Publications by authors named "Michael Maes"

576 Publications

Differential aberrant connectivity of precuneus and anterior insula may underpin the diagnosis of schizophrenia and mood disorders.

World J Psychiatry 2021 Dec 19;11(12):1274-1287. Epub 2021 Dec 19.

Psychiatry and Medical Psychology, Medical University, Plovdiv 4002, Bulgaria.

Background: Over the past decade, resting-state functional magnetic resonance imaging (rs-fMRI) has concentrated on brain networks such as the default mode network (DMN), the salience network (SN), and the central executive network (CEN), allowing for a better understanding of cognitive deficits observed in mental disorders, as well as other characteristic psychopathological phenomena such as thought and behavior disorganization.

Aim: To investigate differential patterns of effective connectivity across distributed brain networks involved in schizophrenia (SCH) and mood disorders.

Methods: The sample comprised 58 patients with either paranoid syndrome in the context of SCH ( = 26) or depressive syndrome (Ds) ( = 32), in the context of major depressive disorder or bipolar disorder. The methods used include rs-fMRI and subsequent dynamic causal modeling to determine the direction and strength of connections to and from various nodes in the DMN, SN and CEN.

Results: A significant excitatory connection from the dorsal anterior cingulate cortex to the anterior insula (aI) was observed in the SCH patient group, whereas inhibitory connections from the precuneus to the ventrolateral prefrontal cortex and from the aI to the precuneus were observed in the Ds group.

Conclusion: The results delineate specific patterns associated with SCH and Ds and offer a better explanation of the underlying mechanisms of these disorders, and inform differential diagnosis and precise treatment targeting.
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http://dx.doi.org/10.5498/wjp.v11.i12.1274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717032PMC
December 2021

Intersections between Copper, β-Arrestin-1, Calcium, FBXW7, CD17, Insulin Resistance and Atherogenicity Mediate Depression and Anxiety Due to Type 2 Diabetes Mellitus: A Nomothetic Network Approach.

J Pers Med 2022 Jan 1;12(1). Epub 2022 Jan 1.

Department of Psychiatry, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria.

Type 2 diabetes mellitus (T2DM) is frequently accompanied by affective disorders with a prevalence of comorbid depression of around 25%. Nevertheless, the biomarkers of affective symptoms including depression and anxiety due to T2DM are not well established. The present study delineated the effects of serum levels of copper, zinc, β-arrestin-1, FBXW7, lactosylceramide (LacCer), serotonin, calcium, magnesium on severity of depression and anxiety in 58 men with T2DM and 30 healthy male controls beyond the effects of insulin resistance (IR) and atherogenicity. Severity of affective symptoms was assessed using the Hamilton Depression and Anxiety rating scales. We found that 61.7% of the variance in affective symptoms was explained by the multivariate regression on copper, β-arrestin-1, calcium, and IR coupled with atherogenicity. Copper and LacCer (positive) and calcium and BXW7 (inverse) had significant specific indirect effects on affective symptoms, which were mediated by IR and atherogenicity. Copper, β-arrestin-1, and calcium were associated with affective symptoms above and beyond the effects of IR and atherogenicity. T2DM and affective symptoms share common pathways, namely increased atherogenicity, IR, copper, and β-arrestin-1, and lowered calcium, whereas copper, β-arrestin-1, calcium, LacCer, and FBXW7 may modulate depression and anxiety symptoms by affecting T2DM.
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http://dx.doi.org/10.3390/jpm12010023DOI Listing
January 2022

In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach.

Mol Psychiatry 2022 Jan 12. Epub 2022 Jan 12.

Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil.

In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, intersections among the rs10754558 variant, age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.
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http://dx.doi.org/10.1038/s41380-021-01431-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752583PMC
January 2022

In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach.

Mol Psychiatry 2022 Jan 12. Epub 2022 Jan 12.

Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil.

In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, intersections among the rs10754558 variant, age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.
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http://dx.doi.org/10.1038/s41380-021-01431-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752583PMC
January 2022

Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost-utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study).

BMJ Open 2022 Jan 6;12(1):e055351. Epub 2022 Jan 6.

