Depression, one of the most common diseases in older adults, carries significant risk for morbidity and mortality. Because of the burgeoning population of older adults, the enormous burden of late-life depression, and the limited efficacy of current antidepressants in older adults, biologically plausible models that translate into depression prevention efforts are needed. Insomnia predicts depression recurrence, and is a modifiable target for depression prevention. Yet, it is not known how insomnia gets converted into biological- and affective risk for depression, which is critical for identification of molecular targets for pharmacologic interventions, and for refinement of insomnia treatments that target affective responding to improve efficacy. This study will use an inflammatory challenge (i.e., endotoxin) to probe acute inflammatory- and depression responses (primary outcome) in older adults as a function of insomnia. Older adults with insomnia show chronic inflammation; sleep disturbance also activates inflammatory signaling; chronic inflammation primes acute inflammatory responses; chronic inflammation, as well as acute inflammatory reactivity, predict depression over the following year; and finally, endotoxin induces acute inflammation along with depressive symptoms, with preliminary evidence that ?two-hits? (i.e., sleep disturbance and inflammatory challenge) are associated with exaggerated increases in depression, especially in women. In this placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (60-80 y; stratified by sex) with insomnia (n=80) vs. comparisons without insomnia (n=80), we hypothesize that older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia.
We aim to: 1) examine differences in depressive symptoms and measures of negative affect responding as a function of insomnia and inflammatory challenge; 2) examine differences in measures of positive affect responding as a function of insomnia and inflammatory challenge; and 3) examine differences in experimentally-induced inflammation in relation to depressive symptoms and measures of negative- and positive affect responding as a function of insomnia. If the hypotheses are confirmed, older adults with two ?hits?, insomnia and inflammation, would represent a high risk group to be prioritized for monitoring and for depression prevention efforts using treatments that target insomnia or inflammation. Moreover, this study will inform the development of mechanism-based treatments that target affect responses in addition to sleep behaviors, and which might also be coupled with efforts to reduce inflammation to optimize efficacy of depression prevention.

Public Health Relevance

Late-life depression is a significant public health concern, and effective interventions for prevention and treatment are needed. Insomnia and inflammation are modifiable targets for depression prevention, and this study is significant in using an experimental approach (i.e., inflammatory challenge) to probe acute inflammatory- and depression responses as a function of insomnia, which will inform identification of molecular targets for pharmacologic interventions, and improvement of insomnia treatments to prevent depression in older adults.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG051944-02
Application #
9345997
Study Section
Special Emphasis Panel (ZRG1-BBBP-Z (02)M)
Program Officer
Nielsen, Lisbeth
Project Start
2016-09-15
Project End
2021-04-30
Budget Start
2017-06-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
$530,945
Indirect Cost
$186,175
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095