Background: Interferon-induced depression represents a major complication in antiviral treatment of chronic hepatitis C virus (HCV) infection.
Aim: To evaluate in a placebo-controlled study the efficacy of a selective serotonin reuptake inhibitor (SSRI) in HCV patients on antiviral therapy with interferon-associated depression.
Methods: 100 HCV outpatients were included in a randomised, double-blind, placebo-controlled study. During interferon therapy (peginterferon alfa-2b plus ribavirin), depression was monitored using the Hospital Anxiety and Depression Scale (HADS). Patients with clinically relevant interferon-induced depression (HADS ⩾9) were randomly assigned to placebo or citalopram (SSRI, 20 mg/day).
Results: In 28 patients (28%), HADS scores increased to >8 during interferon therapy. They were treated with placebo (n = 14) or SSRI (n = 14). HADS scores declined significantly in SSRI patients within four weeks of therapy (p<0.001) but not in placebo patients. This difference between subgroups was statistically significant (p = 0.032). Unblinding became necessary in five placebo patients as a result of intolerable depression. Rescue medication (20 mg citalopram) led to a significant decrease in HADS scores (p = 0.008). All citalopram patients were able to complete interferon therapy as planned. As an interim analysis showed a significant superiority of SSRI over placebo, the study was terminated prematurely. Three patients, who became depressed afterwards, were treated in an unblinded fashion with citalopram.
Conclusions: The findings demonstrate clearly that citalopram treatment is highly effective in HCV patients on interferon therapy, when initiated after the onset of clinically relevant depressive symptoms. This suggests that a general SSRI prophylaxis is not necessary in these patients.
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Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and affects approximately 170 million people globally.1 2 The infection becomes chronic in approximately 85% of all cases and progresses to liver cirrhosis in 15–20%. Furthermore, hepatocellular carcinoma develops in at least 1–4% of HCV-infected cirrhosis patients.3
Combination therapy with pegylated interferon (peginterferon) alfa and ribavirin for 24 or 48 weeks, depending on the viral genotype, represents the current approved treatment standard for chronic HCV infection. A sustained virological response (SVR) is achieved in 46–80% of patients, depending mainly on factors such as virus genotype, gender and early viral kinetics.4 5
Major depression or clinically significant depressive symptoms occur in an average of one third of HCV patients treated with peginterferon plus ribavirin. The reported incidence rates vary widely across studies, however, and range from less than 15% up to 44%.6–11 This side effect may lead to reduced quality of life as well as non-compliance or even discontinuation of interferon therapy,12–14 underscoring the need for an adequate antidepressant treatment strategy to relieve depression occurring during antiviral treatment.15
There is growing evidence that selective serotonin reuptake inhibitors (SSRI) may alleviate interferon-associated depression. A number of previously published studies, eg in patients with malignant melanoma16 but also in HCV patients17–19 suggest the efficiency of SSRI prescribed in an open label fashion. The efficacy of SSRI treatment has, however, so far not been proved in a placebo-controlled study. In addition, it is not clear if general SSRI prophylaxis should be recommended or if antidepressant treatment may be initiated after the onset of clinically relevant depression.16–19
We addressed these questions in a placebo-controlled study in patients with chronic hepatitis C treated with an interferon-based antiviral therapy. Citalopram was chosen as antidepressive medication because this drug has been shown to be suitable for patients with chronic advanced liver disease (fibrosis, cirrhosis). Citalopram is safe and well tolerated within the therapeutic dose range of 20–60 mg daily.20 21
Our objective was to evaluate in a placebo-controlled study the efficacy of the SSRI citalopram when given after the onset of interferon-associated depression in HCV patients on antiviral therapy. We hypothesised that depression scores would significantly and rapidly decline in the subgroup of citalopram-treated patients, allowing them to complete the antiviral treatment as scheduled.