Teaching, Research & Innovation Unit, Parc Sanitari Sant Joan de Déu, St. Boi de Llobregat, Spain

Introduction: There is evidence that low-dose naltrexone (LDN; <5.0 mg/day) reduces pain and improves the quality of life of people with fibromyalgia syndrome (FMS). However, no randomised controlled trials with long-term follow-ups have been carried out. The INNOVA study will evaluate the add-on efficacy, safety, cost-utility and neurobiological effects of LDN for reducing pain in patients with FMS, with a 1-year follow-up.

Methods And Analysis: A single-site, prospective, randomised, double-blinded, placebo-controlled, parallel design phase III trial will be performed. Eligibility criteria include being adult, having a diagnosis of FMS and experiencing pain of 4 or higher on a 10-point numerical rating scale. Participants will be randomised to a LDN intervention group (4.5 mg/day) or to a placebo control group. Clinical assessments will be performed at baseline (T0), 3 months (T1), 6 months (T2) and 12 months (T3). The primary endpoint will be pain intensity. A sample size of 60 patients per study arm (120 in total), as calculated prior to recruitment for sufficient power, will be monitored between January 2022 and August 2024. Assessment will also include daily ecological momentary evaluations of FMS-related symptoms (eg, pain intensity, fatigue and sleep disturbance), and side effects via ecological momentary assessment through the Pain Monitor app during the first 3 months. Costs and quality-adjusted life years will be also calculated. Half of the participants in each arm will be scanned with MRI at T0 and T1 for changes in brain metabolites related to neuroinflammation and central sensitisation. Inflammatory biomarkers in serum will also be measured.

Ethics And Dissemination: This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and community engagement activities.

Trial Registration Number: NCT04739995.
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http://dx.doi.org/10.1136/bmjopen-2021-055351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739052PMC
January 2022

The collaborative outcomes study on health and functioning during infection times in adults (COH-FIT-Adults): Design and methods of an international online survey targeting physical and mental health effects of the COVID-19 pandemic.

J Affect Disord 2022 02 19;299:393-407. Epub 2021 Jul 19.

University of Padua, Neurosciences Department, Padua, Italy. Electronic address:

Background: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed.

Methods: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others.

Results: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive.

Limitations: . Cross-sectional survey, preponderance of non-representative participants.

Conclusions: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics.
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http://dx.doi.org/10.1016/j.jad.2021.07.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288233PMC
February 2022

Exploring interleukin-6, lipopolysaccharide-binding protein and brain-derived neurotrophic factor following 12 weeks of adjunctive minocycline treatment for depression.

Acta Neuropsychiatr 2021 Dec 23:1-8. Epub 2021 Dec 23.

IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia.

This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.
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http://dx.doi.org/10.1017/neu.2021.44DOI Listing
December 2021

Leukocyte telomere length is not shortened in methamphetamine dependence or methamphetamine-induced psychosis but is increased following traumatic events.

World J Biol Psychiatry 2022 Jan 7:1-9. Epub 2022 Jan 7.

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

Objective: This study aims to examine the effects of methamphetamine (MA) use and dependence and MA withdrawal symptoms on the telomere length and whether shortening of the latter is associated with MA-induced psychosis (MIP).

Methods: This study included 185 MA-abuse, 118 MA-dependent, and 67 MIP patients, diagnosed using DSM-IV criteria. The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) questionnaire was employed to collect MA-related data. MIP was confirmed using the Methamphetamine Experience Questionnaire (MEQ). The leukocyte telomere length was measured using real-time polymerase chain reaction measuring the Telomere/Single gene ratio (T/S ratio). Data were analysed using multivariate statistical analyses.

Results: There were no significant associations between the T/S ratio and severity of MA-use, MIP, and MA withdrawal symptoms. MIP was significantly predicted by alcohol dependence, antisocial personality disorder, and MA-use severity. There were significantly positive associations between the T/S ratio and previous traumatic and life-threatening events. The T/S ratio was not affected by alcohol and nicotine dependence. Alcohol and nicotine dependence, antisocial personality disorder, and severity of MA use increased risk of MA withdrawal symptoms.

Conclusion: MIP and MA-use severity are not associated with leukocyte telomere length, but previous traumatic and life-threatening events are associated with increased telomere length.
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http://dx.doi.org/10.1080/15622975.2021.2016957DOI Listing
January 2022

Effective Connectivity between Major Nodes of the Limbic System, Salience and Frontoparietal Networks Differentiates Schizophrenia and Mood Disorders from Healthy Controls.

