Skip to main content Accessibility help

Prevalence of anti-N-methyl-d-aspartate (NMDA) receptor antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis

  • T. A. Pollak (a1) (a2), R. McCormack (a1) (a2), M. Peakman (a3) (a4), T. R. Nicholson (a2) and A. S. David (a2)...

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a ‘purely’ psychotic illness without overt neurological symptoms.


We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis.


Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69–9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94–2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used.


A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.

Corresponding author
* Address for correspondence: Dr T. A. Pollak, Section of Cognitive Neuropsychiatry, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. (Email:
Hide All
Adams, RA, Stephan, KE, Brown, HR, Frith, CD, Friston, KJ (2013). The computational anatomy of psychosis. Frontiers in Psychiatry 4, 47.
Bamne, M, Wood, J, Chowdari, K, Watson, AM, Celik, C, Mansour, H, Klei, L, Gur, RC, Bradford, LD, Calkins, ME, Santos, AB, Edwards, N, Kwentus, J, McEvoy, JP, Allen, TB, Savage, RM, Nasrallah, HA, Gur, RE, Perry, RT, Go, RC, Devlin, B, Yolken, R, Nimgaonkar, VL (2012). Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure. Schizophrenia Bulletin 38, 11491154.
Bechter, K (2013). Updating the mild encephalitis hypothesis of schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 42, 7191.
Benros, ME, Mortensen, PB, Eaton, WW (2012). Autoimmune diseases and infections as risk factors for schizophrenia. Annals of the New York Academy of Sciences 1262, 5666.
Benros, ME, Nielsen, PR, Nordentoft, M, Eaton, WW, Dalton, SO, Mortensen, PB (2011). Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. American Journal of Psychiatry 168, 13031310.
Blomstrom, A, Karlsson, H, Wicks, S, Yang, S, Yolken, RH, Dalman, C (2012). Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring – a matched case-control study. Schizophrenia Research 140, 2530.
Bokesch, PM, Izykenova, GA, Justice, JB, Easley, KA, Dambinova, SA (2006). NMDA receptor antibodies predict adverse neurological outcome after cardiac surgery in high-risk patients. Stroke 37, 14321436.
Cahalan, S (2012). Brain On Fire: My Month of Madness. Particular Books: London.
Carroll, BT, Goforth, HW, Thomas, C, Ahuja, N, McDaniel, WW, Kraus, MF, Spiegel, DR, Franco, KN, Pozuelo, L, Munoz, C (2007). Review of adjunctive glutamate antagonist therapy in the treatment of catatonic syndromes. Journal of Neuropsychiatry and Clinical Neurosciences 19, 406412.
Choe, CU, Karamatskos, E, Schattling, B, Leypoldt, F, Liuzzi, G, Gerloff, C, Friese, MA, Mulert, C (2013). A clinical and neurobiological case of IgM NMDA receptor antibody associated encephalitis mimicking bipolar disorder. Psychiatry Research 208, 194196.
Corlett, PR, Honey, GD, Krystal, JH, Fletcher, PC (2011). Glutamatergic model psychoses: prediction error, learning, and inference. Neuropsychopharmacology 36, 294315.
Correll, CM (2013). Antibodies in epilepsy. Current Neurology and Neuroscience Reports 13, 348.
Creten, C, van der Zwaan, S, Blankespoor, RJ, Maatkamp, A, Nicolai, J, van Os, J, Schieveld, JN (2011). Late onset autism and anti-NMDA-receptor encephalitis. Lancet 378, 98.
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, 10911098.
Dalmau, J, Tuzun, E, Wu, HY, Masjuan, J, Rossi, JE, Voloschin, A, Baehring, JM, Shimazaki, H, Koide, R, King, D, Mason, W, Sansing, LH, Dichter, MA, Rosenfeld, MR, Lynch, DR (2007). Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Annals of Neurology 61, 2536.
Daniels, J (2009). Catatonia: clinical aspects and neurobiological correlates. Journal of Neuropsychiatry and Clinical Neurosciences 21, 371380.
Demjaha, A, Murray, RM, McGuire, PK, Kapur, S, Howes, OD (2012). Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. American Journal of Psychiatry 169, 12031210.
Dickerson, F, Stallings, C, Origoni, A, Vaughan, C, Katsafanas, E, Khushalani, S, Yolken, R (2013). A combined marker of inflammation in individuals with mania. PLoS One 8, e73520.
Dickerson, F, Stallings, C, Vaughan, C, Origoni, A, Khushalani, S, Yolken, R (2012). Antibodies to the glutamate receptor in mania. Bipolar Disorders 14, 547553.
Egerton, A, Brugger, S, Raffin, M, Barker, GJ, Lythgoe, DJ, McGuire, PK, Stone, JM (2012). Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 37, 25152521.
Fink, M (2013). Rediscovering catatonia: the biography of a treatable syndrome. Acta Psychiatrica Scandinavica. Supplementum 441, 147.
