Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: a double blind, randomised, placebo controlled trial

While current pharmacotherapies are efficacious, there remain a clear shortfall between symptom remission and functional recovery. With the explosion in our understanding of the biology of these disorders, the time is ripe for the investigation of novel therapies. Recently depression is conceptualized as an immune-inflammatory and nitro-oxidative stress related disorder. Minocycline is a tetracycline antibiotic that has anti-inflammatory, pro-oxidant, glutamatergic, neurotrophic and neuroprotective properties that make it a viable target to explore as a new therapy. This double blind, randomised, placebo controlled adjunctive trial will investigate the benefits of 200 mg/day of minocycline treatment, in addition to any usual treatment, as an adjunctive treatment for moderate-severe major depressive disorder. Sixty adults are being randomised to 12 weeks of treatment (with a 4 week follow-up post-discontinuation). The primary outcome measure for the study is mean change on the Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcomes including the Social and Occupational Functioning Assessment Scale (SOFAS), Clinical Global Impressions (CGI), Hamilton Rating Scale for Anxiety (HAM-A), Patient Global Impression (PGI), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and Range of Impaired Functioning Tool (LIFE-RIFT). Biomarker analyses will also be conducted at baseline and week 12. The study has the potential to provide new treatment targets, both by showing efficacy with a new class of \u27antidepressant\u27 but also through the analysis of biomarkers that may further inform our understanding of the pathophysiology of unipolar depression

The effects of tryptophan catabolites on negative symptoms and deficit schizophrenia are partly mediated by executive impairments: Results of partial least squares path modeling

Aim & Objective: To delineate the associations between executive impairments and changes in tryptophan catabolite (TRYCAT) patterning, negative symptoms and deficit schizophrenia. Methods: We recruited 80 schizophrenic patients and 40 healthy controls and assessed 10 key cognitive tests using the Cambridge Neuropsychological Test Automated Battery (CANTAB), IgA/IgM responses to tryptophan catabolites (TRYCATs), the Scale for the Assessment of Negative Symptoms (SANS) and Positive and Negative Syndrome Scale. Results: Partial Least Squares path modeling shows that a large part of the variance in negative symptoms and the deficit phenotype (39-53%) is explained by executive impairments, TRYCAT levels and male sex and that 53.4% of the variance in executive impairments is explained by TRYCATs, lower education, age and a familial history of psychosis. Specific indirect effects of TRYCATs, age and education on negative symptoms are mediated by executive impairments. Nevertheless, sustained attention, memory and emotion recognition also mediate the effects of TRYCATS, lower education and male sex on negative symptoms. Conclusion: Deficit schizophrenia is accompanied by a broader spectrum of cognitive impairments than nondeficit schizophrenia, including executive functions, sustained attention, episodic and semantic memory and emotion recognition. Furthermore, neuro-immune disorders underpin executive impairments, whilst neuro-immune disorders coupled with executive and other cognitive impairments to a large extent determine negative symptoms and the deficit phenotype

In (deficit) schizophrenia, a general cognitive decline (G-CoDe) partly mediates the effects of neuro-immune and neuro-oxidative toxicity on the symptomatome and quality of life

Objective: Schizophrenia and deficit schizophrenia are accompanied by neurocognitive impairments. The aim of this study was to examine whether a general factor underpins impairments in key Cambridge Neuropsychological Test Automated Battery (CANTAB) probes, verbal fluency (VFT), world list memory (WLM), true recall, and Mini Mental State Examination (MMSE). Methods: We recruited 80 patients with schizophrenia and 40 healthy controls. All patients were assessed using CANTAB tests, namely paired-association learning (PAL), rapid visual information (RVP), spatial working memory (SWM), one touch stocking (OTS), intra/extradimensional set shifting (IED), and emotional recognition test (ERT). Results: We found that a general factor, which is essentially unidimensional, underlies those CANTAB, VFT, WLM, True Recall, and MMSE scores. This common factor shows excellent psychometric properties and fits a reflective model and, therefore, reflects a general cognitive decline (G-CoDe) comprising deficits in semantic and episodic memory, recall, executive functions, strategy use, rule acquisition, visual sustained attention, attention set-shifting, and emotional recognition. Partial least Square analysis showed that 40.5% of the variance in G-Code is explained by CCL11, IgA to tryptophan catabolites, and increased oxidative toxicity; and that G-CoDe explains 44.8% of the variance in a general factor extracted from psychosis, hostility, excitation, mannerism, negative symptoms, formal thought disorders, and psychomotor retardation; and 40.9% in quality of life scores. The G-CoDe is significantly greater in deficit than in nondeficit schizophrenia. Conclusions: A common core shared by a multitude of neurocognitive impairments (G-CoDe) mediates the effects of neurotoxic pathways on the phenome of (deficit) schizophrenia

Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophrenia

Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophreni

Breakdown of the Paracellular Tight and Adherens Junctions in the Gut and Blood Brain Barrier and Damage to the Vascular Barrier in Patients with Deficit Schizophrenia

Breakdown of the Paracellular Tight and Adherens Junctions in the Gut and Blood Brain Barrier and Damage to the Vascular Barrier in Patients with Deficit Schizophreni

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression

How to construct a bottom-up nomothetic network model and disclose novel nosological classes by integrating risk resilience and adverse outcome pathways with the phenome of schizophrenia

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

In Schizophrenia, Increased Plasma IgM/IgA Responses to Gut Commensal Bacteria Are Associated with Negative Symptoms, Neurocognitive Impairments, and the Deficit Phenotype

In Schizophrenia, Increased Plasma IgM/IgA Responses to Gut Commensal Bacteria Are Associated with Negative Symptoms, Neurocognitive Impairments, and the Deficit Phenotyp

Episodic memory and delayed recall are significantly more impaired in younger patients with deficit schizophrenia than in elderly patients with amnestic mild cognitive impairment

Background Both amnestic mild cognitive impairment (aMCI) and schizophrenia, in particular deficit schizophrenia, are accompanied by cognitive impairments. The aim of the present study was to examine the cognitive differences between aMCI and (non)deficit schizophrenia. Methods Towards this end we recruited 60 participants with aMCI, 40 with deficit and 40 with nondeficit schizophrenia and 103 normal volunteers. Cognitive measures were assessed with the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) using the Verbal Fluency Test (VFT), Boston Naming Test (BNT), Mini-Mental State Examination (MMSE), Word list memory (WLM), Word list recall (WLRecall) and Word list recognition (WLRecognition). Data were analyzed using multivariate analyses and machine learning techniques. Results BNT scores were significantly lower in aMCI as compared with nondeficit schizophrenia. Patients with deficit schizophrenia had significantly lower MMSE, WLM, WL True Recall and WL Recognition than aMCI patients, while WL False Recall was significantly higher in deficit schizophrenia than in aMCI. Neural network importance charts show that deficit and nondeficit schizophrenia are best separated from aMCI using total BNT score, while WLM and WL false Recall follow at a distance. Conclusions Patients with schizophrenia and aMCI have a significantly different neurocognitive profile. Memory impairments, especially in episodic memory, are significantly worse in younger patients with deficit schizophrenia as compared with elderly patients with aMCI, while the latter show more dysnomia than patients with schizophrenia

First episode psychosis and schizophrenia are systemic neuro-immune disorders triggered by a biotic stimulus in individuals with reduced immune regulation and neuroprotection

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory systems (CIRS) and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AN-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of FES. However, the protein–protein interaction (PPI) network of FEP/FES is not established. The aim of the current study was to delineate a) the characteristics of the PPI network of AN-FEP and its transition to FES; and b) the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. Toward this end, we used PPI network, enrichment, and annotation analyses. FEP and FEP/FES are strongly associated with a response to a bacterium, alterations in Toll-Like Receptor-4 and nuclear factor-κB signaling, and the Janus kinases/signal transducer and activator of the transcription proteins pathway. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation, and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation, in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin and Wnt/catenin signaling, and adherens junction organization. Multiple interactions between reduced brain derived neurotrophic factor, E-cadherin, and β-catenin and disrupted schizophrenia-1 (DISC1) expression increase the vulnerability to the neurotoxic effects of immune molecules, including cytokines and complement factors. In summary: FEP and FES are systemic neuro-immune disorders that are probably triggered by a bacterial stimulus which induces neuro-immune toxicity cascades that are overexpressed in people with reduced anti-inflammatory and miRNA protections, cell–cell junction organization, and neurotrophin and Wnt/catenin signaling