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(Drug information on 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.17,18
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(Drug information on 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.