Search

The binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research. The study's objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores. This study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors, SBs), lifetime and current SBs and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers including apolipoprotein (Apo)A, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices. We were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7 % of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features. The outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including SBs. • Depression should not be represented as a binary variable, but rather as multiple continuous scores. • These continuous scores include recurrence of illness, suicidal behaviors, and the phenome. • We show how to build nomothetic models that include biomarkers and adverse childhood experiences. • These continuous scores are designated as Research and Diagnostic Algorithmic Rules (RADAR). • These RADAR scores can be integrated into a RADAR graph, a personalized fingerprint of the patient. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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

Major depression (MDD) and a lifetime history of MDD are characterized by increased nitrosylation, while bipolar disorder type 1 (BP1), but not BP2, is accompanied by highly increased levels of oxidative stress and nitric oxide (NO) production. Nevertheless, it is unknown whether nitrosylation is involved in BP and whether there are differences in nitrosylation between BP1 and BP2. Serum IgM antibodies directed against nitroso (NO)-adducts were examined in MDD, BP1, BP2 and healthy controls, namely IgM responses to NO-cysteine, NO-tryptophan (NOW), NO-arginine and NO-albumin (SBA) in association with IgA/IgM responses to LPS of Gram-negative bacteria, IgG responses to oxidized low-density lipoprotein (ox-LDL) and serum peroxides. Serum IgM levels against NO adducts were significantly higher in BP1 and MDD as compared with healthy controls, whereas BP2 patients occupied an intermediate position. IgM responses to NO-albumin were significantly higher in BP1 and MDD than in BP2 patients. There were highly significant associations between the IgM responses to NO-adducts and IgG responses to ox-LDL and IgA/IgM responses to Gram-negative bacteria. BP1 and MDD are characterized by an upregulation of the nitrosylome (the proteome of nitrosylated proteins) and increased IgM responses to nitrosylated conjugates. Increased nitrosylation may be driven by increased bacterial translocation and is associated with lipid peroxidation processes. Innate-like (B1 and marginal zone) B cells and increased nitrosylation may play a key role in the major affective disorders through activation of immune-inflammatory and oxidative pathways, cardiovascular comorbidity and impairments in antioxidant defenses, neuro-glial interactions, synaptic plasticity, neuroprotection, neurogenesis. • Serum IgM levels against NO adducts are significantly increased in bipolar type 1 (BP1) and major depression (MDD). • There are significant associations between these IgM responses and IgG responses to oxidized LDL and IgA/IgM responses to Gram-negative bacteria. • BP1 and MDD are characterized by an upregulation of the nitrosylome and increased IgM responses to nitrosylated conjugates. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that nitro-oxidative pathways play an important role in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD) and maybe anxiety disorders. The current study aims to examine superoxide dismutase (SOD1), catalase, lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), malondialdehyde (MDA), glutathione (GSH), paraoxonase 1 (PON1), high-density lipoprotein cholesterol (HDL), and uric acid (UA) in participants with and without generalized anxiety disorder (GAD) co-occurring or not with BD, MDD, or tobacco use disorder. Z unit-weighted composite scores were computed as indices of nitro-oxidative stress driving lipid and protein oxidation. SOD1, LOOH, NOx, and uric acid were significantly higher and HDL and PON1 significantly lower in participants with GAD than in those without GAD. GAD was more adequately predicted by increased SOD + LOOH + NOx and lowered HDL + PON1 composite scores. Composite scores of nitro-oxidative stress coupled with aldehyde and AOPP production were significantly increased in participants with comorbid GAD + MDD as compared with all other study groups, namely MDD, GAD + BD, BD, GAD, and healthy controls. In conclusion, GAD is characterized by increased nitro-oxidative stress and lipid peroxidation and lowered lipid-associated antioxidant defenses, while increased uric acid levels in GAD may protect against aldehyde production and protein oxidation. This study suggests that increased nitro-oxidative stress and especially increased SOD1 activity, NO production, and lipid peroxidation as well as lowered HDL-cholesterol and PON1 activity could be novel drug targets for GAD especially when comorbid with MDD. [ABSTRACT FROM AUTHOR]

Background: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic- pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). Methods: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the ‘leaky gut’) in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. Results: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. Conclusions: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives. [ABSTRACT FROM AUTHOR]

The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood–brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed. [ABSTRACT FROM AUTHOR]

Introduction N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD. Methods A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (COEXH) (secondary outcome), and quit rates as defined by COEXH<6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses. Results NAC treatment significantly reduced the daily number of cigarettes used (Δ mean±SD = −10.9 ± 7.9 in the NAC-treated versus −3.2 ± 6.1 in the placebo group) and COEXH (Δ mean± SD = −10.4 ± 8.6 ppm in the NAC-treated versus −1.5 ± 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by COEXH<6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder. Conclusions These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD. [ABSTRACT FROM AUTHOR]

Abstract: Objective: There is evidence that major depression is characterized by oxidative and nitrosative stress (O&NS). The aim of this study is to examine IgM-mediated autoimmune responses against a variety of modified neo-epitopes formed by O&NS damage to self-epitopes in chronic depression. Methods: Serum IgM antibodies directed against conjugated oleic and azelaic acid, malondialdehyde (MDA), phosphatidyl inositol (Pi), and conjugated nitric-oxide (NO) adducts, i.e., NO-tryptophan, NO-tyrosine, NO-arginine, and NO-cysteinyl, were determined in 33 healthy controls and 74 depressed patients subdivided into 28 patients with chronic (duration >2 year) and 46 without chronic depression. Results: Serum IgM levels against all neoepitopes were significantly higher in depressed patients than in healthy controls. Moreover, the IgM levels were significantly higher, except Pi, in chronically depressed patients than in non-chronically depressed patients. Conclusions: Depression is characterized by IgM-related autoimmune responses directed against neo-epitopes that are normally hidden from the immune system but that became immunogenic secondary to damage by O&NS. The results show that the generation of neoantigenic determinants that lead to (auto)immune responses is strongly associated with chronic depression. Discussion: The damage caused by O&NS to auto-epitopes and the consequent formation of O&NS modified neoantigenic determinants may increase the risk to develop depression and in particular chronic depression through transition to autoimmune reactions. This has implications for understanding the immuno-inflammatory and oxidative-autoimmune pathways that lead to chronic depression and neuroprogression in that illness. [Copyright &y& Elsevier]

