Onset Of Major Depressive Disorder Research Articles

Neurocognitive dysfunction in adolescents with recent onset major depressive disorder: a cross-sectional comparative study.

The aim of this study was to examine the neurocognitive deficits associated with the first episode of major depressive disorder (recent onset depression, ROD) in adolescents as compared to adult patients. Cross-sectional neurocognitive data from the baseline assessments of the PRONIA study with N = 650 (55.31% females) were analyzed. Based on a principal component analysis of eleven neurocognitive tests, we constructed an overall neurocognitive performance (NP) score. We examined mean score differences in NP between the groups of healthy controls (HC) and ROD and between adolescents (15-21years) and adults (22-40years) within a GLM approach. This accounts for unbalanced data with focus on interaction effects while controlling for effects of medication and educational years. Our results show lower NP for the ROD as compared to the HC group (d = -0.29, p = .046) and lower NP for the adolescent group as compared to the adult group (d = -0.29; p < .039). There was no interaction between these two group effects (F = 1.11; p = .29). Our findings suggest that the detrimental effect of ROD on neurocognitive functioning is comparable in adolescent and adult patients, since lower scores in adolescent patients are explained by effects of age and education. Neurocognitive impairment is an under addressed issue in clinical treatment guidelines for adolescent MDD. We suggest efficient monitoring in clinical practice by using an aggregate of the Digit Symbol Substitution Test and the Trail Making Test B, which highly correlated with the overall score of NP (r = 0.82).

The reward positivity as a predictor of first lifetime onsets of depression, anxiety, and suicidal ideation in high-risk adolescents

BackgroundReduced reward Positivity (RewP), an electroencephalography (EEG) marker elicited by feedback indicating reward, has been associated with an increased risk for depression in adolescence. However, the predictive capability of RewP in predicting the first-lifetime onset of depressive disorders, as opposed to anxiety and suicidal ideation in high-risk populations, has not been thoroughly investigated. In this study, the authors examine if RewP predicts the first-lifetime onset of depression, anxiety, and suicidal ideation over 18 months in familial high-risk adolescents. MethodsThe sample included 145 adolescents (64.8% male), aged 11–17 years, who had at least one parent with a history of mood and anxiety disorders and completed baseline and at least one follow-up measurement. At baseline, RewP was measured using a simple gambling task, their current internalizing symptoms were assessed using self-report questionnaires, and the youth’s psychiatric diagnoses were evaluated with diagnostic interviews. The same interview was administered to the adolescents again at 9 months and 18 months later. ResultsLogistic regression models showed that higher RewP scores significantly predicted a lower likelihood of developing a first onset of Major Depressive Disorder (MDD) over 18 months, even after controlling for sex, age, and baseline internalizing symptoms. In contrast, RewP did not significantly predict the first onset of anxiety disorders or suicidal ideation. ConclusionsReduced RewP precedes the first onset of depression in high-risk adolescents, highlighting RewP's predictive capability in predicting depression risk in predisposed populations. Blunted RewP could complement self-reported symptoms in screening and prevention.

Structural connectivity of thalamic subnuclei in major depressive disorder: An ultra-high resolution diffusion MRI study at 7-Tesla

BackgroundThe thalamus serves as a central relay station within the brain, and thalamic connectional anomalies are increasingly thought to be present in major depressive disorder (MDD). However, the use of conventional MRI scanners and acquisition techniques has prevented a thorough examination of the thalamus and its subnuclear connectional profile. We combined ultra-high field diffusion MRI acquired at 7.0 Tesla to map the white matter connectivity of thalamic subnuclei. MethodsFifty-three MDD patients and 12 healthy controls (HCs) were involved in the final analysis. FreeSurfer was used to segment the thalamic subnuclei, and MRtrix was used to perform the preprocessing and tractography. Fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity, and streamline count of thalamic subnuclear tracts were measured as proxies of white matter microstructure. Bayesian multilevel model was used to assess group differences in white matter metrics for each thalamic subnuclear tract and the association between these white matter metrics and clinical features in MDD. ResultsEvidence was found for reduced whiter matter metrics of the tracts spanning from all thalamic subnuclei among MDD versus HC participants. Moreover, evidence was found that white matter in various thalamic subnuclear tracts is related to medication status, age of onset and recurrence in MDD. ConclusionsStructural connectivity was generally reduced in thalamic subnuclei in MDD participants. Several clinical characteristics are related to perturbed subnuclear thalamic connectivity with cortical and subcortical circuits that govern sensory processing, emotional function, and goal-directed behavior.

