Molecular signatures of major depression.
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ABSTRACT:
SUBMITTER: Cai N
PROVIDER: S-EPMC4425463 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
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Project description:Major depressive disorder (MDD) is a highly prevalent mental illness whose therapy management remains uncertain, with more than 20% of patients who do not achieve response to antidepressants. Therefore, identification of reliable biomarkers to predict response to treatment will greatly improve MDD patient medical care. Due to the inaccessibility and lack of brain tissues from living MDD patients to study depression, researches using animal models have been useful in improving sensitivity and specificity of identifying biomarkers. In the current study, we used the unpredictable chronic mild stress (UCMS) model and correlated stress-induced depressive-like behavior (n = 8 unstressed vs. 8 stressed mice) as well as the fluoxetine-induced recovery (n = 8 stressed and fluoxetine-treated mice vs. 8 unstressed and fluoxetine-treated mice) with transcriptional signatures obtained by genome-wide microarray profiling from whole blood, dentate gyrus (DG), and the anterior cingulate cortex (ACC). Hierarchical clustering and rank-rank hypergeometric overlap (RRHO) procedures allowed us to identify gene transcripts with variations that correlate with behavioral profiles. As a translational validation, some of those transcripts were assayed by RT-qPCR with blood samples from 10 severe major depressive episode (MDE) patients and 10 healthy controls over the course of 30 weeks and four visits. Repeated-measures ANOVAs revealed candidate trait biomarkers (ARHGEF1, CMAS, IGHMBP2, PABPN1 and TBC1D10C), whereas univariate linear regression analyses uncovered candidates state biomarkers (CENPO, FUS and NUBP1), as well as prediction biomarkers predictive of antidepressant response (CENPO, NUBP1). These data suggest that such a translational approach may offer new leads for clinically valid panels of biomarkers for MDD.
| S-EPMC5550836 | biostudies-literature
Project description:Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles.
| S-EPMC3309534 | biostudies-literature
Project description:ObjectivesBrain molecular aging, the pervasive and consistent transcriptome changes associated with normal brain aging, appears to overlap with disease pathways and may be anticipated in neurodegenerative and neuropsychiatric diseases, including major depressive disorder (MDD). Here, we characterize the global interaction of MDD-related gene changes with age, starting from our previous report of downregulated brain-derived neurotrophic factor (BDNF) and BDNF-dependent genes in the amygdala of women with MDD.MethodsA large-scale gene expression data set in the amygdala from a postmortem cohort of 21 women with MDD and 21 age-matched controls (age range: 16-74 years) was analyzed for correlations of gene transcript changes with age, in the presence or absence of a diagnosis of MDD.Results1) The age-related decrease in BDNF transcripts observed in control subjects corresponds with further age-related decreases in BDNF and BDNF-dependent gene expression in MDD subjects; 2) most MDD-related genes are frequently age-regulated in both MDD and control subjects; 3) the effects of MDD and age are positively correlated; 4) most genes that are age-dependent in control subjects display greater age effects in MDD subjects; and 5) the increased prevalence of age effects in MDD corresponds to similar trends in controls, rather than representing de novo age effects.ConclusionsMDD strongly associates with robust and anticipated gene expression changes that occur during normal aging of the brain, suggesting that an older molecular age of the brain represents an early biological event and/or a marker of risk for subsequent onset of MDD symptoms.
| S-EPMC3615087 | biostudies-literature
Project description:BACKGROUND:Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex. METHODS:To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type-specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]). RESULTS:Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types. CONCLUSIONS:The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.
| S-EPMC6014892 | biostudies-literature
Project description:Major depressive disorder (MDD) is a complex and multifactorial psychiatric disorder that causes serious health, social, and economic concerns worldwide. The main treatment of the symptoms is through antidepressant (AD) drugs. However, not all patients respond properly to these drugs. Omic sciences are widely used to analyze not only biomarkers for the AD response but also their molecular mechanism. In this review, we aimed to focus on omics data to better understand the molecular mechanisms involving AD effects on MDD. We consistently found, from preclinical to clinical data, that glutamatergic transmission, immune/inflammatory processes, energy metabolism, oxidative stress, and lipid metabolism were associated with traditional and potential new ADs. Despite efforts of studies investigating biomarkers of response to ADs, which could contribute to personalized treatment, there is no biomarker panel available for clinical application. From clinical genomic studies, we found that the main findings contribute to the development of pharmacogenomic tests for AD efficacy for each patient. Several studies pointed at DRD2, PXDNL, CACNA1E, and CACNA2D1 genes as potential targets for MDD treatment and the efficacy and rapid-antidepressant effect of ketamine. Finally, more in-depth studies of the molecular targets pointed here are needed to determine the clinical relevance and provide further evidence for precision MDD treatment.
