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Neuropsychiatric side effects associated with interferon-alfa plus ribavirin therapy: Treatment and prevention

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


Few well designed studies are available to provide definitive guidance on preventing or alleviating the many neuropsychiatric side effects associated with interferon-alfa (IFN-alfa) plus ribavirin. Fortunately, several placebo-controlled studies confirm clinical experience by demonstrating that side effects can be managed effectively in many patients. Nonetheless, the recommendations that follow are based mainly upon observational studies and experience in treatment of psychiatric syndromes in other settings.

The guidelines found on product information sheets (ie, dosage reduction of IFN-alfa as a treatment for depression) are not sufficiently comprehensive to address the clinical issues that arise during treatment. They do not adequately consider the tradeoff between managing depression and the reduction in efficacy of treatment associated with a dose reduction, especially early in the course of therapy. In addition, the effectiveness of dose-reduction in resolving treatment-emergent neuropsychiatric side effects remains to be conclusively determined.

We believe that a better strategy is to use all techniques at our disposal (pharmacological and psychosocial) to allow patients to tolerate full doses of IFN-alfa/ribavirin for an appropriate period while minimizing negative impact on emotional and physical well-being and daily functioning.

This topic review will summarize the treatment and prevention of neuropsychiatric side effects in patients receiving IFN-alfa plus ribavirin for hepatitis C virus infection. Recognition and risk factors are presented separately. (See "Neuropsychiatric side effects associated with interferon plus ribavirin for treatment of hepatitis C: Recognition and risk factors".)


Patients who are candidates for interferon-alfa (IFN-alfa) are often referred to psychiatrists to evaluate the risk of adverse psychiatric outcomes [1]. The role of the psychiatrist includes:

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Literature review current through: Nov 2017. | This topic last updated: Jun 15, 2017.
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  1. Lotrich FE. Psychiatric clearance for patients started on interferon-alpha-based therapies. Am J Psychiatry 2013; 170:592.
  2. Rifai MA, Loftis JM, Hauser P. Interferon-alpha treatment of patients with Hepatitis C: the role of a comprehensive risk-benefit assessment. CNS Drugs 2005; 19:719.
  3. Knott A, Dieperink E, Willenbring ML, et al. Integrated psychiatric/medical care in a chronic hepatitis C clinic: effect on antiviral treatment evaluation and outcomes. Am J Gastroenterol 2006; 101:2254.
  4. Schaefer M, Hinzpeter A, Mohmand A, et al. Hepatitis C treatment in "difficult-to-treat" psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects. Hepatology 2007; 46:991.
  5. Marron MM, Anderson SJ, Garrity J, et al. Association of Baseline Sleep Quality With Trajectories of Depressive Symptoms in Patients Undergoing Interferon Treatment. Psychosom Med 2015; 77:911.
  6. Raison CL, Woolwine BJ, Demetrashvili MF, et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther 2007; 25:1163.
  7. Nelligan JA, Loftis JM, Matthews AM, et al. Depression comorbidity and antidepressant use in veterans with chronic hepatitis C: results from a retrospective chart review. J Clin Psychiatry 2008; 69:810.
  8. Schaefer M, Capuron L, Friebe A, et al. Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol 2012; 57:1379.
  9. Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol 2013; 10:588.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Schäfer M, Schmidt F, Amann B, et al. Adding low-dose antidepressants to interferon alpha treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis. Neuropsychobiology 2000; 42 Suppl 1:43.
  16. Farah A. Interferon-induced depression treated with citalopram. J Clin Psychiatry 2002; 63:166.
  17. Gleason OC, Yates WR. Five cases of interferon-alpha-induced depression treated with antidepressant therapy. Psychosomatics 1999; 40:510.
  18. Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 2002; 63:194.
  19. Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-alpha. Am J Gastroenterol 1993; 88:760.
  20. Schramm TM, Lawford BR, Macdonald GA, Cooksley WG. Sertraline treatment of interferon-alfa-induced depressive disorder. Med J Aust 2000; 173:359.
  21. Yoshida K, Higuchi H, Takahashi H, Shimizu T. Favorable effect of milnacipran on depression induced by interferon-alpha. J Neuropsychiatry Clin Neurosci 2003; 15:242.
  22. Hou XJ, Xu JH, Wang J, Yu YY. Can antidepressants prevent pegylated interferon-α/ribavirin-associated depression in patients with chronic hepatitis C: meta-analysis of randomized, double-blind, placebo-controlled trials? PLoS One 2013; 8:e76799.
  23. Jiang HY, Deng M, Zhang YH, et al. Specific serotonin reuptake inhibitors prevent interferon-α-induced depression in patients with hepatitis C: a meta-analysis. Clin Gastroenterol Hepatol 2014; 12:1452.
  24. Udina M, Hidalgo D, Navinés R, et al. Prophylactic antidepressant treatment of interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry 2014; 75:e1113.
  25. Sarkar S, Schaefer M. Antidepressant pretreatment for the prevention of interferon alfa-associated depression: a systematic review and meta-analysis. Psychosomatics 2014; 55:221.
  26. Su KP, Lai HC, Yang HT, et al. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol Psychiatry 2014; 76:559.
  27. Kraus MR, Schäfer A, Schöttker K, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut 2008; 57:531.
  28. 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.
  29. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington 2013.
  30. 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.
  31. Kraus MR, Schäfer A, Scheurlen M. Paroxetine for the prevention of depression induced by interferon alfa. N Engl J Med 2001; 345:375.
  32. Hauser P, Soler R, Reed S, et al. Prophylactic treatment of depression induced by interferon-alpha. Psychosomatics 2000; 41:439.
  33. Schaefer M, Schwaiger M, Berg T. Citalopram for the prevention of interferon-alpha associated depression in psychiatric risk patients (abstract). Hepatology 2003; 38:320A.
  34. Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003; 37:443.
  35. Van Thiel DH, Friedlander L, De Maria N, et al. Treatment of chronic hepatitis C in individuals with pre-existing or confounding neuropsychiatric disease. Hepatogastroenterology 1998; 45:328.
  36. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326:1250.
  37. Malani AK, Ammar H. Medical management of depression. N Engl J Med 2006; 354:646.
  38. Hirschfeld RM, Montgomery SA, Aguglia E, et al. Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry 2002; 63:826.
  39. Girardin FR, Gex-Fabry M, Berney P, et al. Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study. Am J Psychiatry 2013; 170:1468.
  40. Capuron L, Gumnick JF, Musselman DL, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002; 26:643.
  41. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 2003; 21:4635.
  42. Greco T, Eckert G, Kroenke K. The outcome of physical symptoms with treatment of depression. J Gen Intern Med 2004; 19:813.
  43. 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.
  44. Pockros PJ, Shiffman ML, Schiff ER, et al. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004; 40:1450.
  45. Schwartz AL, Thompson JA, Masood N. Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Oncol Nurs Forum 2002; 29:E85.
  46. Sugawara Y, Akechi T, Shima Y, et al. Efficacy of methylphenidate for fatigue in advanced cancer patients: a preliminary study. Palliat Med 2002; 16:261.
  47. Sarhill N, Walsh D, Nelson KA, et al. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care 2001; 18:187.
  48. Jones EA. Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. Lancet 1999; 354:397.
  49. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 2005; 52:2495.
  50. Quarantini LC, Miranda-Scippa A, Schinoni MI, et al. Effect of amantadine on depressive symptoms in chronic hepatitis C patients treated with pegylated interferon: a randomized, controlled pilot study. Clin Neuropharmacol 2006; 29:138.
  51. 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.
  52. 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.
  53. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2005; 6:346.
  54. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005; 119:5.
  55. Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005; 116:109.
  56. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004; 50:2974.
  57. Fava M, Mallinckrodt CH, Detke MJ, et al. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry 2004; 65:521.
  58. Yucel A, Ozyalcin S, Koknel Talu G, et al. The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study. Eur J Pain 2005; 9:407.
  59. Ozyalcin SN, Talu GK, Kiziltan E, et al. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 2005; 45:144.
  60. Guldiken S, Guldiken B, Arikan E, et al. Complete relief of pain in acute painful diabetic neuropathy of rapid glycaemic control (insulin neuritis) with venlafaxine HCL. Diabetes Nutr Metab 2004; 17:247.
  61. Bulut S, Berilgen MS, Baran A, et al. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg 2004; 107:44.
  62. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004; 110:697.
  63. Forssell H, Tasmuth T, Tenovuo O, et al. Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial. J Orofac Pain 2004; 18:131.
  64. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001; 57:1583.
  65. Semenchuk MR, Davis B. Efficacy of sustained-release bupropion in neuropathic pain: an open-label study. Clin J Pain 2000; 16:6.
  66. Freynhagen R, Muth-Selbach U, Lipfert P, et al. The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med Res Opin 2006; 22:257.
  67. Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 2004; 62:1706.
  68. 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.
  69. Altshuler LL, Post RM, Leverich GS, et al. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152:1130.