Risk Of Major Depressive Disorder Research Articles

Is racism like other trauma exposures? Examining the unique mental health effects of racial/ethnic discrimination on posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD).

Although scholars have increasingly drawn attention to the potentially traumatic nature of racial/ethnic discrimination, diagnostic systems continue to omit these exposures from trauma definitions. This study contributes to this discussion by examining the co-occurrence of conventional forms of potentially traumatic experiences (PTEs) with in-person and online forms of racism-based potentially traumatic experiences (rPTEs) like racial/ethnic discrimination. Additionally, we investigated the unique association of rPTEs with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD), accounting for demographics and other PTEs. Participants were (N = 570) 12-to-17-year-old (Mage = 14.53; 51.93% female) ethnoracially minoritized adolescents (54.21% Black; 45.79% Latiné). Youth completed online surveys of PTEs, in-person and online rPTEs, and mental health. Bivariate analyses indicated that youth who reported in-person and online rPTEs were more likely to experience all conventional PTEs. Accounting for demographics and conventional PTEs, in-person and online rPTEs were significantly associated with PTSD (in-person: aOR = 2.60, 95% CI [1.39, 4.86]; online: aOR = 2.74, 95% CI [1.41, 5.34]) and GAD (in-person: aOR = 2.94, 95% CI [1.64, 5.29]; online: aOR = 2.25, 95% CI [1.24, 4.04]) and demonstrated the strongest effect sizes of all trauma exposures. In-person, but not online, rPTEs were linked with an increased risk for MDD (aOR = 4.47, 95% CI [1.77, 11.32]). Overall, rPTEs demonstrated stronger associations with PTSD, MDD, and GAD compared to conventional PTEs. Findings align with racial trauma frameworks proposing that racial/ethnic discrimination is a unique traumatic stressor with distinct mental health impacts on ethnoracially minoritized youth. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Micronutrients and Major Depression: A Mendelian Randomisation Study.

Various vitamins and minerals have been implicated in the aetiology of depression. To estimate the effects of micronutrient exposures on major depressive disorder (MDD) and recurrent depression (rMDD) using Mendelian randomisation (MR), a method using genetic data to estimate causal effects given certain assumptions. We undertook a comprehensive bidirectional MR study of multiple micronutrient exposures on MDD and rMDD. Summary statistics were obtained from the Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWASs) of MDD (cases = 116,209; controls = 314,566) and rMDD (cases = 17,451; controls = 62,482). None of the micronutrients with available genetic instruments were strongly associated with MDD or rMDD using traditional MR methods. However, using methods to increase analytical power by accounting for genetically correlated variants (e.g., cIVW) highlighted five micronutrients with possible causal effects. Point estimates for rMDD were the largest magnitude, with three micronutrients suggestive of a protective effect: serum iron (ORcIVW 0.90 per SD increase; 95% CI 0.85-0.95; p = 0.0003); erythrocyte copper (ORcIVW 0.97; 95% CI 0.95-0.99; p = 0.0004); and 25(OH) vitamin D (ORcIVW 0.81; 0.66-0.99; p = 0.04). Apparent adverse effects of increased selenium on the risk of MDD (ORcIVW 1.03; 95% CI 1.02-1.05; p = 0.0003) and rMDD (ORcIVW 1.08; 95% CI 1.00-1.08; p = 0.06), and serum magnesium on rMDD (ORcIVW 1.21; 1.01-1.44; p = 0.04); were less consistent between methods and may be driven by pleiotropy. Our results suggest weak evidence for a protective effect of iron, copper and 25(OH)D on major depressive outcomes, with mixed evidence for selenium and magnesium. There was no evidence to support a causal effect of any other micronutrients on MDD or rMDD, although genetic instruments were lacking, with insufficient power to detect small but important effects. Future micronutrient supplementation trials should ensure ample statistical power given modest causal effect estimates and consider potential risks of supplementation, as some micronutrient effect estimates suggested potential harm in excess.

Breakfast skipping is linked to a higher risk of major depressive disorder and the role of gut microbes: a mendelian randomization study

Breakfast skipping is linked to a higher risk of major depressive disorder and the role of gut microbes: a mendelian randomization study

Association between vegetable intake and major depressive disorder: results from National Health and Nutrition Examination Survey 2005-2018 and bidirectional two-sample Mendelian randomisation.

