Etiology Of Major Depressive Disorder Research Articles

Lipids in major depressive disorder: new kids on the block or old friends revisited?

Major depressive disorder (MDD) is a psychiatric mood disorder that results in substantial functional impairment and is characterized by symptoms such as depressed mood, diminished interest, impaired cognitive function, and vegetative symptoms such as disturbed sleep. Although the exact etiology of MDD is unclear, several underlying mechanisms (disturbances in immune response and/or stress response) have been associated with its development, with no single mechanism able to account for all aspects of the disorder. Currently, about 1 in 3 patients are resistant to current antidepressant therapies. Providing an alternative perspective on MDD could therefore pave the way for new, unexplored diagnostic and therapeutic solutions. The central nervous system harbors an enormous pool of lipids and lipid intermediates that have been linked to a plethora of its physiological functions. The aim of this review is therefore to provide an overview of the implications of lipids in MDD and highlight certain MDD-related underlying mechanisms that involve lipids and/or their intermediates. Furthermore, we will also focus on the bidirectional relationship between MDD and the lipid-related disorders obesity and type 2 diabetes.

Lower loss rate of serotonergically modulated neuronal accumulator for time in patients with major depressive disorder

Major depressive disorder (MDD) is characterized by dramatic and persistent worsening of mood, as well as a subjective feeling of time slowing. However, experimental data on time perception are inconsistent. As serotonergic dysfunction implicated in MDD etiology, we aim to examine time perception in MDD through the framework of lossy temporal integration model, previously also related to serotonergic transmission. Thirty-one patients with recurrent depressive disorder in partial remission and thirty control participants, without a history of psychiatric and neurological disorders, performed duration discrimination of visual stimuli (duration ranges from 3.2 to 6.4 s) and subjective minute production tasks. To infer about central serotonergic transmission, an electroencephalogram in response to the 1000 Hz tone of different intensity (50, 60, 70 and 80 dB SPL) was recorded. Patients with MDD shorten the past durations in the duration discrimination task significantly less than controls, thus being more objective. No difference in the subjective minute production was recorded. Patients with MDD have also exhibited larger auditory evoked potentials in response to the tones of high intensity (70 and 80 dB SPL) when compared with the controls. This resulted in a steeper slope of auditory evoked potentials by intensity function. These converging findings suggest a lower loss rate of neuronal temporal accumulator modulated by serotonergic transmission in patients with MDD.

Enlarged cross-sectional area of the left vagus nerve in patients with major depressive disorder.

Autonomic dysfunction and a chronic low-grade inflammation are supposed to play a role in the etiology of major depressive disorder (MDD). The vagus nerves (VN) form a major part of the parasympathetic nervous system and of the gut-brain axis. They are supposed to exert anti-inflammatory and epithelial barrier protective effects in the gut. A reduced vagal activity was described in patients with MDD. We aimed to examine the VN in patients with MDD with high-resolution ultrasound (HRUS) and hypothesized that the cross-sectional area (CSA) and the echogenicity of the VNs were altered in comparison to healthy controls. The echogenicity (gray scale mean) and the CSA of the cervical VNs at the level of the thyroid gland and both median nerves were examined with HRUS in 50 patients with MDD and 50 matched healthy controls. The left VN-CSA was significantly larger in the MDD group compared to the control group (1.7 ± 0.4 mm2 versus 1.5 ± 0.4 mm2; p = 0.045). The CSA of the right VN and both median nerves (MN) were similar between groups. In MDD subgroup analyses, recurrent depressive disorders were the main contributing factor for the left VN-CSA enlargement. Echogenicity was not altered in the VN and MN between groups. The enlargement of the left VN-CSA in patients with MDD, and especially in these patients with recurrent depressive disorders, might turn out as a promising imaging biomarker. Longitudinal studies are warranted to examine whether the VNs-CSA change in the course of MDD.

Sestrin-2 and hypoxia-ınducible factor-1 alpha levels in major depressive disorder and its subtypes.

