Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C


Dr A. H. Miller, Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, 5th floor, Atlanta, GA 30322, USA.


Background Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established.

Aim To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication.

Methods Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Results Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher’s exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1–18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate.

Conclusion This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.


Significant depressive symptoms occur in 20–60% of patients treated with interferon (IFN)-alpha and ribavirin for hepatitis C virus (HCV) infection.1–12 These symptoms contribute to impaired quality of life13 and are recognized as a major reason for treatment discontinuation, non-compliance and IFN-alpha/ribavirin dose reduction,14–20 all of which can contribute to treatment failure.21–23 Depressive symptoms may also represent an independent risk factor for poor virologic response.24, 25 These findings highlight the need to examine potential therapeutic options for managing depression during IFN-alpha/ribavirin therapy.

Antidepressants are the mainstay for treating depression associated with IFN-alpha/ribavirin therapy in HCV patients.12 The available literature, which primarily consists of open-label, non-randomized reports, indicates that many patients who develop depressive symptoms during IFN-alpha/ribavirin treatment improve significantly and can continue anti-viral therapy when administered antidepressants.1, 26–31 Nevertheless, comprehensive monitoring of depressive symptoms and timely initiation of antidepressant treatment during IFN-alpha therapy presents a challenge to clinicians, who may not have ready access to mental health resources and are otherwise consumed by the competing demands of managing a clinical practice.

One strategy to obviate the challenges and complications presented by depression during IFN-alpha/ribavirin therapy is to pretreat patients with antidepressants. Recent open trials suggest that antidepressant pre-treatment may reduce depression during anti-viral therapy.27, 32, 33 This observation is consistent with prior findings that pre-treatment with the antidepressant paroxetine reduced the incidence of major depression in patients receiving high-dose IFN-alpha monotherapy for malignant melanoma.34 Nevertheless, limited double-blind, placebo-controlled data are available in HCV patients,35 who present unique treatment challenges, including increased rates of substance abuse and other psychiatric co-morbidities,19, 36 as well as use of ribavirin, which may independently contribute to depressive symptoms.2 Moreover, because depression during IFN-alpha/ribavirin therapy for HCV is far from universal, routine antidepressant pre-treatment may needlessly expose a number of patients to the risks/side effects of antidepressant medication.12

Accordingly, we endeavoured to evaluate whether pre-treatment with paroxetine would be associated with reduced depression in patients receiving IFN-alpha and ribavirin for treatment of HCV using a randomized, double-blind, placebo-controlled design.



Of 82 patients screened, 61 patients between the ages of 18 and 65, who were serum positive for anti-HCV antibodies or HCV-RNA by reverse transcription-polymerase chain reaction, were enrolled between February 2000 and January 2005 at four academic medical centres (Atlanta, GA [n = 32], Philadelphia, PA [n = 9], New York, NY [n = 15] and Chicago, IL [n = 5]) (Figure 1). All subjects provided written informed consent, and study procedures were approved a priori by each site’s Institutional Review Board (IRB). Exclusion criteria included decompensated liver disease; liver disease of any cause other than HCV; unstable cardiovascular, endocrinologic, haematologic, renal or neurologic disease; history of schizophrenia or bipolar disorder; diagnosis of major depression or substance abuse/dependence within 6 months of study entry [determined by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition (SCID)],37 or a score < 24 on the Mini Mental State Exam, indicating more than mild cognitive impairment.38 Patients were required to be off all psychotropic medications (except zolpidem [Ambien] for sleep) at least 2 weeks prior to baseline.

Figure 1.

 Study flow diagram.

Study procedures


Patients were randomly assigned in double-blind fashion to commence 26 weeks of either paroxetine (Paxil, GlaxoSmithKline, Philadelphia, PA, USA) or placebo. Paroxetine was chosen based on a double-blind placebo-controlled trial demonstrating efficacy of this agent in reducing the development of major depression in patients receiving high-dose IFN-alpha monotherapy for cancer as well as several open-label trials in patients receiving IFN-alpha/ribavirin for HCV.26, 34 Prior to randomization, subjects were stratified based on past history of major depression (n = 15) or no history of mood disorder (n = 46). A computer-generated randomization list prepared by the study statistician was supplied to each site, which, in turn, allocated randomization assignments and dispensed study drug. Study personnel and subjects were blinded to group assignment.

