- The most important thing to recognize about the neuropsychiatric effects of interferon (IFN)-α is that they have little respect for the tidy diagnostic categories presented in DSM-IV.
- The most common symptoms appear to be fatigue, anhedonia, insomnia, anxiety, irritability, emotional lability, cognitive disturbance, and aches and pains.
- The best single guide for identifying patients likely to benefit from prophylactic psychiatric treatment is the presence of mood and/or anxiety symptoms before the start of (IFN)-α therapy.
- Many clinicians routinely start antidepressants in all patients before initiating (IFN)-α therapy.
The fact that treatment with interferon (IFN)-α has become the world’s foremost human model for studying how the innate immune system promotes depression points to a disturbing clinical truth: patients who elect to receive (IFN)-α therapy for any of the several disease states to which it is applied face a high likelihood of experiencing a multitude of psychiatric symptoms severe enough to affect their social and occupational functioning and overall well-being.1 Indeed, with the development of effective strategies for addressing other common adverse effects such as anemia, behavioral morbidity has become a primary impediment to the successful use of (IFN)-α, which highlights the clinical importance of learning to recognize and treat (IFN)-α–induced psychiatric symptoms.2
Given the large number of patients who receive (IFN)-α and ribavirin for the treatment of chronic hepatitis C virus (HCV) infection (as well as a smaller patient population who receive (IFN)-α for cancer), it is likely that many psychiatric clinicians will be called on at one time or another to treat patients who are undergoing (IFN)-α therapy. This article reviews the types of symptoms commonly induced by (IFN)-α and their prevalence. Risk factors for psychiatric symptoms and strategies to prevent and manage such symptoms are also reviewed.
Types and Prevalence of Neuropsychiatric Symptoms
Perhaps the most important thing to recognize about the neuropsychiatric effects of (IFN)-α is that they have little respect for the tidy diagnostic categories presented in DSM-IV. Indeed, (IFN)-α induces a wide range of neuropsychiatric symptoms that—depending on their presentation in each individual patient—can best be conceived of in terms of various diagnostic rubrics, including depression, anxiety, sickness, and mania/hypomania. In many patients, diagnostic labels are less useful than a focus on the individual symptoms themselves. A good rule of thumb is that in the context of (IFN)-α therapy, symptoms are more real than the psychiatric diagnoses under which we try to subsume them, and many patients will be bothered by symptoms even when they do not meet strict DSM-IV diagnostic criteria for a specific disorder. For example, patients who initially report only 1 or 2 symptoms (especially fatigue or insomnia) will experience a depressive syndrome with ongoing treatment, or on closer questioning, will reveal a full spectrum of depressive symptoms.3
During INF-α therapy for HCV infection (which is by far the most common context for therapy), the most frequent symptoms appear to be fatigue, anhedonia, insomnia, anxiety, irritability, emotional lability, cognitive disturbance, and aches and pains.4,5 Unremitting depressed mood and associated symptoms such as hopelessness/helplessness and guilt appear to be less common.5.6 Consistent with these symptoms, (IFN)-α treatment has been associated with both suicidal ideation and completed suicides.4,7
Depression is the most widely recognized syndrome associated with (IFN)-α treatment. Rates of depression vary widely among studies, probably as a result of premorbid risk factors in the populations studied, the dosage of (IFN)-α, and the way that depression is defined. In general, studies suggest that clinically relevant depression will develop in 20% to 80% of patients who receive (IFN)-α and that significant fatigue will develop in up to 80% of patients.8-10 Study findings suggest that 40% of patients who receive pegylated (IFN)-α-2b plus ribavirin for HCV infection will meet criteria for moderate or greater severity of depressive symptoms at some point during the first 6 months of therapy.11
Most patients who experience depression begin to manifest symptoms within the first 2 months of treatment, which makes the early phase of therapy an especially important time for careful psychiatric monitoring and intervention.10-12 Whereas depression scores tend to increase over time, some evidence suggests that fatigue develops early in treatment and then tends to plateau or actually decline.8,11 The weekly pegylated preparation of (IFN)-α that most patients are currently receiving tends to worsen symptoms in the first few days following the injection; symptoms gradually improve over the ensuing days.
