Schizophrenia Phenomenology Comprises a Bifactorial General Severity and a Single-group Factor, Which Are Differently Associated with Neurotoxic Immune and Immune-regulatory Pathways

Abstract

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR).Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity.The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors.We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia ("OSOS"); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated).Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:Recently, we established that, in stable phase schizophrenia, positive and negative symptoms cannot be considered to be two different dimensions because one single latent trait (latent vector) underlies both symptom domains and other key symptoms of schizophrenia, including formal thought disorders (disorders in concrete and abstract thought processes, including loosed associations, fluid thinking, illogical and disorganized thinking) and psychomotor retardation (including slow movements and motor responses and aberrations in gross and fine motor performance) [11,12]. Moreover, we established that positive and negative symptom domains are Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: Neurocognitive and Symptom Correlates

“…on the 6 OS variables (even without FDR correction). In previous studies using the same study sample we showed that there were no significant effects of the drug state on the other biomarkers listed in table 1 [4,11]. Table 4 shows significant logistic regression models predicting deficit schizophrenia using different biomarkers sets.…”

“…Moreover, these OSTOX/ANTIOX biomarkers explained a large part of the variance in a general factor extracted from the symptom domains and neurocognitive tests, reflecting OSOS. As reported previously, this single latent trait is essentially unidimensional and underpins the key domains of schizophrenia which are, therefore, manifestations of this common underlying construct [4][5][6]36]. This latent OSOS factor, which reflects the late phenome of schizophrenia, indicates disorders in neuronal circuits including in the "prefronto-striato-thalamic, prefrontoparietal, prefronto-temporal, and dorsolateral prefrontal cortex, as well as hippocampus and amygdala" [4,5,81,82].…”

“…The same IRS/CIRS theory proposed that the combined neurotoxic effects of IRS/CIRS products such as IL-1β, IL-6, IL-4, TNF-α, CCL2, CCL11, and TRYCATs may cause neuroprogression (damage to neuronal functions including neuroplasticity, synaptic sampling, neurogenesis, neurotransmission and apoptotic processes) thereby inducing impairments in episodic and semantic memory and executive functions and schizophrenia symptom domains including psychosis, hostility, excitation, mannerism and negative (PHEMN) symptoms, psychomotor retardation and formal thought disorders [3][4][5][6].…”

“…While different schizophrenia subtypes (including first-episode psychosis, acute schizophrenic episodes, and chronic schizophrenia) show activated IRS and CIRS pathways, one of the subtypes, namely deficit schizophrenia, is characterized by an overwhelmingly activated IRS coupled with severe deficits in CIRS functions [7][8][9][10][11]. The latter phenotype is characterized (as compared with non-deficit schizophrenia and healthy controls) by increased neurotoxicity through elevated IL-1β, TNF-α and CCL11 levels, and signs of breakdown of gut-paracellular and vascular pathways as well as the blood-brain-barrier, increased bacterial translocation with increased IgA/IgM levels to LPS of Gram-negative bacteria, and increased IgA responses to neurotoxic TRYCATs including picolinic and xanthurenic acid [4,6,9,[11][12][13]. Moreover, deficit schizophrenia is also characterized by severe deficits in the CIRS including a) lowered natural IgM-mediated responses to multiple oxidative specific epitopes (OSEs) especially malondialdehyde and azelaic acid [10], which are produced by innate-like B1 and marginal zone B cells and, as a component of the innate immune system, have anti-inflammatory, housekeeping anti-bacterial functions [10,14]; b) lowered IgM responses to TRYCATs [15], and c) lowered activity of paraoxonase 1 (PON1) activity, a strong antioxidant enzyme that is part of innate immunity and has anti-inflammatory and anti-bacterial activities [16].…”

In Schizophrenia, Depression and Anxiety Symptoms Are Driven by Immune-Inflammatory Pathways.

“…Schizophrenia is a chronic mental illness affecting around 1% of the world population (Janoutová et al, 2016). Schizophrenia is characterized by a symptomatome (defined as the aggregate of symptoms) comprising psychotic symptoms, hostility, excitation, mannerism (PHEM), negative symptoms, psychomotor retardation (PMR), and formal thought disorders (FTD) (Maes et al, 2019b;Almulla et al, 2020b;Maes et al, 2020b). In fact, the symptomatome of schizophrenia should be conceptualized as a single latent trait extracted from all those symptom domains, which reflect overall severity of symptoms of schizophrenia (OSOS) (Maes et al, 2020b).…”