Administration of study medications

Following baseline assessment, patients commenced taking one tablet of either paroxetine (10 mg) or placebo a day. After 3 days, the dose was raised to two tablets daily as tolerated. At study week 4 (2 weeks after commencing IFN-alpha), based on the depressive symptoms, study medication could be increased up to four tablets per day at the discretion of study psychiatrists. Patients remained on study medication for 26 weeks unless they dropped out or were terminated. This dosing strategy was designed to provide antidepressant treatment throughout the period of greatest risk for new onset depression, while limiting the burden of a prolonged treatment trial. Two weeks after initiation of study medication, patients began IFN-alpha/ribavirin under the supervision of treating gastroenterologists. Because this study occurred during the transition to pegylated IFN-alpha, 22 subjects received non-pegylated IFN-alfa-2b (Intron A, Schering Plough, Kenilworth, NJ, USA), 20 received pegylated IFN-alfa-2b (Pegintron, Schering Plough) and 10 received pegylated IFN-alfa-2a (PEGASYS, Roche, Basel, Switzerland). IFN-alpha/ribavirin dosage decisions were made by treating physicians and were not controlled by study protocol. Concomitant psychotropic medications were not allowed, with exception of zolpidem for insomnia.

Assessment of depression

Patients were evaluated at baseline (prior to administration of study drug) and following 4, 8, 12, 16, 20 and 24 weeks of IFN-alpha/ribavirin. At each visit, trained clinicians employed the mood disorders module from the SCID to determine whether patients met criteria for major depression.37 Depressive symptom severity was evaluated by using the clinician-administered Montgomery Asberg Depression Rating Scale (MADRS), a 10-item scale sensitive to symptom change during antidepressant treatment.39 The MADRS has been frequently used to measure depressive symptoms during IFN-alpha therapy and exhibits improved internal consistency in patients with co-morbid medical conditions compared with other clinician-administered questionnaires.40–45 In addition to providing a continuous measure of depressive symptoms, the following scores for the MADRS have been correlated with global severity measures of depression and have been used as ‘cut-off’ scores for levels of severity of depressive symptoms: mild, 15; moderate, 25; and severe, 31.46, 47 To enhance inter-rater reliability on the MADRS within and between study sites, training videotapes were employed.

Safety evaluation

Spontaneously reported treatment–emergent adverse events were recorded and coded by severity, frequency, duration and impact on treatment.48 Life-threatening adverse events were reported to the IRB of the relevant study site. Depressive symptoms judged to pose an impediment to further IFN-alpha/ribavirin treatment or to significantly interfere with daily function resulted in study termination, breaking the blind, and referral for psychiatric care.

Assessment of substance abuse

Subjects with a history of substance abuse as determined by SCID were administered the Addiction Severity Index (ASI) at each visit.49

Statistical analysis

Planned primary outcome measures included differences between groups in incidence of major depression as well as depressive symptom scores. Other outcome measures included treatment–emergent side effects, need for IFN-alpha or ribavirin dosage reduction and study discontinuation. The study was not designed/powered to assess group differences in IFN-alpha treatment discontinuation or viral response. Chi-squared analysis (or Fisher’s exact test where appropriate) was used to compare number/percent of patients meeting criteria for major depression during IFN-alpha/ribavirin therapy in paroxetine- vs. placebo-treated patients. The same strategy was used to evaluate the number/percent of patients meeting cut-off scores for normal and mild, moderate or severe depression according to the MADRS. Chi-squared analyses were also used to compare rates of treatment–emergent adverse events, need for dosage reduction and study discontinuation.

