Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Hypothesis
  • Published:

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

Abstract

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1β, TNF-α or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1β, TNF-α or even IL-18, in patients with poststroke depression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Fisher SH . Psychiatric considerations of cerebral vascular disease. Am J Cardiol 1961; 7: 379–385.

    PubMed  CAS  Google Scholar 

  2. Meyer A . The anatomical facts and clinical varieties of traumatic insanity. Am J Insanity 1904; 60: 373–442.

    Google Scholar 

  3. Robinson RG, Szetela B . Mood change following left hemispheric brain injury. Ann Neurol 1981; 9: 447–453.

    PubMed  CAS  Google Scholar 

  4. Starkstein SE, Robinson RG, Price TR . Comparison of cortical and subcortical lesions in the production of post-stroke mood disorders. Brain 1987; 110: 1045–1059.

    PubMed  Google Scholar 

  5. Astrom M, Adolfsson R, Asplund K . Major depression in stroke patients: a 3-year longitudinal study. Stroke 1993; 24: 976–982.

    PubMed  CAS  Google Scholar 

  6. Morris PLP, Robinson RG, Raphael B, Hopwood MJ . Lesion location and post-stroke depression. J Neuropsychiatry Clin Neurosci 1996; 8: 399–403.

    PubMed  CAS  Google Scholar 

  7. Herrmann M, Bartles C, Wallesch C-W . Depression in acute and chronic aphasia: symptoms, pathoanatomical-clinical correlations and functional implications. J Neurol Neurosurg Psychiatry 1993; 56: 672–678.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Herrmann M, Walesch C-W . Depressive changes in stroke patients. Disabil Rehabil 1993; 15: 55–66.

    PubMed  CAS  Google Scholar 

  9. Vataja R, Leppavuori A, Pohjasvaara T, Mantyla R, Aronen HJ, Salonen O et al. Post-stroke depression and lesion location revisited. J Neuropsychiatry Clin Neurosci 2004; 16: 156–162.

    PubMed  CAS  Google Scholar 

  10. Vataja R, Pohjasvaara T, Leppavuori A, Mantyla R, Aronen HJ, Salonen O et al. Magnetic resonance imaging correlates of depression after ischemic stroke. Arch Gen Psychiatry 2001; 58: 925–931.

    PubMed  CAS  Google Scholar 

  11. Bolla-Wilson K, Robinson RG, Starkstein SE, Boston J, Price TR . Lateralization of dementia of depression in stroke patients. Am J Psychiatry 1989; 146: 627–634.

    PubMed  CAS  Google Scholar 

  12. Spalletta G, Guida G, De Angelis D, Caltagirone C . Predictors of cognitive level and depression severity are different in patients with left and right hemispheric stroke within the first year of illness. J Neurol 2002; 249: 1541–1551.

    PubMed  Google Scholar 

  13. Spalletta G, Pasini A, Costa A, De Angelis D, Ramundo N, Paolucci S et al. Alexithymic features in stroke: effects of laterality and gender. Psychosom Med 2001; 63: 944–950.

    PubMed  CAS  Google Scholar 

  14. Spalletta G, Ripa A, Bria P, Caltagirone C, Robinson RG . Response of emotional unawareness following stroke to antidepressant treatment. Am J Geriatr Psychiatry 2006; 14: 220–227.

    PubMed  Google Scholar 

  15. Bhogal SK, Teasell R, Foley N, Speechley M . Lesion location and post-stroke depression. Systematic review of the methodological limitations in the literature. Stroke 2004; 35: 794–802.

    PubMed  Google Scholar 

  16. Robinson RG, Bloom FE . Pharmacological treatment following experimental cerebral infarction: implications for understanding psychological symptoms of human stroke. Biol Psychiatry 1977; 12: 669–680.

    PubMed  CAS  Google Scholar 

  17. Reis DJ, Gilad G, Pickel VM, Joh TH . Reversible changes in the activities and amounts of tyrosine hydroxylase in dopamine neurons of the substantia nigra in response to axonal injury as studied by immunochemical and immunocytochemical methods. Brain Res 1978; 144: 325–342.

    PubMed  CAS  Google Scholar 

  18. Bryer JB, Starkstein SE, Votypka V, Parikh RM, Price TR, Robinson RG . Reduction of CSF monoamine metabolites in post-stroke depression. J Neuropsychiatry Clin Neurosci 1992; 4: 440–442.

    PubMed  CAS  Google Scholar 

  19. Mayberg HS, Robinson RG, Wong DF, Parikh RM, Bolduc P, Starkstein SE et al. PET imaging of cortical S2-serotonin receptors after stroke: lateralized changes and relationship to depression. Am J Psychiatry 1988; 145: 937–943.