The role of gender factors influencing multiple dimensions of somatic symptoms in major depressive disorder patients with suicidal ideation: insights from the Chinese NSSD study

BackgroundThe study aimed to explore the influence of gender on the prevalence of various somatic symptoms and their associations with suicidal ideation (SI) among patients with major depressive disorder (MDD).MethodsWe recruited 3,275 patients with MDD from the National Survey on Symptomatology of Depression (NSSD), among whom 1,745 patients had SI. The clinical characteristics and the prevalence of somatic symptoms across 20 dimensions in MDD patients with SI were compared between male and female patients. Spearman correlation analysis and logistic regression analysis were used to explore the relationship between somatic symptoms and SI.ResultsIn patients with SI, 32.2% of female participants attributed the onset of MDD to physical concerns, whereas 27% of male patients held a similar perspective (P = 0.032). Female patients exhibited a higher prevalence of early insomnia (64.6% vs. 70.2%) and a lower prevalence of hypersomnia (17.2% vs. 12.9%) and urinary system symptoms (25.0% vs. 17.8%). Logistic regression analysis indicated that female patients displayed a broader range of somatic symptoms identified as risk factors for SI, including increased appetite, respiratory symptoms, circulatory system symptoms, limb pain, and various others.ConclusionThis study unveils gender-specific patterns in somatic symptoms among MDD patients with SI, highlighting the clinical significance of these symptoms in diagnosis and intervention. Understanding how physical concerns contribute to MDD, especially among females, underscores the need for tailored clinical approaches. Recognizing and addressing these symptoms could guide more effective suicide prevention strategies and enhance MDD management in clinical practice.

12270 Adolescent PCOS With Unexpected, Sudden-onset GAD And MDD: A Call For Vigilance In Longitudinal PCOS Care

Abstract Disclosure: K.I. Sarkisian: None. T. Aliabadi: None. F.Z. Stanczyk: None. Background: Polycystic Ovary Syndrome (PCOS) is a multifaceted endocrine disorder often associated with psychiatric disorders, yet the integration of psychiatric monitoring and multidisciplinary care following diagnosis remains understated as a guideline of clinical management of PCOS post-diagnosis. Historically, psychiatric comorbidities in PCOS have been attributed to social and personal factors such as self-image and self-esteem. However, the present patient’s denial of thoughts of disordered eating and lack of self-esteem related to acne or hirsutism challenges these assumptions.Clinical Case: A 13-year-old girl presented with classic symptoms of PCOS, including hirsutism, irregular and painful periods, and premature adrenarche. Laboratory investigations revealed an elevated total testosterone level (58 ng/dL, normal&amp;lt;38 ng/dL), consistent with PCOS. Previously, the patient had not expressed any concerns about mood. However psychological symptoms emerged alongside the physical symptoms. A psychological assessment performed by a licensed therapist revealed moderate-to-severe generalized anxiety disorder (GAD), which had rapidly worsened in a matter of weeks. Both the patient and the patient’s parents denied prior symptoms of moderate-to-severe anxiety before the onset of PCOS symptoms. Over the course of follow-up spanning 47 months, the patient documented symptoms, tracking both mood and PCOS fluctuations. During the follow-up period, the patient’s mood worsened, leading to the formal diagnosis of Major Depressive Disorder (MDD), despite a low assessed risk, no family history, and no symptoms prior to her PCOS development. The diagnoses of GAD and MDD were later confirmed through neuropsychiatric testing by a licensed psychologist.Clinical Lessons: While this presentation may not be considered novel in the context of PCOS, its overwhelming prevalence underscores the need for heightened awareness and research on the topic. The patient, previously considered low-risk for psychiatric conditions, experienced an unexpected onset of GAD and MDD concurrently with the diagnosis of PCOS. It is imperative to recognize that PCOS patients defy the conventional categorization of ‘healthy’ individuals concerning psychiatric care. This notion holds significance not only in clinical practice but also in research endeavors. Merely attributing psychiatric comorbidities in PCOS patients to social factors overlooks the unforeseen presentations of psychiatric disorders, as demonstrated in this patient. These manifestations cannot be solely attributed to social aspects of identity-insecurity, emphasizing the need for a more nuanced, proactive approach to psychiatric care in PCOS. This is crucial for achieving the best long-term prognosis and quality of life in affected individuals. Presentation: 6/1/2024

Differential effects of lifetime stressors on major depressive disorder severity: a longitudinal community-based cohort study.

