Multiple lipid species, particularly phosphatidylethanolamines (PEs) and triglycerides (TGs), were significantly associated with depressive symptoms after FDR correction in longitudinal models, supporting further mechanistic and biomarker investigations.
Abstract
Background Depression is a highly prevalent condition with a substantial health burden and known links to metabolic dysfunction. We investigated plasma metabolites and lipids associated with depressive symptoms at baseline, including sex- and race-specific differences, and subsequently examined longitudinal associations of baseline metabolites and lipids with depressive symptoms over follow-up. Methods Baseline plasma samples were profiled for 162 metabolites and 195 lipid species using targeted mass spectrometry in the REasons for Geographic And Racial Differences in Stroke (REGARDS) stroke case-cohort. Depressive symptoms were assessed using the 4-item Center for Epidemiologic Studies Depression Scale (CES-D-4) at baseline and during follow-up. Cross-sectional associations were evaluated using weighted logistic regression, and longitudinal associations were assessed using weighted generalized estimating equations. Effect modification by sex and race was examined. Model 1 was adjusted for age, race, and sex (and time in longitudinal analyses). Model 2 was further adjusted for body mass index, smoking status, alcohol use, physical activity, perceived stress, and incident stroke. False discovery rate (FDR) correction was applied to account for multiple testing. Results Of 1,938 participants, 205 had depressive symptoms at baseline. At baseline, several metabolites (e.g., glycine, cyclic AMP) and lipid species were nominally associated with depressive symptoms, though none remained significant after FDR correction. In longitudinal analyses, stronger and more consistent associations emerged. Higher levels of anserine (OR=1.27, 95% CI: 1.16-1.39) and glucose (OR=1.36, 95% CI: 1.10-1.68) were associated with increased odds of depressive symptoms, with anserine remaining significant after FDR correction. Multiple lipid species, particularly phosphatidylethanolamines (PEs) and triglycerides (TGs), were significantly associated with depressive symptoms after FDR correction in longitudinal models. Significant sex interactions were observed for several lipid species, with stronger positive associations in females and attenuated or inverse associations in males. Conclusions In this stroke-enriched case-cohort, PEs and TGs were associated with depressive symptoms over time. Sex-specific lipid differences highlight biological heterogeneity. These results identify amino acid, phospholipid, and triacylglycerol pathways in depressive symptoms, supporting further mechanistic and biomarker investigations.
Pre-clinical depressive symptoms are associated with a moderately increased risk of Parkinson’s disease, particularly among people with a high genetic susceptibility to PD, and metabolomic profiles account for a significant portion of this relationship.
OBJECTIVE
To examine the association between depressive symptoms and advanced cardiovascular-kidney-metabolic (CKM) syndrome among U.S. adults and to determine whether this association differs by demographic, socioeconomic, and behavioral factors.
METHODS
This cross-sectional study used National Health and Nutrition Examination Survey data. Depressive symptoms were assessed using the Patient Health Questionnaire-9. CKM stages were defined using the American Heart Association framework and categorized as nonadvanced CKM, stages 0 to 2, versus advanced CKM, stages 3 to 4. Survey-weighted logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for advanced CKM. Interaction terms tested effect modification by age, sex, race and ethnicity, poverty-income ratio, education, and smoking status.
RESULTS
The study included 30,244 adults. Overall, 16% of adults had advanced CKM, and 8% had depressive symptoms. In fully adjusted sex-stratified models, depressive symptoms were associated with higher odds of advanced CKM among women (OR, 2.24; 95% CI, 1.74-2.88) and men (OR, 1.75; 95% CI, 1.34-2.28). Interaction estimates indicated a stronger association among women (OR, 1.58; 95% CI, 1.12-2.23; P=0.010) and a weaker association at age ≥65 versus 30-49 years (OR, 0.42; 95% CI, 0.27-0.67; P<.001).
CONCLUSIONS
Depressive symptoms were associated with higher odds of advanced CKM in both women and men, with a stronger association among women and a weaker association at ages ≥65 versus 30-49. These findings support integrating mental health screening into cardiometabolic and kidney disease prevention strategies, emphasizing age- and sex-specific vulnerabilities.
