• Users Online: 376
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 155-160

Depression and inflammation: Pathophysiology and therapeutic implications

Department of Physiology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India

Date of Web Publication9-Jun-2016

Correspondence Address:
Deepti Jangpangi
C/O Mr. Pankaj Pangtey, C 2/11, Flat No. 3, First Floor, IGNOU Road, Saidula Jaib Ext, New Delhi - 110 030
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2348-3334.183728

Rights and Permissions

Depression may result in far reaching adverse health outcomes in addition to impaired sociooccupational or quality of life. Depression is commonly associated with greater cardiovascular morbidity and mortality. Dysregulated inflammation has been suggested as one of the plausible underlying mechanism relating the two. Several studies have reported elevated levels of proinflammatory cytokines and acute phase proteins in depression patients. The proinflammatory cytokines have been shown to alter various signaling pathway relevant to depression such as neurotransmitter metabolism, neuroendocrine dysfunction, and synaptic plasticity after reaching the brain. Potential pathways which have been implicated in mediating the depression and inflammation include the tryptophan-kynurenine pathway, hypothalamic-pituitary-adrenal axis dysregulation, and neuronal plasticity. Inflammation appears to play a pivotal role in the pathophysiology of depression but only in subset of depressive patients. It may prove to be an effective target to develop several treatment modalities and thus open avenues for development of potential therapeutic strategies in vulnerable at risk depressive patients.

Keywords: Cardiovascular disease, depression, inflammation

How to cite this article:
Jangpangi D. Depression and inflammation: Pathophysiology and therapeutic implications. CHRISMED J Health Res 2016;3:155-60

How to cite this URL:
Jangpangi D. Depression and inflammation: Pathophysiology and therapeutic implications. CHRISMED J Health Res [serial online] 2016 [cited 2022 Jan 20];3:155-60. Available from: https://www.cjhr.org/text.asp?2016/3/3/155/183728

  Introduction Top

Major depressive disorder (MDD) is a psychiatric illness of major public health importance. The implications of MDD extends from having a decreased quality of life and altered sociooccupational functioning to increased cardiovascular morbidity and mortality risk, which have been found to be associated with depression. [1],[2] Moreover, depression has been listed as the third leading cause of disease burden worldwide which further adds to its paramount importance as an illness. [3]

For several decades depletion or imbalance of monoaminergic neurotransmission has been accepted as an etiology of Depressive disorder and majority of current treatment modalities focus on targeting the monoamines relevant to depression. [4] However, current therapeutic approaches in a form of conventional antidepressants have not been able to achieve remission in the minority of patients. [5] Therefore, there is a current and pressing need to look further into the role of other neurobiological mechanisms that contributes to depression which may help in developing novel and effective therapeutic strategies by targeting them. [6]

There are accumulating evidence indicating an association of inflammation and depression. Several studies have revealed an increase in inflammatory markers in patients of depression. [7] In the current review, we will discuss the potential mechanisms linking inflammation and depression and further its therapeutic implications.

  Research methodology Top

Electronic databases of MEDLINE (PubMed) and Google Scholar search engines were searched for relevant studies and reviews published from 1990 to 2015. The keywords used were "major depression," "inflammation," "innate immune response," "proinflammatory cytokines," "Pathophysiology," and "cardiovascular disease." In addition, the reference list of relevant recently published articles and reviews were also screened. Titles, abstracts, and full-texts of peer-reviewed articles about related topics published in English were included.