J Pers Med 2021 Oct 28;11(11). Epub 2021 Oct 28.

Department of Psychiatry and Medical Psychology and Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria.

This study was conducted to examine whether there are quantitative or qualitative differences in the connectome between psychiatric patients and healthy controls and to delineate the connectome features of major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BD), as well as the severity of these disorders. Toward this end, we performed an effective connectivity analysis of resting state functional MRI data in these three patient groups and healthy controls. We used spectral Dynamic Causal Modeling (spDCM), and the derived connectome features were further subjected to machine learning. The results outlined a model of five connections, which discriminated patients from controls, comprising major nodes of the limbic system (amygdala (AMY), hippocampus (HPC) and anterior cingulate cortex (ACC)), the salience network (anterior insula (AI), and the frontoparietal and dorsal attention network (middle frontal gyrus (MFG), corresponding to the dorsolateral prefrontal cortex, and frontal eye field (FEF)). Notably, the alterations in the self-inhibitory connection of the anterior insula emerged as a feature of both mood disorders and SCZ. Moreover, four out of the five connectome features that discriminate mental illness from controls are features of mood disorders (both MDD and BD), namely the MFG→FEF, HPC→FEF, AI→AMY, and MFG→AMY connections, whereas one connection is a feature of SCZ, namely the AMY→SPL connectivity. A large part of the variance in the severity of depression (31.6%) and SCZ (40.6%) was explained by connectivity features. In conclusion, dysfunctions in the self-regulation of the salience network may underpin major mental disorders, while other key connectome features shape differences between mood disorders and SCZ, and can be used as potential imaging biomarkers.
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http://dx.doi.org/10.3390/jpm11111110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623155PMC
October 2021

First Episode Psychosis and Schizophrenia Are Systemic Neuro-Immune Disorders Triggered by a Biotic Stimulus in Individuals with Reduced Immune Regulation and Neuroprotection.

Cells 2021 10 28;10(11). Epub 2021 Oct 28.

Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory systems (CIRS) and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AN-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of FES. However, the protein-protein interaction (PPI) network of FEP/FES is not established. The aim of the current study was to delineate a) the characteristics of the PPI network of AN-FEP and its transition to FES; and b) the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. Toward this end, we used PPI network, enrichment, and annotation analyses. FEP and FEP/FES are strongly associated with a response to a bacterium, alterations in Toll-Like Receptor-4 and nuclear factor-κB signaling, and the Janus kinases/signal transducer and activator of the transcription proteins pathway. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation, and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation, in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin and Wnt/catenin signaling, and adherens junction organization. Multiple interactions between reduced brain derived neurotrophic factor, E-cadherin, and β-catenin and disrupted schizophrenia-1 (DISC1) expression increase the vulnerability to the neurotoxic effects of immune molecules, including cytokines and complement factors. In summary: FEP and FES are systemic neuro-immune disorders that are probably triggered by a bacterial stimulus which induces neuro-immune toxicity cascades that are overexpressed in people with reduced anti-inflammatory and miRNA protections, cell-cell junction organization, and neurotrophin and Wnt/catenin signaling.
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http://dx.doi.org/10.3390/cells10112929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616258PMC
October 2021

New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses.

Int J Mol Sci 2021 Nov 9;22(22). Epub 2021 Nov 9.

Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Londrina, Paraná 86057-970, Brazil.

This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of , , , , , , , and . Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches and . Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with , , , , , , , and pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that , and were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1.
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http://dx.doi.org/10.3390/ijms222212108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619767PMC
November 2021

Exploring the Impact of Flavonoids on Symptoms of Depression: A Systematic Review and Meta-Analysis.

Antioxidants (Basel) 2021 Oct 20;10(11). Epub 2021 Oct 20.

Department of Medicine and Health Sciences "V. Tiberio", University of Molise, 86100 Campobasso, Italy.

