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

• Type of Material: Article
• Authors: Andrew H Miller, Emory University; Vladimir Maletic, University of South Carolina; Charles L. Raison, Emory University
• Language: English
• Date: 2009-05-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009, Elsevier
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2008.11.029
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 65
• Issue: 9
• Start Page: 732
• End Page: 741
• Grant/Funding Information: This study was supported in part by grants from the National Institutes of Health (NIH) (K05 MH069124, K23 MH064619, R01 MH070553, R01 HL073921, T32 MH020018), an NIH/National Center for Research Resources (NCRR) General Clinical Research Center Grant (M01 RR00039), and the Centers for Disease Control and Prevention.; Andrew H. Miller has received research support from Schering-Plough, Centocor, and GlaxoSmithKline.
• Keywords: monoamines; inflammation; Cytokines; depression; hypothalamic-pituitary-adrenal axis; stress; excitotoxicity
• Research Categories: Psychology, Physiological; Health Sciences, General; Health Sciences, Pathology

Abstract

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.