Skip to main content
Top
Published in: Current Psychiatry Reports 6/2011

01-12-2011 | Unipolar Disorders (Michael E. Thase, Section Editor)

Is Depression an Inflammatory Disorder?

Authors: Charles L. Raison, Andrew H. Miller

Published in: Current Psychiatry Reports | Issue 6/2011

Login to get access

Abstract

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.
Literature
1.
go back to reference Blume J, Douglas SD, Evans DL. Immune suppression and immune activation in depression. Brain Behav Immun. 2011;25:221–9.PubMedCrossRef Blume J, Douglas SD, Evans DL. Immune suppression and immune activation in depression. Brain Behav Immun. 2011;25:221–9.PubMedCrossRef
2.
go back to reference O’Connor MF, Bower JE, Cho HJ, et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun. 2009;23:887–97.PubMedCrossRef O’Connor MF, Bower JE, Cho HJ, et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun. 2009;23:887–97.PubMedCrossRef
3.
go back to reference De Berardis D, Conti CM, Serroni N, et al. The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature. Int J Immunopathol Pharmacol. 2010;23:417–22.PubMed De Berardis D, Conti CM, Serroni N, et al. The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature. Int J Immunopathol Pharmacol. 2010;23:417–22.PubMed
4.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
5.
go back to reference Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.PubMedCrossRef Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.PubMedCrossRef
6.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
7.
go back to reference Zorilla E, Luborsky L, McKay J, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15:199–226.CrossRef Zorilla E, Luborsky L, McKay J, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15:199–226.CrossRef
8.
go back to reference • 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. PubMedCrossRef • 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. PubMedCrossRef
9.
go back to reference Vaccarino V, Johnson BD, Sheps DS, et al. Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol. 2007;50:2044–50.PubMedCrossRef Vaccarino V, Johnson BD, Sheps DS, et al. Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol. 2007;50:2044–50.PubMedCrossRef
10.
go back to reference Huang TL, Lin FC. High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania. Progr Neuropsychopharmacol Biol Psychiatry. 2007;31:370–2.CrossRef Huang TL, Lin FC. High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania. Progr Neuropsychopharmacol Biol Psychiatry. 2007;31:370–2.CrossRef
11.
go back to reference Liukkonen T, Silvennoinen-Kassinen S, Jokelainen J, et al. The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biol Psychiatry. 2006;60:825–30.PubMedCrossRef Liukkonen T, Silvennoinen-Kassinen S, Jokelainen J, et al. The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biol Psychiatry. 2006;60:825–30.PubMedCrossRef
12.
go back to reference Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study. Eur Heart J. 2004;25:492–9.PubMedCrossRef Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study. Eur Heart J. 2004;25:492–9.PubMedCrossRef
13.
go back to reference Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med. 2003;65:347–56.PubMedCrossRef Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med. 2003;65:347–56.PubMedCrossRef
14.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
15.
go back to reference Vidula H, Tian L, Liu K, et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Ann Intern Med. 2008;148:85–93.PubMed Vidula H, Tian L, Liu K, et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Ann Intern Med. 2008;148:85–93.PubMed
16.
go back to reference Ridker PM. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–43.PubMedCrossRef Ridker PM. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–43.PubMedCrossRef
17.
go back to reference Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007;65:S253–9.PubMedCrossRef Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007;65:S253–9.PubMedCrossRef
18.
go back to reference Heikkila K, Ebrahim S, Lawlor DA. A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health. 2007;61:824–33.PubMedCrossRef Heikkila K, Ebrahim S, Lawlor DA. A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health. 2007;61:824–33.PubMedCrossRef
19.
go back to reference Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–34.PubMedCrossRef Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–34.PubMedCrossRef
20.
go back to reference Laurin D, David Curb J, Masaki KH, et al. Midlife C-reactive protein and risk of cognitive decline: a 31-year follow-up. Neurobiol Aging. 2009;30:1724–7.PubMedCrossRef Laurin D, David Curb J, Masaki KH, et al. Midlife C-reactive protein and risk of cognitive decline: a 31-year follow-up. Neurobiol Aging. 2009;30:1724–7.PubMedCrossRef
21.