Stressors across the lifespan are associated with the onset of major depressive disorder (MDD) and increased severity of depressive symptoms. However, it is unclear how lifetime stressors are related to specific MDD subtypes. The present study aims to examine the relationships between MDD subtypes and stressors experienced across the lifespan while considering potential confounders. Data analyzed were from the Zone d'Épidémiologie Psychiatrique du Sud-Ouest de Montréal (N = 1351). Lifetime stressors included childhood maltreatment, child-parent bonding, and stressful life events. Person-centered analyses were used to identify the clusters/profiles of the studied variables and multinomial logistic regression analyses were performed to examine the relationships between stressors and identified MDD subtypes. Intersectional analysis was applied to further examine how distal stressors interact with proximal stressors to impact the development of MDD subtypes. There was a significant association between proximal stressors and melancholic depression, whereas severe atypical depression and moderate depression were only associated with some domains of stressful life events. Additionally, those with severe atypical depression and melancholic depression were more likely to be exposed to distal stressors such as childhood maltreatment. The combinations of distal and proximal stressors predicted a greater risk of all MDD subtypes except for moderate atypical depression. MDD was characterized into four subtypes based on depressive symptoms and severity. Different stressor profiles were linked with various MDD subtypes. More specific interventions and clinical management are called to provide precision treatment for MDD patients with unique stressor profiles and MDD subtypes.

Associations Between Psychological Stress and the Risk of First Onset of Major Depression Disorder: Results from a Longitudinal Study in 6,985 Chinese First-Year Students.

Youth and young adults have a high prevalence of major depressive disorder (MDD). Limited longitudinal research has explored the relationship between different dimensions of psychological stress and MDD. This study aimed to estimate the effect of psychological stress on the risk of first onset MDD in a sample of Chinese freshmen. Using a longitudinal design, 8079 Chinese first-year students were recruited at baseline, and 6985 were followed up one year later. The Psychological Stress Scale for College Students was utilized to evaluate the levels of psychological stress. MDD was evaluated using the Chinese version of the Composite International Diagnostic Interview (CIDI-3.0). Logistic regression modeling was utilized to estimate the associations between dimensions of psychological stress and the risk of MDD. Two dimensions of psychological stress, namely learning stress (OR=1.05, 95% CI:1.01-1.09, P=0.017) and economic stress (OR=1.11, 95% CI:1.04-1.19, P=0.001), were significantly associated with the risk of MDD. Other dimensions of psychological stress (specify family stress, interpersonal stress, intimate relationship stress, employment stress and appearance stress) were not associated with MDD. Psychological stress, especially learning and economic stresses, could increase the risk of MDD in university students. These factors should be incorporated into mental health prevention and intervention programs at universities to reduce the risks of MDD.

Exploring causal association between functional/structural connectivity and major depression disorder: A bidirectional Mendelian randomization study

ObjectivesPrior observational studies have suggested a correlation between major depressive disorder (MDD) and communication imbalances within the resting-state brain network (RSN), but the causal relationship remains unclear. This research uses Mendelian randomization (MR) analysis to explore the potential causal effects between functional connectivity (FC), structural connectivity (SC) and MDD. MethodsTwo-sample bidirectional MR analysis was employed in this study. Inverse variance weighted (IVW) was used to explore the causal relationship between the FC/SC and MDD, with various methods such as MR-Egger to conduct sensitivity analyses. ResultsThe IVW analysis results showed that higher genetic predicted dorsal attention network FC, limbic network SC, and dorsal attention network SC were associated with an increased risk of MDD (β: 15.08, 95%CI: 5.89–24.27, p = 0.001; β: 3.79, 95%CI: −0.22-7.8, p = 0.034; β: 9.89, 95%CI: 0.88–18.90, p = 0.031). Reverse MR analysis demonstrated that a genetically predicted elevated risk of MDD was associated with reduced frontal parietal network FC (β: −0.00046, p = 0.041). ConclusionsThe study suggests a causal relationship between the FC and SC within specific RSNs and the risk of MDD. Abnormalities in the dorsal attention network FC/SC and the limbic network SC were risk factors for MDD. The FC abnormality of the frontal parietal network may be the downstream influence following the MDD onset. Further investigation is needed to determine the potential utility of these neuroimaging markers in the prevention of MDD or the evaluation of treatment efficacy.

