Sex differences in depressive and socioemotional responses to an inflammatory challenge: implications for sex differences in depression

Abstract

Substantial evidence demonstrates that inflammatory processes may underlie depression for a subset of patients, including work showing that healthy subjects exposed to an inflammatory challenge show increases in depressed mood and feelings of social disconnection. However, despite the fact that depression is two times as likely to occur in females than males, the vast majority of this work has been carried out in males. Thus, the objective of this study was to determine whether females (vs males) would show greater increases in proinflammatory cytokines, depressed mood, and social disconnection in response to an inflammatory challenge. One hundred and fifteen healthy participants (69 female) completed this double-blind, placebo-controlled, randomized clinical trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), depressed mood, and feelings of social disconnection were assessed hourly. Results showed that endotoxin (vs placebo) led to increases in proinflammatory cytokines (TNF-α, IL-6), depressed mood, and feelings of social disconnection. Females exposed to endotoxin showed greater increases in depressed mood and feelings of social disconnection. Furthermore, increases in TNF-α and IL-6 were correlated with increases in social disconnection for females but not for males. These sex differences in the relationships between inflammatory and socioemotional responses to an inflammatory challenge may be particularly important for understanding why females are two times as likely as males to develop depressive disorders.

Figures

Figure 1

Changes in cytokines. Changes over time in the endotoxin and placebo groups (split by sex) in plasma levels of (a) interleukin-6 (IL-6) and (b) tumor necrosis factor-α (TNF-α) (raw values that have not been log-transformed are shown). Cytokines were assessed at baseline (T0) and then approximately every hour after injection for the next 6 h (T1–T6). Because participants completed a neuroimaging session (reported separately) starting at exactly 2 h after injection, T2 was assessed before this scanning session at 1 h and 40 min after injection, and T3 was assessed immediately after the scan at 3 h and 30 min after injection; T4–T6 were assessed hourly after T3. Error bars depict the standard error of the mean.

Figure 2

Changes in socioemotional responses. Changes over time in the endotoxin and placebo groups (split by sex) in (a) depressed mood and (b) feelings of social disconnection. Similar to the assessment of cytokines, socioemotional responses were assessed at baseline (T0) and then approximately every hour after injection for the next 6 h (T1–T6). T2 was assessed at 1 h and 40 min after injection; T3 was assessed at 3 h and 30 min after injection; and T4–T6 were assessed hourly after T3. Timepoints with asterisks indicate significant condition by sex interactions at individual timepoints controlling for baseline values. Error bars depict the standard error of the mean.

Figure 3

Correlations between social disconnection and cytokines. Correlations between changes (T2–T0) in feelings of social disconnection and changes in interleukin-6 (IL-6) (T2–T0) reported separately for (a) females and (b) males, and correlations between changes (T2–T0) in feelings of social disconnection and changes in tumor necrosis factor-α (TNF-α) for (c) females and (d) males. All values reported here and all analyses controlled for body mass index (BMI).