Research reportA randomized trial of paroxetine to prevent interferon-α-induced depression in patients with hepatitis C
Introduction
Interferon-α (IFN-α) based therapies are the current approved treatments for hepatitis C virus (HCV) and malignant melanoma (Hancock et al., 2004, Strader et al., 2004). IFN-α-induced neuropsychiatric adverse effects were first documented during the initial studies of HCV treatment (Hoofnagle et al., 1986, Renault et al., 1987, Renault and Hoofnagle, 1989). Major depression occurs in approximately 30% of patients undergoing IFN-α and ribavirin treatment for HCV (Constant et al., 2005, Hauser et al., 2002, Loftis and Hauser, 2004, Raison et al., 2005) and suicidal ideation may occur in as many as one-third of patients (Dieperink et al., 2004, Janssen et al., 1994). IFN-α-induced neuropsychiatric adverse effects are problematic as they can result in the reduction or discontinuation of HCV treatments (Dieperink et al., 2000, Rifai and Rosestein, 2005). Furthermore, clinicians have been reluctant to engage patients with HCV in IFN-α and ribavirin treatments due to concerns about precipitating or worsening neuropsychiatric illness (Hauser, 2004).
Case reports detailing the use of antidepressant medication in patients with HCV infection during IFN-α and ribavirin treatment documented the effectiveness of selective serotonin reuptake inhibitors (SSRIs), as well as tricyclic antidepressants in the treatment of IFN-α-induced depression (Levenson and Fallon, 1993, Goldman, 1994, Valentine and Meyers, 1995). Several open-label trials showed the effectiveness of SSRIs (citalopram and paroxetine) in the treatment of IFN-α-induced depression in patients with HCV (Hauser et al., 2002, Kraus et al., 2001, Kraus et al., 2005a).
To our knowledge, there has been no published placebo-controlled trial on the use of antidepressants for the prevention of IFN-α-induced depression in patients with HCV infection. Hauser et al. (2000) in a case report described the first use of fluoxetine for prophylactic treatment of depression induced by high-dose IFN-α in a patient with malignant melanoma. In a subsequent placebo-controlled trial in patients with malignant melanoma, Musselman et al. (2001) found that prophylactic paroxetine was efficacious in preventing depression induced by high-dose IFN-α (10–20 million Units 3–5 times weekly). Nonetheless, Kraus et al. (2001) argued that the prophylactic approach to using SSRIs is not justifiable in patients with HCV infection who are receiving lower doses of regular IFN-α (3 to 5 million Units 3 times a week) than that used in patients with malignant melanoma.
Given the significant association between HCV infection and neuropsychiatric illness, as well as the frequent development of neuropsychiatric adverse effects with antiviral therapy, there is a pressing need to systematically assess the effectiveness of antidepressants in the prophylaxis of IFN-α-induced depression (Hauser, 2004, Yovtcheva et al., 2001, Schaefer et al., 2003). Recently, two small separate open-label trials demonstrated that prophylactic antidepressants are effective in the treatment and prevention of IFN-α-induced depression in patients with HCV and a current psychiatric disorder, as well as patients with histories of IFN-α-induced depression (Kraus et al., 2005a, Schaefer et al., 2005).
This study is the first placebo-controlled trial of prophylactic SSRI medication to prevent IFN-α-induced depression in patients with HCV and no current psychiatric or substance use disorders. We hypothesized that (a) patients receiving paroxetine would be less likely than those receiving placebo to develop IFN-α-induced depression, and (b) patients receiving paroxetine would be more likely to complete IFN-α and ribavirin treatment.
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Participants
Thirty-three patients with HCV were recruited from Veterans Affairs Medical Centers in Salem, Virginia and Portland, Oregon. Subjects were included if they were 18 years or older, had a diagnosis of HCV, and were eligible for IFN-α and ribavirin treatment. Individuals were excluded from participating if they were ineligible for IFN-α, had hypersensitivity to paroxetine, active delirium, or met diagnostic criteria (American Psychiatric Association, 1994) for a current major depressive disorder,
Results
Table 1 presents a comparison of demographic differences of subjects assigned to the paroxetine and placebo groups. The groups did not differ with respect to race/ethnicity, HCV genotype, history of major depression, history of alcohol or substance use disorder, or history of other psychiatric disorders. The rate of IFN-α-induced major depression in the entire sample was 33.3% (11/33). Major depression developed in 35.7% of patients assigned to the paroxetine group (5 of 14), compared with
Discussion
This study is the first placebo-controlled trial to evaluate the utility of an antidepressant medication (paroxetine) in the prevention of IFN-α-induced depression in patients with HCV infection. There are several important findings from this study that are pertinent to the treatment of patients with HCV infection. First, the prophylactic use of paroxetine did not decrease the incidence of IFN-α-induced depression; second, paroxetine was effective in the treatment of IFN-α-induced depression
Acknowledgements
This study was supported in part by a grant from GlaxoSmithKline. Dr. Peter Hauser is on the Speaker's Bureau and has received grant support from GlaxoSmithKline.
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2014, PsychosomaticsCitation Excerpt :Escitalopram (OR = 0.44; 95% CI, 0.23–0.85; p = 0.015) and citalopram (OR = 0.22; 95% CI, 0.06–0.78; p = 0.019) were significantly superior to placebo treatment regarding the reduction of major depressive episodes during INF treatment, whereas the differences between the paroxetine-treated patients and the placebo group did not reach significance (Figure 4). Patients with pre-existing or active psychiatric disorders (affective disorders and drug addiction) were included in 7 trials with 408 participants6,26–31 and were excluded in one trial with 181 participants.13 Antidepressant pretreatment reduced the overall incidence of major depressive episodes in patients with pre-existing psychiatric disorders (OR = 0.44; 95% CI, 0.25–0.78; p = 0.005) and in patients without pre-existing psychiatric disorders (OR = 0.37; 95% CI, 0.14–0.93; p = 0.036, Figure 4).