The objective of this study is to measure the levels of sestrin-2 (SESN2) and hypoxia-inducible factor-1 alpha (HIF-1α), which can be determinants in the relevant physiopathology and etiology, assessment of the clinical severity, and identification of new treatment targets in major depressive disorder (MDD) and its subtypes. A total of 230 volunteers, including 153 patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and 77 healthy controls, were included in the study. Of the MDD patients included in the study, 40 had melancholic features, 40 had anxious distress features, 38 had atypical features, and the remaining 35 had psychotic features. All participants were administered the Beck's Depression Inventory (BDI) and Clinical Global Impressions-Severity (CGI-S) scale. Serum SESN2 and HIF-1α levels of the participants were measured using the enzyme-linked immunosorbent assay (ELISA) method. The HIF-1α and SESN2 values of the patient group were found to be significantly lower than those of the control group (p < 0.05). The HIF-1α and SESN2 values were significantly lower in patients with melancholic, anxious distress, and atypical features compared to the control group (p < 0.05). The HIF-1α and SESN2 levels did not differ significantly between patients with psychotic features and the control group (p > 0.05). The findings of the study suggested that knowledge of SESN2 and HIF-1α levels may contribute to the explanation of the etiology of MDD, objective assessment of the severity of the disease, and identification of new treatment targets.

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.

Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

Chronic fluoxetine treatment in socially-isolated rats modulates the prefrontal cortex synaptoproteome

Exposure to chronic social isolation (CSIS) and synapse dysfunction have been implicated in the etiology of major depressive disorder (MDD). Fluoxetine (Flx) has been widely used to treat MDD, but its mechanisms of action remain elusive. We employed comparative synaptoproteomics to investigate the changes in the levels of proteins and molecular signaling pathways in prefrontal cortical samples of adult male Wistar rats exposed to CSIS, a rat model of depression, and CSIS rats treated with chronic Flx and controls, using liquid chromatography coupled to tandem mass spectrometry. Flx-treated control rats showed a decreased level of proteins involved in vesicle-mediated transport, and a predominantly increased level of exocytosis-associated proteins. CSIS significantly reduced the level of proteins involved in the ATP metabolic process, clathrin-dependent endocytosis, and proteolysis. Flx treatment in CSIS rats stimulated synaptic vesicle trafficking by increasing the regulation of exo/endocytosis-associated proteins, proteins involved in synaptic plasticity including neurogenesis, Cox5a, mitochondria-associated proteins involved in oxidative phosphorylation, and ion transport proteins (Slc8a2, Atp1b2). Flx treatment resulted in an increased synaptic vesicle dynamic, plasticity and mitochondrial functionality, and a suppression of CSIS-induced impairment of these processes. Biological significanceIdentifying biomarkers of MDD and treatment response is the goal of many studies. Contemporary studies have shown that many molecular alterations associated with the pathophysiology of MDD reside within the synapse. As part of this research, a growing importance is the use of proteomics, as monitoring the changes in protein levels enables the identification of (possible) biochemical pathways and processes of importance for the development of depressive-like behavior and the efficacy of antidepressant treatments. We profiled proteomic changes representative of the development of CSIS-induced depressive-like behavior and the antidepressant effects of Flx. Our study has identified synaptosomal proteins and altered molecular pathways that may be potential markers of prefrontal cortical synaptic dysfunction associated with depressive-like behavior, and further clarified the mechanisms of depressive-like behavior and mode of action of Flx. Our findings indicate potential PFC synaptic targets for antidepressant treatment.

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder.