Abstract: Schizophrenia and depression are two common and debilitating psychiatric conditions. Up to 61% of schizophrenic patients have comorbid clinical depression, often undiagnosed. Both share significant overlaps in underlying biological processes, which are relevant to the course and treatment of both conditions. Shared processes include changes in cell‐mediated immune and inflammatory pathways, e.g. increased levels of pro-inflammatory cytokines and a Th1 response; activation of oxidative and nitrosative stress (O&NS) pathways, e.g. increased lipid peroxidation, damage to proteins and DNA; decreased antioxidant levels, e.g. lowered coenzyme Q10, vitamin E, glutathione and melatonin levels; autoimmune responses; and activation of the tryptophan catabolite (TRYCAT) pathway through induction of indoleamine-2,3-dioxygenase. Both show cognitive and neurostructural evidence of a neuroprogressive process. Here we review the interlinked nature of these biological processes, suggesting that schizophrenia is immunologically primed for an increased expression of depression. Such a conceptualization explains, and incorporates, many of the current perspectives on the nature of schizophrenia and depression, and has implications for the nature of classification and treatment of both disorders. An early developmental etiology to schizophrenia, driven by maternal infection, with subsequent impact on offspring immuno-inflammatory responses, creates alterations in the immune pathways, which although priming for depression, also differentiates the two disorders. [Copyright &y& Elsevier]

Depression is a complex progressive disorder accompanied by activation of inflammatory and Th-1 driven pathways, oxidative and nitrosative stress (O&NS), lowered antioxidant levels, mitochondrial dysfunctions, neuroprogression and increased bacterial translocation. In depression, activation of immuno-inflammatory pathways is associated with an increased risk for cardio-vascular disorder (CVD). Because of the inflammatory component, the use of cyclooxygenase 2 (COX-2) inhibitors, such as celecoxib, has been advocated to treat depression. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this selective review on the effects of COX-2 inhibitors aggravating the abovementioned pathways. COX-2 inhibitors may induce neuroinflammation, exacerbate Th1 driven responses, increase lipid peroxidation, decrease the levels of key antioxidants, damage mitochondria and aggravate neuroprogression. COX-2 inhibitors may aggravate bacterial translocation and CVD through Th1-driven mechanisms. COX-2 inhibitors may aggravate the pathophysiology of depression. Since Th1 and O&NS pathways are risk factors for CVD, the use of COX-2 inhibitors may further aggravate the increased risk for CVD in depression. Selectively targeting COX-2 may not be a viable therapeutic approach to treat depression. Multi-targeting of the different pathways that play a role in depression is more likely to yield good treatment results. [ABSTRACT FROM AUTHOR]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and depression are considered to be neuro-immune disorders (Maes and Twisk, BMC Medicine 8:35, ). There is also evidence that depression and ME/CFS are accompanied by oxidative and nitrosative stress (O&NS) and by increased autoantibodies to a number of self-epitopes some of which have become immunogenic due to damage by O&NS. The aim of this study is to examine IgM-mediated autoimmune responses to different self-epitopes in ME/CFS versus depression. We examined serum IgM antibodies to three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine); acetylcholine; and conjugated NO-modified adducts in 26 patients with major depression; 16 patients with ME/CFS, 15 with chronic fatigue; and 17 normal controls. Severity of fatigue and physio-somatic (F&S) symptoms was measured with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale. Serum IgM antibodies to the three anchorage molecules and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with F&S symptoms. The autoimmune activity directed against conjugated acetylcholine did not differ significantly between ME/CFS and depression, but was greater in the patients than controls. Partially overlapping pathways, i.e. increased IgM antibodies to a multitude of neo-epitopes, underpin both ME/CFS and depression, while greater autoimmune responses directed against anchorage molecules and oxidatively modified neo-epitopes discriminate patients with ME/CFS from those with depression. These autoimmune responses directed against neoantigenic determinants may play a role in the dysregulation of key cellular functions in both disorders, e.g. intracellular signal transduction, cellular differentiation and apoptosis, but their impact may be more important in ME/CFS than in depression. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recently, we discovered that depression is accompanied by increased IgM and IgA responses directed against gram negative gut commensals. The aim of this study was to replicate these findings in a larger study group of depressed patients and to examine the associations between the IgA and IgM responses to gut commensals and staging of depression as well as the fatigue and somatic (F&S) symptoms of depression. Methods: We measured serum concentrations of IgM and IgA against the LPS of gram-negative enterobacteria, i.e. Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in 112 depressed patients and 28 normal controls. The severity of F&S symptoms was measured using the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale. Results: The prevalences and median values of serum IgM and IgA against LPS of these commensals were significantly higher in depressed patients than in controls. The IgM levels directed against the LPS of these commensal bacteria were significantly higher in patients with chronic depression than in those without. The immune responses directed against LPS were not associated with melancholia or recurrent depression. There was a significant correlation between the IgA response directed against LPS and gastro-intestinal symptoms. Discussion: The results indicate that increased bacterial translocation with immune responses to the LPS of commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression. Bacterial translocation may a) occur secondary to systemic inflammation in depression and intensify and perpetuate the primary inflammatory response once the commensals are translocated; or b) be a primary trigger factor associated with the onset of depression in some vulnerable individuals. The findings suggest that “translocated” gut commensal bacteria activate immune cells to elicit IgA and IgM responses and that this phenomenon may play a role in the pathophysiology of (chronic) depression by causing progressive amplifications of immune pathways. [Copyright &y& Elsevier]

Background: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS. Methods: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients. Results: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS. Conclusions: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared 'pathway phenotype', i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy. [ABSTRACT FROM AUTHOR]

