Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications
Abstract
BACKGROUND: Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. METHODS: We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. RESULTS: MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. CONCLUSIONS: We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.
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Particularly strong evidence implicates inflammation in the development of depressive symptoms and major depressive disorder.
“Particularly strong evidence implicates inflammation in the development of depressive symptoms and major depressive disorder (MDD).[4][5][6]”
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Self-citation
- Authors
- Alesci, S., Martinez, P. E., Kelkar, S., Ilias, I., Ronsaville, D. S., Listwak, S. J., Ayala, A. R., Licinio, J., Gold, H. K., Kling, M. A., Chrousos, G. P., & Gold, P. W.
- Affiliations
- National Institutes of Health (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Alesci, Salvatore
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2005-05
- Volume
- 90
- Issue
- 5
- Pages
- 2522-2530
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2109668208
- Cited by
- 372
- References
- 59
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 15 · 2023: 13 · 2022: 14 · 2021: 12 · 2020: 15 · 2019: 14 · 2018: 19 · 2017: 24 · 2016: 24 · 2015: 14 · 2014: 19 · 2013: 19 · 2012: 25
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, interleukin-6, circadian rhythm, cortisol, hypothalamic-pituitary-adrenal axis, approximate entropy, physiological complexity, mood, coronary heart disease risk, bone loss
- MeSH terms
- Adult, Circadian Rhythm, Major Depressive Disorder, Female, Humans, Hydrocortisone, Male, Middle Aged, Pain Measurement, Interleukin-6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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