The retrograde endocannabinoid (eCB) pathway is closely associated with the etiology of major depressive disorder (MDD) at both pathophysiological and genetic levels. This study aimed to investigate the potential role of genetic mutations in the eCB pathway and underlying mechanisms in Han Chinese patients with MDD. A total of 96 drug-naïve patients with first-episode MDD and 62 healthy controls (HCs) were recruited. Whole-exome sequencing was performed to identify the gene mutation profiles in patients with MDD. Results were filtered to focus on low-frequency variants and rare mutations (minor allele frequencies <0.05) related to depressive phenotypes. Enrichment analyses were performed for 146 selected genes to examine the pathways in which the most significant enrichment occurred. A protein-protein interaction (PPI) network analysis was performed to explore the biological functions of the eCB pathway. Finally, based on current literature, a preliminary analysis was conducted to explore the effect of genetic mutations on the function of this pathway. Our analysis identified 146 (15.02%) depression-related genetic mutations in patients with MDD when compared with HCs, and 37 of the mutations were enriched in the retrograde eCB signaling pathway. Seven hub genes in the eCB pathway were closely related to mitochondrial function, including Complex I genes (NDUFS4, NDUFV2, NDUFA2, NDUFA12, NDUFB11) and genes associated with protein (PARK7) and enzyme (DLD) function in the regulation of mitochondrial oxidative stress. These results indicate that genetic mutations in the retrograde eCB pathway represent potential etiological factors associated with the pathogenesis of MDD.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis.

Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I² = 72%) and the chi-square test (χ² = 18.32; p = 0.003). This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Structural covariance network of the hippocampus-amygdala complex in medication-naïve patients with first-episode major depressive disorder.

The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder (MDD). Each of these structures consists of several heterogeneous subfields. We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus-amygdala complex in medication-naïve patients with first-episode MDD. High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode, medication-naïve, and noncomorbid MDD patients and 81 age-, sex-, and education level-matched healthy control participants (HCs). The structural covariance network (SCN) was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions; the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions, controlled for age, sex, education level, and intracranial volume. The global and nodal graph metrics were calculated and compared between groups. Compared with HCs, the SCN within the hippocampus-amygdala complex in patients with MDD showed a shortened mean characteristic path length, reduced modularity, and reduced small-worldness index. At the nodal level, the left hippocampal tail showed increased measures of centrality, segregation, and integration, while nodes in the left amygdala showed decreased measures of centrality, segregation, and integration in patients with MDD compared with HCs. Our results provide the first evidence of atypical topologic characteristics within the hippocampus-amygdala complex in patients with MDD using structure network analysis. It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.

Meta-analysis of epigenome-wide association studies of major depressive disorder

Epigenetic mechanisms have been hypothesized to play a role in the etiology of major depressive disorder (MDD). In this study, we performed a meta-analysis between two case–control MDD cohorts to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in MDD. Using samples from two Cohorts (a total of 298 MDD cases and 63 controls with repeated samples, on average ~ 1.8 samples/subject), we performed an EWAS meta-analysis. Multiple cytosine-phosphate-guanine sites annotated to TNNT3 were associated with MDD reaching study-wide significance, including cg08337959 (p = 2.3 × 10–11). Among DMPs with association p values less than 0.0001, pathways from REACTOME such as Ras activation upon Ca2+ influx through the NMDA receptor (p = 0.0001, p-adjusted = 0.05) and long-term potentiation (p = 0.0002, p-adjusted = 0.05) were enriched in this study. A total of 127 DMRs with Sidak-corrected p value < 0.05 were identified from the meta-analysis, including DMRs annotated to TNNT3 (chr11: 1948933 to 1949130 [6 probes], Sidak corrected P value = 4.32 × 10–41), S100A13 (chr1: 153599479 to 153600972 [22 probes], Sidak corrected P value = 5.32 × 10–18), NRXN1 (chr2: 50201413 to 50201505 [4 probes], Sidak corrected P value = 1.19 × 10–11), IL17RA (chr22: 17564750 to 17565149, Sidak corrected P value = 9.31 × 10–8), and NPFFR2 (chr4: 72897565 to 72898212, Sidak corrected P value = 8.19 × 10–7). Using 2 Cohorts of depression case–control samples, we identified DMPs and DMRs associated with MDD. The molecular pathways implicated by these data include mechanisms involved in neuronal synaptic plasticity, calcium signaling, and inflammation, consistent with reports from previous genetic and protein biomarker studies indicating that these mechanisms are involved in the neurobiology of depression.

