Mechanisms Of Major Depressive Disorder Research Articles

The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder

BackgroundInflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear.MethodsForty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6–8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1β, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment.ResultsSerum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1β, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1β, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents.ConclusionsOur study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets.

The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation, mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. This review aims to highlight the inflammatory mechanisms (neuroinflammation, peripheral inflammation, and gut dysbiosis) involved in the pathophysiology of MDD and to explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines of evidence have indicated that in addition to antidepressants, physical exercise, probiotics, and nutraceuticals (agmatine, ascorbic acid, and vitamin D) possess anti-inflammatory effects that may contribute to their antidepressant properties. Further studies are necessary to explore the therapeutic benefits of these alternative therapies for MDD.

Plasma circRNA HIPK2 as a putative biomarker for the diagnosis and prediction of therapeutic effects in major depressive disorder

BackgroundCircular RNAs (circRNAs) are a prevalent type of non-coding RNAs exhibiting extensive expression in mammalian cells. Owing to their involvement in diverse pathophysiological mechanisms of major depressive disorder (MDD) and their inherent stability in peripheral blood, circRNAs have emerged as potential biomarkers of considerable significance. This study aimed to identify and validate circular RNA HIPK2 (circHIPK2) in MDD patients and to investigate its potential as a biomarker for the diagnosis and prognosis of MDD. MethodsPatients with MDD (n = 81) and healthy controls (HCs) (n = 48) were recruited for our study (October 2022 to June 2023). The expression of circHIPK2 in plasma was assessed using absolute quantitative polymerase chain reaction (qPCR). ResultsThe expression of circHIPK2 in plasma of patients with MDD exhibited a significant increase compared to HCs. The circHIPK2 levels showed an area under the curve (AUC) of 0.796, corresponding to a specificity of 97.9% and a sensitivity of 60.4% in diagnosing MDD. Additionally, the rate of change in circHIPK2 over a 14-day period exhibited an AUC curve of 0.819, indicating its predictive value for antidepressive effects. ConclusionsCircHIPK2 could serve as a potential biomarker for diagnosing MDD and predicting therapeutic effects of MDD.

Aberrant degree centrality profiles during rumination in major depressive disorder.

Rumination is closely linked to the onset and maintenance of major depressive disorder (MDD). Prior neuroimaging studies have identified the association between self-reported rumination trait and the functional coupling among a network of brain regions using resting-state functional magnetic resonance imaging (MRI). However, little is known about the underlying neural circuitry mechanism during active rumination in MDD. Degree centrality (DC) is a simple metric to denote network integration, which is critical for higher-order psychological processes such as rumination. During an MRI scan, individuals with MDD (N = 45) and healthy controls (HC, N = 46) completed a rumination state task. We examined the interaction effect between the group (MDD vs. HC) and condition (rumination vs. distraction) on vertex-wise DC. We further characterized the identified brain region's functional involvement with Neurosynth and BrainMap. Network-wise seed-based functional connectivity (FC) analysis was also conducted for the identified region of interest. Finally, exploratory correlation analysis was conducted between the identified region of interest's network FCs and self-reported in-scanner affect levels. We found that a left superior frontal gyrus (SFG) region, generally overlapped with the frontal eye field, showed a significant interaction effect. Further analysis revealed its involvement with executive functions. FCs between this region, the frontoparietal, and the dorsal attention network (DAN) also showed significant interaction effects. Furthermore, its FC to DAN during distraction showed a marginally significant negative association with in-scanner affect level at the baseline. Our results implicated an essential role of the left SFG in the rumination's underlying neural circuitry mechanism in MDD and provided novel evidence for the conceptualization of rumination in terms of impaired executive control.

Systematic reviews and meta-analyses on major depressive disorder: a bibliometric perspective.

