Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied.

A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers.

Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR = 1.29 [1.18–1.42]), diabetes (HR = 1.25 [1.13–1.38]) and chronic obstructive pulmonary disease (COPD) (HR = 1.74 [1.50–2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR = 1.45 [1.03–2.05]), diabetes (OR = 1.01 [1.01–1.02]) and COPD (OR = 1.04 [1.02–1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions.

Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged ≤55 years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

The role of loneliness and social isolation in the progression from incident type 2 diabetes mellitus (T2DM) to subsequent depression remains underexplored. Further investigation is essential to better understand how these factors influence disease progression.

This study enrolled 427,594 participants without T2DM and depression at baseline. Multistate models were employed to assess the impact of loneliness and social isolation on transitions from a healthy state to incident T2DM, then to subsequent depression, and finally to death. These associations were further examined across individuals with varying glycemic statuses, including normal glucose tolerance and prediabetes.

Over a median follow-up period of 13.66 years, 14,141 incident cases of T2DM, 1,149 subsequent cases of depression, and 33,024 death events were recorded. Loneliness and social isolation were associated with elevated risks of disease progression across most transitions. For the transition from incident T2DM to subsequent depression, the loneliness group exhibited a significantly higher risk (HR = 1.802, 95% CI: 1.521–2.135) compared to the no-loneliness group. Similarly, the most isolated group had an HR of 1.390 (95% CI: 1.185–1.632) compared to the least isolated group. Additionally, participants with prediabetes faced a higher risk of developing depression following T2DM compared to those with normal glucose tolerance. Interaction analyses revealed that employment status and history of cancer modified the association between loneliness and the transition from baseline to death.

These findings underscore the importance of targeted interventions to address loneliness and social isolation, potentially reducing the risk of disease progression and mortality in individuals with T2DM.

To examine global, regional and national trends in dietary fibre and added sugar consumption and to assess their implications for non-communicable disease (NCD) prevalence.

This study used a longitudinal ecological design. Dietary fibre (1990–2018) and added sugar (1990–2020) intake data were obtained from the Global Dietary Database (GDD). Intakes were analysed across GDD regions, age groups, education levels and urbanisation status. Subsequently, mixed-effects models were used to assess the association between NCD prevalence and intakes of fibre, added sugar and the fibre-to-added-sugar ratio, adjusting for socio-demographic index (SDI), national income and urbanisation.

The GDD covers dietary intake estimates for 185 countries and territories.

Globally, median dietary fibre intake rose from 14·8 to 21·6 g/d, while added sugar intake increased from 7·7 % to 10·5 % of total energy intake. Fibre intake increased in all regions except high-income countries, where it declined from 21·5 to 16·4 g/d. In contrast, added sugar intake increased in all regions except Latin America and the Caribbean (15·6 % to 13·3 % of total energy). Intake patterns were associated with education and urbanisation levels, with higher added sugar intake observed in countries with a higher SDI (r = 0·195, P = 0·008). The association between dietary fibre-to-added-sugar ratio was not significantly associated with NCD prevalence (β = –10·15, P = 0·067).

This study highlights global disparities in dietary fibre and added sugar consumption, driven by regional, educational and urbanisation factors. These findings underscore the need for targeted interventions to improve nutrition and reduce the NCD burden.

Prior observational studies have reported conflicting results regarding whether antidepressant treatment reduces long-term dementia risk, likely due to confounding by indication and reverse causation. We aimed to investigate the association between baseline antidepressant use and incident dementia, incorporating cognitive and neuroimaging outcomes.

We conducted a prospective cohort study using UK Biobank participants free of dementia at baseline. Antidepressant use was self-reported at baseline (2006–2010). Incident dementia was identified through linked electronic health records until December 19, 2022. Cox proportional hazards models estimated hazard ratios (HRs) for all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VD), adjusting for sociodemographic, lifestyle, health-related, antidepressant indication factors, and co-medication of other anticholinergics. In subsamples, cognitive performance (n = 57,330) and structural brain imaging (n = 42,276) were examined as intermediate outcomes.

