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Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 24575

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Prof. Dr. Michael Maes

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Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Interests: depression; ME/CFS; schizophrenia; immune-inflammatory pathways; oxidative and nitrosative stress; antioxidants; intracellular signaling pathways; machine learning; nomothetic networks; molecular mechanisms; T cells; macrophages; neuroinflammation; leaky gut; bacterial translocation; microbiome; connectome; bioinformatics; systems biomedicine; new drug targets

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Dear Colleagues,

Major psychoses, such as major depression, bipolar disorder, and schizophrenia, are incapacitating conditions that impact brain function, neurocognition, and quality of life. There is evidence that these disorders are characterized by activation of the immune-inflammatory response (IRS) and the compensatory immune-regulatory (CIRS) systems, as well as decreased neuroprotection. First-episode psychosis and schizophrenia, as well as deficit schizophrenia, are strongly linked to bacterial responses; increased production of proinflammatory cytokines such as TNF-α, IL-1, and IL-6; as well as associated nitro-oxidative stress pathways and indicators of microglial activation. According to theory, peripheral immune pathways may cause increased neurotoxicity in brain areas, resulting in connectome disorders and white and gray matter plasticity aberrations. The latter may mediate the effects of peripheral immune activation, which causes neurocognitive deficits and schizophrenia phenotypes. Mood disorders are characterized by a similar activation of peripheral IRS and CIRS pathways, as well as a decrease in antioxidant defenses, which leads to an increase in nitro-oxidative stress pathways and autoimmune responses. Intersections between early childhood trauma and immune and nitro-oxidative pathways are strongly linked to the phenome of mood disorders. According to theory, these peripheral pathways can cause neuro-affective toxicity, which could explain the phenome of mood disorders. Nonetheless, many issues remain unresolved: a) what are the characteristics of schizophrenia phenotypes, such as treatment schizophrenia, first- and multiple-episode schizophrenia, and deficit schizophrenia; and b) what are the characteristics of depression versus manic episodes, as well as the distinctions between unipolar and bipolar disorder? Furthermore, there are scarce data on these disorders' interactomes, potential trigger factors, biological functions, pathways, molecular patterns, and cellular components that underpin changes in the connectome, cognitome, and phenome. To generate new knowledge, new drug targets, new nomothetic models of these disorders, and machine learning, including nomothetic networks and bioinformatics, should be used. Precision psychiatry requires a combined nomothetic and idiographic approach.

Prof. Dr. Michael Maes
Guest Editor

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Keywords

mood disorders
psychosis spectrum and phenotypes
immune activation
leaky gut
compensatory immune-regulatory system
early lifetime trauma
molecular mechanisms
intracellular signaling
machine learning
bioinformatics

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Published Papers (8 papers)

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Research

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16 pages, 1580 KiB

Open AccessArticle

Exploration of the Gut Microbiome in Thai Patients with Major Depressive Disorder Shows a Specific Bacterial Profile with Depletion of the Ruminococcus Genus as a Putative Biomarker

by Michael Maes, Asara Vasupanrajit, Ketsupar Jirakran, Pavit Klomkliew, Prangwalai Chanchaem, Chavit Tunvirachaisakul and Sunchai Payungporn

Cells 2023, 12(9), 1240; https://doi.org/10.3390/cells12091240 - 25 Apr 2023

Cited by 15 | Viewed by 3015

Abstract

Maes et al. (2008) published the first paper demonstrating that major depressive disorder (MDD) is accompanied by abnormalities in the microbiota–gut–brain axis, as evidenced by elevated serum IgM/IgA to lipopolysaccharides (LPS) of Gram-negative bacteria, such as Morganella morganii and Klebsiella Pneumoniae. The latter aberrations, which point to increased gut permeability (leaky gut), are linked to activated neuro-immune and oxidative pathways in MDD. To delineate the profile and composition of the gut microbiome in Thai patients with MDD, we examined fecal samples of 32 MDD patients and 37 controls using 16S rDNA sequencing, analyzed α- (Chao1 and Shannon indices) and β-diversity (Bray–Curtis dissimilarity), and conducted linear discriminant analysis (LDA) effect size (LEfSe) analysis. Neither α- nor β-diversity differed significantly between MDD and controls. Rhodospirillaceae, Hungatella, Clostridium bolteae, Hungatella hathewayi, and Clostridium propionicum were significantly enriched in MDD, while Gracillibacteraceae family, Lutispora, and Ruminococcus genus, Ruminococcus callidus, Desulfovibrio piger, Coprococcus comes, and Gemmiger were enriched in controls. Contradictory results have been reported for all these taxa, with the exception of Ruminococcus, which is depleted in six different MDD studies (one study showed increased abundance), many medical disorders that show comorbidities with MDD, and animal MDD models. Our results may suggest a specific profile of compositional gut dysbiosis in Thai MDD patients, with increases in some pathobionts and depletion of some beneficial microbiota. The results suggest that depletion of Ruminococcus may be a more universal biomarker of MDD that may contribute to increased enteral LPS load, LPS translocation, and gut–brain axis abnormalities. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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16 pages, 1366 KiB