Abstract: The tryptophan catabolite (TRYCAT) pathway is induced by indoleamine 2,3-dioxygenase (IDO), which upon activation depletes plasma tryptophan (TRP) and increases the synthesis of TRYCATs. Both phenomena are associated with somatization and depression. The aims of this study are to examine whether disorders in the TRYCAT pathway are specific to depression or somatization and whether the diagnoses somatization, depression, and comorbid depression+somatization reflect qualitatively distinct clinical and biological categories. Plasma TRP, the kynurenine (KY)/TRP and KY/kynurenic acid (KA) ratios were measured in 36 patients with somatization, 35 depressed and 38 depressed+somatization patients and 22 controls. Using pattern recognition methods, the diagnosis comorbid depression+somatization could not be validated, while there was an important overlap between depression and somatization, which form one continuum. Cluster analysis detected a) a control cluster; b) a cluster with lower tryptophan, and higher KY/TRP and KY/KA ratios and somatization scores; and c) a cluster with increased depression but lower KY/TRP values. The differences between both patient clusters were quantitative and not qualitative. Within the patient group, cluster analysis has generated a “pathway phenotype”, i.e. aberrations in the TRYCAT pathway, which are associated with somatization rather than with depression. [Copyright &y& Elsevier]

Abstract: This paper reviews that cell-mediated-immune (CMI) activation and inflammation contribute to depressive symptoms, including anhedonia; anxiety-like behaviors; fatigue and somatic symptoms, e.g. illness behavior or malaise; and mild cognitive impairment (MCI). These effects are in part mediated by increased levels of pro-inflammatory cytokines (PICs), e.g. interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF)α, and Th-1-derived cytokines, such as IL-2 and interferon (IFN)γ. Moreover, new pathways, i.e. concomitants and sequels of CMI activation and inflammation, were detected in depression: (1) Induction of indoleamine 2,3-dioxygenase (IDO) by IFNγ and some PICs is associated with depleted plasma tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic and depressogenic tryptophan catabolites. (2) Increased bacterial translocation may cause depression-like behaviors by activating the cytokine network, oxidative and nitrosative stress (O&NS) pathways and IDO. (3) Induction of O&NS causes damage to membrane ω3 PUFAs, functional proteins, DNA and mitochondria, and autoimmune responses directed against intracellular molecules that may cause dysfunctions in intracellular signaling. (4) Decreased levels of ω3 PUFAs and antioxidants, such as coenzyme Q10, glutathione peroxidase or zinc, are associated with an increased inflammatory potential; more oxidative damage; the onset of specific symptoms; and changes in the expression or functions of brain 5-HT and N-methyl-d-aspartate receptors. (5) All abovementioned factors cause neuroprogression, that is a combination of neurodegeneration, neuronal apoptosis, and lowered neurogenesis and neuroplasticity. It is concluded that depression may be the consequence of a complex interplay between CMI activation and inflammation and their sequels/concomitants which all together cause neuroprogression that further shapes the depression phenotype. Future research should employ high throughput technologies to collect genetic and gene expression and protein data from patients with depression and analyze these data by means of systems biology methods to define the dynamic interactions between the different cell signaling networks and O&NS pathways that cause depression. [Copyright &y& Elsevier]

Abstract: Background: There is evidence that depression is accompanied by oxidative and nitrosative stress (O&NS), as indicated by increased free radical levels, lipid peroxidation, and lowered antioxidant levels. The aims of the present study are to examine whether depression is accompanied by autoimmune responses directed against a) neoepitopes that are formed following O&NS damage; and b) the major anchorage molecules, i.e. palmitic and myristic acids and S-farnesyl-l-cysteine. Methods: We examined serum IgM antibodies to the conjugated fatty acids, palmitic and myristic acids; acetylcholine; S-farnesyl-l-cysteine; and NO-modified adducts in 26 depressed patients and 17 normal controls. Severity of depression was measured with the Hamilton Depression Rating Scale and severity of fatigue and somatic (F&S) symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Results: The prevalences and mean values for the serum IgM levels directed against conjugated palmitic and myristic acids, acetylcholine, S-farnesyl-l-cysteine; and the conjugated NO adducts, NO-tyrosine, NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine were significantly higher in depressed patients than in normal controls. The autoimmune responses were significantly related to FF symptoms, such as fatigue and a flu-like malaise, whereas the indicants of nitrosative stress were related to gastro-intestinal and autonomic symptoms. Discussion: Depression is characterized by IgM-related autoimmune responses directed against a) neoepitopes that are normally not detected by the immune system but that due to damage by O&NS have become immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic acids, and S-farnesyl-l-cysteine. These autoimmune responses play a role in the inflammatory and O&NS pathophysiology of depression and may mediate the cellular dysfunctions that contribute to neuroprogression, e.g. aberrations in signal transduction, cellular differentiation and apoptosis. [Copyright &y& Elsevier]

Abstract: The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990–1993 (Maes et al.). Recently, it was reported that – based on meta-analysis results – depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression. [Copyright &y& Elsevier]

Abstract: There is a significant ‘comorbidity’ between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy. This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2′-5′ oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS. Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways. Depression and ME/CFS are not ‘comorbid’ disorders, but should be regarded as ‘co-associated disorders’ that are clinical manifestations of shared pathways. [Copyright &y& Elsevier]

Abstract: Background: Major depression is characterized by a decreased antioxidant status, an induction of the inflammatory and oxidative and nitrosative (IO&NS) pathways and inflammatory-neurodegenerative (I&ND) pathways. This study examines two markers of oxidative stress in depression, i.e. plasma peroxides and serum oxidized LDL (oxLDL) antibodies. Methods: Blood was sampled in 54 patients with major depression (mean±SD age=43.5±11.6years) and 37 normal volunteers (43.6±11.1years). The severity of illness was measured by means of the Hamilton Depression Rating Scale. The Fibromyalgia and Chronic Fatigue Syndrome Rating Scale was used to measure severity of “psychosomatic” symptoms in depression. Results: We found significantly higher plasma peroxides (p =0.002) and serum oxLDL antibodies (p =0.0002) in depressed patients as compared to normal controls. There was no significant correlation between both markers and both independently from each other predicted major depression. There were significant correlations between the oxLDL antibodies and the scores on two items of the FF scale, i.e. gastro-intestinal symptoms and headache. Discussion: The results show that major depression is accompanied by increased oxidative stress and lipid peroxidation. These results further extend the IO&NS pathophysiology of major depression. Since increased peroxides and oxLDL antibodies are predictors of coronary artery disease (CAD) and neurodegeneration, our findings suggest that IO&NS pathways are involved in the increased incidence of both CAD and neurodegeneration in depression. [ABSTRACT FROM AUTHOR]

