Is Depression an Inflammatory Disorder?
- 2.5k Downloads
Studies consistently report that groups of individuals with major depressive disorder (MDD) demonstrate increased levels of a variety of peripheral inflammatory biomarkers when compared with groups of nondepressed individuals. These findings are often interpreted as meaning that MDD, even in medically healthy individuals, may be an inflammatory condition. In this article, we examine evidence for and against this idea by looking more closely into what the actual patterns of inflammatory findings indicate in terms of the relationship between MDD and the immune system. Data are presented in support of the idea that inflammation only contributes to depression in a subset of patients versus the possibility that the depressogenic effect of inflammatory activation is more widespread and varies depending on the degree of vulnerability any given individual evinces in interconnected physiologic systems known to be implicated in the etiology of MDD. Finally, the treatment implications of these various possibilities are discussed.
KeywordsMajor depression Fatigue Immune Inflammation Cytokines Interleukin-6 Tumor necrosis factor-α p38 mitogen-activated kinase Psychosocial stress Glucocorticoids Autonomic nervous system Tryptophan Kynurenine Quinolinic acid
Dr. Miller has received grant support and support for travel to meetings from the National Institute of Mental Health.
Dr. Raison has served as a consultant for Biolex Therapeutics and Pamlab.
Dr. Miller has served as a consultant for Schering-Plough Corp., GlaxoSmithKline, Abbott Laboratories, AstraZeneca, Roche, Pfizer, H. Lundbeck A/S, Wyeth, and Johnson & Johnson and has received grant support from Schering-Plough Corp., GlaxoSmithKline, and Centocor.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 8.• Pasco JA, Nicholson GC, Williams LJ, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry 2010;197:372–7. This study was among the first to demonstrate that inflammatory biomarkers predict future depressive status, which is consistent with a causal role for inflammatory processes in the development of depression, even in the absence of documented medical illness. PubMedCrossRefGoogle Scholar
- 14.Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511.PubMedCrossRefGoogle Scholar
- 33.• Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 2010;68:748–54. This study demonstrated that acute exposure to lipopolysaccharide reduces ventral striatal responses to rewarding stimuli, which associates with induction of anhedonia in otherwise nondepressed individuals. This finding collaborates with other data demonstrating a tropism of proinflammatory cytokines for the basal ganglia, and demonstrates that cytokines are capable of producing brain changes observed frequently in MDD. PubMedCrossRefGoogle Scholar
- 35.•• Harrison NA, Brydon L, Walker C, et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009;66:407–14. This was a seminal paper showing that typhoid vaccine induces depressed mood independent of changes in the cingulate cortex that are also commonly observed in MDD. PubMedCrossRefGoogle Scholar
- 55.• Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2011, Epub. This is a comprehensive review of known data supporting a role for inflammation in the pathophysiology and treatment of MDD. Google Scholar
- 67.• Felger JC, Alagbe O, Pace TW, et al. Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue. Brain Behav Immun. 2011, Epub. This study demonstrated that activity in inflammation-related intracellular signaling cascades in response to an initial inflammatory stimulus (IFN-α) strongly predicts the later development of depressive symptoms during chronic cytokine exposure. Google Scholar
- 76.•• Raison CL, Dantzer R, Kelley KW, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 2010;15:393–403. Data in this article support a recent conceptual shift in the role of tryptophan metabolism in the etiology of depression from a focus on reduced serotonin to increased catabolites along the kynurenine pathway. PubMedCrossRefGoogle Scholar
- 82.Wang Y, Yang F, Liu YF, et al. Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett. 2011, Epub.Google Scholar