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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]

Abstract: Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation. Methods: We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale). Results: The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise. Discussion: The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder. [Copyright &y& Elsevier]

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: 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]

Abstract: Background: There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an important role in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Activation of inflammatory and CMI pathways, including increased levels of cytokines, is known to induce fatigue and somatic symptoms. Given the broad spectrum inflammatory state in ME/CFS, the aim of this study was to examine whether inflammatory and CMI biomarkers are increased in individuals with ME/CFS. Methods: In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls. The severity of ME/CFS was measured with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Results: Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection. Conclusions: The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα. [Copyright &y& Elsevier]

Abstract: Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin. Methods: To study the relationships between the IgA/IgM responses to the LPS of microbiota, inflammation, CMI and the symptoms of ME/CFS we measured the IgA/IgM responses to the LPS of 6 different enterobacteria, serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). Severity of symptoms was assessed by the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Results: Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability. Conclusions: The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients. [Copyright &y& Elsevier]

Abstract: Background: Depression is characterized by inflammation and cell-mediated immune (CMI) activation and autoimmune reactions directed against a multitude of self-epitopes. There is evidence that the inflammatory response in depression causes dysfunctions in the metabolism of 5-HT, e.g. lowering the 5-HT precursor tryptophan, and upregulating 5-HT receptor mRNA. This study has been undertaken to examine autoimmune activity directed against 5-HT in relation to CMI activation and inflammation. Methods: 5-HT antibodies were examined in major depressed patients (n=109) versus normal controls (n=35) in relation to serum neopterin and lysozyme, and plasma pro-inflammatory cytokines (PIC), i.e. interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα). Severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS) and severity of fatigue and somatic symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Results: The incidence of anti-5-HT antibody activity was significantly higher in depressed patients (54.1%), and in particular in those with melancholia (82.9%), than in controls (5.7%). Patients with positive 5-HT antibodies showed increased serum neopterin and lysozyme, and plasma TNFα and IL-1; higher scores on the HDRS and FF scales, and more somatic symptoms, including malaise and neurocognitive dysfunctions. There was a significant association between autoimmune activity to 5-HT and the number of previous depressive episodes. Discussion: The autoimmune reactions directed against 5-HT might play a role in the pathophysiology of depression and the onset of severe depression. The strong association between autoimmune activity against 5-HT and inflammation/CMI activation is explained by multiple, reciprocal pathways between these factors. Exposure to previous depressive episodes increases the incidence of autoimmune activity directed against 5-HT, which in turn may increase the likelihood to develop new depressive episodes. These findings suggest that sensitization (kindling) and staging of depression are in part based on progressive autoimmune responses. [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: Background: Major depression is characterised by increased nitric oxide (NO) levels. Inhibition of the NO synthesizing enzymes, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), results in antidepressant-like effects, whereas the expression of iNOS and nNOS is increased in depression. Recent studies have indicated that NOS participates in the mechanisms of antidepressants. The aim of this study was to examine whether a single nucleotide polymorphism (SNP) present in the genes encoding iNOS and nNOS can contribute to the risk of developing recurrent depressive disorder (rDD). Methods: The study was carried out in a group of 181 depressive patients and 149 control subjects of Polish origin. SNPs were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. Results: The genotype distributions of the polymorphisms in exon 22 of the NOS2A gene and in exon 29 of the nNOS gene were significantly different between rDD patients and controls. The results showed that the G/A SNP of the gene encoding iNOS was associated with an increased susceptibility to rDD, whereas A/A homozygous carriers had a decreased risk of developing rDD. There was also a significant association between the C/T SNP of the gene encoding nNOS; the presence of the CC homozygous genotype decreased the risk of rDD, whereas the T allele and T/T homozygous genotype increased the vulnerability to rDD. Conclusions: Our results suggest that polymorphisms in the iNOS and nNOS genes confer an increased susceptibility or resistance to rDD. Future research should examine genetic variants and their associations to the expression of NOSs and NO level in depressive patients. [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]

Abstract: There is now evidence that chronic fatigue syndrome (CFS) is accompanied by immune disorders and by increased oxidative stress. The present study has been designed in order to examine the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia alvei; Pseudomonas aeruginosa, Morganella morganii, Proteus mirabilis, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in CFS patients, patients with partial CFS and normal controls. We found that the prevalences and median values for serum IgA against the LPS of enterobacteria are significantly greater in patients with CFS than in normal volunteers and patients with partial CFS. Serum IgA levels were significantly correlated to the severity of illness, as measured by the FibroFatigue scale and to symptoms, such as irritable bowel, muscular tension, fatigue, concentration difficulties, and failing memory. The results show that enterobacteria are involved in the etiology of CFS and that an increased gut–intestinal permeability has caused an immune response to the LPS of gram-negative enterobacteria. It is suggested that all patients with CFS should be checked by means of the IgA panel used in the present study and accordingly should be treated for increased gut permeability. [Copyright &y& Elsevier]

Abstract: The present study examines serum zinc concentrations in patients with chronic fatigue syndrome (CFS) versus normal volunteers. Serum zinc levels were determined by means of an atomic absorption method. We found that serum zinc was significantly lower in the CFS patients than in the normal controls. There was a trend toward a significant negative correlation between serum zinc and the severity of CFS and there was a significant and negative correlation between serum zinc and the subjective experience of infection. We found that serum zinc was significantly and negatively correlated to the increase in the alpha2 protein fraction and positively correlated to decreases in the expression of mitogen-induced CD69+ (a T cell activation marker) on CD3+ as well as CD3+CD8+ T cells. These results show that CFS is accompanied by a low serum zinc status and that the latter is related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong anti-oxidant, the present results further support the findings that CFS is accompanied by increased oxidative stress. The results of these reports suggest that some patients with CFS should be treated with specific antioxidants, including zinc supplements. [Copyright &y& Elsevier]

Background: COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like and physiosomatic symptoms.Aims: To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest computed tomography scan anomalies (CCTAs), oxygen saturation (SpO2), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs).Method: The above biomarkers were assessed in 60 COVID-19 patients and 30 healthy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales.Results: Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO2% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. One common "infection-immune-inflammatory (III) core" underpins pneumonia-associated CCTAs, lowered SpO2 and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms.Discussion: Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO2 which may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Many biochemical, immunological, and neuropsychiatric changes are associated with end-stage renal disease (ESRD). Neuronal damage biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), S100 calcium-binding protein B (S100B), ionized calcium-binding adaptor molecule-1 (IBA1), and myelin basic protein (MBP) are among the less-studied biomarkers of ESRD. We examined the associations between these neuro-axis biomarkers, inflammatory biomarkers, e.g., C-reactive protein (CRP), interleukin (IL-6), IL-10, and zinc, copper, and neuropsychiatric symptoms due to ERSD. ELISA techniques were used to measure serum levels of neuronal damage biomarkers in 70 ESRD patients, and 46 healthy controls. ESRD patients have higher scores of depression, anxiety, fatigue, and physiosomatic symptoms than healthy controls. Aberrations in kidney function tests and the number of dialysis interventions are associated with the severity of depression, anxiety, fibro-fatigue and physiosomatic symptoms, peripheral inflammation, nestin, and NFL. Serum levels of neuronal damage biomarkers (NFL, MBP, and nestin), CRP, and interleukin (IL)-10 are elevated, and serum zinc is decreased in ESRD patients as compared with controls. The neuronal damage biomarkers NFL, nestin, S100B and MBP are associated with the severity of one or more neuropsychiatric symptom domains. Around 50 % of the variance in the neuropsychiatric symptoms is explained by NFL, nestin, S00B, copper, and an inflammatory index. The severity of renal dysfunction and/or the number of dialysis interventions may induce peripheral inflammation and, consequently, neurotoxicity to intermediate filament proteins, astrocytes, and the blood-brain barrier, leading to the neuropsychiatric symptoms of ESRD. • ESRD patients have higher scores of depression, anxiety, and fatigue. • Kidney function decline and dialysis treatments cause peripheral inflammation. • NFL, MBP, and nestin are associated with the severity of neuropsychiatric symptoms. • Serum levels of NFL, MBP, nestin, CRP, and IL-10 are elevated in ESRD patients. [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]

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]

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]

Background: Suicide attempts (SA) frequently occur in patients with mood disorders and schizophrenia, which are both accompanied by activated immune-inflammatory and nitro-oxidative (IO&NS) pathways.Methods: We searched PubMed, Google Scholar, and Web of Science, for articles published from inception until February 1, 2021. We included studies that compared blood biomarkers in psychiatric patients with (SA+) and without SA (SA-) and heathy controls and we combined different IO&NS biomarkers into immune, inflammatory, and neurotoxic profiles and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence interval (CI).Findings: Our search included 51 studies comprising 4.945 SA+ patients and 24.148 controls. We stratified the control group into healthy controls and SA- patients. SA+ patients showed significantly (p<0.001) increased immune activation (SMD: 1.044; CI: 0.599, 1.489), inflammation (SMD: 1.109; CI: 0.505, 1.714), neurotoxicity (SMD: 0.879; CI: 0.465, 1.293), and lowered neuroprotection (SMD: 0.648; CI: 0.354, 0.941) as compared with healthy controls. When compared with SA- patients, those with SA+ showed significant (p<0.001) immune activation (SMD: 0.290; CI: 0.183, 0.397), inflammation (SMD: 0.311; CI: 0.191, 0.432), and neurotoxicity (SMD: 0.315; CI: 0.198, 0.432), and lowered neuroprotection (SMD: 0.341; CI: 0.167, 0.515). Patients with current, but not lifetime, SA showed significant (p<0.001) levels of inflammation and neurotoxicity as compared with controls.Conclusions: Patients with immune activation are at a higher risk of SA which may be explained by increased neurotoxicity due to inflammation and nitro-oxidative stress. This meta-analysis discovered new biomarkers of SA and therapeutic targets to treat individuals with SA. [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]

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]

Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS).Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle.Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively.Discussion: The novel case definition "MCAS" is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis. [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: To examine oxidative & nitrosative stress (O&NS) biomarkers at the end of term in relation to perinatal affective symptoms, neuro-immune biomarkers and pregnancy-related outcome variables.Methods: We measured plasma advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP), -sulfhydryl (-SH), peroxides (LOOH) and paraoxonase (PON)1 activity in pregnant women with and without prenatal depression and non-pregnant controls.Results: Pregnancy is accompanied by significantly increased AOPP and NOx, and lowered TRAP, -SH and LOOH. Increased O&NS and lowered LOOH and -SH levels are associated with prenatal depressive and physio-somatic symptoms (fatigue, pain, dyspepsia, gastro-intestinal symptoms). Increased AOPP and NOx are significantly associated with lowered -SH, TRAP and zinc, and with increased haptoglobin and C-reactive protein levels. Increased O&NS and lowered TRAP and PON 1 activity, at the end of term predict mother (e.g. hyperpigmentation, labor duration, caesarian section, cord length, breast milk flow) and baby (e.g. sleep and feeding problems) outcome characteristics.Conclusions: Pregnancy is accompanied by interrelated signs of O&NS, lowered antioxidant defenses and activated neuro-immune pathways. Increased O&NS at the end of term is associated with perinatal depressive and physio-somatic symptoms and may predict obstetric and behavioral complications in mother and baby. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) is a key factor in diabetes mellitus, metabolic syndrome (MetS) and obesity and may occur in mood disorders and tobacco use disorder (TUD), where disturbances of immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways are important shared pathophysiological pathways.Methods: This study aimed to a) examine IR and β-cell function as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity and β cell function (HOMA-B) and glucotoxicity (conceptualized as increased glucose levels versus lowered HOMA-B values) in 74 participants with major depressive disorder (MDD) and bipolar disorder, with and or without MetS and TUD, versus 46 healthy controls, and b) whether IR is associated with IO&NS biomarkers, including nitric oxide metabolites (NOx), lipid hydroperoxides (LOOH), plasma advanced oxidation protein products (AOPP), C-reactive protein (CRP), haptoglobin (Hp) and uric acid.Results: Mood disorders are not associated with changes in IR or glucotoxicity, although the number of mood episodes may increase IR. 47.8% of the variance in HOMA-IR is explained by AOPP and body mass index (BMI, both positively) and NOx, Hp and TUD (all inversely). 43.2% of the variance in HOMA-B is explained by NOx, Hp and age (all inversely associated) and higher BMI and sex. The glucotoxic index is strongly associated with NOx, Hp and BMI (positively), male gender and lower education.Limitations: This is a cross-sectional study and therefore we cannot draw firm conclusions on causal associations.Conclusions: Activated IO&NS pathways (especially increased Hp and NOx) increase glucotoxicity and exert very complex effects modulating IR. Mood disorders are not associated with increased IR. [ABSTRACT FROM AUTHOR]

Background: A significant subset of patients infected by the hepatitis C virus (HCV) develops a major depressive episode (MDE) during Interferon-alpha (IFN-α) based immunotherapy. We performed a systematic review of studies which examined biological mechanisms contributing to the onset of a MDE during IFN-α-based immunotherapy for HCV.Methods: Major electronic databases were searched from inception up until 15th February 2016 for peer-reviewed prospective studies that had enrolled HCV infected patients who received IFN-α treatment. A diagnosis of MDE had to be established by means of a standardized diagnostic interview at baseline and endpoint.Results: Eight unique references met inclusion criteria. A total of 826 participants with HCV (37.3% females, mean age 46.7 years) were included in this systematic review. The overall MDE incidence rate was 34.8%, with follow-up ranging between 4 and 48 weeks. The methodological quality varied across selected studies. It was observed that Interleukin-6, salivary cortisol, arachidonic acid / eicosapentaenoicacid plus docosahexaenoic acid ratio, and genetic polymorphisms may present variations which are linked to a predisposition to INF-α-induced depression.Limitations: A meta-analysis could not be performed due to the diverse biological mechanisms investigated and the lack of replicated evidence.Conclusions: This systematic review indicates that several potential mechanisms may be implicated in the onset of a MDE following IFN-α-based immunotherapy for chronic HCV. However, replicated evidence is lacking and therefore the mechanisms involved in IFN-α-induced depression in humans remain unclear. [ABSTRACT FROM AUTHOR]

Objective This study examines the effects of malondialdehyde (MDA) and uric acid on insulin resistance and atherogenicity in subjects with and without mood disorders, the metabolic syndrome (MetS) and tobacco use disorder (TUD). Methods We included 314 subjects with depression and bipolar depression, with and without the MetS and TUD and computed insulin resistance using the updated homeostasis model assessment (HOMA2IR) and atherogenicity using the atherogenic index of plasma (AIP), that is log10 (triglycerides/high density lipoprotein (HDL) cholesterol. Results HOMA2IR is correlated with body mass index (BMI) and uric acid levels, but not with mood disorders and TUD, while the AIP is positively associated with BMI, mood disorders, TUD, uric acid, MDA and male sex. Uric acid is positively associated with insulin and triglycerides and negatively with HDL cholesterol. MDA is positively associated with triglyceride levels. Comorbid mood disorders and TUD further increase AIP but not insulin resistance. Glucose is positively associated with increasing age, male gender and BMI. Discussion The results show that mood disorders, TUD and BMI together with elevated levels of uric acid and MDA independently contribute to increased atherogenic potential, while BMI and uric acid are risk factors for insulin resistance. The findings show that mood disorders and TUD are closely related to an increased atherogenic potential but not to insulin resistance or the MetS. Increased uric acid is a highly significant risk factor for insulin resistance and increased atherogenic potential. MDA, a marker of lipid peroxidation, further contributes to different aspects of the atherogenic potential. Mood disorders and TUD increase triglyceride levels, lower HDL cholesterol and are strongly associated with the atherogenic, but not insulin resistance, component of the MetS. [ABSTRACT FROM AUTHOR]

Background: There is a significant comorbidity between mood disorders and tobacco use disorder (TUD), which may be related to both genetic and environmental factors. Gene variants of the 5-HT transporter, such as STin2 VNTR (a variable number of tandem repeats in the functional serotonin transporter intron 2) may be associated with mood disorders and TUD.Aims: This study aimed to delineate the association between the STin2 genetic polymorphism and comorbid TUD and mood disorders, including depression or bipolar disorder.Methods: We examined the STin2 VNTR polymorphism in never-smokers (n=113); patients with mood disorders without TUD (n=62); patients with TUD without mood disorders (n=90); and patients with both disorders (n=95).Results: We found a significant association between the STin2 genetic polymorphism and the above diagnostic groups whereby the STin2.12 allele shows a positive association with comorbid TUD and mood disorders (Odds ratio=3.07, 95% CI=1.41-6.68), while the STin2.10/10 homozygous genotype shows a negative association (Odds ratio=0.34, 95% CI=0.16-0.74). Adjusting for years of education, age, gender, marital status and ethnicity did not change these results, but showed that TUD was associated with lower education levels and less stable relationships, whereas mood disorders were related to female gender. A family history of TUD was significantly associated with TUD in subjects without mood disorders only.Conclusions: The STin2.12 allele is positively and the STin2.10/10 genotype is negatively associated with comorbid TUD and mood disorders, depression or bipolar depression, suggesting that biological endophenotypes, e.g. disorders in serotonin metabolism, may in part underpin this comorbidity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Major depression and bipolar disorder are accompanied by the activation of immune-inflammatory and Oxidative and Nitrosative Stress (O&NS) pathways and lowered levels of antioxidants. Paraoxonase (PON)1 (EC 3.1.8.1) is an antioxidant bound to High Density Lipoprotein (HDL). Polymorphisms in the PON1 Q192R coding sequence determine three functional genotypes, i.e. 192QQ, 192QR and 192RR. Aims: This study was carried out to delineate the associations of plasma PON1 activity and functional PON1 Q192R genotypes in major depression and bipolar disorder. Methods: PON1 status that is plasma PON1 abundance and three functional PON1 Q192R genotypes were assayed in 91 major depressed and 45 bipolar patients and compared to 199 normal controls. Results: Major depression, but not bipolar disorder, was accompanied by lowered PON1 activity. PON1 activity was decreased by smoking and a diagnosis by genotype interaction (i.e. lower PON1 in major depression with the QQ genotype). Logistic regression showed that smoking by QQ genotype significantly increased the odds of bipolar disorder and that major depression was predicted by plasma PON1 activity, serum HDL cholesterol and interactions between genotype×smoking. Discussion: The results suggest that lowered plasma PON1 activity is a trait marker of major depression and that PONQ192R gene–environment (smoking) interactions differentially predict the odds of depression and bipolar disorder. Limitations: Association studies are prone to a risk of false positive findings and replication is essential. Conclusions: The findings suggest that there are differential PON1 Q192R functional genotype×environment interactions in major depression and bipolar disorder. The effects of lowered PON1 activity may contribute to increased O&NS and immune-inflammatory burden in depression. PON1 status may contribute to the comorbidity between depression and other immune- and O&NS-related disorders, e.g. cardiovascular disorder. [Copyright &y& Elsevier]

