Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity

Kaestner, Florian; Hettich, Michael; Peters, Marvin; Sibrowski, W.; Hetzel, Günter; Ponath, Gerald; Arolt, Volker; Cassens, U.; Rothermundt, Matthias

doi:10.1016/j.jad.2005.03.012

Cited by 164 publications

(120 citation statements)

References 33 publications

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“…Thus, our result of increased microglial QUIN expression in suicidal MDD patients is in line with the hypothesis of a systemic MPS activation during acute disease phases of depression [2][3][4][5][6][7][8][9]14]. Due to the excitotoxic properties of QUIN, our findings are also supporting the neurodegeneration hypothesis of depression [15].…”

Section: Discussionsupporting

confidence: 90%

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Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Steiner

Walter

Gos

et al. 2012

Neurology, Psychiatry and Brain Research

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Background: Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described. Methods: Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects. Results: Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.

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Section: Discussionsupporting

confidence: 90%

“…Previous research has suggested that these specific monocyte-derived cytokines are increased in the peripheral blood of acutely depressed patients [2][3][4][5][6][7] along with elevated monocyte counts [8,9]. Furthermore, lymphocyte and natural killer cell abnormalities have been described [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Steiner

Walter

Gos

et al. 2012

Neurology, Psychiatry and Brain Research

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“…A contradiction between this hypothesis and the first hypothesis is that cortisol inhibits inflammation and the immune response, whereas depression is associated with both elevated cortisol and increased inflammatory markers. A recent finding possibly explains this contradiction by showing that melancholic depressed patients had increased HPA axis activity and no signs of inflammation, whereas non-melancholic depressed patients did show signs of inflammation and normal HPA axis activity [43].…”

Section: Discussionmentioning

confidence: 99%

Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis

et al. 2006

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Aims/hypothesis: Evidence strongly suggests that depression and type 2 diabetes are associated, but the direction of the association is still unclear. Depression may occur as a consequence of having diabetes, but may also be a risk factor for the onset of type 2 diabetes. This study examined the latter association by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. Methods: Medline and PsycInfo were searched for articles published up to January 2005. All studies that examined the relationship between depression and the onset of type 2 diabetes were included. Pooled relative risks were calculated using fixed and random effects models. To explore sources of heterogeneity between studies, subgroup analyses and meta-regression analyses were performed. Results: Nine studies met our inclusion criteria for this meta-analysis. The pooled relative risk was 1.26 (1.13-1.39) using the fixed effects model and 1.37(1.14-1.63) using the random effects model. Heterogeneity between studies could not be explained by (1) whether studies controlled for undetected diabetes at baseline; (2) the method of diabetes assessment at followup; (3) the baseline overall risk of diabetes in the study population; and (4) follow-up duration. Conclusions/ interpretation: Depressed adults have a 37% increased risk of developing type 2 diabetes mellitus. The pathophysiological mechanisms underlying this relationship are still unclear and warrant further research. A randomised controlled study is needed to test whether effective prevention or treatment of depression can reduce the incidence of type 2 diabetes and its health consequences.

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“…118 Different types of MD were observed to exhibit different immune profiles, the subgroup of melancholic depressed patients showed a decreased type 1 activation accompanied with a marked activation of the HPA axis, whereas the non-melancholic depressed patients showed signs of inflammation such as increased monocyte count and increased levels of IL-1b and a2-macroglobulin. 73,119 Moreover, the plasma levels and expression in the brain of intercellular adhesion molecule-1 (ICAM-1) seem to be related to depression: both, in patients treated with IFN-a 57 and in patients after acute coronary syndromes, 120 soluble ICAM-1 levels were observed to be associated with depressive symptoms. Moreover, increased expression of ICAM-1 was found in the prefrontal cortex of elder depressive patients.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

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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Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity

Cited by 164 publications

References 33 publications

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis

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

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