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
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