Inflammation-induced depressed mood and reward responsivity as a function of age in female adults: a randomized controlled trial of endotoxin.
Level 2 - randomized trial
Individual randomized controlled trial in humans
PubMed 41298372 · doi:10.1038/s41398-025-03752-2
What was done
This randomized, double-blind, placebo-controlled trial examined age differences in affective and reward responsivity to acute inflammation in healthy females. Participants included 40 younger (ages 25–44) and 53 older (ages 60–80) female adults who received either low-dose endotoxin (0.8 ng/kg body weight) or placebo. Self-reported depressed mood was measured pre-infusion and hourly over 9 hours. Reward motivation, sensitivity, and learning were measured at baseline and 2.5 hours post-infusion using the Effort Expenditure for Rewards Task (EEfRT) and Probabilistic Reward Task (PRT). Blood samples were also collected.
What was found
Age significantly moderated the effect of endotoxin on depressed mood (p = 0.0005): endotoxin increased depressed mood in younger females (p < 0.0001) but had no effect in older females (p = 0.99). Age also moderated the effect on EEfRT reward sensitivity (p = 0.01), with a significant decrease in younger females (p = 0.004) and no effect in older females (p = 0.43), alongside a trend for EEfRT reward motivation (p = 0.09). Age did not moderate PRT reward learning (p = 0.51); endotoxin significantly reduced PRT reward learning across both age groups (p = 0.04).
Why it matters
These findings suggest that younger females exhibit heightened psychological and reward vulnerability to acute inflammation compared to older females. This provides experimental support for age-dependent inflammatory mechanisms in depression and indicates anti-inflammatory treatments may differ in efficacy across age groups.
Limits
The study included only healthy females, limiting generalizability to males and clinical populations with major depressive disorder. The sample size was modest (n = 93 total across two age strata and trial arms). An acute endotoxin challenge models transient systemic inflammation rather than chronic low-grade inflammation typical of real-world mood disorders, and specific blood cytokine values were not detailed in the abstract.
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