| S-EPMC8739385 | biostudies-literature
Project description:Background: Major Depressive Disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for MDD suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesized that regulatory genomic processes are involved in the pathology of both MDD and suicidality. Methods: Genome-wide patterns of DNA methylation were assessed in depressed MDD suicide completers (n=20) and compared to non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focussed on identifying differentially methylated regions (DMRs) associated with suicidal depression, and epigenetic variation was explored in the context of polygenic risk scores for major depression and MDD suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed MDD suicide completers and polygenic burden for MDD and MDD suicide attempt. Results: We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite-pyrosequencing and replicated in a second set of MDD suicide samples, which is characterized by significant hypomethylation in both cortical brain regions in MDD MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for MDD suicide attempt, but not major depression. MDD suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Conclusions: Our data suggest there are coordinated changes in DNA methylation associated with MDD suicide that may offer novel insights into the molecular pathology associated with depressed MDD suicide completers.
2016-11-01 | GSE88890 | GEO
Project description:Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.
| S-EPMC7547155 | biostudies-literature
Project description:Blood samples taken from healthy controls and patients with major depression were analyzed for differences in microRNA expression. Patients were treated with either electroconvulsive therapy or ketamine and samples were again analyzed to determine if these treatments affected microRNA expression. Baseline microRNA expression profiles were studied to see if they could predict treatment response.
2016-08-31 | GSE81152 | GEO
Project description:The success of serotonin-selective reuptake inhibitors has lent support to the monoamine theory of major depressive disorder (MDD). This issue has been addressed in a number of molecular imaging studies by positron emission tomography or single-photon emission computed tomography of serotonin reuptake sites (5-HTT) in the brain of patients with MDD, with strikingly disparate conclusions. Our meta-analysis of the 18 such studies, totaling 364 MDD patients free from significant comorbidities or medication and 372 control subjects, revealed reductions in midbrain 5-HTT (Hedges' g=-0.49; 95% CI: (-0.84, -0.14)) and amygdala (Hedges' g=-0.50; 95% CI: (-0.78, -0.22)), which no individual study possessed sufficient power to detect. Only small effect sizes were found in other regions with high binding (thalamus: g=-0.24, striatum: g=-0.32, and brainstem g=-0.22), and no difference in the frontal or cingulate cortex. Age emerged as an important moderator of 5-HTT availability in MDD, with more severe reductions in striatal 5-HTT evident with greater age of the study populations (P<0.01). There was a strong relationship between severity of depression and 5-HTT reductions in the amygdala (P=0.01). Thus, molecular imaging findings indeed reveal widespread reductions of ∼10% in 5-HTT availability in MDD, which may predict altered spatial-temporal dynamics of serotonergic neurotransmission.
| S-EPMC4083395 | biostudies-literature
Project description:Molecular neuroimaging studies provide mounting evidence that neuroinflammation plays a contributory role in the pathogenesis of major depressive disorder (MDD). This has been the focus of a number of positron emission tomography (PET) studies of the 17-kDa translocator protein (TSPO), which is expressed by microglia and serves as a marker of neuroinflammation. In this meta-analysis, we compiled and analyzed all available molecular imaging studies comparing cerebral TSPO binding in MDD patients with healthy controls. Our systematic literature search yielded eight PET studies encompassing 238 MDD patients and 164 healthy subjects. The meta-analysis revealed relatively increased TSPO binding in several cortical regions (anterior cingulate cortex: Hedges' g = 0.6, 95% CI: 0.36, 0.84; hippocampus: g = 0.54, 95% CI: 0.26, 0.81; insula: g = 0.43, 95% CI: 0.17, 0.69; prefrontal cortex: g = 0.36, 95% CI: 0.14, 0.59; temporal cortex: g = 0.39, 95% CI: -0.04, 0.81). While the high range of effect size in the temporal cortex might reflect group-differences in body mass index (BMI), exploratory analyses failed to reveal any relationship between elevated TSPO availability in the other four brain regions and depression severity, age, BMI, radioligand, or the binding endpoint used, or with treatment status at the time of scanning. Taken together, this meta-analysis indicates a widespread ∼18% increase of TSPO availability in the brain of MDD patients, with effect sizes comparable to those in earlier molecular imaging studies of serotonin transporter availability and monoamine oxidase A binding.
| S-EPMC9549359 | biostudies-literature