Skip to main content

Advertisement

SpringerLink
Log in

Deficit Schizophrenia Is Characterized by Defects in IgM-Mediated Responses to Tryptophan Catabolites (TRYCATs): a Paradigm Shift Towards Defects in Natural Self-Regulatory Immune Responses Coupled with Mucosa-Derived TRYCAT Pathway Activation

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Deficit schizophrenia is accompanied by mucosa-associated activation of the tryptophan catabolite (TRYCAT) pathway, as indicated by increased IgA responses to noxious (NOX) TRYCATs, but not regulatory or protective (PRO) TRYCATs, suggesting increased neurotoxic, excitotoxic, inflammatory, and oxidative potential. No previous studies examined IgM-mediated autoimmune responses to the TRYCAT pathway in deficit versus nondeficit schizophrenia. We measured IgM responses to NOX TRYCATs, namely, quinolinic acid (QA), 3-OH-kynurenine (3HK), picolinic acid (PA), and xanthurenic (XA) acid, and PRO TRYCATs, including kynurenic acid (KA) and anthranilic acid (AA), in 40 healthy controls and 40 deficit and 40 nondeficit schizophrenic patients. We computed the IgM responses to NOX (QA + PA + 3HK + XA)/PRO (AA + KA) ratio and ∆ differences in IgA − IgM TRYCAT values and NOX/PRO ratio. Deficit schizophrenia is characterized by significantly attenuated IgM responses to all TRYCATs and NOX/PRO ratio and highly increased ∆IgA − IgM NOX/PRO ratio as compared to nondeficit schizophrenia and healthy controls. The negative symptoms of schizophrenia are significantly and positively associated with increased IgM responses directed against the KA/3HK ratio and ∆IgA − IgM NOX/PRO ratio. The findings support the view that deficit schizophrenia is a distinct subtype of schizophrenia that may be significantly discriminated from nondeficit schizophrenia. Deficit schizophrenia is accompanied by a highly specific defect in IgM isotype-mediated regulatory responses directed to the TRYCAT pathway. Lowered IgM regulatory responses together with mucosa-derived activation of the TRYCAT pathway may contribute to neuroprogression, negative symptoms, and deficit schizophrenia. All in all, a highly specific defect in the compensatory (anti-)inflammatory reflex system (CIRS), namely, natural IgM-mediated regulatory responses, may underpin deficit schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kanchanatawan B, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Ormstad H, Anderson G, Maes M (2017) Deficit, but not nondeficit, schizophrenia is characterized by mucosa-associated activation of the tryptophan catabolite (TRYCAT) pathway with highly specific increases in IgA responses directed to picolinic, xanthurenic and quinolinic acid. Mol Neurobiol

  2. Anderson G, Maes M (2013) Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Prog Neuro-Psychopharmacol Biol Psychiatry 42:5–19

    Article  CAS  Google Scholar 

  3. Morris G, Berk M, Carvalho A, Caso JR, Sanz Y, Walder K, Maes M (2016) The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmune disease. Mol Neurobiol 27

  4. Smith RS, Maes M (1995) The macrophage-T-lymphocyte theory of schizophrenia: additional evidence. Med Hypotheses 45:135–141

    Article  CAS  PubMed  Google Scholar 

  5. Noto C, Ota VK, Santoro ML, Ortiz BB, Rizzo LB, Higuchi CH, Cordeiro Q, Belangero SI et al (2015) Effects of depression on the cytokine profile in drug naïve first-episode psychosis. Schizophr Res 164:53–58

    Article  PubMed  Google Scholar 

  6. Noto C, Ota VK, Santoro ML, Gouvea ES, Silva PN, Spindola LM, Cordeiro Q, Bressan RA, Gadelha A, Brietzke E, Belangero SI, Maes M (2015) Depression, cytokine, and cytokine by treatment interactions modulate gene expression in antipsychotic naïve first episode psychosis. Mol Neurobiol Oct 22

  7. Noto C, Maes M, Ota VK, Teixeira AL, Bressan RA, Gadelha A, Brietzke E (2015) High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry 27:1–8

    Google Scholar 

  8. Flatow J, Buckley P, Miller BJ (2013) Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry 74:400–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldsmith DR, Rapaport MH, Miller BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia. bipolar disorder and depression Mol Psychiatry. doi:10.1038/mp.2016.3

    PubMed  Google Scholar 

  10. Kita T, Morrison PF, Heyes MP, Markey SP (2002) Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. J Neurochem 82:258–268