Identifying Key Genes and Approved Medications Associated with Major Depressive Disorder Using Network Analysis and Systems Biology

Objective: Major depressive disorder (MDD) stands as one of the serious psychiatric conditions that detrimentally affect patients' quality of life and leads to a significant part of disability worldwide. Due to the limited understanding of the basic molecular mechanisms of depression and antidepressant medications, a clear understanding of the onset and development of MDD is unavailable. This study aims to figure out the pivotal genes and pathways implicated in the MDD development and identify medications that can potentially improve MDD treatment based on their relation with the key genes. Method: Symbols of human coding genes were retrieved from the HUGO Gene Nomenclature Committee database. These symbols were then queried for MDD-related associations using a Python script in PubMed. Subsequently, genes with two or more related articles to MDD were selected. A union of our search data and MDD-related genes in the DisGeNET database was found. The gene interaction network was generated and analyzed utilizing the STRING and Cytoscape, respectively. Finally, a drug-gene network was constructed and medications that can affect multiple genes were selected. Results: The union of our search data and DisGeNET data contained 1734 genes. Based on network analysis, TNF, IL1B, IL6, STAT1, and STAT3 were identified as the key genes in the MDD pathogenesis. Eleven drugs that affect more than one gene were detected through a drug-gene network. These medications include Acitretin, Adalimumab, Alteplase, Cisplatin, Digoxin, Etanercept, Infliximab, Insulin, Omeprazole, Pentoxifylline, and Rabeprazole. Conclusion: In summary, our findings identified five genes as key genes in MDD development, as well as medications related to key genes. This study provides a new vision of the pathogenesis and treatment of MDD. However, further experimental and clinical studies are necessary.

A Grant Report: Examining the Efficacy of Remote Photobiomodulation Therapy in Adolescents with Major Depressive Disorder

Major depressive disorder (MDD) is a prevalent mental health condition affecting a significant portion of the population worldwide. This condition can impact individuals of all ages, including adolescents, leading to an impact on various aspects of their lives. Adolescence is a crucial phase of human development, characterized by several neurobiological changes. The onset of MDD during this period can result in damage not only to teenagers but also might have long-lasting implications for their future as adults. Notably, the onset of MDD in adolescents is often associated with various biomarkers, such as increased levels of inflammatory cytokines (e.g., IL-6, TNF-α), oxidative stress markers, and alterations in neurotransmitter levels, indicating a complex interplay of biological factors. Therefore, early intervention is essential for addressing MDD during this phase. Photobiomodulation therapy (PBMT) emerges as an innovative and promising approach that utilizes light, especially in the near-infrared (NIR) and red spectra, to trigger biological and therapeutic effects. Notably, targeting the skull and abdomen with PBMT might explore the bidirectional communication between the intestinal system and the central nervous system in a remote and/or systemic way. In this context, we present the rationale and design of an ongoing study aiming to assess the efficacy of PBMT on depressive symptoms and biomarkers associated with oxidative stress and mitochondrial function in adolescents with MDD.

Neural correlates of anhedonia in young adults with subthreshold depression: A graph theory approach for cortical-subcortical structural covariance

BackgroundAnhedonia is an enduring symptom of subthreshold depression (StD) and predict later onset of major depressive disorder (MDD). Brain structural covariance describes the inter-regional distribution of morphological changes compared to healthy controls (HC) and reflects brain maturation and disease progression. We investigated neural correlates of anhedonia from the structural covariance. MethodsT1-weighted brain magnetic resonance images were acquired from 79 young adults (26 StD, 30 MDD, and 23 HC). Intra-individual structural covariance networks of 68 cortical surface area (CSAs), 68 cortical thicknesses (CTs), and 14 subcortical volumes were constructed. Group-level hubs and principal edges were defined using the global and regional graph metrics, compared between groups, and examined for the association with anhedonia severity. ResultsGlobal network metrics were comparable among the StD, MDD, and HC. StD exhibited lower centralities of left pallidal volume than HC. StD showed higher centralities than HC in the CSAs of right rostral anterior cingulate cortex (ACC) and pars triangularis, and in the CT of left pars orbitalis. Less anhedonia was associated with higher centralities of left pallidum and right amygdala, higher edge betweenness centralities in the structural covariance (EBSC) of left postcentral gyrus-parahippocampal gyrus and LIPL-right amygdala. More anhedonia was associated with higher centralities of left inferior parietal lobule (LIPL), left postcentral gyrus, left caudal ACC, and higher EBSC of LIPL-left postcentral gyrus, LIPL-right lateral occipital gyrus, and left caudal ACC-parahippocampal gyrus. LimitationsThis study has a cross-sectional design. ConclusionsStructural covariance of brain morphologies within the salience and limbic networks, and among the salience-limbic-default mode-somatomotor-visual networks, are possible neural correlates of anhedonia in depression.

Regional brain structural network topology mediates the associations between white matter damage and disease severity in first-episode, Treatment-naïve pubertal children with major depressive disorder

Puberty is a vulnerable period for the onset of major depressive disorder (MDD) due to considerable neurodevelopmental changes. Prior diffusion tensor imaging (DTI) studies in depressed youth have had heterogeneous participants, making assessment of early pathology challenging due to illness chronicity and medication confounds. This study leveraged whole-brain DTI and graph theory approaches to probe white matter (WM) abnormalities and disturbances in structural network topology related to first-episode, treatment-naïve pediatric MDD. Participants included 36 first-episode, unmedicated adolescents with MDD (mean age 15.8 years) and 29 age- and sex-matched healthy controls (mean age 15.2 years). Compared to controls, the MDD group showed reduced fractional anisotropy in the internal and external capsules, unveiling novel regions of WM disruption in early-onset depression. The right thalamus and superior temporal gyrus were identified as network hubs where betweenness centrality changes mediated links between WM anomalies and depression severity. A diagnostic model incorporating demographics, DTI, and network metrics achieved an AUROC of 0.88 and a F1 score of 0.80 using a neural network algorithm. By examining first-episode, treatment-naïve patients, this work identified novel WM abnormalities and a potential causal pathway linking WM damage to symptom severity via regional structural network alterations in brain hubs.

A classic prescription alleviates inflammation in CUMS model mice via modulating MYDGF/MAP4K4/NF-κB signaling pathway, verified through UPLC-HRMS and proteomics analysis

BackgroundXiaoyaosan (XYS), a renowned classical traditional Chinese medicinal formula utilized in addressing major depressive disorder (MDD), has garnered significant acclaim for its remarkable efficacy in clinical application. The onset of major depressive disorder (MDD) often correlates with chronic unpredictable mild stress (CUMS), a pivotal instigating factor in its development.Aim of the study: This study aims to clarify the potential anti-inflammatory mechanisms of XYS in treating CUMS model mice. Materials and methodsUtilizing cutting-edge ultra high-performance liquid chromatography - high-resolution mass spectrometry (UPLC-HRMS), the active constituents of XYS were discerned, while employing proteomics analysis to delve into the potential mechanisms of its efficacy. Molecular docking studies, alongside subsequent in vivo experiments utilizing CUMS model mice, were conducted to corroborate the findings derived from the proteomics analysis. ResultsIn vivo experiments demonstrated that XYS not only markedly ameliorated behavioral markers but also attenuated serum inflammatory markers and suppressed IL-6 and TNF-α expression within the brains of CUMS model mice. Proteomics analysis suggested that the pivotal anti-inflammatory mechanism of XYS against CUMS-induced damage might involve modulation of the MAPK signaling pathway. Utilizing UPLC-HRMS, the active constituents of XYS were successfully identified, while molecular docking investigations explored interactions between XYS and MYDGF, PKC, MAP4K4, P-p65, p65, P-IKBα, and IKBα. The findings revealed XYS's regulatory influence on the MYDGF/MAP4K4/NF-κB signaling cascade. ConclusionsThis study is the first to our knowledge to demonstrate that XYS can alleviate inflammation in CUMS model mice by modulating the MYDGF/MAP4K4/NF-κB signaling pathway.

Inflammation and immune system pathways as biological signatures of adolescent depression—the IDEA-RiSCo study

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world’s adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14–16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p < 0.001), interferon signaling (z-score = 2.464, p < 0.001), interferon alpha/beta signaling (z-score = 3.873, p < 0.001), and complement signaling (z-score = 2, p = 0.002) were upregulated in adolescents with MDD compared with adolescents without MDD independently from their level of risk. The up-regulation of such inflammation-related pathways was observed in females but not in males. Inflammatory-related pathways involved in the production of cytokines and in interferon and complement signaling were identified as key indicators of adolescent depression, and this effect was present only in females.

