Etiology Of Major Depressive Disorder Research Articles

Epigenetic Modifications and Neuroplasticity in the Pathogenesis of Depression: A Focus on Early Life Stress.

Major depressive disorder (MDD) is a debilitating mental illness, and it is considered to be one of the leading causes of disability globally. The etiology of MDD is multifactorial, involving an interplay between biological, psychological, and social factors. Early life represents a critical period for development. Exposure to adverse childhood experiences is a major contributor to the global burden of disease and disability, doubling the risk of developing MDD later in life. Evidence suggests that stressful events experienced during that timeframe play a major role in the emergence of MDD, leading to epigenetic modifications, which might, in turn, influence brain structure, function, and behavior. Neuroplasticity seems to be a primary pathogenetic mechanism of MDD, and, similarly to epigenetic mechanisms, it is particularly sensitive to stress in the early postnatal period. In this review, we will collect and discuss recent studies supporting the role of epigenetics and neuroplasticity in the pathogenesis of MDD, with a focus on early life stress (ELS). We believe that understanding the epigenetic mechanisms by which ELS affects neuroplasticity offers potential pathways for identifying novel therapeutic targets for MDD, ultimately aiming to improve treatment outcomes for this debilitating disorder.

The Interplay between MiR-134/BDNF and LKB1/AMPK/SIRT1 Accentuates the Antidepressant Efficacy of Empagliflozin in Ovariectomized Rats.

Major depressive disorder (MDD) is considered a major cause of suicide worldwide. As previous studies revealed that neuroinflammation is a significant factor in the etiology of MDD, this study proposed to unravel the possible antidepressant effect of Empagliflozin (EMPA) through targeting miRNA-134 (miR-134)/brain-derived neurotrophic factor (BDNF) and liver kinase B1 (LKB1)/adenosine 5'-monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) axes in ovariectomized (OVX) female rats. Rats were assigned randomly to four groups: Sham operation (SO), OVX, OVX + EMPA (10 mg/kg/day, p.o.), and OVX + EMPA + Dorsomorphin (DORSO) (25 μg/day/rat, i.v.). Drugs were administered for 28 days after 2 weeks of surgery. EMPA debilitated OVX-induced depressive-like behavior by mitigating the immobility time in the tail suspension test and forced swimming test. Moreover, EMPA curtailed OVX-induced alterations of serum estradiol, hippocampal serotonin, miR-134 expression, as well as BDNF. EMPA also dwindled OVX-induced changes of hippocampal p-LKB1/LKB1, p-AMPK/AMPK, SIRT1, and inflammatory markers (nuclear factor-kappa-B, interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha). Additionally, the EMPA-treated group exhibited marked improvement in different brain regions' histopathology. However, DORSO coadministration reversed most of EMPA's beneficial effects. The current study displayed the modulatory role of EMPA on miR-134/BDNF and LKB1/AMPK/SIRT1 axes, thus offering a partial explanation of its antidepressant efficacy and proposing EMPA as a novel therapeutic avenue for MDD.

Intracranial Directed Connectivity Links Subregions of the Prefrontal Cortex to Major Depression.

Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.

The Antidepressant Action of Fluoxetine Involves the Inhibition of Dlx5/6 in Cortical GABAergic Neurons through a TrkB-Dependent Pathway.

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.

Elucidating genetic and molecular basis of altered higher-order brain structure-function coupling in major depressive disorder

Previous studies have shown that major depressive disorder (MDD) patients exhibit structural and functional impairments, but few studies have investigated changes in higher-order coupling between structure and function. Here, we systematically investigated the effect of MDD on higher-order coupling between structural connectivity (SC) and functional connectivity (FC). Each brain region was mapped into embedding vector by the node2vec algorithm. We used support vector machine (SVM) with the brain region embedding vector to distinguish MDD patients from health controls (HCs) and identify the most discriminative brain regions. Our study revealed that MDD patients had decreased higher-order coupling in connections between the most discriminative brain regions and local connections in rich-club organization and increased higher-order coupling in connections between the ventral attentional network and limbic network compared with HCs. Interestingly, transcriptome-neuroimaging association analysis demonstrated the correlations between regional rSC-FC coupling variations between MDD patients and HCs and α/β-hydrolase domain-containing 6 (ABHD6), β 1,3-N-acetylglucosaminyltransferase-9(β3GNT9), transmembrane protein 45B (TMEM45B), the correlation between regional dSC-FC coupling variations and retinoic acid early transcript 1E antisense RNA 1(RAET1E-AS1), and the correlations between regional iSC-FC coupling variations and ABHD6, β3GNT9, katanin-like 2 protein (KATNAL2). In addition, correlation analysis with neurotransmitter receptor/transporter maps found that the rSC-FC and iSC-FC coupling variations were both correlated with neuroendocrine transporter (NET) expression, and the dSC-FC coupling variations were correlated with metabotropic glutamate receptor 5 (mGluR5). Further mediation analysis explored the relationship between genes, neurotransmitter receptor/transporter and MDD related higher-order coupling variations. These findings indicate that specific genetic and molecular factors underpin the observed disparities in higher-order SC-FC coupling between MDD patients and HCs. Our study confirmed that higher-order coupling between SC and FC plays an important role in diagnosing MDD. The identification of new biological evidence for MDD etiology holds promise for the development of innovative antidepressant therapies.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype

The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity. Therefore, this study examined the effect of TCDD on depression-like behaviors. Female mice were fed standard chow or a high-fat diet (HFD) for 11 weeks, and their weight was recorded. Subsequently, they were tested for baseline sucrose preference and splash test grooming. Then, TCDD (0.1 µg/kg/day) or vehicle was administered orally for 28 days, and mice were examined for their sucrose preference and performances in the splash test, forced swim test (FST), and Morris water maze (MWM) task. TCDD significantly decreased sucrose preference, increased FST immobility time, and decreased groom time in chow-fed mice. HFD itself significantly reduced sucrose preference. However, TCDD significantly increased FST immobility time and decreased groom time in HFD-fed mice. A small decrease in bodyweight was observed only at the fourth week of daily TCDD administration in chow-fed mice, and no significant effects of TCDD on bodyweights were observed in HFD-fed mice. TCDD did not have a significant effect on spatial learning in the MWM. Thus, this study demonstrated that TCDD induces a depression-like state, and the effects were not due to gross lethal toxicity. This study further suggests that more studies should examine a possible role for AhR and AhR-active environmental pollutants in precipitating or worsening MDD.

Treatment of Patient with Recurrent Major Depressive Disorder: A Case Report

Introduction: The alteration of biogenic amines, in particular norepinephrine and serotonin, is a hypothesis that is frequently put forward in relation to the etiology of major depressive disorder. This study was aimed to present the recurrent major depressive disorder in a forty years old woman. Case presentation: A 40-year-old woman, presented to our mental health unit with symptoms of a low mood, which she described as similar to previous episodes of depression. Two decades ago, she underwent an evaluation and received a diagnosis of severe depression for the first time. Throughout that duration, she received imipramine (tricyclic antidepressant/TCA) at dosages of up to 150 mg per day, resulting in favorable outcomes. She claimed that she abstained from illicit substances and has not undergone any distressing events in the recent past. Although she was confident that she was experiencing another severe depression, she expressed a desire to avoid using imipramine this time due to its adverse effects, including dry mouth, dry eyes, and diarrhea. The patient was diagnosed as recurrent major depressive disorder without psychotic symptoms. Conclusion: The likelihood of experiencing additional bouts of major depression is higher when there have been multiple prior episodes, residual symptoms of depression between episodes, and the coexistence of other psychiatric or chronic medical conditions. Prior episodes of serious depression that responded well to treatment have a greater probability of reaching remission in future episodes. First-line treatment options for major depressive disorder include selective serotonin reuptake inhibitors (SSRIs) such as bupropion, venlafaxine, mirtazapine, and duloxetine.