Finke, C, Kopp, UA, Pruss, H, Dalmau, J, Wandinger, KP, Ploner, CJ (2012). Cognitive deficits following anti-NMDA receptor encephalitis. Journal of Neurology, Neurosurgery and Psychiatry 83, 195198.
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 (2013). Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Molecular Psychiatry. Published online: 3 September 2013 . doi:10.1038/mp.2013.110.
Haussleiter, IS, Emons, B, Schaub, M, Borowski, K, Brune, M, Wandinger, KP, Juckel, G (2012). Investigation of antibodies against synaptic proteins in a cross-sectional cohort of psychotic patients. Schizophrenia Research 140, 258259.
Henneberg, AE, Horter, S, Ruffert, S (1994). Increased prevalence of antibrain antibodies in the sera from schizophrenic patients. Schizophrenia Research 14, 1522.
Hughes, EG, Peng, X, Gleichman, AJ, Lai, M, Zhou, L, Tsou, R, Parsons, TD, Lynch, DR, Dalmau, J, Balice-Gordon, RJ (2010). Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. Journal of Neuroscience 30, 58665875.
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 (2010). N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133, 16551667.
Kanbayashi, T, Tsutsui, K, Tanaka, K, Boku, S, Ito, W, Imanishi, A, Suda, H, Takahashi, J, Inomata, Y, Takeshima, M, Kosaka, M, Yaegashi, K, Yuasa, W, Mori, A, Nishino, S, Takahashi, Y, Shimizu, T (2012). Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. Paper presented at the 21st Congress of the European Sleep Research Society, Paris, France, 48 September 2012.
Kanbayashi, T, Tsutsui, K, Tanaka, K, Ito, W, Boku, S, Sagawa, Y, Tokunaga, J, Sato, M, Nishino, S, Shimizu, T (2011). Anti-NMDA receptor antibody positive patients with various psychiatric and sleep symptoms. Paper presented at the Sleep and Biological Rhythms Conference, Worldsleep2011, Kyoto, Japan, 1620 October 2011.
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. Journal of the American Medical Association Neurology 70, 11331139.
Khandaker, GM, Zimbron, J, Dalman, C, Lewis, G, Jones, PB (2012). Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. Schizophrenia Research 139, 161168.
Khandaker, GM, Zimbron, J, Lewis, G, Jones, PB (2013). Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychological Medicine 43, 239257.
Kinon, BJ, Zhang, L, Millen, BA, Osuntokun, OO, Williams, JE, Kollack-Walker, S, Jackson, K, Kryzhanovskaya, L, Jarkova, N (2011). A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. Journal of Clinical Psychopharmacology 31, 349355.
Lancaster, E, Dalmau, J (2012). Neuronal autoantigens – pathogenesis, associated disorders and antibody testing. Nature Reviews. Neurology 8, 380390.
Lauvsnes, MB, Omdal, R (2012). Systemic lupus erythematosus, the brain, and anti-NR2 antibodies. Journal of Neurology 259, 622629.
Lennox, BR, Coles, AJ, Vincent, A (2012). Antibody-mediated encephalitis: a treatable cause of schizophrenia. British Journal of Psychiatry 200, 9294.
Lennox, BR, Deakin, J, Zandi, M, Scoriels, L, Cox, A, Coles, A, Vincent, A (2013). Anti neuronal cell surface antibodies as a cause of schizophrenia. Schizophrenia Bulletin 39 (Suppl. 1), S1S358. Abstracts for the 14th International Congress on Schizophrenia Research (ICOSR), S6.
Leweke, FM, Gerth, CW, Koethe, D, Klosterkotter, J, Ruslanova, I, Krivogorsky, B, Torrey, EF, Yolken, RH (2004). Antibodies to infectious agents in individuals with recent onset schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 254, 48.
Liu, J, Moghaddam, B (1995). Regulation of glutamate efflux by excitatory amino acid receptors: evidence for tonic inhibitory and phasic excitatory regulation. Journal of Pharmacology and Experimental Therapeutics 274, 12091215.
Mackay, G, Ahmad, K, Stone, J, Sudlow, C, Summers, D, Knight, R, Will, R, Irani, SR, Vincent, A, Maddison, P (2012). NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease. Journal of Neurology 259, 19791981.
Manto, M, Dalmau, J, Didelot, A, Rogemond, V, Honnorat, J (2010). In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet Journal of Rare Diseases 5, 31.
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, 11201121.
Moghaddam, B, Adams, BW (1998). Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 13491352.
Moghaddam, B, Javitt, D (2012). From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37, 415.
Moscato, EH, Jain, A, Peng, X, Hughes, EG, Dalmau, J, Balice-Gordon, RJ (2010). Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies. European Journal of Neuroscience 32, 298309.
