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Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: a Nomothetic Network Psychiatry Approach

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Abstract

There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: to compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (–SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, and total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n = 40) and non-deficit (n = 40) schizophrenia and healthy controls (n = 40). Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered –SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (odds ratio = 3.15, p < 0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, and IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas –SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. When overall severity of schizophrenia increases, multiple immune and oxidative (especially protein oxidation indicating chlorinative stress) neurotoxicities and impairments in immune-protective resilience become more prominent and shape a distinct nosological entity, namely deficit schizophrenia. The nomothetic network psychiatry approach allows building causal-pathway-phenotype models using machine learning techniques.

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Abbreviations

Th:

T helper

TRYCATs:

Tryptophan catabolites

IRS:

Immune-inflammatory response system

CIRS:

Compensatory immune regulatory system

IL:

Interleukin

sIL-1RA:

Soluble IL-1 receptor antagonist

TNF:

Tumor necrosis factor

PHEMN:

Psychosis, hostility, excitation, mannerism, negative symptoms

PA:

Picolinic acid

XA:

Xanthurenic acid

OSE:

Oxidative-specific epitopes

MDA:

Malondialdehyde

PON:

Paraoxonase

O&NS:

Oxidative and nitrosative stress

LOOH:

Lipid hydroperoxides

NOx:

Nitric oxide metabolites

TRAP:

Radical-trapping antioxidant parameter

AOPP:

Advanced oxidation protein products

–SH:

Thiol groups

SDS:

Schedule for Deficit Schizophrenia

PANSS:

Positive and Negative Syndrome Scale

SANS:

Scale for the Assessment of Negative Symptoms

PMR:

Psychomotor retardation

FTD:

Formal thought disorders

CERAD:

Consortium to Establish a Registry for Alzheimer’s Disease

CANTAB:

Cambridge Neuropsychological Test Automated Battery

WLM:

World List Memory test

VFT:

Verbal Fluency Test

MMSE:

Mini-Mental State Examination

SWM:

Spatial working memory

TUD:

Tobacco use disorder

BMI:

Body mass index

CMPA:

4-(Chloromethyl)phenyl acetate

AREase:

Arylesterase

3OSTOX:

Oxidative stress toxicity index

3ANTIOX:

Antioxidant index

3OHK:

3-OH-kynurenine

AA:

Anthranilic acid

KA:

Kynurenic acid

NOX/PRO:

Noxious/protective ratio

4PRORESIL:

Index of protective resilience against neuro-immune, neuro-oxidative, and bacterial stressors

8MITOTOX:

Index of multiple immune and oxidative toxicities

GLM:

Generalized linear model

FDR:

False discovery rate

PLS:

Partial least squares

AVE:

Average extracted variance

LV:

Latent vector

OSOS:

Overall severity of schizophrenia

CTD:

Confirmatory tetrad analysis

NNP:

Nomothetic network psychiatry

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Acknowledgements

We are thankful for the contribution of the Postgraduate Laboratory of the University Hospital of Londrina and research support given by Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project and Ratchadapiseksompotch Funds, Faculty of Medicine, Chulalongkorn University.

Authorships

BK and MM made the design of the study. BK recruited and screened the participants. MM performed statistical analyses. AKM, APM, LOS, JVLP, EGM, SS, and DSB performed the assays. AFC and MS contributed in a meaningful way to the intellectual content of this paper. All authors agreed upon the final version of the paper.

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).

Author information

Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, 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 & Andre F. Carvalho

  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. Department of Psychiatry, University of Toronto and Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada

    Andre F. Carvalho

  7. Neurosciences Department, University of Padua, Padua, Italy

    Marco Solmi

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  1. Michael Maes
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  2. Sunee Sirivichayakul
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  3. Andressa Keiko Matsumoto
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Correspondence to Michael Maes.

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The authors declare that they have no conflict of interest.

Ethical Statement

The study was approved by 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. Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: a Nomothetic Network Psychiatry Approach. Mol Neurobiol 57, 4578–4597 (2020). https://doi.org/10.1007/s12035-020-02047-5

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