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Major depressive disorder (MDD) and its severe subtype, major dysmood disorder (MDMD), are distinguished by activation of inflammatory and growth factor subnetworks, which are associated with recurrence of illness (ROI) and adverse childhood experiences (ACEs). Nerve growth factor (NGF) plays a crucial role in facilitating neuro-immune communications and may regulate the inflammatory response. Methods: The present study examined the effects of ACEs and ROI on culture supernatant NGF, stem cell factor (SCF), stem cell GF (SCGF), hepatocyte GF (HGF), and macrophage colony-stimulating factor (M-CSF), in relation to a neurotoxicity (NT) cytokine profile. Results: NGF levels are lower in MDD (p = 0.003), particularly MDMD (p < 0.001), as compared with normal controls. ROI and ACE were significantly and inversely associated with NGF (≤0.003) and the NGF/NT ratio (≤0.001), whereas there are no effects of ACEs and ROI on SCF, SCGF, HGF, or M-CSF. Lowered NGF (p = 0.003) and the NGF/NT ratio (p < 0.001) are highly significantly and inversely associated with the severity of the current depression phenome, conceptualized as a latent vector extracted from the current severity of depression, anxiety, and suicidal behaviors. We found that one validated and replicable latent vector could be extracted from NGF, ROI, and the depression phenome, which therefore constitutes a novel ROI-NGF-pathway-phenotype. ACEs explained 59.5% of the variance in the latter pathway phenotype (p < 0.001). Conclusions: The imbalance between decreased NGF and increased neurotoxic cytokines during the acute phase of severe depression may contribute to decreased neuroprotection, increased neuro-affective toxicity, and chronic mild inflammation. [ABSTRACT FROM AUTHOR]

Background: Neuro-immune pathways are engaged in antenatal and postpartum depression. Aims: To determine if immune profiles influence the severity of prenatal depression above and beyond the effects of adverse childhood experiences (ACE), premenstrual syndrome (PMS), and current psychological stressors. Methods: Using the Bio-Plex Pro human cytokine 27-plex test kit, we assayed M1 macrophage, T helper (Th)-1, Th-2, Th-17, growth factor, chemokine, and T cell growth immune profiles as well as indicators of the immune inflammatory response system (IRS) and compensatory immunoregulatory system (CIRS) in 120 pregnant females in the early (<16 weeks) and late (>24 weeks) pregnancy. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess severity of antenatal depression. Results: Cluster analyses showed that the combined effects of ACE, relationship dissatisfaction, unwanted pregnancy, PMS, and upregulated M1, Th-1, Th-2, and IRS immune profiles and the ensuing early depressive symptoms shape a stress-immune-depression phenotypic class. Elevated IL-4, IL-6, IL-8, IL-12p70, IL-15, IL-17, and GM-CSF are the cytokines associated with this phenotypic class. All immune profiles (except CIRS) were significantly associated with the early EPDS score, independent of the effects of psychological variables and PMS. There was a shift in immune profiles from early to late pregnancy, with an increase in the IRS/CIRS ratio. The late EPDS score was predicted by the early EPDS score, adverse experiences, and immune profiles, mainly the Th-2 and Th-17 phenotypes. Conclusions: Activated immune phenotypes contribute to early and late perinatal depressive symptoms above and beyond the effects of psychological stressors and PMS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Machine learning approaches, such as soft independent modeling of class analogy (SIMCA) and pathway analysis, were introduced in depression research in the 1990s (Maes et al.) to construct neuroimmune endophenotype classes. The goal of this paper is to examine the promise of precision psychiatry to use information about a depressed person's own pan-omics, environmental, and lifestyle data, or to tailor preventative measures and medical treatments to endophenotype subgroups of depressed patients in order to achieve the best clinical outcome for each individual. Three steps are emerging in precision medicine: (1) the optimization and refining of classical models and constructing digital twins; (2) the use of precision medicine to construct endophenotype classes and pathway phenotypes, and (3) constructing a digital self of each patient. The root cause of why precision psychiatry cannot develop into true sciences is that there is no correct (cross-validated and reliable) model of clinical depression as a serious medical disorder discriminating it from a normal emotional distress response including sadness, grief and demoralization. Here, we explain how we used (un)supervised machine learning such as partial least squares path analysis, SIMCA and factor analysis to construct (a) a new precision depression model; (b) a new endophenotype class, namely major dysmood disorder (MDMD), which is a nosological class defined by severe symptoms and neuro-oxidative toxicity; and a new pathway phenotype, namely the reoccurrence of illness (ROI) index, which is a latent vector extracted from staging characteristics (number of depression and manic episodes and suicide attempts), and (c) an ideocratic profile with personalized scores based on all MDMD features. [ABSTRACT FROM AUTHOR]

