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Recognizing and Treating Interferon-α–Induced Neuropsychiatric Symptoms

Recognizing and Treating Interferon-α–Induced Neuropsychiatric Symptoms


  • 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.


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