Pathogenesis Of Major Depressive Disorder Research Articles

M1/M2 polarization in major depressive disorder: Disentangling state from trait effects in an individualized cell-culture-based approach

Accumulating evidence indicates the specific involvement of inflammatory processes in major depressive disorder (MDD), particularly affecting innate immunity. Most immune alterations have so far been determined based on plasma or cerebrospinal fluid cytokine levels. To precisely characterize putative innate immune-mediated mechanisms in MDD pathogenesis, we sought to disentangle “state” from “trait” effects in a patient-specific cell model by quantifying the impact of patient-derived autologous sera (AS) on patient-specific monocyte-derived macrophages (Mo-MФs) polarization in vitro.Mo-MФs were generated from 28 patients with moderate to severe MDD and 28 age-, sex-, smoking status- and BMI-matched healthy controls (HC). Cells were treated either with AS or fetal calf serum (FCS) and polarized into M1 (LPS), M2 (IL-10, IL-4, TGF-β) or M0 (unstimulated) macrophages. Polarization capacity was quantified by means of specific M1 (CCR7, CD86, CXCL10, IL-12p70, TNF-α, IL-6, IL-1β, IL-12p40, IL-23, IP-10) and M2 (CD206, IL-10, TARC, IL-1RA) markers.Compared to HC, significantly increased M1-polarization was observed for MDD patients in the presence of FCS, however, polarization in AS enriched media determined an increased M2-polarization in patients. Moreover, female MDD patients exhibited increased M1- and decreased M2-polarization in both conditions compared to male MDD patients.Our data suggests that Mo-MФs derived from patients with MDD exhibit facilitated M1-polarization under traditional cell culture conditions and an increased potential for M2-polarization when cultured in AS. Striking inter-individual variation and pronounced gender effects highlight the potential utility of our personalized cell model-based approach to aid diagnostic and therapeutic decisions.

Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid

Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). KA antagonizes α7 nicotinic acetylcholine receptor (α7nAChR). Here, we investigated the involvement of KA in depression-like behavior in KMO knockout (KO) mice. KYN, KA, and anthranilic acid but not TRP or 3-hydroxyanthranilic acid were elevated in the prefrontal cortex of KMO KO mice. The mRNA levels of KAT1 and α7nAChR but not KAT2−4, α4nAChR, or β2nAChR were elevated in the prefrontal cortex of KMO KO mice. Nicotine blocked increase in locomotor activity, decrease in social interaction time, and prolonged immobility in a forced swimming test, but it did not decrease sucrose preference in the KMO KO mice. Methyllycaconitine (an α7nAChR antagonist) antagonized the effect of nicotine on decreased social interaction time and prolonged immobility in the forced swimming test, but not increased locomotor activity. Galantamine (an α7nAChR allosteric agonist) blocked the increased locomotor activity and prolonged immobility in the forced swimming test, but not the decreased social interaction time in the KMO KO mice. In conclusion, elevation of KA levels contributes to depression-like behaviors in KMO KO mice by α7nAChR antagonism. The ameliorating effects of nicotine and galantamine on depression-like behaviors in KMO KO mice are associated with the activation of α7nAChR.

Interactions Between Glycogen Synthase Kinase-3β Gene Polymorphisms, Negative Life Events, and Susceptibility to Major Depressive Disorder in a Chinese Population.

Background: Recent studies suggest that glycogen synthase kinase (GSK)-3β is involved in the development of major depressive disorder (MDD). The aim of this study was to investigate the interaction between GSK-3β polymorphism (rs6438552, rs334558, and rs2199503) and negative life events in the pathogenesis of major depressive disorder (MDD).Methods: DNA genotyping was performed on peripheral blood leukocytes in 550 patients with MDD and 552 age- and gender-matched controls. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). A chi-square method was employed to assess the gene-environment interaction (G × E).Results: Differences in rs6438552, rs334558, and rs2199503 genotype distributions were observed between MDD patients and controls. Significant G × E interactions between allelic variation of rs6438552, rs334558, and rs2199503 and negative life events were observed. Individuals with negative life events and carrying genotypes of rs6438552 A+, rs334558 A+, and rs2199503G+ have increased the risk of depression.Conclusions: These results indicate that interactions between the GSK-3β rs6438552, rs334558, and rs2199503 polymorphisms and environment increases the risk of developing MDD.

