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The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours (SB) and cognitive deficits; the effects of adverse childhood experiences (ACEs) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc). We determined isometric log-ratio abundances or prevalences of gut microbiome phyla, genera, and species by analysing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing. Six microbiome taxa accounted for 36% of the variance in the depression phenome, namely Hungatella and Fusicatenibacter (positive associations) and Butyricicoccus, Clostridium, Parabacteroides merdae , and Desulfovibrio piger (inverse association). This profile (labelled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to SB. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae , and Romboutsi a were positively associated, while Proteobacteria and Clostridium sensu stricto were negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current SB. In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and SB and possibly for the prevention of future episodes. [ABSTRACT FROM AUTHOR]

The purpose of this study is to describe how to use the precision nomothetic psychiatry approach to (a) delineate the associations between schizophrenia symptom domains, including negative symptoms, psychosis, hostility, excitation, mannerism, formal thought disorders, psychomotor retardation (PHEMFP), and cognitive dysfunctions and neuroimmunotoxic and neuro-oxidative pathways and (b) create a new endophenotype class based on these features. We show that all symptom domains (negative and PHEMFP) may be used to derive a single latent trait called overall severity of schizophrenia (OSOS). In addition, neurocognitive test results may be used to extract a general cognitive decline (G-CoDe) index, based on executive function, attention, semantic and episodic memory, and delayed recall scores. According to partial least squares analysis, the impacts of adverse outcome pathways (AOPs) on OSOS are partially mediated by increasing G-CoDe severity. The AOPs include neurotoxic cytokines and chemokines, oxidative damage to proteins and lipids, IgA responses to neurotoxic tryptophan catabolites, breakdown of the vascular and paracellular pathways with translocation of Gram-negative bacteria, and insufficient protection through lowered antioxidant levels and impairments in the innate immune system. Unsupervised machine learning identified a new schizophrenia endophenotype class, named major neurocognitive psychosis (MNP), which is characterised by increased negative symptoms and PHEMFP, G-CoDe and the above-mentioned AOPs. Based on these pathways and phenome features, MNP is a distinct endophenotype class which is qualitatively different from simple psychosis (SP). It is impossible to draw any valid conclusions from research on schizophrenia that ignores the MNP and SP distinctions. [ABSTRACT FROM AUTHOR]

The top-down Diagnostic and Statistical Manual/International Statistical Classification of Diseases categories of mood disorders are inaccurate, and their dogmatic nature precludes both deductive (as indisputable) and inductive (as top-down) remodelling of case definitions. In trials, psychiatric rating scale scores employed as outcome variables are invalid and rely on folk psychology-like narratives. Using machine learning techniques, we developed a new precision nomothetic model of mood disorders with a recurrence of illness (ROI) index, a new endophenotype class, namely Major Dysmood Disorder (MDMD), characterised by increased ROI, a more severe phenome, and more disabilities. Nonetheless, our previous studies did not compute Research and Diagnostic Algorithmic Rules (RADAR) to diagnose MDMD and score ROI, lifetime (LT), and current suicidal behaviours, as well as the phenome of mood disorders. Here, we provide rules to compute bottom-up RADAR scores for MDMD, ROI, LT and current suicidal ideation and attempts, the phenome of mood disorders, and the lifetime trajectory of mood disorder patients from a family history of mood disorders and substance abuse to adverse childhood experiences, ROI, and the phenome. We also demonstrate how to plot the 12 major scores in a single RADAR graph, which displays all features in a two-dimensional plot. These graphs allow the characteristics of a patient to be displayed as an idiomatic fingerprint, allowing one to estimate the key traits and severity of the illness at a glance. Consequently, biomarker research into mood disorders should use our RADAR scores to examine pan-omics data, which should be used to enlarge our precision models and RADAR graph. [ABSTRACT FROM AUTHOR]

Kim YK, Maes M. The role of the cytokine network in psychological stress. Although a considerable amount of evidence has shown that psychological stress alters peripheral and brain cytokines, the physiological significance of cytokine alteration in psychological stress remains to be elucidated. The aims of this review are to analyze the influence of acute and chronic psychological stresses on the cytokine network in animals and in humans, and to explore the pathophysiological implication of the cytokine changes in psychological stress. Acute psychological stress may increase proinflammatory cytokines both in animals and in humans, and increase T-helper-1 cell cytokines in humans. Investigations into the effect of chronic psychological stress on cytokine production in animals gives mixed results. However, in humans, academic exam stress or care-giver's stress appears to induce a shift in the Th1/Th2 cytokine balance toward a Th2 response and increase proinflammatory cytokines. Psychological stress-induced cytokines stimulate the activity of indoleamine 2,3 dioxygenase (IDO) and could induce serotonin depletion-related disorders such as depression in susceptible individuals. Psychological stress-induced production of cytokines may increase the risk for human diseases, such as cardiovascular disease and exacerbation of autoimmune diseases. Proinflammatory cytokines may also play a regulatory role in glucocorticoid resistance and may be involved in wound healing and skin barrier function alterations. Finally, psychological stress-induced production of cytokines may play a role in neurodegenerative changes in the brain. [ABSTRACT FROM AUTHOR]