    PubMed  CAS  Google Scholar 

  20. Barone FC, Feuerstein GZ . Inflammatory mediator and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999; 19: 819–834.

    PubMed  CAS  Google Scholar 

  21. Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM et al. An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J Neuroimmunol 2003; 139: 93–101.

    PubMed  CAS  Google Scholar 

  22. Lindsberg PJ, Grau AJ . Inflammation and infection as risk factors for ischemic stroke. Stroke 2003; 34: 2518–2532.

    PubMed  Google Scholar 

  23. Grundy RI, Rothwell NJ, Allan SM . Site-specific actions of interleukin-1 on excitotoxic cell death in the rat striatum. Brain Res 2002; 926: 142–148.

    PubMed  CAS  Google Scholar 

  24. Allan SM, Tyrrell PJ, Rothwell NJ . Interleukin-1 and neuronal injury. Nat Rev Immunol 2005; 5: 629–640.

    PubMed  CAS  Google Scholar 

  25. Rothwell NJ . Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003; 17: 152–157.

    PubMed  Google Scholar 

  26. Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA . Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol 2003; 140: 471–476.

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005; 76: 1366–1372.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S et al. Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke 1995; 26: 1393–1398.

    PubMed  CAS  Google Scholar 

  29. Kostulas N, Pelidou SH, Kivisakk P, Kostulas V, Link H . Increased IL-1b, IL-8 and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke 1999; 30: 2174–2179.

    PubMed  CAS  Google Scholar 

  30. Um YY, Moon KS, Lee KM, Kim HM . Interleukin-1 gene cluster polymorphisms in cerebral infarction. Cytokine 2003; 23: 41–46.

    PubMed  CAS  Google Scholar 

  31. Seripa D, Dorbrina A, Margaglione M, Matera MG, Gravina C, Vecile E et al. Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke. Cerebrovasc Dis 2003; 15: 276–281.

    PubMed  CAS  Google Scholar 

  32. Lee BC, Ahn SY, Doo HK, Yim SV, Lee HJ, Jin SY et al. Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the interleukin-1 receptor antagonist and tumor necrosis factor-alpha genes, but not the interleukin-1beta gene. Neurosci Lett 2004; 357: 33–36.

    PubMed  CAS  Google Scholar 

  33. Allan SM, Rothwell NH . Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001; 10: 734–744.

    Google Scholar 

  34. Ferrarese C, Mascaurucci P, Zoia C, Cavarretta R, Frigo M, Begni B et al. Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metab 1999; 19: 1004–1009.

    PubMed  CAS  Google Scholar 

  35. Kouwenhoven M, Carlstrom C, Ozenci V, Link H . Matrix metalloproteinase and cytokine profiles in monocytes over the course of stroke. J Clin Immunol 2001; 21: 365–375.

    PubMed  CAS  Google Scholar 

  36. Intiso D, Zarrelli MM, Lagioia G, Di Rienzo F, Checchia De Ambrosio C, Simone P et al. Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stoke patients. Neurol Sci 2003; 24: 390–396.

    Google Scholar 

  37. Zaremba J, Losy J . Early TNF-alpha levels correlate with ischaemic stroke severity. Acta Neurol Scand 2001; 104: 288–295.

    PubMed  CAS  Google Scholar 

  38. Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR . C-reactive protein and outcome after ischemic stroke. Stroke 1999; 30: 981–985.

    PubMed  CAS  Google Scholar 

  39. DiNapoli M, Papa F, Bocola V . C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001; 32: 917–924.

    CAS  Google Scholar 

  40. Arenillas JF, Alvarez-Sabin J, Molina CA, Chaco P, Montaner J, Rovira A et al. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke 2003; 34: 2463–2468.

    PubMed  CAS  Google Scholar 

  41. Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR . Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 1995; 37: 800–805.

    PubMed  CAS  Google Scholar 

  42. Kim JS, Yoon SS, Kim YH, Ryu JS . Serial measurement of interleukin-6 transforming growth factor-beta, and S-100 protein in patients with acute stroke. Stroke 1996; 27: 1553–1557.

    PubMed  CAS  Google Scholar 

  43. Vila N, Castillo J, Davalos A, Chamorro A . Pro-inflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 2000; 31: 2325–2329.

    PubMed  CAS  Google Scholar 

  44. Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4: 2.

    PubMed  PubMed Central  Google Scholar 

  45. Revilla M, Obach V, Cervera A, Davalos A, Castillo J, Chamorro A . A-174 G/C polymorphism of the interleukin-6 gene in patients with lacunar infarctions. Neurosci Lett 2002; 324: 29–32.

