Development of a Novel Staging Model for Affective Disorders Using Partial Least Squares Bootstrapping: Effects of Lipid-Associated Antioxidant Defenses and Neuro-Oxidative Stress

Maes, Michaël; Moraes, Juliana Brum; Congio, Ana; Bonifácio, Kamila Landucci; Barbosa, Décio Sabbatini; Vargas, Heber Odebrecht; Michelin, Ana Paula; Carvalho, André F.; Nunes, Sandra Odebrecht Vargas

doi:10.1007/s12035-019-1552-z

Cited by 64 publications

(83 citation statements)

References 109 publications

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“…In this regard, epilepsy per se is accompanied by a neurocognitive decline (42). In patients with schizophrenia reduced PON1 activity is strongly associated with neurocognitive deficits (37) while in mood disorders lowered PON1 status is associated with staging of the disorder, which is characterized by increased neurocognitive deficits (43).…”

Section: Discussionmentioning

confidence: 99%

“…Our study indicates that genetically determined decreases in PON1 CMPAase activity as well as lowered PON1 enzyme activities, which occur independently from PON1 genotype, may be causally related to TLE and its psychiatric comorbidities. As such, alterations in CMPAase and PON1 activities, which are secondary to oxidative stressors (25,43) or environmental factors including nutritional factors and smoking may also be involved (25). Interestingly, tobacco use, which lowers PON1 activity, is associated with focal or generalized seizures (44,45) indicating that chemicals in tobacco smoke may have pro-convulsive effects (46).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Borowczyk et al (49) reported that PON1 may hydrolyze homocysteine thiolactone, a toxic metabolite that is capable of inducing epileptic seizures in rats and is implicated in neurodegenerative disorders. Importantly, in oxidative stress conditions, PON1 may be damaged by increased MPO activity and elevated production of peroxynitrite and hypochlorous acid, leading to lowered antioxidant defenses and thus an increased vulnerability to oxidation of LDL and HDL, which in turn will lower the protective effects of HDL (43). Therefore, a well-functioning antioxidant system is important to prevent lipid peroxidation and conditions characterized by PON1 gene-associated decreases in PON1 activity (like TLE and MTS) are accompanied by increased risk to develop lipid oxidation.…”

Section: Discussionmentioning

confidence: 99%

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Lowered Paraoxonase 1 Activities May Explain the Comorbidities Between Temporal Lobe Epilepsy or Mesial Temporal Sclerosis and Comorbid Depression, Anxiety and Psychosis

Michelin¹,

Maes²,

Supasitthumrong³

et al. 2020

Preprint

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Background: Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase (PON)1 status may occur in TLE and those psychiatric conditions. Methods: We examined paraoxonase (PON)1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in 40 normal controls and 104 TLE patients, 27 without comorbidities, and 77 with comorbidities including mood disorders (n=25), anxiety disorders (n=27) and psychosis (n=25). Outcomes: CMPAase and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than in normal controls. The areas under the ROC curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (±0.037) for MTS. Partial Least Squares (PLS) path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (p<0.0001) and psychopathology (p<0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination scores. Interpretation: The severity of TLE and comorbidities are to a large extent explained by lowered PON1 enzyme activities and by effects of the Q192R genotype which are mediated by lowered CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Lowered Paraoxonase 1 Activities May Explain the Comorbidities Between Temporal Lobe Epilepsy or Mesial Temporal Sclerosis and Comorbid Depression, Anxiety and Psychosis

Michelin¹,

Maes²,

Supasitthumrong³

et al. 2020

Preprint

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“…As such, the learned nomothetic network models objectivate the symptomatome and phenomenome of mental illness and translate causome and AOP data into clinical psychiatric scores using computer science, a process called reification (Stoyanov, 2020). Figure 1 shows a comprehensive mood disorder model based on causal reasoning and previously reported results on the causome, AOPs, and phenome (including staging) in MDD, BP1, and BP2 (Maes et al, 2018;2019a;2019b;2019c;Moreira et al, 2019a;2019b;Nunes et al, 2018;Moraes et al, 2018;Maes and Carvalho, 2018;Sowa-Kucma et al, 2018a;2018b;Siwek et al, 2017). Evidence shows that increased reactive oxygen and nitrogen species (RONS) and nitrooxidative toxicity (NOSTOX) and associated neuro-immune activation are key AOPs in mood disorders (Maes et al, 2010;2011;Maes et al, 2018;2019a;2019b;2019c).…”

