Chronic stress and stress-related mental illnesses such as major depressive disorder (MDD) constitute some of the leading causes of disability worldwide with a higher prevalence in women compared to men. However, preclinical research into stress and MDD is heavily biased toward using male animals only. Aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to the development of MDD and several animal models of MDD have been established based on HPA axis dysregulation. In the present study, we compared stress biomarkers and behavior of male and female mice after acute and chronic restraint stress to investigate potential effects of sex differences in the stress response. Further, the validity of the interrupted repeated restraint stress (IRRS) model as an animal model for the HPA axis disturbances seen in MDD was assessed. After acute stress, female mice showed increased corticosterone secretion and changes in molecular markers suggesting increased HPA axis feedback sensitivity. Acute stress-induced signs of anxiety-like behavior were observed in male mice only suggesting that female mice may be more resilient to the anxiogenic effects of acute stress. Males and females responded similarly to IRRS with no sustained perturbations in HPA axis biomarkers. The IRRS model did not adequately translate to the changes reported in MDD with HPA axis overactivity and more severe perturbation models are likely needed. However, in alignment with previous studies, these data support that there are important sex differences in the HPA axis and that these may contribute to the etiology of stress-related psychiatric disorders.

Dyadic coping interventions alleviate emotional problems in patients and families with a variety of chronic illnesses. Current coping research on depression focuses mainly on the individual level. This study examined the experiences of people with depression and their spouses, using a dyadic coping perspective to support the implementation of a targeted dyadic intervention.

Semi-structured, in-depth interviews were conducted with patients with depression and their spouses. The data were organized and analysed using Colaizzi's seven-step method.

The experiences of individuals with depression and their spouses were categorized into four themes and 12 subthemes: delays in medical care (delays in medical decision-making, delays in in-hospital care), spousal maladjustment (perceived stress of the illness, role conflict, negative emotions), coexistence of positive and negative dyadic coping strategies (shared coping, positive communication, emotional support, negative communication, overprotectiveness), and confusion and needs (fear of illness prognosis, desire for continuity of care).

Healthcare professionals should promote positive dyadic coping among individuals with depression and their spouses while caring for depressive illnesses. They should strengthen individuals' knowledge of the disease, attend to spouses' physical and mental health, explore couple-centred dyadic intervention strategies, and improve continuity in the healthcare system.

The study was designed to fully map and display the hierarchy of depressive symptomology among first-episode and recurrent major depressive disorder (MDD) patients.

This cross-sectional study included 3249 MDD patients from the National Survey on Symptomatology of Depression (NSSD). The prevalences of 64 sets of depressive symptoms in first-episode and recurrent MMD were fully described and compared. Logistic regression and random forest models were used to assess the relative importance of the symptoms in distinguishing first-episode MDD from recurrent MDD.

The prevalences of the total 64 sets of the symptoms ranged from 5.7 % to 80.0 %, and depressed mood (80.0 %), pleasure loss (76.0 %), interest loss (72.0 %), low energy (72.0 %), later insomnia (65.0 %) were the top 5 symptoms. 24 symptoms that had a significantly higher prevalence in recurrent MDD patients than those of first-episode MDD patients were identified, especially memory loss (59.0 % vs. 49 %, p < 0.001), suicide history (17.9 % vs. 8.9 %), sense of decreased ability (69.7 % vs. 60.8 %, p < 0.001). The results from logistic regression and random forest analyses consistently indicated that the differences in the prevalences of suicidal behavior, memory loss, and late insomnia may be the most important distinguishing characteristics between first-episode and recurrent MDD.

The findings may help develop screening tools for MDD in clinics and provide clues for further mechanistic studies for the recurrence of MDD.

Because of the study's cross-sectional design, causal conclusions could not be drawn between the differences in the prevalences of symptoms and recurrence of MDD.

Active information gathering is a fundamental cognitive process that enables organisms to navigate uncertainty and make adaptive decisions. Here we synthesise current knowledge on the behavioural, neural, and computational mechanisms underlying information sampling in healthy people and across several brain disorders. The role of cortical and subcortical regions spanning limbic, insular, fronto-parietal, and striatal systems is considered, along with the contributions of key neurotransmitters involving norepinephrine, dopamine, and serotonin. We also examine how various clinical conditions, including schizophrenia, obsessive-compulsive disorder, and Parkinson's disease have an impact on information gathering behaviours. To account for the findings, we outline a neuroeconomic perspective on how the brain may evaluate the costs and benefits of acquiring information to resolve uncertainty. This work highlights how active information gathering is a crucial brain process for adaptive behaviour in healthy individuals and how its breakdown is relevant to several psychiatric and neurological conditions. The findings have important implications for developing novel computational assays as well as targeted interventions in brain disorders.

The mechanisms connecting childhood socioeconomic status (SES) to later-life depression remain underexplored. This study aims to examine the mediating roles of education level and subjective social status (SSS) between childhood SES and later-life depression among middle-aged and older adults in China, with a focus on potential gender differences.

5485 individuals aged 45 years and older from the 2022 China Family Panel Study were selected for analysis. Depression was assessed via the short form of the Center for Epidemiological Studies Depression Scale. Childhood SES was derived through principal component analysis. The bootstrap program was used to test the chained mediation effects.

The average depression score among the participants was 6.00 ± 4.365. Childhood SES, education level, and subjective social status were negatively associated with depression (P < 0.05). The chain mediation effect was significant for all participants, with education level exhibiting a 2.4 times stronger mediating effect in women than in men. Additionally, a negative correlation was observed between participants' education level and their present SSS (P < 0.05), which contributed to a positive chain-mediated effect that links childhood SES to depression (Effect = 0.011, 95%CI = 0.006 to 0.016).

Retrospective self-reported data and a cross-sectional design.

Poorer childhood SES was associated with an increased risk of later-life depression in middle-aged and older adults, and this relationship can be partially explained by education level and subjective social status. Attention should be given to those with poor childhood SES to improve their subjective perception of social status along with educational attainment.

Insulin resistance (IR) and depression are increasingly recognized as interconnected conditions in aging, potentially linked through chronic low-grade inflammation ("inflammaging"). The triglyceride-glucose (TyG) index has emerged as a validated surrogate marker of IR, yet its relationship with inflammatory biomarkers and depressive symptoms in older adults remains underexplored.