    Article  CAS  PubMed  Google Scholar 

  11. Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 48:512–529

    Article  PubMed  Google Scholar 

  12. Davis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, Debnath M, McGrath J et al (2016) A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis. Neurosci Biobehav Rev 65:185–194

    Article  PubMed  PubMed Central  Google Scholar 

  13. Carpenter WT Jr, Heinrichs DW, Wagman AM (1988) Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 145:578–583

    Article  PubMed  Google Scholar 

  14. Kirkpatrick B, Galderisi S (2008) Deficit schizophrenia: an update. World Psychiatry 7:143–147

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ahmed AO, Strauss GP, Buchanan RW, Kirkpatrick B, Carpenter WT (2015) Are negative symptoms dimensional or categorical? Detection and validation of deficit schizophrenia with Taxometric and latent variable mixture models. Schizophr Bull 41:879–891

    Article  PubMed  Google Scholar 

  16. Fischer BA, Keller WR, Arango C, Pearlson GD, McMahon RP, Meyer WA, Francis A, Kirkpatrick B et al (2012) Cortical structural abnormalities in deficit versus nondeficit schizophrenia. Schizophr Res 136:51–54

    Article  PubMed  PubMed Central  Google Scholar 

  17. Roomruangwong C, Kanchanatawan B, Carvalho AF, Sirivichayakul S, Duleu S, Geffard M, Maes M (2016) Body image dissatisfaction in pregnant and non-pregnant females is strongly predicted by immune activation and mucosa-derived activation of the tryptophan catabolite (TRYCAT) pathway. World J Biol Psychiatry 30:1–10

    Article  Google Scholar 

  18. Roomruangwong C, Kanchanatawan B, Sirivichayakul S, Anderson G, Carvalho AF,Duleu S, Geffard M, Maes M (2016) IgA/IgM responses to tryptophan and tryptophan catabolites (TRYCATs) are differently associated with prenatal depression, physio-somatic symptoms at the end of term and premenstrual syndrome. Mol Neurobiol Apr 1

  19. Duleu S, Mangas A, Sevin F, Veyret B, Bessede A, Geffard M (2010) Circulating antibodies to IDO/THO pathway metabolites in Alzheimer’s disease. Int J Alzheimers Dis 15; 2010

  20. Roomruangwong C, Kanchanatawan B, Sirivichayakul S, Anderson G, Carvalho AF, Duleu S, Geffard M, Maes M (2016). IgA/IgM responses to Gram-negative bacteria are not associated with prenatal depression, but with physio-somatic symptoms and activation of the tryptophan catabolite pathway at the end of term and postnatal anxiety. CNS Neurological Disorders – Drug Targets

  21. Severance EG, Prandovszky E, Castiglione J, Yolken RH (2015) Gastroenterology issues in schizophrenia: why the gut matters. Curr Psychiatry Rep 17:27

    Article  PubMed  PubMed Central  Google Scholar 

  22. Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, Tsuji NM, Nagakubo D et al (2009) Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. J Immunol 183:5608–5614

    Article  CAS  PubMed  Google Scholar 

  23. Cherayil BJ (2009) Indoleamine 2,3-dioxygenase in intestinal immunity and inflammation. Inflamm Bowel Dis 15:1391–1396

    Article  PubMed  Google Scholar 

  24. Maes M, Berk M, Goehler L, Song C, Anderson G, Gałecki P, Leonard B (2012) Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 10:66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maes M, Meltzer HY, Bosmans E (1994) Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand 89:346–351

    Article  CAS  PubMed  Google Scholar 

  26. Maes M, Meltzer HY, Buckley P, Bosmans E (1995) Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 244:325–329

    Article  CAS  PubMed  Google Scholar 

  27. Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W, Scharpé S (1997) Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 66:1–11

    Article  CAS  PubMed  Google Scholar 

  28. Borovcanin M, Jovanovic I, Radosavljevic G, Djukic Dejanovic S, Bankovic D, Arsenijevic N, Lukic ML (2012) Elevated serum level of type-2 cytokine and low IL-17 in first episode psychosis and schizophrenia in relapse. J Psychiatr Res 46:1421–1426

    Article  PubMed  Google Scholar 

  29. Stahl D, Sibrowski W (2003) Regulation of the immune response by natural IgM: lessons from warm autoimmune hemolytic anemia. Curr Pharm Des 9:1871–1880

    Article  CAS  PubMed  Google Scholar 

  30. Maes M, Mihaylova I, Leunis JC (2006) Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett 27:615–621

    CAS  PubMed  Google Scholar 

  31. Schwartz-Albiez R, Monteiro RC, Rodriguez M, Binder CJ, Shoenfeld Y (2009) Natural antibodies, intravenous immunoglobulin and their role in autoimmunity, cancer and inflammation. Clin Exp Immunol 158(Suppl 1):43–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127:344–354