This study aimed to evaluate the association between vegetable intake and major depressive disorder (MDD) through cross-sectional analysis and bidirectional two-sample Mendelian randomisation (MR). Cross-sectional analysis was conducted on National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and the corresponding Food Patterns Equivalents Database (FPED). Genome-wide association study (GWAS) data were obtained from UK Biobank and Psychiatric Genomics Consortium (PGC) dataset. Logistic regression analysis was performed after calculating the weights of the samples. Inverse variance weighted, MR-Egger and weighted median methods were used to evaluate the causal effects. A Patient Health Questionnaire-9 score ≥ 10 was considered to indicate MDD. Low vegetable intake was defined as < 2 cups of vegetables per day. 30 861 U.S. adults from NHANES. The GWAS data sample size related to vegetable intake were comprised 448 651 and 435 435 cases respectively, while the GWAS data sample size associated with MDD encompassed 500 199 cases. There were 23 249 (75·33 %) participants with low vegetable intake. The relationship between vegetable intake and MDD was nonlinear. In the multivariate model adjusted for sex, age, education, marital status, poverty income ratio, ethnicity and BMI, participants with low vegetable intake were associated with an increased risk of MDD (OR = 1·53, 95 % CI (1·32, 1·77), P < 0·001). Bidirectional MR showed no causal effects between vegetable intake and MDD. Cross-sectional analysis identified a significant relationship between vegetable intake and MDD, whereas the results from bidirectional two-sample MR did not support a causal role.

Identification and experimental validation of hub genes underlying depressive-like behaviors induced by chronic social defeat stress.

Introduction: Major depressive disorder (MDD), characterized by severe neuropsychiatric symptoms and significant cognitive deficits, continues to present both etiological and therapeutic challenges. However, the specific underlying mechanisms and therapeutic targets remain unclear. Methods: We analyzed human postmortem dorsolateral prefrontal cortex (dlPFC) samples from MDD patients using datasets GSE53987 and GSE54568, identifying three key genes: AGA, FBXO38, and RGS5. To model depressive-like behavior, we employed chronic social defeat stress (CSDS) and subsequently measured the expression of AGA, FBXO38, and RGS5 in the dlPFC using qPCR and Western blot analysis following CSDS exposure. Results: CSDS significantly induced depressive-like behavior, and both the protein and transcriptional expression levels of AGA, FBXO38, and RGS5 in the dlPFC of mice were markedly reduced after stress, consistent with findings from datasets GSE53987 and GSE54568. Conclusion: Our research suggests that AGA, FBXO38, and RGS5 are potential biomarkers for MDD and could serve as valuable targets for MDD risk prediction.

The antidepressant effect of Komagataella pastoris KM 71 H in maternal separation mice model mediated by the microbiota-gut-brain axis

BackgroundThe intestinal microbiota plays a fundamental role in maintaining host health, especially during childhood, a critical period for its establishment. Early life stress can lead to shifts in gut microbiota composition, thus increasing the risk of major depressive disorder (MDD) in adulthood. The supplementation with probiotics restores intestinal permeability and the health of gut microbial communities, therefore being potential study targets for the treatment of MDD. In this sense, the yeast Komagataella pastoris was reported as a promising probiotic with antidepressant effect. MethodsHence, the present study aims to investigate this effect in mice submitted to maternal separation (MS) 3 h per day from PND2 to PND14. Adult mice and mothers were treated with K. pastoris KM71H (8 log UFC.g−1/per animal, i.g.) or PBS (500 µl, i.g.) for 14 days. After behavioral tests, the animals were euthanized, followed by hippocampi and intestines removal for biochemical analysis. ResultsOn behavioral tests, K. pastoris KM71H treatment reduced the immobility time in TST of adult mice and increased the grooming activity in splash test of adult mice and mothers induced by MS. The probiotic treatment restored plasma corticosterone levels and glucocorticoid receptor expression in hippocampi, alongside nitrate/nitrite levels and superoxide dismutase activity in intestine, in addition to reducing reactive species levels in both structures. Moreover, it also normalized the fecal pH and water content of feces. ConclusionThus, we conclude that K. pastoris KM71H is a promising therapeutic strategy for the treatment of MDD.