D van West, M Maes. Polyunsaturated fatty acids in depression. [ABSTRACT FROM AUTHOR]

Background: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. Objectives: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. Methods: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5′-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). Results: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). Conclusion: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS. [ABSTRACT FROM AUTHOR]

Background: Long coronavirus disease 2019 (LC) is a chronic sequel of acute COVID-19. The exact pathophysiology of the affective, chronic fatigue and physiosomatic symptoms (labelled as "physio-affective phenome") of LC has remained elusive. Objective: The current study aims to delineate the effects of oxygen saturation (SpO2) and body temperature during the acute phase on the physio-affective phenome of LC. Method: We recruited 120 LC patients and 36 controls. For all participants, we assessed the lowest SpO2 and peak body temperature during acute COVID-19, and the Hamilton Depression and Anxiety Rating Scale (HAMD/HAMA) and Fibro Fatigue (FF) scales 3–4 months later. Results: Lowered SpO2 and increased body temperature during the acute phase and female sex predict 60.7% of the variance in the physio-affective phenome of LC. Using unsupervised learning techniques, we were able to delineate a new endophenotype class, which comprises around 26.7% of the LC patients and is characterised by very low SpO2 and very high body temperature, and depression, anxiety, chronic fatigue, and autonomic and gastro-intestinal symptoms scores. Single latent vectors could be extracted from both biomarkers, depression, anxiety and FF symptoms or from both biomarkers, insomnia, chronic fatigue, gastro-intestinal and autonomic symptoms. Conclusion: The newly constructed endophenotype class and pathway phenotypes indicate that the physio-affective phenome of LC is at least in part the consequence of the pathophysiology of acute COVID-19, namely the combined effects of lowered SpO2, increased body temperature and the associated immune-inflammatory processes and lung lesions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the β-endorphin – mu opioid receptor (MOR) and immune-inflammatory system. Methods: The present study examines dynorphin, KOR, β-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males. Results: Serum dynorphin, KOR, β-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and β-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence. Conclusion: Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress. [ABSTRACT FROM AUTHOR]

Objective: To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms. Methods: Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle. Results: Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase. Discussion: Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings. [ABSTRACT FROM AUTHOR]

Objective: The aim of the current study was to examine whether and to what extent mood disorders, comprising major depression and bipolar disorder, are accompanied by structural changes in the brain as measured using voxel-based morphometry (VBM). Methods: We performed a VBM study using a 3Т MRI system (GE Discovery 750w) in patients with mood disorders (n=50), namely, 39 with major depression and 11 with bipolar disorder compared to 42 age-, sex- and education-matched healthy controls. Results: Our results show that depression was associated with significant decreases in grey matter (GM) volume of the regions located within the medial frontal and anterior cingulate cortex on the left side and middle frontal gyrus, medial orbital gyrus, inferior frontal gyrus (triangular and orbital parts) and middle temporal gyrus (extending to the superior temporal gyrus) on the right side. When the patient group was separated into bipolar disorder and major depression, the reductions remained significant only for patients with major depressive disorder. Conclusions: Using VBM the present study was able to replicate decreases in GM volume restricted to frontal and temporal regions in patients with mood disorders, mainly major depression, compared with healthy controls. [ABSTRACT FROM AUTHOR]

Background: Borna disease virus (BDV) predominantly infects horses and sheep, causing a broad range of behavioural disorders. It is controversial whether BDV infects humans and causes psychiatric disorders. Objectives: We searched for BDV-derived nucleic acids in blood of race horses and jockeys riding the horses. Methods: We assayed for the BDV genome in RNA extracted from peripheral blood mononuclear cells (PBMC) of 39 race horses and 48 jockeys. Two polymerase chain reaction protocols [one-tube reverse transcription–polymerase chain reaction (RT-PCR) and two-step RT-PCR] were used to assay BDV p24 and p40 transcripts. Results: The p24 and p40 viral nucleic acid sequences were not detected in the PBMC RNAs from any of the race horses or jockeys. Conclusions: These data do not support an epidemiological association between BDV infection, race horses and humans. [ABSTRACT FROM AUTHOR]

Background: It is controversial whether Borna disease virus (BDV) infects humans and causes psychiatric disorders. Objectives: The relationship between BDV infection and schizophrenia with deficit syndrome was investigated. Study design: Using the Schedule for the Deficit Syndrome, 62 schizophrenic in-patients were selected from three psychiatric hospitals. RNA was extracted from peripheral blood mononuclear cells and analyzed using nested reverse transcriptase-polymerase chain reaction with primers to detect BDV p24 and p40. Results and conclusions: BDV transcripts were not detected in samples from any of the 62 schizophrenic patients. These data do not support an etiologic association between BDV infection and the deficit form of schizophrenia. [ABSTRACT FROM AUTHOR]