This study investigated the association between the TyG index, depressive symptoms, and circulating inflammatory molecules in cognitively healthy older adults, with emphasis on sex-specific differences and the potential mediating role of vascular endothelial growth factor (VEGF).

In this retrospective study, 118 non-diabetic older adults (mean age 74.1 years; 52.5 % men) with preserved cognition (MMSE ≥27) were assessed. Depressive symptoms were measured using the Geriatric Depression Scale (GDS), while cytokines and growth factors were quantified via multiplex immunoassay. The TyG index was calculated from fasting glucose and triglyceride levels. Multiple linear regression models controlled for age, sex, BMI, and medication use.

Depressive symptoms (GDS ≥5) were present in 31.35 % of participants. Those with depression had lower levels of anti-inflammatory cytokines and elevated levels of VEGF and MCP-1. TyG index correlated with both GDS scores (r = 0.239, p = 0.017) and VEGF (r = 0.271, p = 0.005), with significant associations observed only in women. VEGF emerged as a key mediator in the TyG-depression link in women (R2 = 0.425).

These findings suggest a sex-specific metabolic-inflammatory signature in late-life depression. VEGF may serve as a mechanistic link between IR and depressive symptoms in older women, supporting sex-tailored interventions.

Mitochondria dysfunction plays a pivotal role in major depressive disorder (MDD), but the causal link between mitochondria dysfunction and MDD remains unclear.

This study aimed to explore the causal effects of mitochondrial-related genes (MRGs) on MDD by integrating multi-omics data.

Summary statistics of DNA methylation, gene expression, and protein for MRGs were obtained from the corresponding quantitative trait loci in European ancestry individuals. GWAS summary statistics for MDD were sourced from the Psychiatric Genomics Consortium (PGC, discovery) and FinnGen R10 study (replication). Summary-data-based Mendelian Randomization (SMR) was performed to assess the association between DNA methylation, gene expression, and protein abundances of MRGs with the risk of MDD. Colocalization analysis was employed to assess the potential shared genetic variants between MRGs and MDD. Two-sample MR was conducted to assess the sensitivity of the SMR results. Single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-seq data were used to explore the candidate MRG expression.

We identified methylation levels of PPTC7 (cg08752433) and methylation levels of VRS2 (cg07945879, cg14935711, cg00244776, cg15848685, cg12457901, cg16958594) associated with a decreased risk of MDD. Conversely, the methylation levels of VRS2 (cg26784891, cg05853013, cg04966294) and MRPL46 (cg00200755) were associated with increased risk of MDD. High expression of COQ8A and TRMT10C were associated with an increased risk of MDD. Notably, COQ8A was predominantly expressed in both inhibitory and excitatory neurons in MDD patients.

This study established a causal relationship between mitochondrial dysfunction and MDD, identifying candidate MRGs, and providing potential diagnostic and therapeutic targets for MDD.

Depression, prevalent globally, significantly impacts psychological and physical health. As a burgeoning biomarker, C-reactive protein-to-albumin ratio (CAR) offers insights into metabolism-immune status and disease diagnosis. This exploratory investigation seeks to elucidate the relationship between CAR and depression.

This cross-sectional investigation utilized data from the National Health and Nutrition Examination Survey (NHANES). Depression was assessed using the PHQ-9 questionnaire. To examine the relationship between CAR and depression risk, we employed a multivariable logistic regression analysis and a restricted cubic spline (RCS) approach. Furthermore, subgroup analyses were performed to validate the consistency of the findings across specific populations.

This investigation enrolled 13,159 adult participants, comprising 8.15 % with depression. Compared with participants without depression, those diagnosed with depression showed a significantly higher CAR level. Each one - unit increase in log10-transformed CAR (log-CAR) was associated with an 58 % increase in the incidence of depression (Odds Ratio = 1.58, 95 % Confidence Interval: 1.33-1.88). A non-linear dose-response relationship was detected between CAR and depression risk (non-linear p < 0.001). Furthermore, the strength of this association persisted undiminished throughout multiple subgroup analyses. Notably, among individuals with a prior history of metabolic diseases, the observed association remained consistent.

A distinct positive correlation was observed between CAR and depression in U.S. adults. Further large-scale, well-controlled studies are needed to validate the reliability and establish the generalizability of these findings.

Depressive disorders are a main cause of disability already in children and adolescents, in whom the clinical picture somewhat differs from adult-onset depression. Depression is also a frequent comorbidity in somatic and mental disorders and has been considered an actionable outcome for, for example, patients at clinical high-risk for psychoses (CHRP). Thus, we studied sociodemographic and clinical predictors of depression/dysthymia in an underage sample with focus on those considered at CHRP. Our baseline sample (N = 676) included CHR-P patients (n = 183), inpatients admitted for non-psychotic, non-affective disorders (n = 277), and community participants (n = 216) of age 8.0-17.9 years (43.8 % male). They were interviewed for mental disorders and symptoms with various instruments, including the Mini International Neuropsychiatric Interview for Children and Adolescents, which was also used to assess depression/dysthymia in the CHR-P group at one- and two-year-follow up (n = 117/73). Stepwise logistic regression analyses were used to first identify a cross-sectional baseline model in the complete sample that was then tested prospectively in CHR-P patients. The baseline model included nationality and 13 clinical variables, particularly mild depressive symptoms. Variables contributing significantly to the prediction of persistence or new occurrence of depression/dysthymia varied over time, indicating that depression/dysthymia in CHR-P minors may require different predictors depending on the follow-up time. Furthermore, the prospective accuracy of ruling out depression/dysthymia was superior to the accuracy of ruling it in. This lower positive likelihood ratio might be overcome in future by stepwise approaches that further stratify risk in those CHR-P minors identified as at increased risk of depression/dysthymia.

Previous studies indicated that the notion that 20-40 % of patients with major depressive disorder (MDD) have cognitive impairments (CI). The mechanism of cognitive deficits in MDD is largely unknown. Recent evidence suggests that metabolic changes may be associated with poorer cognitive outcomes in MDD.

We recruited 105 right-handed, untreated youth with MDD patients, and 68 demographically matched healthy controls (HCs), and underwent the MATRICS Consensus Cognitive Battery (MCCB) assessment and proton magnetic resonance spectroscopy (1H-MRS) scan in the anterior cingulate gyrus (ACC) and putamen. Differential and association analysis was performed to investigate the relationship between cognitive performance and neurometabolism ratios of ACC and putamen in MDD groups.