    PubMed  CAS  Google Scholar 

  46. Pola R, Fex A, Gaetani E, Flore R, Serricchio M, Pola P . Synergistic effect of −174G/C polymorphism in the interleukin-6 gene promoter and 469E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke. Stroke 2003; 34: 881–885.

    PubMed  CAS  Google Scholar 

  47. Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffart GU et al. Multiple levels of regulation of the interleukin-6 system in stroke. Stroke 2003; 34: 1864–1869.

    PubMed  CAS  Google Scholar 

  48. Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S et al. Intrathecal release of pro- and anti-inflammatory cytokines during stroke. Clin Exp Immunol 1997; 110: 492–499.

    PubMed  PubMed Central  CAS  Google Scholar 

  49. Kostulas N, Kivisakk P, Huang Y, Matusevicius D, Kostulas V, Link H . Ischemic stroke is associated with a systemic increase of blood mononuclear cells expressing interleukin-8 mRNA. Stroke 1998; 29: 462–466.

    PubMed  CAS  Google Scholar 

  50. Grau AJ, Aulmann M, Lichy C, Meiser H, Buggle F, Brandt T et al. Increased cytokine release by leucocytes in survivors of stroke at young age. Eur J Clin Invest 2001; 31: 999.

    PubMed  CAS  Google Scholar 

  51. Grau AJ, Reis A, Buggle F, Al-Khalaf A, Werle E, Valois N et al. Monocyte function and plasma levels of interleukin-8 in acute ischemic stroke. J Neurol Sci 2001; 192: 41–47.

    PubMed  CAS  Google Scholar 

  52. Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF . IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci 2005; 28: 487–493.

    PubMed  CAS  Google Scholar 

  53. Dinarello CA . The IL-1 family and inflammatory diseases. Clin Exp Rheumatol 2002; 20 (5 Suppl 27): S1–S13.

    PubMed  CAS  Google Scholar 

  54. Dinarello CA . Interleukin-18, a pro-inflammatory cytokine. Eur Cytokine Netw 2000; 11: 483–486.

    PubMed  CAS  Google Scholar 

  55. Plater-Zyberk C, Joosten LA, Helsen MM, Sattonnet-Roche P, Siegfried C, Alouani S et al. Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J Clin Invest 2001; 108: 1825–1832.

    PubMed  PubMed Central  CAS  Google Scholar 

  56. Bossu P, Neumann D, Del Giudice E, Ciaramella A, Gloaguen I, Fantuzzi G et al. IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease. Proc Natl Acad Sci USA 2003; 100: 14181–14186.

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Culhane AC, Hall MD, Rothwell NJ, Luheshi GN . Cloning of rat brain interleukin-18 cDNA. Mol Psychiatry 1998; 3: 362–366.

    PubMed  CAS  Google Scholar 

  58. Conti B, Park LC, Calingasan NY, Kim Y, Kim H, Bae Y et al. Cultures of astrocytes and microglia express interleukin 18. Brain Res Mol Brain Res 1999; 67: 46–52.

    PubMed  CAS  Google Scholar 

  59. Wheeler RD, Brough D, Le Feuvre RA, Takeda K, Iwakura Y, Luheshi GN et al. Interleukin-18 induces expression and release of cytokines from murine glial cells: interactions with interleukin-1 beta. J Neurochem 2003; 85: 1412–1420.

    PubMed  CAS  Google Scholar 

  60. Blankenberg S, Luc G, Ducimetiere P, Arveiler D, Ferrieres J, Amouyel P et al. Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2003; 108: 2453–2459.

    PubMed  CAS  Google Scholar 

  61. Mallat Z, Corbaz A, Scoazec A, Besnard S, Leseche G, Chvatchko Y et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation 2001; 104: 1598–1603.

    PubMed  CAS  Google Scholar 

  62. Hedtjarn M, Leverin AL, Eriksson K, Blomgren K, Mallard C, Hagberg H . Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci 2002; 22: 5910–5919.

    PubMed  CAS  PubMed Central  Google Scholar 

  63. Jander S, Schroeter M, Stoll G . Interleukin-18 expression after focal ischemia of the rat brain: association with the late-stage inflammatory response. J Cereb Blood Flow Metab 2002; 22: 62–70.

    PubMed  CAS  Google Scholar 

  64. Wheeler RD, Boutin H, Touzani O, Luheshi GN, Takeda K, Rothwell NJ . No role for interleukin-18 in acute murine stroke-induced brain injury. J Cereb Blood Flow Metab 2003; 23: 531–535.

