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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

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Abstract

Breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways was established in (deficit) schizophrenia. The aim of this study was to delineate (a) the differences in these pathways between stable-phase, first (FES) and multiple (MES) episode schizophrenia and (b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS) deterioration in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum C1q circulating immune complexes (CIC), leaky gut, immune activation, and oxidative stress toxicity (OSTOX). We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES was associated with higher IgA CIC-C1q, IgA directed to cadherin, catenin, and plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria as compared with FES and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and IgA CIC-C1q formation, and MES, including immune and oxidative neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.

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Data Availability

The datasets generated during the current study will be made available from the corresponding author on reasonable request once the dataset has been fully exploited by the authors.

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Funding

This research has been supported by the Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project.

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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, Vic, Geelong, Australia

    Michael Maes

  4. Immunosciences Lab., Inc., Los Angeles, CA, USA

    Aristo Vojdani

  5. Cyrex Labs, LLC, Phoenix, AZ, USA

    Aristo Vojdani

  6. Department of Preventive Medicine, Loma Linda University, Loma Linda, CA, USA

    Aristo Vojdani

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

    Sunee Sirivichayakul

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

    Decio S. Barbosa

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Contributions

All the contributing authors have participated in the manuscript. MM and BK designed the study. BK recruited patients and completed diagnostic interviews and rating scale measurements. MM carried out the statistical analyses. SS and DC performed the biomarker assays. All authors contributed to interpretation of the data and writing of the manuscript.

Corresponding author

Correspondence to Michael Maes.

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Ethics Approval and Consent to Participate

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 (No. 298/57). All participants and their guardians (parents or other close family members) gave written informed consent prior to participation in this study.

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The authors declare no competing interests.

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Maes, M., Vojdani, A., Sirivichayakul, S. et al. 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 58, 3319–3334 (2021). https://doi.org/10.1007/s12035-021-02343-8

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