Skip to main content

Inflammation, Glutamate, and Glia in Depression: A Literature Review

  • Leah McNally, Zubin Bhagwagar and Jonas Hannestad

Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-α treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

Corresponding author
Please direct all correspondence to: Jonas Hannestad, MD, PhD, Yale University School of Medicine, Department of Psychiatry, Clinical Neuroscience Research Unit, 34 Park St., New Haven, CT 06519; Tel: 203-974-7536, Fax: 203-974-7662; E-mail:
Hide All
1.Kessler, RC, Chiu, WT, Demler, O, Merikangas, KR, Walters, EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617627.
2.Kessler, RC, Berglund, P, Delmer, O, Jin, R, Merikangas, KR, Walters, EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:590592.
3.Murray, CJ, Lopez, AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997;349:14361442.
4.Zheng, D, Macera, CA, Croft, JB, Giles, WH, Davis, D, Scott, WK. Major depression and allcause mortality among white adults in the United States. Ann Epidemiol. 1997;7:213218.
5.Cuijpers, P, Smit, F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72:227236.
6.Rivelli, S, Jiang, W. Depression and ischemic heart disease: what have we learned from clinical trials? Curr Opin Cardiol. 2007;22:286291.
7.Taylor, MJ, Freemantle, N, Geddess, JR, Bhagwagar, Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63:12171223.
8.Irwin, MR, Miller, AH. Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav Immun. 2007;21:374383.
9.Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:4546.
10.Raison, CL, Capuron, L, Miller, AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:2431.
11.Penninx, BW, Kritchevsky, SB, Yaffe, K, et, al. Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition Study. Biol Psychiatry. 2003;54:566572.
12.Bremmer, MA, Beekman, AT, Deeg, DJ, et, al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008;106:249255.
13.Zorrilla, EP, Luborsky, L, McKay, JR, et al.The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15:199226.
14.Tuglu, C, Kara, SH, Caliyurt, O, Vardar, E, Abay, E. Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psychopharmacology (Berl). 2003;170:429433.
15.Myint, AM, Leonard, BE, Steinbusch, HW, Kim, YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005;88:167173.
16.Leonard, BE. The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:767780.
17.Kenis, G, Maes, M. Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol. 2002;5:401412.
18.Hestad, KA, Tønseth, S, Støen, CD, Ueland, T, Aukrust, P. Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J Ect. 2003;19:183188.
19.Eller, T, Vasar, V, Shlik, J, Maron, E. Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008,15;32:445450.
20.van den Biggelaar, AH, Gussekloo, J, de Craen, AJ. Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol. 2007;42:693701.
21.Campbell, SJ, Deacon, RM, Jiang, Y, Ferrari, C, Pitossi, FJ, Anthony, DC. Overexpression of IL-1 beta by adenoviral-mediated gene transfer in the rat brain causes a pro-longed hepatic chemokine response, axonal injury and the suppression of spontaneous behaviour. Neurobiol Dis. 2007;27:151–63.
22.Reyes, TM, Coe, CL. Interleukin-1 beta differentially affects interleukin-6 and soluble interleukin-6 receptor in the blood and central nervous system of the monkey. J Neuroimmunol. 1996;66:135141.
23.Levine, J, Barak, Y, Chengappa, KN, Rapoport, A, Rebey, M, Barak, V. Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology. 1999;40:7176.
24.Foster, SL, Hargreaves, DC, Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447:972978.
25.Asnis, GM, De La Garza, R 2nd. Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol. 2006;40:322335.
26.Taylor, JL, Grossberg, SE. The effects of interferon-alpha on the production and action of other cytokines. Semin Oncol. 1998;25:2329.
27.Juengling, FD, Ebert, D, Gut, O. Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology (Berl). 2000;152:383389.
28.Tanaka, H, Maeshima, S, Shigekawa, Y, et, al. Neuropsychological impairment and decreased regional cerebral blood flow by interferon treatment in patients with chronic hepatitis: a preliminary study. Clin Exp Med. 2006;6:124128.
29.Michie, HR, Manogue, KR, Spriggs, DR, et, al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl Med. 1988;318:14811486.