R. Fraser, Tatiana M. Davidson, R. J. Walker et al.· Biopsychosocial science and...· 0 citations
Background: Metabolomic studies of depression have yielded heterogeneous findings, potentially because metabolic correlates differ across symptoms and metabolic states. We examined symptom-specific metabolomic associations and whether body mass index (BMI) modifies these relationships. Methods: We analyzed 83,717 Estonian Biobank participants (70.6% female) with 249 Nightingale metabolite measures and 14 lifetime depressive symptoms. Logistic regression models progressively adjusted for sociodemographic, lifestyle, medication, and BMI factors. BMI-related attenuation and metabolite x BMI interactions were evaluated, followed by self-organizing map analyses of broader metabolic context. Results: Before BMI adjustment, 660 metabolite-symptom associations were Bonferroni-significant; 136 were significant after BMI adjustment, including 105 retained associations. Weight-related associations showed the strongest BMI dependence: none of 199 weight-gain associations and 2 of 115 weight-loss associations were retained. Among 691 preselected metabolite-symptom pairs, 211 (30.5%) showed significant metabolite x BMI interactions after false discovery rate correction. Six systemic metabolic profiles were identified, but only 3 of 211 BMI-sensitive pairs showed additional profile-dependent heterogeneity. Conclusions: Circulating metabolic correlates of depressive symptoms are heterogeneous and strongly dependent on symptom phenotype and BMI-related metabolic context. These findings suggest that metabolic biomarkers in depression should be interpreted in relation to both symptom presentation and metabolic state rather than as uniform correlates of the disorder.
S. Kurvits, N. Taba, Estonian biobank research team et al.· medRxiv· 0 citations
Depression may identify a clinically relevant risk state among people receiving haemodialysis and require validation in larger, prospectively sampled cohorts, including potential sex differences in routine biomarkers.
C. Duperrex, G. Smith, S. Rahman et al.· medRxiv· 0 citations
BACKGROUND
Depression is increasingly conceptualized as a biologically heterogeneous condition, with immune-inflammatory and metabolic dysregulation implicated in specific symptom dimensions rather than overall depressive severity. However, it remains unclear whether different combinations of inflammatory and metabolic burden define distinct clinical depressive phenotypes.
METHODS
In this cross-sectional multicenter study on major depressive episodes (MDE), inflammatory and metabolic burden were indexed by C-reactive protein (CRP) and a composite continuous metabolic syndrome score (cMetS). Participants were classified into four immune-metabolic profiles based on the combination of high/low CRP status and high/low metabolic burden. Somatic symptoms, anhedonia, subjective cognitive complaints, and objective cognitive performance were assessed using standardized psychometric and neuropsychological measures. Associations were examined using covariance and multivariable regression models, including four-category profiles and CRP-cMetS interaction terms, with sensitivity analyses using continuous biomarkers.
RESULTS
Among 221 patients, immune-metabolic profiles differed for somatic symptoms (p = 0.001; η²p = 0.079), anhedonia (p = 0.006; η²p = 0.065), and cognition (Digit-Symbol-Substitution Test [DSST]: p = 0.039; η²p = 0.042). In regression models, the High CRP/High cMetS group was associated with greater somatic symptom burden (β = 5.10, p = 0.001) and poorer cognitive performance (DSST: β = -7.43, p = 0.036; Trail-Making Test-B: β = 41.44, p = 0.008), whereas the High CRP/Low cMetS profile was selectively associated with greater anhedonia (β = 2.93, p < 0.001). Significant CRP×cMetS interactions emerged for anhedonia (p = 0.023). Sensitivity analyses using continuous biomarkers showed convergent results.
CONCLUSIONS
These findings suggest that distinct combinations of inflammatory and metabolic burden may characterize partly distinct depressive phenotypes across hedonic, somatic, and cognitive domains, supporting the relevance of integrated immune-metabolic profiling for biologically informed stratification and potentially more targeted therapeutic approaches.
M. Di Nicola, M. Pepe, A. Aguglia et al.· Psychoneuroendocrinology· 0 citations
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