    PubMed  CAS  Google Scholar 

  65. Zaremba J, Losy J . Interleukin-18 in acute ischaemic stroke patients. Neurol Sci 2003; 24: 117–124.

    PubMed  CAS  Google Scholar 

  66. Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR . Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 1995; 37: 800–805.

    PubMed  CAS  Google Scholar 

  67. Krupinski J, Kumar P, Kumar S, Kaluza J . Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke 1996; 27: 852–857.

    PubMed  CAS  Google Scholar 

  68. Perini F, Morra M, Alecci M, Galloni E, Marchi M, Toso V . Temporal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischemic stroke patients. Neurol Sci 2001; 22: 289–296.

    PubMed  CAS  Google Scholar 

  69. Vila N, Castillo J, Davalos A, Esteve A, Planas AM, Chamorro A . Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke 2003; 34: 671–675.

    PubMed  CAS  Google Scholar 

  70. Licinio J, Wong ML . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.

    PubMed  CAS  Google Scholar 

  71. Schiepers OJ, Wichers MC, Maes M . Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 201–217.

    PubMed  CAS  Google Scholar 

  72. Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.

    PubMed  CAS  Google Scholar 

  73. Bluthe RM, Pawlowski M, Suarez S, Parnet P, Pittman Q, Kelley KW et al. Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice. Psychoneuroendocrinology 1994; 19: 197–207.

    PubMed  CAS  Google Scholar 

  74. Dantzer R . Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 2001; 15: 7–24.

    PubMed  CAS  Google Scholar 

  75. Maes M, Bosmans E, Meltzer HY, Scharpe S, Suy E . Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry 1993; 150: 1189–1193.

    PubMed  CAS  Google Scholar 

  76. Anisman H, Ravindran AV, Griffiths J, Merali Z . Interleukin-1 beta production in dysthymia before and after pharmacotherapy. Biol Psychiatry 1999; 46: 1649–1655.

    PubMed  CAS  Google Scholar 

  77. Levine J, Barak Y, Chengappa KN, Rapoport A, Rebey M, Barak V . Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology 1999; 40: 171–176.

    PubMed  CAS  Google Scholar 

  78. Owen BM, Eccleston D, Ferrier IN, Young AH . Raised levels of plasma interleukin-1 beta in major and postviral depression. Acta Psychiatr Scand 2001; 103: 226–228.

    PubMed  CAS  Google Scholar 

  79. Penninx BW, Kritchevsky SB, Yaffe K, Newman AB, Simonsick EM, Rubin S et al. Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composisiton study. Biol Psychiatry 2003; 54: 566–572.

    PubMed  CAS  Google Scholar 

  80. 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: 429–433.

    CAS  Google Scholar 

  81. Tiemeier H, Hofman A, van Tuijl HR, Kiliaan AJ, Meijer J, Breteler M . Inflammatory proteins and depression in the elderly. Epidemiology 2003; 14: 103–107.

    PubMed  Google Scholar 

  82. Maes M, Kenis G, Kubera M . In humans, corticotropin releasing hormone antagonizes some of the negative immunoregulatory effects of serotonin. Neuro Endocrinol Lett 2003; 24: 420–424.

    PubMed  CAS  Google Scholar 

  83. Merendino RA, Di Rosa AE, Di Pasquale G, Minciullo PL, Mangraviti C, Costantino A et al. Interleukin-18 and CD30 serum levels in patients with moderate-severe depression. Mediators Inflamm 2002; 11: 265–267.

    PubMed  PubMed Central  Google Scholar 

  84. Kokai M, Kashiwamura S, Okamura H, Ohara K, Morita Y . Plasma interleukin-18 levels in patients with psychiatric disorders. J Immunother 2002; 25 (Suppl 1): S68–S71.

    PubMed  CAS  Google Scholar 

  85. Maes M, Vandoolaeghe E, Ranjan R, Bosmans E, Bergmans R, Desnyder R . Increased serum interleukin-1-receptor-antagonist concentrations in major depression. J Affect Disord 1995; 36: 29–36.

    PubMed  CAS  Google Scholar 

  86. Kubera M, Kenis G, Bosmans E, Zieba A, Dudek D, Nowak G et al. Plasma levels of interleukin-6, interleukin-10, and interleukin-1 receptor antagonist in depression: comparison between the acute state and after remission. Pol J Pharmacol 2000; 52: 237–241.

    PubMed  CAS  Google Scholar 

  87. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H . Cytokine production and serum proteins in depression. Scand J Immunol 1995; 41: 534–538.

    PubMed  CAS  Google Scholar 

  88. Capuron L, Ravaud A, Dantzer R . Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy. J Clin Oncol 2000; 18: 2143–2151.

