Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Biological psychiatry (Impact Factor: 10.26). 02/2009; 65(9):732-41. DOI: 10.1016/j.biopsych.2008.11.029
Source: PubMed


Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

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Available from: Charles L Raison, Jan 16, 2014
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    • "NF-κB, p38 MAPK, and signal transducer and activator of transcription 5 (STAT5) are major mediators of pro-inflammatory cytokines, which inhibit GR function (Pace et al., 2007). The relationship between pro-inflammatory cytokines and GR resistance was initially investigated in patients with inflammatory diseases (Pace and Miller, 2009). Glucocorticoid receptor signaling was inhibited by IL-1β in patients with inflammatory bowel syndrome who did not respond to glucocorticoid treatment. "
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    ABSTRACT: Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation,which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus–pituitary–adrenal (HPA) axis have close interactionswith pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation.
    • "Depression is related to several neurobiological changes [1] [2]. Research on the possible molecular pathways of depression demonstrated that the increased cell dysfunction in cortical and limbic areas of the brain can be observed in individuals suffering from depression [3] [4] and is strongly related to the decrease in neurotrophic activity [5]. "
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    ABSTRACT: The pathophysiology of depression is related to neurobiological changes that occur in the monoamine system, hypothalamic-pituitary-adrenal axis, neurogenesis system and the neuroimmune system. In recent years, there has been a growing interest in the research of the effects of exercise on brain function, with a special focus on its effects on brain-derived neurotrophic factor (BDNF), cortisol and other biomarkers. Thus, the aim of this study is to present a review investigating the acute and chronic effects of aerobic exercise on BDNF and cortisol levels in individuals with depression. It was not possible to establish an interaction between aerobic exercise and concentration of BDNF and cortisol, which may actually be the result of the divergence of methods, such as type of exercises, duration of the sessions, and prescribed intensity and frequency of sessions.
    CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 11/2015; · 2.63 Impact Factor
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    • "Neuroscience (2014), recurrence of anxiety and depression (Kiecolt-Glaser et al., 2003; Kinsey et al., 2007; Miller et al., 2009; O'Connor et al., 2009; Hansel et al., 2010). Moreover, social defeat causes region-specific infiltration of peripheral myeloid cells into the brain parenchyma of BM-chimeric mice that is associated with the development of anxiety-like behavior (Wohleb et al., 2013, 2014b). "

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