Inflammatory Exposure and Depression in Older Adults With Insomnia: A Randomized Clinical Trial

Importance: Insomnia and inflammation are prevalent in older adults, and both are risk factors for late-life depression. Older adults with insomnia who are exposed to inflammatory challenge may be more vulnerable to depression. Objective: To determine whether inflammatory exposure induces greater increases in depressive mood and symptoms in older adults with insomnia disorder compared to those without insomnia. Design, Setting, and Participants: This assessor-blinded, parallel-condition randomized clinical trial was conducted from August 2017 to November 2022 at a single site in Los Angeles, California, among a community-based sample of 160 nondepressed adults aged 60 years or older (53 with insomnia disorder and 107 without insomnia, or control). Data analysis occurred from July 2023 to August 2024. Interventions: Participant groups stratified by insomnia status were randomized to 2 conditions: endotoxin or placebo. Main Outcomes and Measures: The primary outcome was depressed mood, assessed by the Profiles of Mood States depression subscale (POMS-D). Secondary outcomes were depressive symptom severity and inflammatory cytokines. Results: Among 160 randomized participants eligible for the study (mean [SD] age, 65.9 [4.6] years; 84 female participants [52.5%]), 79 participants (26 with insomnia, 53 control participants) were randomized to endotoxin and 81 (27 with insomnia, 54 control participants) to placebo. All randomized participants completed the protocol. Compared to placebo, endotoxin induced increases in POMS-D to a significantly greater extent in those with insomnia than controls (condition × group interaction, F10,1478 = 4.7; P < .001), with a similar effect for observer-rated POMS-D mood (condition × group interaction, F3,450 = 5.5; P = .001), as well as clinically meaningful increases in observer-rated measures of depressive symptoms. Endotoxin induced similar increases in inflammatory cytokines in both groups. Moderation analyses found that the inflammatory response was associated with increases in POMS-D in the insomnia group (β = 0.33; 95% CI, 0.26-0.41; P < .001) but not in control participants. Conclusions and Relevance: In this randomized clinical trial, older adults with insomnia showed an exaggerated vulnerability to depressive mood and symptoms in response to inflammatory challenge. Older adults with insomnia should undergo vigilant depression monitoring during periods of inflammatory exposure; selective depression prevention strategies that target both insomnia and inflammatory phenotypes are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03256760.