Recent evidence suggests that diet modifies key biological factors associated with the development of depression. It has been suggested that this could be due to the high flavonoid content commonly found in many plant foods, beverages and dietary supplements. Our aim was to conduct a systematic review to evaluate the effects of dietary flavonoids on the symptoms of depression. A total of 46 studies met the eligibility criteria. Of these, 36 were intervention trials and 10 were observational studies. A meta-analysis of 36 clinical trials involving a total of 2788 participants was performed. The results showed a statistically significant effect of flavonoids on depressive symptoms (mean difference = -1.65; 95% C.I., -2.54, -0.77; < 0.01). Five of the 10 observational studies included in the systematic review reported significant results, suggesting that a higher flavonoid intake may improve symptoms of depression. Further studies are urgently required to elucidate whether causal and mechanistic links exist, along with substantiation of functional brain changes associated with flavonoid consumption.
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http://dx.doi.org/10.3390/antiox10111644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615051PMC
October 2021

Intertwined associations between oxidative and nitrosative stress and endocannabinoid system pathways: Relevance for neuropsychiatric disorders.

Prog Neuropsychopharmacol Biol Psychiatry 2022 Mar 24;114:110481. Epub 2021 Nov 24.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria. Electronic address:

The endocannabinoid system (ECS) appears to regulate metabolic, cardiovascular, immune, gastrointestinal, lung, and reproductive system functions, as well as the central nervous system. There is also evidence that neuropsychiatric disorders are associated with ECS abnormalities as well as oxidative and nitrosative stress pathways. The goal of this mechanistic review is to investigate the mechanisms underlying the ECS's regulation of redox signalling, as well as the mechanisms by which activated oxidative and nitrosative stress pathways may impair ECS-mediated signalling. Cannabinoid receptor (CB)1 activation and upregulation of brain CB2 receptors reduce oxidative stress in the brain, resulting in less tissue damage and less neuroinflammation. Chronically high levels of oxidative stress may impair CB1 and CB2 receptor activity. CB1 activation in peripheral cells increases nitrosative stress and inducible nitric oxide (iNOS) activity, reducing mitochondrial activity. Upregulation of CB2 in the peripheral and central nervous systems may reduce iNOS, nitrosative stress, and neuroinflammation. Nitrosative stress may have an impact on CB1 and CB2-mediated signalling. Peripheral immune activation, which frequently occurs in response to nitro-oxidative stress, may result in increased expression of CB2 receptors on T and B lymphocytes, dendritic cells, and macrophages, reducing the production of inflammatory products and limiting the duration and intensity of the immune and oxidative stress response. In conclusion, high levels of oxidative and nitrosative stress may compromise or even abolish ECS-mediated redox pathway regulation. Future research in neuropsychiatric disorders like mood disorders and deficit schizophrenia should explore abnormalities in these intertwined signalling pathways.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110481DOI Listing
March 2022

Biogeography of the large intestinal mucosal and luminal microbiome in cynomolgus macaques with depressive-like behavior.

Mol Psychiatry 2021 Nov 1. Epub 2021 Nov 1.

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Most previous studies in the pathophysiology of major depressive disorder (MDD) focused on fecal samples, which limit the identification of the gut mucosal and luminal microbiome in depression. Here, we address this knowledge gap. Male cynomolgus macaques (Macaca fascicularis) were randomly assigned to a chronic unpredictable mild stress (CUMS) group, or to an unstressed control group. Behavioral tests were completed in both groups. At endpoint, microbe composition of paired mucosal and luminal samples from cecum, ascending, transverse, and descending colons were determined by 16S ribosomal RNA gene sequencing. The levels of 34 metabolites involved in carbohydrate or energy metabolism in luminal samples were measured by targeted metabolomics profiling. CUMS macaques demonstrated significantly more depressive-like behaviors than controls. We found differences in mucosal and luminal microbial composition between the two groups, which were characterized by Firmicutes and Bacteriodetes at the phylum level, as well as Prevotellaceae and Lachnospiraceae at the family level. The majority of discriminative microbes correlated with the depressive-like behavioral phenotype. In addition, we found 27 significantly different microbiome community functions between the two groups in mucosa, and one in lumen, which were mainly involved in carbohydrate and energy metabolism. A total of nine metabolites involved in these pathways were depleted in CUMS animals. Together, CUMS macaques with depressive-like behaviors associated with distinct alterations of covarying microbiota, carbohydrate and energy metabolism in mucosa and lumen. Further studies should focus on the mucosal and luminal microbiome to provide a deeper spatiotemporal perspective of microbial alterations in the pathogenesis of MDD.
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http://dx.doi.org/10.1038/s41380-021-01366-wDOI Listing
November 2021

Adverse childhood experiences combined with emotional and physical abuse by the partner predict antenatal depression.