An intent-to-treat analysis was used to analyse continuous measures of depression severity in combination with a mixed-effects model repeated measures approach (PROC MIXED procedure in SAS). This analytic strategy includes all randomized subjects in the analysis (even if they dropped out prior to initiating therapy with IFN-alpha/ribavirin), but, at any given visit, only considers data available from subjects who remain in the study at that time point (i.e. no carry forward method is used). The mixed-effects model repeated measures approach has been used extensively in neuropsychiatric clinical trials and has been found to be less vulnerable to Types I and II errors in the context of missing data (e.g. early drop-outs) compared with last observation carried forward methods.50 Factors included in the PROC MIXED procedure were treatment group, visit, site, past depression history and interactions between these variables. Because recent data suggest that the contribution of past depression history to symptom development during IFN-alpha/ribavirin treatment is largely accounted for by an association with increased depressive symptoms prior to treatment,2 the PROC MIXED procedure was repeated with baseline MADRS score (evaluated by median split) added to the model. Patients with baseline depression scores above the median on a standard depression rating scale were recently found to be at significantly increased risk for major depression during IFN-alpha/ribavirin therapy.50Post hoc differences between specific means of interest were conducted by using a protected t-statistic and least square means. All statistical tests were two-sided with a significance level set at P < 0.05.

Sample size calculations were based on a previous antidepressant trial in cancer patients where 44% of placebo-treated patients developed major depression during IFN-alpha therapy compared with 11% of paroxetine-treated subjects.34 Given a projected incidence of major depression in the placebo group of 40% and a rate of 10% in paroxetine-treated subjects, it was determined that a sample size of 100 (120 with a projected drop-out rate of ∼17%) would give a power of 0.95 to detect a significant difference between groups using an uncorrected chi-squared test of significance and a two-sided alpha level of 0.05. Nevertheless, because of prolonged recruitment and inability to enroll a sufficient number of subjects during the designated project period, recruitment was closed after enrollment of 61 subjects. This reduction in sample size decreased the power of the trial to 0.78. However, as noted below, the low rate of major depression in the sample as a whole (17%) and in placebo-treated patients (20%) further compromised the power of the trial to detect differences between groups in the development of major depression.


Sample characteristics

Baseline characteristics of patients randomized to paroxetine (n = 28) vs. placebo (n = 33) are indicated in Table 1. Patients assigned to paroxetine were slightly but significantly older (51.1[6.5] vs. 46.6[8.2] years, t = 2.38, d.f. = 59, P = 0.02). Other relevant variables including history of substance abuse were similar between groups. The median MADRS score for the sample (n = 61) was 3.0. For subjects who received at least one dose of IFN-alpha, the two groups were well-balanced in terms of type of IFN-alpha administered [IFN-alpha-2b: 39% (9/23) paroxetine group vs. 45% (13/29) placebo group; pegylated IFN-alpha-2b: 39% (9/23) paroxetine group vs. 38% (11/29) placebo group; pegylated IFN-alpha-2a: 22% (5/23) paroxetine group vs. 17% (5/29) placebo group; χ2 = 0.24, d.f. = 2, P = 0.89] . Mean maximal MADRS scores during IFN-alpha/ribavirin treatment were no different between non-pegylated vs. pegylated preparations of IFN-alpha [16.1 (SD7.9) vs. 16.9 (SD11.5), respectively, t = –0.21, d.f. = 27, P = 0.83]. Starting doses of ribavirin also did not differ between groups [1104.3 mg (SD118.6) for paroxetine vs. 1055.2 mg (SD184.5) for placebo, t = 1.16, d.f. = 48.2, P = 0.25]. Finally, the mean maximum number of pills of study medication taken during the study did not differ between patients randomized to paroxetine vs. placebo [2.61(SD0.69) pills vs. 2.70(SD0.92) pills, respectively, P = 0.82]. The equivalent mean maximal dose of paroxetine was 26 mg/day, which is within the recommended therapeutic range of this medication (20–50 mg/day).51

Table 1.   Baseline characteristics of study sample
CharacteristicPlacebo (n = 33)Paroxetine (n = 28)
  1. t = 2.38, d.f. = 59, P = 0.02.

Sex (M/F)20/1315/13
Age (years)
 Mean (SD) 46.6 (8.2)51.1 (6.5)*
 Range28–65 38–66
Race no. (%)
 African American 10 (30.3)10 (35.7)
 Caucasian 17 (51.5)11 (39.3)
 Hispanic 5 (15.2)7 (25.0)
 Other 1 (3.0)0 (0.0)
Education no. (%)
 Less than high school 8 (24.2)5 (17.9)
 High school17 (51.5)18 (64.3)
 College, graduate school6 (18.2)5 (17.9)
 Unknown 2 (6.1)0 (0.0)
History of major depression
 No. (%)8 (24%)7 (25%)
History of substance abuse
 No. (%)21 (64%)18 (64%)
Baseline MADRS (score)
 Mean (SD)5.2 (5.2)3.5 (3.6)
 Range0–24 0–15


Nine subjects exited the study after taking at least one dose of study medication but prior to receiving IFN-alpha/ribavirin. Twenty subjects dropped from the study during IFN-alpha/ribavirin treatment but prior to study completion. Reasons for early discontinuation are provided in Table 2. Patients randomized to paroxetine had a significantly lower rate of study discontinuation after INF-alpha/ribavirin therapy was initiated (paroxetine, n = 5/23; placebo, n = 15/29, χ2 = 4.9, d.f. = 1, P = 0.03). No patients were removed from the study as a result of active substance abuse. One patient from the paroxetine group was discontinued due to the week 12 ‘stopping rule’, which evolved during the course of the study.

Table 2.   Disposition of study non-completers
  1. * χ2 = 4.9, d.f. = 1, P < 0.05.

Terminated study prior to initiation of IFN-alpha/ribavirin therapy45
 Withdrew consent11
 Non-compliant with study medication21
 Side effects of study medication11
 Lost to follow-up02
Terminated study after initiation of IFN-alpha/ribavirin therapy155*
 Intolearble side effects94
 Protocol deviation (lost to follow-up, non-compliant)60
 Lack of viral response01

Development of major depression

Seventeen percent of patients who received at least one dose of IFN-alpha/ribavirin (nine out of 52) met diagnostic criteria for major depression at least once during IFN-alpha/ribavirin treatment. No differences were observed in the development of major depression between those randomized to paroxetine vs. placebo (3/23 paroxetine vs. 6/29 placebo, P = 0.71, Fisher’s exact test).

Depression severity

As shown in Table 3, according to published MADRS cut-off scores for global depression severity, the number/percent of patients meeting criteria for mild, moderate or severe depression at any point during IFN-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher’s exact test). Indeed, only two out of 23 subjects (9%) who were assigned to paroxetine and received at least one dose of IFN-alpha/ribavirin reached a cut-off score of moderate or severe depression (MADRS ≥ 25) during IFN-alpha/ribavirin therapy (a potential reason for dosage reduction or discontinuation), compared with eight out of 29 patients (28%) assigned to placebo.

Table 3.   Number/percent of patients meeting MADRS criteria for mild, moderate or severe depression by group during IFN-alpha/ribavirin therapy
GroupNormal (MADRS < 15)Mild (MADRS ≥ 15)Moderate (MADRS ≥ 25)Severe (MADRS ≥ 31)
  1. MADRS, Montgomery Asberg Depression Rating Scale; IFN, interferon.

  2. * Significantly different from placebo group (P = 0.02, Fisher’s exact test).

Placebo (n = 29)5 (17%)16 (55%)6 (21%)2 (7%)
Paroxetine* (n = 23)13 (57%)8 (35%)2 (9%)0 (0%)

When MADRS scores were analyzed as a continuous measure, group (paroxetine vs. placebo), visit and study site were all associated with depressive symptoms during the trial (F[1,55] = 5.07, P < 0.05 for group; F[6231] = 10.34, P < 0.001 for visit; F[3,55] = 9.25, P < 0.0001 for site). MADRS scores increased significantly during IFN-alpha/ribavirin therapy in both paroxetine- and placebo-treated groups. Post hoc analyses revealed that depression scores at all time points during IFN-alpha/ribavirin therapy were significantly greater than depression scores at baseline in both groups (P < 0.05). Patients randomized to paroxetine demonstrated lower depressive symptom severity scores during the study, with significant differences between groups being manifested at 16 and 20 weeks of IFN-alpha/ribavirin treatment (Figure 2). No group by visit interaction was observed (F[6231] = 0.58, P = 0.75). The site effect appeared to be accounted for by differences in MADRS scores across sites (in particular, higher MADRS scores at the Chicago site) despite standardized training. Nevertheless, no interaction was observed between site and group assignment, indicating that differences in MADRS scores across sites did not differ as a function of group assignment and therefore did not contribute to differences between groups.