go back to reference Capuron L, Fornwalt FB, Knight BT, et al. Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord. 2009;119:181–5.PubMedCrossRef Capuron L, Fornwalt FB, Knight BT, et al. Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord. 2009;119:181–5.PubMedCrossRef
22.
go back to reference Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric side effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19:1–19.CrossRef Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric side effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19:1–19.CrossRef
23.
go back to reference Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961–6.PubMedCrossRef Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961–6.PubMedCrossRef
24.
go back to reference Capuron L, Gumnick JF, Musselman DL, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacol. 2002;26:643–52.CrossRef Capuron L, Gumnick JF, Musselman DL, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacol. 2002;26:643–52.CrossRef
25.
go back to reference Prather AA, Rabinovitz M, Pollock BG, Lotrich FE. Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality. Brain Behav Immun. 2009;23:1109–16.PubMedCrossRef Prather AA, Rabinovitz M, Pollock BG, Lotrich FE. Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality. Brain Behav Immun. 2009;23:1109–16.PubMedCrossRef
26.
go back to reference Raison CL, Borisov AS, Woolwine BJ, et al. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010;15:535–47.PubMedCrossRef Raison CL, Borisov AS, Woolwine BJ, et al. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010;15:535–47.PubMedCrossRef
27.
28.
go back to reference Schafer A, Scheurlen M, Seufert J, et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible association with interferon-induced depression. J Hepatol. 2010;52:10–5.PubMedCrossRef Schafer A, Scheurlen M, Seufert J, et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible association with interferon-induced depression. J Hepatol. 2010;52:10–5.PubMedCrossRef
29.
go back to reference Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160:1342–5.PubMedCrossRef Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160:1342–5.PubMedCrossRef
30.
go back to reference Wright CE, Strike PC, Brydon L, Steptoe A. Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun. 2005;19:345–50.PubMedCrossRef Wright CE, Strike PC, Brydon L, Steptoe A. Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun. 2005;19:345–50.PubMedCrossRef
31.
go back to reference Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–52.PubMedCrossRef Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–52.PubMedCrossRef
32.
go back to reference Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–63.PubMedCrossRef Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–63.PubMedCrossRef
33.
go back to reference • 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. PubMedCrossRef • 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. PubMedCrossRef
34.
go back to reference Harrison NA, Brydon L, Walker C, et al. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66:415–22.PubMedCrossRef Harrison NA, Brydon L, Walker C, et al. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66:415–22.PubMedCrossRef
35.
go back to reference •• 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. PubMedCrossRef •• 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. PubMedCrossRef
36.
go back to reference Brydon L, Harrison NA, Walker C, et al. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008;63:1022–9.PubMedCrossRef Brydon L, Harrison NA, Walker C, et al. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008;63:1022–9.PubMedCrossRef
37.
go back to reference Capuron L, Pagnoni G, Demetrashvili MF, et al. Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacol. 2007;32:2384–92.CrossRef Capuron L, Pagnoni G, Demetrashvili MF, et al. Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacol. 2007;32:2384–92.CrossRef
38.
go back to reference Capuron L, Pagnoni G, Demetrashvili M, et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry. 2005;58:190–6.PubMedCrossRef Capuron L, Pagnoni G, Demetrashvili M, et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry. 2005;58:190–6.PubMedCrossRef
39.
go back to reference Gimeno D, Kivimaki M, Brunner EJ, 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. 2008;39:413–23.PubMedCrossRef Gimeno D, Kivimaki M, Brunner EJ, 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. 2008;39:413–23.PubMedCrossRef
40.
go back to reference Simon GE, Von Korff M, Saunders K, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry. 2006;63:824–30.PubMedCrossRef Simon GE, Von Korff M, Saunders K, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry. 2006;63:824–30.PubMedCrossRef
41.
go back to reference Miller GE, Freedland KE, Carney RM, et al. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun. 2003;17:276–85.PubMedCrossRef Miller GE, Freedland KE, Carney RM, et al. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun. 2003;17:276–85.PubMedCrossRef