Personalized Medicine Using Neuroimmunological Biomarkers in Depressive Disorders.

Major depressive disorder (MDD) is associated with increased suicidal risk and reduced productivity at work. Neuroimmunology, the study of the immune system and nervous system, provides further insight into the pathogenesis and outcome of MDD. Cytokines are the main modulators of neuroimmunology, and their levels are somewhat entangled in depressive disorders as they affect depressive symptoms and are affected by antidepressant treatment. The use of cytokine-derived medication as a treatment option for MDD is currently a topic of interest. Although not very promising, cytokines are also considered as possible prognostic or diagnostic markers for depression. The machine learning approach is a powerful tool for pattern recognition and has been used in psychiatry for finding useful patterns in data that have translational meaning and can be incorporated in daily clinical practice. This review focuses on the current knowledge of neuroimmunology and depression and the possible use of machine learning to widen our understanding of the topic.

Integrating Clinical and Genomic Analyses of Hippocampal-Prefrontal Circuit Disorder in Depression.

Major depressive disorder (MDD) is a prevalent, devastating and recurrent mental disease. Hippocampus (HIP)-prefrontal cortex (PFC) neural circuit abnormalities have been confirmed to exist in MDD; however, the gene-related molecular features of this circuit in the context of depression remain unclear. To clarify this issue, we performed gene set enrichment analysis (GSEA) to comprehensively analyze the genetic characteristics of the two brain regions and used weighted gene correlation network analysis (WGCNA) to determine the main depression-related gene modules in the HIP-PFC network. To clarify the regional differences and consistency for MDD, we also compared the expression patterns and molecular functions of the key modules from the two brain regions. The results showed that candidate modules related to clinical MDD of HIP and PFC, which contained with 363 genes and 225 genes, respectively. Ninety-five differentially expressed genes (DEGs) were identified in the HIP candidate module, and 51 DEGs were identified in the PFC candidate module, with only 11 overlapping DEGs in these two regional modules. Combined with the enrichment results, although there is heterogeneity in the molecular functions in the HIP-PFC network of depression, the regulation of the MAPK cascade, Ras protein signal transduction and Ephrin signaling were significantly enriched in both brain regions, indicating that these biological pathways play important roles in MDD pathogenesis. Additionally, the high coefficient protein–protein interaction (PPI) network was constructed via STRING, and the top-10 coefficient genes were identified as hub genes via the cytoHubba algorithm. In summary, the present study reveals the gene expression characteristics of MDD and identifies common and unique molecular features and patterns in the HIP-PFC network. Our results may provide novel clues from the gene function perspective to explain the pathogenic mechanism of depression and to aid drug development. Further research is needed to confirm these findings and to investigate the genetic regulation mechanisms of different neural networks in depression.

What are the Recurring Theories Regarding the Pathogenesis of Major Depressive Disorder?

Introduction: Several theories regarding the etiology of Major Depressive Disorder (MDD) provoke challenges in defining the exact pathology of the disorder. Among these theories, the most recurring theories were the monoamine hypothesis, cytokine hypothesis, and endocrine factors. Each of these hypotheses are backed with neurobiological studies and provide unique insight on the etiology of MDD. The current state of the literature of MDD is confusing and complex. There are various theories that explain the pathogenesis of MDD, each supported with evidence from pre-clinical and clinical studies. In this review, we aim to explain the most common theories of MDD and identify connections to the pathological mechanisms of this disease. Methods: A literature search considering inclusion/exclusion criteria was conducted to determine the different theories on the pathology of MDD and their limitations. Results: Using the inclusion/exclusion criteria, 44 articles were analyzed to form the basis of our review. Three main theories were found to be the most recurring, the monoamine hypothesis, cytokine hypothesis, and endocrine factors. Discussion: The monoamine hypothesis suggests that MDD is due to a deficiency of monoamines, specifically the hormone 5-HT, or serotonin. In contrast, the cytokine hypothesis proposes that the abnormal regulation of proinflammatory cytokines is linked to MDD through multiple facets. Finally, dysfunction of the hypothalamic–pituitary–adrenal axis is currently being studied as several papers have reported increased cortisol levels in patients with MDD, suggesting a relation between the two. Conclusion: This paper investigates the recurring theories regarding the pathogenesis of Major Depressive Disorder. However, further analysis revealed that the theories contain several inconsistencies that weaken their respective arguments. This includes unanticipated latency of drug effects, contradictory reports, and failed replications. Many argue that these hypotheses are not the cause of Major Depressive Disorder, but rather a concomitant occurrence. Major Depressive Disorder includes diverse symptoms with various external causes, a matter which makes it difficult to accurately define its pathology. Advanced neurobiological research enables easier diagnosis and the development of effective treatments used by clinicians. Consequently, it is imperative to have a thorough understanding of the pathologic process.

Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

Disrupted synaptic plasticity is the hallmark of major depressive disorder (MDD), with accompanying changes at the molecular and cellular levels. Often, the maladaptive molecular changes at the synapse are the result of global transcriptional reprogramming dictated by activity-dependent synaptic modulation. Thus far, no study has directly studied the transcriptome-wide expression changes locally at the synapse in MDD brain. Here, we have examined altered synaptic transcriptomics and their functional relevance in MDD with a focus on the dorsolateral prefrontal cortex (dlPFC). RNA was isolated from total fraction and purified synaptosomes of dlPFC from well-matched 15 non-psychiatric controls and 15 MDD subjects. Transcriptomic changes in synaptic and total fractions were detected by next-generation RNA-sequencing (NGS) and analyzed independently. The ratio of synaptic/total fraction was estimated to evaluate a shift in gene expression ratio in MDD subjects. Bioinformatics and network analyses were used to determine the biological relevance of transcriptomic changes in both total and synaptic fractions based on gene–gene network, gene ontology (GO), and pathway prediction algorithms. A total of 14,005 genes were detected in total fraction. A total of 104 genes were differentially regulated (73 upregulated and 31 downregulated) in MDD group based on 1.3-fold change threshold and p < 0.05 criteria. In synaptosomes, out of 13,236 detectable genes, 234 were upregulated and 60 were downregulated (>1.3-fold, p < 0.05). Several of these altered genes were validated independently by a quantitative polymerase chain reaction (qPCR). GO revealed an association with immune system processes and cell death. Moreover, a cluster of genes belonged to the nervous system development, and psychological disorders were discovered using gene–gene network analysis. The ratio of synaptic/total fraction showed a shift in expression of 119 genes in MDD subjects, which were primarily associated with neuroinflammation, interleukin signaling, and cell death. Our results suggest not only large-scale gene expression changes in synaptosomes, but also a shift in the expression of genes from total to synaptic fractions of dlPFC of MDD subjects with their potential role in immunomodulation and cell death. Our findings provide new insights into the understanding of transcriptomic regulation at the synapse and their possible role in MDD pathogenesis.

Research Domain Criteria (RDoC): A Perspective to Probe the Biological Background behind Treatment Efficacy in Depression.

Major Depressive Disorder(MDD) and its frequent partial response to antidepressants are a major health concern and therefore an important focus of research. Despite the efforts, MDD pathogenesis and the mechanisms of antidepressant action are only partially understood. In the last few years, the need of rethinking the classification of depressive disorders and psychiatric disorders, in general, has been suggested, in order to provide a nosology that reflects more closely the biological background associated with disease pathogenesis and its role/significance in treatment. The classification proposed by the National Institute of Mental Health (NIMH), namely the research domain criteria (RDoC), may represent a key framework to guide research in this direction. A literature search was performed on PubMed and Google Scholar databases in order to retrieve data regarding Antidepressants effects on specific RDoC constructs. Further, the targets of drugs of interest were identified through the Drug bank database, and their possible function within RDoC constructs was discussed. In this review, we summarize and discuss the significance of the results of pre-clinical and clinical studies investigating specific RDoC paradigms relevant to depressive phenotypes and antidepressant effects. The RDoC framework may facilitate a more specific use of antidepressants based on the individual's spectrum of symptoms and the development of new compounds that target specific depressive symptoms.

Yoga in major depressive disorder: molecular mechanisms and clinical utility.