  Depression, Immune System, and Inflammation Top

Immune system is crucial for host survival as it helps in initiating and coordinating the host defense mechanisms against microbial invasion or tissue injury by generating an inflammatory response. Immune system comprises two components first is innate immunity and second adaptive immunity. Innate immune response is one of ancient first line defense mechanism which acts rapidly when encountered with pathogens or tissue damage. [8] Cells of innate immune response such as neutrophils, macrophages, and dendritic cells expressed a germ-line encoded receptors referred as pattern recognition receptors (PRRs). One of the important families of PRR is Toll-like receptors. These receptors which are expressed by cells of innate immune response play a major role in recognition of conserved molecular components known as pathogen-associated molecular patterns (PAMPs) which are commonly found in the majority of pathogens, but not normally found in the host. [9] After recognition of microbes, toll-like receptors binds with PAMP and initiate a cascade of inflammatory signaling pathway resulting in activation of transcription factors such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and interferon regulatory factor 1 (IRF-1). These transcription factors further induce the production of proinflammatory cytokines such as interleukin-6 (IL-6), IL-1, tumor necrosis factor-alpha (TNF-α). [10],[11] These cytokines then enters the blood and activates the acute phase response in the liver, leading to the production of several acute-phase proteins such as C-reactive protein (CRP). [12]

Moreover, innate immunity on activation if not sufficient to eliminate pathogens also leads to activation of microbial-specific adaptive immunity which is mediated by antigen-specific T and B lymphocytes. Cytokines are the soluble proteins that play a pivotal role in mediating immune and subsequently an inflammatory response. [13],[14] The cytokines that up-regulate an immune-inflammatory response are referred as proinflammatory such as IL-6, IL-1, TNF-α and help enhance inflammation and induce changes in infected tissues including redness, heat, swelling, and pain commonly known as signs of inflammation. [8] Besides these, they also orchestrate sociobehavioral changes such as fatigue, social withdrawal, altered sleep and anorexia called as sickness behavior which is strikingly similar to occur in depressive disorders. These behavioral changes in a way aid in containment of infection and recovery. [15] Once the inflammatory response system have succeeded in containing the infection the overall response shifts to anti-inflammatory signals which take over and bring about resolution of inflammation and normal homeostasis. [16] Inflammation is a tightly regulated response to infection or tissue injury which must be regulated precisely as if it is insufficient or in excess may lead to infection, considerable morbidity, and even mortality. [17]

In the current scenario, studies relating the altered innate immune response, inflammation and depression dominates the literature, although there have been studies which have also tried to ascertain the role played by the altered adaptive immune response in depression. In accordance with earlier studies, a recent meta-analytic review has shown the association of depression and stress with a decrease in the percentage of lymphocytes. [18]

There are many observations consistently provided by several studies which have emphasized the role of inflammation in the pathophysiology of depression. Patients of depressive disorder have been found to be having elevated concentrations of several proinflammatory cytokines including IL-1, IL-6, and TNF-α along with acute phase protein CRP not only in peripheral blood but also in cerebrospinal fluid (CSF). [19] A meta-analysis performed by Howren et al., have found each inflammatory marker IL-6, IL-1, CRP was positively associated with depression, with the strongest association found in clinically depressed patients groups. [20] In an another recent study also reveal elevated inflammatory markers IL-6 and TNF-α in MDD patients. [21] Elevated inflammatory cytokines which are found to be present in patients of depression, there levels were found to reduce the following treatment. [22] Although, there are some studies which showed inconclusive and conflicting results since they were unable to find any association. For instance, Kagaya et al. compared depressed patients with age- and sex-matched healthy controls and levels of IL-6, TNF-α, and IL-1 showed no significant differences between the two groups. [23] Similarly, a study by Pan et al. reported no association between depressive symptoms and CRP levels. [24] These observations may be attributed to heterogeneity of disease and methodological differences in studies but also reflect that altered inflammatory response might contribute to etiology of depression only in subpopulation of vulnerable depressive patients. [19]

The other observation which provides insight being the co-occurrence of several inflammatory illnesses with depression prominently being cardiovascular diseases, diabetes, and some autoimmune diseases. [7] Inflammation has been suggested as one of the plausible mechanisms as the common underlying biologic process of low-grade inflammation is present in both of them. [25]

The other finding which is notable in examining the relationship is on exposure of cytokines such as interferon-alpha (IFN-α) and IL-2 which are used for treatment in chronic hepatitis C and cancer have resulted in occurrence of depression in those individuals. Moreover, depressive symptoms which were induced by IFN-α were associated with changes in serum cytokines levels. [26]