J Affect Disord 2022 02 27;298(Pt A):194-201. Epub 2021 Oct 27.

Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

Background: Few studies examined the contributions of childhood adversities, intimate partner violence and social support to antenatal depression (AD). This study aims to 1) evaluate association of these psychosocial factors with AD symptoms in pregnancy; and 2) examine the mediating effect of social support on the relationship between psychosocial stressors and AD symptoms.

Methods: Participants were 120 pregnant women aged from 18 to 49 in less than 16 gestational weeks and attending at Antenatal Care Center at Khon Kaen hospital, Thailand. AD symptoms were assessed by the Edinburgh Postnatal Depression Scale (EPDS). Childhood adversities, intimate partner violence and social support were measured using the Adverse Childhood Experiences Questionnaire (ACE questionnaire), Abuse Assessment Screen (AAS), and Multidimensional Scale of Perceived Social Support (MSPSS).

Results: We found that the EPDS score was significantly and positively associated with adverse childhood experiences (ACEs) and negatively with social support. Partial Least Square analysis showed that 49.1% of the variance in the depressive subdomain of the EPDS score was predicted by ACEs, namely psychological and physical abuse and neglect, emotional or physical abuse by the partner, unplanned pregnancy, and no satisfaction with their relationship. The effects of adverse childhood experience due to neglect on the EDPS score was mediated by social support by friends.

Limitations: ACEs were assessed retrospectively and, therefore, may be susceptible to recall bias.

Conclusion: Prenatal depression scores are to a large extent predicted by psychological distress as indicated by early lifetime trauma, abuse by partner, relation satisfaction, and implications of unintended pregnancy.
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http://dx.doi.org/10.1016/j.jad.2021.10.099DOI Listing
February 2022

Intersections between pneumonia, lowered oxygen saturation percentage and immune activation mediate depression, anxiety, and chronic fatigue syndrome-like symptoms due to COVID-19: A nomothetic network approach.

J Affect Disord 2022 01 24;297:233-245. Epub 2021 Oct 24.

School of Medicine, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, Deakin University, Barwon Health, Geelong, Australia; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria; Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Electronic address:

Background: COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like and physiosomatic symptoms.

Aims: To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest computed tomography scan anomalies (CCTAs), oxygen saturation (SpO), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs).

Method: The above biomarkers were assessed in 60 COVID-19 patients and 30 healthy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales.

Results: Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. One common "infection-immune-inflammatory (III) core" underpins pneumonia-associated CCTAs, lowered SpO and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms.

Discussion: Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO which may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.jad.2021.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541833PMC
January 2022

Physical and mental health impact of COVID-19 on children, adolescents, and their families: The Collaborative Outcomes study on Health and Functioning during Infection Times - Children and Adolescents (COH-FIT-C&A).

J Affect Disord 2022 02 2;299:367-376. Epub 2021 Oct 2.

University of Padua, Neurosciences Department, Padua, Italy. Electronic address:

Background: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial.

Methods: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life.

Results: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries.

Limitations: Cross-sectional and anonymous design.

Conclusions: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth.
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http://dx.doi.org/10.1016/j.jad.2021.09.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486586PMC
February 2022

Wnt/β-catenin pathway proteins in end-stage renal disease.

Biomark Med 2021 10 23;15(15):1423-1434. Epub 2021 Sep 23.

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

To delineate the association of end-stage renal disease (ESRD) and Wnt-proteins including the agonist R-spondin-1, the transducer β-catenin and the antagonists DKK1 and sclerostin. Serum Wnt-pathway proteins levels were measured by ELISA in 60 ESRD patients and 30 normal controls. DKK1 and sclerostin were significantly higher in ESRD than in controls, and β-catenin and the catenin + R-spondin-1/DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer on antagonists (AT/ANTA), were significantly lower in ESRD. Estimated glomerular filtration rate was significantly associated with DKK1 and sclerostin (inversely), β-catenin (positively) and the AT/ANTA ratio (r = 0.468, p < 0.001). Wnt/β-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists.
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http://dx.doi.org/10.2217/bmm-2021-0177DOI Listing
October 2021

Wnt/β-catenin pathway proteins in end-stage renal disease.