Major depressive disorder (MDD) is a mind-body disorder. Cellular aging has been implicated in the pathogenesis of MDD with the altered mind-body communication markers like stress response, immune response, nutrition sensing, and a range of other regulatory feedback systems. In this age of super specializations, one specific target and interventions (preferably a drug) on it are being rigorously sought by the health care community and industry, but have failed in it in the last fifty years in spite of advances in technology. Since, depression is a complex disorder associated with increased incidence of other complex disorders, it must be treated by an integrated holistic approach that can address the complexity of MDD. Interventions targeting accelerated biological aging to increase cellular health in whole body have potential to manage complex conditions like MDD and its overlapping symptoms and comorbidities. Yoga has the potential to be the nexus between, clinical management of MDD and other lifestyle diseases.

Induced Pluripotent Stem Cells (iPSCs) Technology: Potential Targets for Depression.

Major depressive disorder (MDD) is a heterogeneous condition with complex pathophysiology resulting from the interaction between genetic and environmental factors. Despite a reasonable array of therapeutic options, the management of MDD has been marked by an increasing number of treatment resistant cases. Identifying the multiple pathways involved in the pathogenesis of MDD is fundamental to move the field forward and to define novel and more effective therapeutic targets. The current disease models are not able to recapitulate the complexity of this condition. In the last years, induced pluripotent stem cells (iPSCs) have emerged as a unique tool to help the elucidation of the pathophysiology of psychiatric disorders through disease modeling. In addition, the iPSCs may play an important role in the validation of new therapeutic targets.

Identification of Crucial Genes and Diagnostic Value Analysis in Major Depressive Disorder Using Bioinformatics Analysis.

Despite the prevalence and burden of major depressive disorder (MDD), our current understanding of the pathophysiology is still incomplete. Therefore, this paper aims to explore genes and evaluate their diagnostic ability in the pathogenesis of MDD. Firstly, the expression profiles of mRNA and microRNA were downloaded from the gene expression database and analyzed by the GEO2R online tool to identify differentially expressed genes (DEGs) and differentially expressed microRNAs (DEMs). Then, the DAVID tool was used for functional enrichment analysis. Secondly, the comprehensive protein-protein interaction (PPI) network was analyzed using Cytoscape, and the network MCODE was applied to explore hub genes. Thirdly, the receiver operating characteristic (ROC) curve of the core gene was drawn to evaluate clinical diagnostic ability. Finally, mirecords was used to predict the target genes of DEMs. A total of 154 genes were identified as DEGs, and 14 microRNAs were identified as DEMs. Pathway enrichment analysis showed that DEGs were mainly involved in hematopoietic cell lineage, PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, and JAK-STAT signaling pathway. Three important modules are identified and selected by the MCODE clustering algorithm. The top 12 hub genes, including CXCL16, CXCL1, GNB5, GNB4, OPRL1, SSTR2, IL7R, MYB, CSF1R, GSTM1, GSTM2, and GSTP1, were identified as important genes for subsequent analysis. Among these important hub genes, GSTM2, GNB4, GSTP1 and CXCL1 have the good diagnostic ability. Finally, by combining these four genes, the diagnostic ability of MDD can be improved to 0.905, which is of great significance for the clinical diagnosis of MDD. Our results indicate that GSTM2, GNB4, GSTP1 and CXCL1 have potential diagnostic markers and are of great significance in clinical research and diagnostic application of MDD. This result needs a large sample study to further confirm the pathogenesis of MDD.

Gut microbiota dysbiosis in depressed women: The association of symptom severity and microbiota function

BackgroundThe association between abnormal gut microbiome composition and depression is well established. However, the composition and functional capacity of the gut microbiota regarding depressed women has been poorly addressed. MethodsStool samples from 62 female patients with major depressive disorder (MDD) and 46 healthy controls (Con) were analyzed by 16S rRNA gene sequencing; Twenty fecal samples from the patient group and 21 fecal samples from the Con group were further analyzed by shotgun metagenomic sequencing. Psychiatric symptoms and psychological, social, and professional functioning was also assessed. ResultsPhylum Bacteroidetes, proteobaeteria, and Fusobacteria were greatly enriched in patients with MDD, while the Firmicutes and Actinobacteria phyla were consistently higher in Con. Notably, 18 microbial markers were identified on a random forest model and achieve an area under the curve of 0.92 between patients with MDD and the Con group. Forty-five species and their associated function were identified with statistically significant differences between patients with MDD and the Con group. LimitationsThe number of recruited samples, especially samples enrolled for shotgun metagenomic sequencing was relatively small, and the stool samples were collected only at baseline, making it difficult to establish a causal association between changes in gut microbiota compositions and disease remission. ConclusionsThis study characterizes the gut microbiota and their related function in female MDD. The gut microbiota-based biomarkers may be helpful in diagnosis and the altered gut microbial metabolites may contribute to the pathogenesis of MDD in women, representing potential microbial targets.

Roles of 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphisms in First-Episode, Drug-Naive Adult Patients With Depression.

5,10-Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is considered as a predisposition and promising genetic candidate to major depressive disorder (MDD), as it is associated with impaired one-carbon cycles, which may be involved in the pathogenesis of depression. Cortical thickness (CT) and subcortical structure volumes have been extensively studied in MDD and have been proposed as one of the phenotypes for MDD. We intend to discuss the association between CT, subcortical structure volume, and MTHFR C677T polymorphism in first-episode, treatment-naive patients with MDD. In this study, 127 adult patients with MDD and 101 age- and gender-matched healthy controls (HCs) were included. All subjects underwent T1-weighted MRI, MTHFR C677T genotyping, and FreeSurfer software-based morphological analysis. MDD patients have been detected to have significantly decreased volumes in the left nucleus accumbens (P < 0.001). The MTHFR 677 T allele carriers manifested with thinner CT in the left caudal anterior cingulate cortex (cACC, P = 0.009) compared with CC genotype. There were significant genotype-by-diagnosis interactions for the CT in the left cACC (P = 0.009), isthmus cingulate (P = 0.002), medial orbitofrontal lobe (P = 0.012), posterior cingulate (P = 0.030), and the right lateral orbitofrontal lobe (P = 0.012). We also found a trend in the interaction effect on the volume of the left putamen (P = 0.050). Our results revealed that MTHFR C677T polymorphism may be involved in the dysfunction of limbic–cortical–striatal–pallidal–thalamic (LCSPT) circuits mediating emotion processing, which may contribute to pathogenesis of MDD.

Gene-Based Association Analysis Suggests Association of HTR2A With Antidepressant Treatment Response in Depressed Patients

The serotonin [5-hydroxytryptamine (5-HT)] system has been implicated in the pathogenesis of major depressive disorder (MDD). Among the 5-HT receptor subtypes, 5-HT2 is one of the major pharmacological therapeutic targets for MDD. There have been inconsistent findings in previous pharmacogenetic studies investigating the antidepressant therapeutic response using one or several 5-HT2A (HTR2A) genetic polymorphisms. By using gene-based association analysis, we hope to identify genetic variants of HTR2A which are related to MDD susceptibility and its antidepressant therapeutic response. 288 HTR2A single nucleotide polymorphisms in MDD susceptibility have been investigated through a case–control (455 MDD patients and 2, 998 healthy controls) study, as well as in antidepressant efficacy (n = 455) in our current research. The 21-item Hamilton Rating Scale for Depression was used to evaluate measures of antidepressant therapeutic efficacy. From two MDD groups in the antidepressant therapeutic response, by using gene-based analyses, we have identified 14 polymorphisms as suggestive markers for therapeutic response (13 for remission and 1 for response) in both meta- and mega-analyses. All of these HTR2A reported polymorphisms did not reach statistical significance in the case–control association study. This current investigation supported the link between HTR2A variants and antidepressant therapeutic response in MDD but not with MDD susceptibility.