Profiling intimate partner violence in booked pregnant women at Alex Ekwueme Federal University Teaching Hospital Abakaliki and associated puerperal depressive sequelae: a prospective cohort study

BackgroundIntimate partner violence (IPV) in pregnancy is a physical, sexual, psychological or economic harm by a current or former partner or spouse on a pregnant woman. It is a global public health problem that is common but underreported. Women are at increased risk of psychiatric illness in pregnancy and after delivery with the risk of major depressive disorder being highest during the postpartum period. Intimate partner violence in pregnancy may worsen this problem.ObjectivesThe objectives of the study were to determine the prevalence of intimate partner violence (IPV) in pregnancy, incidence of postpartum depression and the relationship between intimate partner violence, delivery outcomes and postpartum depression among booked pregnant women at Alex Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi state, Nigeria (AEFUTHA).Study designThis study was a prospective cohort study.SettingThe antenatal clinic, antenatal ward, labour ward, postpartum clinic and under five clinic of Alex Ekwueme Federal University Teaching Hospital Abakaliki, Ebonyi state, Nigeria were used for the study.Method One hundred and thirty-seven booked pregnant women that received antenatal care at AEFUTHA who met the inclusion criteria and consented to the study, were recruited from 37 weeks to 41 weeks gestation and screened for intimate partner violence and depression. Those with depression were referred for treatment while those that met the inclusion criteria were followed up to delivery and the delivery outcomes documented. They were also followed up to six weeks postpartum when they were screened for postpartum depression. Data were collated, tabulated and then statistically analysed using Statistical Package for Social Science (SPSS) software (version 25, Chicago II, USA). Numerical variables including participant’s age, parity and gestational age were presented as mean, median, frequencies and standard deviation (Mean ± S.D), while categorical variables including occupation, level of education, social class and family type were presented as numbers and percentages. Chi-square test (X2) and relative risk was used for comparison between groups for categorical variables while Fisher’s exact test was used when Chi-square test (X2) was not suitable. Binary regression analysis was used to determine the relationship between intimate partner violence and postpartum depression. A P value of ˂0.05 is considered statistically significant.ResultsThe prevalence of intimate partner violence was 52.6%, as 72 out of the 137 women recruited endured intimate partner violence. The major risk factors for intimate partner violence in the study were low level of education, low social class, polygamy and unemployment. The general incidence of postpartum depression was 29.93% while the incidence among women with intimate partner violence was 56.94%. Women with emotional violence and verbal abuse had a five-fold increase in the incidence of postpartum depression. Sexual violence and physical violence were not statistically significant risk factors for postpartum depression.ConclusionIntimate partner violence is common as seen from the study. It is a significant risk factor for postpartum depression. Women that are emotionally and verbal abused are more likely to have postpartum depression. Screening pregnant women for intimate violence may identify those at risk and allow for proper interventions.

Antidepressants account for the causal effect of major depressive disorder on type 2 diabetes

BackgroundPatients with major depressive disorder (MDD) face an elevated risk of type 2 diabetes (T2D). However, the contribution of the disease itself versus the side effects of antidepressants to this increased risk remains unclear. ObjectiveThis study aimed to investigate the overall and independent effects of MDD and exposure to antidepressants on T2D risk. MethodsSummary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for MDD (N = 500,199), antidepressants (N = 175,161), and T2D (N = 933,970). Bayesian colocalization analysis was used to reveal shared genetic variation between MDD, antidepressants, and T2D. ResultsWe found that both MDD (OR: 1.15, CI: 1.03–1.30, P = 0.016) and antidepressants (OR: 1.37, CI: 1.22–1.53, P = 2.75E-08) have overall causal effects on T2D. While T2D was associated with the risk of antidepressant use (OR: 1.08, CI: 1.06–1.11, P = 8.80E-10), but not with the risk of MDD (OR: 1.00, CI: 0.98–1.01, P = 0.661). Our MVMR analysis showed that the use of antidepressants is associated with higher risks of T2D (OR: 1.21, CI: 1.07–1.37, P = 7.19E-04), while MDD is not linked to the risk of T2D (OR: 1.01, CI: 0.86–1.18, P = 0.799). Colocalization analysis identified two shared genetic loci between antidepressants and T2D. ConclusionsThe elevated T2D risk in MDD patients is chiefly caused by antidepressant use. These findings emphasize the importance of considering the impact of antidepressants on metabolic health in individuals with MDD.