There is a vast amount of evidence-based medicine research on the major depressive disorder (MDD) available in the literature, however, no studies on the overall performance, productivity and impact of such research have been published to date. This study explored and mapped the research outputs of MDD-related systematic reviews and meta-analyses (SR/MA) from a bibliometric perspective. Relevant data were retrieved with search terms on MDD, systematic review and meta-analysis. A total of 4,870 papers with 365,402 citations published from 1983 to 2022 were included in the analysis. The publication output has grown steadily over time with the most publications originating from the USA (1,020; 20.94%), the UK (516; 10.60%) and China (448; 9.20%). The research collaborations between countries were most frequent between the USA and UK (266; 5.46%). Journal of Affective Disorders (379; 7.78%) was the most productive journal, while Cuijpers P was the most productive author (121; 2.48%), and University of Toronto (569; 11.78%) was the most productive institution. The top 10 most cited articles on MDD-related SR/MA had citations ranging from 1,806 to 3,448. The high-frequency keywords were mainly clustered into four themes, including psychiatric comorbidities, clinical trials, treatment, and brain stimulation in MDD. The rapid increase in the number of SR/MA of MDD in recent years highlights the importance of this research field. Psychiatric comorbidities, clinical interventions, and treatment of MDD have been identified as hot topics, while biological mechanisms in MDD are likely to be an emerging research priority.

Prospective study on Maresin-1 and cytokine levels in medication-naïve adolescents with first-episode major depressive disorder.

Inflammation and immune activation may play a role in the pathological mechanism of Major Depressive Disorder (MDD). Evidence from cross-sectional and longitudinal studies of adolescents and adults has shown that MDD is associated with increased plasma pro-inflammatory cytokines (e.g., IL-1β, IL-6). It has been reported that Specialized Pro-resolving Mediators (SPMs) mediate inflammation resolution, and Maresin-1 can activate the process of inflammation and promote inflammation resolution by promoting macrophage phagocytosis. However, no clinical studies have been conducted to evaluate the relationship between the levels of Maresin-1 and cytokine and the severity of MDD symptomatology in adolescents. 40 untreated adolescent patients with primary and moderate to severe MDD and 30 healthy participants as the healthy control (HC) group aged between 13 and 18 years old were enrolled. They received clinical and Hamilton Depression Rating Scale (HDRS-17) evaluation and then, blood samples were collected. Patients in the MDD group were re-evaluated for HDRS-17, and blood samples were taken after a six to eight-week fluoxetine treatment. The adolescent patients with MDD had lower serum levels of Maresin-1 and higher serum levels of interleukin 6 (IL-6) compared with the HC group. Fluoxetine treatment alleviated depressive symptoms in MDD adolescent patients, which was reflected by higher serum levels of Maresin-1 and IL-4 and lower HDRS-17 scores, serum levels of IL-6, and IL-1β. Moreover, the serum level of Maresin-1 was negatively correlated with the depression severity scores on the HDRS-17. Adolescent patients with primary MDD had lower levels of Maresin-1 and higher levels of IL-6 compared with the HC group, implying that the peripheral level of pro-inflammatory cytokines may be elevated in MDD, resulting in the insufficiency of inflammation resolution. The Maresin-1 and IL-4 levels increased after anti-depressant treatment, whereas IL-6 and IL-1β levels decreased significantly. Moreover, Maresin-1 level negatively correlated with depression severity, suggesting that reduced levels of Maresin-1 promoted the progression of MDD.

Screening and identification of key biomarkers of depression using bioinformatics

We aimed to identify the molecular biomarkers of MDD disease progression to uncover potential mechanisms of major depressive disorder (MDD). In this study, three microarray data sets, GSE44593, GSE12654, and GSE54563, were cited from the Gene Expression Omnibus database for performance evaluation. To perform molecular functional enrichment analyses, differentially expressed genes (DEGs) were identified, and a protein–protein interaction network was configured using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape. To assess multi-purpose functions and pathways, such as signal transduction, plasma membrane, protein binding, and cancer pathways, a total of 220 DEGs, including 143 upregulated and 77 downregulated genes, were selected. Additionally, six central genes were observed, including electron transport system variant transcription factor 6, FMS-related receptor tyrosine kinase 3, carnosine synthetase 1, solute carrier family 22 member 13, prostaglandin endoperoxide synthetase 2, and protein serine kinase H1, which had a significant impact on cell proliferation, extracellular exosome, protein binding, and hypoxia-inducible factor 1 signaling pathway. This study enhances our understanding of the molecular mechanism of the occurrence and progression of MDD and provides candidate targets for its diagnosis and treatment.

GluCEST Imaging and Structural Alterations of the Bilateral Hippocampus in First-Episode and Early-Onset Major Depression Disorder.