Adolescent and Adult Transitions From Major Depressive Disorder to Bipolar Disorder

Bipolar disorder (BD) often first appears in adolescence after onset of major depressive disorder (MDD), but diagnosis and treatment are commonly delayed. This delay is a concern because untreated BD is associated with adverse long-term outcomes, a more recurrent disease course and difficult-to-treat illness, and suicide attempts and deaths. To examine the association of age at MDD onset with early transition to BD and the subsequent use of psychiatric inpatient services as a severity indicator. This retrospective cohort study analyzed comprehensive data sourced from the Stockholm MDD Cohort data from 1997 to 2018, which encompass both outpatient and inpatient care. Individuals with an initial MDD episode from January 1, 2010, to December 31, 2013, who transitioned to BD by December 31, 2018, were identified. Data were analyzed between September 5 and December 28, 2023. Post MDD assessments included a depression severity index, comorbidities, psychotherapy, psychotropic drugs, and electroconvulsive therapy. The main outcome was the transition from MDD to BD, dichotomized as occurring early (within 3 years of MDD onset) or late (3 years after MDD onset). Secondary outcomes encompassed the use of psychiatric inpatient services post transition and patterns of medication usage. A robust propensity score matching framework was used to estimate outcomes. The final balanced cohort included 228 individuals, with an equal distribution between adults (n = 114; mean [SD] age, 24.5 [6.3] years; 96 female [84.2%]; 20 experiencing an early transition to BD [17.5%]) and youths (n = 114; mean [SD] age, 15.3 [1.6] years; 93 female [81.6%]; 8 experiencing an early transition to BD [7.0%]). Youths were substantially less likely to transition early (odds ratio, 0.42; 95% CI, 0.20-0.88; P = .02), despite having more outpatient visits (mean [SD] visits per month, 1.21 [1.07] vs 0.97 [0.98] for adults; P = .01). Both groups experienced substantially reduced inpatient care following a BD diagnosis, concurring with a marked decline in antidepressant use without increased lithium use. These findings suggest that adolescents may experience delayed BD progression and that diagnosis substantially reduced inpatient care in all age groups, which coincided with a reduction in the use of antidepressants. These findings may inform pharmacologic strategies in patients with first-episode MDD at risk for BD.

Exploring the mechanisms underlying increased risk of depressive disorder in ethnic minority populations in Europe: A causal loop diagram

BackgroundMultiple ethnic minority populations in Europe show high risk of major depressive disorder (MDD), with ethnic discrimination and low socioeconomic position (SEP) as established risk factors. How this risk is shaped by the interactions between these, and other social factors, remains to be elucidated. We aimed to develop a causal-loop diagram (CLD) to gain a better understanding of how factors at the intersection of ethnic discrimination and SEP dynamically interact to drive MDD risk. MethodsWe iteratively mapped the interactions and feedback loops between factors at the intersection of ethnic discrimination and SEP, drawing input from (i) a series of two interviews with a range of MDD domain experts, (ii) an existing CLD mapping the onset of MDD across psychological, biological, and social dimensions at the level of the individual, and (iii) other relevant literature. ResultsThrough tracing the feedback loops in the resulting CLD, we identified ten driving mechanisms for MDD onset in ethnic minorities (two related to ethnic discrimination, SEP, social network and support, and acculturation, as well as one relating to the living environment and self-stigma towards MDD); and four factors that modulate these mechanisms (recent migration, religious affiliation, neighborhood social environment, and public stigma towards MDD). The intersecting nature of ethnic discrimination and SEP, combined with the reinforcing dynamics of the identified driving mechanisms across time- and spatial scales, underscores the excess exposure to circumstances that increase MDD risk in ethnic minorities. ConclusionsWhile this CLD requires validation through future studies, the intersecting and reinforcing nature of the identified driving mechanisms highlights that tackling the high risk of MDD in ethnic minorities may require intervening at multiple targets, from the individual (e.g., psychological interventions targeting negative beliefs or reducing stress) to the societal level (e.g., addressing labor market discrimination).

Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017).

Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017).

Educational inequalities in major depressive disorder prevalence, timing and duration among adults over the life course: a microsimulation analysis based on the Lifelines Cohort Study.

