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, Ιoannis; Ronsaville, Donna S.; Listwak, Samuel J.; Ayala, Alejandro; Licinio, Júlio; Gold, Herman K.; Kling, Mitchel A.; Chrousos, George P.; Gold, Philip W.

doi:10.1210/jc.2004-1667

Cited by 334 publications

(211 citation statements)

References 52 publications

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“…Nevertheless, our attempts to assess the specific role of central IL-1 in the depression-induced bone loss were unsuccessful because IL1rKO mice were resistant to CMS, namely, they did not exhibit CMS-induced decreases in depressive or skeletal parameters. In addition, it has been recently suggested that depression-induced elevations in the serum levels of another cytokine, IL-6, comprise a risk factor for osteoporosis (25,32). However, this suggestion is not supported by the present findings, which suggest that an increase in blood IL-6 levels is not critically involved in CMS-induced bone loss.…”

Section: Discussioncontrasting

confidence: 98%

“…However, as in the case of ADX mice, animals deficient in IL-1 receptor type I (IL-1rKO mice) do not show significant changes in sucrose preference or bone density in response to CMS ( Table 2). The blood levels of IL-6 are markedly elevated in acute stressful conditions (24) and in depressed patients (25). In addition, IL-6 stimulates bone resorption and bone loss, primarily through activation of osteoclasts and its production and actions are regulated by calciotropic hormones, such as sex steroids, parathyroid hormone, and vitamin D3 (26).…”

Section: Resultsmentioning

confidence: 99%

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Depression induces bone loss through stimulation of the sympathetic nervous system

Yirmiya¹,

Goshen²,

Bajayo³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

138

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Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the ␤-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence.antidepressant ͉ chronic depression ͉ osteoporosis ͉ bone formation ͉ adrenergic signaling

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Section: Discussioncontrasting

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Depression induces bone loss through stimulation of the sympathetic nervous system

Yirmiya¹,

Goshen²,

Bajayo³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

138

View full text Add to dashboard Cite

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“…Additionally, the circadian rhythm of IL-6 secretion is altered in depressed patients. 105 Elevated whole blood IL-6 levels in unmedicated depressed patients were demonstrated to be related to treatment non-response to antidepressant administration, whereas patients with subsequent remission showed markedly lower IL-6 levels. 90 Higher plasma IL-6 concentrations were also found in cancer patients with depression, compared with cancer patients without depression or healthy control subjects.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 97%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…Significant increases in IL-6 levels are also reportedly involved in major depression. 83 Compared to healthy controls, depressed patients show highly elevated IL-6 levels and reversed circadian rhythmicity, with levels peaking at the daytime, even in the absence of overt hypercortisolism. Activation of the immune system by pro-inflammatory mediators is a feature of both the metabolic syndrome and affective disorders.…”

Section: A B C D E F G Hmentioning

confidence: 98%

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

et al. 2006

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Obesity and depression are serious public health problems and also constitute cardiovascular disease risk factors. Research organizations have called for efforts to explore the interrelationship between obesity and depression. A useful starting point is the fact that in both disorders there is dysregulation of stress systems. We review molecular and clinical evidence indicating that the mediators of the stress response are a key locus for geneenvironment interactions in the shared biology of depression and obesity. Scientific milestones include translational paradigms such as mice knockouts, imaging and pharmacogenomic approaches that can identify new therapeutic strategies for those burdened by these two afflictions of contemporary civilization. Perspectives for the future are promising. Our ability to dissect the underpinnings of common and complex diseases with shared substrates will be greatly enhanced by the Genes and Environment Initiative, the emerging Large Scale Studies of Genes and Environment in Common Disease, and the UK Biobank Project.

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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

Abstract: 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.

Cited by 334 publications

References 52 publications

Depression induces bone loss through stimulation of the sympathetic nervous system

Depression induces bone loss through stimulation of the sympathetic nervous system

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

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