Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis

Thomas A Pollak, Angela Vincent, Conrad Iyegbe, Ester Coutinho, Leslie Jacobson, Dan Rujescu, James Stone, Julie Jezequel, Veronique Rogemond, Stephane Jamain, Laurent Groc, Anthony David, Alice Egerton, Rene S Kahn, Jerome Honnorat, Paola Dazzan, Marion Leboyer, Philip McGuire, Thomas A Pollak, Angela Vincent, Conrad Iyegbe, Ester Coutinho, Leslie Jacobson, Dan Rujescu, James Stone, Julie Jezequel, Veronique Rogemond, Stephane Jamain, Laurent Groc, Anthony David, Alice Egerton, Rene S Kahn, Jerome Honnorat, Paola Dazzan, Marion Leboyer, Philip McGuire

Abstract

Background: When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear.

Methods: Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell-based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride.

Results: At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p = .031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects.

Conclusions: These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy.

Keywords: Antipsychotics; Autoantibodies; Biomarkers; First-episode psychosis; Immunopsychiatry; NMDA receptor.

Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
(A) Positive and Negative Syndrome Scale (PANSS) subscale scores by serostatus. (B) Duration of psychosis at baseline. (C) Percentage change in PANSS score after 4 weeks of amisulpride treatment, by serostatus. Neg, negative; NMDAR, NMDA receptor; Pos, positive.

References

    1. Pearlman D.M., Najjar S. Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. Schizophr Res. 2014;157:249–258.
    1. Pollak T.A., McCormack R., Peakman M., Nicholson T.R., David A.S. Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: A systematic review and meta-analysis. Psychol Med. 2014;44:2475–2487.
    1. Jézéquel J., Johansson E.M., Dupuis J.P., Rogemond V., Gréa H., Kellermayer B. Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients. Nat Commun. 2017;8:1791.
    1. Jézéquel J., Rogemond V., Pollak T., Lepleux M., Jacobson L., Gréa H. 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. Biol Psychiatry. 2017;82:766–772.
    1. Dahm L., Ott C., Steiner J., Stepniak B., Teegen B., Saschenbrecker S. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol. 2014;76:82–94.
    1. Lejuste F., Thomas L., Picard G., Desestret V., Ducray F., Rogemond V. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016;3
    1. Punja M., Pomerleau A.C., Devlin J.J., Morgan B.W., Schier J.G., Schwartz M.D. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: An etiology worth considering in the differential diagnosis of delirium. Clin Toxicol (Phila) 2013;51:794–797.
    1. Graus F., Titulaer M.J., Balu R., Benseler S., Bien C.G., Cellucci T. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15:391–404.
    1. Zandi M.S., Deakin J.B., Morris K., Buckley C., Jacobson L., Scoriels L. 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.
    1. Scott J.G., Gillis D., Ryan A.E., Hargovan H., Gundarpi N., McKeon G. The prevalence and treatment outcomes of antineuronal antibody-positive patients admitted with first episode of psychosis. BJPsych Open. 2018;4:69–74.
    1. Kayser M.S., Dalmau J. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr Res. 2016;176:36–40.
    1. Ehrenreich H. Autoantibodies against the N-methyl-d-aspartate receptor subunit NR1: Untangling apparent inconsistencies for clinical practice. Front Immunol. 2017;8:181.
    1. Kahn R.S., Winter van Rossum I., Leucht S., McGuire P., Lewis S.W., Leboyer M. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): A three-phase switching study. Lancet Psychiatry. 2018;5:797–807.
    1. Kay S.R., Fiszbein A., Opler L.A. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–276.
    1. Addington D., Addington J., Schissel B. A depression rating scale for schizophrenics. Schizophr Res. 1990;3:247–251.
    1. Guy W. Rockwell: United States Department of Health, Education, and Welfare; 1976. ECDEU Assessment Manual for Psychopharmacology.
    1. Lingjaerde O., Ahlfors U.G., Bech P., Dencker S.J., Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1–100.
    1. Andreasen N.C., Carpenter W.T., Jr., Kane J.M., Lasser R.A., Marder S.R., Weinberger D.R. Remission in schizophrenia: Proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441–449.
    1. Souaiby L., Gauthier C., Kazes M., Mam-Lam-Fook C., Daban C., Plaze M. Individual factors influencing the duration of untreated psychosis. Early Interv Psychiatry. 2019;13:798–804.
    1. Broussard B., Kelley M.E., Wan C.R., Cristofaro S.L., Crisafio A., Haggard P.J. Demographic, socio-environmental, and substance-related predictors of duration of untreated psychosis (DUP) Schizophr Res. 2013;148:93–98.
    1. Pollak T.A., Kempton M.J., Iyegbe C., Vincent A., Irani S.R., Coutinho E. Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis [published online ahead of print Oct 19] Mol Psychiatry. 2020
    1. Fusar-Poli P., Cappucciati M., Borgwardt S., Woods S.W., Addington J., Nelson B. Heterogeneity of psychosis risk within individuals at clinical high risk: A meta-analytical stratification. JAMA Psychiatry. 2016;73:113–120.
    1. Zhang L., Sander J.W., Zhang L., Jiang X.Y., Wang W., Shuang K. Suicidality is a common and serious feature of anti-N-methyl-D-aspartate receptor encephalitis. J Neurol. 2017;264:2378–2386.
    1. Fusar-Poli P., Cappucciati M., Bonoldi I., Hui L.M., Rutigliano G., Stahl D.R. Prognosis of brief psychotic episodes: A meta-analysis. JAMA Psychiatry. 2016;73:211–220.
    1. Norli E.S., Brinkmann G.H., Kvien T.K., Bjørneboe O., Haugen A.J., Nygaard H. Self-limiting arthritis among patients fulfilling the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a very early arthritis cohort. Semin Arthritis Rheum. 2016;46:272–278.
    1. Pan H., Steixner-Kumar A.A., Seelbach A., Deutsch N., Ronnenberg A., Tapken D. Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: A translational study from chronic life stress to brain injury [published online ahead of print Feb 24] Mol Psychiatry. 2020
    1. Wenke N.K., Kreye J., Andrzejak E., van Casteren A., Leubner J., Murgueitio M.S. N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit. Ann Neurol. 2019;85:771–776.
    1. Pollak T.A., Lennox B.R., Müller S., Benros M.E., Prüss H., Tebartz van Elst L. Autoimmune psychosis: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7:93–108.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere