Skip to main content
SpringerLink
Log in

Neuropsychiatric disorders related to interferon and interleukins treatment

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Certain cytokines such as interferon-α and interleukin-2 are often used in the treatment certain cancers and chronic diseases such as melanoma, hepatitis C infection and multiple sclerosis. Several neuropsychiatric side effects such as depression, anxiety, psychosis, suicidal ideation, hypomanic mood and cognitive impairment were reported in those patients who received those medications. In certain patients with those neuropsychiatric side effects, the symptoms ceased when the medication was stopped. However, in some cases, the cognitive impairment persisted even for years after cessation of the medication. In animal studies, those cytokines could induce sickness behaviour, anxiety behaviour and social anhedonia. The increased in pro-inflammatory cytokines in certain neuropsychiatric disorders was widely reported. In addition, in animal studies, the treatment with interferon-α or interleukin-1 could induce depressive like behaviour. Recently, the role of certain pro-inflammatory cytokines that could enhance the activity of the enzyme, indoleamine 2–3, dioxygenase (IDO) which in turn would increase tryptophan degradation into kynurenine and decrease tryptophan availability of tryptophan in the brain to synthesize serotonin, a neurotransmitter which is necessary for the normal mood state became of interest in pathophysiology of psychiatric disorders. Furthermore, the imbalance in the further downward catabolic kynurenine pathway and their interactions with other neurotransmitters has been proposed to play an important role. The presence of such an imbalance in patients being treated with cytokines and in patients with psychiatric disorders and the possible consequence of those changes on the neuroprotective function in the brain are discussed in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Arolt V, Peters M, Erfurth A, Wiesmann M, Missler U, Rudolf S, Kirchner H, Rothermundt M (2003) S100B and response to treatment in major depression: a pilot study. Eur Neuropsychopharmacol 13:235–239

    PubMed  CAS  Google Scholar 

  • Bannink M, Fekkes D, Van Gool AR, Kruit WH, Sleijfer S, van der Holt B, Eggermont AM, Stoter G, Hengeveld MW (2007) Interferon-alpha influences tryptophan metabolism without inducing psychiatric side effects. Neuropsychobiology 55:225–231

    PubMed  CAS  Google Scholar 

  • Baron S, Tyring SK, Fleischmann WR Jr, Coppenhaver DH, Niesel DW, Klimpel GR, Stanton GJ, Hughes TK (1991) The interferons. Mechanisms of action and clinical applications. Jama 266:1375–1383

    CAS  Google Scholar 

  • Bender DA, McCreanor GM (1985) Kynurenine hydroxylase: a potential rate-limiting enzyme in tryptophan metabolism. Biochem Soc Trans 13:441–443

    PubMed  CAS  Google Scholar 

  • Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, Almerighi C, Verkerk R, Meltzer H, Maes M (2002) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 22:86–90

    PubMed  CAS  Google Scholar 

  • Bozikas V, Petrikis P, Balla A, Karavatos A (2001) An interferon-alpha-induced psychotic disorder in a patient with chronic hepatitis C. Eur Psychiatry 16:136–137

    PubMed  CAS  Google Scholar 

  • Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–118

    PubMed  CAS  Google Scholar 

  • Bunney WE Jr, Davis JM (1965) Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 13:483–494

    PubMed  CAS  Google Scholar 

  • Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH (2003a) Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry 54:906–914

    CAS  Google Scholar 

  • Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH (2003b) Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 160:1342–1345

    PubMed  Google Scholar 

  • Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS, Miller AH (2005) Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 58:190–196

    PubMed  CAS  Google Scholar 

  • Carlin JM, Borden EC, Sondel PM, Byrne GI (1987) Biologic-response-modifier-induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures. J Immunol 139:2414–2418

    PubMed  CAS  Google Scholar 

  • Carlin JM, Borden EC, Sondel PM, Byrne GI (1989) Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes. J Leukoc Biol 45:29–34

    PubMed  CAS  Google Scholar 

  • Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, Serra G, Balestrieri C, Chessa L, Cauli C, Lai ME, Farci P (2007) Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy. Clin Pract Epidemol Ment Health 3:22