PATIENTS AND METHODS
Hepatitis C outpatients were consecutively enrolled at our institution (Medizinische Klinik und Poliklinik II, Department of Gastroenterology and Hepatology, University of Würzburg) between 2002 and 2004. All patients gave written informed consent to participation. The study was approved by the Institutional Review Board for the protection of human subjects at our institution and was carried out in accordance with the Declaration of Helsinki.
At the time of study entry, all patients were serum positive for anti-HCV and had circulating HCV RNA as confirmed by reverse-transcription PCR (Cobas Amplicor; Roche Diagnostics, Basel, Switzerland). The patients had been referred for antiviral combination therapy with peginterferon alfa-2b plus ribavirin to our clinic. Patients with previous therapy attempts (ie, not treatment naive) were included if they fulfilled all other criteria for study participation. Furthermore, patients had to be between 18 and 65 years of age at the time of study entry.
Individuals were excluded from participating in the case of advanced liver cirrhosis (Child stage B or C), co-infections (hepatitis B virus or HIV), severe internal diseases (eg, cancer, ischaemic heart disease or autoimmune disease), current pregnancy or the absence of reliable contraception in female patients, psychiatric illness (severe depression or psychosis), active intravenous drug use or alcohol abuse, or insufficient knowledge of the German language. Patients were also excluded from study participation if they fulfilled any other contraindication to alfa-interferon or ribavirin. As this was the criterion for the initiation of the study medication, patients who already had a Hospital Anxiety and Depression Scale (HADS) score greater than 8 (see below) before interferon therapy were not included. Patients who had had an episode of major depression during a former antiviral therapy were also excluded.
Study design, procedures and interventions
The trial was a randomised, placebo-controlled, double-blind single-centre study including consecutive outpatients with chronic hepatitis C infection from our institution.
In a longitudinal repeated-measures design, we monitored neuropsychiatric symptoms throughout the study period. Subjects were evaluated with respect to their emotional state and psychiatric symptoms once before therapy, three times during antiviral treatment (after 4, 12 and 24 weeks of interferon treatment) and four weeks after the end of therapy. These evaluation time points were previewed for all patients, irrespective of the individuals’ virus genotypes.
Each evaluation time point comprised psychometric monitoring (self-assessment questionnaires, diagnostic interview), medical examination and laboratory testing (eg, blood count, liver enzymes, HCV RNA). The above-mentioned diagnostic interview had the primary purpose of assessing at each evaluation time point whether antiviral therapy could be continued under the given circumstances or if additional or changed medication was necessary. The results of HCV-RNA testing was disclosed to the patients only after the respective psychometric evaluations had been completed.
Depression was assessed using the HADS (German version, as published by Herrmann et al22). HADS is a 14-item questionnaire with the dimensions anxiety and depression. This psychometric instrument was chosen because all of its items solely refer to the emotional state and do not consider somatic symptoms. Moreover, this questionnaire was shown to be suitable for the longitudinal assessment of depressive symptoms in chronic hepatitis C patients in previous studies.8 17–19 According to the questionnaire’s manual, the cutoff value for clinically relevant depression was set to 9 or greater.22 For the purpose of this paper, the results of the HADS depression subscale were used—anxiety measures were not included in the main statistical analyses.
Antiviral treatment for all participating patients consisted of combination therapy with peginterferon alfa-2b (PegIntron, 1.5 μg/kg per week) and weight-adapted ribavirin (Rebetol, 800–1200 mg a day) for 48 weeks (virus genotypes 1 or 4) or 24 weeks (genotypes 2 or 3), respectively.
In the case of newly occurring clinically relevant depression (exclusive psychometric decision criterion: HADS depression ⩾9; intervention group), concomitant study medication was started and the frequency of monitoring was increased. Patients were then randomly assigned in a double-blind fashion either to SSRI (citalopram, 20 mg a day) or placebo medication.
The randomisation process and unblinding procedures were organised and monitored in cooperation with the staff members of the Central Pharmacy of Würzburg University. Citalopram doses and identical placebo tablets were prepared, prepackaged and coded by a research pharmacist also responsible for the computer-generated randomisation list. The research pharmacist was not directly affiliated with the study.
