Sex Differences in Depressive and Socioemotional Responses to an Inflammatory Challenge: Implications for Sex Differences in Depression
Open accessAbstract
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.
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Endotoxin-induced increases in IL-6 and TNF-α are correlated with greater feelings of depressed mood and social disconnection only in women.
“endotoxin-induced increases IL-6 and TNF-α are correlated with greater feelings of depressed mood and social disconnection only in women (Moieni et al, 2015)”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Moieni et al, 2015
The “Relationships between Cytokines and Affective and Social Responses” section reports that increases in both IL-6 and TNF-α correlated with greater social disconnection in women but not men. It also states that neither cytokine’s increase was significantly correlated with depressed mood in either sex, so the depressed-mood part of the claim is unsupported. (LLM, conf=0.92)
Experimental — accuracy not yet measuredWomen are more sensitive to the behavioural effects of inflammation, demonstrating greater increases in depressed mood than men following endotoxin exposure despite a similar magnitude in cytokine (IL-6 and TNF) responses.
“Recent data indicate that women are more sensitive to the behavioural effects of inflammation, demonstrating greater increases in depressed mood than men following endotoxin exposure despite a similar magnitude in cytokine (IL-6 and tumour necrosis factor (TNF)) responses11.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [11]
Endotoxin studies report that fatigue and other sickness symptoms rise and peak two hours after injection.
“Similar results have been observed in endotoxin studies, which document elevations in fatigue and other sickness symptoms that peak 2 hours post injection (Eisenberger et al., 2010; Moieni et al., 2015).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Moieni et al., 2015
Even brief, modest rises in inflammation can produce somatic symptoms, especially fatigue.
“Mild, short-term increases in inflammation are sufficient to cause somatic symptoms, particularly fatigue.”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Moieni et al., 2015
Females show greater increases in depressed mood and social disconnection after endotoxin exposure than males.
“For example, females exhibit greater increases in depressed mood and feelings of social disconnection following endotoxin exposure than males (Eisenberger et al., 2010a, 2009; Moieni et al., 2015).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Moieni et al., 2015
Endotoxin-induced increases in TNF-α and IL-6 correlate with increases in social disconnection in females but not males.
“Moreover, endotoxin-induced increases in TNF-α and IL-6 were correlated with increases in social disconnection for females but not for males (Moieni et al., 2015).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Moieni et al., 2015
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Kruse, J. L., Vasavada, M. M., Olmstead, R., Hellemann, G., Wade, B., Breen, E. C., Brooks, J. O., Congdon, E., Espinoza, R., Narr, K. L., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01268-z · Cited by 48 · see citing works
Self-citationKruse, J. L., Olmstead, R., Hellemann, G., Wade, B., Jiang, J., Vasavada, M. M., Brooks III, J. O., Congdon, E., Espinoza, R., Narr, K. L., et al. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.05.069 · Cited by 46 · see citing works
Self-citationRaison, C. L. (2016) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2016_26 · Cited by 36 · see citing works
Kruse, J. L., Boyle, C. C., Olmstead, R., Breen, E. C., Tye, S. J., Eisenberger, N. I., & Irwin, M. R. (2022) · Scientific Reports · doi:10.1038/s41598-022-16364-3 · Cited by 22 · see citing works
Self-citation
- Authors
- Moieni, M., Irwin, M. R., Jevtic, I., Olmstead, R., Breen, E. C., & Eisenberger, N. I.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Eisenberger, Naomi I
- Venue
- Neuropsychopharmacology
- Published
- 2015-01-19
- Volume
- 40
- Issue
- 7
- Pages
- 1709-1716
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4915253
- OpenAlex
- W2161161114
- Cited by
- 273
- References
- 51
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 15 · 2023: 25 · 2022: 29 · 2021: 26 · 2020: 24 · 2019: 30 · 2018: 25 · 2017: 22 · 2016: 32 · 2015: 10 · 2014: 1
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (UL1TR000124, 5t32gm084903-03)
- National Institute on Aging (R01AG026364, R01AG034588, F31AG048668, P30AG028748)
- National Heart, Lung, and Blood Institute (R01HL095799)
- National Institute of Mental Health (R01MH091352)
- National Institute on Drug Abuse (R01DA032922)
- National Cancer Institute (R01CA160245, R01CA119159)
- National Institute of General Medical Sciences (5T32GM084903)
- NIH Clinical Center
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- sex differences, depression, endotoxin challenge, inflammatory cytokines, interleukin-6, TNF-α, depressive mood, social disconnection
- MeSH terms
- Adolescent, Adult, Analysis of Variance, Depression, Female, Humans, Inflammation, Male, Sex Characteristics, Social Behavior, Cytokines, Illness Behavior, Young Adult, Self Report
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