Depression, Systemic Inflammation, and Prevalent Diabetes: A Counterfactual Mediation Analysis.

THE BIDIRECTIONAL RELATIONSHIP BETWEEN DIABETES MELLITUS AND DEPRESSION: A SYSTEMATIC REVIEW OF BIOLOGICAL AND PSYCHOLOGICAL MECHANISMS

Diabetes mellitus and depression are two major global health challenges that frequently co-occur, with depression being two to three times more prevalent in individuals with diabetes than in the general population. Current evidence confirms a bidirectional relationship, where depression increases the risk of developing type 2 diabetes by 34%, and diabetes elevates the risk of incident depression by 28%. This systematic review explores the complex biological and psychological mechanisms underlying this interplay. Biological pathways include chronic low-grade inflammation characterized by elevated cytokines (IL-6, TNF-α, CRP), dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis resulting in hypercortisolemia, and impaired neuroplasticity linked to reduced levels of brain-derived neurotrophic factor (BDNF). Additionally, central insulin resistance and neurotransmitter alterations in serotonin and dopamine systems further exacerbate both conditions. Psychological and behavioral mediators include the specific emotional burden of diabetes distress, the significant self-management burden associated with insulin therapy and glucose monitoring, and lifestyle factors such as sedentary behavior, poor diet, and sleep disturbances. The presence of comorbid depression is a critical predictor of poor glycemic control (higher HbA1c), increased microvascular complications (retinopathy, nephropathy), and higher mortality rates. Consequently, clinical management must transition toward integrated, multidisciplinary care models that prioritize universal screening and collaborative treatment strategies. Future research should focus on longitudinal studies and the validation of biomarkers to enable precision medicine and improve the long-term prognosis for these patients.

Association between systemic inflammation response index and depression in U.S. adults

Higher SIRI levels were associated with higher odds of clinically relevant depressive symptoms among adults from the National Health and Nutrition Examination Survey 2005 to 2016, with a nonlinear dose-response pattern.

Associations between inflammation and depressive symptoms in diabetes: A scoping review

Depression is a clinically important comorbidity in people living with diabetes, yet biological pathways linking these conditions remain unclear. Chronic inflammation has been proposed as one mechanism connecting metabolic dysfunction with depressive symptoms. This scoping review examined knowledge on inflammation and depression/depressive symptoms in adults with diabetes, with attention to differences by diabetes type and sex. Thirty-seven studies met inclusion criteria, predominantly observational and focused on type 2 diabetes. Inflammatory markers were more frequently associated with depressive symptoms in type 2 diabetes than in type 1. CRP/hs-CRP was the most commonly studied biomarker and was often positively associated with depressive symptoms, while composite immune-metabolic indices reflected depressive symptom burden across studies. In contrast, findings for individual cytokines, including IL-6 and TNF-α, were heterogenous and appeared dependent on adiposity, metabolic health, or vascular comorbidity. Evidence in type 1 diabetes was less uniform, with studies suggesting involvement of vascular, lipid-associated, or non-classical inflammatory pathways. Sex appeared to modify inflammation and depression associations, although patterns varied across biomarkers and study populations. Overall, the literature suggests that inflammation is relevant to depression in diabetes, particularly in type 2, but that this relationship is heterogeneous and shaped by diabetes type, sex, adiposity, and vascular burden.

Depression as a mediator in the link between physical activity and cardiovascular disease: Insights from NHANES 2007–2018 and Mendelian randomization

Causal Model Testing of the Relationship between Body Mass Index and Primary Hypertension: The Mediating Role of Depression, Stress, and Anxiety

Introduction: Primary hypertension is one of the most prevalent diseases in Iran, leading to a significant number of deaths and disabilities annually. Given its high prevalence and associated health risks, the present study aimed to test a causal model of the relationship between body mass index (BMI) and primary hypertension, considering the mediating role of depression, stress, and anxiety. Method: This study was a descriptive cross-sectional research based on structural equation modeling (SEM). The statistical population comprised individuals diagnosed with primary hypertension who were referred to Taleghani Hospital in Tehran. Using a convenience sampling method, 220 participants were selected as the final sample. Participants’ weight, height, and blood pressure were measured, and they completed the Depression, Anxiety, and Stress Scale (DASS). Results: The model testing results indicated that BMI had a direct effect on depression (β = 0.29), anxiety (β = 0.28), and stress (β = 0.43), all significant at p < 0.01. Moreover, depression (β = 0.28), anxiety (β = 0.30), and stress (β = 0.20) had direct effects on blood pressure, all significant at p < 0.001. The mediation analysis further confirmed that depression, anxiety, and stress played mediating roles in the relationship between BMI and blood pressure. Conclusion: The findings of this study demonstrated that the structural model linking BMI to primary hypertension via depression, stress, and anxiety had a good fit. These results highlight the psychological mechanisms underlying the relationship between BMI and hypertension, emphasizing the importance of considering mental health factors in hypertension management.

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis

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