Among 461,464 participants, 33,721 (7.3%) reported baseline antidepressant use. Over a mean follow-up of 13.4 years, 7,922 (1.7%) developed incident dementia. Baseline antidepressant use was associated with higher risks of all-cause dementia (adjusted HR: 1.47, 95% CI 1.36–1.60), AD (1.53, 1.36–1.73), and VD (1.44, 1.23–1.70). Users performed worse on fluid intelligence and prospective memory tasks and showed lower total and gray matter volume, regional reductions in the hippocampal gray matter and basal nucleus, and greater white matter hyperintensity volume.

Baseline antidepressant use was linked to a higher risk of dementia, poorer cognitive performance, and adverse brain structural changes. These findings underscore the importance of judicious prescribing, regular cognitive monitoring, and consideration of non-pharmacological approaches in clinical care.

Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored.

First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes.

Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05–1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08–1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases.

Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.

Neuropsychiatric symptoms (NPSs) are prevalent in Alzheimer’s disease (AD), yet their neurobiological etiology remains elusive. We investigated relationships between NPS subsyndromes, plasma neurofilament light chain (NFL), AD-vulnerable brain atrophy, and cognition.

We included 146 participants from a Chinese cohort. NPSs were assessed using the Neuropsychiatric Inventory Questionnaire and clustered into four subsyndromes (hyperactivity, psychosis, affective, apathy), each graded by severity (none, mild, severe). Sequential mediation analyses examined whether NPSs influence cognition through NFL and atrophy. Additionally, 1534 ADNI participants were enrolled to (1) replicate mediation effects; (2) examine longitudinal relationships of NPSs with incident cognitive decline; and (3) evaluate cognitive discrimination of NPSs and NFL and onset hazards of NPS subsyndromes.

In the discovery cohort, global NPSs burden and three subsyndromes (hyperactivity, affective, apathy) were associated with elevated plasma NFL, poorer global cognition and memory, and reduced brain volumes (all P < 0.05). Sequential mediation revealed that plasma NFL and atrophy mediated the cross-sectional NPSs–cognition relationship, replicated in ADNI. Adding NPSs and NFL improved cognitive discrimination (AUC: 0.6754 to 0.8210, P < 0.001). Additionally, apathy and psychosis showed lower onset hazards than affective and hyperactivity (both P < 0.001).

Baseline NPSs were cross-sectionally associated with elevated NFL, brain atrophy, and poorer cognition. Sequential mediation models supported a pathway linking NPSs to cognition via NFL and atrophy, though longitudinal evidence did not fully confirm temporal directionality. These hypothesis-generating findings require prospective validation.

Social determinants of health (SDHs) exert a significant influence on various health outcomes and disparities. This study aimed to explore the associations between combined SDHs and mortality, as well as adverse health outcomes among adults with depression.

The research included 48,897 participants with depression from the UK Biobank and 7,771 from the US National Health and Nutrition Examination Survey (NHANES). By calculating combined SDH scores based on 14 SDHs in the UK Biobank and 9 in the US NHANES, participants were categorized into favourable, medium and unfavourable SDH groups through tertiles. Cox regression models were used to evaluate the impact of combined SDHs on mortality (all-cause, cardiovascular disease [CVD] and cancer) in both cohorts, as well as incidences of CVD, cancer and dementia in the UK Biobank.

In the fully adjusted models, compared to the favourable SDH group, the hazard ratios for all-cause mortality were 1.81 (95% CI: 1.60–2.04) in the unfavourable SDH group in the UK Biobank cohort; 1.61 (95% CI: 1.31–1.98) in the medium SDH group and 2.19 (95% CI: 1.78–2.68) in the unfavourable SDH group in the US NHANES cohort. Moreover, higher levels of unfavourable SDHs were associated with increased mortality risk from CVD and cancer. Regarding disease incidence, they were significantly linked to higher incidences of CVD and dementia but not cancer in the UK Biobank.

Combined unfavourable SDHs were associated with elevated risks of mortality and adverse health outcomes among adults with depression, which suggested that assessing the combined impact of SDHs could serve as a key strategy in preventing and managing depression, ultimately helping to reduce the burden of disease.