Biomark Med 2021 10 23;15(15):1423-1434. Epub 2021 Sep 23.

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

To delineate the association of end-stage renal disease (ESRD) and Wnt-proteins including the agonist R-spondin-1, the transducer β-catenin and the antagonists DKK1 and sclerostin. Serum Wnt-pathway proteins levels were measured by ELISA in 60 ESRD patients and 30 normal controls. DKK1 and sclerostin were significantly higher in ESRD than in controls, and β-catenin and the catenin + R-spondin-1/DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer on antagonists (AT/ANTA), were significantly lower in ESRD. Estimated glomerular filtration rate was significantly associated with DKK1 and sclerostin (inversely), β-catenin (positively) and the AT/ANTA ratio (r = 0.468, p < 0.001). Wnt/β-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists.
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http://dx.doi.org/10.2217/bmm-2021-0177DOI Listing
October 2021

Wnt/β-catenin pathway proteins in end-stage renal disease.

Biomark Med 2021 10 23;15(15):1423-1434. Epub 2021 Sep 23.

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

To delineate the association of end-stage renal disease (ESRD) and Wnt-proteins including the agonist R-spondin-1, the transducer β-catenin and the antagonists DKK1 and sclerostin. Serum Wnt-pathway proteins levels were measured by ELISA in 60 ESRD patients and 30 normal controls. DKK1 and sclerostin were significantly higher in ESRD than in controls, and β-catenin and the catenin + R-spondin-1/DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer on antagonists (AT/ANTA), were significantly lower in ESRD. Estimated glomerular filtration rate was significantly associated with DKK1 and sclerostin (inversely), β-catenin (positively) and the AT/ANTA ratio (r = 0.468, p < 0.001). Wnt/β-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists.
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http://dx.doi.org/10.2217/bmm-2021-0177DOI Listing
October 2021

Immune, Blood Cell, and Blood Gas Biomarkers of Delirium in Elderly Individuals with Hip Fracture Surgery.

Dement Geriatr Cogn Disord 2021 22;50(2):161-169. Epub 2021 Jul 22.

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

Background: Postoperative delirium in elderly people with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive.

Objectives: The aim of this study was to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers.

Methods: In this prospective study, we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit, Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete blood count and venous blood gas markers were obtained at the same time points.

Results: Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium.

Conclusion: Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process.
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http://dx.doi.org/10.1159/000517510DOI Listing
December 2021

Carotid intima media thickness measurements coupled with stroke severity strongly predict short-term outcome in patients with acute ischemic stroke: a machine learning study.

Metab Brain Dis 2021 Oct 4;36(7):1747-1761. Epub 2021 Aug 4.

Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil.

Acute ischemic stroke (IS) is one of the leading causes of morbidity, functional disability and mortality worldwide. The objective was to evaluate IS risk factors and imaging variables as predictors of short-term disability and mortality in IS. Consecutive 106 IS patients were enrolled. We examined the accuracy of IS severity using the National Institutes of Health Stroke Scale (NIHSS), carotid intima-media thickness (cIMT) and carotid stenosis (both assessed using ultrasonography with doppler) predicting IS outcome assessed with the modified Rankin scale (mRS) three months after hospital admission. Poor prognosis (mRS ≥ 3) at three months was predicted by carotid stenosis (≥ 50%), type 2 diabetes mellitus and NIHSS with an accuracy of 85.2% (sensitivity: 90.2%; specificity: 81.8%). The mRS score at three months was strongly predicted by NIHSS (β = 0.709, p < 0.001). Short-term mortality was strongly predicted using a neural network model with cIMT (≥ 1.0 mm versus < 1.0 mm), NIHSS and age, yielding an area under the receiving operator characteristic curve of 0.977 and an accuracy of 94.7% (sensitivity: 100.0%; specificity: 90.9%). High NIHSS (≥ 15) and cIMT (≥ 1.0 mm) increased the probability of dying with hazard ratios of 7.62 and 3.23, respectively. Baseline NIHSS was significantly predicted by the combined effects of age, large artery atherosclerosis stroke, sex, cIMT, body mass index, and smoking. In conclusion, high values of cIMT and NIHSS at admission strongly predict short-term functional impairment as well as mortality three months after IS, underscoring the importance of those measurements to predict clinical IS outcome.
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http://dx.doi.org/10.1007/s11011-021-00784-7DOI Listing
October 2021