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.

Telomere length and mitochondrial DNA copy number in association with trauma-focused psychotherapy efficacy

Early life adversities (ELA) have been linked to a greater risk for major depressive disorder (MDD) and treatment-resistant depression (TRD). The molecular mechanisms underlying the link between ELA and MDD and/or TRD are yet unknown. It has been suggested that ELA induces an allostatic burden, which in turn promotes oxidative stress and an inflammatory response that are further intensified by the influence of maladaptive coping behaviour. In this study we explored the role of two markers of cellular aging and oxidative stress (telomere length (TL) and mitochondrial DNA copy number mtDNAcn) in TRD and in response to trauma-focused psychotherapies. The study comprised 30 TRD patients receiving trauma-focused psychotherapies and 65 healthy controls. TL and mtDNAcn were measured at baseline and four weeks after the end of the psychotherapy sessions. Response was defined based on reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS). In the case control analysis, the logistic regression model showed that mtDNAcn but not TLT was a significant predictor of diagnosis (chi-square 92.108, p=7.72e-20; contribution of mtDNAcn, B=-9-297, p=0.00009, Table 2). In the TRD sample, LTL and mtDNAcn were inversely correlated with MADRS score at baseline (TL, Pearson’s r=-0.478, p=0.008; mtDNAcn, Pearson’s r=-0.656, p=0.00008), but there was no difference in either TL or mtDNAcn between responders and non-responders. In conclusion, our findings support an involvement of cellular aging in TRD, and suggest that TLA and mtDNAcn are not predictors or mediators of response to trauma-focused psychotherapies.

Effect of childhood trauma on cognitive function in individuals with major depressive disorder and healthy controls

BackgroundIndividuals with major depressive disorder (MDD) exhibit cognitive impairment, while childhood trauma (CT) is associated with an elevated risk of both MDD and cognitive dysfunction. The effect of CT on cognitive function in MDD patients and healthy controls (HCs) is unclear. MethodsMDD patients and HCs were enrolled between December 2013 and December 2016. The Childhood Trauma Questionnaire (CTQ) was used to assess CT. Depressive symptoms and cognitive function were assessed at baseline and after 8-week acute-phase treatment with selective serotonin reuptake inhibitors (SSRIs) in MDD patients. ResultsA total of 909 people were included in the analysis. The interaction between MDD and CT had a main effect on Digit Symbol-Coding Test (DSCT), Stroop Color Test (SCT), and Stroop Color-Word Test (SCWT) scores. The effect of CT on cognitive function disappeared after adjusting for MDD diagnosis and years of education. Neglect could predict poor performance on SCT and SCWT in the HC group. After acute-phase treatment with SSRIs, CT did not significantly predict changes in cognitive function or depressive symptoms. LimitationsThe CTQ assessment might cause recall bias, and the cross-sectional design could not establish the causal link between CT and cognitive function. ConclusionThe effect of CT on cognitive function was modulated by MDD diagnosis and years of education. CT did not predict changes in depressive symptoms or cognitive function after acute-phase treatment with SSRIs. The direct influence of CT on cognitive function in MDD patients may be over-estimated. Trial registrationClinicalTrials.gov: NCT02023567; registration date: December 2013.

Psychobiological Stress Response Profiles in Current and Remitted Depression: A Person-Centered, Multisystem Approach

