Abstract
SummaryConverging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.
Highlights
Major depressive disorder (MDD) is a highly prevalent psychiatric disease associated with a substantial disease burden (Whiteford et al, 2013) and increased mortality (Machado et al, 2018; Plana-Ripoll et al, 2019)
We investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with major depressive disorder (MDD) compared with matched healthy controls (HC)
Despite comparable body mass index (BMI) scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia
Summary
Major depressive disorder (MDD) is a highly prevalent psychiatric disease associated with a substantial disease burden (Whiteford et al, 2013) and increased mortality (Machado et al, 2018; Plana-Ripoll et al, 2019). Comorbid depression is common in patients with cardiometabolic disorders (Gold et al, 2020) and accumulating evidence from large-scale epidemiological studies has revealed a bidirectional association between MDD and an increased risk for heart disease (Nicholson et al, 2006), diabetes (Mezuk et al, 2008), and metabolic syndrome (Pan et al, 2012). This seems to extend to subclinical metabolic dysregulation, as a metabolomics analysis in 5,283 cases and 10,145 healthy controls revealed evidence for a distinct profile of dyslipidemia in MDD (Bot et al, 2020). These mainly comprise genes that are involved in inflammatory pathways
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