    PubMed  Google Scholar 

  • Cassidy EM, Manning D, Byrne S, Bolger E, Murray F, Sharifi N, Wallace E, Keogan M, O, Keane V (2002) Acute effects of low-dose interferon-alpha on serum cortisol and plasma interleukin-6. J Psychopharmacol 16:230–234

    PubMed  CAS  Google Scholar 

  • Chiarugi A, Calvani M, Meli E, Traggiai E, Moroni F (2001) Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages. J Neuroimmunol 120:190–198

    PubMed  CAS  Google Scholar 

  • Cotter DR, Pariante CM, Everall IP (2001) Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 55:585–595

    PubMed  CAS  Google Scholar 

  • Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E (2005) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31(8):1616–1626

    PubMed  Google Scholar 

  • De La Garza R 2nd (2005) Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia. Neurosci Biobehav Rev 29:761–770

    Google Scholar 

  • De La Garza R 2nd, Asnis GM, Pedrosa E, Stearns C, Migdal AL, Reinus JF, Paladugu R, Vemulapalli S (2005) Recombinant human interferon-alpha does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats. Prog Neuropsychopharmacol Biol Psychiatry 29:781–792

    Google Scholar 

  • Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 47:411–418

    PubMed  CAS  Google Scholar 

  • Delgado PL, Price LH, Miller HL, Salomon RM, Licinio J, Krystal JH, Heninger GR, Charney DS (1991) Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 27:321–330

    PubMed  CAS  Google Scholar 

  • Dell’Osso L, Pini S, Maggi L, Rucci P, Del Debbio A, Carlini M, Baldini A, Ferrari G, Manca E, Beverini E, Amore M, Scarallo V, Semeraro Q, Brunetto M, Bonino F, Maj M (2007) Subthreshold mania as predictor of depression during interferon treatment in HCV+ patients without current or lifetime psychiatric disorders. J Psychosom Res 62:349–355

    PubMed  Google Scholar 

  • Dietrich DE, Hauser U, Peters M, Zhang Y, Wiesmann M, Hasselmann M, Rudolf S, Jungling O, Kirchner H, Munte TF, Arolt V, Emrich HM, Johannes S, Rothermundt M (2004) Target evaluation processing and serum levels of nerve tissue protein S100B in patients with remitted major depression. Neurosci Lett 354:69–73

    PubMed  CAS  Google Scholar 

  • Dusheiko G (1997) Side effects of alpha interferon in chronic hepatitis C. Hepatology 26:112S–121S

    PubMed  CAS  Google Scholar 

  • Dutcher J (2002a) Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology (Williston Park) 16:4–10

    Google Scholar 

  • Dutcher J (2002b) High-dose interleukin-2 in metastatic disease: renal cell carcinoma and melanoma. Oncology (Williston Park) 16:3

    Google Scholar 

  • Dutcher JP, Logan T, Gordon M, Sosman J, Weiss G, Margolin K, Plasse T, Mier J, Lotze M, Clark J, Atkins M (2000) Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study. Clin Cancer Res 6:3442–3450

    PubMed  CAS  Google Scholar 

  • Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS (2002a) Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 20:2045–2052

    PubMed  CAS  Google Scholar 

  • Eton O, Rosenblum MG, Legha SS, Zhang W, Jo East M, Bedikian A, Papadopoulos N, Buzaid A, Benjamin RS (2002b) Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma. Cancer 95:127–134

    PubMed  CAS  Google Scholar 

  • Farkkila M, Iivanainen M, Roine R, Bergstrom L, Laaksonen R, Niemi ML, Cantell K (1984) Neurotoxic and other side effects of high-dose interferon in amyotrophic lateral sclerosis. Acta Neurol Scand 70:42–46

    PubMed  CAS  Google Scholar 

  • Fattovich G, Giustina G, Favarato S, Ruol A (1996) A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 24:38–47

    PubMed  CAS  Google Scholar 

  • Felger JC, Alagbe O, Hu F, Mook D, Freeman AA, Sanchez MM, Kalin NH, Ratti E, Nemeroff CB, Miller AH (2007) Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression. Biol Psychiatry 62:1324–1333

    PubMed  CAS  Google Scholar 

  • Fishman SL, Murray JM, Eng FJ, Walewski JL, Morgello S, Branch AD (2008) Molecular and bioinformatic evidence of hepatitis C virus evolution in brain. J Infect Dis 197:597–607