Use of the Montreal Cognitive Assessment Thai Version to Discriminate Amnestic Mild Cognitive Impairment from Alzheimer's Disease and Healthy Controls: Machine Learning Results.

Dement Geriatr Cogn Disord 2021 29;50(2):183-194. Epub 2021 Jul 29.

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

Background: The Montreal Cognitive Assessment (MoCA) is an effective and applicable screening instrument to confirm the diagnosis of amnestic mild cognitive impairment (aMCI) from patients with Alzheimer's disease (AD) and healthy controls (HCs).

Objectives: This study aimed to determine the reliability and validity of the following: (a) Thai translation of the MoCA (MoCA-Thai) and (b) delineate the key features of aMCI based on the MoCA subdomains.

Methods: This study included 60 HCs, 61 aMCI patients, and 60 AD patients. The MoCA-Thai shows adequate psychometric properties including internal consistency, concurrent validity, test-retest validity, and inter-rater reliability.

Results: The MoCA-Thai may be employed as a diagnostic criterion to make the diagnosis of aMCI, whereby aMCI patients are discriminated from HC with an area under the receiver-operating characteristic (AUC-ROC) curve of 0.813 and from AD patients with an AUC-ROC curve of 0.938. The best cutoff scores of the MoCA-Thai to discriminate aMCI from HC is ≤24 and from AD > 16. Neural network analysis showed that (a) aberrations in recall was the most important feature of aMCI versus HC with impairments in language and orientation being the second and third most important features and (b) aberrations in visuospatial skills and executive functions were the most important features of AD versus aMCI and that impairments in recall, language, and orientation but not attention, concentration, and working memory, further discriminated AD from aMCI.

Conclusions: The MoCA-Thai is an appropriate cognitive assessment tool to be used in the Thai population for the diagnosis of aMCI and AD.
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http://dx.doi.org/10.1159/000517822DOI Listing
December 2021

Increased nitro-oxidative toxicity in association with metabolic syndrome, atherogenicity and insulin resistance in patients with affective disorders.

J Affect Disord 2021 11 18;294:410-419. Epub 2021 Jul 18.

Health Sciences Graduation Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil. Electronic address:

Background: There is a strong comorbidity between mood disorders and metabolic syndrome (MetS). Increased levels of reactive oxygen and nitrogen species (RONS) and nitro-oxidative stress toxicity (NOSTOX) partially underpin this comorbidity.

Aims: To examine the associations of RONS/NOSTOX biomarkers with MetS after adjusting for the significant effects of mood disorders (major depression, and bipolar type 1 and 2), generalized anxiety disorder (GAD), tobacco use disorder (TUD), and male sex.

Methods: The study included subjects with (n=65) and without (n=107) MetS and measured levels of superoxide dismutase 1 (SOD1), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) and computed z unit-weighted composite scores which reflect RONS/NOSTOX. The study included 105 patients with mood disorders, 46 with GAD, and 95 with TUD.

Results: MetS was associated with increased levels of MDA and AOPP, independently from mood disorders, TUD, sex and GAD. Atherogenicity and insulin resistance (IR) were significantly associated with a NOSTOX composite score. Mood disorders, TUD, GAD, male sex and MetS independently contribute to increased RONS/NOSTOX. The RONS/NOSTOX profile of MetS was different from that of GAD, which showed increased SOD1 and NOx levels. TUD was accompanied by increased SOD1, LOOH and MDA, and male sex by increased LOOH and AOPP.

Conclusions: MetS is characterized by increased lipid peroxidation with aldehyde formation and chlorinative stress, and atherogenicity and IR are strongly mediated by RONS/NOSTOX. Partially shared RONS/NOSTOX pathways underpin the comorbidity of MetS with mood disorders, GAD, and TUD.
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http://dx.doi.org/10.1016/j.jad.2021.07.057DOI Listing
November 2021

The Reification of the Clinical Diagnosis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) as an Immune and Oxidative Stress Disorder: Construction of a Data-driven Nomothethic Network and Exposure of ME/CFS Subgroups.