Thirty-nine patients defined as CI group (>1.5 SD below the normal mean of MCCB in two or more MCCB domains) and 67 patients for NCI (without CI) group. The CI group exhibited significantly higher Cho/Cr ratios in the right ACC when compared to the NCI group and HCs groups. Both CI and NCI groups showed significantly higher Cho/Cr ratios in the left putamen compared to the HCs. Meanwhile, the number of episodes were positively correlated with the Cho/Cr ratios in the left putamen (r = 0.35, p = 0.035) in CI group.

Our findings suggest that both CI and NCI MDD may experience putamen dysfunction. Additionally, the frequency of depressive episodes appears to have a cumulative effect on alterations in the Cho/Cr ratios in the putamen. Concurrently, an increased Cho/Cr ratio in the ACC is linked to widespread cognitive deficits in MDD patients. These results may point to a subgroup of patients who could benefit from interventions aimed at modulating brain functional status.

Simultaneously modulating the glutamatergic and monoaminergic systems represents a promising strategy for treating depression. In this study, a series of multi-target antagonists targeting both NMDAR and monoamine transporters (SERT, DAT, and NET) was designed and evaluated for their antidepressant potential in vitro and in vivo. Among these heterocycle-fused phenylcyclohexylamine derivatives, compound A16 demonstrated potent and relatively balanced multi-target activity (A16: IC50(NMDAR): IC50(SERT): IC50(DAT): IC50(NET) = 1.8:1.0:1.9:1.3) compared to the lead compound S1. Pharmacokinetic studies revealed that A16 exhibited moderate clearance in microsomes and favorable oral brain exposure in mice. In vivo assessments showed that A16 and its R-isomer A17 exhibited significant antidepressant-like effects in the forced swim test and tail suspension test in mice. Notably, A17 demonstrated significant antidepressant-like effects at doses as low as 1 mg/kg, with no indication of addiction risk at 20 mg/kg. Collectively, these findings identify A17, a heterocycle-fused phenylcyclohexylamine as a promising scaffold for developing non-addictive, rapid-acting antidepressants.

Adverse experiences are critical determinants of late-life depressive symptomatology. Understanding how these experiences influence later-life health outcomes remains a research priority. This study examines the longitudinal associations between self-reported adverse childhood experiences (ACEs) and adverse adult experiences (AAEs) with depressive symptoms in older adults, as well as the underlying mechanisms.

A sample of 3941 adults aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS) was analyzed. K-means for Longitudinal Data (KML), Logistic regression, and Bayesian Kernel Machine Regression (BKMR) models were employed to assess the effects of adverse experiences. Subgroup and mediation analyses were also performed.

The high depressive symptomatology cluster (n = 1432) demonstrated significant associations with six ACEs: childhood hunger (OR = 1.23, 95%CI:1.03-1.47), dangerous growth environments (OR = 1.34, 95%CI:1.09-1.65), childhood loneliness (OR = 1.45, 95%CI:1.20-1.74), bullying (OR = 1.2, 95%CI:1.01-1.43), parental depression (OR = 1.80, 95%CI:1.50-2.16), and parental disability (OR = 1.44, 95%CI:1.03-2.02). Comprehensive effect estimation of ACEs indicated an 85.9% probability of a high depression score for those with all adverse experiences. AAEs like prolonged bed rest (OR = 1.39, 95%CI:1.08-1.79), and lifetime discrimination (OR = 1.37, 95%CI:1.12-1.66) independently predicted symptom severity. Effect modification analysis revealed stronger ACE impacts among individuals with higher cognitive reserve (OR = 3.32, 95%CI:2.34-4.70). Mediation analysis identified arthritis or rheumatism as a partial mediator of the ACE-depression pathway (natural indirect effect = 1.04, 95%CI:1.02-1.05).

Self-reported ACEs and AAEs demonstrate persistent associations with depressive symptoms in later life, mediated by chronic morbidity and moderated by cognitive reserve.

Dextromethorphan/bupropion (D/B) is an innovative pharmacological treatment for major depressive disorder. Nevertheless, the current evidence regarding the safety profile of D/B is predominantly derived from clinical trials, thus hindering the timely updating of adverse event (AE) data for this medication. Therefore, this study conducted data mining and analysis of AE signals (especially for suicide/self-injury) associated with D/B using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

This study used the disproportionality method to systematically evaluate the associations between D/B and potential AEs and compared these AEs with AEs related to bupropion and esketamine by using data from the FAERS collected between the third quarter of 2022 and the second quarter of 2024.

A total of 2451 AE reports identifying D/B as the "primary suspect" were collected. From these reports, 81 preferred terms and 24 system organ classifications were identified, with a predominant focus on psychiatric disorders (22.07%) and nervous system disorders (18.77%). These AEs were mostly found in individuals aged 18-44 years. The median time to onset for D/B-related AEs was determined to be 2 days. Nearly 20 novel AEs identified during the labelling process were detected, such as a sensation of inebriation and panic attacks. Importantly, the risk signals for suicide/self-injury associated with D/B were significantly lower than those associated with bupropion and esketamine. However, these signals cannot be ignored in view of their serious consequences.

Psychiatric and nervous system disorders, such as suicidal/self-injurious behaviours, require careful monitoring in clinical applications. It is imperative to conduct traditional pharmacoepidemiological research to evaluate whether D/B is linked to an increased risk of dissociative disorders in the future. Moreover, health care professionals should remain vigilant for AE signals not listed in package inserts.

Major depressive disorder is one of the most common psychiatric disorders, and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in depression. Dorsal raphe nucleus (DRN), as the main origin of producing serotonin in the brain, is an important functional brain region in depressive disorders. However, the relationship between NLRP3 in the DRN and depression has not been clarified in previous studies. So, we focus on demonstrating the role of NLRP3 expressed in DRN in depression. In this study, the male C57BL/6 J mice were exposed to chronic unpredictable mild stimulation and the expression and cellular localization of NLRP3 in DRN were analyzed. Subsequently, the mice were treated with the NLRP3 inhibitor MCC950 to inhibit NLRP3 inflammasome, and the expression of NLRP3 was knocked down in certain cells within the DRN of NLRP3fl/fl mice to investigate the role of NLRP3 in regulating depressive phenotype. Compared with the control group, the expression of NLRP3 in DRN of CUMS group was significantly increased, especially in the microglia and neuron. Furthermore, treatment with the NLRP3 inhibitor induced a significant antidepressant effect, and the depressive phenotype of NLRP3fl/fl mice was rescued after knocking down NLRP3 in the microglia or neuron. In addition, the expression levels of related molecules in the NLRP3 inflammasome pathway were significantly higher in the CUMS group compared to the control group. These results illustrated that NLRP3 played an important role in regulating depressive phenotype in DRN, and suggested a new therapy target for depression.