Decreased functional connectivity in patients with major depressive disorder and a history of childhood traumatization through experiences of abuse

BackgroundChildhood trauma (CT) increases vulnerability for the development of major depressive disorder (MDD). Alterations in resting-state functional connectivity (RSFC) have frequently been reported for MDD. These alterations may be much more prominent in depressive patients with a history of CT. The present study aims to compare RSFC in different brain networks of patients with MDD and CT (MDD+CT) vs. MDD and no CT compared to healthy controls. Methods45 patients (22 with CT) were compared to 23 age-and-gender-matched healthy control subjects. Demographic parameters, severity of MDD, severity of CT and comorbid anxiety disorders were assessed. For assessment of RSFC alterations, a seed-based approach within five well-established RSFC networks was used. ResultsCT in MDD patients predicts severity of comorbid anxiety. A significant decrease in in-between network RSFC-values of MDD patients compared to controls was found in the network pairs of default mode network (DMN) – dorsal attention network (DAN), ventral attention network (VAN) – DMN and DAN – affective network (AN). MDD+CT patients presented more aberrant RSFC than MDD-CT patients. MDD scores predicted the decrease in RSFC for MDD patients. Higher Childhood Trauma Questionnaire (CTQ) scores are linked to reduced functional connectivity (FC) between DMN – DAN. ConclusionsOur study shows reduced RSFC in MDD patients for DMN – DAN, VAN – DMN, DAN – AN and MDD+CT patients presented more aberrant RSFC so that we suspect CT to be a considerable factor in the etiology of MDD. Through dysregulated neural circuits, CT is likely to contribute to a distinct MDD pathophysiology.

Stress Reduces Extracellular ATP in the Prefrontal Cortex and Activates the Prefrontal Cortex–Lateral Habenula Pathway for Depressive-like Behavior

Major depressive disorder (MDD) is a common and devastating mental disorder that causes feelings of sadness and anhedonia (loss of pleasure or interest in activities), lack of motivation, cognitive deficits, and vegetative symptoms. It is the leading cause of disability around the world, affecting 4.4% of world’s population. Although the etiology of MDD remains unclear, recent research has begun to unravel its pathophysiological mechanisms. Arguably, three brain regions stand out as most involved in MDD—the prefrontal cortex (PFC), the hippocampus, and the amygdala—of which the PFC seems to be most consistently impaired in MDD (1).

Not Only Gene Discovery: Genome-wide Association Studies and Polygenic Risk Scores as Tools to Dissect the Heterogeneity of Major Depressive Disorder

Large-scale genome-wide association studies (GWASs) based on biobanks and meta-analyses of many cohorts have revolutionized our ability to investigate the polygenic architecture of psychiatric disorders and traits. This has been possible because of national and international collaborations such as the Psychiatric Genomics Consortium (PGC) ( 1 Sullivan P.F. Agrawal A. Bulik C.M. Andreassen O.A. Borglum A.D. Breen G. et al. Psychiatric genomics: An update and an agenda. Am J Psychiatry. 2018; 175: 15-27 Crossref PubMed Scopus (292) Google Scholar ). While combining cohorts with different characteristics and various phenotypic assessments led to uncovering hundreds of loci associated with major depressive disorder (MDD) ( 2 Levey D.F. Stein M.B. Wendt F.R. Pathak G.A. Zhou H. Aslan M. et al. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat Neurosci. 2021; 24: 954-963 Crossref PubMed Scopus (47) Google Scholar ), this has limited our ability to investigate the genetic heterogeneity of MDD. Owing to the massive sample sizes required to identify the small individual effects of single risk loci, it is not useful to directly compare gene discovery of GWASs of different MDD subtypes because the sample size available for each subtype is a primary driver of a GWAS’s statistical power. Indeed, although minimal phenotyping may reduce the specificity of MDD loci identified by GWASs ( 3 Cai N. Revez J.A. Adams M.J. Andlauer T.F.M. Breen G. Byrne E.M. et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet. 2020; 52: 437-447 Crossref PubMed Scopus (92) Google Scholar ), sample size still trumps phenotyping when focusing only on gene discovery. SEE CORRESPONDING ARTICLE ON PAGE 227 The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between SubtypesBiological PsychiatryVol. 92Issue 3PreviewMajor depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery—often achieved with a trade-off in the depth of phenotyping. Full-Text PDF

Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

The molecular pathomechanisms of major depressive disorder (MDD) are still not completely understood. Here, we follow the hypothesis, that mitochondria dysfunction which is inevitably associated with bioenergetic disbalance is a risk factor that contributes to the susceptibility of an individual to develop MDD. Thus, we investigated molecular mechanisms related to mitochondrial function in induced neuronal progenitor cells (NPCs) which were reprogrammed from fibroblasts of eight MDD patients and eight non-depressed controls. We found significantly lower maximal respiration rates, altered cytosolic basal calcium levels, and smaller soma size in NPCs derived from MDD patients. These findings are partially consistent with our earlier observations in MDD patient-derived fibroblasts. Furthermore, we differentiated MDD and control NPCs into iPS-neurons and analyzed their passive biophysical and active electrophysiological properties to investigate whether neuronal function can be related to altered mitochondrial activity and bioenergetics. Interestingly, MDD patient-derived iPS-neurons showed significantly lower membrane capacitance, a less hyperpolarized membrane potential, increased Na+ current density and increased spontaneous electrical activity. Our findings indicate that functional differences evident in fibroblasts derived from MDD patients are partially present after reprogramming to induced-NPCs, could relate to altered function of iPS-neurons and thus might be associated with the aetiology of major depressive disorder.

Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder.

Increasing evidence supports the notion that neuroinflammation plays a critical role in the etiology of major depressive disorder (MDD), at least in a subset of patients. By virtue of their capacity to transform into reactive states in response to inflammatory insults, microglia, the brain’s resident immune cells, play a pivotal role in the induction of neuroinflammation. Experimental studies have demonstrated the ability of microglia to recognize pathogens or damaged cells, leading to the activation of a cytotoxic response that exacerbates damage to brain cells. However, microglia display a wide range of responses to injury and may also promote resolution stages of inflammation and tissue regeneration. MDD has been associated with chronic priming of microglia. Recent studies suggest that altered microglial morphology and function, caused either by intense inflammatory activation or by senescence, may contribute to depression and associated impairments in neuroplasticity. In this context, modifying microglia phenotype by tuning inflammatory pathways might have important translational relevance to harness neuroinflammation in MDD. Interestingly, it was recently shown that different microglial phenotypes are associated with distinct metabolic pathways and analysis of the underlying molecular mechanisms points to an instrumental role for energy metabolism in shaping microglial functions. Here, we review various canonical pro-inflammatory, anti-inflammatory and metabolic pathways in microglia that may provide new therapeutic opportunities to control neuroinflammation in brain disorders, with a strong focus on MDD.

The possible role of the Microbiota-Gut-Brain-Axis in the etiology of Major depressive Disorder (MDD) The possible role of the Microbiota-Gut-Brain-Axis in the etiology of Major depressive Disorder (MDD) The possible role of the Microbiota-Gut-Brain-Axis in the etiology of Major depressive Disorder (MDD)

Introduction1.Introduction MDD is a heterogeneous disorder, with a wide variety of symptoms and inconsistent treatment response, and is not completely understood. A dysregulated stress system is a consistent finding, however, and exhaustion is a consistent trait in adolescent patients. In order to open up our thinking about MDD we take up the challenge to reframe depression, specifically focusing on the possible role of the Microbiota-Gut-Brain-Axis in the etiology of MDD.ObjectivesWe propose a ‘bidirectional feedback hypothesis’: microbiota can promote or inhibit a pro-inflammatory state, (in)directly altering the hypothalamic pituitary adrenal (HPA) axis response and the microbiome and further increasing or decreasing its pro-inflammatory state. The aim is to show that the pro-inflammatory state is an integral part of a HPA axis stress spiralling mechanism that plays a role in the etiology of MDD.MethodsA systematic review based on publications from PubMed, Embase and PsycInfoResultsThe etiology of MDD can be understood as sliding down a spiral. This stress spiralling mechanism can be promoted or inhibited by: 1.factors such as a poor lifestyle or (pre-existing) illness 2.bettering someone’s lifestyle, coping behavior or providing pro-/prebiotics in combination with personalised therapeutics.Conclusions We argue that an interdisciplinary One Health approach is the most promising preventive and therapeutic option for MDD.DisclosureNo significant relationships.