    PubMed  CAS  Google Scholar 

  • Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD (2001) Evidence for a cerebral effect of the hepatitis C virus. Lancet 358:38–39

    PubMed  CAS  Google Scholar 

  • Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, Wesnes KA, Taylor-Robinson SD (2002) Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 35:433–439

    PubMed  Google Scholar 

  • Forton DM, Hamilton G, Allsop JM, Grover VP, Wesnes K, O, Sullivan C, Thomas HC, Taylor-Robinson SD (2008) Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study. J Hepatol 49:316–322

    PubMed  CAS  Google Scholar 

  • Gal EM, Sherman AD (1980) L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res 5:223–239

    PubMed  CAS  Google Scholar 

  • Garcia-Pares G, Domenech C, Gil M (2002) Psychosis induced by interferon-alpha. Psychosomatics 43:428–429

    PubMed  Google Scholar 

  • Gez E, Rubinov R, Gaitini D, Meretyk S, Best LA, Native O, Stein A, Erlich N, Beny A, Zidan J, Haim N, Kuten A (2002) Interleukin-2, interferon-alpha, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma: a prospective phase II study: the experience of Rambam and Lin Medical Centers 1996–2000. Cancer 95:1644–1649

    PubMed  CAS  Google Scholar 

  • Grabe HJ, Ahrens N, Rose HJ, Kessler C, Freyberger HJ (2001) Neurotrophic factor S100 beta in major depression. Neuropsychobiology 44:88–90

    PubMed  CAS  Google Scholar 

  • Grant RS, Kapoor V (1998) Murine glial cells regenerate NAD, after peroxide-induced depletion, using either nicotinic acid, nicotinamide, or quinolinic acid as substrates. J Neurochem 70:1759–1763

    PubMed  CAS  Google Scholar 

  • Grant RS, Naif H, Espinosa M, Kapoor V (2000) IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress. Redox Rep 5:101–104

    PubMed  CAS  Google Scholar 

  • Guillemin GJ, Smith DG, Kerr SJ, Smythe GA, Kapoor V, Armati PJ, Brew BJ (2000) Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis. Redox Rep 5:108–111

    PubMed  CAS  Google Scholar 

  • Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armati PJ, Croitoru J, Brew BJ (2001) Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 78:842–853

    PubMed  CAS  Google Scholar 

  • Guillemin GJ, Smythe G, Takikawa O, Brew BJ (2005a) Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 49:15–23

    PubMed  Google Scholar 

  • Guillemin GJ, Wang L, Brew BJ (2005b) Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex. J Neuroinflammation 2:16

    PubMed  Google Scholar 

  • Guillemin GJ, Lim CK, Smythe GA, Garner B, Kapoor V, Takikawa O, Brew BJ (2007) Characterization of the kynurenine pathway in human neurons. J Neurosci 27:12884–12892

    PubMed  CAS  Google Scholar 

  • Hayaishi O (1980) Biochemical and medical aspects of tryptophan metabolism. Elsevier/North-Holland Biomedical, Amsterdam

    Google Scholar 

  • Hetzel G, Moeller O, Evers S, Erfurth A, Ponath G, Arolt V, Rothermundt M (2005) The astroglial protein S100B and visually evoked event-related potentials before and after antidepressant treatment. Psychopharmacology (Berl) 178:161–166

    CAS  Google Scholar 

  • Heyes MP, Achim CL, Wiley CA, Major EO, Saito K, Markey SP (1996) Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J 320(Pt 2):595–597

    PubMed  CAS  Google Scholar 

  • Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21:7463–7473

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Na C, Escalona PR, Boyko OB, Nemeroff CB, Krishnan KR (1991) A magnetic resonance imaging study of putamen nuclei in major depression. Psychiatry Res 40:95–99

    PubMed  CAS  Google Scholar 

  • Iivanainen M, Laaksonen R, Niemi ML, Farkkila M, Bergstrom L, Mattson K, Niiranen A, Cantell K (1985) Memory and psychomotor impairment following high-dose interferon treatment in amyotrophic lateral sclerosis. Acta Neurol Scand 72:475–480

    Article  PubMed  CAS  Google Scholar 

  • Kim JP, Choi DW (1987) Quinolinate neurotoxicity in cortical cell culture. Neuroscience 23:423–432