• First episode major depression is accompanied by increased adverse childhood experiences (ACEs) and negative life events (NLEs). • A significant part of the impact of ACEs and NLEs on the major depression phenome is mediated by activated immune and growth factors networks. • ACEs and NLEs are highly significantly correlated with different cytokines/chemokines/growth factors, especially with interleukin (IL)−16, CCL27, stem cell growth factor, and platelet-derived growth factor. This research assessed the effects of adverse childhood experiences (ACEs) and negative life events (NLEs) on forty-eight cytokines/chemokines/growth factors, in 71 FE-MDMD patients and forty heathy controls. ACEs are highly significantly associated with the classical M1 macrophage, T helper (Th)-1, Th-1 polarization, IRS, and neurotoxicity immune profiles, and not with the alternative M2, and Th-2 immune profiles. There are highly significant correlations between ACEs and NLEs and different cytokines/chemokines/growth factors, especially with interleukin (IL)-16, CCL27, stem cell growth factor, and platelet-derived growth factor. Partial Least Squares analysis showed that 62.3 % of the variance in the depression phenome (based on severity of depression, anxiety and suicidal behaviors) was explained by the regression on IL-4 (p = 0.001, inversely), the sum of ACEs + NLEs (p < 0.0001), and a vector extracted from 10 cytokines/chemokines/growth factors (p < 0.0001; both positively associated). The latter partially mediated (p < 0.0001) the effects of ACE + NLEs on the depression phenome. In conclusion, part of the effects of ACEs and NLEs on the depression phenome is mediated via activation of immune and growth factor networks. These pathways have a stronger impact in subjects with lowered activities of the compensatory immune-regulatory system. [ABSTRACT FROM AUTHOR]

Background: The aim is to examine whether biomarkers of the immune-inflammatory response (IRS) and endogenous opioid (EOS) systems are associated with affective symptoms in schizophrenia.Methods: We recruited 115 schizophrenia patients and 43 healthy controls and assessed the Hamilton Depression (HDRS) and Anxiety (HAM-A) rating Scale scores as well as serum levels of interleukin (IL)-6, IL-10, eotaxin (CCL11), high mobility group box 1 (HMGB1), Dickkopf-related protein 1 (DKK1), and mu (MOR) and kappa (KOR) opioid receptors.Results: The HDRS and HAM-A scores are significantly and positively correlated with a) psychosis, hostility, excitation, mannerism, negative symptoms, psychomotor retardation, and formal thought disorders; and b) lowered scores on semantic and episodic memory, executive functions, and attention tests as measured with the Brief Assessment of Cognition in Psychiatry. Both HDRS and HAM-A are significantly increased in non-responders to treatment as compared with partial responders. Both affective scores are strongly associated with a latent vector extracted from all symptoms, reflecting overall severity of schizophrenia symptoms (OSOS), and neurocognitive test scores, reflecting a generalized cognitive decline (G-CoDe). The HDRS score was strongly and positively associated with IL-6, HMGB1, KOR, and MOR levels, and the HAM-A score with IL-6, IL-10, CCL11, HMGB1, KOR, and MOR levels. A single latent trait may be extracted from OSOS, G-CoDe, and the HDRS and HAMA scores, and this latent vector score is strongly predicted by HMGB1, MOR, and DKK1.Conclusion: Immune-inflammatory and EOS pathways contribute to the phenome of schizophrenia, which comprises OSOS, affective, and physiosomatic symptoms, and G-CoDe. [ABSTRACT FROM AUTHOR]

Objective: To explore illness-related factors in patients with major depressive disorder (MDD) recipients of adjunctive minocycline (200 mg/day) treatment. The analysis included participants experiencing MDD from a 12-week, double blind, placebo-controlled, randomized clinical trial (RCT). Methods: This is a sub-analysis of a RCT of all 71 participants who took part in the trial. The impact of illness chronicity (illness duration and number of depressive episodes), systemic illness (endocrine, cardiovascular and obesity), adverse effects and minocycline were evaluated as change from baseline to endpoint (12-week) using ANCOVA. Results: There was a consistent but statistically non-significant trend on all outcomes in favour of the use of adjunctive minocycline for participants without systemic illness, less illness chronicity, and fewer adverse effects. Conclusion: Understanding the relationship between MDD and illness chronicity, comorbid systemic illness, and adverse effects, can potentially better characterise those individuals who are more likely to respond to adjunctive anti-inflammatory medications. [ABSTRACT FROM AUTHOR]