Figure 2.

 Mean (±SEM) Montgomery-Asberg Depression Rating Scale scores during the first 24 weeks of therapy with interferon (IFN)-alpha and ribavirin in patients randomized to treatment with either the antidepressant paroxetine (n = 28) or placebo (n = 33). Depressive symptom scores increased during IFN-alpha/ribavirin therapy in both groups; however, patients receiving paroxetine exhibited significantly lower depression scores than patients randomized to placebo. The number of subjects in each group continuing in the study at each time point is indicated below the x-axis. *P < 0.05 compared with placebo.

Depression severity as a function of depression history and baseline depression

Past depression history was not associated with MADRS scores during treatment. In contrast, baseline MADRS score [categorized based on a median split (>3 vs. ≤3)] exhibited a significant main effect on depression symptom severity (F[1,42] = 18.71, P < 0.0001), and a significant interaction was observed between baseline MADRS score and group assignment (F[1,42] = 4.49, P < 0.05). Indeed, as shown in Figure 3a, group assignment (paroxetine vs. placebo) had no effect on depressive symptoms in patients with baseline MADRS scores equal to or below the median (MADRS ≤ 3). On the other hand, in patients with baseline MADRS scores above the median, those randomized to paroxetine demonstrated significantly reduced depressive symptoms during the study when compared with those randomized to placebo (Figure 3b). Based on the post hoc analyses, these differences were statistically significant beginning at week 12 and continuing throughout the study. The maximal mean difference between groups on the MADRS was 10.3 points [95% CI: 2.1–18.5] at 20 weeks, representing a maximal effect size of 1.41 (95% CI: 0.24–2.53). No differences were found within or between paroxetine and placebo groups above or below the median depression score at baseline regarding the type of IFN-alpha preparation, initial ribavirin dose or mean maximal number of pills taken.

Figure 3.

 Mean (±SEM) Montgomery-Asberg Depression Rating Scale (MADRS) scores as a function of baseline depressive symptom status and antidepressant treatment. (Panel a) In patients with low levels of depressive symptoms at baseline (MADRS ≤ 3), depressive symptoms during IFN-alpha/ribavirin therapy remained low and were no different in patients assigned to paroxetine vs. placebo. (Panel b) In patients with elevated depressive symptoms at baseline (MADRS > 3), patients assigned to paroxetine exhibited significantly lower depressive symptoms during the study compared with placebo. The number of subjects in each group continuing in the study at each time point is indicated below the x-axis in each panel. *P < 0.05 compared with placebo; **P < 0.01 compared with placebo.

Adverse events

Adverse events occurring in ≥10% of patients are listed in Table 4. Muscle and joint pain were more common in placebo-treated patients, and dizziness was more common in paroxetine-treated patients. No patient in either treatment group spontaneously expressed suicidal ideation nor did any patient develop symptoms consistent with mania. No differences were found between groups in dosage reduction of either IFN-alpha or ribavirin [5/23 for paroxetine vs. 5/29 for placebo, continuity adjusted χ2 = 0.003, d.f. = 1, P = 0.96 (P = 0.73)], nor were there differences between the groups in use of erythropoietin (2/23 for paroxetine vs. 2/29 for placebo).

Table 4.   Prevalence of treatment–emergent adverse events
Adverse eventPlacebo (n = 33)Paroxetine (n = 28)
  1. * χ2 = 4.4, d.f. = 1, P < 0.05; ** χ2 = 6.0, d.f. = 1, P ≤ 0.01.

Headache20 (61)12 (43)
Sleep disturbance14 (42)14 (50)
Fatigue15 (45)16 (57)
Muscle or joint pain*24 (73)13 (46)
Loss of appetite9 (27)13 (46)
Nausea or vomiting13 (39)15 (54)
Dizziness**4 (12)11 (39)
Gastrointestinal distress9 (27)10 (36)
Skin problems10 (30)5 (18)
Hair loss4 (12)3 (11)
Injection site reaction5 (15)3 (11)
Upper respiratory symptoms7 (21)8 (29)
Oral symptoms2 (6)5 (18)
Flu-like symptoms12 (36)12 (43)
Sexual dysfunction3 (9)4 (14)