MICRO-RNA AS DIAGNOSTIC MODALITY OF MAJOR DEPRESSIVE DISORDER

Introduction – Major Depressive Disorder (MDD) is a chronic mental health disorder, with suicidal ideation, but until now an exact diagnostic approach has not been found. For the limitations of the current diagnosis, such as subjective reports of patients or their families with mental status examinations, there is still a lack of objective diagnostic results. In this case, it is still a challenge for researchers. Neutropic factors, hypothalamic-pituitary-adrenal hormones (HPA), indicators of inflammation, and metabolic factors, were found to be novel biomarkers for MDD. However, these biomarkers show limited sensitivity and specificity. The most recent diagnostic development effort is the use of microRNA as a diagnostic modality approach for MDD. Methods – This study uses a qualitative method by collecting valid journals with certain inclusion and exclusion criteria. The keywords used were MDD, microRNA, and Diagnostic. There are journals used as the source of this literature review which come from valid scientific sources such as NCBI, ScienceDirect, and PubMed which were published in the last 10 years. Results – The results of the miRNA-124-3p expression test showed a significant difference between the healthy control group and the MDD patient group. The specificity and sensitivity of miRNA-221-3p, miRNA-451a, miRNA-34a-5p, and let-7d-3p showed high accuracy in the diagnosis of MDD. Discuss – The unknown etiology of MDD makes some patients have no results or significant progress of their depression in clinical settings which is contributed by gene regulatory pathway that shows high significance associated with neural function brain in depressive disorders such as apoptotic pathway, P13K-Akt signaling, axon guidance, neurotrophin signaling pathway, mTOR signaling pathway. Conclusion- The diagnostic effectiveness of miRNA in major depressive disorder can be significantly enhanced by using miRNA expression coding and has been proven by various tests. Therefore, this research is expected to be an innovation in diagnosing MDD for further research. Keywords: MDD, depression, microRNA, diagnostic

Neutrophil to Lymphocyte Ratio in Patients with Major Depressive Disorder

Introduction: Depression is common mood disorder that is linked to systemic inflammation. The neutrophil-lymphocyte ratio (NLR) is a non-specific inflammatory marker that is inexpensive and easy to measure. Low-grade inflammation occurs in a subgroup of patients with Major Depressive disorder (MDD). Objective: To examine the role of inflammation in the etiology of depression based on the NLR in MDD patients who are undergoing no pharmacological therapy. Methods: This observational study was carried out in the Department of Psychiatry of Jahurul Islam Medical College Hospital (JIMCH), Bajitpur, Kishoregonj between December 2013 and May 2014. Subjects between the ages of 18 and 65 were included in the study that involved 61 subjects with diagnosed MDD, who received no pharmacological therapy of depression within the past 01 month were included in the study, while the control group included 67 healthy subjects with having no psychiatric disease. A sociodemographic information form and a Beck Depression Scale were administered, and the blood was taken for biochemical analysis and complete blood parameters were evaluated in the hematology laboratory of JIMCH. All data were expressed as mean±SD. For statistical analysis, Chi-square test (χ2) was used to compare categorical variables, frequencies, and ratios. An independent sample ‘t’ test was used to compare normally distributed variables between two groups. Results: In the present study, we found Significance difference in the NLR, neutrophil count, lymphocyte percentage and leukocyte values of the patient group when compared with control group (P<0.05). Conclusion: The study reveals that NLR tends to be higher in patients with MDD, and a high NLR value supports the view that inflammation is a critical factor in the etiology of MDD. JAFMC Bangladesh. Vol 19, No 1 (June) 2023: 72-75

Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression.

Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile. EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico. Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity. We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD.

Acute Stress Increases Striatal Connectivity With Cortical Regions Enriched for μ and κ Opioid Receptors

BackgroundUnderstanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated 1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC) and 2) how such effects are related to gene expression and receptor maps. MethodsAcross 115 participants (37 control, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABAA (gamma-aminobutyric acid A) receptor distribution maps derived from positron emission tomography. ResultsResults revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen, and amygdala with regions from the ventral attention/salience network, frontoparietal network, and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1, OPRK1, SST, GABRA3, GABRA5), similar to previous genetic MDD studies. ConclusionsAcute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes that have previously been associated with imaging abnormalities in MDD and are rich in μ and κ opioid receptors. These findings point to overlapping circuitry underlying stress response, reward, and MDD.

Genome-wide DNA methylation analysis in female veterans with military sexual trauma and comorbid PTSD/MDD

BackgroundMilitary sexual trauma (MST) is a prevalent issue within the U.S. military. Victims are more likely to develop comorbid diseases such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Nonetheless, not everyone who suffers from MST develops PTSD and/or MDD. DNA methylation, which can regulate gene expression, might give us insight into the molecular mechanisms behind this discrepancy. Therefore, we sought to identify genomic loci and enriched biological pathways that differ between patients with and without MST, PTSD, and MDD. MethodsSaliva samples were collected from 113 female veterans. Following DNA extraction and processing, DNA methylation levels were measured through the Infinium HumanMethylationEPIC BeadChip array. We used limma and bump hunting methods to generate the differentially methylated positions and differentially methylated regions (DMRs), respectively. Concurrently, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome to find enriched pathways. ResultsA DMR close to the transcription start site of ZFP57 was differentially methylated between subjects with and without PTSD, replicating previous findings and emphasizing the potential role of ZFP57 in PTSD susceptibility. In the pathway analyses, none survived multiple correction, although top GO terms included some potentially relevant to MST, PTSD, and MDD etiology. ConclusionWe conducted one of the first DNA methylation analyses investigating MST along with PTSD and MDD. In addition, we found one DMR near ZFP57 to be associated with PTSD. The replication of this finding indicates further investigation of ZFP57 in PTSD may be warranted.