Chronic fatigue and fibromyalgia symptoms frequently occur in major depressive disorder (MDD). The pathophysiology of these symptoms may in part, be ascribed to activated immune pathways, although it is unclear whether muscular factors play a role in their onset. The aim of the present study is to examine the role of muscle proteins in major depression in association with symptoms of chronic fatigue and fibromyalgia. We measured serum levels of agrin, talin-2, titin, and creatine phosphokinase (CPK) as well as the FibroFatigue (FF), the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory (BDI-II) scores in 60 MDD patients and 30 healthy controls. The results show a significant increase in agrin and talin-2 in MDD patients as compared with controls. There were highly significant correlations between agrin and HAM-D, BDI-II and FF scores. Agrin, but not talin or titin, was significantly and positively associated with all 12 items of the FF scale. We found that a large part of the variance in HAM-D (47.4%), BDI-II (43.4%) and FF (43.5%) scores was explained by the regression on agrin, smoking, female sex (positively associated) and education (inversely associated). CPK was significantly and inversely associated with the total FF score and with muscle and gastro-intestinal symptoms, fatigue, a flu-like malaise, headache and memory, autonomic and sleep disturbances. These results suggest that aberrations in neuromuscular (NMJs) and myotendinous junctions play a role in MDD and that the aberrations in NMJs coupled with lowered CPK may play a role in chronic fatigue and fibromyalgia symptoms in MDD. Moreover, the increase of agrin in MDD probably functions as part of the compensatory immune-regulatory system (CIRS). [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is characterized by elevated activity of peripheral neuro-immune and neuro-oxidative pathways, which may cause neuro-affective toxicity by disrupting neuronal circuits in the brain. No study has explored peripheral indicators of neuroaxis damage in MDD in relation to serum inflammatory and insulin resistance (IR) biomarkers, calcium, and the physio-affective phenome consisting of depressive, anxious, chronic fatigue, and physiosomatic symptoms. Serum levels of phosphorylated tau protein 217 (P-tau217), platelet-derived growth factor receptor beta (PDGFR), neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), C-reactive protein (CRP), calcium and the HOMA2-insulin resistance (IR) index were measured in 94 MDD patients and 47 controls. 61.1 % of the variance in the physio-affective phenome (conceptualized as a factor extracted from depression, anxiety, fatigue and physiosomatic symptoms) is explained by the regression on GFAP, NF-L, P-tau2017, PDGFRβ and HOMA2-IR (all positively associated), and decreased calcium. In addition, CRP and HOMA2-IR predicted 28.9 % of the variance in the neuroaxis index. We observed significant indirect effects of CRP and calcium on the physio-affective phenome which were partly mediated by the four neuroaxis biomarkers. Annotation and enrichment analysis revealed that the enlarged GFAP, P-tau217, PDGFR, and NF-L network was enriched in glial cell and neuronal projections, the cytoskeleton and axonal transport, including a mitochondrion. Peripheral inflammation and IR may damage the astroglial and neuronal projections thereby interfering with mitochondrial transport. This neurotoxicity, combined with inflammation, IR and lowered calcium, may, at least in part, induce the phenome of MDD. • Major depressive disorder (MDD) is characterized by neuro-immune pathways • Serum biomarkers of astroglial and neuronal injuries are increased in MDD • These injuries are partly explained by insulin resistance and inflammation • Astroglial and neuronal projection toxicity are characteristics of MDD • Projection toxicity, IR and inflammation contribute to the phenome of MDD. [ABSTRACT FROM AUTHOR]

Background: Some months after the remission of acute COVID-19, some individuals show depressive symptoms, which are predicted by increased peak body temperature (PBT) and decreased blood oxygen saturation (SpO2). No data indicate whether Long COVID is associated with increased insulin resistance (IR) in association with neuroimmune and oxidative (NIO) processes. Methods: This case control and retrospective cohort study used the homeostasis Model Assessment 2 (HOMA2) calculator© to compute β-cell function, insulin sensitivity and resistance (HOMA2-IR) and measured the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HAMD) in 86 Long COVID patients and 39 controls. Results: Long COVID (3-4 months after the acute infection) is accompanied by increased HOMA2-IR, fasting blood glucose, and insulin levels; 33.7% of the patients versus 0% of the controls had HOMA2-IR values >1.8, suggesting IR. Increased IR was predicted by PBT during acute infection, and associated with depressive symptoms above and beyond the effects of NIO pathways (NLRP3 inflamasome, myeloperoxidase, protein oxidation). There were no significant associations between increased IR and the activated NIO pathways during Long COVID. Conclusion: Long COVID is associated with new-onset IR which may contribute to the onset of depressive symptoms due to Long COVID by enhancing overall neurotoxicity. [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]

Objectives: To delineate the effects of white matter hyperintensities (WMHs) as measured by Fluid-attenuated inversion recovery (FLAIR) and infarction volume as measured by Diffusion-weighted imaging (DWI) on post-stroke depression symptoms.Methods: Baseline National Institutes of Health Stroke Score (NIHSS) and Modified Rankin Scale (mRS) scores, and FLAIR and DWI MRIs to assess WMHs and acute infarct volumes, respectively, were assessed in 47 patients (≥55 years) with acute ischemic stroke and 17 normal controls. The Montgomery-Åsberg Depression Rating Scale (MDRS) was assessed three months after the stroke.Results: The MADRS score was significantly increased in stroke patients as compared with normal controls. The MADRS scale is not unidimensional and cannot be used as an accurate indicator of depression severity in stroke patients. Three months after stroke, key depressive (sadness and inability to feel) and concentration-tension symptoms, and lassitude are significantly predicted by the infarct volume. Right side infarction strongly predicts key depressive symptoms and left side infarction strongly predicts concentration-tension and lassitude scores. Total WMHs significantly predict key depressive and concentration-tension symptoms, and lassitude, with these effects being mediated by right and left DWI stroke volumes and associated disabilities.Conclusions: Interactions between age, hypertension, a chronic atherosclerotic process, and acute stroke account for the onset of key depressive symptoms three months after the acute infarct. Chronic and acute neuro-immune and neuro-oxidative stress pathways associated with the formation of WMHs and acute stroke may explain the incidence of post-stroke key depressive and concentration-tension symptoms, and lassitude. [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]

Major depressive disorder (MDD) is a common, severe and disabling neuropsychiatric disorder with a heterogenous etiology. Among the most widely recognized etiological models, immunopathogenesis is a predominant one. Numerous studies have demonstrated aberrant levels of inflammatory markers in the peripheral blood, cerebrospinal fluid (CSF) and brain of patients with MDD. Multiple studies including meta-analyses have reported increased peripheral levels of acute phase proteins, and pro-inflammatory cytokines, particularly IL-1β, TNF-α, and IL-6 in MDD. Postmortem brain studies similarly demonstrated upregulated expressions of these pro-inflammatory cytokines. This along with evidence of monocytic, lymphocytic and microglial activation, suggest an activated inflammatory response system (IRS) in MDD. A few studies show increased levels of anti-inflammatory cytokines or defective inflammatory pathways and a deficit in T cell maturation and responses in MDD patients. This suggests the presence of a Compensatory Immune Response System (CIRS), which can counterbalance the effects of IRS in major depression. More recently, simultaneously increased levels of both the pro-and anti-inflammatory cytokines are reported in the brain of MDD patients; this indicates activity of both the IRS and CIRS in MDD. The IRS and CIRS are the evolutionarily conserved and integral elements of an overarching system. The relevance of a dysregulated IRS-CIRS system in the neurobiological construct of MDD is just beginning to be understood. Speculation is rife that the disrupted IRS-CIRS elements might determine the onset, episodes, neuroprogressive processes, treatment response as well as recovery of patients with MDD. Notably, the signatures of an activated IRS-CIRS might emerge as potential biomarkers of MDD. Herein, an attempt has been made to highlight the biology and pathobiological relevance of IRS-CIRS activation in MDD and provide an insight into the role of these components in pharmacological therapy. • Altered Inflammatory Response System (IRS) is evident in major depression disorder (MDD). • A defective Compensatory Immune Response System (CIRS) seems to affect IRS and CIRS balance in MDD. • Deficit in IRS and CIRS axis seems to contribute to neuroprogressive changes in MDD. [ABSTRACT FROM AUTHOR]

