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 sphingolipid rheostat – the interconversion between pro-apoptotic ceramide (Cer) and pro-survival sphingosine-1-phosphate (S1P) – governs female reproductive homeostasis. This review integrates mechanistic evidence across the reproductive continuum to elucidate how compartmentalised disruptions of this axis drive divergent pathologies.

A systematic search up to 2026 across PubMed and Web of Science identified molecular mechanisms and translational models linking sphingolipid signalling to ovarian ageing, polycystic ovary syndrome (PCOS), endometriosis, adenomyosis and uterine fibroids.

Pathological Cer accumulation drives mitochondrial outer membrane permeabilisation (MOMP) and cytochrome c release, accelerating follicular atresia in primary ovarian insufficiency (POI). Conversely, PCOS is associated with heterogeneous remodeling of follicular-fluid sphingolipids, compromising oocyte competence. Within uterine and peritoneal microenvironments, a hyper-activated S1P axis operating via S1PR1–3 networks acts as a core pathogenic engine. This axis exhibits a threshold-dependent dual nature: low thresholds promote homeostatic survival, whereas high thresholds drive M2 macrophage polarisation for immune evasion and cross-link with TGF-β/Smad and Activin A cascades to stimulate fibroblast-to-myofibroblast transdifferentiation (FMT) and extracellular matrix deposition in endometriosis and fibroids. Additionally, the SphK/S1P axis amplifies chronic pelvic pain by modulating nerve growth factor (NGF) and transient receptor potential vanilloid 4 channels.

The sphingolipid axis constitutes a unifying molecular rheostat in reproductive medicine. Mapping these compartmentalised lipidomic signatures enables high-resolution diagnostics, while targeted sub-receptor antagonists and non-hormonal drug repurposing offer promising, fertility-preserving therapeutic frontiers. However, successfully translating these lipid-targeted interventions into clinical practice demands addressing key bottlenecks regarding systemic off-target toxicities and engineering advanced, tissue-specific delivery platforms.

Gambling disorder (GD) poses severe impacts on both individuals and society. Impairment in risky decision-making is a key behavioral characteristic of GD, but the underlying cognitive processes of these deficits remain unclear.

This study decomposed the risky decision-making processes of GD with cognitive computational modeling.

A total of 100 participants with GD and 59 healthy controls (HCs) were recruited to complete psychometric assessments and the Balloon Analog Risk Task. Since GD involved abnormal loss evaluation in decision-making, we developed a novel cognitive model incorporating diminishing loss sensitivity and revealed the processes underlying the risk-taking behaviors with hierarchical Bayesian analysis.

GD participants exhibited stronger loss aversion (p < 0.001) but faster-diminishing loss sensitivity (p < 0.001), regardless of severity, which drove the deficits in the overall performance of risky decision-making (p < 0.001) (Fig1). Overconfident prior belief (p = 0.002) and higher updating rate (p < 0.001) were observed among participants with GD (Fig3). Diminishing loss sensitivity was negatively correlated with impulsivity (p = 0.021), and loss aversion was negatively related to craving for gambling (p = 0.027) (Fig4).Table 1.

Demographic and clinical characteristics of participants

This research provides novel perspectives on the cognitive processes underlying the risky decision-making of GD patients, highlighting the role of diminishing loss sensitivity during loss evaluation and its clinical implications, which inspires future research on assessment and psychotherapy for GD.

None Declared

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.

Two functional genetic polymorphisms, ADH1B rs1229984 and ALDH2 rs671, play key roles in ethanol metabolism and are especially prevalent in East Asian populations. The rs1229984 variant accelerates the conversion of ethanol to acetaldehyde, whereas rs671 reduces enzymatic activity for converting acetaldehyde into acetic acid. These variants affect alcohol use disorder risk and have been implicated in various systemic conditions.

To investigate the broader associations of ADH1B rs1229984 and ALDH2 rs671 with habitual alcohol use in large, unselected populations.

We analysed data from 146 374 Taiwanese adults (aged 20–90 years) enrolled in the Taiwan Biobank.

Both variants showed clear associations with habitual alcohol use. The ADH1B rs1229984 CC genotype was associated with a higher prevalence of drinking, indicating a substantial contribution to alcohol-related behaviour. The ALDH2 rs671 A allele was linked to markedly reduced drinking, reflecting known intolerance among carriers rather than implying a uniformly larger effect than ADH1B. Beyond alcohol use, rs671 showed a protective association with gout, whereas rs1229984 was not significantly associated with chronic diseases after correction.

In this large population sample, both ADH1B rs1229984 and ALDH2 rs671 demonstrate meaningful, genotype-dependent effects on habitual alcohol use. Their combined effects underscore the importance of evaluating gene–gene interactions rather than attributing disproportionate influence to a single locus.

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.

Depressive disorder (DD) is a widespread mental illness that lacks objective diagnostic biomarkers, complicating early detection and personalised treatment. This study investigated the diagnostic value of serum interferon-gamma (IFN-γ), nerve growth factor (NGF), and their ratio, alongside thyroid peroxidase antibody (TPOAb) and glial fibrillary acidic protein (GFAP), in patients with DD compared to healthy controls.

A total of 238 participants (118 with DD and 120 controls) were enrolled. Depression severity was assessed using DSM-5 and HAM-D criteria. Serum biomarkers were measured using enzyme-linked immunosorbent assays (ELISA), and receiver operating characteristic (ROC) analysis was performed to assess diagnostic performance.

DD patients exhibited significantly lower IFN-γ and higher NGF levels than controls (both p < 0.001), resulting in a markedly reduced IFN-γ/NGF ratio. The IFN-γ/NGF ratio achieved the highest diagnostic accuracy (AUC = 0.858, sensitivity = 82.20%, specificity = 77.50%), outperforming IFN-γ (AUC = 0.766) and NGF (AUC = 0.848) alone. TPOAb and GFAP levels did not differ significantly between groups.

The IFN-γ/NGF ratio is a promising biomarker for depressive disorder, offering superior diagnostic accuracy over individual immune or neurotrophic markers. This composite index may support more objective and biologically informed diagnosis in clinical psychiatry.