Section: Introductionmentioning

confidence: 98%

Towards A New Model and Classification of Mood Disorders based on Risk Resilience, Neuro-Affective Toxicity, Staging, and Phenome Features Using the Nomothetic Network Psychiatry Approach

Maes¹,

Brum²,

Bonifácio³

et al. 2020

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Current diagnoses of mood disorders are not cross validated. The aim of the current paper is to explain how machine learning techniques can be used to a) construct a model which ensembles risk/resilience (R/R), adverse outcome pathways (AOPs), staging, and the phenome of mood disorders, and b) disclose new classes based on these feature sets. This study was conducted using data of 67 healthy controls and 105 mood disordered patients. The R/R ratio, assessed as a combination of the paraoxonase 1 (PON1) gene, PON1 enzymatic activity, and early life time trauma (ELT), predicted the high-density lipoprotein cholesterol – paraoxonase 1 complex (HDL-PON1), reactive oxygen and nitrogen species (RONS), nitro-oxidative stress toxicity (NOSTOX), staging (number of depression and hypomanic episodes and suicidal attempts), and phenome (the Hamilton Depression and Anxiety scores and the Clinical Global Impression; current suicidal ideation; quality of life and disability measurements) scores. Partial Least Squares pathway analysis showed that 44.2% of the variance in the phenome was explained by ELT, RONS/NOSTOX, and staging scores. Cluster analysis conducted on all those feature sets discovered two distinct patient clusters, namely 69.5% of the patients were allocated to a class with high R/R, RONS/NOSTOX, staging, and phenome scores, and 30.5% to a class with increased staging and phenome scores. This classification cut across the bipolar (BP1/BP2) and major depression disorder classification and was more distinctive than the latter classifications. We constructed a nomothetic network model which reunited all features of mood disorders into a mechanistically transdiagnostic model.

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“…A recent meta-analysis in MDD and BD shows lowered levels of key antioxidants and total antioxidant capacity and overall disruption of oxidative stress pathways in patients with MDD versus healthy controls (Liu et al, 2015). MDD and BP1 patients may show increased oxidative and nitrosative stress as compared to controls and BP2 patients while the latter group does not appear to differ from controls (Maes et al, 2019a;2019b).…”

Section: Introductionmentioning

confidence: 99%

Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia is Present

Simeonova

Stoyanov

Leunis³

et al. 2019

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Major depression (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis. Gut dysbiosis may occur in bipolar disorder (BD) and there are differences between MDD and BD type 1 (BP1) and -2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria in 29 BP1, 37 BP2, 44 MDD and 30 healthy individuals. MDD plus BD was best discriminated from controls by increased IgM/IgA responses to Pseudomonas aeruginosa. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses, especially C. koseri. IgG responses to oxidized low-density lipoprotein were significantly associated with signs of increased bacterial translocation. In conclusion, not only MDD but also BP1 and BP2 are accompanied by an immune response due to the increased load of plasma LPS of gut commensal bacteria while these aberrations in the gut-brain axis are most pronounced in BP1 and patients with melancholic features. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.

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Development of a Novel Staging Model for Affective Disorders Using Partial Least Squares Bootstrapping: Effects of Lipid-Associated Antioxidant Defenses and Neuro-Oxidative Stress

Cited by 64 publications

References 109 publications

Lowered Paraoxonase 1 Activities May Explain the Comorbidities Between Temporal Lobe Epilepsy or Mesial Temporal Sclerosis and Comorbid Depression, Anxiety and Psychosis

Lowered Paraoxonase 1 Activities May Explain the Comorbidities Between Temporal Lobe Epilepsy or Mesial Temporal Sclerosis and Comorbid Depression, Anxiety and Psychosis

Towards A New Model and Classification of Mood Disorders based on Risk Resilience, Neuro-Affective Toxicity, Staging, and Phenome Features Using the Nomothetic Network Psychiatry Approach

Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia is Present

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