Muller, N, Myint, AM, Krause, D, Weidinger, E, Schwarz, MJ (2013). Anti-inflammatory treatment in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 42, 146153.
Na, KS, Jung, HY, Kim, YK (2012). The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. Published online: 1 November 2012 . doi:10.1016/j.pnpbp.2012.10.022.
Northoff, G (2002). What catatonia can tell us about ‘top-down modulation’: a neuropsychiatric hypothesis. Behavioral and Brain Sciences 25, 555577; discussion 578–604.
Obregon, DF, Velasco, RM, Wuerz, TP, Catalano, MC, Catalano, G, Kahn, D (2011). Memantine and catatonia: a case report and literature review. Journal of Psychiatric Practice 17, 292299.
Papanastasiou, E, Stone, JM, Shergill, S (2013). When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia. British Journal of Psychiatry 202, 9193.
Pollak, TA, Lennox, BR, Vincent, A, Nicholson, TR (2012). Antibody-mediated encephalitis and psychosis. British Journal of Psychiatry 200, 344; author reply 344–345.
Pruss, H, Holtje, M, Maier, N, Gomez, A, Buchert, R, Harms, L, Ahnert-Hilger, G, Schmitz, D, Terborg, C, Kopp, U, Klingbeil, C, Probst, C, Kohler, S, Schwab, JM, Stoecker, W, Dalmau, J, Wandinger, KP (2012). IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology 78, 17431753.
Punja, M, Pomerleau, AC, Devlin, JJ, Morgan, BW, Schier, JG, Schwartz, MD (2013). Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clinical Toxicology 51, 794797.
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, 213214.
Ribbe, K, Friedrichs, H, Begemann, M, Grube, S, Papiol, S, Kastner, A, Gerchen, MF, Ackermann, V, Tarami, A, Treitz, A, Flogel, M, Adler, L, Aldenhoff, JB, Becker-Emner, M, Becker, T, Czernik, A, Dose, M, Folkerts, H, Freese, R, Gunther, R, Herpertz, S, Hesse, D, Kruse, G, Kunze, H, Franz, M, Lohrer, F, Maier, W, Mielke, A, Muller-Isberner, R, Oestereich, C, Pajonk, FG, Pollmacher, T, Schneider, U, Schwarz, HJ, Kroner-Herwig, B, Havemann-Reinecke, U, Frahm, J, Stuhmer, W, Falkai, P, Brose, N, Nave, KA, Ehrenreich, H (2010). The cross-sectional GRAS sample: a comprehensive phenotypical data collection of schizophrenic patients. BMC Psychiatry 10, 91.
Rolls, ET, Deco, G (2011). A computational neuroscience approach to schizophrenia and its onset. Neuroscience and Biobehavioral Reviews 35, 16441653.
Rowland, LM, Bustillo, JR, Mullins, PG, Jung, RE, Lenroot, R, Landgraf, E, Barrow, R, Yeo, R, Lauriello, J, Brooks, WM (2005). Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. American Journal of Psychiatry 162, 394396.
Scott, O, Richer, L, Forbes, K, Sonnenberg, L, Currie, A, Eliyashevska, M, Goez, HR (2013). Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis: an unusual cause of autistic regression in a toddler. Journal of Child Neurology. Published online: 3 October 2013 . doi:10.1177/0883073813501875.
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. Journal of the American Medical Association Psychiatry 70, 271278.
Stone, JM, Dietrich, C, Edden, R, Mehta, MA, De Simoni, S, Reed, LJ, Krystal, JH, Nutt, D, Barker, GJ (2012). Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Molecular Psychiatry 17, 664665.
Titulaer, MJ, McCracken, L, Gabilondo, I, Armangue, T, Glaser, C, Iizuka, T, Honig, LS, Benseler, SM, Kawachi, I, Martinez-Hernandez, E, Aguilar, E, Gresa-Arribas, N, Ryan-Florance, N, Torrents, A, Saiz, A, Rosenfeld, MR, Balice-Gordon, R, Graus, F, Dalmau, J (2013). Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurology 12, 157165.
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.
Vitaliani, R, Mason, W, Ances, B, Zwerdling, T, Jiang, Z, Dalmau, J (2005). Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Annals of Neurology 58, 594604.
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, 8691.
Weissman, JD, Khunteev, GA, Heath, R, Dambinova, SA (2011). NR2 antibodies: risk assessment of transient ischemic attack (TIA)/stroke in patients with history of isolated and multiple cerebrovascular events. Journal of the Neurological Sciences 300, 97102.
Wright, P, Nimgaonkar, VL, Donaldson, PT, Murray, RM (2001). Schizophrenia and HLA: a review. Schizophrenia Research 47, 112.
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, 686688.
Zhang, Q, Tanaka, K, Sun, P, Nakata, M, Yamamoto, R, Sakimura, K, Matsui, M, Kato, N (2012). Suppression of synaptic plasticity by cerebrospinal fluid from anti-NMDA receptor encephalitis patients. Neurobiology of Disease 45, 610615.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed