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Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative-specific epitopes (OSEs), which are a first-line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls. Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all five Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the receiver operating characteristic curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the negative subscale score of the Positive and Negative Syndrome Scale was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the five enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini-Mental State Examination, Boston naming test, Verbal Fluency, and Word List Memory test scores. These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia. [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]

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]

Eotaxin is increased in neurodegenerative disorders and schizophrenia, and preclinical studies indicate that eotaxin may induce cognitive deficits. This study aims to examine whether peripheral levels of eotaxin impact cognitive functioning in healthy volunteers and formal thought disorder (FTD) and psychopathology in schizophrenia patients. Serum levels of eotaxin were assayed and cognitive tests were performed on a sample of 40 healthy participants and 80 schizophrenia patients. Among healthy participants, eotaxin levels were significantly associated with episodic/semantic memory, executive functions, Mini Mental State Examination, emotion recognition, and sustained attention. In addition, age-related effects on these cognitive measures were partly mediated by eotaxin. The super-variable "age-eotaxin" predicted a large part of the variance in cognitive functions among healthy participants, and hence, eotaxin may act as an "accelerated brain aging chemokine" (ABAC). In schizophrenia, eotaxin levels had a strong impact on formal thought disorders and psychopathology. In schizophrenia, increased eotaxin strongly impacts memory and sustained attention, which together to a large extent determine FTD. FTD together with memory deficits predicts around 92.5% of the variance in psychopathology. Moreover, the effects of eotaxin are partially mediated by executive functioning, while the effects of male sex on FTD and psychopathology are mediated by eotaxin. In healthy subjects, eotaxin strongly impacts executive functioning and multiple cognitive domains. In schizophrenia, peripheral levels of eotaxin strongly impact both negative symptoms and psychosis (hallucinations and delusions), and these eotaxin effects are mediated by impairments in frontal functioning, memory, sustained attention, and FTD. Eotaxin is an endogenous cognitive deteriorating chemokine (ECDC) and a novel therapeutic target for age-related cognitive decline and schizophrenia as well. [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]

The depression, anxiety and physiosomatic symptoms (DAPS) of schizophrenia are associated with negative symptoms and changes in tryptophan catabolite (TRYCAT) patterning. The aim of this study is to delineate the associations between DAPS and psychosis, hostility, excitation, and mannerism (PHEM) symptoms, cognitive tests as measured using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and IgA/IgM responses to TRYCATs. We included 40 healthy controls and 80 participants with schizophrenia. Depression and anxiety symptoms were measured with The Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales, respectively. Physiosomatic symptoms were assessed with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF). Negative symptoms as well as CERAD tests, including Verbal Fluency Test (VFT), Mini-Mental State Examination (MMSE), Word List Memory (WLM), and WL Delayed Recall were measured, while ratios of IgA responses to noxious/protective TRYCATs (IgA NOX_PRO) were computed. Schizophrenia symptoms consisted of two dimensions, a first comprising PHEM and negative symptoms, and a second DAPS symptoms. A large part of the variance in DAPS was explained by psychotic symptoms and WLM. Of the variance in HAM-D, 58.9% was explained by the regression on excitement, IgA NOX_PRO ratio, WLM, and VFT; 29.9% of the variance in HAM-A by psychotic symptoms and IgA NOX/PRO; and 45.5% of the variance in FF score by psychotic symptoms, IgA NOX/PRO, and WLM. Neural network modeling shows that PHEM, IgA NOX_PRO, WLM, and MMSE are the dominant variables predicting DAPS. DAPS appear to be driven by PHEM and negative symptoms coupled with impairments in episodic memory, especially false memory creation, while all symptom dimension and cognitive impairments may be driven by an increased production of noxious TRYCATs, including picolinic, quinolinic, and xanthurenic acid. [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]