BackgroundA dysregulated stress response, including exaggerated affective reactivity and abnormal hypothalamic–pituitary–adrenal (HPA) axis responsivity, has been implicated in the etiology, maintenance and relapse of major depressive disorder (MDD). Among adolescents, discordant affective and physiological stress response profiles have been linked to negative affective outcomes and increased risk for psychopathology. Whether these findings extend to adults with varying degree of MDD risk is unclear, as are possible links to various risk factors. MethodsWe used a person-centered, multisystem approach in a sample of 119 unmedicated adults with current or remitted MDD, as well as individuals without past MDD to evaluate psychobiological stress response profiles. Multi-trajectory modeling was applied to positive affect, negative affect, and salivary cortisol (CORT) levels in response to the Maastricht Acute Stress Test. ResultsAnalyses identified four within-person profiles, one typical, Normative (n=32, 26.9%); and three atypical: CORT Hyperreactivity Affective Stability (n=17, 14.3%), CORT Hyporeactivity Affective Reactivity #1 (n=45, 37.8%), and CORT Hyporeactivity Affective Reactivity #2 (n=25, 21.0%). Validating the assumption of a Normative profile and increased risk for psychopathology in non-normative stress-response profiles, coherent associations emerged between stress response profiles and clinical status, depression severity, anhedonia, perceived stress, childhood adversity and reports of well-being, suggesting increased risk for psychopathology for individuals with a hyperreactive or discordant hyporeactive stress response profiles. ConclusionThis work advances our understanding of stress response mechanisms in MDD and underscores the potential of targeted interventions to enhance resilience and reduce psychopathology based on individual stress response profiles.

The Associations between Depression and Sugar Consumption Are Mediated by Emotional Eating and Craving Control in Multi-Ethnic Young Adults.

Individuals with mental health conditions such as depression are vulnerable to poor dietary habits, potentially due to the maladaptive eating behaviors often used to regulate negative emotion. However, the specific dietary components most associated with depression, as well as the mediating roles of emotion regulation and other eating behaviors, remains ambiguous in young adults. For this cross-sectional evaluation, a total of 151 (86 F, 65 M; BMI: 22.0 ± 5.1 kg/m2; age: 21.4 ± 2.5 y) multi-ethnic participants (50 White, 36 Black, 60 Asian, and 5 White Hispanic) completed a digital 24-h dietary recall and self-reported measures of depressive symptoms, emotional regulation, and eating behaviors. LASSO regression was used to identify the dietary variables most associated with each subscale and to remove extraneous dietary variables, and multiple regression and mediation analyses were conducted for the remaining variables. Out of >100 dietary factors included, only added sugar in the combined sample (p = 0.043), and relative sugar in females (p = 0.045), were retained and positively associated with depressive symptoms. However, the relationships between depression and added and relative sugar intake were mediated by craving control and emotional eating, respectively. Individuals with higher added sugar intake (p = 0.012-0.037), and females with higher relative sugar intake (p = 0.029-0.033), had significantly higher odds of risk for major depression disorder and the use of mental health medications. Added and relative sugar intake are significantly associated with depressive symptoms in young adults, but these relationships may be mediated by facets of emotional dysregulation, such as emotional eating and craving control.

Association of air pollutants with psychiatric disorders: a two-sample Mendelian randomization

BackgroundThe link between air pollution and increased risk of psychiatric disorders has been growing in evidence. However, the causal relationship between air pollution and psychiatric disorders remains poorly understood. MethodsSingle-nucleotide polymorphisms associated with air pollutants (including NOx, NO2, PM2.5, PM2.5–10, and PM10) from the UK Biobank were used as instrumental variables. Summary-level data for psychiatric disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, and obsessive-compulsive disorder) were procured from the Psychiatric Genomics Consortium and FinnGen consortium. Two-sample Mendelian randomization (MR) analysis was conducted to analyze the causal associations. ResultsThe MR analysis revealed significant associations between certain air pollutants and specific types of psychiatric disorders. The inverse-variance weighted model of preliminary analysis indicated that genetically predicted NO2 was associated with increased risks of major depressive disorder (odds ratio [OR]: 1.13, 95 % confidence intervals [CI]: 1.00–1.28, P = 0.041), bipolar disorder (OR: 1.26, 95 % CI: 1.00–1.58, P = 0.0497), schizophrenia (OR: 1.57, 95 % CI: 1.23–2.00, P < 0.001), attention deficit hyperactivity disorder (OR: 1.61, 95 % CI: 1.25–2.09, P < 0.001) and autism spectrum disorder (OR: 1.39, 95 % CI: 1.01–1.91, P = 0.044). Genetically predicted PM2.5 showed a positive association with the risk of major depressive disorder (OR: 1.21, 95 % CI: 1.06–1.39, P = 0.006), bipolar disorder (OR: 1.32, 95 % CI: 1.03–1.69, P = 0.030) and attention deficit hyperactivity disorder (OR: 1.57, 95 % CI: 1.16–2.12, P = 0.004). In addition, our results also indicated that NOx (OR: 1.64, 95 % CI: 1.21–2.21, P = 0.0012) and PM10 (OR: 1.70, 95 % CI: 1.23–2.36, P = 0.0014) could increase the risk of attention deficit hyperactivity disorder. ConclusionsThe MR analysis provides evidence for the causality of different air pollutants on specific psychiatric disorders, underscoring the importance of mitigating air pollution to reduce the risk of psychiatric disorders.

