Pathophysiology of Major Depression by Clinical Stages.
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ABSTRACT:
SUBMITTER: de Menezes Galvao AC
PROVIDER: S-EPMC8374436 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Individual characteristics of pathophysiology and course of depressive episodes are at present not considered in diagnostics. There are no biological markers available that can assist in categorizing subtypes of depression and detecting molecular variances related to disease-causing mechanisms between depressed patients. Identification of such differences is important to create patient subgroups, which will benefit from medications that specifically target the pathophysiology underlying their clinical condition. To detect characteristic biological markers for major depression, we analyzed the cerebrospinal fluid (CSF) proteome of depressed vs control persons, using two-dimensional polyacrylamide gel electrophoresis and time-of-flight (TOF) mass spectrometry peptide profiling. Proteins of interest were identified by matrix-assisted laser desorption ionization TOF mass spectrometry (MALDI-TOF-MS). Validation of protein markers was performed by immunoblotting. We found 11 proteins and 144 peptide features that differed significantly between CSF from depressed patients and controls. In addition, we detected differences in the phosphorylation pattern of several CSF proteins. A subset of the differentially expressed proteins implicated in brain metabolism or central nervous system disease was validated by immunoblotting. The identified proteins are involved in neuroprotection and neuronal development, sleep regulation, and amyloid plaque deposition in the aging brain. This is one of the first hypothesis-free studies that identify characteristic protein expression differences in CSF of depressed patients. Proteomic approaches represent a powerful tool for the identification of disease markers for subgroups of patients with major depression.
| S-EPMC3280652 | biostudies-literature
Project description:While exposure to adverse life events and subsequent dysregulation of the stress hormone response broadly confer risk for depression, the specific molecular mechanisms mediating this risk are poorly understood. Through pharmacologic activation of the stress hormone response in blood cells we demonstrate that common genetic variants in long-range enhancer elements moderate the immediate transcriptome response to stress, and that these genetic differences are associated with increased risk for depression in the context of early adversity. Using imaging genetics we then link these common risk variants with dysregulated amygdala reactivity, an important trigger of the stress hormone response. The transcripts regulated by these risk variants in peripheral blood were also responsive to stress and stress hormone receptor activation in murine brain. Network modeling approaches suggest that these differences in transcriptional activation may mediate stress-related risk for depression by altering a functional gene network related to proteasome degradation and synaptic plasticity. A Dexamethasone Suppression Test was performed in 160 male subjects. Baseline and stimulated (3 hours after 1.5 mg dexamethasone p.o.) whole blood samples were analyzed using Illumina Human HT-12 v3 arrays.
2013-09-01 | E-GEOD-46743 | biostudies-arrayexpress
Project description:BackgroundWe recently reported increased levels of neutrophils, monocytes and C-reactive protein (CRP) correlated with symptom severity in acute schizophrenia. Here, we investigated if a similar pattern of innate immune system activation occurs in major depression (MD).MethodsWe assessed differential blood counts, CRP, depression symptoms (HAMD-21) and psychosocial functioning (GAF) in controls (n = 129) and patients with first (FEMD: n = 82) or recurrent (RMD: n = 47) disease episodes of MD at baseline (T0; hospital admission) and after 6-weeks treatment (T6).ResultsConsidering smoking, BMI and gender as covariates, neutrophils (FEMD: p = 0.034, RMD: p = 0.034) and CRP (FEMD: p < 0.001, RMD: p = 0.021) were higher, and eosinophils (FEMD: p = 0.005, RMD: p = 0.004) lower in patients versus controls at T0. Baseline lymphocyte counts were elevated in RMD (p = 0.003) but not FEMD. Results were confirmed by analyses of nonsmokers. At follow-up, eosinophils rose significantly in FEMD (p = 0.011) but no significant changes were observed in RMD. Improvement in HAMD-21 correlated with T0-T6 changes of neutrophil counts in FEMD (r = 0.364, p = 0.024). Compared with our previous schizophrenia study, raised baseline neutrophil and reduced eosinophil counts in MD had smaller effect sizes and treatment had a weaker association with T0-T6 changes in neutrophils. In addition, lymphocytes were elevated at T0 in recurrent MD but not in schizophrenia patients.ConclusionsThese findings suggest that innate immunity may be involved in early stages of MD, and adaptive immunity may be involved in chronic disease. Thus, further studies may lead to new disease stage-dependent MD treatment strategies targeting different aspects of immune system activation.
| S-EPMC8981816 | biostudies-literature
Project description:Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.
| S-EPMC2680424 | biostudies-literature
Project description:The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.