Young people with depression experience loneliness and internalized stigma. Stigma might make disclosing depression to others difficult, thus increasing loneliness and reducing the opportunity for treatment. Knowing whether internalized stigma predicts loneliness and secrecy reinforces the need for stigma reduction efforts. The aim of this research was to examine the independent effects of internalized stigma and clinical depression on loneliness and mental health secrecy in young people with a range of depressive symptoms (Mood and Feelings Questionnaire score ≥ 27). A total of 275 young people (Mage = 20.53, SD = 2.17) were recruited and completed the Internalized Stigma of Mental Illness Inventory, the 5-Item Link's Secrecy Scale, and the UCLA Loneliness Scale at baseline and again at 1-month follow-up (N = 172, Mage = 20.40, SD = 2.00). Results showed that internalized stigma was associated with baseline loneliness (β = 0.57, 95% CI: 7.87-11.75, p < 0.001), baseline secrecy (β = 0.40, 95% CI: 0.23-0.45, p < 0.001), and secrecy over time (β = 0.20, 95% CI: 0.04-0.30, p = 0.009). This work highlights the need to develop targeted interventions to reduce stigma and encourage mental health disclosure and help-seeking behaviors among young people with depression.

To examine the association between different insomnia symptom trajectories and subsequent depressive symptoms, as well as the reverse.

This was a secondary analysis of a population-based study on the natural course of insomnia in Canada, and 3030 participants (18-94 years) with valid data were included. Two separate analyses were conducted for the distinct objectives of the current study, which required different samples. Participants who exhibited the designated outcomes at baseline were excluded from each analysis. Growth mixture modeling was used to identify insomnia and depressive symptom trajectories over five years, measured by Insomnia Severity Index (ISI) and Beck Depression Inventory-II (BDI-II), respectively. Cases with clinically significant depressive symptoms at follow-ups were defined as reporting at least moderate depressive symptoms (BDI-II ≥ 20) and one core symptom of depression, while insomnia disorder at follow-ups was identified according to a validated algorithm using a combination of criteria from DSM-4 and ICSD-3 and self-reported use of sleep medication.

Five insomnia symptom trajectories were identified over five years: stable good sleepers (24 %), stable low insomnia severity (35 %), gradual improvements in symptoms (6 %), persistent insomnia symptoms (31 %), and progressive worsening of symptoms (5 %). Compared with good sleepers, the other insomnia trajectory groups all had higher risks of clinically significant depressive symptoms at follow-ups, especially those with progressive symptoms (harzad ratio [HR]: 19.77 [10.30 to 37.93]). In a parallel analysis, four depression trajectories emerged: noncases (49 %), stable low depressive severity (38 %), moderate symptoms improving over time (7 %), and progressive worsening of symptoms (6 %). Compared with noncases, the other depression trajectory groups all showed elevated risks of insomnia disorder, especially those with progressive worsening of symptoms (HR: 6.85 [5.26 to 8.93]).

Our findings support a close relationship between insomnia and depressive symptoms, especially when both symptoms become progressive or persistent.

Depression is recognized as a chronic mental illness, also influenced by neurotransmitter homeostasis, with its incidence increasing annually worldwide. This condition inflicts significant physical and psychological harm, severely compromising human health. It exhibits a broad morbidity spectrum, and some current treatments and medications are hindered by short-term efficacy, strong side effects, and other limitations.

Due to the limitations, it is imperative to explore new treatment approaches and develop targeted drugs. Ferroptosis, a cell death mode dependent on iron, is believed to be intricately linked to the onset of depression. Thus, modulating cellular ferroptosis presents a promising avenue for the targeted therapy of depression.

We conducted a comprehensive search of databases such as PubMed, Elsevier ScienceDirect, Google Scholar, and CNKI, using keywords such as "ferroptosis", "depression", "iron death", "safety", "efficacy", and "effectiveness". Our review included original scientific articles, clinical trials, meta-analyses, and review papers published up to February 2025, focusing on studies excluding non-natural products.

Several natural products derived from plant, animal, or microbial sources effectively target ferroptosis, alleviating depressive symptoms and demonstrating unique and favorable outcomes. This review provides an exhaustive overview of the sources, pharmacological actions, mechanisms, efficacy, and safety of these natural products, highlighting their potential clinical benefits and offering a comprehensive perspective on their properties.

This study offers concrete ideas and valuable insights for the development and application of these natural products in the targeted treatment of depression.

We previously identified seven distinct multimorbidity clusters associated with major depressive disorder through a comprehensive analysis of 1.2 million individuals of multiple cohorts. These clusters, characterized by unique clinical, genetic, and psychiatric and somatic illness risk profiles, implicate divergent treatment pathways and disease management strategies. This study aims to deepen the understanding of these clusters by analyzing drug prescriptions, evaluating the effectiveness of antidepressant treatment strategies, and identifying potential markers for personalized medicine. Utilizing drug prescription data in the format of ATC codes, we performed epidemiological assessments, including multimorbidity (number of diseases), polypharmacy (number of chemical substances), and drug burden (number of prescriptions) analyses across the clusters. We applied linear regression models to assess strength and predictive capability of cluster membership on various metrics, and logistic regression to explore associations with treatment-resistant depression. We also quantified and visualized common antidepressant treatment sequences within each cluster. Our findings indicate significant variations in polypharmacy and drug burden across clusters, with distinct patterns emerging that correlate with the clusters' profiles. Clusters liable to multimorbidity have higher drug burden, even after correction for number of diseases. Furthermore, the three clusters with higher risk for MDD showed different antidepressant treatment profiles; two required significantly more antidepressant prescriptions and had a higher risk for TRD. The detailed pharmacological profiling presented in this study not only corroborates the initial cluster definitions but also enhances our predictive capabilities for treatment outcomes in MDD. By linking pharmacological data with comorbidity profiles, we pave the way for targeted therapeutic interventions.