Study investigators and subjects were blinded to the actual group assignment. Screening, recruitment and handing out of the study medications were performed by the hepatologist in the outpatient clinic.
Individuals of both subgroups of the intervention group (expected total rate of approximately 30–35%7 8 10) underwent four additional evaluation time points (depression event and start of concomitant medication (Tev0), as well as 1 (Tev1), 2 (Tev2) and 4 weeks (Tev4) later). At these time points, HADS testing was performed. In addition, patients were evaluated clinically with respect to severe depression. If the therapist and the patient considered a safe continuation and completion of the interferon therapy impossible because of depression, the study had to be terminated. In these cases, a rescue medication was to be offered to the patients depending on their study medication: citalopram 20 mg a day for patients of the placebo group and an increase in the citalopram dose from 20 to 40 mg for patients of the SSRI group, respectively. Patients on rescue medication underwent the same tight evaluation schedule as outlined above (after 1, 2 and 4 weeks).
The Statistical Package for the Social Sciences software (SPSS for Windows, German version 12.0.2G,23 SPSS Inc, Chicago, Illinois, USA) was used for all presented statistical analyses.
If not otherwise stated, all performed statistical test procedures were two-tailed and were considered to be statistically significant at p<0.050. T tests for independent samples and analysis of variance (one-way ANOVA) were performed to test for differences in continuous variables (mainly depression scores) between patient subgroups (eg, SSRI versus placebo group). χ2 tests were used to compare frequencies of categorical variables between patient subgroups. In order to address the main study question, the dependent variable “HADS depression score” was analyzed using a two-factorial general linear model with one independent factor (SSRI versus placebo) and one dependent factor (time course).
Sample size calculation
The following considerations refer to the optimal sample size of the patient subgroup above the cutoff value for clinically relevant depression.
Given a significance level of 0.05 and a statistical power of 0.80 (type II error 0.20), the optimum sample size is 28 when a medium effect size (f = 0.25) is expected (example for repeated measures ANOVA (within factors and within–between interaction) with two equal groups and three repetitions).24 25 Exact calculation parameters are: f = 0.25; α = 0.05; number of groups 2; number of repetitions 3; assumed correlation between repeated measures 0.5; non-sphericity correction epsilon 1; critical F2,52 = 3.175; total sample size 28; actual power 0.812.
In the case of large effect sizes (ie, f = 0.40 for ANOVA), an even smaller sample size would be sufficient (a total of 12 patients for f = 0.40).25
A total patient sample size recruited of N = 100 would be expected to produce 30 to 35 cases (roughly one third of HCV patients on interferon therapy7 8 10) of interferon-induced depression (HADS ⩾9) and should be sufficient in the face of the given sample size calculations and underlying research questions.
A total of 107 HCV patients were considered suitable for study enrolment and gave written consent to study participation. Seven of these had to be excluded from the study very early (refusal to undergo study assessments) and could therefore not contribute to the final analyses, because of the lack of any longitudinal data.
Of the remaining 100 patients, 28 (28%) were identified to fulfil the cutoff criterion for antidepressant intervention and were randomly allocated to either placebo (n = 14) or SSRI (n = 14). After an interim analysis in February 2006 had shown a significant advantage for the SSRI group, the study was terminated for ethical reasons.
This interim analysis was performed after 100 patients had started their interferon therapy and a total of 28 patients had completed at least the first four weeks of study medication with repetitive HADS testing. As at that time there was already a significant difference in the HADS scores of the two groups in favour of the SSRI-treated patients, further inclusion of patients meeting the criteria for randomisation was stopped. Three patients, who had HADS scores >8 afterwards, were therefore treated with 20 mg citalopram a day in an unblinded and open-label fashion.
Therefore, the total rate of patients who required concomitant antidepressant therapy according to the study criteria was 31% (SVR in 21 of 31 patients with depression versus 50 of 69 patients without interferon-induced depression; see table 1).