Curr Top Med Chem 2021 Oct;21(16):1488-1499

Monnet Research Center, Louvain-La-Neuve, Belgium.

The approach towards myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010, 8, 35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity.This bottom- up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.
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http://dx.doi.org/10.2174/1568026621666210727170147DOI Listing
October 2021

The Reification of the Clinical Diagnosis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) as an Immune and Oxidative Stress Disorder: Construction of a Data-driven Nomothethic Network and Exposure of ME/CFS Subgroups.

Curr Top Med Chem 2021 Oct;21(16):1488-1499

Monnet Research Center, Louvain-La-Neuve, Belgium.

The approach towards myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010, 8, 35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity.This bottom- up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.
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http://dx.doi.org/10.2174/1568026621666210727170147DOI Listing
October 2021

Statins: Neurobiological underpinnings and mechanisms in mood disorders.

Neurosci Biobehav Rev 2021 09 13;128:693-708. Epub 2021 Jul 13.

Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, VIC, Australia; Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia; Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia. Electronic address:

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.012DOI Listing
September 2021

A proof-of-concept study of maternal immune activation mediated induction of Toll-like receptor (TLR) and inflammasome pathways leading to neuroprogressive changes and schizophrenia-like behaviours in offspring.

Eur Neuropsychopharmacol 2021 Nov 11;52:48-61. Epub 2021 Jul 11.

Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India. Electronic address:

Infection, particularly prenatal infection, leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes that drive prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviours through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-6, TNF-α and IL-17A assessed after 24 hours were observed in both the poly (I:C) and LPS-treated rats, while IL-1β was only elevated in LPS-treated rats, indicating MIA. The offspring of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviours, deficits in social behaviours and prepulse inhibition. The hippocampus of offspring rats showed increased expression of Tlr3, Tlr4, Nlrp3, Il1b, and Il18 of poly (I:C) and Tlr4, Nlrp3, Cas1, Il1b, and Il18 of LPS-treated dams. Furthermore, Tlr and inflammasome genes were associated with social deficits and impaired prepulse inhibition in offspring rats. The results suggest that MIA due to prenatal infection can trigger TLR and inflammasome pathways and enhances the risk of schizophrenia-like behaviours in the later stages of life of the offspring.
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http://dx.doi.org/10.1016/j.euroneuro.2021.06.009DOI Listing
November 2021

BDNF in antipsychotic naive first episode psychosis: Effects of risperidone and the immune-inflammatory response system.

J Psychiatr Res 2021 09 6;141:206-213. Epub 2021 Jul 6.

GAPi (Early Psychosis Group), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil; Schizophrenia Program (PROESQ), Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.

Brain-derived neurotrophic factor (BDNF) and the immune-inflammatory response system (IRS) have been implicated in the pathophysiology of schizophrenia. However, no research examined the associations between BDNF and immune activation both before and after treatment in antipsychotic-naïve first episode psychosis (AN-FEP). This study aims to examine serum BDNF levels and their association with IRS and the compensatory immune-regulatory reflex system (CIRS) in AN-FEP before and after risperidone treatment. We included 31 AN-FEP and 22 healthy controls. AN-FEP showed reduced levels of BDNF as compared to controls, and BDNF levels normalized after treatment with risperidone. BDNF levels were inversely correlated with a greater IRS response. Higher levels of IRS/CIRS biomarkers were associated with lower levels of BDNF including M1 macrophage, T-helper (Th)-1, Th-2, and Th-17, and T-regulatory (Treg) cell responses. Our findings indicate that AN-FEP is characterized by decreased levels of BDNF, which are normalized after treatment with risperidone. BDNF levels were inversely associated with activated immune-inflammatory pathways. The findings support the hypothesis that, increased IRS is linked to neurotoxicity, and that a decrease in BDNF may be part of the IRS/CIRS responses in FEP and, thus, be involved in the development of psychosis.
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http://dx.doi.org/10.1016/j.jpsychires.2021.07.011DOI Listing
September 2021
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