| S-EPMC5546325 | biostudies-literature
Project description:BackgroundA substantial proportion of individuals with late-life major depression could be classified as having a suspected non-Alzheimer disease pathophysiology (SNAP), as indicated by a negative test for the biomarker β-amyloid (Aβ-) but a positive test for neurodegeneration (ND+). This study investigated the clinical features, characteristic patterns of brain atrophy and hypometabolism, and implications regarding pathology in this population.MethodsForty-six amyloid-negative patients with late-life major depressive disorder (MDD) patients, including 23 SNAP (Aβ-/ND+) and 23 Aβ-/ND- MDD subjects, and 22 Aβ-/ND-healthy control subjects were included in this study. Voxel-wise group comparisons between the SNAP MDD, Aβ-/ND- MDD and control subjects were performed, adjusting for age, gender and level of education. For exploratory comparisons, 8 Aβ+/ND- and 4 Aβ+/ND + MDD patients were included in the Supplementary Material.ResultsThe SNAP MDD patients had atrophy extending to regions outside the hippocampus, predominately in the medial temporal, dorsomedial and ventromedial prefrontal cortex; hypometabolism involving a large portion of the lateral and medial prefrontal cortex in addition to the bilateral temporal, parietal and precuneus cortex within typical Alzheimer disease regions were observed. Metabolism ratios of the inferior to the medial temporal lobe were significantly elevated in the SNAP MDD patients. We further discussed the implications with regards to underlying pathologies.ConclusionThe present study demonstrated characteristic patterns of atrophy and hypometabolism in patients with late-life major depression with SNAP. Identifying individuals with SNAP MDD may provide insights into currently unspecified neurodegenerative processes. Future refinement of neurodegeneration biomarkers is essential in order to identify potential pathological correlates while in vivo reliable pathological biomarkers are not forthcoming.
| S-EPMC10749882 | 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:BackgroundPsychotic major depression (PMD) is a subtype of depression with a poor prognosis. Previous studies have failed to find many differences between patients with PMD and those with non-psychotic major depression (NMD) or schizophrenia (SZ). We compared sociodemographic factors (including season of conception) and clinical characteristics between patients with PMD, NMD, and schizophrenia. Our aim was to provide data to help inform clinical diagnoses and future etiology research.MethodsThis study used data of all patients admitted to Shandong Mental Health Center from June 1, 2016 to December 31, 2017. We analyzed cases who had experienced an episode of PMD (International Classification of Diseases, Tenth Revision codes F32.3, F33.3), NMD (F32.0-2/9, F33.0-2/9), and SZ (F20-20.9). Data on sex, main discharge diagnosis, date of birth, ethnicity, family history of psychiatric diseases, marital status, age at first onset, education, allergy history, and presence of trigger events were collected. Odds ratios (OR) were calculated using logistic regression analyses. Missing values were filled using the k-nearest neighbor method.ResultsPMD patients were more likely to have a family history of psychiatric diseases in their first-, second-, and third-degree relatives ([OR] 1.701, 95% confidence interval [CI] 1.019-2.804) and to have obtained a higher level of education (OR 1.451, 95% CI 1.168-1.808) compared with depression patients without psychotic features. Compared to PMD patients, schizophrenia patients had lower education (OR 0.604, 95% CI 0.492-0.741), were more often divorced (OR 3.087, 95% CI 1.168-10.096), had a younger age of onset (OR 0.934, 95% CI 0.914-0.954), less likely to have a history of allergies (OR 0.604, 95% CI 0.492-0.741), and less likely to have experienced a trigger event 1 year before first onset (OR 0.420, 95% CI 0.267-0.661). Season of conception, ethnicity, and sex did not differ significantly between PMD and NMD or schizophrenia and PMD.ConclusionsPMD patients have more similarities with NMD patients than SZ patients in terms of demographic and clinical characteristics. The differences found between PMD and SZ, and PMD and NMD correlated with specificity of the diseases. Furthermore, allergy history should be considered in future epidemiological studies of psychotic disorders.
| S-EPMC8004453 | 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:ObjectiveThe N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically heterogeneous populations.MethodData were analyzed from 4 studies of treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82), and at day 7 (n = 71). Univariate Pearson correlations were performed for each variable with percent change from baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (P ≤ .05, 2-tailed).ResultsHigher body mass index correlated with greater HDRS improvement at 230 minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37, P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7 (standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized β = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent change variance at 230 minutes, day 1, and day 7, respectively.ConclusionsDespite its post hoc nature, this study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.
| S-EPMC4310499 | biostudies-literature