Open AccessFeature PaperArticle

HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV)

by Tomasz Pawlowski, Krzysztof Malyszczak, Dariusz Pawlak, Małgorzata Inglot, Małgorzata Zalewska, Anna Grzywacz, Marek Radkowski, Tomasz Laskus, Justyna Janocha-Litwin and Dorota Frydecka

Cells 2023, 12(6), 970; https://doi.org/10.3390/cells12060970 - 22 Mar 2023

Cited by 1 | Viewed by 2090

Abstract

Background: Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. Materials and methods: The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery–Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times—at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. Results: Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, L_G/L_G, and S/L_G) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. Conclusions: Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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21 pages, 1430 KiB

Open AccessArticle

Increased Lipid Peroxidation and Lowered Antioxidant Defenses Predict Methamphetamine Induced Psychosis

by Hussein Kadhem Al-Hakeim, Mazin Fadhil Altufaili, Abbas F. Almulla, Shatha Rouf Moustafa and Michael Maes

Cells 2022, 11(22), 3694; https://doi.org/10.3390/cells11223694 - 21 Nov 2022

Cited by 6 | Viewed by 2238

Abstract

Background: a significant percentage of methamphetamine (MA) dependent patients develop psychosis. The associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. Objective: the aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied by increased nitro-oxidative stress and whether the latter is associated with MIP. Method: we recruited 30 healthy younger males and 60 acutely intoxicated males with MA dependence and assessed severity of MA use and dependence and psychotic symptoms during intoxication, and serum oxidative toxicity (OSTOX) biomarkers including oxidized high (oxHDL) and low (oxLDL)-density lipoprotein, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO), and antioxidant defenses (ANTIOX) including HDL-cholesterol, zinc, glutathione peroxidase (GPx), total antioxidant capacity (TAC), and catalase-1. Results: a large part (50%, n = 30) of patients with MA dependence could be allocated to a cluster characterized by high psychosis ratings including delusions, suspiciousness, conceptual disorganization and difficulties abstract thinking and an increased OSTOX/ANTIOX ratio. Partial Least Squares analysis showed that 29.9% of the variance in MIP severity (a first factor extracted from psychosis, hostility, excitation, mannerism, and formal thought disorder scores) was explained by HDL, TAC and zinc (all inversely) and oxLDL (positively). MA dependence and dosing explained together 44.7% of the variance in the OSTOX/ANTIOX ratio. Conclusions: MA dependence and intoxication are associated with increased oxidative stress and lowered antioxidant defenses, both of which increase risk of MIP during acute intoxication. MA dependence is accompanied by increased atherogenicity due to lowered HDL and increased oxLDL and oxHDL. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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30 pages, 3513 KiB

Open AccessArticle

Adverse Childhood Experiences Predict the Phenome of Affective Disorders and These Effects Are Mediated by Staging, Neuroimmunotoxic and Growth Factor Profiles

by Michael Maes, Muanpetch Rachayon, Ketsupar Jirakran, Pimpayao Sodsai, Siriwan Klinchanhom, Monojit Debnath, Agnieska Basta-Kaim, Marta Kubera, Abbas F. Almulla and Atapol Sughondhabirom

