Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

Abstract

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.

Methods: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.

Results: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.

Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

Keywords: Biomarkers; Cardiovascular; Depression; Metabolites; Metabolomics; Pooled analysis.

Figure 1.

Polar plot illustrating pooled odds ratios (OR) and 95% confidence intervals for the association of the 51 lipids, fatty acids and various low-molecular-weight metabolites with depression. *Significant at false discovery rate q < .05. Dotted circle indicates an OR of 1. Density: high-density lipoprotein (HDL) subfraction 2 (HDL₂), 1.063–1.125 g/mL; HDL₃, 1.125–1.210 g/mL. AcAce, acetoacetate; Ace, acetate; Ala, alanine; Alb, albumin; ApoA1, apolipoprotein A-I; ApoB, apolipoprotein B; bOHBut, 3-hydroxybutyrate; C, cholesterol; Cit, citrate; CLA, conjugated linoleic acids; Crea, creatinine; D, mean diameter; DAG, diglycerides; DHA, docosahexaenoic acid; Est, esterified; FA, fatty acids; FALen, estimated fatty acids chain length; FAw3, ω-3 fatty acids; FAw6, ω-6 fatty acids; Glc, glucose; Gln, glutamine; Gp, glycoprotein acetyls, mainly α1-acid glycoprotein; His, histidine; IDL, intermediate-density lipoprotein; Ile, isoleucine; LA, linoleic acid (18:2); Lac, lactate; Leu, leucine; LDL, low-density lipoprotein; MUFA, monounsaturated fatty acids (16:1, 18:1); PC, phosphatidylcholine and other cholines; Phe, phenylalanine; PUFA, polyunsaturated fatty acids; Remnant, non-HDL, non-LDL cholesterol; SFA, saturated fatty acids; SM, sphingomyelins; TG, triglycerides; TotCho, total cholines; TotFA, total fatty acids; TotPG, total phosphoglycerides; Tyr, tyrosine; UnsatDeg, estimated degree of unsaturation; Val, valine; VLDL, very-low-density lipoprotein.

Figure 2.

Pooled odds ratios (OR) and 95% confidence intervals for the association of the 98 lipid measures of lipoprotein subclasses with depression. *Significant at false discovery rate q < .05. Dotted circle indicates an OR of 1. Particle sizes: extremely large (XXL) very-low-density lipoprotein (VLDL), >75 nm; very large (XL) VLDL, 64 nm; large (L) VLDL, 53.6 nm; medium (M) VLDL, 44.5 nm; small (S) VLDL, 36.8 nm; very small (XS) VLDL, 31.3 nm; intermediate-density lipoprotein (IDL), 28.6 nm; L low-density lipoprotein (LDL), 25.5 nm; M LDL, 23.0 nm; S LDL, 18.7 nm; XL high-density lipoprotein (HDL), 14.3 nm; L HDL, 12.1 nm; M HDL, 10.9 nm; S HDL, 8.7 nm. C, total cholesterol; CE, cholesterol ester; FC, free cholesterol; L, total lipids; P, particle concentration; PL, phospholipids; TC, triglycerides.