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 IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD 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 NFKB1, RELA and SP1 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data from 40 healthy controls and 80 patients with schizophrenia. Using partial least squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and the phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores. [ABSTRACT FROM AUTHOR]

Although autism spectrum disorder (ASD) is a multifaceted neurodevelopmental syndrome, accumulating evidence indicates that oxidative stress and inflammation are common features of ASD. Flavonoids, one of the largest and best-investigated classes of plant-derived compounds, are known to exert antioxidant, anti-inflammatory, and neuroprotective effects. This review used a systematic search process to assess the available evidence on the effect of flavonoids on ASD. A comprehensive literature search was carried out in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. A total of 17 preclinical studies and 4 clinical investigations met our inclusion criteria and were included in the final review. Most findings from animal studies suggest that treatment with flavonoids improves oxidative stress parameters, reduces inflammatory mediators, and promotes pro-neurogenic effects. These studies also showed that flavonoids ameliorate the core symptoms of ASD, such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination. However, there are no randomized placebo-controlled trials that support the clinical efficacy of flavonoids in ASD. We only found open-label studies and case reports/series, using only two flavonoids such as luteolin and quercetin. These preliminary clinical studies indicate that flavonoid administration may improve specific behavioral symptoms of ASD. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of flavonoids on features of ASD. These promising preliminary results may provide the rationale for future randomized controlled trials aimed at confirming these outcomes. [ABSTRACT FROM AUTHOR]

Background: Long-term coronavirus disease 2019 (long COVID) is associated with physio-somatic (chronic fatigue syndrome and somatic symptoms) and affective (depression and anxiety) symptoms. The severity of the long COVID physio-affective phenome is largely predicted by increased peak body temperature (BT) and lowered oxygen saturation (SpO2) during the acute infectious phase. This study aims to delineate whether the association of BT and SpO2 during the acute phase and the long COVID physio-affective phenome is mediated by neurotoxicity (NT) resulting from activated immune-inflammatory and oxidative stress pathways. Methods: We recruited 86 patients with long COVID (3–4 months after the acute phase) and 39 healthy controls and assessed serum C-reactive protein (CRP), caspase 1, interleukin (IL) 1β, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPPs), total antioxidant capacity (TAC), and calcium (Ca), as well as peak BT and SpO2 during the acute phase. Results: Cluster analysis revealed that a significant part (34.9%) of long COVID patients (n = 30) show a highly elevated NT index as computed based on IL-1β, IL-18, caspase 1, CRP, MPO, and AOPPs. Partial least squares analysis showed that 61.6% of the variance in the physio-affective phenome of long COVID could be explained by the NT index, lowered Ca, and peak BT/SpO2 in the acute phase and prior vaccinations with AstraZeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1β, AOPPs, and MPO. Conclusion: The infection–immune–inflammatory core of acute COVID-19 strongly predicts the development of physio-affective symptoms 3–4 months later, and these effects are partly mediated by neuro-immune and neuro-oxidative pathways. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Major depressive disorder and major depressive episodes (MDD/MDE) are characterized by the activation of the immune–inflammatory response system (IRS) and the compensatory immune–regulatory system (CIRS). Cannabidiol (CBD) is a phytocannabinoid isolated from the cannabis plant, which is reported to have antidepressant-like and anti-inflammatory effects. The aim of the present study is to examine the effects of CBD on IRS, CIRS, M1, T helper (Th)-1, Th-2, Th-17, T regulatory (Treg) profiles, and growth factors in depression and healthy controls. Culture supernatant of stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) whole blood of 30 depressed patients and 20 controls was assayed for cytokines using the LUMINEX assay. The effects of three CBD concentrations (0.1 µg/mL, 1 µg/mL, and 10 µg/mL) were examined. Depression was characterized by significantly increased PHA + LPS-stimulated Th-1, Th-2, Th-17, Treg, IRS, CIRS, and neurotoxicity profiles. CBD 0.1 µg/mL did not have any immune effects. CBD 1.0 µg/mL decreased CIRS activities but increased growth factor production, while CBD 10.0 µg/mL suppressed Th-1, Th-17, IRS, CIRS, and a neurotoxicity profile and enhanced T cell growth and growth factor production. CBD 1.0 to 10.0 µg/mL dose-dependently decreased sIL-1RA, IL-8, IL-9, IL-10, IL-13, CCL11, G-CSF, IFN-γ, CCL2, CCL4, and CCL5, and increased IL-1β, IL-4, IL-15, IL-17, GM-CSF, TNF-α, FGF, and VEGF. In summary, in this experiment, there was no beneficial effect of CBD on the activated immune profile of depression and higher CBD concentrations can worsen inflammatory processes. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms. This paper examines the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), CFS-like (Fibro-fatigue Scale) symptoms and immune–inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylcer-amide (CD17) in RA. The serum biomarkers were assayed in 118 RA and 50 healthy controls. Results were analyzed using the new precision nomothetic psychiatry approach. We found significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tender and swollen joints, and patient and evaluator global assessment scores. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning psychopathology and RA symptoms was explained by immune–inflammatory pathways, rheumatoid factor, anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels. We constructed a new endophenotype class comprising patients with very high immune–inflammatory markers, CD17, RA, affective and CF-like symptoms, and tobacco use disorder. We extracted a reliable and replicable latent vector (pathway phenotype) from immune data, psychopathology, and RA-severity scales. Depression, anxiety, and CFS-like symptoms due to RA are manifestations of the phenome of RA and are mediated by the effects of the same immune–inflammatory, autoimmune, and other pathways that underpin the pathophysiology of RA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The authors of this research study intended to verify whether there are any changes in gene expression in depressed patients without coexisting inflammatory diseases for selected immune-inflammatory factors that are particularly important in autoimmune disease pathogenesis (IL-17, IL-21, IL-23, IL-35, Foxp3). Methods: The study was carried out on a group of 190 patients with depression and 100 healthy volunteers. The severity of depressive symptoms was assessed using the Hamilton Depression Scale. RT-PCR was used to evaluate mRNA expression and ELISA was used to measure protein expression of these genes. Results: The level of gene expression for IL-17, IL-21, IL-23, and IL-35 was substantially higher in the group of patients with depression compared to the control group. The mean mRNA expression of Foxp3 was considerably reduced in patients suffering from depressive disorders. There was a statistically significant correlation between the number of hospitalizations and the expression of specific inflammatory factors. Conclusions: Expression of specific inflammatory genes may be a factor in the etiopathogenesis of depressive disorders. The duration of the disease seems to be more important for the expression of the genes in question than the severity of depression. These cytokines may affect the metabolism of neurotransmitters and neuroendocrine functions in the brain as well as be a marker and a new potential therapeutic target for recurrent depressive disorders. [ABSTRACT FROM AUTHOR]