Depressive disorder is a multifactorial diseases, that one of the typical feature are cognitive impairments. The aim of this study was to determine the total antioxidant status (TAS) in patients with recurrent depressive disorder (rDD) and to define relationship between plasma levels of TAS and the cognitive performance. Design and methods: the study comprised 74 subjects: patients with rDD ( n = 45) and healthy subjects ( n = 29). Cognitive function assessment was based on: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. Statistically significant differences were found in the intensity of depression symptoms, measured by the Hamilton Depression Rating Scale (HDRS) on therapy onset versus the examination results after 8 weeks of treatment ( p < 0.001). The level of TAS was substantially higher in patients with rDD ( p = 0.01). For rDD patients, elevated TAS levels were associated with worse cognitive test performance. The higher was the concentration of plasma TAS, the greater was the severity of depressive symptoms measured by HDRS before and after pharmacotherapy. (1) Higher concentration of plasma TAS in rDD patients is associated with the severity of depressive symptoms. (2) Elevated levels of plasma TAS are related to impairment of short-term declarative memory, long-term declarative-memory, verbal fluency and working memory. [ABSTRACT FROM AUTHOR]

• Mood disorders can feature disturbances in lipid metabolism, oxidative stress and inflammation. • Statins are extensively prescribed for cardiovascular disease for their lipid-lowering properties. • Pleiotropic effects of statins include anti-inflammatory and anti-oxidative action. • Growing evidence suggests statins may have potential as adjunctive psychotropic agents. • Larger scale clinical trials are needed to better assess the utility of statins in mood disorders. 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. [ABSTRACT FROM AUTHOR]

Background: Transfusion dependent thalassemia (TDT) patients are treated with continued blood transfusions and show a higher prevalence of depression. TDT with consequent iron overload and inflammation is associated with increased severity of depressive symptoms in TDT children.Aim Of the Study: To construct a pathway-phenotype which combines iron overload and neuro-immune biomarkers with depressive symptom subdomains in TDT children.Methods: We measured iron status parameters (iron, ferritin, transferrin saturation percentage) and inflammatory (interleukin-1β and tumour necrosis factor-α) biomarkers in TDT (n=111) and healthy (n=53) children and analyzed the results using machine learning.Results: Cluster analysis separated TDT children with depression from those without depression and revealed two depressive subgroups one with low self-esteem and another with increased social-irritability scores. Exploratory factor analysis validated four depressive symptom dimensions as reliable constructs, namely key depressive, physiosomatic, lowered self-esteem and social-irritability dimensions. Partial Least Squares showed that 73.0% of the variance in a latent vector extracted from those four clinical subdomains, immune-inflammatory and iron overload biomarkers was explained by exposure variables including the number of blood transfusions and hospitalizations and use of deferoxamine. The exposure data, iron and immune biomarkers, and symptom subdomains are reflective manifestations of a single latent trait, which shows internal consistency reliability and predictive relevance.Conclusions: The nomological network combining exposure, pathways and behavioral phenome manifestations provides an index of overall severity and disease risk and, therefore, constitutes a new drug target, indicating that iron overload and immune activation should be targeted to treat depression due to TDT. [ABSTRACT FROM AUTHOR]

Major depression is accompanied by increased IgM-mediated autoimmune responses to oxidative specific epitopes (OSEs) and nitric oxide (NO)-adducts. These responses were not examined in bipolar disorder type 1 (BP1) and BP2. IgM responses to malondialdehyde (MDA), phosphatidinylinositol, oleic acid, azelaic acid, and NO-adducts were determined in 35 healthy controls, and 47 major depressed (MDD), 29 BP1, and 25 BP2 patients. We also measured serum peroxides, IgG to oxidized LDL (oxLDL), and IgM/IgA directed to lipopolysaccharides (LPS). IgM responses to OSEs and NO-adducts (OSENO) were significantly higher in MDD and BP1 as compared with controls, and IgM to OSEs higher in MDD than in BP2. Partial Least Squares (PLS) analysis showed that 57.7% of the variance in the clinical phenome of mood disorders was explained by number of episodes, a latent vector extracted from IgM to OSENO, IgG to oxLDL, and peroxides. There were significant specific indirect effects of IgA/IgM to LPS on the clinical phenome, which were mediated by peroxides, IgM OSENO, and IgG oxLDL. Using PLS we have constructed a data-driven nomothetic network which ensembled causome (increased plasma LPS load), adverse outcome pathways (namely neuro-affective toxicity), and clinical phenome features of mood disorders in a data-driven model. Based on those feature sets, cluster analysis discovered a new diagnostic class characterized by increased plasma LPS load, peroxides, autoimmune responses to OSENO, and increased phenome scores. Using the new nomothetic network approach, we constructed a mechanistically transdiagnostic diagnostic class indicating neuro-affective toxicity in 74.3% of the mood disorder patients. [ABSTRACT FROM AUTHOR]

Background: Hypertension, atherogenicity and insulin resistance are major risk factors of cardiovascular disorder (CVD), which shows a strong comorbidity with major depression (MDD) and bipolar disorder (BD). Activated oxidative and nitrosative stress (O&NS), inflammatory pathways, and increased atherogenicity are shared pathways underpinning CVD and mood disorders.Methods: The current study examined the effects of lipid hydroperoxides (LOOH), superoxide dismutase (SOD), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) on systolic (SBP) and diastolic (DBP) blood pressure in 96 mood disordered patients and 60 healthy controls.Results: A large part of the variance in SBP (31.6%) was explained by the regression on a z unit-weighted composite score (based on LOOH, AOPP, SOD, NOx) reflecting nitro-oxidative stress toxicity (NOSTOX), coupled with highly sensitive C-reactive protein, body weight and use of antihypertensives. Increased DBP was best predicted (23.8%) by body mass index and NOSTOX. The most important O&NS biomarkers predicting an increased SBP were in descending order of significance: LOOH, AOPP and SOD. Higher levels of the atherogenic index of plasma, HOMA2 insulin resistance index and basal thyroid-stimulating hormone also contributed to increased SBP independently from NOSTOX. Although there were no significant changes in SBP/DBP in mood disorders, the associations between NOSTOX and blood pressure were significant in patients with mood disorders but not in healthy controls.Conclusions: Activated O&NS pathways including increased lipid peroxidation and protein oxidation, which indicates hypochlorous stress, are the most important predictors of an increased BP, especially in patients with mood disorders. [ABSTRACT FROM AUTHOR]