    PubMed  CAS  Google Scholar 

  89. Capuron L, Ravaud A, Gualde N, Bosmans E, Dantzer R, Maes M et al. Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy. Psychoneuroendocrinology 2001; 26: 797–808.

    PubMed  CAS  Google Scholar 

  90. Bonaccorso S, Puzella A, Marino V, Pasquini M, Biondi M, Artini M et al. Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatry Res 2001; 105: 45–55.

    PubMed  CAS  Google Scholar 

  91. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al. Paroxetine for the prevention of depression induced by high-dose interferon alpha. N Engl J Med 2001; 344: 961–966.

    CAS  PubMed  Google Scholar 

  92. Wichers M, Maes M . The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 2002; 5: 375–388.

    PubMed  CAS  Google Scholar 

  93. Turnbull AV, Rivier CL . Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999; 79: 1–71.

    CAS  PubMed  Google Scholar 

  94. Anisman H, Kokkinidis L, Merali Z . Further evidence for the depressive effects of cytokines: anhedonia and neurochemical changes. Brain Behav Immun 2002; 16: 544–556.

    PubMed  CAS  Google Scholar 

  95. Hu B, Hissong BD, Carlin JM . Interleukin-1 enhances indoleamine 2, 3-dioxygenase activity by increasing specific mRNA expression in human mononuclear phagocytes. J Interferon Cytokine Res 1995; 15: 617–624.

    PubMed  CAS  Google Scholar 

  96. Fujigaki S, Saito K, Sekikawa K, Tone S, Takikawa O, Fujii H et al. Lipopolysaccharide induction of indoleamine 2, 3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism. Eur J Immunol 2001; 31: 2313–2318.

    PubMed  CAS  Google Scholar 

  97. Pemberton LA, Kerr SJ, Smythe G, Brew BJ . Quinolinic acid production by macrophages stimulated with IFN-gamma, TNF-alpha, and IFN-alpha. J Interferon Cytokine Res 1997; 17: 589–595.

    PubMed  CAS  Google Scholar 

  98. Babcock TA, Carlin JM . Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine 2000; 12: 588–594.

    PubMed  CAS  Google Scholar 

  99. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R . Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002; 7: 468–473.

    CAS  PubMed  Google Scholar 

  100. Liebau C, Baltzer AW, Schmidt S, Roesel C, Karreman C, Prisack JB et al. Interleukin-12 and interleukin-18 induce indoleamine 2, 3-dioxygenase (IDO) activity in human osteosarcoma cell lines independently from interferon-gamma. Anticancer Res 2002; 22: 931–936.

    PubMed  CAS  Google Scholar 

  101. Jander S, Schroeter M, Stoll G . Interleukin-18 expression after focal ischemia of the rat brain: association with the late-stage inflammatory response. J Cereb Blood Flow Metab 2002; 22: 62–70.

    PubMed  CAS  Google Scholar 

  102. Morris PLP, Robinson RG, Andrezejewski P, Samuels J, Price TR . Association of depression with 10-year post-stroke mortality. Am J Psychiatry 1993; 150: 124–129.

    PubMed  CAS  Google Scholar 

  103. House A, Knapp P, Bamford J, Vail A . Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke 2001; 32: 696–701.

    PubMed  CAS  Google Scholar 

  104. Parikh RM, Robinson RG, Lipsey JR, Starkstein SE, Fedoroff JP, Price TR . The impact of post-stroke depression on recovery in activities of daily living over two year follow-up. Arch Neurol 1990; 47: 785–789.

    PubMed  CAS  Google Scholar 

  105. Downhill Jr JE, Robinson RG . Longitudinal assessment of depression and cognitive impairment following stroke. J Nerv Ment Dis 1994; 182: 425–431.

    PubMed  Google Scholar 

  106. Castanon N, Leonard BE, Neveu PJ, Yirmiya R . Effects of antidepressants on cytokine production and actions. Brain Behav Immun 2002; 16: 569–574.

    PubMed  CAS  Google Scholar 

  107. O'Brien SM, Scott LV, Dinan TG . Antidepressant therapy and C-reactive protein levels. Br J Psychiatry 2006; 188: 449–452.

    PubMed  Google Scholar 

  108. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367: 29–35.

    PubMed  CAS  Google Scholar 

  109. Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller 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: 680–684.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R G Robinson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spalletta, G., Bossù, P., Ciaramella, A. et al. The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines. Mol Psychiatry 11, 984–991 (2006). https://doi.org/10.1038/sj.mp.4001879

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001879

Keywords

This article is cited by

Search

Quick links