The frequent occurrence of irritability (and when severe, rage) and mood lability suggests that many patients treated with (IFN)-α have manic or hypomanic symptoms either in
addition or in contradistinction to depression. In a study directly examining the issue, 50% of patients in whom a DSM-IV mood disorder developed during (IFN)-α/ribavirin therapy met criteria for irritable hypomania, and 2% of the total population (10% of all mood disorders) met criteria for full mania, with classic symptoms such as euphoria and hypersexuality.6 The more symptoms of depression, the more likely patients were to also have hypomanic or mixed presentations, pointing to the limited usefulness of an either/or diagnostic approach to symptoms that emerge during (IFN)-α therapy. Whether a patient should be viewed as depressed or manic has clear psychiatric treatment implications; however, this distinction is often difficult in patients who are being treated with (IFN)-α because hypomanic symptoms are typically accompanied not by elation and energy but by dysphoria and fatigue.
1. Dan AA, Martin LM, Crone C, et al. Depression, anemia and health-related quality of life in chronic hepatitis C. J Hepatol. 2006;44:491-498.
2. 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: 2060-2065.
3. Wichers MC, Koek GH, Robaeys G, et al. Early increase in vegetative symptoms predicts (IFN)-αlpha-induced cognitive-depressive changes. Psychol Med. 2005;35:433-441.
4. Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19: 105-123.
5. Lotrich FE, Rabinovitz M, Gironda P, Pollock BG. Depression following pegylated interferon-alpha: characteristics and vulnerability. J Psychosom Res. 2007; 63:131-135.
6. 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;66:1050-1057.
7. Dieperink E, Ho SB, Tetrick L, et al. Suicidal ideation during interferon-alpha2b and ribavirin treatment of patients with chronic hepatitis C. Gen Hosp Psychiatry. 2004;26:237-240.
8. Maddock C, Landau S, Barry K, et al. Psychopathological symptoms during interferon-alpha and ribavirin treatment: effects on virologic response. Mol Psychiatry. 2005;10:332-333.
9. 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; 18:41-46.
10. 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-S178.
11. Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005;66:41-48.
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;25:34-38.
13. 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;25:1163-1174.
14. 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;58:15-18.
15. 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;46:991-998.
16. Kraus MR, Schäfer A, Csef H, Scheurlen M. Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C. World J Gastroenterol. 2005;11:1769-1774.
17. Wichers MC, Kenis G, Leue C, et al. Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment. Biol Psychiatry. 2006;60:77-79.
18. Bull SJ, Huezo-Diaz P, Binder EB, et al. Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry. 2008 May 6. [Epub ahead of print].
19. 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: 961-966.
20. Morasco BJ, Rifai MA, Loftis JM, et al. A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C. J Affect Disord. 2007;103:83-90.
21. 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;57:531-536.
22. 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;26:643-652.
23. Greco T, Eckert G, Kroenke K. The outcome of physical symptoms with treatment of depression. J Gen Intern Med. 2004;19:813-818.
24. Morrow GR, Hickok JT, Roscoe JA, et al; University of Rochester Cancer Center Community Clinical Oncology Program. 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;21:4635-4641.
25. Pockros PJ, Shiffman ML, Schiff ER, et al; PROACTIVE Study Group. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology. 2004;40:1450-1458.
26. 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-E90.
27. 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;16:1091-1099.
28. Altshuler LL, Post RM, Leverich GS, et al. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152: 1130-1138.
Dan AA, Martin LM, Crone C, et al. Depression, anemia and health-related quality of life in chronic hepatitis C. J Hepatol. 2006;44:491-498.
Morasco BJ, Rifai MA, Loftis JM, et al. A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C. J Affect Disord. 2007;103:83-90.
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;25:1163-1174.