Beta-thalassemia major patients are treated with repeated blood transfusions, which may cause iron overload, which in turn may induce immune aberrations, and show an increased risk of depression. The aim of the present study is to examine whether repeated blood transfusions, iron overload, and immune-inflammatory responses are associated with depression in children (6–12 years) with transfusion-dependent thalassemia (TDT). The Children's Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%), and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in TDT with (n = 54) and without (n = 57) a major depression-like episode (MDLE) and in healthy children (n = 55). The results show that MDLE due to TDT is associated with a greater number of blood transfusions and increased iron overload and IL-1β levels. Partial least squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, iron overload, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of iron overload on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by iron overload and the path from iron overload to immune activation. Iron overload is also associated with increased IL-10 and lower CCL11 levels, but these alterations are not significantly associated with depression. In conclusion, blood transfusions may be causally related to MDLE in TDT children and their effects are in part mediated by increased iron overload and the consequent immune-inflammatory response. The results suggest that effects of iron overload and its consequences including inflammation and oxidative stress toxicity may cause MDLE. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate iron overload and immune-inflammatory responses and to prevent MDLE in children with TDT. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) and bipolar depression (BD) both share increased immune-inflammatory activation. However, there are unclear patterns of differences in peripheral immune profiles between them.Methods: We examined such differences in 245 MDD and 59 BD patients, recruited in the same center, who were in an acute depressive episode of moderate severity. Hierarchical binary logistic regression analyses and generalized linear models were used to compare levels of plasma biomarkers between groups and to predict dichotomous classification.Results: Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, IL-12 and IL-10 were significantly higher in MDD than in BD, whereas IL-6, sTNFR2, IL-18, IL-33, ST2 (IL1R Like 1) and KLOTHO were significantly higher in BD than in MDD. Moreover, logistic regression analyses correctly classified BD and MDD patients with 98.1% accuracy, using a combination of IL-6, IL-8, ST2, sTNFR2 (directly associated with BD) and IL-12 and TNF-α (directly associated with MDD). Patients with MDD with melancholic features showed higher IL-1β levels than those without melancholia. The sTNFR1 / sTNFR2 ratio significantly predicted MDD and state and trait anxiety and negative affect. Results remained significant after covariate adjustment, including drug use.Limitations: Cross-sectional study. Lack of control comparison group. Differences in exposure to medications among participants.Conclusions: Differences in immune profiles between BD and MDD patients exist, especially for the compensatory immune-regulatory system (CIRS): increased IL-10 is the primary immune-regulatory mechanism in MDD, while increased sTNFR2 and KLOTHO are the primary regulatory mechanisms in BD. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients. Methods: We measured serum zinc and copper, interleukin (IL)-1β, IL-4, IL-6, IL-18, interferon-γ, and transforming growth factor-β1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later. Results: We found significantly reduced serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) and the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper. During treatment, there was a significant inverse association between serum zinc and immune activation. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS. Conclusions: Lower zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is associated with alterations in calcium (Ca) and magnesium (Mg), as well as circulating pro- and anti-inflammatory cytokines. Anti-inflammatory drugs are commonly used as adjuvant treatments for MDD. However, no studies examined the effects of a combinatorial treatment with sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg levels in MDD. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of sertraline and ketoprofen on Ca and Mg (both total and ionized). In the same patients, we also examined the associations between both cations and IL-1β, IL-4, IL-6, IL-18, IFN-γ, TGF-β1, zinc, and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was assessed using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for 2 months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit-weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, lowered levels of both cations play a role in the pathophysiology of major depression. Antidepressant-induced increases in Ca are associated with clinical efficacy and attenuation of the immune response. The suppressant effect of antidepressants on Mg levels is probably a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg. [ABSTRACT FROM AUTHOR]

Abstract Objective Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) and aberrations in endogenous opioids play a role in the pathophysiology of major depressive disorder (MDD). There are no studies which examined the associations between both systems in MDD. The aim of the present study was to examine the relation between β-Endorphin (β-EP), Endomorphin-2, and their mu-opioid receptor (MOR) as well as interleukin (IL)-6 and IL-10, an anti-inflammatory cytokine, in MDD patients. Method The study included 60 depressed drug-free male patients and 30 matched controls. Serum β-EP, Endomorphin-2, MOR, IL-6 and IL-10 levels were measured using ELISA techniques. Results The results revealed a significant increase in serum β-EP, MOR, IL-6 and IL-10 in MDD patients versus healthy controls. MOR levels were strongly associated with IL-10 levels. There were no significant correlations between endogenous opioids and IL-6 and IL-10. Conclusion The results show that MOR levels may function as a possible component of the CIRS whilst there is no evidence that β-EP and EM-2 may modify the IRS. The significant correlation between MOR levels and IL-10 may be explained through central activation of the HPA-axis and increased B-cell numbers expressing MOR as a response to cytokine over-secretion in MDD. [ABSTRACT FROM AUTHOR]