This randomized, double-blind, placebo-controlled trial addressed the role of antidepressants in preventing depression induced by IFN-alpha/ribavirin therapy in HCV patients.1, 26–32, 35, 52 No differences in the rates of major depression were found between treatment groups, although the rate of major depression in the sample as a whole was low (17%). Nevertheless, using published MADRS cut-off scores of global depression severity, the number/percent of subjects meeting criteria for mild, moderate or severe depression was significantly lower in paroxetine- vs. placebo-treated patients. In addition, when MADRS scores were evaluated as a continuous measure of depression severity, patients assigned to paroxetine exhibited slightly but significantly lower depression scores compared with placebo, especially during the later stages of the study. Interestingly, when patients were divided according to their baseline depression score, subjects who scored equal to or below the median exhibited relatively low depression scores throughout the study, and no differences were observed between paroxetine- vs. placebo-treated patients. In contrast, patients with baseline depression scores above the median exhibited relatively high depression scores during the study that were significantly lower from weeks 12 to 24 in paroxetine-treated subjects. Because of the relatively small sample size and high number of drop-outs, the findings provide preliminary support for antidepressant pre-treatment to prevent depression in HCV patients, especially those with elevated baseline depressive symptoms. Future prospective studies limited to patients with mild-to-moderate depressive symptoms at baseline, who are then randomized to either antidepressant or placebo, are clearly warranted.

Consistent with previous reports in cancer patients using a double-blind, placebo-controlled design and in HCV patients using open-label treatment strategies, the results of this preliminary study support the notion that antidepressant pre-treatment may limit the depressive burden experienced by HCV patients during IFN-alpha/ribavirin therapy.1, 26–31, 34 Indeed, although no difference in the rates of major depression was found between groups, there was a threefold decrease in the per cent of patients who met criteria for moderate or severe depression according to the MADRS in paroxetine- vs. placebo-treated patients who received at least one dose of IFN-alpha/ribavirin. These data suggest that continuous measures of depression may be more sensitive than standard diagnostic instruments (such as the SCID) for identifying distress in IFN-alpha/ribavirin-treated patients and in detecting the influence of antidepressant treatment strategies.

As it has been previously reported, depressive symptoms at baseline in this study were associated with higher depressive symptom scores during IFN-alpha/ribavirin therapy, suggesting that patients who enter treatment with even sub-clinical mood disturbances are at an increased risk for developing clinically significant depressive symptoms during anti-viral therapy.1, 2, 9, 10, 34, 53–55 That patients with current depressive symptoms at baseline should benefit from antidepressant prophylaxis is consistent with two recent open-label trials.27, 33 For example, Schaefer et al.27 found that patients with mild-to-moderate depressive symptoms at baseline and/or a past history of a mood, personality and/or substance abuse disorder developed significantly less major depression during the first 6 months of IFN-alpha/ribavirin therapy when pretreated with the antidepressant, citalopram. Similarly, Kraus et al.33 observed that prophylactic treatment with the antidepressant, paroxetine, significantly reduced depressive symptoms in patients who had previously developed depression on IFN-alpha therapy. Of note, however, in a recent double-blind, placebo-controlled study by Morasco et al.,35 paroxetine pre-treatment was shown to have no effect on depressive symptoms in a group of patients carefully screened for current depression and substance abuse. Taken together with the findings of the current study, these results suggest that HCV patients at risk for IFN-alpha-induced depression, especially those with current psychiatric symptoms at baseline, may be most likely to respond to antidepressant prophylaxis, whereas patients with no current psychiatric distress are unlikely to benefit. In this context, it should be noted that in contradistinction to some,56 but not all previous studies,1, 3, 11 a past depression history was not associated with the development of depressive symptoms or response to paroxetine in this study; however, these results should be interpreted with caution given the reduced sample size.