Another link which might explain the association of depression and altered inflammatory response in medically healthy individual is stress which is considered as a major risk factor for depression has been observed to activate inflammatory signaling pathways both in the periphery and in central nervous system (CNS). [27] Experimental studies carried out in animals have reported that psychological stressors increase proinflammatory cytokines levels including IL-1β and TNF-α in the brain as well as in periphery. [28] The sympathetic nervous system may also provide a link between stress and depression as stress-induced activation of the sympathetic nervous system has been found to be associated with proinflammatory cytokines activation in the periphery. [29],[30] Recent meta-analysis has drawn special attention to the role of a short (s) allele polymorphic variant in the promoter region of the serotonin transporter (SERT) gene (5-HTTLPR) in the propensity to depression in the presence of stressor. Those subjects who were carrying this less functional short allele polymorphic variant have reduced uptake of neurotransmitter serotonin into the presynaptic neurons of the brain and showed greater sensitivity to stress. [31]

Most studies conducted are cross-sectional in nature studying the association between inflammatory markers and depression does not tell about the causal direction of the association. Whether depression is resulting in inflammatory pathways activation or inflammatory illness/stress is culminating in depressive symptoms or whether there is a bidirectional relationship is still unclear. There are some prospective studies which have addressed the directionality of association. Stewart et al. reported baseline beck depression inventory-II (BDI-II) which is used to assess depressive symptoms was a predictor of 6-year change in IL-6 but baseline IL-6 did not predict 6 year change in BDI-II. [32] While Gimeno et al. studied both directions of association and reported baseline IL-6 and CRP were predictive of 12-year change in cognitive symptoms of depression. Thus, it can be said that depression-inflammation relationship is bidirectional and complex. [33]

  Potential pathways mediating depression and inflammation Top

The different routes by which peripheral cytokines signal the brain has been proposed [30] are firstly through the leaky areas of the blood-brain barrier (BBB) like a circumventricular organ. Second, by directly across the BBB via binding with their specific transporters present in BBB. Another mechanism by which cytokines can reach the brain is along the afferent vagal fibers. Finally, an endothelial cell present in BBB gets activated by peripheral cytokines which then result in increased release of cytokines.

As we know that depression exhibits increased levels of cytokines in the peripheral blood. A bidirectional relationship seems to exist between peripheral and central neuronal pathways since peripheral cytokines once reaching the brain bring about changes by modulating several signaling pathways which are relevant to depression including neurotransmitter metabolism, neuroendocrine function, neuronal plasticity, and excitotoxicity. [34] Microglia astrocytes which are cells of the neuronal system have receptors and are capable of producing cytokines in the brain following signaling by peripheral cytokines. [19]

  Depression and Tryptophan-Kynurenine Pathway Top

Serotonin is a major neurotransmitter in the brain whose dysregulation plays a major etiological role in depression. Inflammatory cytokines by the modulating serotonergic system may mediate depressive symptoms. [35]

Tryptophan is an essential amino acid required as a substrate for serotonin (5-HT) synthesis with the help of enzyme tryptophan hydroxylase. Proinflammatory cytokines like IFN-γ, TNF-α have been implicated in upregulation of indoleamine 2,3 dioxygenase (IDO) which is a rate limiting enzyme in the tryptophan-kynurenine pathway, by activation of several signaling pathways such as signal transducer and activator of transcription 1α, IRF-1, p38 MAPK, and NF-κB. IFNs are most notable inducer of IDO. [36]

IDO leads to increased formation of kynurenine from tryptophan resulting in decrease availability of tryptophan as a substrate for serotonin synthesis in neurons. Cytokines induce IDO expression in several immune cells including macrophages and microglia. [37] Moreover, the role of kynurenine metabolites has also been proposed in the development of depression. Kynurenine further metabolized to 3 hydroxy kynurenine and quinolinic acid in astrocytes and glia. These kynurenine metabolites have neurotoxic properties due to their ability to generate reactive oxygen species. [38] Quinolinic acid being a N-methyl-D-aspartate (NMDA) agonist stimulate increased glutamate release further resulting in CNS excitotoxicity. One of the metabolites referred as kynurenic acid being NMDA antagonist has been termed neuroprotective. [39] Moreover, it has also been shown that cytokines by inducing the neuronal SERT activity decrease the availability of serotonin for serotonergic neurotransmission. [40] Besides serotonin, researches in animal studies suggest the role of cytokines in decreasing the concentration of dopamine by stimulating nitric oxide (NO) synthesis and thereby decreasing the availability of tetrahydrobiopterin (BH4) which acts as a cofactor for tyrosine hydroxylase which is a rate-limiting enzyme in dopamine synthesis. As BH4 also required for NO synthesis. [41]

  Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Depression Top

Hypothalamic-pituitary-adrenal (HPA) axis is a central neuroendocrine system that regulates stress response in the body. Current researches have consistently emphasized the role of HPA axis dysfunction in the pathophysiology of depression. [42] Evidence suggest that cytokines can activate HPA axis and have been shown to stimulate the release of corticotropin-releasing hormone (CRH) in the brain. Patients of depression have been found to have elevated levels of cortisol in plasma, urine, and also increased levels of CRH in CSF. [43] When CRH has been administered in lab animals, it resulted in various behavioral alterations as those found in depression. [44]

Another mechanism by which cytokines may lead to HPA axis dysfunction is by inducing glucocorticoid resistance implying decreased responsiveness to glucocorticoids by impairing the functionality of glucocorticoid receptors (GRs) and also decreasing the expression of GRs. [45] Hyperactivity of CRH partly may have occurred due to altered glucocorticoid-mediated feedback inhibition of CRH production due to glucocorticoid resistance as demonstrated by nonsuppression of glucocorticoid cortisol to dexamethasone during dexamethasone suppression test. [46] Cytokines and their signaling pathways may affect GR function at several levels of glucocorticoid-mediated GR signaling. The expression of GR, GR-alpha isoform which is required for binding glucocorticoids during glucocorticoid signaling pathways is found to be reduced in patients of depression. [47] Cytokines have also been implicated in decreasing the function of GR by inducing various signaling proteins such as MAPK and interfering the cortisol-GR translocation from cytoplasm to the nucleus and also further preventing the GR complex binding to DNA thus impairing glucocorticoid signaling. [45],[48]

  Neuronal plasticity Top

Neuronal plasticity is an ability of the brain to adapt itself against several environmental challenges. The proinflammatory cytokines when dysregulated in CNS either due to inflammation or environmental stimuli like stress have shown to decrease neurogenesis, inducing of apoptosis and also causing modulation of synaptic function through an increase in α-amino -3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. [49],[50] Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor which is an important mediator of neurogenesis and neuron survival and found in brain regions involved in plasticity might provide a link between inflammation and neural plasticity. Animal studies have found decreased BDNF gene expression following the administration of proinflammatory cytokines or lypopolysacharide (LPS). [51]

  Therapeutic implications Top

The role of inflammation in the pathophysiology of depression may provide a novel therapeutic strategy targeting inflammation in subset of patients exhibiting increased in inflammatory cytokines. The therapeutic treatment for depression targeting inflammation is still in the investigative stage, and several antidepressants have shown to decrease the inflammatory cytokines in patients of depression. [52] TNF-α antagonist infliximab has proved to be useful in improving depression in treatment-resistant depressive patients with increased inflammatory cytokines. [53] Agents like celecoxib which target inflammatory signaling are cyclooxygenase-2 inhibitors which if used along with antidepressant treatment have shown to increase the efficacy of antidepressant in depressive patients. [54] The inhibitor of IDO, 1 methyl tryptophan have also shown to inhibit LPS-induced depressive-like behavior in animal studies [55] and glutamate receptor antagonist such as NMDA antagonist ketamine have also proved to be useful. [56]