Alterations of neurotransmitters and related metabolites in the habenula from CUMS-susceptible and -resilient rats

Although major depressive disorder (MDD) has caused severe mental harm to overwhelming amounts of patients, the pathogenesis of MDD remains to be studied. Due to the in-depth discussion of the mechanism of new antidepressants like ketamine, the habenula (Hb) was reported to be significant in the onset of MDD and the antidepressant mechanism. In the Hb of depressive-like rodents, various molecular mechanisms and neuronal electrical activities have been reported, but neurotransmitters disorder in response to stress are still unclear. Thus, we divided stress-susceptible and stress-resilient rats after exposure to chronic unpredictable mild stress (CUMS). Multiple metabolites in the Hb were determined by liquid chromatography-tandem mass spectrometry. Based on this approach, we found that glutamate was significantly increased in susceptible group and resilient group, while dopamine was significant decreased in two groups. Gamma-aminobutyric acid was significantly upregulated in susceptible group but downregulated in resilient group. Our study firstly provides quantitative evidence regarding alterations of main neurotransmitters in the Hb of CUMS rats, showing the different role of neurotransmitters in stress susceptibility and stress resilience.

Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder.

Findings from epidemiological studies, biomarker measurements and animal experiments suggest a role for aberrant immune processes in the pathogenesis of major depressive disorder (MDD). Microglia, the resident immune cells of the brain, are likely to play a key role in these processes. Previous post-mortem studies reported conflicting findings regarding microglial activation and an in-depth profiling of those cells in MDD is lacking. The aim of this study was therefore to characterize the phenotype and function of microglia in MDD. We isolated microglia from post-mortem brain tissue of patients with MDD (n = 13-19) and control donors (n = 12-25). Using flow cytometry and quantitative Polymerase Chain Reaction (qPCR), we measured protein and mRNA levels of a panel of microglial markers across four different brain regions (medial frontal gyrus, superior temporal gyrus, thalamus, and subventricular zone). In MDD cases, we found a significant upregulation of CX3CR1 and TMEM119 mRNA expression and a downregulation of CD163 mRNA expression and CD14 protein expression across the four brain regions. Expression levels of microglial activation markers, such as HLA-DRA, IL6, and IL1β, as well as the inflammatory responses to lipopolysaccharide and dexamethasone were unchanged. Our findings suggest that microglia enhance homeostatic functions in MDD but are not immune activated.

Differential and unique patterns of synaptic miRNA expression in dorsolateral prefrontal cortex of depressed subjects

Altered synaptic plasticity is often associated with major depressive disorder (MDD). Disease-associated changes in synaptic functions are tightly correlated with altered microRNA (miRNA) expression. Here, we examined the role of miRNAs and their functioning at the synapse in MDD by examining miRNA processing machinery at synapse and sequencing miRNAs and analyzing their functions in synaptic and total tissue fractions obtained from dorsolateral prefrontal cortex (dlPFC) of 15 MDD and 15 matched non-psychiatric control subjects. A total of 333 miRNAs were reliably detected in the total tissue fraction. Multiple testing following the Benjamini–Hochberg false discovery rate [FDR] showed that 18 miRNAs were significantly altered (1 downregulated 4 up and 13 downregulated; p < 0.05) in MDD subjects. Out of 351 miRNAs reliably expressed in the synaptic fraction, 24 were uniquely expressed at synapse. In addition, 8 miRNAs (miR-215-5p, miR-192-5p, miR-202-5p, miR-19b-3p, miR-423-5p, miR-219a-2-3p; miR-511-5p, miR-483-5p showed significant (FDR corrected; p < 0.05) differential regulation in the synaptic fraction from dlPFC of MDD subjects. In vitro transfection studies and gene ontology revealed involvement of these altered miRNAs in synaptic plasticity, nervous system development, and neurogenesis. A shift in expression ratios (synaptic vs. total fraction) of miR-19b-3p, miR-376c-3p, miR-455-3p, and miR-337-3p were also noted in the MDD group. Moreover, an inverse relationship between the expression of precursor (pre-miR-19b-1, pre-miR-199a-1 and pre-miR-199a-2) and mature (miR-19b-3p, miR-199a-3p) miRNAs was found. Although not significantly, several miRNA processing enzymes (DROSHA [95%], DICER [17%], TARBP2 [38%]) showed increased expression patterns in MDD subjects. Our findings provide new insights into the understanding of the regulation of miRNAs at the synapse and their possible roles in MDD pathogenesis.