Regarding adverse events, treatment with paroxetine did not appreciably increase the side effect burden and reduced muscle and joint pains, replicating analgesic effects observed for paroxetine in patients receiving high-dose IFN-alpha for cancer.34 On the other hand, paroxetine-treated patients reported higher rates of dizziness, a common side effect of this medication. Despite case studies linking IFN-alpha with mania, 42 no patients evinced clear manic symptoms. Finally, there was no evidence of increased suicidal ideation as a result of paroxetine administration

Several limitations of the current study warrant consideration. A much smaller than anticipated percentage of patients met criteria for major depression (17%), despite marked increases in depressive symptoms. This low depression rate is consistent with other recent studies where new onset major depression rates ranged from 11% to 16%.3, 26, 42 Thus, although no difference was seen between groups in percentage of patients who developed major depression during IFN-alpha/ribavirin therapy, given the reduced sample size and low rate of major depression, the study was underpowered to evaluate this outcome. Indeed, given an incidence of major depression of 20% in placebo-treated patients (and a projected rate of 5–10% in paroxetine-treated patients), a total sample size of 150–400 subjects would be required to detect a significant difference between groups in the development major depression at a power of 0.80.

The relatively small sample size also contributed to the study being underpowered for detecting the differences between groups in other relevant outcome variables, including IFN-alpha and/or ribavirin dosage reduction/discontinuation. Nevertheless, among patients who received at least one dose of IFN-alpha (n = 52), rates of study termination were significantly lower in patients randomized to paroxetine. This finding is of great potential therapeutic importance given the strong association between treatment discontinuation and poor viral outcome.21–23 Nonetheless, a larger prospective study appropriately powered to examine this issue is clearly indicated before more definitive conclusions can be reached.

An additional major limitation was the high drop-out rate. Fifteen per cent of subjects dropped out prior to randomization to study medication and 38% of those remaining dropped out after initiation of IFN-alpha/ribavirin treatment. Although these drop-out rates are higher than have been typically observed in IFN-alpha clinical trials for HCV, they are consistent with the 37% drop-out rate in a recent trial of over 4000 subjects, which enrolled from the US academic- and community-based settings similar to the current study.57

Finally, patients were screened for major depression and other psychiatric disorders, and thus the results may not generalize to HCV populations with higher rates of current mood disturbance or with a greater burden of past psychiatric illness.36, 58 However, our results suggest that antidepressant pre-treatment might show a larger effect in more psychiatrically impaired populations that are the norm in many treatment centres.19, 59, 60

In conclusion, the data provide preliminary indication that targeted antidepressant prophylaxis in patients with mild-to-moderate depressive symptoms prior to IFN-alpha/ribavirin treatment may be an effective strategy to limit depressive symptoms during therapy and thereby improve treatment tolerability. Future studies examining a larger sample of at-risk patients are warranted to elaborate the full spectrum of potential benefits of targeted antidepressant treatment.


The authors would like to thank the many patients who gave their time and effort to help complete this study. The trial was registered with with the identifier NTC00209118.


Declaration of personal interests

Charles L. Raison has served as a speaker, a consultant or an advisory board member for Schering-Plough, Wyeth, Lilly and Centocor.

John M. Zajecka has served as a speaker, a consultant or an advisory board member for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Cyberonics, Lilly, Pfizer, GlaxoSmithKline, and Wyeth, and has received research funding from AstraZeneca, Bristol-Myers Squibb, McNeil, and Somaxon.

Dwight L. Evans has served as a consultant or an advisory board member for Abbott, Astra Zeneca, Bristol Myers Squibb/Otsuka, Eli Lilly, Forest, GlaxoSmithKline, Janssen/Johnson and Johnson, Neuronetics, Pfizer, Somerset, Wyeth, Pamlab and LLC, and has received research funding from GlaxoSmithKline.

Gregory M. Asnis has served as a speaker, a consultant or an advisory board member for Sanofi-Aventis and Bristol Myers Squibb, and has received research funding from AstraZeneca, Forest Research, Cephalon, Sanofi-Aventis, Janssen/Johnson and Johnson and GlaxoSmithKline.

Andrew H. Miller has served as a speaker, a consultant or an advisory board member for Schering-Plough and Centocor, and has received research funding from Janssen/Johnson and Johnson, GlaxoSmithKline, and Schering-Plough.

Declaration of funding interests

This study was funded in part by Schering-Plough and GlaxoSmithKline and by grants from the National Institute of Mental Health (MH060723, MH64619, MH00680 and MH60723) and NIH/NCRR General Clinical Research Center grant (M01 RR00039).