Association between serum and urinary environmental metal levels and major depressive disorder: a study based on logistic regression and quantile regression.

Major depressive disorder (MDD) is a prevalent mental disorder globally. Increasing evidence suggests that Environmental Metal (EM) play a crucial role in MDD. Therefore, this study investigated the roles of barium (Ba), cesium (Cs), nickel (Ni), manganese (Mn), lead (Pb), mercury (Hg), cadmium (Cd), and tin (Sn) in the etiology of MDD. The study included 72 MDD patients and 75 healthy controls (HCs) from the Second People's Hospital of Zhumadian, China. Inductively coupled plasma mass spectrometer (ICP-MS) measured the metal levels in serum and urine samples from both groups. Significant differences in serum and urine levels of EMs were observed between MDD patients and HCs. After adjusting for age, gender, and BMI, logistic regression and quantile regression models revealed significant associations between EMs and MDD. In serum samples, higher Sn levels (OR = 1.22, p = 0.044) increased MDD risk, whereas higher Cs levels (OR = 0.02, p < 0.001), Cd (OR = 0.06, p = 0.047), and Mn (OR = 0.54, p = 0.016) decreased MDD risk. In urine samples, higher Ba levels (OR = 0.94, p = 0.015), Ni (OR = 0.87, p = 0.0024), Sn (OR = 1.62, p < 0.001), and Mn (OR = 0.77, p = 0.037) were significantly associated with MDD. Sn significantly positively predicted HAMD-24 scores at the 0.50 and 0.75 quantiles (β = 0.96, p = 0.018; β = 1.25, p = 0.008) as did Pb (β = 5.15, p = 0.001; β = 4.19, p = 0.004). Ba positively predicted depressive symptoms across all quantiles (all p < 0.05). Hg positively predicted HAMD-24 scores at the 0.50 quantile (β = 9.20, p = 0.050). These findings underscore EMs' importance in depression, aiding in targeted interventions for varying degrees of depression and necessitating future studies to clarify causality and mechanisms.

Elevated VCAM-1 levels in peripheral blood are associated with brain structural and functional alterations in major depressive disorder

BackgroundVascular cell adhesion molecule-1 (VCAM-1) is a well-known biomarker of endothelial activation. This study aimed to determine whether changes in peripheral VCAM-1 levels occurred in major depressive disorder (MDD) patients and explored immune-brain interactions based on neuroimaging. MethodsThis study included 165 subjects (80 healthy controls [HCs] and 85 MDD patients). Of them, 133 underwent magnetic resonance imaging. VCAM-1 was measured using a commercially available Enzyme-Linked Immunosorbent Assay kit following the manufacturer's instructions. The gray matter volume (GMV) and surface-based functional connectivity (FC) were calculated based on Schaefer parcellation 400 parcels. ResultsCompared with the HCs, MDD patients exhibited significantly higher level of VCAM-1. The correlation analysis showed that VCAM-1 had a significant negative correlation with GMV of the right medial frontal cortex (MFC) and postcentral (PostCG). The mediation analyses showed that VCAM-1 mediated the association between group and GMV of PostCG and the FC of left ventral prefrontal cortex (vPFC) with right inferior parietal lobe (IPL). ConclusionsThis study showed that a high level of VCAM-1 was associated to the decreased GMV in the right MFC and PostCG, and mediated the FC of the left vPFC with right IPL. These findings suggested that VCAM-1 might contribute to the etiology of MDD by influencing brain structure and function. LimitationsThe cross-sectional design makes it difficult to determine the causal relationship and dynamic effect among VCAM-1, brain structure/function features, and depressive symptoms.

Does decreased autophagy and dysregulation of LC3A in astrocytes play a role in major depressive disorder?

Astrocytic dysfunction contributes to the molecular pathogenesis of major depressive disorder (MDD). However, the astrocytic subtype that mainly contributes to MDD etiology and whether dysregulated autophagy in astrocytes is associated with MDD remain unknown. Using a single-nucleus RNA sequencing (snRNA-seq) atlas, three astrocyte subtypes were identified in MDD, while C2 State-1Q astrocytes showed aberrant changes in both cell proportion and most differentially expressed genes compared with other subtypes. Moreover, autophagy pathways were commonly inhibited in astrocytes in the prefrontal cortices (PFCs) of patients with MDD, especially in C2 State-1Q astrocytes. Furthermore, by integrating snRNA-seq and bulk transcriptomic data, we found significant reductions in LC3A expression levels in the PFC region of CUMS-induced depressed mice, as well as in postmortem PFC tissues and peripheral blood samples from patients with MDD. These results were further validated by qPCR using whole-blood samples from patients with MDD and healthy controls. Finally, LC3A expression in the whole blood of patients with MDD was negatively associated with the severity of depressive symptoms. Overall, our results underscore autophagy inhibition in PFC astrocytes as a common molecular characteristic in MDD and might reveal a novel potential diagnostic marker LC3A.

Etiology and Treatment of Major Depressive Disorder - From a Psychodynamic Theory Perspective

The purpose of this review article is to give an overview of how Psychodynamic Theory examines the etiology of Major Depressive Disorder and their corresponding therapeutic treatment. Method used in this article is literature review from Google Scholar and Elton B. Stephens Company (EBSCO) host database provided by The Ohio State University. Result explains the evolution of Psychodynamic Theory from Drive theory, to Ego Psychology, Object Relations, and Self Psychology. Moreover, the mechanisms and procedures of the therapies with good therapeutic effects are reviewed and analyzed. Specifically, psychodynamic therapy including Mindfulness-based Therapy, dream analysis, inkblot therapy, and Cognitive Behavior Therapy. As psychological therapy is test-effective, psychological approaches from interpretive pole to supportive pole with different modern therapy such as Cognitive Behavior Therapy and Mindfulness-based Therapy are being discussed. Risk factors that may lead to countertransference and discordant therapeutic relationships are presented. The present study provides suggestions for future research focusing on comorbidity of mental disorder. For treatment practice, this study emphasizes on culture difference and individual differences.

Association between rare earth elements and depression: Evidence from pilot mice model of chronic unpredictable mild stress-induced depression and human studies of major depressive disorder

The etiology of Major Depressive Disorder (MDD) has been associated with levels of trace elements in the human body. The source of trace elements in the human body may be rare earth elements (REEs). Our study aimed to identify the potential relationship between t REEs in blood and brain samples and depression from two paths: animal experiments and population studies. In the animal experiments, 35 adult Sprague–Dawley rats were randomly allocated to the control group (n = 14) and treatment group (n = 21), which received the chronic unpredictable mild stress (CUMS) procedure for four weeks and further categorized into the sensitive group (n = 9) and resilient group (n = 12) by sucrose water preference test. Then, all rats were executed to obtain serum and brain tissue samples. We also recruited 197 participants and divided them into the major depressive disorder (MDD) group (n = 100) and the control group (n = 97) then serum samples were collected for REEs detection. Our finding reported that significant differences were found in the levels of La and Ce in blood samples from different groups in the CUMS rat model (sensitive group < resilient group < control group) (all p < 0.05), with similar patterns for other elements (Pr, Nd, and Y) (but p > 0.5). No significant inter-group difference was reported in rat brain tissue samples. After adjusting for demographic variables, we found that the concentrations of all five REEs (La, Ce, Pr, Nd, Y) were lower in depression group than in control group (all p < 0.01). The current conjoint animal and human data supported appropriate levels of REEs have a certain protective effect on body health. These results may be attributed to Hormesis effects. Whether the possible favorable effects of REEs on improving symptoms of depression or can be applied to drug development remains to be further investigated.

Trace Elements Levels in Major Depressive Disorder-Evaluation of Potential Threats and Possible Therapeutic Approaches.

The multifactorial etiology of major depressive disorder (MDD) includes biological, environmental, genetic, and psychological aspects. Recently, there has been an increasing interest in metallomic studies in psychiatry, aiming to evaluate the role of chosen trace elements in the MDD etiology as well as the progression of symptoms. This narrative review aims to summarize the available literature on the relationship between the concentration of chosen elements in the serum of patients with MDD and the onset and progression of this psychiatric condition. The authors reviewed PubMed, Web of Science, and Scopus databases searching for elements that had been investigated so far and further evaluated them in this paper. Ultimately, 15 elements were evaluated, namely, zinc, magnesium, selenium, iron, copper, aluminium, cadmium, lead, mercury, arsenic, calcium, manganese, chromium, nickel, and phosphorus. The association between metallomic studies and psychiatry has been developing dynamically recently. According to the results of current research, metallomics might act as a potential screening tool for patients with MDD while at the same time providing an assessment of the severity of symptoms. Either deficiencies or excessive amounts of chosen elements might be associated with the progression of depressive symptoms or even the onset of the disease among people predisposed to MDD.