Glutamate dysregulation is one of the key pathogenic mechanisms of major depressive disorder (MDD), and glutamate chemical exchange saturation transfer (GluCEST) has been used for glutamate measurement in some brain diseases but rarely in depression. To investigate the GluCEST changes in hippocampus in MDD and the relationship between glutamate and hippocampal subregional volumes. Cross-sectional. Thirty-two MDD patients (34% males; 22.03 ± 7.21 years) and 47 healthy controls (HCs) (43% males; 22.00 ± 3.28 years). 3.0 T; magnetization prepared rapid gradient echo (MPRAGE) for three-dimensional T1-weighted images, two-dimensional turbo spin echo GluCEST, and multivoxel chemical shift imaging (CSI) for proton magnetic resonance spectroscopy (1 H MRS). GluCEST data were quantified by magnetization transfer ratio asymmetry (MTRasym ) analysis and assessed by the relative concentration of 1 H MRS-measured glutamate. FreeSurfer was used for hippocampus segmentation. The independent sample t test, Mann-Whitney U test, Spearman's correlation, and partial correlation analysis were used. P < 0.05 was considered statistically significant. In the left hippocampus, GluCEST values were significantly decreased in MDD (2.00 ± 1.08 [MDD] vs. 2.62 ± 1.41 [HCs]) and showed a significantly positive correlation with Glx/Cr (r = 0.37). GluCEST values were significantly positively correlated with the volumes of CA1 (r = 0.40), subiculum (r = 0.40) in the left hippocampus and CA1 (r = 0.51), molecular_layer_HP (r = 0.50), GC-ML-DG (r = 0.42), CA3 (r = 0.44), CA4 (r = 0.44), hippocampus-amygdala-transition-area (r = 0.46), and the whole hippocampus (r = 0.47) in the right hippocampus. Hamilton Depression Rating Scale scores showed significantly negative correlations with the volumes of the left presubiculum (r = -0.40), left parasubiculum (r = -0.47), and right presubiculum (r = -0.41). GluCEST can be used to measure glutamate changes and help to understand the mechanism of hippocampal volume loss in MDD. Hippocampal volume changes are associated with disease severity. 2 TECHNICAL EFFICACY: Stage 1.

Cerebral blood flow changes and their genetic mechanisms in major depressive disorder: a combined neuroimaging and transcriptome study.

Extensive research has shown abnormal cerebral blood flow (CBF) in patients with major depressive disorder (MDD) that is a heritable disease. The objective of this study was to investigate the genetic mechanisms of CBF abnormalities in MDD. To achieve a more thorough characterization of CBF changes in MDD, we performed a comprehensive neuroimaging meta-analysis of previous literature as well as examined group CBF differences in an independent sample of 133 MDD patients and 133 controls. In combination with the Allen Human Brain Atlas, transcriptome-neuroimaging spatial association analyses were conducted to identify genes whose expression correlated with CBF changes in MDD, followed by a set of gene functional feature analyses. We found increased CBF in the reward circuitry and default-mode network and decreased CBF in the visual system in MDD patients. Moreover, these CBF changes were spatially associated with expression of 1532 genes, which were enriched for important molecular functions, biological processes, and cellular components of the cerebral cortex as well as several common mental disorders. Concurrently, these genes were specifically expressed in the brain tissue, in immune cells and neurons, and during nearly all developmental stages. Regarding behavioral relevance, these genes were associated with domains involving emotion and sensation. In addition, these genes could construct a protein-protein interaction network supported by 60 putative hub genes with functional significance. Our findings suggest a cerebral perfusion redistribution in MDD, which may be a consequence of complex interactions of a wide range of genes with diverse functional features.