    Article  CAS  PubMed  Google Scholar 

  33. Maes M, Kubera M, Mihaylova I, Geffard M, Galecki P, Leunis JC, Berk M (2013) Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: implications for the pathways to chronic depression and neuroprogression. J Affect Disord 149:23–29

    Article  CAS  PubMed  Google Scholar 

  34. Maes M, Leunis JC (2014) Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in myalgic encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett 35:577–585

    CAS  PubMed  Google Scholar 

  35. Kittirathanapaiboon P, Khamwongpin M (2005) The validity of the Mini International Neuropsychiatric Interview (M.I.N.I.) Thai version: Suanprung Hospital, Department of Mental Health

  36. Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT Jr (1989) The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res 30:119–123

    Article  CAS  PubMed  Google Scholar 

  37. Andreasen NC (1989) The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl 7:49–758

    Google Scholar 

  38. Kay SR, Fiszbein A, Opler LA (1986) Negative Symptom Rating Scale: limitations in psychometric and research methodology. Psychiatry Res 19:169–173

    Article  CAS  PubMed  Google Scholar 

  39. Overall JE, Gorham DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10:799–812

    Article  Google Scholar 

  40. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO (1991) The Fagerström test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict 86:1119–1127

    Article  CAS  PubMed  Google Scholar 

  41. Lim CK, Brew BJ, Sundaram G, Guillemin GJ (2010) Understanding the roles of the kynurenine pathway in multiple sclerosis progression. Int J Tryptophan Res 3:157–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jhamandas K, Boegman RJ, Beninger RJ, Bialik M (1990) Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites. Brain Res 529:185–191

    Article  CAS  PubMed  Google Scholar 

  43. Behan WM, Stone TW (2002) Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists. Br J Pharmacol 135:1435–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maes M, Mihaylova I, Ruyter MD, Kubera M, Bosmans E (2007) The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression and other conditions characterized by tryptophan depletion induced by inflammation. Neuro Endocrinol Lett 28:826–831

    CAS  PubMed  Google Scholar 

  45. Anderson G, Ojala J (2010) Alzheimer’s and seizures: interleukin-18, indoleamine 2,3-dioxygenase and quinolinic acid. Int J Tryptophan Res 3:169–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bosco MC, Rapisarda A, Massazza S, Melillo G, Young H, Varesio L (2000) The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and −1 beta in macrophages. J Immunol 164:3283–3291

    Article  CAS  PubMed  Google Scholar 

  47. Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ (2009) Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res 16:77–86

    Article  CAS  PubMed  Google Scholar 

  48. Majláth Z, Török N, Toldi J, Vécsei L (2016) Memantine and kynurenic acid: current neuropharmacological aspects. Curr Neuropharmacol 14:200–209

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lugo-Huitrón R, Blanco-Ayala T, Ugalde-Muñiz P, Carrillo-Mora P, Pedraza-Chaverrí J, Silva-Adaya D, Maldonado PD, Torres I et al (2011) On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol Teratol 33:538–547

    Article  PubMed  Google Scholar 

  50. Rio GF, Silva BV, Martinez ST, Pinto AC (2015) Anthranilic acids from isatin: an efficient, versatile and environmentally friendly method. An Acad Bras Cienc 87:1525–1529

    Article  PubMed  Google Scholar 

  51. García-Lara L, Pérez-Severiano F, González-Esquivel D, Elizondo G, Segovia J (2015) Absence of aryl hydrocarbon receptors increases endogenous kynurenic acid levels and protects mouse brain against excitotoxic insult and oxidative stress. J Neurosci Res 93:1423–1433

    Article  PubMed  Google Scholar 

  52. Trecartin KV, Bucci DJ (2011) Administration of kynurenine during adolescence, but not during adulthood, impairs social behavior in rats. Schizophr Res 133:156–158

    Article  PubMed  PubMed Central  Google Scholar 

  53. Iaccarino HF, Suckow RF, Xie S, Bucci DJ (2013) The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: implications for schizophrenia. Schizophr Res 150:392–397

    Article  PubMed  Google Scholar 

  54. Boullerne A, Petry KG, Geffard M (1996) Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. J Neuroimmunol 65:75–81