Educational inequalities in major depressive disorder (MDD) pose a major challenge. Tackling this issue requires evidence on the long-term impact of intervening on modifiable factors, for example lifestyle and psychosocial factors. For this reason, we aimed to simulate the development of educational inequalities in MDD across the life course, and to estimate the potential impact of intervening on modifiable factors. We used data from the prospective Dutch Lifelines Cohort Study to estimate the required input for a continuous-time microsimulation. The microsimulation allowed us to project the development of educational inequalities in MDD between ages 18 and 65, and to assess the potential benefit of intervening on quality of social contacts, health literacy and smoking. On average, an additional 19.1% of individuals with low education will ever experience MDD between ages 18 and 65 compared with those with high education. Additionally, individuals with low education generally will develop MDD 0.9 years earlier and spend 1.2 years more with MDD, than individuals with high education. Improving the quality of social contacts in individuals with low education produced the largest effect; it would reduce the inequalities in the prevalence, onset and duration of MDD by an average of 18.4%, 18.3% and 28.6%, respectively. Intervening on modifiable factors, particularly quality of social contacts, in individuals with low education could help reduce the estimated educational inequalities in MDD over the life course.

Identification of novel endoplasmic reticulum-related genes and their association with immune cell infiltration in major depressive disorder

BackgroundSeveral lines of evidence point to an interaction between genetic predisposition and environmental factors in the onset of major depressive disorder (MDD). This study is aimed to investigate the pathogenesis of MDD by identifying key biomarkers, associated immune infiltration using bioinformatic analysis and human postmortem sample. MethodsThe Gene Expression Omnibus (GEO) database of GSE98793 was adopted to identify hub genes linked to endoplasmic reticulum (ER) stress-related genes (ERGs) in MDD. Another GEO database of GSE76826 was employed to validate the novel target associated with ERGs and immune infiltration in MDD. Moreover, human postmortem sample from MDD patients was utilized to confirm the differential expression analysis of hub genes. ResultsWe discovered 12 ER stress-related differentially expressed genes (ERDEGs). A LASSO Cox regression analysis helped construct a diagnostic model for these ERDEGs, incorporating immune infiltration analysis revealed that three hub genes (ERLIN1, SEC61B, and USP13) show the significant and consistent expression differences between the two groups. Western blot analysis of postmortem brain samples indicated notably higher expression levels of ERLIN1 and SEC61B in the MDD group, with USP13 also tending to increase compared to control group. LimitationsThe utilization of the MDD gene chip in this analysis was sourced from the GEO database, which possesses a restricted number of pertinent gene chip samples. ConclusionsThese findings indicate that ERDEGs especially including ERLIN1, SEC61B, and USP13 associated the infiltration of immune cells may be potential diagnostic indicators for MDD.

Chronic social defeat stress induces the down-regulation of the Nedd4L-GLT-1 ubiquitination pathway in the prefrontal cortex of mice.

Stressful life events contribute to the onset of major depressive disorder (MDD). We recently demonstrated abnormalities in ubiquitination in the pathophysiology of MDD. However, the underlying molecular mechanisms remain unclear. We investigated the involvement of the ubiquitination system-mediated glutamatergic dysfunction in social impairment induced by chronic social defeat stress (CSDS). Adult C57BL/6J mice were exposed to aggressor ICR male mice for 10 consecutive days. Social impairment was induced by CSDS in the social interaction test 1 days after the last stress exposure. In terms of brain microdialysis, CSDS reduced depolarization-evoked glutamate release in the prefrontal cortex (PFC), which was reversed by a glutamate transporter 1 (GLT-1) inhibitor. Interestingly, the expression of ubiquitinated, but not total GLT-1, was decreased in the PFC of mice exposed to CSDS. The expression of neural precursor cells expressing developmentally downregulated gene 4-like (Nedd4L: E3 ligase for GLT-1), and ubiquitin-conjugating enzyme E2D2 (Ube2d2: E2 ubiquitin-conjugating enzyme for Nedd4L) was also reduced in CSDS mice. Furthermore, the downregulation of the Nedd4L-GLT-1 ubiquitination pathway decreased SIT ratio, but up-regulation increased it even in non-CSDS mice. Taken together, the decrease in GLT-1 ubiquitination may reduce the release of extracellular glutamate induced by high-potassium stimulation, which may lead to social impairment, while we could not find differences in GLT-1 ubiquitination between susceptible and resistant CSDS mice. In conclusion, GLT-1 ubiquitination could play a crucial role in the pathophysiology of MDD and is an attractive target for the development of novel antidepressants.