Cells 2022, 11(9), 1564; https://doi.org/10.3390/cells11091564 - 7 May 2022

Cited by 26 | Viewed by 3782

Abstract

Adverse childhood experiences (ACEs) enhance pro-inflammatory and pro-oxidant responses. In affective disorders, recent precision nomothetic psychiatry studies disclosed new pathway phenotypes, including an ROI—reoccurrence of illness (ROI)—oxidative stress latent construct. The aim of the present study is to delineate a) whether ACEs sensitize the M1 macrophage, the T helper cells (Th)1, Th2, and Th17, the IRS (immune-inflammatory-responses system), the CIRS (compensatory immunoregulatory system), and the neuroimmunotoxic and growth factor (GF) profiles and whether they are associated with ROI and the phenome of affective disorders and b) the molecular pathways underpinning the effects of the ACEs. We collected supernatants of stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) and unstimulated diluted whole blood in 20 healthy controls and 30 depressed patients and measured a panel of 27 cytokines/GF using a Luminex method. ACEs (comprising mental and physical trauma, mental neglect, domestic violence, family history of mental disease, and parent loss) are accompanied by the increased stimulated, but not unstimulated, production of M1, Th1, Th2, Th17, IRS, neuroimmunotoxic, and GF profiles and are strongly correlated with ROI and the phenome. A latent vector extracted from the ROI features (recurrent episodes and suicidal behaviors) and the IRS/neuroimmunotoxic/GF profiles explains 66.8% of the variance in the phenome and completely mediates the effects of ACEs on the phenome. Enrichment analysis showed that the ACE-associated sensitization of immune/GF profiles involves JAK-STAT, nuclear factor-κB, tumor necrosis factor-α, G-protein coupled receptor, PI3K/Akt/RAS/MAPK, and hypoxia signaling. In summary, the ACE-induced sensitization of immune pathways and secondary immune hits predicts the phenome of affective disorders. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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23 pages, 6323 KiB

Open AccessArticle

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

by Michael Maes, Kitiporn Plaimas, Apichat Suratanee, Cristiano Noto and Buranee Kanchanatawan

Cells 2021, 10(11), 2929; https://doi.org/10.3390/cells10112929 - 28 Oct 2021

Cited by 22 | Viewed by 3122

Abstract

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. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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Review

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38 pages, 3379 KiB

Open AccessReview

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

by George Anderson, Abbas F. Almulla, Russel J. Reiter and Michael Maes

Cells 2023, 12(9), 1237; https://doi.org/10.3390/cells12091237 - 25 Apr 2023

Cited by 8 | Viewed by 3469

Abstract

Although previously restricted to a limited number of medical conditions, there is a growing appreciation that ‘autoimmune’ (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8⁺ T cell and B-cell ‘autoimmune’-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8⁺ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many ‘autoimmune’/‘immune-mediated’ disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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18 pages, 657 KiB

Open AccessReview

Targeting Underlying Inflammation in Carcinoma Is Essential for the Resolution of Depressiveness

by Milica M. Borovcanin, Katarina Vesić, Dragana Arsenijević, Maja Milojević-Rakić, Nataša R. Mijailović and Ivan P. Jovanovic

Cells 2023, 12(5), 710; https://doi.org/10.3390/cells12050710 - 23 Feb 2023

Cited by 2 | Viewed by 1976

Abstract

In modern clinical practice and research on behavioral changes in patients with oncological problems, there are several one-sided approaches to these problems. Strategies for early detection of behavioral changes are considered, but they must take into account the specifics of the localization and phase in the course and treatment of somatic oncological disease. Behavioral changes, in particular, may correlate with systemic proinflammatory changes. In the up-to-date literature, there are a lot of useful pointers on the relationship between carcinoma and inflammation and between depression and inflammation. This review is intended to provide an overview of these similar underlying inflammatory disturbances in both oncological disease and depression. The specificities of acute and chronic inflammation are considered as a basis for causal current and future therapies. Modern therapeutic oncology protocols may also cause transient behavioral changes, so assessment of the quality, quantity, and duration of behavioral symptoms is necessary to prescribe adequate therapy. Conversely, antidepressant properties could be used to ameliorate inflammation. We will attempt to provide some impetus and present some unconventional potential treatment targets related to inflammation. It is certain that only an integrative oncology approach is justifiable in modern patient treatment. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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19 pages, 2090 KiB

Open AccessReview

The Tryptophan Catabolite or Kynurenine Pathway in a Major Depressive Episode with Melancholia, Psychotic Features and Suicidal Behaviors: A Systematic Review and Meta-Analysis

by Abbas F. Almulla, Yanin Thipakorn, Asara Vasupanrajit, Chavit Tunvirachaisakul, Gregory Oxenkrug, Hussein K. Al-Hakeim and Michael Maes

Cells 2022, 11(19), 3112; https://doi.org/10.3390/cells11193112 - 2 Oct 2022

Cited by 12 | Viewed by 3772

Abstract

Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways, which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4647 participants including 2332 unipolar (MDD) and bipolar (BD) depressed patients and 2315 healthy controls. Severe patients showed significant lower (p < 0.0001) TRP (standardized mean difference, SMD = −0.517, 95% confidence interval, CI: −0.735; −0.299) and TRP/CAAs (SMD = −0.617, CI: −0.957; −0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD = 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD = 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD = −0.260, CI: −0.487; −0.034) in severe MDD/BD. Patients with affective disorders with melancholic and psychotic features and suicidal behaviors showed normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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