Our aims were to investigate the association between dietary MCFAs and depression, with a focus on potential mediating factors.

A total of 11,085 participants from NHANES were included in this study. The total intake of MCFAs, including octanoic acid (C8:0), decanoic acid (C10:0), and lauric acid (C12:0), was derived, and their respective ratios to total fatty acids were calculated as exposure. Depression was defined as a score of ≥10 on the Patient Health Questionnaire-9 (PHQ-9). Weighted logistic regression was used to analyze the relationship between MCFAs and depression. The contribution of MCFAs was assessed using weighted quartile sum (WQS). C-reactive protein (CRP) was included as a potential mediator in the analysis of underlying mechanisms.

The highest quartile (Q4) of dietary MCFAs was associated with a significantly greater likelihood of depression compared to the lowest quartile (Q1) (ORtotal MCFAs: 1.36, 95 % CI: 1.07-1.65; ORC8:0: 1.46, 95 % CI: 1.15-1.77; ORC10:0: 1.38, 95 % CI: 1.06-1.60; and ORC12:0: 1.31, 95 % CI: 1.03-1.68), but no significant associations were observed for Q2 and Q3. The WQS results indicated that C12:0 contributed the most to the association between total MCFAs and depression (weight percentage: 49.1 %). CRP partially mediated the association between the Q4 of MCFAs and depression, with a mediation proportion of 7.6 % to 9.1 %.

Excessive intake of MCFAs is associated with a higher risk of depression, particularly for C12:0, with CRP partially mediating this association.

Depression affects millions, and current treatments have limitations, necessitating new approaches. Earlier research confirms Hyperforin's ability to reduce anhedonic behaviors in mice and modulate gut microbiota. This study aims to identify specific metabolic changes induced by Hyperforin that could illuminate its impact on gut microbiome metabolism, possibly uncovering novel metabolites for developing antidepressant therapies.

Following the chronic stress model, untargeted metabolomic analysis of fecal samples was conducted to identify metabolic changes induced by Hyperforin. Bioinformatics tools analyzed the origins of differentially expressed metabolites and their correlation with Akkermansia muciniphila and Muribaculum intestinale. The significant metabolite Carbocysteine was further investigated for its antidepressant effects using behavioral assays in a mouse model of depression. Additionally, the response of the colonic mucus barrier was evaluated using Periodic Acid-Schiff (PAS) staining, scanning electron microscopy (SEM), and enzyme-linked immunosorbent assays (ELISA).

Hyperforin significantly altered fecal metabolite profiles in stressed mice, with a notable shift in 239 metabolites mainly associated with co-metabolism pathways and microbiota-specific processes. Among these, Carbocysteine emerged as a key metabolite linked to beneficial bacteria Akkermansia muciniphila and Muribaculum intestinale, with its levels significantly elevated following Hyperforin treatment. Behavioral assessments indicated that Carbocysteine supplementation ameliorated depressive-like behaviors in the chronic restraint stress mouse model. It also enhanced colonic mucus production and integrity.

Our research highlights Hyperforin's role in modulating gut microbiota metabolism and identifies Carbocysteine as a potential antidepressant. These findings advance our understanding of the gut-brain axis (GBA) in depression and pave the way for developing new therapeutics.

Many patients with major depressive disorder (MDD) experience limited treatment effectiveness due to an incomplete understanding of its neurobiological underpinnings. This review integrates neuroimaging and genetic data to examine structural and functional brain changes in MDD, alongside their genetic bases. A PRISMA-guided systematic review of imaging transcriptomics over the past decade was conducted using PubMed and Web of Science. Studies included MRI scans of both MDD patients and healthy controls, as well as brain-wide gene expression data, excluding those that were purely meta-analytical, lacked spatial correlations, or involved transdiagnostic analyses. Of the 206 studies reviewed, 20 met the inclusion criteria. Consistent patterns across studies reveal that key biological processes-such as synaptic signaling, calcium ion binding, neurodevelopment, immune regulation, and neurotransmitter transport-play a central role in brain alterations associated with MDD. Additionally, our findings suggest that electroconvulsive therapy (ECT) may alleviate symptoms by modulating these shared pathways. This review underscores the link between brain changes in MDD and specific gene expression profiles, offering insights that could inform more targeted therapeutic approaches.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent mental disorders in psychiatry, but their overlapping symptoms often complicate precise diagnoses. This study aims to explore differential brain activation patterns in healthy controls (HC), MDD, and GAD groups through functional near-infrared spectroscopy (fNIRS) during the verbal fluency task (VFT) to enhance the accuracy of clinical diagnoses.

This study recruited 30 patients with MDD, 45 patients with GAD, and 34 demographically matched HCs. Hemodynamic changes in the prefrontal cortex (PFC) and temporal lobes were measured using a 48-channel fNIRS during the VFT task. Demographics information, clinical characteristics and VFT performance were also recorded.

Compared to HCs, both MDD and GAD share a neurobiological phenotype of hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (mPFC) during VFT. Moreover, MDD patients exhibited significantly greater hypoactivation in the left DLPFC and mPFC than GAD patients.

Although both GAD and MDD patients exhibit disrupted cortical function, the impairment is less severe in GAD. These findings provide preliminary neurophysiological evidence supporting the utility of the fNIRS-VFT paradigm in differentiating GAD from MDD. This approach may complement traditional diagnostic methods, inform targeted interventions, and ultimately enhance patient outcomes.

The effect of basal metabolic rate (BMR) on depression was unclear. This study investigated the potential role of BMR in the association of polycyclic aromatic hydrocarbons (PAHs) exposure and depression.

The study based on the National Health and Nutrition Examination Survey (NHANES). BMR was calculated using both the revised Harris-Benedict equation (BMR1) and the Mifflin-St Jeor equation (BMR2). Generalized linear and logistic regression models were applied to examine the associations between PAH metabolites, BMR, and depression. Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression (BKMR) were utilized to analyze the combined effects of multiple PAH metabolites. Mediation analysis was conducted to explore the role of BMR.