Prefrontal cortex astrocytes in major depressive disorder: exploring pathogenic mechanisms and potential therapeutic targets.

Major depressive disorder (MDD) is a prevalent mental health condition characterized by persistent feelings of sadness and hopelessness, affecting millions globally. The precise molecular mechanisms underlying MDD remain elusive, necessitating comprehensive investigations. Our study integrates transcriptomic analysis, functional assays, and computational modeling to explore the molecular landscape of MDD, focusing on the DLPFC. We identify key genomic alterations and co-expression modules associated with MDD, highlighting potential therapeutic targets. Functional enrichment and protein-protein interaction analyses emphasize the role of astrocytes in MDD progression. Machine learning is employed to develop a predictive model for MDD risk assessment. Single-cell and spatial transcriptomic analyses provide insights into cell type-specific expression patterns, particularly regarding astrocytes. We have identified significant genomic alterations and co-expression modules associated with MDD in the DLPFC. Key genes involved in neuroactive ligand-receptor interaction pathways, notably in astrocytes, have been highlighted. Additionally, we developed a predictive model for MDD risk assessment based on selected key genes. Single-cell and spatial transcriptomic analyses underscored the role of astrocytes in MDD. Virtual screening of compounds targeting GPR37L1, KCNJ10, and PPP1R3C proteins has identified potential therapeutic candidates. In summary, our comprehensive approach enhances the understanding of MDD's molecular underpinnings and offers promising opportunities for advancing therapeutic interventions, ultimately aiming to alleviate the burden of this debilitating mental health condition. KEY MESSAGES: Our investigation furnishes insightful revelations concerning the dysregulation of astrocyte-associated processes in MDD. We have pinpointed specific genes, namely KCNJ10, PPP1R3C, and GPR37L1, as potential candidates warranting further exploration and therapeutic intervention. We incorporate a virtual screening of small molecule compounds targeting KCNJ10, PPP1R3C, and GPR37L1, presenting a promising trajectory for drug discovery in MDD.

Interactive effect of air pollution and genetic risk of depression on processing speed by resting-state functional connectivity of occipitoparietal network

BackgroundAir pollution, a reversible environmental factor, was significantly associated with the cognitive domains that are impaired in major depressive disorder (MDD), notably processing speed. Limited evidence explores the interactive effect of air pollution and the genetic risk of depression on cognition. This cross-sectional study aims to extend the research by specifically examining how this interaction influences depression-related cognitive impairment and resting-state brain function.MethodsEligible participants were 497 healthy adult volunteers (48.7% males, mean age 24.5) living in Beijing for at least 1 year and exposed to relatively high air pollution from the local community controlling for socioeconomic and genomic. Six months’ ambient air pollution exposures were assessed based on residential addresses using monthly averages of fine particulate matter with a diameter of less than or equal to 2.5 μm (PM2.5). A cross-sectional analysis was conducted using functional magnetic resonance imaging (fMRI) and cognitive performance assessments. The polygenic risk score (PRS) of MDD was used to estimate genetic susceptibility.ResultsUsing a general linear model and partial least square regression, we observed a negative association between resting-state local connectivity in precuneus and PRS-by-PM2.5 interactive effect (PFWE = 0.028), indicating that PM2.5 exposure reduced the spontaneous activity in precuneus in individuals at high genetic risk for MDD. DNA methylation and gene expression of the SLC30A3 gene, responsible for maintaining zinc-glutamate homeostasis, was suggestively associated with this local connectivity. For the global functional connectivity, the polygenic risk for MDD augmented the neural impact of PM2.5 exposure, especially in the frontal-parietal and frontal-limbic regions of the default mode network (PFDR < 0.05). In those genetically predisposed to MDD, increased PM2.5 exposure positively correlated with resting-state functional connectivity between the left angular gyrus and left cuneus gyrus. This connectivity was negatively associated with processing speed.ConclusionsOur cross-sectional study suggests that air pollution may be associated with an increased likelihood of cognitive impairment in individuals genetically predisposed to depression, potentially through alterations in the resting-state function of the occipitoparietal and default mode network.