The diagnostic utility of miRNA and elucidation of pathological mechanisms in major depressive disorder

AimsOur study aims to explore how miRNAs can elucidate the molecular mechanisms of major depressive disorder (MDD) by comparing the miRNA levels in the blood serum of patients with depression and healthy individuals. It also explores the potential of miRNAs to differentiate between depressed patients and healthy controls. Methods60 healthy controls (n = 45 females) were matched to 60 depressed patients (n = 10 unmedicated) for age (±7), sex, ethnicity, and years of education. Depression severity was measured using the Hamilton Depression Rating Scale, and venous blood was collected using PAXgene Blood RNA tubes for miRNA profiling. To further identify the depression-related biological pathways that are influenced by differentially expressed miRNAs, networks were constructed using QIAGEN Ingenuity Pathway Analysis. Receiver operating characteristic (ROC) analyses were also conducted to examine the discriminative ability of miRNAs to distinguish between depressed and healthy individuals. ResultsSix miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690 and miR-6895-3p) showed to be considerably down-regulated in unmedicated depressed patients relative to healthy controls. miR-542-3p, in particular, also has experimentally verified mRNA targets that are predicted to be associated with MDD. ROC analyses found that a panel combining miR-542-3p, miR-181b-3p and miR-3690 produced an area under the curve value of 0.67 in distinguishing between depressed and healthy individuals. ConclusionsmiRNAs — most notably, miR-542-3p, miR-181b-3p and miR-3690 — may be biomarkers with targets that are implicated in the pathophysiology of depression. They could also be used to distinguish between depressed and healthy individuals with reasonable accuracy.

Comprehensive analysis of endoplasmic reticulum stress and immune infiltration in major depressive disorder.

Major depressive disorder (MDD) is a life-threatening, debilitating mental health condition. An important factor in the development of depression is endoplasmic reticulum stress (ERS). However, their roles in MDD have not yet been established. The goal of this study was to examine ERS and its underlying molecular mechanisms in MDD. We used data from two microarray datasets (GSE98793 and GSE39653) and the GeneCards database to examine the reticulum stress-related differentially expressed genes (ERSR-DEGs) associated with MDD. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were used to further investigate the function and mechanism of ERS in MDD. Moreover, we constructed protein-protein interaction (PPI) networks to identify hub genes as well as the regulatory network of microRNAs (miRNAs), transcription factors (TFs), and potential drugs related to ERSR-DEGs. CIBERSORT was then used to evaluate the immune activity of MDD samples and conduct a correlation analysis between the hub genes and immune cells. In total, 37 ERSR-DEGs and five hub genes were identified (NCF1, MAPK14, CASP1, CYBA, and TNF). Functional enrichment analysis revealed that ERSR-DEGs were predominantly enriched in inflammation-and immunity-related pathways, such as tumor necrosis factor signaling, NF-κB signaling, and Toll-like receptor signaling pathways. Additionally, 179 miRNAs, 25 TFs, and 15 potential drugs were tested for their interactions with the ERSR-DEGs. CIBERSORT found high proportions of Tregs, monocytes, and macrophages M0 in the MDD samples. Among these, hub genes showed a significant correlation with immune cell infiltration in patients with MDD. NCF1, MAPK14, CASP1, CYBA, and TNF are potential ERS-related biomarkers for the diagnosis of MDD. Our research has revealed a significant correlation between immune cells and ERS-related genes with MDD. Not only did our study contribute to a better understanding of the regulatory mechanisms of ERS in underlying MDD pathology, but it also established a paradigm for future studies on ERS.

Altered gamma oscillations and beta–gamma coupling in drug-naive first-episode major depressive disorder: Association with sleep and cognitive disturbance

ObjectiveGamma oscillations contribute to the pathogenesis mechanisms of major depressive disorder (MDD) have been proposed, but gamma activity is not well characterized. This study is the first attempt to investigate the altered gamma oscillations in first-episode MDD, particularly the beta–gamma coupling, and to determine the potential symptomatic relationship with the identified gamma dysregulation. MethodsResting electroencephalography was recorded for 43 drug-naive first-episode MDD and 57 healthy control (HC) subjects. Integrated analysis of relative spectral power, weighted phase lag index, and phase–amplitude coupling (PAC) were utilized to reveal the alterations of gamma activities. Pearson's correlation was implemented to identify the relationship between altered gamma activities and the clinical depressive symptoms, which were categorized into four factors: anxiety somatization, retardation, cognitive disturbance, and sleep disturbance. ResultsCompared with HC subjects, MDD patients showed not only significantly decreased gamma powers in the left temporal and the bilateral occipital regions but also weakened gamma connectivity between the left hemisphere and the right frontal region. Furthermore, attenuated beta–gamma PAC of MDD patients was observed in the left temporal regions. Importantly, the suppression of left occipital mid- and high gamma oscillations were negatively correlated with sleep disturbance, while the deficits in left temporal beta–mid-gamma PAC and beta–high gamma PAC showed negative correlations with cognitive disturbance. LimitationsImportant limitations are the small sample size and the possible inclusion of bipolar depression in the MDD group. ConclusionsOur findings provide the first evidence that in first-episode MDD, aberrant gamma powers and beta–gamma coupling are associated with sleep and cognitive impairments, respectively, deepening our understanding of the physiological mechanisms underlying sleep and cognitive symptoms in first-episode MDD. Altered gamma oscillations emerge as promising biomarkers for diagnosing MDD.

