Recognizing and Treating Interferon-α–Induced Neuropsychiatric Symptoms

August 2, 2008
Charles L. Raison, MD

Volume 25, Issue 9

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

CHECK POINTS

  • 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.

Risk Factors

A number of premorbid factors have been identified that increase the risk of psychiatric symptoms during (IFN)-α therapy. The most frequently replicated risk factor-and probably 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 (ie, at baseline).4,10,13 Studies suggest that patients with even mildly severe depressive symptoms at baseline are at increased risk for clinically significant depression during treatment. A past history of major depression is also a risk factor for (IFN)-α–induced symptoms, which may derive primarily from the fact that patients with past major depression are much more likely to have at least mildly severe depressive symptoms before treatment.4,11,14 Interestingly, the presence of psychiatric conditions per se does not appear to be a significant risk factor. For example, a history of substance abuse does not appear to increase depression risk, and studies suggest that well-managed patients with major psychiatric disorders such as schizophrenia are as likely as any others to tolerate and derive benefit from (IFN)-α therapy.15

In addition to premorbid factors, studies have identified risks that are inherent in the treatment itself. For example, ribavirin has been shown to increase the depressive burden of (IFN)-α treatment and to contribute to fatigue via its proclivity to induce anemia.11 Increasing duration and dosage of (IFN)-α treatment also appears to heighten the risk of symptom development. Pegylated preparations of (IFN)-α do not appear to differ significantly from older forms of (IFN)-α in terms of neuropsychiatric burden.16

Recent studies have identified novel risks for (IFN)-α–induced depression. Patients in whom neurovegetative and somatic symptoms (eg, fatigue, insomnia) develop early in treatment are at much greater risk than others of manifesting the full spectrum of depressive symptoms later in treatment.3 Depression is also more likely to develop in patients who have elevated inflammatory markers before treatment and in patients with specific forms of the gene for the proinflammatory cytokine interleukin-6 and the serotonin transporter.17,18Treatment Options
 

If we could look into the future and know exactly when depressogenic factors were going to strike our patients, we could provide psychiatric protection. Unlike the vagaries of psychological stress, (IFN)-α treatment typically starts and ends on a schedule that is predetermined, which means that we as clinicians can know ahead of time when the trouble is going to start and determine what steps can be taken to minimize the impact. Practically, this means that clinicians have 2 options with which to deal with (IFN)-α–induced neuropsychiatric symptoms: prophylaxis and symptomatic treatment. Fortunately, data suggest that both strategies are effective, with the most appropriate choice dependent on the individual patient. The algorithm (Figure) summarizes various interventions for treating (IFN)-α–induced depression.

The first evidence that pretreatment with an antidepressant effectively protects against (IFN)-α–induced major depression came from a randomized, double-blind, placebo-controlled trial of paroxetine in patients who had received high-dose (IFN)-α monotherapy (ie, without ribavirin) for malignant melanoma. In that study, paroxetine reduced the incidence of major depression during the first 3 months of (IFN)-α therapy from 45% to 11% and allowed a much higher percentage of patients to continue treatment as a result of diminished (IFN)-α neurotoxicity, without adding an appreciable adverse-effect burden.19

Based in large part on this landmark study, many clinicians now routinely start antidepressants in all patients before initiating (IFN)-α therapy. However, the wisdom of this one-size-fits-all approach should be tempered by 2 recent, double-blind, placebo-controlled trials of antidepressant prophylaxis in patients who had received relatively low doses of (IFN)-α in combination with ribavirin for the treatment of HCV infection.

The first of these trials found no benefit of pretreatment with the SSRI paroxetine. However, a second and much larger study found that paroxetine pretreatment reduced the development of mild, moderate, and severe depressive symptoms during (IFN)-α/ribavirin therapy when compared with placebo.13,20 A clinically important caveat emerged from a secondary analysis of data from this second study. Only patients with mild or more severe depressive symptoms before the start of (IFN)-α therapy benefited from the SSRI pretreatment. On the other hand, study participants without depressive symptoms at baseline had, on average, only mild increases in symptoms during (IFN)-α/ribavirin therapy and derived no benefit from antidepressant pretreatment.

Together with multiple studies showing that subsyndromal depressive/anxiety symptoms at baseline are a robust predictor of INF-α–induced depression, these findings paint a consistent picture that antidepressant pretreatment may not be a universal panacea but can be of significant benefit for most patients with premorbid mood and anxiety symptoms.4 Whether antidepressant pretreatment would also differentially benefit patients with a past history of depression without current symptoms is not known, but common sense suggests this group might also benefit from pretreatment. We would also recommend pretreating those patients who had significant depressive symptoms during earlier (IFN)-α therapy trials.