The study included 8323 participants. A 100 kcal/day increase in BMR1 and BMR2, the depression risk increased by 5 % (95%CI: 1.00, 1.10) and 7 % (95%CI: 1.02, 1.13), respectively. WQS model indicated that mixed PAH metabolites were negatively associated with BMR1 (β: -0.06, P = 0.020) and BMR2 (β: -0.06, P = 0.014). BKMR models showed that when all PAH metabolites were at P75 compared to P50, BMR1 and BMR2 decreased by 20.54 and 20.31 units, respectively, while the depression risk increased by 0.23 units (95 % CI: 0.07, 0.38). Mediation analyses suggested that BMR exerted a competitive mediation effect in the association between 1-NAP, 2-FLU, 1-PHE, 1-PYR, and depression.

PAH exposure led to a reduction in BMR and contributed to depression at high levels of exposure. An increase in BMR mitigated the impact of PAH exposure on depression.

The demethylase fat mass and obesity-related associated protein (FTO) is strongly associated with depression. Aging is a risk factor for synaptic plasticity damage in the brain and leads to neurocognitive dysfunctions. FTO-dependent m6A modification plays an important role in neurodevelopment and cognitive function. However, whether FTO is associated with susceptibility to depression in different age groups remains unknown.

We subjected 3-and 12-month-old C57BL/6J male mice to chronic unpredictable mild stress (CUMS) for 6 weeks, of which 3 weeks were used for hippocampal injection of FTO knockdown adeno-associated virus 9 shRNA (FTO-KD AAV9). Finally, 36 male mice in each 3-month-old and 12-month-old groups were divided into three groups (n = 12): Sham, CUMS, and FTO-KD. After 6 weeks, we assessed behavioral deficits (depressive and anxiety-like behaviors and cognitive impairment) by behavioral tests and hippocampal neuronal damage (dendritic spine density, neuronal atrophy, and expression of proteins associated with synaptic plasticity) by molecular biochemical experiments.

The results showed that 12-month-old C57BL/6J mice were more likely to develop depression-like behavior and spatial learning and memory impairment induced by CUMS than 3-month-old mice. Chronic stress-induced depression-like behavior and cognitive impairment worsened after the FTO-KD intervention. In the hippocampus of 3- and 12-month-old mice, CUMS induced the downregulation of FTO, nerve growth factor (NGF), reelin, and synaptic plasticity-related proteins. It also caused abnormal brain-derived neurotrophic factor (BDNF)- the tropomyosin-related kinase B (TrkB) signaling, reduced density of dendritic spines, and an increased number of neuronal pyknotic nuclei, leading to neuronal disarray, which was more significant in 12-month-old animals. FTO deficiency accelerated neuronal damage in the hippocampus of 12-month-old CUMS mice.

This study provides rodent evidence that FTO deficiency may increase the susceptibility to depression in older adults by impairing hippocampal neuronal function and neuronal synaptic plasticity in an age-dependent manner. This suggests that the development of FTO activators may be an effective treatment for depression in older adults.

At present, there are no definitive biomarkers for major depressive disorder (MDD). Previous studies prompted that neuroimmunoinflammation is involved in the pathogenesis of depression and its factors become potential diagnostic biomarkers. Non-human primates exhibit depression-like behavior similar to humans in chronically stressed environments. Therefore, in the present study, after completing Whole transcriptome sequencing of peripheral blood, neurology-related and inflammatory molecules in plasma and cerebrospinal fluid were measured by Olink proximity extension assay technology simultaneously in 4 natural depressive-like (DL) cynomolgus monkeys and 4 normal controls to screen potential biological markers. Further, postmortem brain tissues and peripheral blood RNA sequencing data from MDD patients available in the Gene Expression Omnibus (GEO) database were used for cross-species validation. Compared to control monkeys, depressive-like monkeys exhibited elevated levels of neurocan (NCAN). RNA sequencing revealed Toll-like receptor 4 (TLR4) and the interacting S100 calcium-binding protein A family as key molecules in the inflammatory gene network. GEO brain tissue data showed up-regulation of S100A8 and S100A9 in the anterior cingulate cortex of MDD patients. These findings suggest that depressive-like monkeys are in a state of chronic low-grade inflammation and identify NCAN and TLR4 inflammatory network molecules as potential biomarkers of MDD.

Depression is associated with inflammation, and the uric acid to HDL-C cholesterol ratio (UHR) has emerged as a potential marker of increased inflammation; however, the association between UHR and depression is unclear. Therefore, we aimed to explore this association in a sample from the general US population.

We conducted a cross-sectional study of 11,444 participants ≥20 years of age from the 2009-2014 NHANES database. We conducted weighted multivariate logistic regression analyses and restricted cubic spline function (RCS) models exploring the association between UHR and risk of depression, as well as subgroup analyses and tests of interaction.

UHR was positively associated with depression, especially in participants who drank alcohol (interaction P < 0.05).The prevalence of depression increased by 4 % for each 1-unit increase in UHR (OR = 1.04, 95 % CI = 1.02, 1.07, P = 0.003). After dividing the UHR into quartiles compared with the lowest reference group for UHR, participants in the fourth quartile had a significantly increased risk of depression after full adjustment (OR = 1.36, 95 % CI = 1.03, 1.80, P = 0.033).There was a linear dose-response relationship between the UHR and the risk of depression (P for nonlinear = 0.744).

As this was a cross-sectional study, we could not determine a causal relationship between UHR and depression.

The UHR is positively associated with an increased prevalence of depression among adults in the U.S.

The rising prevalence of youth depression underscores the need to identify modifiable factors for prevention and intervention. This study aims to investigate the protective role of Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet on depressive symptoms in adolescents.

Participants were identified from the Adolescent Brain Cognitive Development study. Adherence to the MIND diet was measured by the Child Nutrition Assessment or the Block Kids Food Screener. Depressive symptoms were measured annually using the Child Behavior Checklist's depression subscale. We utilized regression analyses and cross-lagged panel modeling (CLPM) to examine longitudinal associations. Additional analyses adjusted for polygenic risk scores for depression, and changes in Body Mass Index (BMI) and waist-to-height ratio.

Of the 8459 children (52.3 % male; mean age 10.9 [SD, 0.6] years), 2338 (27.6 %) demonstrated high MIND diet adherence, while 2120 (25.1 %) showed low adherence. High adherence was prospectively associated with reduced depressive symptoms (adjusted β, -0.64, 95 % CI, -0.73 to -0.55; p < 0.001) and 46 % lower odds of clinically relevant depression (adjusted odds ratio, 0.54, 95 % CI, 0.39 to 0.75; p < 0.001) at two-year follow-up. CLPM analyses showed significant cross-lag paths from MIND diet scores to less depressive symptoms across three time points. These associations persisted independently of changes in BMI and waist-to-height ratios, and were not significantly moderated by genetic predisposition to depression.

