Inflammation and Depression
Major depressive disorder (MDD) is a complex illness and it is likely that alterations in several interacting systems underlie its pathogenesis. Numerous hypotheses have been proposed to elucidate its origins. The inflammatory hypothesis emphasises the role of psycho-neuroimmunological dysfunctions. This is based on several observations: subsets of MDD patients have an altered peripheral immune system, with impaired cellular immunity and increased levels of proinflammatory cytokines; cytokines can influence neurotransmitter metabolism, neuroendocrine function and regional brain activity, all of which are relevant to depression; acute administration of cytokines causes sickness behaviour which shares features with depression, and patients undergoing cytokine treatment develop depressive symptoms. In this chapter, we discuss the evidence linking inflammation and MDD, looking at data from clinical and animal studies, the role of stress, possible mechanisms and the involvement of genetic polymorphisms. Further understanding of pathways involved is still needed. This will be vital for the identification of new drug targets and preventative strategies.
KeywordsCytokines Inflammatory Neuroendocrine Neurotransmitter Stress
CMP has been funded by the UK MRC since 1999, first as a Clinical Training Fellow, and currently as an MRC Clinician Scientist Fellow. His research is also funded by the NIHR South London and Maudsley NHS Foundation Trust and Institute of Psychiatry Specialist Biomedical Research Centre for Mental Health, the NARSAD, the APIRE, the British Academy and the European Union Framework 7. PZ is funded by a NARSAD Young Investigator Award. The authors have no relevant financial interest to disclose.
- Baune BT, Dannlowski U, Domschke K, Janssen DG, Jordan MA, Ohrmann P, Bauer J, Biros E, Arolt V, Kugel H, Baxter AG, Suslow T (2010) The interleukin 1 beta (IL1B) gene is associated with failure to achieve remission and impaired emotion processing in major depression. Biol Psychiatry 67:543–549PubMedCrossRefGoogle Scholar
- Ben Menachem-Zidon O, Goshen I, Kreisel T, Ben Menahem Y, Reinhartz E, Ben Hur T, Yirmiya R (2008) Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis. Neuropsychopharmacology 33:2251–2262PubMedCrossRefGoogle Scholar
- Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, Almerighi C, Verkerk R, Meltzer H, Maes M (2002) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 22:86–90PubMedCrossRefGoogle Scholar
- Bull SJ, Huezo-Diaz P, Binder EB, Cubells JF, Ranjith G, Maddock C, Miyazaki C, Alexander N, Hotopf M, Cleare AJ, Norris S, Cassidy E, Aitchison KJ, Miller AH, Pariante CM (2009) Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry 14:1095–1104PubMedCrossRefGoogle Scholar
- Galvao-de Almeida A, Quarantini LC, Sampaio AS, Lyra AC, Parise CL, Parana R, de Oliveira IR, Koenen KC, Miranda-Scippa A, Guindalini C (2011) Lack of association of indoleamine 2,3-dioxygenase polymorphisms with interferon-alpha-related depression in hepatitis C. Brain Behav Immun 25:1491–1497PubMedCrossRefGoogle Scholar
- Kuzumaki N, Ikegami D, Imai S, Narita M, Tamura R, Yajima M, Suzuki A, Miyashita K, Niikura K, Takeshima H, Ando T, Ushijima T, Suzuki T (2010) Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse 64:721–728Google Scholar
- Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785PubMedCrossRefGoogle Scholar
- Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11:680–684PubMedCrossRefGoogle Scholar
- Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, Spivey JR, Saito K, Miller AH (2010b) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15:393–403PubMedCrossRefGoogle Scholar
- Rondanelli M, Giacosa A, Opizzi A, Pelucchi C, La Vecchia C, Montorfano G, Negroni M, Berra B, Politi P, Rizzo AM (2011) Long chain omega 3 polyunsaturated fatty acids supplementation in the treatment of elderly depression: effects on depressive symptoms, on phospholipids fatty acids profile and on health-related quality of life. J Nutr Health Aging 15:37–44PubMedCrossRefGoogle Scholar
- Smith AK, Simon JS, Gustafson EL, Noviello S, Cubells JF, Epstein MP, Devlin DJ, Qiu P, Albrecht JK, Brass CA, Sulkowski MS, McHutchinson JG, Miller AH (2011) Association of a polymorphism in the indoleamine-2,3-dioxygenase gene and interferon-alpha-induced depression in patients with chronic hepatitis C. Mol Psychiatry. [Epub ahead of print]Google Scholar
- Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367:29–35PubMedCrossRefGoogle Scholar