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

Salvatore Alesci, Pedro E. Martinez, Sujata Kelkar, Ioannis Ilias, Donna S. Ronsaville, Samuel J. Listwak, Alejandro R Ayala, Julio Licinio, Herman K. Gold, Mitchel A. Kling, George P. Chrousos, Philip W. Gold

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2522-2530
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number5
DOIs
StatePublished - May 1 2005
Externally publishedYes

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Circadian Rhythm
Major Depressive Disorder
Interleukin-6
Depression
Plasmas
Entropy
Hydrocortisone
Coronary Disease
Bone
Teaching Rounds
Bone and Bones
Cushing Syndrome
Periodicity
Menstrual Cycle
Time measurement
Visual Analog Scale
Diagnostic and Statistical Manual of Mental Disorders
Osteoporosis
Body Mass Index
Cardiovascular Diseases

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Alesci, Salvatore; Martinez, Pedro E.; Kelkar, Sujata; Ilias, Ioannis; Ronsaville, Donna S.; Listwak, Samuel J.; Ayala, Alejandro R; Licinio, Julio; Gold, Herman K.; Kling, Mitchel A.; Chrousos, George P.; Gold, Philip W.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 5, 01.05.2005, p. 2522-2530.

Research output: Contribution to journalArticle

Alesci, Salvatore ; Martinez, Pedro E. ; Kelkar, Sujata ; Ilias, Ioannis ; Ronsaville, Donna S. ; Listwak, Samuel J. ; Ayala, Alejandro R ; Licinio, Julio ; Gold, Herman K. ; Kling, Mitchel A. ; Chrousos, George P. ; Gold, Philip W. / 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. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 5. pp. 2522-2530.
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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.",
author = "Salvatore Alesci and Martinez, {Pedro E.} and Sujata Kelkar and Ioannis Ilias and Ronsaville, {Donna S.} and Listwak, {Samuel J.} and Ayala, {Alejandro R} and Julio Licinio and Gold, {Herman K.} and Kling, {Mitchel A.} and Chrousos, {George P.} and Gold, {Philip W.}",
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T1 - 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

T2 - Clinical implications

AU - Alesci, Salvatore

AU - Martinez, Pedro E.

AU - Kelkar, Sujata

AU - Ilias, Ioannis

AU - Ronsaville, Donna S.

AU - Listwak, Samuel J.

AU - Ayala, Alejandro R

AU - Licinio, Julio

AU - Gold, Herman K.

AU - Kling, Mitchel A.

AU - Chrousos, George P.

AU - Gold, Philip W.

PY - 2005/5/1

Y1 - 2005/5/1

N2 - 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.

AB - 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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