  Conclusion Top

The review highlights the etiological role inflammation plays in the pathophysiology of depression. Depression being of multifactorial etiology resulting from the interaction of environmental and genetic factors, therefore not every depression patient will exhibit dysregulated inflammation but occur in subgroup of depression patients. [19] The inflammation could provide a potential therapeutic strategy in subset of depression patients exhibiting increased inflammation and treatment resistant to conventional antidepressants. The identification of potential inflammatory biomarkers further will not only aid in identifying vulnerable, at-risk patients but will also assist in preventing cardiovascular morbidity and mortality found to be associated with depressive disorder.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Grover S, Dutt A, Avasthi A. An overview of Indian research in depression. Indian J Psychiatry 2010;52 Suppl 1:S178-88.  Back to cited text no. 1
Carney RM, Freedland KE, Miller GE, Jaffe AS. Depression as a risk factor for cardiac mortality and morbidity: A review of potential mechanisms. J Psychosom Res 2002;53:897-902.  Back to cited text no. 2
Charlson FJ, Stapelberg NJ, Baxter AJ, Whiteford HA. Should global burden of disease estimates include depression as a risk factor for coronary heart disease? BMC Med 2011;9:47.  Back to cited text no. 3
Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 2000;61 Suppl 6:4-6.  Back to cited text no. 4
Robinson DS. Remission of depression: How effective are antidepressants? Prim Psychiatry 2005;12:17-8.  Back to cited text no. 5
Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358:55-68.  Back to cited text no. 6
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24-31.  Back to cited text no. 7
Barton GM. A calculated response: Control of inflammation by the innate immune system. J Clin Invest 2008;118:413-20.  Back to cited text no. 8
Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature 2007;449:819-26.  Back to cited text no. 9
Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009;21:317-37.  Back to cited text no. 10
Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response. Biochem J 2009;420:1-16.  Back to cited text no. 11
Maes M. A review on the acute phase response in major depression. Rev Neurosci 1993;4:407-16.  Back to cited text no. 12
Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. The immune system in health and disease. Harrison′s Principles of Internal Medicine. 19 th ed. New York: McGraw Hill; 2015.  Back to cited text no. 13
Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. Psychol Bull 2014;140:774-815.  Back to cited text no. 14
Maes M, Berk M, Goehler L, Song C, Anderson G, Galecki P, et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 2012;10:66.  Back to cited text no. 15
Serhan CN. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 2007;25:101-37.  Back to cited text no. 16
Tracey KJ. The inflammatory reflex. Nature 2002;420:853-9.  Back to cited text no. 17
Miller AH. Depression and immunity: A role for T cells? Brain Behav Immun 2010;24:1-8.  Back to cited text no. 18
Krishnadas R, Cavanagh J. Depression: An inflammatory illness? J Neurol Neurosurg Psychiatry 2012;83:495-502.  Back to cited text no. 19
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosom Med 2009;71:171-86.  Back to cited text no. 20
Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and meta-regression. J Affect Disord 2012;139:230-9.  Back to cited text no. 21
Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis. Neuropsychopharmacology 2011;36:2452-9.  Back to cited text no. 22
Kagaya A, Kugaya A, Takebayashi M, Fukue-Saeki M, Saeki T, Yamawaki S, et al. Plasma concentrations of interleukin-1beta, interleukin-6, soluble interleukin-2 receptor and tumor necrosis factor alpha of depressed patients in Japan. Neuropsychobiology 2001;43:59-62.  Back to cited text no. 23
Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PLoS One 2008;3:e1392.  Back to cited text no. 24
Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R, et al. Illness, cytokines, and depression. Ann N Y Acad Sci 2000;917:478-87.  Back to cited text no. 25
Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ, et al. Activation of central nervous system inflammatory pathways by interferon-alpha: Relationship to monoamines and depression. Biol Psychiatry 2009;65:296-303.  Back to cited text no. 26
Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 2008;105:751-6.  Back to cited text no. 27
O′Connor KA, Johnson JD, Hansen MK, Wieseler Frank JL, Maksimova E, Watkins LR, et al. Peripheral and central proinflammatory cytokine response to a severe acute stressor. Brain Res 2003;991:123-32.  Back to cited text no. 28
Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN, et al. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 2005;135:1295-307.  Back to cited text no. 29