Higher adherence to the MIND dietary pattern was longitudinally associated with decreased risk of depressive symptoms in adolescents. Promoting MIND diet may represent a promising strategy for depression prevention in adolescent populations.

Recent studies have linked branched-chain amino acids (BCAAs) metabolism with the risk of major depressive disorder (MDD). However, it is unclear whether associations of plasma BCAA levels with MDD are causal or driven by reverse causality.

Mendelian randomization (MR) was used to investigate the causal association of genetically determined BCAA levels with the risk of MDD. The large genome-wide association study (GWAS) datasets on plasma BCAA levels (n = 115,051) were obtained from the UK Biobank. The summary GWAS dataset for MDD was obtained from the Psychiatric Genomics Consortium (n = 1,035,760). We applied the inverse variance-weighted (IVW) method to explore the causal relationships between BCAA levels and MDD, followed by multiple pleiotropy and heterogeneity tests.

Our results demonstrated that genetically determined circulating total BCAAs (odds ratio (OR): 1.05, 95 % confidence interval (CI): 1.01-1.10, P = 0.016), leucine (OR: 1.06, 95 % CI: 1.02-1.11, P = 7.22 × 10-3), and isoleucine (OR: 1.08, 95 % CI: 1.01-1.16, P = 0.032) levels were associated with an increased risk of MDD. There was suggestive evidence supporting the causal effect of valine levels on MDD (OR: 1.04, 95 % CI: 1.00-1.08, P = 0.075). Bidirectional MR analysis did not provide evidence of reverse causality.

We report evidence supporting the causal role of BCAAs in the development of MDD. This study offers new insights into the mechanisms and treatment of MDD.

Depression and anxiety are disabling and high incidence mental disorders characterized by phenotypic heterogeneity. Currently available treatments show severe limitations. Thus, there is an urgent need for effective treatments in this population. In the search for novel rapid-acting antidepressants, the psychedelic psilocybin has emerged as a promising therapy in several clinical trials. However, its antidepressant mechanism of action is still not well understood. The aim of the present study was to evaluate the therapeutic potential of psilocybin in ameliorating the adverse behavioural and neurochemical consequences of chronic stress. To this end, a chronic unpredictable mild stress (CUMS) animal model was used, and psilocybin treatment was administered (two doses of 1 mg/kg, i.p., administered 7 days apart). Psilocybin reversed impairments in anhedonia and behavioural despair dimensions of depressive phenotype but not in apathy-related behaviour. Psilocybin administration was also able to exert an anxiolytic-like effect on treated animals. Physiological alterations caused by stress, indicative of a hyperactive hypothalamic-pituitary-adrenal axis (HPA), were not reversed by psilocybin. When neuroplasticity-related proteins were assessed in cerebral cortex, brain-derived neurotrophic factor (BDNF) was found to be decreased in stressed animals, and treatment did not reverse such impairment. Psilocybin administration increased the expression and function of serotonin-2A-receptor (5HT2AR) in brain cortex of control and CUMS groups. Furthermore, psilocybin treatment caused a selective increase in the expression of glucocorticoid-receptor (GR) in brain cortex of CUMS mice. In conclusion, psilocybin was able to rescue impairments in the depressive phenotype, and to induce anxiolytic-like effects. Furthermore, an enhancement in sensitivity to psilocybin-induced HTR was observed following a booster dose. Altogether, this work provides new knowledge on the putative benefit/risk actions of psilocybin and contributes to the understanding of the therapeutic mechanism of action of psychedelics.

Major depressive disorder (MDD) is a devastating mental disorder characterized by considerable clinical and biological heterogeneity. While comparable clinical symptoms may represent a common pathological endpoint, it is conceivable that distinct neurophysiological mechanisms underlie their manifestation. In this study, both static and model-based dynamic functional connectivity were employed as predictive variables in the normative model to map multilevel functional developmental trajectories and determined clusters of distinguishable MDD subgroups in a large multi-site resting fMRI dataset of 2428 participants (healthy controls: N = 1128; MDD: N = 1300). An independent cohort of 72 participants (healthy controls: N = 35; MDD: N = 37) with both resting fMRI and task-based fMRI data was utilized to validate the identified MDD subtypes and explore subtype-specific task-based neural representations. Our findings indicated brain-wide, interpatient heterogeneous multilevel brain functional deviations in MDD. We identified two distinct and reproducible MDD subtypes, exhibiting comparable severity of clinical symptoms but opposing patterns of multilevel functional deviations. Specifically, MDD subtype 1 displayed positive deviations in the frontoparietal and default mode networks, coupled with negative deviations in the occipital and sensorimotor networks. Conversely, MDD subtype 2 exhibited a significantly contrasting deviation pattern. Additionally, we found that these two identified MDD subtypes exhibited different neural representations during empathic processing, while the subtypes did not differ during implicit face processing. These findings underscore the neurobiological complexity of MDD and highlights the need for a multifaceted approach to diagnosis and treatment that can be tailored specifically to individual subtypes, facilitating personalized and more effective interventions for individuals with MDD.

Depression is the most prevalent psychiatric illness, and its pathogenesis is associated with neuroinflammation. Follistatinlike protein 1 (FSTL1), a novel inflammatory protein, participates in the pathogenesis of diseases related to neuroinflammation. Therefore, we aimed to investigate the effect of FSTL1 in the pathogenesis of depression mediated using neuroinflammation-mediated models. Our results showed that lipopolysaccharide (LPS) administration could induce despair-like behavior and increase proinflammatory cytokine levels in both male and female mice. Then, a significant positive correlation between hippocampal Fstl1 mRNA expression, microglial activation and desperate-like behaviors was observed in male mice. Moreover, knockdown FSTL1 significantly reduced microglial activation and the expression of proinflammatory cytokines, while overexpression of Fstl1 in hippocampus could exacerbate the activation of microglial under the LPS-induced condition in male mice. Mechanically, knockdown Fstl1 inhibited LPS-induced activation of BV2 microglia and reduced the production of proinflammatory cytokines, thereby protecting the survival of HT22 neurons. In conclusion, our results implied that Fstl1 may modulate despair-like behaviors through regulation of microglial activation and neuronal viability, which would lay the experimental and theoretical foundation for the neuroinflammatory mechanisms underlying depression.