42.
go back to reference Ranjit N, Diez-Roux AV, Shea S, et al. Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis. Arch Intern Med. 2007;167:174–81.PubMedCrossRef Ranjit N, Diez-Roux AV, Shea S, et al. Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis. Arch Intern Med. 2007;167:174–81.PubMedCrossRef
43.
go back to reference Dai J, Miller AH, Bremner JD, et al. Adherence to the Mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men: a twin study. Circulation. 2008;117:169–75.PubMedCrossRef Dai J, Miller AH, Bremner JD, et al. Adherence to the Mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men: a twin study. Circulation. 2008;117:169–75.PubMedCrossRef
44.
go back to reference Zampelas A, Panagiotakos DB, Pitsavos C, et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: the ATTICA study. J Am Coll Cardiology. 2005;46:120–4.CrossRef Zampelas A, Panagiotakos DB, Pitsavos C, et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: the ATTICA study. J Am Coll Cardiology. 2005;46:120–4.CrossRef
45.
go back to reference Irwin MR, Wang M, Campomayor CO, et al. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166:1756–62.PubMedCrossRef Irwin MR, Wang M, Campomayor CO, et al. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166:1756–62.PubMedCrossRef
46.
go back to reference McDade TW, Hawkley LC, Cacioppo JT. Psychosocial and behavioral predictors of inflammation in middle-aged and older adults: the Chicago Health, Aging, and Social Relations study. Psychosom Medicine. 2006;68:376–81.CrossRef McDade TW, Hawkley LC, Cacioppo JT. Psychosocial and behavioral predictors of inflammation in middle-aged and older adults: the Chicago Health, Aging, and Social Relations study. Psychosom Medicine. 2006;68:376–81.CrossRef
47.
go back to reference Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370:851–8.PubMedCrossRef Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370:851–8.PubMedCrossRef
48.
go back to reference Bailey MT, Kinsey SG, Padgett DA, et al. Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b+ cells. Physiol Behav. 2009;98:351–8.PubMedCrossRef Bailey MT, Kinsey SG, Padgett DA, et al. Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b+ cells. Physiol Behav. 2009;98:351–8.PubMedCrossRef
49.
go back to reference Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–3.PubMedCrossRef Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–3.PubMedCrossRef
50.
go back to reference Capuron L, Su S, Miller AH, et al. Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry. 2008;64:896–900.PubMedCrossRef Capuron L, Su S, Miller AH, et al. Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry. 2008;64:896–900.PubMedCrossRef
51.
go back to reference Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharm Ther. 2005;22:101–10.CrossRef Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharm Ther. 2005;22:101–10.CrossRef
52.
go back to reference Anisman H, Gibb J, Hayley S. Influence of continuous infusion of interleukin-1beta on depression-related processes in mice: corticosterone, circulating cytokines, brain monoamines, and cytokine mRNA expression. Psychopharmacol (Berl). 2008;199:231–44.CrossRef Anisman H, Gibb J, Hayley S. Influence of continuous infusion of interleukin-1beta on depression-related processes in mice: corticosterone, circulating cytokines, brain monoamines, and cytokine mRNA expression. Psychopharmacol (Berl). 2008;199:231–44.CrossRef
53.
go back to reference Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12:988–1000.PubMedCrossRef Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12:988–1000.PubMedCrossRef
54.
go back to reference Dantzer R, O’Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.PubMedCrossRef Dantzer R, O’Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.PubMedCrossRef
55.
go back to reference • 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. • 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.
56.
go back to reference Caspi A, Hariri AR, Holmes A, et al. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry. 2010;167:509–27.PubMedCrossRef Caspi A, Hariri AR, Holmes A, et al. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry. 2010;167:509–27.PubMedCrossRef
57.
go back to reference Bull SJ, Huezo-Diaz P, Binder EB, et al. Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry. 2008;14:1095–104.PubMedCrossRef Bull SJ, Huezo-Diaz P, Binder EB, et al. Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry. 2008;14:1095–104.PubMedCrossRef
58.
go back to reference Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160:1554–65.PubMedCrossRef Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160:1554–65.PubMedCrossRef
59.
go back to reference Vaccarino V, Lampert R, Bremner JD, et al. Depressive symptoms and heart rate variability: evidence for a shared genetic substrate in a study of twins. Psychosom Med. 2008;70:628–36.PubMedCrossRef Vaccarino V, Lampert R, Bremner JD, et al. Depressive symptoms and heart rate variability: evidence for a shared genetic substrate in a study of twins. Psychosom Med. 2008;70:628–36.PubMedCrossRef