    Article  CAS  PubMed  Google Scholar 

  55. Boullerne AI, Petry KG, Meynard M, Geffard M (1995) Indirect evidence for nitric oxide involvement in multiple sclerosis by characterization of circulating antibodies directed against conjugated S-nitrosocysteine. J Neuroimmunol 60:117–124

    Article  CAS  PubMed  Google Scholar 

  56. Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R (2011) The new “5-HT” hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 35:702–721

    Article  CAS  Google Scholar 

  57. Lee M, Jayathilake K, Dai J, Meltzer HY (2011) Decreased plasma tryptophan and tryptophan/large neutral amino acid ratio in patients with neuroleptic-resistant schizophrenia: relationship to plasma cortisol concentration. Psychiatry Res 185:328–333

    Article  CAS  PubMed  Google Scholar 

  58. Walsh MJ, Tourtellotte WW, Potvin AR (1983) Central nervous system immunoglobulin synthesis in neurological disease. Chapter 19: Neurobiology of Cerebrospinal Fluid 2. Editors: Wood, James H. (Ed.) 331–368

  59. Deardorff WJ, Shobassy A, Grossberg GT (2015) Safety and clinical effects of EVP-6124 in subjects with Alzheimer’s disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev Neurother 15:7–17

    Article  CAS  PubMed  Google Scholar 

  60. Marder SR (2016) Alpha-7 nicotinic agonist improves cognition in schizophrenia. Evid Based Ment Health 19:60

    Article  PubMed  Google Scholar 

  61. Koola MM (2016) Kynurenine pathway and cognitive impairments in schizophrenia: pharmacogenetics of galantamine and memantine. Schizophr Res Cogn 4:4–9

    Article  PubMed  PubMed Central  Google Scholar 

  62. Erhardt S, Schwieler L, Imbeault S, Engberg G (2016) The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology

  63. Sommansson A, Nylander O, Sjöblom M (2013) Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo. J Pineal Res 54:282–291

    Article  CAS  PubMed  Google Scholar 

  64. Markus RP, Silva CL, Franco DG, Barbosa EM Jr, Ferreira ZS (2010) Is modulation of nicotinic acetylcholine receptors by melatonin relevant for therapy with cholinergic drugs? Pharmacol Ther 126:251–262

    Article  CAS  PubMed  Google Scholar 

  65. Anderson G, Maes M (2014) Local melatonin regulates inflammation resolution: a common factor in neurodegenerative, psychiatric and systemic inflammatory disorders. CNS Neurol Disord Drug Targets 13:817–827

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research has been supported by the Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project, and IDRPHT, Talence and Gemac, Saint Jean d’Illac, France.

Author’s Contributions

All contributing authors have participated in the manuscript. MM and BK designed the study. BK recruited and clinically examined cases and controls. All authors contributed to interpretation of the data and writing of the manuscript. MM carried out the statistical analyses.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Buranee Kanchanatawan & Michael Maes

  2. Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Sunee Sirivichayakul & Kiat Ruxrungtham

  3. Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil

    André F. Carvalho

  4. IDRPHT, Research Department, Talence, France

    Michel Geffard

  5. GEMAC, Saint Jean d’Illac, France

    Michel Geffard

  6. CRC Scotland & London, Eccleston Square, London, UK

    George Anderson

  7. IMPACT Strategic Research Center, Deakin University, Geelong, Australia

    Michael Maes

  8. Department of Psychiatry, Faculty of Medicine, State University of Londrina, Londrina, Brazil

    Michael Maes

  9. Revitalis, Waalre, The Netherlands

    Michael Maes

  10. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

Authors
  1. Buranee Kanchanatawan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sunee Sirivichayakul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kiat Ruxrungtham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. André F. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michel Geffard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. George Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Maes.

Ethics declarations

All participants, controls and patients, provided written informed consent prior to participation in this study. The study was conducted according to Thai and international ethics and privacy laws. Approval for the study was obtained from the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, which is in compliance with the International Guideline for Human Research protection as required by the Declaration of Helsinki, The Belmont Report, CIOMS Guideline, and International Conference on Harmonization in Good Clinical Practice (ICH-GCP).

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanchanatawan, B., Sirivichayakul, S., Ruxrungtham, K. et al. Deficit Schizophrenia Is Characterized by Defects in IgM-Mediated Responses to Tryptophan Catabolites (TRYCATs): a Paradigm Shift Towards Defects in Natural Self-Regulatory Immune Responses Coupled with Mucosa-Derived TRYCAT Pathway Activation. Mol Neurobiol 55, 2214–2226 (2018). https://doi.org/10.1007/s12035-017-0465-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0465-y

Keywords

Search

Navigation