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Neuropsychiatric side effects associated with interferon plus ribavirin for treatment of hepatitis C: Recognition and risk factors

Charles L Raison, MD
Nezam H Afdhal, MD, FRCPI
Section Editor
Jonathan M Silver, MD
Deputy Editor
David Solomon, MD


Neuropsychiatric side effects are common in patients who receive interferon plus ribavirin, and these adverse effects can cause treatment failure and clinical decisions to not start treatment in the first place [1]. The regimen of interferon plus ribavirin is rarely used in the United States.

This topic reviews recognition and risk factors for neuropsychiatric side effects in patients receiving interferon plus ribavirin for hepatitis C virus infection. Treatment and prevention of these side effects are discussed separately. (See "Neuropsychiatric side effects associated with interferon-alfa plus ribavirin therapy: Treatment and prevention".)


The neuropsychiatric side effect most often associated with interferon plus ribavirin for hepatitis C virus is depression. Depression occurs on a continuum ranging from subsyndromal symptoms to minor depression and major depression. The clinical manifestations and diagnosis of the different types of depression are discussed separately. (See "Unipolar depression in adults: Assessment and diagnosis".)

Studies of depression associated with interferon plus ribavirin vary in the type of depression that was assessed. Some studies have characterized depression as a single symptom (feeling down or sad) [2,3], while other studies have defined depression as a syndrome characterized by a defined set of emotional and physical symptoms [4-8]. In still other studies [1,9-11], depression was assessed as a severity score on questionnaires that asked about symptoms not necessarily recognized as part of major depression in the American Psychiatric Association's Diagnostic and Statistical Manual, Fifth Edition (DSM-5) [12]. Generally, depression is more common when viewed as a single symptom or as a score on a rating scale than when it is defined as the syndrome of major depression (table 1) [13].

The incidence of unipolar major depression in patients with hepatitis C who are treated with interferon plus ribavirin is high. A meta-analysis of 22 prospective observational studies examined the incidence of major depression in 1391 euthymic patients with chronic hepatitis C who started interferon plus ribavirin [14]. Following onset of treatment, the cumulative incidence of major depression was as follows at:


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Literature review current through: Sep 2016. | This topic last updated: Mar 23, 2016.
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  1. Guadagnino V, Trotta MP, Carioti J, et al. Does depression symptomatology affect medication compliance during the first weeks of anti-HCV therapy in intravenous drug users? Dig Liver Dis 2006; 38:119.
  2. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:958.
  3. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975.
  4. Maddock C, Baita A, Orrù MG, et al. Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms. J Psychopharmacol 2004; 18:41.
  5. Kraus MR, Schäfer A, Faller H, et al. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002; 16:1091.
  6. Horikawa N, Yamazaki T, Izumi N, Uchihara M. Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study. Gen Hosp Psychiatry 2003; 25:34.
  7. Schaefer M, Schwaiger M, Garkisch AS, et al. Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol 2005; 42:793.
  8. Beratis S, Katrivanou A, Georgiou S, et al. Major depression and risk of depressive symptomatology associated with short-term and low-dose interferon-alpha treatment. J Psychosom Res 2005; 58:15.
  9. Dan AA, Martin LM, Crone C, et al. Depression, anemia and health-related quality of life in chronic hepatitis C. J Hepatol 2006; 44:491.
  10. Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005; 66:41.
  11. Reichenberg A, Gorman JM, Dieterich DT. Interferon-induced depression and cognitive impairment in hepatitis C virus patients: a 72 week prospective study. AIDS 2005; 19 Suppl 3:S174.
  12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  13. Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 2005; 19:105.
  14. Udina M, Castellví P, Moreno-España J, et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry 2012; 73:1128.
  15. Janssen HL, Brouwer JT, van der Mast RC, Schalm SW. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994; 21:241.
  16. Laguno M, Blanch J, Murillas J, et al. Depressive symptoms after initiation of interferon therapy in human immunodeficiency virus-infected patients with chronic hepatitis C. Antivir Ther 2004; 9:905.
  17. Bagheri H, Fouladi A, Barange K, et al. Follow-up of adverse drug reactions from peginterferon alfa-2b-ribavirin therapy. Pharmacotherapy 2004; 24:1546.
  18. Raison CL, Broadwell SD, Borisov AS, et al. Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C. Brain Behav Immun 2005; 19:23.
  19. Maddock C, Landau S, Barry K, et al. Psychopathological symptoms during interferon-alpha and ribavirin treatment: effects on virologic response. Mol Psychiatry 2005; 10:332.
  20. Bernstein D, Kleinman L, Barker CM, et al. Relationship of health-related quality of life to treatment adherence and sustained response in chronic hepatitis C patients. Hepatology 2002; 35:704.
  21. Simon GE, VonKorff M, Piccinelli M, et al. An international study of the relation between somatic symptoms and depression. N Engl J Med 1999; 341:1329.
  22. 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.
  23. 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.
  24. Kraus MR, Schäfer A, Faller H, et al. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry 2003; 64:708.
  25. 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; 89:356.
  26. Kanno A, Yamada M, Abe M, Okamoto Y. A case of interferon alpha-induced manic psychosis in chronic hepatitis C. Tohoku J Exp Med 1999; 187:79.
  27. Strite D, Valentine AD, Meyers CA. Manic episodes in two patients treated with interferon alpha. J Neuropsychiatry Clin Neurosci 1997; 9:273.
  28. Hosoda S, Takimura H, Shibayama M, et al. Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis. Psychiatry Clin Neurosci 2000; 54:565.
  29. Lotrich FE. Psychiatric clearance for patients started on interferon-alpha-based therapies. Am J Psychiatry 2013; 170:592.
  30. Capuron L, Ravaud A. Prediction of the depressive effects of interferon alfa therapy by the patient's initial affective state. N Engl J Med 1999; 340:1370.
  31. Fontana RJ, Schwartz SM, Gebremariam A, et al. Emotional distress during interferon-alpha-2B and ribavirin treatment of chronic hepatitis C. Psychosomatics 2002; 43:378.
  32. Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of neuropsychiatric symptoms associated with interferon-alpha-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003; 44:104.
  33. Miyaoka H, Otsubo T, Kamijima K, et al. Depression from interferon therapy in patients with hepatitis C. Am J Psychiatry 1999; 156:1120.
  34. Cotler SJ, Wartelle CF, Larson AM, et al. Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C. J Viral Hepat 2000; 7:211.
  35. Hauser P, Khosla J, Aurora H, et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7:942.
  36. Kraus MR, Schäfer A, Csef H, et al. Compliance with therapy in patients with chronic hepatitis C: associations with psychiatric symptoms, interpersonal problems, and mode of acquisition. Dig Dis Sci 2001; 46:2060.
  37. Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry 2005; 62:1097.
  38. Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126:1302.