    PubMed  CAS  Google Scholar 

  • Kim YK, Myint AM, Lee BH, Han CS, Lee HJ, Kim DJ, Leonard BE (2004) Th1, Th2 and Th3 cytokine alteration in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28:1129–1134

    PubMed  CAS  Google Scholar 

  • Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105:751–756

    PubMed  CAS  Google Scholar 

  • Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB (1992) Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch Gen Psychiatry 49:553–557

    CAS  Google Scholar 

  • Kronfol Z, Remick DG (2000) Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 157:683–694

    PubMed  CAS  Google Scholar 

  • Larson SJ, Hartle KD, Ivanco TL (2007) Acute administration of interleukin-1beta disrupts motor learning. Behav Neurosci 121:1415–1420

    PubMed  CAS  Google Scholar 

  • Leonard BE (2007) Inflammation, depression and dementia: are they connected? Neurochem Res 32:1749–1756

    PubMed  CAS  Google Scholar 

  • Lotrich FE, Rabinovitz M, Gironda P, Pollock BG (2007) Depression following pegylated interferon-alpha: characteristics and vulnerability. J Psychosom Res 63:131–135

    PubMed  Google Scholar 

  • Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H (1997) Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9:853–858

    PubMed  CAS  Google Scholar 

  • Makino M, Kitano Y, Komiyama C, Takasuna K (2000) Human interferon-alpha increases immobility in the forced swimming test in rats. Psychopharmacology (Berl) 148:106–110

    CAS  Google Scholar 

  • Mangoni A (1974) The “kynurenine shunt” and depression. Adv Biochem Psychopharmacol 11:293–298

    PubMed  CAS  Google Scholar 

  • Mattson K, Niiranen A, Iivanainen M, Farkkila M, Bergstrom L, Holsti LR, Kauppinen HL, Cantell K (1983) Neurotoxicity of interferon. Cancer Treat Rep 67:958–961

    PubMed  CAS  Google Scholar 

  • Meyers CA, Obbens EA, Scheibel RS, Moser RP (1991a) Neurotoxicity of intraventricularly administered alpha-interferon for leptomeningeal disease. Cancer 68:88–92

    PubMed  CAS  Google Scholar 

  • Meyers CA, Scheibel RS, Forman AD (1991b) Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 41:672–676

    PubMed  CAS  Google Scholar 

  • Miller CL, Llenos IC, Dulay JR, Weis S (2006) Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res 1073–1074:25–37

    PubMed  Google Scholar 

  • Musso T, Gusella GL, Brooks A, Longo DL, Varesio L (1994) Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes. Blood 83:1408–1411

    PubMed  CAS  Google Scholar 

  • Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61:519–525

    PubMed  CAS  Google Scholar 

  • Myint AM, Leonard BE, Steinbusch HW, Kim YK (2005) Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 88:167–173

    PubMed  CAS  Google Scholar 

  • Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007a) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98:143–151

    PubMed  CAS  Google Scholar 

  • Myint AM, O, Mahony S, Kubera M, Kim YK, Kenny C, Kaim-Basta A, Steinbusch HW, Leonard BE (2007b) Role of paroxetine in interferon-alpha-induced immune and behavioural changes in male Wistar rats. J Psychopharmacol 21:843–850

    PubMed  CAS  Google Scholar 

  • Niiranen A, Laaksonen R, Iivanainen M, Mattson K, Farkkila M, Cantell K (1988) Behavioral assessment of patients treated with alpha-interferon. Acta Psychiatr Scand 78:622–626

    PubMed  CAS  Google Scholar 

  • Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindstrom LH, Nordin C, Karanti A, Persson P, Erhardt S (2005) Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80:315–322

    PubMed  CAS  Google Scholar 

  • Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95:13290–13295

    PubMed  CAS  Google Scholar 

  • Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187

    PubMed  CAS  Google Scholar 

  • Poutiainen E, Hokkanen L, Niemi ML, Farkkila M (1994) Reversible cognitive decline during high-dose alpha-interferon treatment. Pharmacol Biochem Behav 47:901–905

    PubMed  CAS  Google Scholar 

  • Quarantini LC, Bressan RA, Galvao A, Batista-Neves S, Parana R, Miranda-Scippa A (2007) Incidence of psychiatric side effects during pegylated interferon- alpha retreatment in nonresponder hepatitis C virus-infected patients. Liver Int 27:1098–1102

    PubMed  CAS  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098

    PubMed  CAS  Google Scholar 

  • Rohatiner AZ, Prior PF, Burton AC, Smith AT, Balkwill FR, Lister TA (1983) Central nervous system toxicity of interferon. Br J Cancer 47:419–422

    PubMed  CAS  Google Scholar 

  • Rothermundt M, Arolt V, Wiann M, Missler U, Peters M, Rudolf S, Kirchner H (2001) S-100B is increased in melancholic but not in non-melancholic major depression. J Affect Disord 66:89–93

    PubMed  CAS  Google Scholar 

  • Saito K, Ohta Y, Nagamura Y, Sasaki E, Ishiguro I (1990) Relationship between L-tryptophan uptake and L-tryptophan 2,3-dioxygenase activity in rat hepatocytes. Biochem Int 20:71–80

    PubMed  CAS  Google Scholar 

  • Salter M, Pogson CI (1985) The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetes. Biochem J 229:499–504

    PubMed  CAS  Google Scholar 

  • Satyanarayana U, Rao BS (1980) Dietary tryptophan level and the enzymes of tryptophan NAD pathway. Br J Nutr 43:107–113

    PubMed  CAS  Google Scholar 

  • Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Schmidt F, Grunze H, Lieb K (2002) Interferon alpha (IFNalpha) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 26:731–746

    PubMed  CAS  Google Scholar 

  • Schildkraut JJ, Gordon EK, Durell J (1965) Catecholamine metabolism in affective disorders. I. Normetanephrine and VMA excretion in depressed patients treated with imipramine. J Psychiatr Res 3:213–228

    PubMed  CAS  Google Scholar 

  • Schroeter ML, Abdul-Khaliq H, Diefenbacher A, Blasig IE (2002) S100B is increased in mood disorders and may be reduced by antidepressive treatment. Neuroreport 13:1675–1678

    PubMed  CAS  Google Scholar 

  • Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50:521–530

    PubMed  CAS  Google Scholar 

  • Schwarz MJ, Chiang S, Muller N, Ackenheil M (2001) T-helper-1 and T-helper-2 responses in psychiatric disorders. Brain Behav Immun 15:340–370

    PubMed  CAS  Google Scholar 

  • Schwieler L, Erhardt S (2003) Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid. Neuropsychopharmacology 28:1770–1777

    PubMed  CAS  Google Scholar 

  • Seifert F, Struffert T, Hildebrandt M, Blumcke I, Bruck W, Staykov D, Huttner HB, Hilz MJ, Schwab S, Bardutzky J (2008) In vivo detection of hepatitis C virus (HCV) RNA in the brain in a case of encephalitis: evidence for HCV neuroinvasion. Eur J Neurol 15:214–218

    PubMed  CAS  Google Scholar 

  • Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034–5043

    PubMed  CAS  Google Scholar 

  • Shepard PD, Joy B, Clerkin L, Schwarcz R (2003) Micromolar brain levels of kynurenic acid are associated with a disruption of auditory sensory gating in the rat. Neuropsychopharmacology 28:1454–1462

    PubMed  CAS  Google Scholar 

  • Smedley H, Katrak M, Sikora K, Wheeler T (1983) Neurological effects of recombinant human interferon. Br Med J (Clin Res Ed) 286:262–264

    CAS  Google Scholar 

  • Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306

    PubMed  CAS  Google Scholar 

  • Smith SA, Carr FP, Pogson CI (1980) The metabolism of L-tryptophan by isolated rat liver cells. Quantification of the relative importance of, and the effect of nutritional status on, the individual pathways of tryptophan metabolism. Biochem J 192:673–686

    PubMed  CAS  Google Scholar 

  • Song C, Leonard BE (2005) The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev 29:627–647

    PubMed  Google Scholar 

  • Song C, Horrobin DF, Leonard BE (2006) The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats. Pharmacopsychiatry 39:88–99

    PubMed  CAS  Google Scholar 

  • Song C, Manku MS, Horrobin DF (2008) Long-chain polyunsaturated fatty acids modulate interleukin-1beta-induced changes in behavior, monoaminergic neurotransmitters, and brain inflammation in rats. J Nutr 138:954–963

    PubMed  CAS  Google Scholar 

  • Sudom K, Turrin NP, Hayley S, Anisman H (2004) Influence of chronic interleukin-2 infusion and stressors on sickness behaviors and neurochemical change in mice. Neuroimmunomodulation 11:341–350

    PubMed  CAS  Google Scholar 

  • Takahashi S (1976) Reduction of blood platelet serotonin levels in manic and depressed patients. Folia Psychiatr Neurol Jpn 30:475–486

    PubMed  CAS  Google Scholar 

  • Takahashi S (1977) Monoamine oxidase activity in blood platelets from manic and depressed patients. Folia Psychiatr Neurol Jpn 31:37–48

    PubMed  CAS  Google Scholar 

  • Tamam L, Yerdelen D, Ozpoyraz N (2003) Psychosis associated with interferon alfa therapy for chronic hepatitis B. Ann Pharmacother 37:384–387

    PubMed  Google Scholar 

  • Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. Faseb J 5:2516–2522

    PubMed  CAS  Google Scholar 

  • Telio D, Sockalingam S, Stergiopoulos V (2006) Persistent psychosis after treatment with interferon alpha: a case report. J Clin Psychopharmacol 26:446–447

    PubMed  Google Scholar 

  • Thomson LM, Sutherland RJ (2006) Interleukin-1beta induces anorexia but not spatial learning and memory deficits in the rat. Behav Brain Res 170:302–307

    PubMed  CAS  Google Scholar 

  • Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P (1998) Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol 25:39–47

    PubMed  CAS  Google Scholar 

  • Viswanathan K, Dhabhar FS (2005) Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc Natl Acad Sci USA 102:5808–5813

    PubMed  CAS  Google Scholar 

  • Weissenborn K, Bokemeyer M, Ahl B, Fischer-Wasels D, Giewekemeyer K, van den Hoff J, Kostler H, Berding G (2004a) Functional imaging of the brain in patients with liver cirrhosis. Metab Brain Dis 19:269–280

    PubMed  Google Scholar 

  • Weissenborn K, Krause J, Bokemeyer M, Hecker H, Schuler A, Ennen JC, Ahl B, Manns MP, Boker KW (2004b) Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 41:845–851

    PubMed  Google Scholar 

  • Wichers MC, Maes M (2004) The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 29:11–7

    PubMed  Google Scholar 

  • Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10:538–544

    PubMed  CAS  Google Scholar 

  • Wichers MC, Kenis G, Leue C, Koek G, Robaeys G, Maes M (2006) Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment. Biol Psychiatry 60:77–79

    PubMed  CAS  Google Scholar 

  • Wichers MC, Kenis G, Koek GH, Robaeys G, Nicolson NA, Maes M (2007) Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res 62:207–214

    PubMed  Google Scholar 

  • Yasui H, Takai K, Yoshida R, Hayaishi O (1986) Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients. Proc Natl Acad Sci USA 83:6622–6626

    PubMed  CAS  Google Scholar 

  • Zalcman S, Murray L, Dyck DG, Greenberg AH, Nance DM (1998) Interleukin-2 and -6 induce behavioral-activating effects in mice. Brain Res 811:111–121

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The authors have no conflict of interest to be disclosed.

Author information

Authors and Affiliations

  1. Laboratory Section for Psychoneuroimmunology and Therapeutic Drug Monitoring, Ludwig-Maximilians University, Nussbaumstrasse 7, 80336, Munich, Germany

    Aye Mu Myint, Markus J. Schwarz & Brian E. Leonard

  2. Department of Psychiatry and Psychobiology, University of Maastricht, Maastricht, The Netherlands

    Aye Mu Myint, Harry W. M. Steinbusch & Brian E. Leonard

Authors
  1. Aye Mu Myint
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus J. Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harry W. M. Steinbusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian E. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aye Mu Myint.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Myint, A.M., Schwarz, M.J., Steinbusch, H.W.M. et al. Neuropsychiatric disorders related to interferon and interleukins treatment. Metab Brain Dis 24, 55–68 (2009). https://doi.org/10.1007/s11011-008-9114-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-008-9114-5

Keywords

Search

Navigation