Excessive zinc (Zn) intake can lead to Zn toxicity, causing adverse effects in gastrointestinal system. To date, there remains no definitive consensus on the mechanisms by which Zn overload induces cell death and intestinal injury. This study was to assess the toxicity mechanism of Zn overload in intestine, with a particular concentrate on oxidative stress and energy metabolism. We first explore the effects of short- and long-term Zn imbalances on intestinal health in mice. We found that the Zn imbalances resulted in oxidative damage, and impaired ketoglutarate dehydrogenase (α-KGDH) activity, which collectively contributed to a detrimental impact on the integrity of the intestinal barrier in mice. We next determined the dynamics of oxidative stress and energy metabolism in Zn overload treatment IPEC-J2 cells. Excessive Zn activated reactive oxygen species (ROS) overproduction and the PKC-NOX oxidative stress pathway. Moreover, the increase of mitochondrial Zn2+ caused mitochondrial ROS accumulation and influenced the expressions of α-KGDH andisocitrate dehydrogenase (IDH), two pivotal rate-limiting enzymes in tricarboxylic acid (TCA) cycle. Zn overload also significantly inhibited the expressions of key nicotinamide adenine dinucleotide (NAD+) synthesis enzymes, namely NMNAT1 and NAMPT, leading to a notable decline of NAD+ and ATP. Furthermore, rescue experiments showed supplementation of NAD+ or boosting NAD+ synthesis, but not antioxidants addition, could rescue Zn toxicity. The collective findings suggest NAD+ reduction is the primary factor contributing to intestinal Zn toxicity, although ROS also plays a role. This indicates that the modulation of NAD+ synthesis may prove an effective strategy for the minimization or elimination of Zn toxicity.

Despite growing awareness of the mental health damage caused by air pollution, the epidemiologic evidence on impact of air pollutants on major mental disorders (MDs) remains limited. We aim to explore the impact of various air pollutants on the risk of major MD.

This prospective study analyzed data from 170 369 participants without depression, anxiety, bipolar disorder, and schizophrenia at baseline. The concentrations of particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5), particulate matter with aerodynamic diameter > 2.5 μm, and ≤ 10 μm (PM2.5–10), nitrogen dioxide (NO2), and nitric oxide (NO) were estimated using land-use regression models. The association between air pollutants and incident MD was investigated by Cox proportional hazard model.

During a median follow-up of 10.6 years, 9 004 participants developed MD. Exposure to air pollution in the highest quartile significantly increased the risk of MD compared with the lowest quartile: PM2.5 (hazard ratio [HR]: 1.16, 95% CI: 1.09–1.23), NO2 (HR: 1.12, 95% CI: 1.05–1.19), and NO (HR: 1.10, 95% CI: 1.03–1.17). Subgroup analysis showed that participants with lower income were more likely to experience MD when exposed to air pollution. We also observed joint effects of socioeconomic status or genetic risk with air pollution on the MD risk. For instance, the HR of individuals with the highest genetic risk and highest quartiles of PM2.5 was 1.63 (95% CI: 1.46–1.81) compared to those with the lowest genetic risk and lowest quartiles of PM2.5.

Our findings highlight the importance of air pollution control in alleviating the burden of MD.

Depression is a significant mental health concern affecting the overall well-being of adolescents and young adults. Recently, the prevalence of depression has increased among young people. Nonetheless, there is little research delving into the longitudinal epidemiology of adolescent depression over time.

To investigate the longitudinal epidemiology of depression among adolescents and young adults aged 10–24 years.

Our research focused on young people (aged 10–24 years) with depression, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. We explored the age-standardised prevalence, incidence and disability-adjusted life-years (DALYs) of depression in different groups, including various regions, ages, genders and sociodemographic indices, from 1990 to 2019.

The prevalence, incidence and DALYs of depression in young people increased globally between 1990 and 2019. Regionally, higher-income regions like High-Income North America and Australasia recorded rising age-standardised prevalence and incidence rates, whereas low- or middle-income regions mostly saw reductions. Nationally, countries such as Greenland, the USA and Palestine reported the highest age-standardised prevalence and incidence rates in 2019, whereas Qatar witnessed the largest growth over time. The burden disproportionately affected females across age groups and world regions. The most prominent age effect on incidence and prevalence rates was in those aged 20–24 years. The depression burden showed an unfavourable trend in younger cohorts born after 1980, with females reporting a higher cohort risk than males.

Between 1990 and 2019, the general pattern of depression among adolescents varied according to age, gender, time period and generational cohort, across regions and nations.