Upregulation of HDAC9 in hippocampal neurons mediates depression-like behaviours by inhibiting ANXA2 degradation

Major depressive disorder (MDD) is a pervasive and devastating mental disease. Broad spectrum histone deacetylase (HDAC) inhibitors are considered to have potential for the treatment of depressive phenotype in mice. However, due to its non-specific inhibition, it has extensive side effects and can not be used in clinical treatment of MDD. Therefore, finding specific HDAC subtypes that play a major role in the etiology of MDD is the key to develop corresponding specific inhibitors as antidepressants in the future. Copy number variation in HDAC9 gene is thought to be associated with the etiology of some psychiatric disorders. Herein, we found that HDAC9 was highly expressed in the hippocampus of chronic restraint stress (CRS) mouse model of depression. Upregulation of HDAC9 expression in hippocampal neurons of mice induced depression-like phenotypes, including anhedonia, helplessness, decreased dendritic spine density, and neuronal hypoexcitability. Moreover, knockdown or knockout of HDAC9 in hippocampal neurons alleviated depression-like phenotypes caused by chronic restraint stress (CRS) in WT mice. Importantly, using immunoprecipitation–mass spectrometry (IP–MS), we further found that Annexin A2 (ANXA2) was coupled to and deacetylated by HDAC9. This coupling resulted in the inhibition of ubiquitinated ANXA2 degradation and then mediates depression-like behavior. Overall, we discovered a previously unrecognized role for HDAC9 in hippocampal neurons in the pathogenesis of depression, indicating that inhibition of HDAC9 might be a promising clinical strategy for the treatment of depressive disorders.

Longitudinal early epigenomic signatures inform molecular paths of therapy response and remission in depressed patients.

The etiology of major depressive disorder (MDD) involves the interaction between genes and environment, including treatment. Early molecular signatures for treatment response and remission are relevant in a context of personalized medicine and stratification and reduce the time-to-decision. Therefore, we focused the analyses on patients that responded or remitted following a cognitive intervention of 8 weeks. We used data from a randomized controlled trial (RCT) with MDD patients (N = 112) receiving a cognitive intervention. At baseline and 8 weeks, blood for DNA methylation (Illumina Infinium MethylationEPIC 850k BeadChip) was collected, as well as MADRS. First, responders (N = 24; MADRS-reduction of at least 50%) were compared with non-responders (N = 60). Then, we performed longitudinal within-individual analyses, for response (N = 21) and for remission (N = 18; MADRS smaller or equal to 9 and higher than 9 at baseline), respectively, as well as patients with no change in MADRS over time. At 8 weeks the sample comprised 84 individuals; 73 patients had DNA methylation for both time-points. The RnBeads package (R) was used for data cleaning, quality control, and differential DNA-methylation (limma). The within-individual paired longitudinal analysis was performed using Welch's t-test. Subsequently gene-ontology (GO) pathway analyses were performed. No CpG was genome-wide significant CpG (p < 5 × 10-8). The most significant CpG in the differential methylation analysis comparing response versus non-response was in the IQSEC1 gene (cg01601845; p = 1.53 × 10-6), linked to neurotransmission. The most significant GO-terms were linked to telomeres. The longitudinal response analysis returned 67 GO pathways with a p < 0.05. Two of the three most significant pathways were linked to sodium transport. The analysis for remission returned 46 GO terms with a p-value smaller than 0.05 with pathways linked to phosphatase regulation and synaptic functioning. The analysis with stable patients returned mainly GO-terms linked to basic cellular processes. Our result suggest that DNA methylation can be suitable to capture early signs of treatment response and remission following a cognitive intervention in depression. Despite not being genome-wide significant, the CpG locations and GO-terms returned by our analysis comparing patients with and without cognitive impairment, are in line with prior knowledge on pathways and genes relevant for depression treatment and cognition. Our analysis provides new hypotheses for the understanding of how treatment for depression can act through DNA methylation and induce response and remission.