30.Suffredini, AF, Hochstein, HD, McMahon, FG. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli 0:113 endotoxin. J Infect Dis. 1999;179:12781282.
31.Reichenberg, A, Yirmiya, R, Schuld, A, et, al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445452.
32.Wright, CE, Strike, PC, Brydon, L, Steptoe, A. Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun. 2005;19:345350.
33.Müller, N, Schwarz, MJ, Dehning, S, et, al. 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. 2006;11:680684.
34.Tyring, S, Gottlieb, A, Papp, K, et, al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:2935.
35.Simen, BB, Duman, CH, Simen, AA, Duman, RS. TNF alpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiatry. 2006;59:775785.
36.Benton, T, Staab, J, Evans, DL. Medical co-morbidity in depressive disorders. Ann Clin Psychiatry. 2007;19:289303.
37.Elenkov, IJ. Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem Int. 2008;52:4051.
38.Huffman, JC, Smith, FA, Quinn, DK, Fricchione, GL. Post-Ml psychiatric syndromes: six unanswered questions. Harv Rev Psychiatry. 2006;14:305318.
39.Constant, A, Castera, L, Dantzer, R, et al.Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66:10501057.
40.Bower, JE. Cancer-related fatigue: links with inflammation in cancer patients and survivors. Brain Behav Immun. 2007;21:863871.
41.Stewart, JC, Janicki, DL, Muldoon, MF, Sutton-Tyrrell, K, Kamarck, TW. Negative emotions and 3-year progression of subclinical atherosclerosis. Arch Gen Psychiatry. 2007;64:225233.
42.Papakostas, GI, Nutt, DJ, Hallett, LA, Tucker, VL, Krishen, A, Fava, M. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors. Biol Psychiatry. 2006;60:13501355.
43.Capuron, L, Pagnoni, G, Demetrashvili, MF, et al.Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology. 2007;32:23842392.
44.Neumeister, A. Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull. 2003;37:99115.
45.Müller, N, Schwarz, MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12:9881000.
46.Capuron, L, Neurauter, G, Musselman, DL, et al.Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54:906914.
47.Pittenger, C, Sanacora, G, Krystal, JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disord Drug Targets. 2007;6:101115.
48.Palucha, A, Pilc, A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther. 2007;115:116147.
49.Sanacora, G, Gueorguieva, R, Epperson, CN, et al.Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004;61:705713.
50.Bhagwagar, Z, Wylezinska, M, Jezzard, P, et al.Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry. 2007;61:806812.
51.Berman, RM, Cappiello, A, Anand, A, et al.Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351354.
52.Zarate, CA Jr, Singh, JB, Carlson, PJ, et al.A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856864.
53.Zarate, CA Jr, Payne, JL, Quiroz, J, et al.An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161:171174.
54.Sanacora, G, Kendell, SF, Levin, Y, et al.Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61:822825.
55.Saito, K, Crowley, JS, Markey, SP, Heyes, MP. A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J Biol Chem. 1993;268:1549615503.
56.Myint, AM, Kim, YK, Verkerk, R, Scharpé, S, Steinbusch, H, Leonard, B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;98:143151.
57.Fedele, E, Foster, AC. An evaluation of the role of extracellular amino acids in the delayed neurodegeneration induced by quinolinic acid in the rat striatum. Neuroscience. 1993;52:911917.
58.Pocock, JM, Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30:527535.
59.Shibakawa, YS, Sasaki, Y, Goshima, Y, et al.Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth. 2005;95:803810.
60.Rosi, S, Vazdarjanova, A, Ramirez-Amaya, V, Worley, PF, Barnes, CA, Wenk, GL. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience. 2006;142:13031315.
61.Danbolt, NC. Glutamate uptake. Prog Neurobiol. 2001;65:1105.
62.Bergles, DE, Jahr, CE. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci. 1998;18:77097716.
63.Rothstein, JD, Dykes-Hoberg, M, Pardo, CA, et al.Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675686.
64.Tanaka, K, Watase, K, Manabe, T, et al.Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276:16991702.
65.Vercellino, M, Merola, A, Piacentino, C, et al.Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol. 2007;66:732739.