A growing evidence base suggests that antidepressants also significantly improve (IFN)-α–induced neuropsychiatric symptoms once they develop.4 In addition to a number of case series, a recent double-blind placebo-controlled trial found that citalopram was significantly better than placebo in reducing depressive symptoms in patients in whom major depression developed during (IFN)-α/ribavirin therapy for HCV infection.4,21 Interestingly, in a study that found no benefit for antidepressant prophylaxis, when patients with (IFN)-α–induced depression were switched from placebo to paroxetine they showed significant improvement in symptoms. This finding further supports the notion that antidepressants are effective once symptoms have developed with (IFN)-α therapy.20

Several clinical challenges in treating (IFN)-α–induced neuropsychiatric adverse effects deserve special mention. Fatigue is the most common neuropsychiatric effect associated with (IFN)-α.22 As a result, it is especially disconcerting that SSRIs (the most commonly used antidepressants) are not optimal treatment choices for fatigue in either medically healthy or ill patients.23,24 Paroxetine was significantly more effective than placebo in reducing depressed mood, anxiety, and cognitive complaints but not in reducing fatigue, sleep complaints, and appetite loss in patients who had received high-dose (IFN)-α monotherapy for malignant melanoma.22

Many patients with full-blown (IFN)-α–induced depression may feel better emotionally (eg, less sad, more hopeful, less irritable) following treatment with an SSRI but may well be left with inadequately controlled fatigue and other neurovegetative/ physical symptoms. Conversely, patients who present with (IFN)-α–induced fatigue without other prominent depressive symptoms may derive no benefit at all from SSRI treatment, while being subjected to the additional adverse effects (eg, loss of libido, GI complaints, disrupted sleep) associated with these agents.

Before considering pharmacological interventions for patients with fatigue without depression, the clinician should suggest behavioral strategies that improve fatigue and help patients adjust their activities to its presence. Unfortunately, IFN or ribavirin dosage reduction does not reliably improve fatigue. We suggest that patients conserve energy by taking frequent rest periods, napping if possible, and spreading out physical and household tasks throughout the day. A gradual exercise-tolerance program that includes light exercise, such as a daily walk, can be useful if initiated at the beginning of therapy to condition patients to a higher level of activity and improve physical functioning and help them better cope with fatigue.

At present, growth factors used to maintain adequate hemoglobin levels are the best documented treatment for fatigue associated with antiviral therapy.25 Because of a lack of adequate controlled trials, further recommendations for agents to treat (IFN)-α/ribavirin–induced fatigue must be considered provisional, because they are based on data from other disease states. Having said this, significant data suggest that agents that modulate catecholamine signaling in the CNS reliably reduce fatigue and increase wakefulness.

Psychostimulants (especially methylphenidate and dextroamphetamine) reduce fatigue in healthy controls and in patients with multiple medical comorbidities and have been reported to be of value during (IFN)-α treatment when combined with exercise.26 Our clinical experience suggests that many patients with (IFN)-α/ribavirin–induced fatigue improve significantly with the addition of one of these agents to their regimen (either as an add-on to an antidepressant in patients with a full panoply of depressive symptoms or as a single agent in fatigued patients without other depressive symptoms). However, psychostimulants are associated with abuse liability, which can make their use problematic in many patients with substance-abuse issues. A potential alternative is the wakefulness-promoting agent modafinil.

A final therapeutic challenge harkens back to the diagnostic challenge of separating depression from irritable hypomania/mania in patients who receive (IFN)-α. Findings indicate that most cases of (IFN)-α–induced irritability respond well to SSRI antidepressants.22,27 Serotonergic antidepressants are the first choice for treating mild to moderate irritability. However, as irritability worsens or as a patient’s insight into his or her condition diminishes, the clinician needs to consider that antidepressants might actually worsen the situation, because antidepressants may lead to manic symptoms.28 (IFN)-α–induced mania should be considered a psychiatric emergency and may require acute hospitalization. Although limited data are available, widespread clinical experience suggests that atypical antipsychotics are often rapidly effective in (IFN)-α–treated patients manifesting dysphoric mania. Adjunctive benzodiazepines can also be useful for treatment of acute symptoms.9

References:

References


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 chang

es. Psychol M

ed. 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.

Evidence-Based References


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.