Monocyte abundance and glycolytic reprogramming associate with motivational impairment in depression

Inflammation and altered glucose metabolism are implicated in motivational anhedonia, a core feature of major depression (MD) that is sensitive to energy homeostasis. We previously reported preliminary evidence that MD with elevated inflammation is characterized by greater monocyte abundance and monocyte transcriptional signatures consistent with increased glycolysis - a cellular metabolic state reflecting heightened energetic cost to sustain pro-inflammatory functions. However, whether monocyte abundance and cellular bioenergetics directly relate to motivational impairment in MD remains unclear. We first examined monocyte cell counts in relation to self-reported motivation in a larger cohort of 178 medically stable, medication-free adults with MD (Study 1). These analyses were complemented by assessments of glycolytic and mitochondrial metabolism in intact monocytes using Seahorse XF assays in a smaller cohort of similarly enrolled patients with MD (Study 2, n = 40). In Study 1, circulating monocyte percentage was associated with greater self-reported reduced motivation (β = 0.17, SE = 0.08, p = 0.035). In Study 2, bioenergetic assays in isolated monocytes revealed that elevated inflammation (CRP ≥ 3 mg/L) was associated with increased glycolysis (β = 0.97, SE = 0.33, p = 0.005) and greater glycolytic shift (β = 0.92, SE = 0.34, p = 0.011), consistent with a hypermetabolic monocyte phenotype. Greater glycolytic shift predicted lower effort-based motivation as objectively measured by the effort expenditure for rewards task (EEfRT; β = -0.58, SE = 0.24, p = 0.021). Mediation analysis showed that glycolytic shift mediated the association between CRP and low effort-based motivation (ACME = -0.15, 95% CI [-0.37, -0.01], p = 0.032), suggesting that inflammatory burden may relate to reduced reward motivation through its association with monocyte metabolic programming. Exploratory analyses in Study 2 indicated that glycolytic shift was also related to greater monocyte abundance (β = 0.37, SE = 0.17, p = 0.042). Furthermore, replicating the findings of Study 1, higher monocyte percentage was associated with lower effort-based motivation in Study 2 (β = 0.46, SE = 0.22, p = 0.041). Together, these findings suggest that monocyte abundance and immunometabolism may represent a link between peripheral inflammation and its impact on motivational impairment in depression.