Construction of gene-classifier and co-expression network analysis of genes in association with major depressive disorder

Because the pathogenesis of major depressive disorder (MDD) is still unclear and the accurate diagnosis remains unavailable, we aimed to analyze its molecular mechanisms and develop a gene classifier to improve diagnostic accuracy. We extracted differentially expressed genes from two datasets, GSE45642 (from brain tissue samples) and GSE98793 (from blood samples), and found three key modules to have a significant correlation with MDD traits by weighted gene coexpression network analysis. Hub genes were identified from the key modules according to the connectivity degree in the network and subjected to least absolute shrinkage and selection operator regression analysis. A total of eighty-five hub genes were selected to construct the gene classifier, which had considerable ability to recognize MDD patients in the training set and test set. In addition, the relationship between the key MDD modules and brain tissues indicated that the anterior cingulate should be a notable region in the study of MDD pathogenesis. The results of Gene Ontology (GO) and pathway enrichment analyses reiterate the relationship between depression and immunity. Therefore we identified MDD hub genes in the InnateDB database, and found 14 genes involved in both MDD and the inflammatory response.

Association of the TLR4 gene with depressive symptoms and antidepressant efficacy in major depressive disorder

At present, the etiology and pathogenesis of major depressive disorder(MDD) are still unclear. Some studies have shown that toll-like receptor 4 may play an important role in MDD. However, little is currently known about the association between TLR4 single gene polymorphisms (SNPs) and depressive symptoms and antidepressant efficacy.The aim of this study is to analyze whether TLR4 SNPs are associated with depressive symptoms and antidepressant efficacy. The study consisted of 438 patients with first-episode depression. We analyzed three TLR4 SNPs (rs1927911, rs11536889, and rs7873784) and obtained the baseline and 6-week scores using the 17-item Hamilton Depression Rating Scale (HAMD17) and its five-factor model. Allelic and genotypic association tests between TLR4 SNPs and HAMD17 total and cluster scores were performed with UNPHASED, while chi-square tests to analyze the association between TLR4 SNPs and response to antidepressants were performed with SPSS. Patients with the rs1927911-GG genotype exhibited higher scores of anxiety (physical symptoms) and anxiety (somatic). Patients with rs1927911-G also exhibited higher anxiety (physical symptoms) and anxiety (somatic) scores. Patients with rs11536889-GG had significantly lower suicide scores and higher psychomotor retardation scores. Patients with rs11536889-G also had significantly lower suicide scores and higher psychomotor retardation scores. Patients with rs7873784-G had higher anxiety (physical symptoms) and anxiety (psychological) scores. There was no significant difference between antidepressant efficacy and TLR4 gene polymorphisms. These findings provide evidence that TLR4 plays an important role in anxiety, suicide, and other symptoms in patients with MDD. No relationship was found between TLR4 gene polymorphisms and antidepressant efficacy in this study. Further research is needed on gene polymorphisms and the expression of TLR4 in patients with MDD.

Association between arginine catabolism and major depressive disorder: A protocol for the systematic review and meta-analysis of metabolic pathway.

Background:Alterations in the levels of arginine and its related catabolic products (ie, ornithine, citrulline, and argininosuccinate) in the urea and nitric oxide cycles were reported to play roles in the pathogenesis of major depressive disorder (MDD). The aim of this meta-analysis study is to explore the associations between arginine with its related catabolic products and MDD, and to discuss the possible role of arginine catabolism in the pathoetiology of MDD.Methods:This study will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The English language literature published in the databases of PubMed, EMBASE, PsycINFO and Web of Science will be systematically searched. Forest plots will be used to estimate the associations between arginine and its related catabolic products with MDD. Subgroup analysis and meta-regression will also be performed to investigate the source of the potential heterogeneity. Sensitivity analysis will be performed to strengthen the results and to investigate whether any single study would have a significant effect on the results of meta-analysis. Publication bias will be tested for using the funnel plot with Begg test and Egger test. The Newcastle-Ottawa Scale will be applied to assess the risk of bias of observational studies.Results:An integrated assessment of arginine with its related catabolic products may contribute to predict the risk of MDD.Ethics and dissemination:The results of associations between arginine with its related catabolic products and MDD will be reported in a peer-reviewed publication. With our findings from this meta-analysis, we hope to provide the most up-to-date evidence for the contributions of arginine and related catabolic products to predict the risk of MDD.Systematic review registration:The protocol of current meta-analysis has been registered at the Open Science Framework [Available at: https://doi.org/10.17605/osf.io/7fn59].