60.
go back to reference Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry. 2008;64:527–32.PubMedCrossRef Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry. 2008;64:527–32.PubMedCrossRef
61.
go back to reference Masten CL, Eisenberger NI, Borofsky LA, et al. Subgenual anterior cingulate responses to peer rejection: a marker of adolescents’ risk for depression. Dev Psychopathol. 2011;23:283–92.PubMedCrossRef Masten CL, Eisenberger NI, Borofsky LA, et al. Subgenual anterior cingulate responses to peer rejection: a marker of adolescents’ risk for depression. Dev Psychopathol. 2011;23:283–92.PubMedCrossRef
62.
go back to reference Sheline YI, Barch DM, Price JL, et al. The default mode network and self-referential processes in depression. Proc Natl Acad Sci USA. 2009;106:1942–7.PubMedCrossRef Sheline YI, Barch DM, Price JL, et al. The default mode network and self-referential processes in depression. Proc Natl Acad Sci USA. 2009;106:1942–7.PubMedCrossRef
63.
go back to reference Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161:1957–66.PubMedCrossRef Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161:1957–66.PubMedCrossRef
64.
go back to reference 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;66:1050–7.PubMedCrossRef 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;66:1050–7.PubMedCrossRef
65.
go back to reference Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19:105–23.PubMedCrossRef Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19:105–23.PubMedCrossRef
66.
go back to reference Sockalingam S, Links PS, Abbey SE. Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update. J Viral Hepat. 2011;18:153–60.PubMedCrossRef Sockalingam S, Links PS, Abbey SE. Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update. J Viral Hepat. 2011;18:153–60.PubMedCrossRef
67.
go back to reference • 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. • 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.
68.
go back to reference Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160:1342–5.PubMedCrossRef Capuron L, Raison CL, Musselman DL, et al. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003;160:1342–5.PubMedCrossRef
69.
go back to reference Robaeys G, De Bie J, Wichers MC, et al. Early prediction of major depression in chronic hepatitis C patients during peg-interferon alpha-2b treatment by assessment of vegetative-depressive symptoms after four weeks. World J Gastroenterol. 2007;13:5736–40.PubMed Robaeys G, De Bie J, Wichers MC, et al. Early prediction of major depression in chronic hepatitis C patients during peg-interferon alpha-2b treatment by assessment of vegetative-depressive symptoms after four weeks. World J Gastroenterol. 2007;13:5736–40.PubMed
70.
go back to reference Wichers MC, Koek GH, Robaeys G, et al. Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychol Med. 2005;35:433–41.PubMedCrossRef Wichers MC, Koek GH, Robaeys G, et al. Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychol Med. 2005;35:433–41.PubMedCrossRef
71.
go back to reference Wichers MC, Kenis G, Koek GH, et al. Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res. 2007;62:207–14.PubMedCrossRef Wichers MC, Kenis G, Koek GH, et al. Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res. 2007;62:207–14.PubMedCrossRef
72.
go back to reference Kenis G, Prickaerts J, van Os J, et al. Depressive symptoms following interferon-alpha therapy: mediated by immune-induced reductions in brain-derived neurotrophic factor? Int J Neuropsychopharmacol. 2011;14:247–53.PubMedCrossRef Kenis G, Prickaerts J, van Os J, et al. Depressive symptoms following interferon-alpha therapy: mediated by immune-induced reductions in brain-derived neurotrophic factor? Int J Neuropsychopharmacol. 2011;14:247–53.PubMedCrossRef
73.
go back to reference Capuron L, Neurauter G, Musselman DL, et al. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54:906–14.PubMedCrossRef Capuron L, Neurauter G, Musselman DL, et al. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54:906–14.PubMedCrossRef
74.
go back to reference Capuron L, Ravaud A, Neveu PJ, et al. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry. 2002;7:468–73.PubMedCrossRef Capuron L, Ravaud A, Neveu PJ, et al. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry. 2002;7:468–73.PubMedCrossRef
75.
go back to reference Bonaccorso S, Marino V, Puzella A, et al. 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. 2002;22:86–90.PubMedCrossRef Bonaccorso S, Marino V, Puzella A, et al. 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. 2002;22:86–90.PubMedCrossRef
76.
go back to reference •• 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. PubMedCrossRef •• 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. PubMedCrossRef