Decreased functional coupling within default mode network in major depressive disorder with childhood trauma

ObjectiveChildhood trauma (CT) has been supported to be a high-risk factor for major depressive disorder (MDD), but the neural mechanism linking CT and depression remains unclear. The aim of this study is to deepen our understanding of this issue by establishing the neuroimaging correlations between CT and depression. MethodsA sample of 123 MDD patients (91 with moderate-to-severe CT and 32 with no or low CT) and 79 healthy controls (HC, 33 with moderate-to-severe CT and 46 with no or low CT) participated. All participants completed assessments of depression level, anxiety, recent perceived stress, and resting-state functional MRI scan. ResultsParticipants with moderate-to-severe CT showed elevated depression level and trait anxiety, and reduced spontaneous neural activity in left inferior temporal gyrus (ITG). Abnormalities of seed-based functional connectivity (FC) of left ITG – bilateral precuneus/posterior cingulate cortex (PCC), left middle temporal gyrus (MTG), left medial orbitofrontal cortex (mOFC), and bilateral medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC) were observed. CT was associated with decreased FCs in MDD, but with increased FCs in HC. The total altered FCs of left ITG – bilateral precuneus/PCC and left mOFC mediated relationship between CT and depression in MDD, and total altered FCs and trait anxiety have a significant chain mediation effect in the association between CT and depression in HC. ConclusionThese findings highlight the changes of default mode network (DMN) functions and trait anxiety as targets of CT. The decreased functional coupling within DMN may be involved in the mechanism of MDD following CT.

SparNet: A Convolutional Neural Network for EEG Space-Frequency Feature Learning and Depression Discrimination.

Depression affects many people around the world today and is considered a global problem. Electroencephalogram (EEG) measurement is an appropriate way to understand the underlying mechanisms of major depressive disorder (MDD) to distinguish depression from normal control. With the development of deep learning methods, many researchers have adopted deep learning models to improve the classification accuracy of depression recognition. However, there are few studies on designing convolution filters for spatial and frequency domain feature learning in different brain regions. In this study, SparNet, a convolutional neural network composed of five parallel convolutional filters and the SENet, is proposed to learn EEG space-frequency domain characteristics and distinguish between depressive and normal control. The model is trained and tested by the cross-validation method of subject division. The results show that SparNet achieves a sensitivity of 95.07%, a specificity of 93.66%, and an accuracy of 94.37% in classification. Therefore, our results can conclude that the proposed SparNet model is effective in detecting depression using EEG signals. It also indicates that the combination of spatial information and frequency domain information is an effective way to identify patients with depression.

Family Conflict Associated With Intrinsic Hippocampal-OFC Connectivity in Adolescent Depressive Disorder.

BackgroundFamily environment and life events have long been suggested to be associated with adolescent depression. The hippocampus plays a crucial role in the neural mechanism of major depressive disorder (MDD) through memory during stressful events. However, few studies have explored the exact neural mechanisms underlying these associations. Thus, the current study aimed to explore alterations in hippocampal functional connectivity (FC) in adolescent MDD based on resting-state functional magnetic resonance imaging and further investigate the relationship between hippocampal FC, environmental factors, and clinical symptom severity.MethodsHippocampal FC was calculated using the seed-based approach with the bilateral hippocampus as the seed for 111 adolescents with and without MDD; comparisons were made between participants with MDD and controls. We applied the Chinese version of the Family Environment Scale (FES-CV) and Adolescents Self-Rating Life Events Checklist (ASLEC) to evaluate family environment and life stress. Their relationship with hippocampal FC alterations was also investigated.ResultsWe found that compared to controls, adolescents with MDD showed decreased connectivity between the left hippocampus and bilateral orbital frontal cortex (OFC) and right inferior temporal gyrus. In addition, the hippocampal-OFC connectivity was negatively correlated with conflict scores of the FES-CV in the MDD group and mediated the association between family conflict and depressive and anxiety symptoms.ConclusionOur findings are novel in the field and demonstrate how family conflict contributes to MDD symptomatology through hippocampal-OFC connectivity; these findings may provide potential targets for personalized treatment strategies.

