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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

Clinical Neuroendocrinology Branch (S.A., P.E.M., D.S.R., S.J.L., M.A.K., P.W.G.), National Institute of Mental Health, and Pediatric and Reproductive Endocrinology Branch (S.K., I.I., A.R.A., G.P.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pharmacogenomics (J.L.), University of California, Los Angeles, Los Angeles, California 90095; and Cardiac Unit (H.K.G.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Salvatore Alesci, M.D., Ph.D., Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Building 10, Room 2D46, MSC 1284, Bethesda, Maryland 20892-1284. E-mail: alescisa{at}mail.nih.gov.

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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