Testing the causal relationship of fat and sugar intake with depression and cortisol: a Mendelian Randomisation study

Unhealthy diets high in fat and sugar content may have an impact on psychological health and increase the risk of Major Depressive Disorder (MDD) and stress levels. On the other hand, MDD and stress might be related to food choices and intake. However, it is not clear whether diet, and specifically fat and sugar intake, is causally related to stress and MDD, and whether this relationship may be bi-directional. This study utilised Mendelian Randomisation (MR) to investigate the causal nature of the relationship of fat and sugar intake with MDD and cortisol (as a proxy of stress), and to shed light on the direction of this relationship. Summary-level data for all exposure and outcome variables were obtained from large-scale, non-overlapping GWASs in individuals of European ancestry. Bidirectional analyses were performed: one with macronutrients as exposures and one with MDD/cortisol as exposures. Random-effects inverse-variance weighted regression was used as the primary analytic method for genetic instruments with at least two single nucleotide polymorphisms (SNPs) available (and individual Wald ratio was used when only one SNP was available). Higher levels of genetically predicted relative sugar intake were causally associated with lower MDD risk, for both genome-wide significant p-value threshold of p < 1 × 10−8, (OR = 0.553, 95% CI: 0.395-0.775) and relaxed p-value threshold of p < 1 × 10−6 (OR = 0.786, 95% CI: 0.630–0.981). No reverse causality was detected in the opposite direction as MDD was not associated with sugar consumption. The associations observed for all the other pairs of variables were weak and imprecise. A number of limitations was present in the study, such as low-SNP based heritability for some exposures, inability to prove whether variants were correlated with unmeasured confounders and self-reporting of MDD data. Lifestyle and/or pharmacological interventions targeting sugar-related physiological mechanisms may help to reduce depressive symptoms. However, more research is necessary on short- and long-term effects of sugar on the risk of MDD. Additionally, future studies should investigate whether the amount and type of sugar consumed may underlie the impact of sugar on mood and stress levels.

Associations of Polygenic Risk for Depression, Traditional Chinese Medicine Constitution, and Depression: A Population-Based Study in Taiwan.

To comprehensively investigate the risk factors associated with depression, traditional Chinese medicine constitution (TCMC) has been found to be related to depression. However, the underlying mechanism remains unclear. This study examined the association between the concept of unbalanced TCMCs and major depressive disorder (MDD), investigated the overlapping polygenic risks between unbalanced TCMC and MDD, and performed a mediation test to establish potential pathways. In total, 11,030 individuals were recruited from the Taiwan Biobank, and the polygenic risk score (PRS) for MDD for each participant was calculated using the data from the Psychiatric Genomics Consortium. Unbalanced TCMC were classified as yang-deficiency, yin-deficiency, and stasis. The MDD PRS was associated with yang-deficiency odds ratio [OR] per standard deviation increase in standardized (PRS = 1.07, p = 0.0080), yin-deficiency (OR = 1.07, p = 0.0030), and stasis constitution (OR = 1.06, p = 0.0331). Yang-deficiency (OR = 2.07, p < 0.0001) and stasis constitutions (OR = 1.65, p = 0.0015) were associated with an increased risk of MDD. A higher number of unbalanced constitutions was associated with MDD (p < 0.0001). The effect of MDD PRS on MDD was partly mediated by yang-deficiency (10.21%) and stasis (8.41%) constitutions. This study provides evidence for the shared polygenic risk mechanism underlying depression and TCMC and the potential mediating role of TCMC in the polygenic liability for MDD.

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus.

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.