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Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM Directed to Malondialdehyde and Paraoxonase 1 Activity

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A Correction to this article was published on 18 January 2022

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Abstract

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in a cross-sectional study that enrolled schizophrenia patients with (n = 40) and without (n = 40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial least squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), which lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA, and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

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Abbreviations

IL-6:

Interleukin-6

Th:

T helper

IDO:

Indoleamine-2,3-dioxygenase

TRYCATs:

Tryptophan catabolites

OSOS:

Overall severity of schizophrenia

PHEM:

Psychosis, hostility, excitation and mannerism

TNF:

Tumor necrosis factor

IFN:

Interferon

IRS:

Immune-inflammatory response system

CIRS:

Compensatory immune-regulatory system

sTNFR:

Soluble TNF receptor

sIL-1RA:

Soluble IL-1R antagonist

OSE:

Oxidative-specific epitope

PON:

Paraoxonase

MDA:

Malondialdehyde

SDS:

Schedule for the Deficit Schizophrenia

SANS:

Scale for the Assessment of Negative Symptoms

PANNS:

Positive and Negative Syndrome Scale

BPRS:

Brief Psychiatric Rating Scale

HDRS:

Hamilton Depression Rating Scale

FTD:

Formal thought disorders

PMR:

Psychomotor retardation

CERAD:

Consortium to Establish a Registry for Alzheimer’s Disease

CANTAB:

Cambridge Neuropsychological Test Automated Battery

MMSE:

Mini-Mental State Examination

VFT:

Verbal fluency test

WLM:

Word list memory

TUD:

Tobacco use disorder

BMI:

Body mass index

CMPA:

4-(Chloromethyl)phenyl acetate

AREase:

Aryl-esterase

FDR:

False discovery rate

PLS:

Partial least squares

LV:

Latent vector

ESF:

Electronic supplementary file

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Funding

The study was supported by the Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project and Ratchadapiseksompotch Funds, Faculty of Medicine, Chulalongkorn University, grant numbers RA60/042 (to BK) and RA61/050 (to MM). EGM is a senior fellow, Fundação Araucária (059/2019), Paraná, Brazil.

Author information

Authors and Affiliations

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

    Michael Maes & Buranee Kanchanatawan

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

    Michael Maes

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

    Michael Maes

  4. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Sunee Sirivichayakul

  5. Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil

    Andressa Keiko Matsumoto, Ana Paula Michelin, Laura de Oliveira Semeão, João Victor de Lima Pedrão, Estefania G. Moreira & Decio S. Barbosa

  6. Johnson and Johnson, Beerse, Belgium

    Annabel Maes

  7. Research Department, IDRPHT, Talence, France

    Michel Geffard

  8. Department of Psychiatry, University of Toronto and Centre for Addiction and Mental Health (CAMH), Bell Gateway Building, 100 Stokes Street, 4th Floor, Toronto, ON, M6J 1H4, Canada

    Andre F. Carvalho

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  1. Michael Maes
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Contributions

All the contributing authors have participated in the manuscript. All authors contributed to interpretation of the data and writing of the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Andre F. Carvalho.

Ethics declarations

All participants, as well as the guardians of patients (parents or other close family members), provided written informed consent to take part in the study. Approval for the study was obtained from the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (No 298/57), 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 on Good Clinical Practice (ICH-GCP).

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Maes, M., Sirivichayakul, S., Matsumoto, A.K. et al. Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM Directed to Malondialdehyde and Paraoxonase 1 Activity. Mol Neurobiol 57, 2333–2345 (2020). https://doi.org/10.1007/s12035-020-01882-w

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