66.McEwen, BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005;54(5 suppl 1):2023.
67.Duman, RS, Monteggia, LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:11161127.
68.Fuchs, E, Czéh, B, Kole, MH, Michaelis, T, Lucassen, PJ. Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol. 2004;14(suppl 5):S481S490.
69.Block, ML, Zecca, L, Hong, JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:5769.
70.Li, L, Lu, J, Tay, SS, Moochhala, SM, He, BP. The function of microglia, either neuroprotection or neurotoxicity, is determined by the equilibrium among factors released from activated microglia in vitro. Brain Res. 2007;1159:817.
71.Hanisch, UK, Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:13871394.
72.Pinteaux, E, Rothwell, NJ, Boutin, H. Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia. 2006;53:551556.
73.Hutchinson, PJ, O'Connell, MT, Rothwell, NJ, et al.Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1 beta, and their endogenous inhibitor IL-1 ra. J Neurotrauma. 2007;24:15451557.
74.Qin, L, Wu, X, Block, ML, et al.Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453462.
75.Maeda, J, Higuchi, M, Inaji, M, et al.Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res. 2007;1157:100111.
76.Mastronardi, C, Whelan, F, Yildiz, OA, et al, Caspase 1 deficiency reduces inflammation-induced brain transcription. Proc Natl Acad Sci USA. 2007;104:72057210.
77.Tikka, TM, Koistinaho, JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166:75277533.
78.Ishikawa, J, Ishikawa, A, Nakamura, S. Interferon-alpha reduces the density of monoaminergic axons in the rat brain. Neuroreport. 2007;18:137140.
79.Hashioka, S, Klegeris, A, Monji, A, et al.Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol. 2007;206:3342.
80.Hannestad, J, Levanti, MB, Vega, JA. Distribution of neurotrophin receptors in human palatine tonsils: an immunohistochemical study. J Neuroimmunol. 1995;58:131137.
81.García-Suáez, O, Hannestad, J, Esteban, I, Sainz, R, Naves, FJ, Vega, JA. Expression of the TrkB neurotrophin receptor by thymic macrophages. Immunology. 1998;94:235241.
82.Asami, T, Ito, T, Fukumitsu, H, Nomoto, H, Furukawa, Y, Furukawa, S. Autocrine activation of cultured macrophages by brain-derived neurotrophic factor. Biochem Biophys Res Commun. 2006;344:941947.
83.Martinowich, K, Manji, H, Lu, B. New insights into BDNF function in depression and anxiety. Nat Neurosci. 2007;10:10891093.
84.Rajkowska, G, Miguel-Hidalgo, JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6:219233.
85.Nägler, K, Mauch, DH, Pfrieger, FW. Glia-derived signals induce synapse formation in neurones of the rat central nervous system. J Physiol. 2001;533(pt 3):665679.
86.Ullian, EM, Sapperstein, SK, Christopherson, KS, Barres, BA. Control of synapse number by glia. Science. 2001;291:657661.
87.Kim, JP, Choi, DW. Quinolinate neurotoxicity in cortical cell culture. Neuroscience. 1987;23:423432.
88.Myint, AM, Kim, YK. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses. 2003;61:519525.
89.Tapia, R. Release and uptake of glutamate as related to excitotoxicity. Rev Bras Biol. 1996;56(suppl 1,pt 1):165174.
90.Lobsiger, CS, Cleveland, DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci. 2007;10:13551360.
91.Frizzo, ME, Dall'Onder, LP, Dalcin, KB, Souza, DO. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol. 2004;24:123128.
92.Fatemi, SH, Laurence, JA, Araghi-Niknam, M, et al.Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. Schizophr Res. 2004;69:317323.
93.Si, X, Miguel-Hidalgo, JJ, O'Dwyer, G, Stockmeier, CA, Rajkowska, G. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology. 2004;29:20882096.
94.Haddy, N, Sass, C, Maumus, S, et al.Biological variations, genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations: STANISLAS cohort. Eur J Hum Genet. 2005;13:109117. Kloet, ER, Joëls, M, Holsboer, F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463475.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed