Pharmacy World and Science

, Volume 25, Issue 1, pp 11–20 | Cite as

Neuropsychiatric side effects of interferon‐alfa therapy

  • A.R. Van Gool
  • W.H.J. Kruit
  • G. Stoter
  • F.K. Engels
  • A.M.M. Eggermont


Aim: Immunotherapy with interferon‐alfa (IFN‐alfa) is used in a variety of diseases in‐ and outside clinical trials (e.g. chronic hepatitis, melanoma, chronic myelogenous leukemia, renal cell carcinoma, multiple myeloma). Treatment with IFN‐alfa can cause (severe) neuropsychiatric side effects. The purpose of this article is to give an updated review of data on the incidence, manifestations and prediction of psychiatric side effects of immunotherapy with IFN‐alfa. Furthermore, the article gives an overview of the management strategies and of the various theories on the pathophysiology of behavioural effects induced by cytokines.Methods: Use was made of computerized searches and of checking cross‐references of articles and book chapters. The data on the incidence, manifestations and prediction are arranged by source of information, by target symptoms and by method of ascertainment.Results: Different sources of information exist, e.g. adverse event reports of clinical trials, case descriptions and research specifically targeted on neuropsychiatric side effects. IFN‐alfa is capable of inducing depressive symptoms and syndromes; the evidence for the induction of other psychiatric side effects is weaker. The depressive syndromes induced by IFN‐alfa are in need of a more precise characterization. The results of studies on prediction of side effects are contradictory. Guidelines on managing psychiatric side effects predominantly arise from practical experience and common sense. Patient education plays a pivotal role. At this moment, there is no comprehensive theory on the pathophysiology of cytokine‐induced psychiatric side effects.Conclusion: There is sufficient empirical support for a causal relation between IFN‐alfa and the development of depressive symptoms and syndromes. Practical management of neuropsychiatric side effects begins before the start of therapy and should consist of repeated patient education, drug treatment and supportive measures. There are diverging theories on the pathophysiological backgrounds.

Adverse drug reaction Depression Interferon Neuropsychiatric Side effect 


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  1. 1.
    Fauci AS, Braunwald E, Isselbacker KJ, Wilson JD, Martin JB, Kasper DL et al., editors. Harrisons' principles of internal medicine, 14th ed. New York: McGraw-Hill, 1998.Google Scholar
  2. 2.
    Vial T, Descotes J. Clinical toxicity of interferons. Drug Saf 1994; 10(2): 115–50.Google Scholar
  3. 3.
    Dusheiko G. Side effects of alpha interferon in hepatitis C. Hepatology 1997; 26(3 Suppl 1): 112S–21S.Google Scholar
  4. 4.
    Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000; 157(6): 867–76.Google Scholar
  5. 5.
    Kirkwood JM, Resnick GD, Cole BF. Efficacy, safety and riskbenefit analysis of adjuvant interferon alfa-2b adjuvant therapy in melanoma. Semin Oncol 1997; 24(1 Suppl 4): 16–23.Google Scholar
  6. 6.
    Donnelly S. Patient management strategies for interferon alfa-2b as adjuvant therapy of high-risk melanoma. Oncol Nurs Forum 1998; 25(5): 921–7.Google Scholar
  7. 7.
    Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau J-L, Maloisel F et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 1997; 337(4): 223–9.Google Scholar
  8. 8.
    Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perillo RP et al. Treatment of chronic hepatitis C with recombinant interferon alfa. N Engl J Med 1989; 321(22): 1501–6.Google Scholar
  9. 9.
    Grob JJ, Dreno B, de la Salmoniere P, Delaunay M, Cupissol D, Guillot B et al. Randomised trial of interferon alfa-2a as adjuvant therapy in resected primary melanoma thicker than 1,5 mm without clinically detectable node metastases. Lancet 1998; 351: 1905–10.Google Scholar
  10. 10.
    McHutchinson JG, Gordon SC, Schiff ER, Schiffman ML, Lee WM, Rustgi VK et al. Interferon alfa-2b alone or in combination with ribavarin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339(21): 1485–92.Google Scholar
  11. 11.
    Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C et al. Interferon alfa-2b alone or in combination with ribavarin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998; 339(21): 1493–9.Google Scholar
  12. 12.
    Gaudin J-L, Faure P, Godinot H, Gerard F, Trepo C. The french experience of treatment of chronic type D hepatitis with a 12-months of interferon alpha-2B. Results of a randomized controlled trial. Liver 1995; 15(1): 45–52.Google Scholar
  13. 13.
    Janssen HL, Brouwer JT, van der Mast RC, Schalm SW. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994; 21(2): 241–3.Google Scholar
  14. 14.
    Fattovich G, Giustina G, Favaroto S, Ruol A, the Investigators of the Italian Liver Association. A survey of adverse events in 11 241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996; 24(1): 38–47.Google Scholar
  15. 15.
    Weiss K. Safety profile of interferon-alpha therapy. Semin Oncol 1998; 25(1)(Suppl I): 9–13.Google Scholar
  16. 16.
    Hosoda S, Takimura H, Shibayama M, Kanamura H, Ikeda K, Kumada H. Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis. Psychiatry Clin Neurosci 2000; 54(5): 565–72.Google Scholar
  17. 17.
    Adams F, Fernandez F, Mavligit G. Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalities. J Neurooncol 1988; 6(4): 355–9.Google Scholar
  18. 18.
    Rifflet H, Vuillemin E, Oberti F et al. Pulsions suicidaires chez des malades atteints d'hépatite chronique C au cours ou au décours du traitement par l'interféron alpha. Gastroenterol Clin Biol 1998; 22(3): 353–7.Google Scholar
  19. 19.
    Van Gool AR, Kruit WHJ, Cornelissen JJ, Berk L, Eggermont AMM, Bannink M. Management of psychiatric adverse events with immunotherapy with interferon-alfa. Acta Neuropsychiatr 1999; 11(4): 120–4.Google Scholar
  20. 20.
    Greenberg DB, Jonasch E, Gadd MA et al. Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes. Cancer 2000; 89(2): 356–62.Google Scholar
  21. 21.
    Lemonnier E, Condat B, Paillère-Martinot ML, Chollet R, Allilaire JF. Syndrome de persécution sous interféron: à propos d'un cas. Société Médico-Psychologique 1996; 154(4): 246–9.Google Scholar
  22. 22.
    Nozaki O, Takagi C, Takaoka K, Takata K, Yoshida M. Psychiatric manifestations accompanying interferon therapy for patients with chronic hepatitis C: an overview of cases in Japan. Psychiatry Clin Neurosci 1997; 51(4): 175–80.Google Scholar
  23. 23.
    Adams F, Quesada JR, Gutterman JU. Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA 1984; 252(7): 938–41.Google Scholar
  24. 24.
    Pavol MA, Meyers CA, Rexer JL, Valentine AD, Mattis PJ, Talpaz M. Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia. Neurology 1995; 45(5): 947–50.Google Scholar
  25. 25.
    Mapou RL, Law WA, Wagner K, Malone JL, Skillman DR. Neuropsychological effects of interferon alfa-n3 treatment in asymptomatic human immunodefiency virus-1-infected individuals. J Neuropsychiatry Clin Neurosci 1996; 8(1): 74–81.Google Scholar
  26. 26.
    Capuron L, Ravaud A, Dantzer R. Timing and specifity of the cognitive changes induced by interleukin-2 and interferon-α treatments in cancer patients. Psychosom Med 2001; 63(3): 376–86.Google Scholar
  27. 27.
    Renault PF, Hoofnagle JH, Park Y, Mullen KD, Jones D, Rustgi V et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987; 147(9): 1577–80.Google Scholar
  28. 28.
    Merimsky O, Reider-Groswasser I, Inbar M, Chaitchik S. Interferon-related mental deterioration and behavioral changes in patients with renal cell carcinoma. Eur J Cancer 1990; 26(5): 596–600.Google Scholar
  29. 29.
    Hensley ML, Peterson BR, Silver RT, Larson RA, Schiffer CA, Szatrowski TP. Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013. J Clin Oncol 2000; 18(6): 1301–8.Google Scholar
  30. 30.
    McDonald, EM, Mann, AH, Thomas, HC. Interferons as mediators of psychiatric morbidity. Lancet 1987;11(Nov 21): 1175–8.Google Scholar
  31. 31.
    Hunt CM, Dominitz JA, Bute BP, Waters B, Blasi U, Williams DM. Effect of interferon-alfa treatment of chronic hepatitis C on health-related quality of life. Dig Dis Sci 1997; 42(12): 2482–6.Google Scholar
  32. 32.
    Malaguernera M, Di Fazio I, Restuccia S, Pistone G, Ferlito L, Rampello L. Interferon-alpha-induced depression in chronic hepatitis C patients: comparison between different types of interferon-alpha. Neuropsychobiology 1998; 37(2): 93–7.Google Scholar
  33. 33.
    Caraceni A, Gangeri L, Martini C, Belli F, Brunelli C, Baldini M et al. Neurotoxicity of interferon-alfa in melanoma therapy. Cancer 1998; 83(3): 482–9.Google Scholar
  34. 34.
    Scalori A, Apale P, Panizzuti F, Mascoli N, Pioltelli P, Pozzi M, et al. Depression during interferon therapy for chronic viral hepatitis: early identification of patients at risk by means of a computerized test. Eur J Gastroenterol Hepatol 2000; 12(5): 505–9.Google Scholar
  35. 35.
    Mulder RT, Ang M, Chapman B, Ross A, Stevens IF, Edgar C. Interferon treatment is not associated with a worsening of psychiatric symptoms in patients with hepatitis C. J Gastroenterol Hepatol 2000; 15(3): 300–3.Google Scholar
  36. 36.
    Ho SB, Nguyen H, Tetrick LL, Opitz GA, Basara ML, Dieperink E. Influence of psychiatric diagnoses on interferon-alpha tretament for chronic hepatitis C in a veteran population. Am J Gastroenterol 2001; 96(1): 157–64.Google Scholar
  37. 37.
    Van Thiel DH, Friedlander L, Molloy PJ, Fagiuoli S, Kania RJ, Caraceni P. Interferon-alfa can be used succesfully in patients with hepatitis C virus positive hepatitis who have a psychiatric illness. Eur J Gastroenterol Hepatol 1995; 7(2): 165–8.Google Scholar
  38. 38.
    Capuron L, Ravaud A. Prediction of the depressive effects of interferon alfa therapy by the patients initial affective state. N Engl J Med 1999; 340(17): 1370.Google Scholar
  39. 39.
    Bonaccorso S, Puzella A, Marino V, Pasquini M, Biondi M, Artini M et al. Immunotherapy 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(1–2): 45–55.Google Scholar
  40. 40.
    Miyoaka H, Otsubo T, Kamijima K, Ishii M, Onuki M, Mitamura K. Depression from interferon therapy in patients with hepatitis C. Am J Psychiatry 1999; 156(7): 1120.Google Scholar
  41. 41.
    Pariante CM, OrrÙ MG, Baita M, et al. Treatment with interferon-alfa in patients with chronic hepatitis and mood and anxiety disorders. Lancet 1999; 354(July 10): 131–2.Google Scholar
  42. 42.
    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(13): 961–6.Google Scholar
  43. 43.
    Kraus MR, Schäfer A, Scheurlen M. Paroxetine for the prevention of depression induced by interferon-alfa. N Engl J Med 2001; 345(5): 375–6.Google Scholar
  44. 44.
    Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002; 26(5): 643–52.Google Scholar
  45. 45.
    Yates WR, Gleason O. Hepatitis C and depression. Depress Anxiety 1998; 7(4): 188–93.Google Scholar
  46. 46.
    Trask PC, Esper P, Riba M, Redman B. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J Clin Oncol 2000; 18(11): 2316–26.Google Scholar
  47. 47.
    Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa and depression. Hepatology 2000; 31(6): 1207–11.Google Scholar
  48. 48.
    Gleason OC, Yates WR. Five cases of interferon-alphainduced depression treated with antidepressant therapy. Psychosomatics 1999; 40(): 510–2.Google Scholar
  49. 49.
    Valentine AD, Meyers CA, Talpaz M. Treatment of neurotxic side effects of interferon-alpha with naltrexone. Cancer Invest 1995; 13(6): 561–6.Google Scholar
  50. 50.
    Renault PF, Hoofnagle JH. Side effects of alpha interferon. Semin Liver Dis 1989; 9(4): 273–7.Google Scholar
  51. 51.
    Konsman JP. Immune-to-brain communication. Academical thesis, University of Groningen, 2000.Google Scholar
  52. 52.
    Dantzer R, Aubert A, Bluthé R-M, Gheusi G, Cremona S, Layé S et al. Mechanisms of the behavioral effects of cytokines. In: Dantzer R, Wollman EE, Yirmiya R, editors. Cytokines, stress and depression. New York: Kluwer Academic / Plenum Publishers 1999.Google Scholar
  53. 53.
    Menkes DB, MacDonald JA. Interferons, serotonin and neurotoxicity. Psychol Med 2000; 30(2): 259–68.Google Scholar
  54. 54.
    Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, 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(1): 86–90.Google Scholar
  55. 55.
    Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002; 7(5): 468–73.Google Scholar
  56. 56.
    Maes M, Smith R, Scharpé. The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology 1995; 20(2); 111–6.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • A.R. Van Gool
    • 1
  • W.H.J. Kruit
    • 2
  • G. Stoter
    • 2
  • F.K. Engels
    • 3
  • A.M.M. Eggermont
    • 4
  1. 1.Department of Psychosocial OncologyErasmus University Medical Center ‐ Daniel den Hoed Cancer CenterRotterdamThe Netherlands E‐mail
  2. 2.Department of Medical OncologyErasmus University Medical Center ‐ Daniel den Hoed Cancer CenterRotterdamThe Netherlands
  3. 3.Department of PharmacyErasmus University Medical CenterRotterdamThe Netherlands
  4. 4.Department of Surgical OncologyErasmus University Medical Center ‐ Daniel den Hoed Cancer CenterRotterdamThe Netherlands

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