Gender differences of genetic etiology in the incidence of major depressive disorder among Han freshmen

Objective: To analyze the gender differences of genetic etiology in the incidence of major depression disorder among Han freshmen. Methods: A 1-year follow-up survey was carried out among 8 079 Han freshmen from Jining, Rizhao and Weifang without lifetime major depressive disorder (MDD) at baseline (April to October 2018) and 4 828 venous blood samples were also collected. After extracting DNA, Sequenom Mass Array time-of-flight mass spectrometry biochip technology was used to detect the genotypes of 17 single nucleotide polymorphisms (SNPs) MDD-related loci. Logistic regression was used for univariate analysis. Generalized multifactor dimension reduction was used to analyze gene-gene interactions. Composite International Diagnostic Interview (CIDI) 3.0 was used for MDD diagnosis. Results: The 1-year incidence of MDD among Han freshmen was 2.23% (95%CI: 1.91%-2.60%) and the gender difference of incidence between males (1.97%, 95%CI: 1.52%-2.56%) and females (2.39%, 95%CI: 1.98%-2.90%) was not statistically significant (P>0.05). AG genotype of rs768705 (nearby gene: TMEM161B) was a risk factor for MDD (OR=1.98, 95%CI: 1.24-2.83). The TC genotype of rs17727765 (nearby gene: CRYBA1) was only a risk factor for MDD in males (OR=9.61, 95%CI: 2.04-45.30). An 8-loci interaction model (PMFBP1, OLFM4, LHPP, ENOX1, TMEM161B, SPPL3, FBXL4 and L3MBTL2) could predict MDD in women with an accuracy rate of 60.05%. No effective prediction model was found for MDD in men. Conclusions: There might be gender differences in the genetic etiology of MDD. Further researches on the genetic causes of MDD in men should be explored.

Altered hippocampus and amygdala subregion connectome hierarchy in major depressive disorder

The hippocampus and amygdala limbic structures are critical to the etiology of major depressive disorder (MDD). However, there are no high-resolution characterizations of the role of their subregions in the whole brain network (connectome). Connectomic examination of these subregions can uncover disorder-related patterns that are otherwise missed when treated as single structures. 38 MDD patients and 40 healthy controls (HC) underwent anatomical and diffusion imaging using 7-Tesla MRI. Whole-brain segmentation was performed along with hippocampus and amygdala subregion segmentation, each representing a node in the connectome. Graph theory analysis was applied to examine the importance of the limbic subregions within the brain network using centrality features measured by node strength (sum of weights of the node’s connections), Betweenness (number of shortest paths that traverse the node), and clustering coefficient (how connected the node’s neighbors are to one another and forming a cluster). Compared to HC, MDD patients showed decreased node strength of the right hippocampus cornu ammonis (CA) 3/4, indicating decreased connectivity to the rest of the brain, and decreased clustering coefficient of the right dentate gyrus, implying it is less embedded in a cluster. Additionally, within the MDD group, the greater the embedding of the right amygdala central nucleus (CeA) in a cluster, the greater the severity of depressive symptoms. The altered role of these limbic subregions in the whole-brain connectome is related to diagnosis and depression severity, contributing to our understanding of the limbic system involvement in MDD and may elucidate the underlying mechanisms of depression.

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice.

Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a “two-hit” stress mouse model. The “two-hit” stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the “two-hit” stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.