Depression is a severe heterogeneous mental illness that is highly co-morbid with other mental and somatic disorders. It poses a significant healthcare burden on both individuals and society. Currently, the use of single-target antidepressants exhibits suboptimal efficacy with significant adverse effects. Acupuncture has been advocated as a practical and effective treatment for depression, due to its low adverse effects rate compared to antidepressant medication. Currently, several studies have shown that acupuncture treatment for depression primarily involves multiple therapeutic mechanisms, including the regulation of specific gene expression, neuropeptide and neurotransmitter release, increasing the expression of neurotrophic factors, suppressing hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, attenuating inflammatory responses, and restoring gut microbiota balance. These therapeutic effects involve the regulation of critical signaling pathways, including the cAMP-responsive element binding protein (CREB) signaling pathway, mitogen-activated protein kinases (MAPK) signaling pathway, mechanistic target of rapamycin (mTOR) signaling pathway, and toll-like receptors (TLR) signaling pathway. Notably, depression-associated molecular mechanisms and signaling pathway dysregulations are closely linked to impaired neural and synaptic plasticity. Acupuncture synergistically modulates the neuro-immune-microbiome multidimensional network and integrates crosstalk among key pathways such as CREB, thereby systemically restoring synaptic plasticity. This multi-dimensional integrative mechanism likely underlies its therapeutic superiority over single-target antidepressants. This review aims to elucidate how acupuncture restores cerebral synaptic plasticity by rectifying depression-related systemic dysfunctions and signaling pathway abnormalities, which will advance our understanding of its regulatory potential in depression treatment and inform the development of precision therapeutic strategies.

Oxidative stress, inflammation and the Keap1-Nrf2 pathway are validated to be related to depression. Theoretically, modulating Keap1 and Nrf2 protein-protein interaction (PPI) should be an effective method to activate Nrf2 for the treatment of major depressive disorders. We previously reported NXPZ-2, a 1,4-diaminonaphthalene, as a Keap1-Nrf2 PPI inhibitor that exhibited promising effects in an Alzheimer's disease (AD) mouse model. However, its pharmacokinetic properties were limited. Herein, we, for the first time, developed a series of heterocyclic substituted diaminonaphthalenes by an "Escape from Flatland" strategy to improve sp3 hybridized carbons. These compounds exhibited strong binding affinity for Keap1. A crystallographic analysis revealed the high-resolution (1.44 Å) binding of CD-10 with the Keap1 protein, elucidating the complexity of CD-10's binding mechanism. In an LPS-stimulated BV2 cell model, CD-10 demonstrated the best anti-oxidative stress and anti-inflammatory potential. Furthermore, CD-10's ability to penetrate the blood-brain barrier has been significantly improved. In a chronic unpredictable mild stress (CUMS) mouse model, treatment with CD-10 effectively alleviated anxiety and depressive behaviors and restored serum neurotransmitter levels by promoting Nrf2 nuclear translocation. Overall, our findings validate that the Keap1-Nrf2 PPI inhibitor holds promise as a preclinical candidate for the treatment of depression.

Prenatal hypoxia (PH) is a common complication of pregnancy, and it is strongly associated with psychiatric disorders such as depression and anxiety in the offspring. However, how prenatal hypoxia contributes to psychiatric disorders in the offspring is unclear. In this study, we established a model of prenatally hypoxic mice, where pregnant females were treated with hypoxia (10.5% O2) during gestational days 12.5-17.5, while controls (CON) were kept in a normoxic (21% O2) environment. Compared to CON offspring, PH male offspring exhibited depression-like behaviors. Prenatal hypoxia resulted in significantly higher protein level of the oxygen-sensitive subunit of hypoxia-inducible factor (Hif-1α) and lower levels of Ten-eleven translocated methylcytosine dioxygenase 1 (Tet1), β-catenin, and downstream Dicer1-miRNAs pathway associated with depressive behavior. Mechanistically, prenatal hypoxia leads to Hif-1α binding to Tet1, which inhibits β-catenin binding to Tet1, leading to an increase in ubiquitination-dependent degradation of β-catenin and down-regulation of the β-catenin-Dicer1-miRNAs pathway. In addition, administration of the β-catenin-specific agonist SKL2001 or overexpressing virus ameliorated the down-regulation of β-catenin-Dicer1-miRNAs signaling and depression-like behavior in PH male offspring. These findings suggest that Hif-1α and β-catenin competition for Tet1 binding is involved in depression-like behaviors in PH offspring, and this study provides important data on the molecular mechanisms by which prenatal hypoxia might be involved in adult psychiatric disorders of fetal origin.

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

A growing body of research has identified the influence of family factors on depression. This study aimed to investigate the effects of different family structures on adolescent depressive symptoms and to investigate the mediating role of adverse childhood experiences between family structure and adolescent depressive symptoms.

Stratified whole cluster sampling was used. Junior and senior high school students were randomly selected from three schools in one district each in urban and rural areas. Depressive symptoms and traumatic events were investigated through the Patient Health Questionnaire-9 (PHQ-9) questionnaire and the Adverse Childhood Experiences International Questionnaire (ACE-IQ). Adolescent family structure types were classified using latent category analysis (LCA), and mediation models were used to explore the mediating effects of adverse childhood experiences (ACEs) between family structure and depressive symptoms.

After LCA analysis, three family structure types were delineated: Nuclear Family, Paternal Grandparents Family (single father + paternal grandparents as primary caregivers), and Paternal Grandparents Family (single mother + maternal grandparents as primary caregivers). Detection rate of depressive symptoms in non-nuclear families was 27.2 %; adolescent depressive symptoms were higher in Paternal Grandparents Family compared to Nuclear Family (OR = 0.823, 95 % CI:0.037,1.610, p < 0.05); the difference in adolescent depressive symptoms in Maternal Grandparents Family was not significant (OR = -0.504, 95 % CI: -1.570,0.561). The mediating effect of emotional neglect was only present in the association between Paternal Grandparents Family and depressive symptoms in secondary school students [β(95 %CI) = 0.490 (0.153,0.845)], with a mediating effect proportion of 58.40 %.

Depressive symptoms are more prominent among secondary school students in non-nuclear families, especially Paternal Grandparents Family. Emotional neglect, which may be triggered by the absence of the mother's role, increases the risk of depressive symptoms among secondary school students.