Insomnia Triples Depression Risk from Inflammation in Older Adults

A new study found that inflammation exposure induced a 3-fold greater increase in depressed mood and depressive symptoms among older adults with insomnia compared to those without insomnia.¹

The study also found that older adults with insomnia had depressed moods for longer, over 6 hours.

“This rigorous, experimentally controlled randomized clinical trial found for the first time that inflammatory challenge with endotoxin induces increases in depressed mood and depressive symptoms in older adults and that depression responses were robustly exaggerated, both in magnitude and duration, in older adults with insomnia compared to those without insomnia,” wrote investigators, led by Michael R. Irwin, MD, from Cousins Center for Psychoneuroimmunology, Jane and Terry Semel Institute for Neuroscience and Human Behavior, at the University of California, Los Angeles.

Insomnia and inflammation, both prevalent in older adults, are risk factors for late-life depression.^2,3 However, who has a greater depression risk: the older adult with insomnia and inflammation or the older adult with inflammation but no insomnia? Investigators sought to compare whether older adults with insomnia had greater increases in depressive mood and symptoms after inflammation exposure.¹

The team conducted this assessor-blinded, parallel-condition randomized clinical trial from August 2017 to November 2022 at a single site in Los Angeles, California, with the analysis taking place from July 2023 to August 2024. The primary outcome was depressed mood, evaluated via the Profiles of Mood States depression subscale (POMS-D). Secondary outcomes included depressive symptom severity and inflammatory cytokines. Endotoxin was used as the inflammation exposure.

The community-based sample had 160 non-depressed adults aged ≥ 60 years (mean age, 65.9 years), with 52.5% females. Among them, 53 had insomnia, and 107 did not (the controls). Most patients were White (75.6%), followed by African American/ Black (11.9%), Hispanic (6.9^), multiracial (3.1%), and Pacific Islander (1.9%).

Participants, stratified by insomnia status, were randomized to the endotoxin 0.8 ng/kg body weight (n = 79; 26 with insomnia, 53 control) or placebo arm (n = 81; 27 with insomnia, 54 control).

Compared to placebo, endotoxin led to a significantly greater increase in depressive symptoms, as seen on the POMS-D in participants with insomnia vs controls (P < .001). Endotoxin also resulted in a significantly greater increase in observer-rated POMS-D among participants with insomnia (P = .001).

Among patients with insomnia, endotoxin induced greater increases in observer-rated POMS-D (MD-AUC, 0.35; 95% CI, 0.03 – 0.67; P < .001) than placebo. No difference was observed in the control arm (MD-AUC, 0.05; 95% CI, 0.00 – 0.09).

Sensitivity analyses showed that endotoxin led to greater increases in POMS-D and observer-rated mood among females (P = .07 and P = .04, respectively. However, no 3-way interaction between condition, sex, and group was found.

Endotoxin resulted in similar increases in inflammatory cytokines in both participants with insomnia and controls. Moderation analyses showed that the inflammatory response was linked to increases in POMS-D in patients with insomnia (95% confidence interval [CI], 0.26 – 0.41; P < .001) but not in controls.

The findings suggest that older patients with insomnia should have vigilant depression monitoring during periods of inflammatory exposure. Depression prevention strategies that target both insomnia (behavioral) and inflammatory (biologic) phenotypes are important for these patients.

“Insomnia not only robs older adults of rest but also primes their immune system to make them uniquely vulnerable to depression when faced with inflammation,” Irwin said in a statement.⁴ “Treatments targeted at this inflammation-related depression may prevent depression and benefit these patients to improve their overall quality of life.”

References

1. Irwin MR, Boyle CC, Cho JH, et al. Inflammatory Exposure and Depression in Older Adults With Insomnia: A Randomized Clinical Trial. JAMA Psychiatry. Published online July 16, 2025. doi:10.1001/jamapsychiatry.2025.1327

2. Perlis ML, Smith LJ, Lyness JM, et al. Insomnia as a risk factor for onset of depression in the elderly. Behav Sleep Med. 2006;4(2):104-113. doi:10.1207/s15402010bsm0402_3

3. Alexopoulos GS, Morimoto SS. The inflammation hypothesis in geriatric depression. Int J Geriatr Psychiatry. 2011 Nov;26(11):1109-18. doi: 10.1002/gps.2672. Epub 2011 Mar 2. PMID: 21370276; PMCID: PMC3160498.

4. Inflammation triples depression risk for older adults with insomnia. EurekAlert! July 16, 2025. https://www.eurekalert.org/news-releases/1090848. Accessed July 25, 2025.