Abstract: Background: Atopy, a common disorder characterized by a sensitivity to allergic reactions, affects a large proportion of the adult population and, as with depression, is associated with immune-inflammatory pathway changes. We sought to determine the role of atopic disorders in depression using data from a randomly-selected, population-based study of men and women. Methods: Cross-sectional data derived from the Geelong Osteoporosis Study for 942 males and 1085 females were analyzed. Depression [major depressive disorder (MDD), minor depression and dysthymia] was assessed using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition. Data on medical conditions, including atopic disorders (asthma, hay fever and eczema), smoking status, alcohol consumption, socioeconomic status, and physical activity were documented by self-report. Logistic regression modeling was used to explore the associations between atopic disorders and depression. Results: Atopic disorders were associated with a 59% increased likelihood of depression [gender and smoking-adjusted odds ratio (OR) 1:50, 95% CI 1.20–1.97]. Sub-group analyses revealed a similar pattern for those with MDD [gender and smoking-adjusted OR 1:54, 95% CI 1.22-1.94]. These associations were independent of socio-demographic characteristics, clinical and lifestyle factors. Limitations: Reliance on self-report for allergic symptoms and cross-sectional nature of study. Conclusion: This population-based study provides evidence of the potential contribution of allergic disorders to depression. Further research is required to elucidate the direction of this association and to further explicate its underlying physiology, including immune-inflammation markers. [Copyright &y& Elsevier]

Abstract: Background: There is evidence that depression is accompanied by inflammation, oxidative and nitrosative stress (O&NS) and metabolic disorders. However links between oxidative stress and suicide attempts in depressed patients are poorly understood. This study examines whether a history of suicide attempts is associated with inflammation, O&NS and metabolic disorders. Methods: Blood specimens were collected from study participants aged 18–60 (N=342) recruited at the State University of Londrina, Brazil, and measured for oxidative stress biomarkers: nitric oxide metabolites (NOx), lipid hydroperoxides, malondialdehyde, advanced oxidation protein products and plasma total antioxidant potential (TRAP); inflammatory biomarkers: fibrinogen, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, interleukin-6 and tumor necrosis factor-α; and metabolic variables. Subjects were divided into those with (n=141) and without (n=201) a history of suicidal attempts. Results: Individuals with a history of suicide attempts had significantly higher levels of NOx and lipid hydroperoxides and lowered TRAP as compared to individuals without suicide attempts. There were no significant associations between a history of suicide attempts and inflammatory and metabolic biomarkers and metabolic syndrome. Logistic regression showed that both unipolar and bipolar disorder, female gender, smoking behavior and lipid hydroperoxides were significantly associated with a history of suicide attempts. The combined effects of oxidative stress, smoking, depression, female gender were independent from classical risk factors, including marital status, years of education and anxiety. Conclusions: O&NS as well as lowered antioxidant levels may play a role in the pathophysiology of suicidal behavior independently from the effects of depression and smoking, both of which are associated with increased O&NS, and classical suicide predictors, such as years of education and marital status. [Copyright &y& Elsevier]

Abstract: Recent research findings suggest that vascular endothelial growth factor (VEGF) participates in the development of depressive disorder. VEGF is involved in neurogenesis and neuroprotection processes, mediated by vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 also plays a role in angiogenesis, a process related to neurogenesis and other biological processes. We examined VEGFR2 (KDR) gene polymorphism, mRNA expression levels, as well as VEGFR2 protein levels in 268 patients diagnosed with a recurrent depressive disorder (rDD) using the ICD-10 criteria, and in 200 healthy controls. Genotyping and gene expression level analysis was performed using polymerase chain reaction (PCR)—based methods. An Enzyme—Linked Immunosorbent Assay (ELISA) was used for measurement of KDR protein levels. Our study found that distribution of KDR polymorphism +1416T/A differs significantly in patients with rDD when compared to healthy subjects, while A allele and AA genotype are risk factors for rDD. KDR mRNA and protein expression are higher in patients with rDD. We also observed a significant association between the −271A/G variant and gene and protein levels. Our study is the first to demonstrate that the KDR gene may serve as a novel genetic marker that could participate in the etiology of rDD. This new pathway may play a role in the inflammatory pathophysiology of depression. [Copyright &y& Elsevier]