiatry.CrossRefGoogle ScholarPubMed
Lennox, BR, Palmer-Cooper, EC, Pollak, T, Hainsworth, J, Marks, J, Jacobson, L, Lang, B, Fox, H, Ferry, B, Scoriels, L, Crowley, H, Jones, PB, Harrison, PJ, Vincent, A (2017) Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. Lancet Psychiatry 4, 42–48.CrossRefGoogle ScholarPubMed
Masdeu, JC, Gonzalez-Pinto, A, Matute, C, Ruiz De Azua, S, Palomino, A, De Leon, J, Berman, KF, Dalmau, J (2012) Serum IgG antibodies against the NR1 subunit of the NMDA receptor not detected in schizophrenia. American Journal of Psychiatry 169, 1120–1121.CrossRefGoogle Scholar
McGuffin, P, Farmer, A, Harvey, I (1991) A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Archives of General Psychiatry 48, 764–770.CrossRefGoogle ScholarPubMed
Paterson, RW, Zandi, MS, Armstrong, R, Vincent, A, Schott, JM (2014) Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. Journal of Neurology Neurosurgery and Psychiatry 85, 625–630.CrossRefGoogle ScholarPubMed
Pathmanandavel, K, Starling, J, Merheb, V, Ramanathan, S, Sinmaz, N, Dale, RC, Brilot, F (2014) Antibodies to surface dopamine-2 receptor and N-methyl-D-aspartate receptor in the first episode of acute psychosis in children. Biological Psychiatry 23, 00547–2.Google Scholar
Pearlman, DM, Najjar, S (2014) Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. Schizophrenia Research 157, 249–258.CrossRefGoogle ScholarPubMed
Pettingill, P, Kramer, HB, Coebergh, JA, Pettingill, R, Maxwell, S, Nibber, A, Malaspina, A, Jacob, A, Irani, SR, Buckley, C, Beeson, D, Lang, B, Waters, P, Vincent, A (2015) Antibodies to GABAA receptor alpha1 and gamma2 subunits: clinical and serologic characterization. Neurology 84, 1233–1241.CrossRefGoogle ScholarPubMed
Pollak, TA, McCormack, R, Peakman, M, Nicholson, TR, David, AS (2014) Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychological Medicine 44, 2475–2487.CrossRefGoogle ScholarPubMed
Rhoads, J, Guirgis, H, McKnight, C, Duchemin, AM (2011) Lack of anti-NMDA receptor autoantibodies in the serum of subjects with schizophrenia. Schizophrenia Research 129, 213–214.CrossRefGoogle ScholarPubMed
Somers, KJ, Lennon, VA, Rundell, JR, Pittock, SJ, Drubach, DA, Trenerry, MR, Lachance, DH, Klein, CJ, Aston, PA, McKeon, A (2011) Psychiatric manifestations of voltage-gated potassium-channel complex autoimmunity. Journal of Neuropsychiatry & Clinical Neuroscience 23, 425–433.CrossRefGoogle ScholarPubMed
Steiner, J, Walter, M, Glanz, W, Sarnyai, Z, Bernstein, HG, Vielhaber, S, Kastner, A, Skalej, M, Jordan, W, Schiltz, K, Klingbeil, C, Wandinger, KP, Bogerts, B, Stoecker, W (2013) 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 70, 271–278.CrossRefGoogle ScholarPubMed
Tsutsui, K, Kanbayashi, T, Tanaka, K, Boku, S, Ito, W, Tokunaga, J, Mori, A, Hishikawa, Y, Shimizu, T, Nishino, S (2012) Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry 12, 37.CrossRefGoogle ScholarPubMed
Wandinger, KP, Saschenbrecker, S, Stoecker, W, Dalmau, J (2011) Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. Journal of Neuroimmunology 231, 86–91.CrossRefGoogle ScholarPubMed
Wright, P, Laing, P, Donaldson, PT, Murray, RM (1999) Schizophrenia: the teratogenic antibody hypothesis. In Psychiatry, Psychoimmunology, and Viruses (ed. Müller, N.), pp. 89–99. Springer Vienna: Vienna.CrossRefGoogle Scholar
Zandi, MS, Irani, SR, Lang, B, Waters, P, Jones, PB, McKenna, P, Coles, AJ, Vincent, A, Lennox, BR (2011) Disease-relevant autoantibodies in first episode schizophrenia. Journal of Neurology 258, 686–688.CrossRefGoogle ScholarPubMed
Zuliani, L, Graus, F, Giometto, B, Bien, C, Vincent, A (2012) Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. Journal of Neurology Neurosurgery and Psychiatry 83, 638–645.CrossRefGoogle ScholarPubMed
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