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A prospective evaluation of the directionality of the depression–inflammation relationship
Open accessAbstract
Cross-sectional studies have found that individuals with depressive disorders or symptoms have elevated levels of inflammatory markers predictive of coronary artery disease, including interleukin-6 (IL-6) and C-reactive protein (CRP). Due to the paucity of prospective studies, however, the directionality of the depression-inflammation relationship is unclear. We evaluated the longitudinal associations between depressive symptoms and both IL-6 and CRP among 263 healthy, older men and women enrolled in the Pittsburgh Healthy Heart Project, a 6-year prospective cohort study. During the baseline and follow-up visits, participants completed the Beck Depression Inventory-II (BDI-II) to assess depressive symptoms and underwent blood draws to quantify serum IL-6 and CRP. Path analyses revealed that baseline BDI-II (beta=0.18, p=0.01, DeltaR(2)=0.02) was a predictor of 6-year change in IL-6, even after adjustment for demographic, biomedical, and behavioral factors as well as other negative emotions. Of all the factors examined, only body-mass index was a stronger predictor of IL-6 change than depressive symptoms. In contrast to these results, baseline IL-6 did not predict 6-year change in BDI-II. Evidence of a weak bidirectional relationship between BDI-II and CRP was also observed; however, neither of these longitudinal associations was significant. The present findings indicate that depressive symptoms may precede and augment some inflammatory processes relevant to coronary artery disease among healthy, older adults. Therefore, our results imply that depression may lead to inflammation and that inflammation may be one of the mechanisms through which depression contributes to cardiovascular risk.
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“Although numerous studies note that associations between negative psychological health and factors that increase cardiovascular risk are likely bidirectional, recent longitudinal studies provide strong evidence that factors such as depression and PTSD precede and predict higher levels of inflammation in both healthy and patient populations. 118,119,124”
From Psychological Health, Well-Being, and the Mind-Heart-Body Connection: A Scientific Statement From the American Heart Association (2021) · cites this paper as [124]
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“Yet, there is also evidence that the inflammation-depression pathway is bidirectional as depressive symptoms predict increases in inflammation in some samples (Huang et al., 2017; Matthews et al., 2010; Stewart et al., 2009).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Stewart et al., 2009
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“Moreover, in another large-scale prospective study of healthy adults, depressive symptoms predicted levels of inflammation 6 years later whereas inflammation did not likewise predict depressive symptoms.[15]”
From SUICIDAL IDEATION IS ASSOCIATED WITH ELEVATED INFLAMMATION IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER: Research Article: Suicidal Ideation and Inflammation (2013) · cites this paper as [15]
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Metadata
- Authors
- Stewart, J. C., Rand, K. L., Muldoon, M. F., & Kamarck, T. W.
- Affiliations
- Indiana University – Purdue University Indianapolis (US)
- University of Pittsburgh (US)
- Corresponding author
- Stewart, Jesse C.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 23
- Issue
- 7
- Pages
- 936-944
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2749896
- OpenAlex
- W1986031269
- Cited by
- 390
- References
- 97
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 18 · 2023: 23 · 2022: 26 · 2021: 24 · 2020: 18 · 2019: 43 · 2018: 20 · 2017: 24 · 2016: 30 · 2015: 26 · 2014: 23 · 2013: 21 · 2012: 18
- FWCI
- 7.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 076858, HL040962, HL056346, HL 076852, R24HL076852, R24HL076858, R01HL056346, P01HL040962)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Health and Mental Health
- Keywords
- depression, depressive symptoms, inflammation, interleukin-6, C-reactive protein, coronary artery disease, cardiovascular risk, older adults, bidirectional relationship, body mass index
- MeSH terms
- Aged, C-Reactive Protein, Coronary Artery Disease, Depression, Female, Humans, Inflammation, Longitudinal Studies, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Psychiatric Status Rating Scales, Surveys and Questionnaires, Risk Factors, Interleukin-6, Multivariate Analysis
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