77.
go back to reference Raison CL, Rye DB, Woolwine BJ, et al. Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry. 2010;68:942–9.PubMedCrossRef Raison CL, Rye DB, Woolwine BJ, et al. Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry. 2010;68:942–9.PubMedCrossRef
78.
go back to reference Wichers MC, Kenis G, Leue C, et al. Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment. Biol Psychiatry. 2006;60:77–9.PubMedCrossRef Wichers MC, Kenis G, Leue C, et al. Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment. Biol Psychiatry. 2006;60:77–9.PubMedCrossRef
79.
go back to reference 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;367:29–35.PubMedCrossRef 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;367:29–35.PubMedCrossRef
80.
go back to reference Muller 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;11:680–4.PubMedCrossRef Muller 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;11:680–4.PubMedCrossRef
81.
go back to reference Akhondzadeh S, Jafari S, Raisi F, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety. 2009;26:607–11.PubMedCrossRef Akhondzadeh S, Jafari S, Raisi F, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety. 2009;26:607–11.PubMedCrossRef
82.
go back to reference Wang Y, Yang F, Liu YF, et al. Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett. 2011, Epub. Wang Y, Yang F, Liu YF, et al. Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett. 2011, Epub.
83.
go back to reference Brunello N, Alboni S, Capone G, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21:219–25.PubMedCrossRef Brunello N, Alboni S, Capone G, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21:219–25.PubMedCrossRef
84.
go back to reference Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21:227–31.PubMedCrossRef Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21:227–31.PubMedCrossRef
85.
go back to reference Zautra AJ, Davis MC, Reich JW, et al. Comparison of cognitive behavioral and mindfulness meditation interventions on adaptation to rheumatoid arthritis for patients with and without history of recurrent depression. J Consult Clin Psychol. 2008;76:408–21.PubMedCrossRef Zautra AJ, Davis MC, Reich JW, et al. Comparison of cognitive behavioral and mindfulness meditation interventions on adaptation to rheumatoid arthritis for patients with and without history of recurrent depression. J Consult Clin Psychol. 2008;76:408–21.PubMedCrossRef
86.
go back to reference Balducci S, Zanuso S, Nicolucci A, et al. Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss. Nutr Metab Cardiovasc Dis. 2009;20:608–17.PubMedCrossRef Balducci S, Zanuso S, Nicolucci A, et al. Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss. Nutr Metab Cardiovasc Dis. 2009;20:608–17.PubMedCrossRef
87.
go back to reference Kohut ML, McCann DA, Russell DW, et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun. 2006;20:201–9.PubMedCrossRef Kohut ML, McCann DA, Russell DW, et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun. 2006;20:201–9.PubMedCrossRef
88.
go back to reference Blumenthal JA, Sherwood A, Babyak MA, et al. Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA. 2005;293:1626–34.PubMedCrossRef Blumenthal JA, Sherwood A, Babyak MA, et al. Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA. 2005;293:1626–34.PubMedCrossRef
89.
go back to reference Pace TW, Negi LT, Sivilli TI, et al. Innate immune, neuroendocrine and behavioral responses to psychosocial stress do not predict subsequent compassion meditation practice time. Psychoneuroendocrinol. 2010;35:310–5.CrossRef Pace TW, Negi LT, Sivilli TI, et al. Innate immune, neuroendocrine and behavioral responses to psychosocial stress do not predict subsequent compassion meditation practice time. Psychoneuroendocrinol. 2010;35:310–5.CrossRef
90.
go back to reference Pace TW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinol. 2009;34:87–98.CrossRef Pace TW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinol. 2009;34:87–98.CrossRef
91.
go back to reference Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.PubMedCrossRef Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.PubMedCrossRef
Metadata
Title
Is Depression an Inflammatory Disorder?
Authors
Charles L. Raison
Andrew H. Miller
Publication date
01-12-2011
Publisher
Current Science Inc.
Published in
Current Psychiatry Reports / Issue 6/2011
Print ISSN: 1523-3812
Electronic ISSN: 1535-1645
DOI
https://doi.org/10.1007/s11920-011-0232-0

Other articles of this Issue 6/2011

Current Psychiatry Reports 6/2011 Go to the issue

UNIPOLAR DISORDERS (MICHAEL E. THASE, SECTION EDITOR)

Measurement-Based Care for Unipolar Depression

Unipolar Disorders (Michael E. Thase, Section Editor)

When She Says “No” to Medication: Psychotherapy for Antepartum Depression

Bipolar Disorders (David S. Janowsky, Section Editor)

Use of Lithium in the Treatment of Bipolar Disorder in Late-Life