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732-41.  Back to cited text no. 30
Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry 2011;68:444-54.  Back to cited text no. 31
Stewart JC, Rand KL, Muldoon MF, Kamarck TW. A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun 2009;23:936-44.  Back to cited text no. 32
Gimeno D, Kivimäki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A, et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 2009;39:413-23.  Back to cited text no. 33
Miller AH, Raison CL. Immune system contributes to the pathophysiology of depression. Focus 2008;6:36-45.  Back to cited text no. 34
Capuron L, Miller AH. Immune system to brain signaling: Neuropsychopharmacological implications. Pharmacol Ther 2011;130:226-38.  Back to cited text no. 35
Fujigaki H, Saito K, Fujigaki S, Takemura M, Sudo K, Ishiguro H, et al. The signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide: Involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways, and synergistic effect of several proinflammatory cytokines. J Biochem 2006;139:655-62.  Back to cited text no. 36
Guillemin GJ, Smythe G, Takikawa O, Brew BJ. Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 2005;49:15-23.  Back to cited text no. 37
Christmas DM, Potokar J, Davies SJ. A biological pathway linking inflammation and depression: Activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat 2011;7:431-9.  Back to cited text no. 38
Schwarcz R, Pellicciari R. Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 2002;303:1-10.  Back to cited text no. 39
Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 2006;31:2121-31.  Back to cited text no. 40
Kitagami T, Yamada K, Miura H, Hashimoto R, Nabeshima T, Ohta T. Mechanism of systemically injected interferon-alpha impending monoamine biosynthesis in rats: Role of nitric oxide as a signal crossing the blood-brain barrier. Brain Res 2003;978:104-14.  Back to cited text no. 41
Zunszain PA, Anacker C, Cattaneo A, Carvalho LA, Pariante CM. Glucocorticoids, cytokines and brain abnormalities in depression. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:722-9.  Back to cited text no. 42
Pariante CM, Miller AH. Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment. Biol Psychiatry 2001;49:391-404.  Back to cited text no. 43
Nemeroff CB. The corticotropin-releasing factor (CRF) hypothesis of depression: New findings and new directions. Mol Psychiatry 1996;1:336-42.  Back to cited text no. 44
Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007;21:9-19.  Back to cited text no. 45
Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000;23:477-501.  Back to cited text no. 46
Matsubara T, Funato H, Kobayashi A, Nobumoto M, Watanabe Y. Reduced glucocorticoid receptor alpha expression in mood disorder patients and first-degree relatives. Biol Psychiatry 2006;59:689-95.  Back to cited text no. 47
De Bosscher K, Haegeman G. Minireview: Latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrinol 2009;23:281-91.  Back to cited text no. 48
Kubera M, Obuchowicz E, Goehler L, Brzeszcz J, Maes M. In animal models, psychosocial stress-induced (neuro) inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:744-59.  Back to cited text no. 49
Khairova RA, Machado-Vieira R, Du J, Manji HK. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 2009;12:561-78.  Back to cited text no. 50
Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R. Brain-derived neurotrophic factor: A bridge between inflammation and neuroplasticity. Front Cell Neurosci 2014;8:430.  Back to cited text no. 51
Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 2013;246:199-229.  Back to cited text no. 52
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry 2013;70:31-41.  Back to cited text no. 53
Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, 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;11:680-4.  Back to cited text no. 54
O′Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N, et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 2009;14:511-22.  Back to cited text no. 55
aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010;67:139-45.  Back to cited text no. 56

This article has been cited by
1 Herbal bioactives in treatment of inflammation: An overview
Mukta Gupta,Naresh Singh,Monica Gulati,Reena Gupta,Kalvatala Sudhakar,Bhupinder Kapoor
South African Journal of Botany. 2021; 143: 205
[Pubmed] | [DOI]
2 The Nrf2 pathway in psychiatric disorders: pathophysiological role and potential targeting
Ranjana Bhandari,Japneet Kaur,Simerpreet Kaur,Anurag Kuhad
Expert Opinion on Therapeutic Targets. 2021;
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Research methodology
Potential pathwa...
Neuronal plasticity
Therapeutic impl...
Depression, Immu...
Depression and T...

 Article Access Statistics
    PDF Downloaded299    
    Comments [Add]    
    Cited by others 2    

Recommend this journal