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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Research Article

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity

Author(s): Michael Maes*, Laura Andrés-Rodríguez, Aristo Vojdani, Sunee Sirivichayakul, Decio S. Barbosa and Buranee Kanchanatawan

Volume 22, Issue 2, 2023

Published on: 22 August, 2022

Page: [215 - 225] Pages: 11

DOI: 10.2174/1871527321666220806100600

Price: $65


Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic), which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs).

Aims: The study aims to examine whether FF symptoms in schizophrenia are associated with the breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial- (BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome.

Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods.

Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively), and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome, and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome.

Conclusion: The physio-somatic symptoms of schizophrenia are driven by various pathways, including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Keywords: Chronic fatigue syndrome, myalgic encephalomyelitis, oxidative stress, neuro-immune, inflammation, bacterial translocation.

Phanthunane P, Vos T, Whiteford H, Bertram M, Udomratn P. Schizophrenia in Thailand: Prevalence and burden of disease. Popul Health Metr 2010; 8: 24.
[] [PMID: 20712909]
Maes M, Vojdani A, Galecki P, Kanchanatawan B. How to construct a bottom-up nomothetic network model and disclose novel nosological classes by integrating risk resilience and adverse outcome pathways with the phenome of Schizophrenia. Brain Sci 2020; 10(9): 645.
[] [PMID: 32957709]
Maes M, Sirivichayakul S, Matsumoto AK, et al. Lowered antioxidant defenses and increased oxidative toxicity are hallmarks of deficit schizophrenia: A nomothetic network psychiatry approach. Mol Neurobiol 2020; 57(11): 4578-97.
[] [PMID: 32754898]
Stoyanov D, Maes MH. How to construct neuroscience-informed psychiatric classification? Towards nomothetic networks psychiatry. World J Psychiatry 2021; 11(1): 1-12.
[] [PMID: 33511042]
Almulla AF, Al-Hakeim HK, Maes M. Schizophrenia phenomenology revisited: Positive and negative symptoms are strongly related reflective manifestations of an underlying single trait indicating overall severity of schizophrenia. CNS Spectr 2020; 20: 1-10.
[] [PMID: 32431263]
Al-Hakeim HK, Almulla AF, Al-Dujaili AH, Maes M. Construction of a neuro-immune-cognitive pathway-phenotype underpinning the phenome of deficit Schizophrenia. Curr Top Med Chem 2020; 20(9): 747-58.
[] [PMID: 31994463]
Maes M, Kanchanatawan B. In (deficit) schizophrenia, a general cognitive decline partly mediates the effects of neuro-immune and neuro-oxidative toxicity on the symptomatome and quality of life. CNS Spectr 2021; 12: 1-10.
[] [PMID: 33843548]
Kanchanatawan B, Sriswasdi S, Maes M. Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophrenia. Metab Brain Dis 2019; 34(1): 267-82.
[] [PMID: 30467771]
Maes M, Vojdani A, Sirivichayakul S, Barbosa DS, Kanchanatawan B. Inflammatory and oxidative pathways are new drug targets in multiple episode schizophrenia and leaky gut, klebsiella pneumoniae, and C1q immune complexes are additional drug targets in first episode Schizophrenia. Mol Neurobiol 2021; 58(7): 3319-34.
[] [PMID: 33675500]
Kanchanatawan B, Sirivichayakul S, Thika S, et al. Physio-somatic symptoms in schizophrenia: Association with depression, anxiety, neurocognitive deficits and the tryptophan catabolite pathway. Metab Brain Dis 2017; 32(4): 1003-16.
[] [PMID: 28258445]
Almulla AF, Al-Hakeim HK, Abed MS, Carvalho AF, Maes M. Chronic fatigue and fibromyalgia symptoms are key components of deficit schizophrenia and are strongly associated with activated immune-inflammatory pathways. Schizophr Res 2020; 222: 342-53.
[] [PMID: 32467068]
Mousa RF, Al-Hakeim HK, Alhaideri A, Maes M. Chronic fatigue syndrome and fibromyalgia-like symptoms are an integral component of the phenome of schizophrenia: Neuro-immune and opioid system correlates. Metab Brain Dis 2021; 36(1): 169-83.
[] [PMID: 32965599]
Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG. A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res 2002; 52(6): 501-9.
[] [PMID: 12069875]
Kittirathanapaiboon P, Khamwongpin M. The Validity of the Mini International Neuropsychiatric Interview (MINI) Thai Version. Suanprung Hospital, Department of Mental Health 2005.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962; 10: 799-812.
Kay SR, Fiszbein A, Lindenmayer JP, Opler LA. Positive and negative syndromes in schizophrenia as a function of chronicity. Acta Psychiatr Scand 1986; 74(5): 507-18.
[] [PMID: 3492863]
Andreasen NC. The scale for the assessment of negative symptoms (SANS): Conceptual and theoretical foundations. Br J Psychiatry Suppl 1989; 7(7): 49-58.
[] [PMID: 2695141]
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62.
[] [PMID: 14399272]
Study protocol for the World Health Organization project to develop a Quality of Life assessment instrument (WHOQOL). Qual Life Res 1993; 2(2): 153-9.
[] [PMID: 8518769]
CANTAB. The most validated cognitive research software. 2018. Available from:
CERAD – An overview: The consortium to establish a registry for Alzheimer’s disease. 1986. Available from:
Maes M, Sirivichayakul S, Kanchanatawan B, Vodjani A. Upregulation of the intestinal paracellular pathway with breakdown of tight and adherens junctions in deficit Schizophrenia. Mol Neurobiol 2019; 56(10): 7056-73.
[] [PMID: 30972627]
Orellana G, Slachevsky A. Executive functioning in schizophrenia. Front Psychiatry 2013; 4: 35.
[] [PMID: 23805107]
Orellana G, Alvarado L. Muñoz-Neira C, Ávila R, Méndez MF, Slachevsky A. Psychosis-related matricide associated with a lesion of the ventromedial prefrontal cortex. J Am Acad Psychiatry Law 2013; 41(3): 401-6.
[PMID: 24051593]
Vojdani A, Vojdani E. Food-Associated Autoimmunities: When Food Breaks Your Immune System. A&G Wilshire, LLC 2019; p. 454.
Rudzki L, Maes M. The Microbiota-Gut-Immune-Glia (MGIG) axis in major depression. Mol Neurobiol 2020; 57(10): 4269-95.
Maes M, Delanghe J, Bocchio Chiavetto L, et al. Haptoglobin polymorphism and schizophrenia: Genetic variation on chromosome 16. Psychiatry Res 2001; 104(1): 1-9.
[] [PMID: 11600184]
Maes M, Delange J, Ranjan R, et al. Acute phase proteins in schizophrenia, mania and major depression: Modulation by psychotropic drugs. Psychiatry Res 1997; 66(1): 1-11.
[] [PMID: 9061799]
Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in Chronic Fatigue Syndrome (CFS): Indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord 2007; 99(1-3): 237-40.
[] [PMID: 17007934]
Maes M, Leunis JC. Normalization of leaky gut in Chronic Fatigue Syndrome (CFS) is accompanied by a clinical improvement: Effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuroendocrinol Lett 2008; 29(6): 902-10.
[PMID: 19112401]
Yang H, Wang H, Levine YA, et al. Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes. JCI Insight 2016; 1(7): e85375.
[] [PMID: 27294203]
Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5(4): 331-42.
[] [PMID: 15803152]
Festoff BW, Sajja RK, van Dreden P, Cucullo L. HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease. J Neuroinflammation 2016; 13(1): 194.
[] [PMID: 27553758]
Al-Dujaili AH, Mousa RF, Al-Hakeim HK, Maes M. High mobility group protein 1 and dickkopf-related protein 1 in Schizophrenia and treatment-resistant Schizophrenia: Associations with interleukin-6, symptom domains, and neurocognitive impairments. Schizophr Bull 2021; 47(2): 530-41.
[] [PMID: 32971537]
Morris G, Maes M. Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Med 2013; 11: 205.
[] [PMID: 24229326]
Bjørklund G, Dadar M, Pivina L, Doşa MD, Semenova Y, Maes M. Environmental, neuro-immune, and neuro-oxidative stress interactions in chronic fatigue syndrome. Mol Neurobiol 2020; 57(11): 4598-607.
[] [PMID: 32761353]
Stoyanov D, Aryutova K, Kandilarova S, et al. Diagnostic task specific activations in functional MRI and aberrant connectivity of insula with middle frontal gyrus can inform the differential diagnosis of psychosis. Diagnostics (Basel) 2021; 11(1): 95.
[] [PMID: 33435624]

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