Characterizing the association between hippocampal reactive astrogliosis, anhedonia-like behaviors, and neurogenesis in a monkey model of stress and antidepressant treatment

With the intention to better understand the biological mechanism of Major Depressive Disorder (MDD) and antidepressants, we looked at the effects of stress and selective serotonin reuptake inhibitors (SSRIs) on a measure of astrocyte reactivity in nonhuman primate (NHP) models of stress. We focused on hippocampal astrocytes because they regulate both neural activity and neurogenesis and have been characterized as a crucial cell type in regulating inflammation in response to stress. During stress, astrocytes become reactive and lose the ability to support neuronal function. In addition, reactive astrocytes can increase inflammatory signals and contribute to behavioral deficits associated with stress. For this project, we hypothesized that stress would lead to astrocyte reactivity in the NHP hippocampus, and that SSRI treatment would be associated with decreased astrocyte reactivity. We also hypothesized that astrocyte reactivity would be positively correlated with anhedonia-like behaviors and reduced neurogenesis in the hippocampus. In this study we show that chronic separation stress in NHPs leads to increased signs of astrogliosis in the NHP hippocampus. Furthermore, we show that measures of increased astrogliosis inversely correlate with adult hippocampal neurogenesis in NHPs, as well as with higher anhedonia scores. Overall, our findings were consistent with our initial hypotheses that hippocampal astrogliosis is an important mechanism in stress-induced cognitive and behavioral deficits. By observing the association between adult separation stress, SSRI treatments, and astrocyte reactivity in the NHP hippocampus, we aimed to provide insight into the non-neuronal cellular changes that occur in the NHP hippocampus during stress and antidepressant treatment.

Self-referential Processing in Remitted Depression: An Event-Related Potential Study

BackgroundIdentifying mechanisms of major depressive disorder that continue into remission is critical, as these mechanisms may contribute to subsequent depressive episodes. Biobehavioral markers related to depressogenic self-referential processing biases have been identified in adults with depression. Thus, we investigated whether these risk factors persisted during remission as well as contributed to the occurrence of stress and depressive symptoms over time. MethodsAt baseline, adults with remitted depression (n = 33) and healthy control subjects (n = 33) were administered diagnostic and stress interviews as well as self-report symptom measures. In addition, participants completed a self-referential encoding task while electroencephalography data were acquired. Stress interviews and self-report symptom measures were readministered at the 6-month follow-up assessment. ResultsDrift diffusion modeling showed that compared with healthy individuals, adults with remitted depression exhibited a slower drift rate to negative stimuli, indicating a slower tendency to reject negative stimuli as self-relevant. At the 6-month follow-up assessment, a slower drift rate to negative stimuli predicted greater interpersonal stress severity among individuals with remitted depression but not healthy individuals while controlling for both baseline depression symptoms and interpersonal stress severity. Highlighting the specificity of this effect, results were nonsignificant when predicting noninterpersonal stress. For self-relevant positive words endorsed, adults with remitted depression exhibited smaller left- than right-hemisphere late positive potential amplitudes; healthy control subjects did not show hemispheric differences. ConclusionsSelf-referential processing deficits persist into remission. In line with the stress generation framework, these biases predicted the occurrence of interpersonal stress, which may provide insight about a potential pathway for the re-emergence of depressive symptoms.

Gene expression profiling in peripheral blood lymphocytes for major depression: preliminary cues from Chinese discordant sib-pair study

The etiology of major depressive disorder (MDD) involves many factors such as heredity and environment. There are very few MDD-related studies in Chinese population using twin or sib-pairs for depression-control samples. Here we used the microarray approach and compared gene expression profiling of peripheral blood lymphocytes from 6 sib-pairs discordant on lifetime history of MDD. Within sib-pair differentially expressed genes are obvious fewer in the 1st, 2nd, and 5th compared with those in the 3rd, 4th, and 6th sib-pairs. Gene expression pattern of these DEGs distinguished MDD individuals from the normal one in 3rd, 4th, and 6th sib-pair but not in the 1st, 2nd, and 5th pair, suggesting heterogeneity of different sib-pairs and somewhat commonalities among the 3rd, 4th, and 6th sib-pairs. Comprehensive protein interaction network analysis revealed two key genes PTH and FGF2 in a dominant network where the majority of the genes were significantly down-regulated. PTH was significantly down-regulated in all the sib-pairs while FGF2 was in the 3rd, 4th, and 6th sib-pairs. KEGG enrichment analysis of all the DEGs in networks showed that PTH and related genes were significantly enriched in the pathway of parathyroid hormone secretion, synthesis, and action while FGF2 and related genes were significantly enriched in the pathways of cancer and specifically breast cancer. Generally reduced expression of these genes in peripheral blood lymphocytes of MDD individuals implied their functional repression associated with MDD. Pending validation in more samples, the findings in this study provided valuable cues for understanding the potential mechanism of MDD, as well as potential markers for the diagnosis and treatment of depression in the Chinese population.

Label-Free Liquid Chromatography-Mass Spectrometry Proteomic Analysis of the Urinary Proteome for Measuring the Escitalopram Treatment Response From Major Depressive Disorder.

Major depressive disorder (MDD) is a common mental disorder that can cause substantial impairments in quality of life. Clinical treatment is usually built on a trial-and-error method, which lasts ~12 weeks to evaluate whether the treatment is efficient, thereby leading to some inefficient treatment measures. Therefore, we intended to identify early candidate urine biomarkers to predict efficient treatment response in MDD patients. In this study, urine samples were collected twice from 19 respondent and 10 non-respondent MDD patients receiving 0-, 2-, and 12-week treatments with escitalopram. Differential urinary proteins were subsequently analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Our two pilot tests suggested that the urine proteome reflects changes associated with major depressive disorder at the early stage of treatment measures. On week 2, 20 differential proteins were identified in the response group compared with week 0, with 14 of these proteins being associated with the mechanisms of MDD. In the non-response group, 60 differential proteins were identified at week 2, with 28 of these proteins being associated with the mechanisms of MDD. In addition, differential urinary proteins at week 2 between the response and non-response groups can be clearly distinguished by using orthogonal projection on latent structure-discriminant analysis (OPLS-DA). Our small pilot tests indicated that the urine proteome can reflect early effects of escitalopram therapy between the response and non-response groups since at week 2, which may provide potential early candidate urine biomarkers to predict efficient treatment measures in MDD patients.

The role of circulating blood microRNA-374 and microRNA-10 levels in the pathogenesis and therapeutic mechanisms of major depressive disorder

Compelling recent evidence suggests that microRNAs (miRNAs) regulate specific mRNA transcripts at the transcriptomic level and coordinately influence complex regulatory networks, which may play a crucial role in the pathogenesis of major depressive disorder (MDD) and the treatment effects of antidepressants. To evaluate the possible involvement of miRNAs in the pathophysiology and therapeutic response of MDD, we conducted a miRNA expression array analysis of the peripheral blood mononuclear cells (PBMCs) of 5 depressed patients and 5 healthy controls (HCs). Subsequently, we chose 2 miRNAs for validation with real-time PCR (RT-PCR) analysis pre- and post-treatment in another group of 25 MDD patients and 25 HCs. In the array, 5 miRNAs were differentially expressed in medication-naïve MDD patients compared to HCs, of which 2 miRNAs were upregulated and 3 were downregulated. Furthermore, in comparison with HCs, MDD patients showed significantly lower expression levels of miR-374b and miR-10a before treatment. After 8 weeks of antidepressant treatment, both miR-374b and the miR-10a expression levels in MDD patients were significantly elevated only in responders. In conclusion, these results indicate the involvement of miR-374b and miR-10a in the biological mechanisms and therapeutic response of MDD, and provide new insights for exploring miRNAs as potential biomarkers for MDD.