(1) Background: Activated immune-inflammatory pathways play an important role in the pathogenesis of depression and pathological obesity. Obesity might promote production of cytokine interleukin 17, which plays a significant role in neuro-immune reactions. The study aimed at assessing the relationship between Body Mass Index (BMI) and IL-17 expression, taking into account the clinical psychiatric variables in patients with depression. (2) Methods: A total of 125 participants took part in the study (95 depressed patients, 30 healthy controls). Data concerning the course of depressive disorders and BMI were collected. The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Reverse transcription polymerase chain reaction (RT-PCR) was used to assess IL-17 gene expression at the mRNA levels, while enzyme-linked immunosorbent assay (ELISA) was used to assess IL-17 expression at the protein level. (3) Results: Patients with more hospitalizations showed significantly higher IL-17 mRNA expression levels and higher BMI. However, no correlation between BMI and IL-17 expression was found in depressed patients. (4) Conclusions: Our study revealed that BMI does not affect IL-17 expression in patients with depression. However, further studies should be conducted to evaluate the effects of IL-17 inhibition on adipose tissue and vice versa. [ABSTRACT FROM AUTHOR]

Background: activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) plays a key role in schizophrenia (SCZ) and treatment resistant SCZ. There are only a few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ. Methods: we examined serum β-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls. Results: serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. β-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and β-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions. Conclusion: the EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, and physical and emotional symptoms. Although its pathophysiology is largely unknown, immune-inflammatory pathways may be involved. We examined serum interleukin (IL)-6, high sensitivity C-reactive protein (hs-CRP), CXCL-8, and IL-10 in 67 female FM patients and 35 healthy women while adjusting for age, body mass index (BMI), and comorbid disorders. We scored the Fibromyalgia Severity Score, Widespread Pain Index (WPI), Symptom Severity Scale (SSS), Hospital Anxiety (HADS-A), and Depression Scale and the Perceived Stress Scale (PSS-10). Clinical rating scales were significantly higher in FM patients than in controls. After adjusting for covariates, IL-6, IL-10, and CXCL-8 were lower in FM than in HC, whereas hs-CRP did not show any difference. Binary regression analyses showed that the diagnosis FM was associated with lowered IL-10, quality of sleep, aerobic activities, and increased HADS-A and comorbidities. Neural networks showed that WPI was best predicted by quality of sleep, PSS-10, HADS-A, and the cytokines, while SSS was best predicted by PSS-10, HADS-A, and IL-10. Lowered levels of cytokines are associated with FM independently from confounders. Lowered IL-6 and IL-10 signaling may play a role in the pathophysiology of FM. [ABSTRACT FROM AUTHOR]