Abstract Major depressed patients show increased bacterial translocation with elevated plasma levels of lipopolysaccharide (LPS), which may trigger immune-inflammatory and neuro-oxidative responses. Recently, an animal model based on chronic LPS administration was developed which was associated with long-lasting depressive-like and neuro-oxidative alterations in female mice. The aim of the current study was to investigate behavioral, neuroimmune and neuroprogressive alterations in female mice 6 weeks after LPS chronic exposure. Female mice received increasing doses of LPS during 5 days at one-month intervals repeated for 4 consecutive months. Six weeks after the last LPS-exposure, we assessed behavioral despair and anhedonia, microglial activation, alterations in tryptophan, 5-HT, kynurenine, quinolinic acid (QUIN) levels and spermidine/spermine N1-acetyltransferase (SAT1) expression in the hippocampus, both with and without fluoxetine administration. Our results show that six weeks post-LPS, mice present behavioral despair and anhedonia in association with increased IBA1 expression (a microglia activation marker), NF-kB p65 and IL-1β levels, indoleamine 2,3-dioxygenase (IDO1) mRNA expression, kynurenine, QUIN levels and QUIN/tryptophan ratio, and lowered tryptophan, 5-HT levels and SAT1 mRNA expression. Fluoxetine reversed the behavioral and neuroimmune alterations but had no effect in the reversal of IDO1 increased expression, QUIN levels and QUIN/tryptophan ratio. In conclusion, our results support the validity of the chronic LPS model of major depression and additionally shows its translational relevance with respect to neuroimmune and neuroprogressive pathways. Highlights • Chronic LPS exposure causes long-lasting behavioral alterations in females. • Chronic LPS induces long-lasting hippocampal neuroinflammatory changes. • LPS decreased tryptophan and 5-HT while increased quinolinic acid levels. • Fluoxetine completely reversed the behavioral while partially reversed the neurochemical alterations. [ABSTRACT FROM AUTHOR]

Activation of immune-inflammatory and oxidative-nitrosative (IO&NS) stress pathways plays a role in major depression (MDD). Evidence suggests that curcumin (500-1000 mg/day), a polyphenol with strong anti-IO&NS properties, may have efficacy either as monotherapy or as an adjunctive treatment for depression. Further controlled trials with extended treatment periods (> 8 weeks) and higher curcumin doses are warranted. This 12-week study was carried out to examine the effects of adjunctive curcumin for the treatment of MDD. In this double-blind, placebo-controlled trial, 65 participants with MDD were randomized to receive either adjunctive curcumin (increasing dose from 500 to 1500 mg/day) or placebo for 12 weeks. Four weeks after the active treatment phase, a follow-up visit was conducted at week 16. Assessments of the primary, i.e., the Montgomery-Asberg Depression Rating Scale (MADRS), and secondary, i.e., the Hamilton Anxiety Rating Scale (HAM-A), outcome measures were rated at baseline and 2, 4, 8, 12, and 16 weeks later. Curcumin was more efficacious than placebo in improving MADRS scores with significant differences between curcumin and placebo emerging at weeks 12 and 16. The effects of curcumin were more pronounced in males compared to females. There were no statistically significant treatment-emerging adverse effects and no significant effects of curcumin on blood chemistry and ECG measurements. Adjunctive curcumin has significant antidepressant effects in participants with MDD as evidenced by significant benefits occurring 12 and 16 weeks after treatment initiation. Curcumin administration was safe and well-tolerated even when combined with antidepressants. Future trials should include treatment-by-sex interactions to examine putative antidepressant effects of immune-modifying compounds. [ABSTRACT FROM AUTHOR]

Aim: We aimed to delineate the effects of immunoglobulin (Ig)M‐mediated autoimmune responses directed against malondialdehyde (MDA) and nitroso (SNO) adducts on nitro‐oxidative stress and depressive and physiosomatic symptoms (DPSS) at the end of term. Methods: IgM responses to MDA, NO (nitroso) adducts formed by nitrosylation, and NO2 tyrosine formed by nitration were measured as well as hydroperoxides (ferrous oxidation xylenol orange), advanced protein oxidation products (AOPP), and NO metabolite (NOx) levels in women at the end of term pregnancy and in normal controls. Results: IgM responses to MDA were significantly and inversely associated with AOPP, ferrous oxidation xylenol orange, and NOx and DPSS. IgM responses to NO adducts were significantly and inversely associated with DPSS and positively with NOx levels. There were significant associations between IgM responses to MDA, NO adducts, and NO2 tyrosine. The DPSS score was predicted by AOPP and a lifetime history of premenstrual syndrome (both positively) and IgM responses to NO adducts (inversely). Furthermore, 71.8% of the variance in the index of nitro‐oxidative stress was explained by lowered IgM responses to MDA, antioxidant levels (zinc, total radical trapping parameter), and inflammatory mediators. Conclusion: Lowered levels of IgM responses to MDA during pregnancy are accompanied by a reduced regulation of nitro‐oxidative processes thereby explaining increased oxidative and nitrosative stress biomarkers in association with DPSS. IgM responses to NO adducts, which reflect nitrosylation as a consequence of increased NO production, regulate DPSS symptoms at the end of term and are a trait marker of major depression. IgM responses to MDA are a key part of the compensatory anti‐inflammatory responses system. [ABSTRACT FROM AUTHOR]

To examine immune-inflammatory and oxidative (I&O) biomarkers in major depression (MDD) and its related phenotypes, we recruited 114 well-phenotyped depressed patients and 50 healthy controls and measured serum levels of interleukin (IL)-1α, soluble IL-1 receptor antagonist (sIL-1RA), soluble IL-2 receptor (sIL-2R), soluble IL-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 60 and 80 kDa (sTNF-R1/R2), and thiobarbituric acid reactive substances (TBARS). Obtained results indicate that MDD is characterized by increased sIL-1RA, sTNF-R1, and TBARS concentrations. Melancholic depression is associated with increased sIL-6R but lowered IL-1α levels. A current episode of depression is accompanied by significantly increased sIL-6R compared to the remitted state. Treatment-resistant depression (TRD) is accompanied by increased sIL-6R and TBARS but lowered sTNF-R2 levels compared to non-TRD patients. These immune markers are not significantly correlated with Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Scale (MADRS), number episodes, or age at onset. Our findings show that increased sIL-1RA, sTNF-R1, and TBARS levels may be trait markers of depression, while increased sIL-6R levels may be a state marker of melancholia and an acute phase of depression. MDD is accompanied by increased lipid peroxidation and simultaneous activation of immune pathways, and the compensatory anti-inflammatory reflex system (CIRS). TRD is characterized by highly increased oxidative stress and probably increased TNFα and IL-6 trans-signalling. Novel treatments for major depression should target oxidative stress pathways, while new treatments for TRD should primary target lipid peroxidation and also activated immune-inflammatory pathways. [ABSTRACT FROM AUTHOR]