Relevant demographic, laboratory, and medical data as well as baseline depression scores (according to the HADS-D) of patients with chronic hepatitis C enrolled in our study are summarised in table 1, stratified for both the intervention group (n = 31) and the remainder of the study sample (n = 69). None of the patients had a history of clinically relevant depression requiring treatment. Furthermore, none of the patients indicated a history of manifest anxiety disorders. A total of 57 study patients (57%) had a history of intravenous drug abuse. Table 2 provides the correspondent information for only the patients who were randomly assigned to receive either placebo or SSRI. There were no significant differences between the subgroups with respect to baseline characteristics. The time interval between the start of interferon-based antiviral treatment and the onset of clinically relevant depression according to the HADS questionnaire was approximately 10 weeks (11.6 weeks in SSRI-treated and 9.2 weeks in placebo-treated subjects).
Time course of HADS depression scores: longitudinal analysis
As expected from previous studies,8 9 15 HADS depression scores in the study group increased significantly during antiviral treatment (F1,99 = 38.287; p<0.001). Four weeks after treatment discontinuation (t5), scores were not significantly different from pretreatment levels (F1,99 = 1.846; p = 0.177).
(The on-therapy increase was not significant for HADS anxiety scores: F1,99 = 2.523; p = 0.115).
Figure 1 displays the time course of repeated testing by HADS after intervention for the SSRI and placebo group, respectively. In the SSRI subgroup, HADS scores decreased significantly (F3,39 = 13.280; p<0.001), reflecting a marked decline in depression within four weeks after the initiation of antidepressant medication. Concerning placebo patients, however, no significant change in HADS scores was found (F3,39 = 1.696; p = 0.184).
ANOVA interaction (time course × therapy arm) was also statistically significant (F3,78 = 2.868; p = 0.042), demonstrating that patients randomly assigned to citalopram showed a significant and persisting relief of interferon-induced depression compared with the placebo group (ANOVA main effect therapy arm: F1,26 = 5.085, p = 0.033; ANOVA main effect time course: F3,78 = 11.523, p<0.001). Separate pairwise comparisons (post-hoc) for each evaluation time point revealed that mean depression scores were significantly lower in the SSRI group at screening time points two and four weeks after the event (Tev2: F1,26 = 5.623, p = 0.025; Tev4: F1,26 = 6.599, p = 0.016), but not after one week of intervention therapy (Tev1: F1,26 = 2.456, p = 0.129).
According to the predefined criteria—impossibility of continuing antiviral therapy because of persisting intolerable depression according to the patient’s and the doctor’s assessment—the intervention therapy was terminated in five patients after four weeks. All five patients turned out to be in the placebo group after unblinding. They were therefore switched to open-labelled SSRI therapy (citalopram, 20 mg a day).
This “rescue medication” was highly effective in all of these patients, with a prompt and significant decrease in HADS scores after one week (F1,4 = 24.675, p = 0.008), comparable to the SSRI group of the controlled intervention study (fig 2). All of these subjects were able to complete the interferon therapy as scheduled (SVR in three of five patients). None of the patients who received citalopram treatment (either immediately or as “rescue medication”) reported side effects in the diagnostic interview that could be attributed to citalopram.
Although chronic HCV infection has been shown to be curable in more than 50% of patients, depending on the virus genotype, the current therapy is far from ideal.4 5 Therapy has to be performed for 48 weeks in genotype 1 patients and for 24 weeks in all others. Interferon alpha induces considerable side effects that may lead to premature discontinuation of therapy in 5–35% of cases.4 5 Among these side effects, psychiatric symptoms, especially depression and irritability, are of the greatest importance.10 16 26 27 A termination of treatment as a result of side effects not only precludes the opportunity of stopping a disease that might otherwise progress to liver cirrhosis or hepatocellular carcinoma but is also of considerable financial impact on the healthcare system, because of the very high cost of antiviral therapy in HCV infection. At present, it is not possible to identify with certainty in advance those patients who will develop such severe depression that a completion of HCV therapy is not feasible. Therefore, a risk group that may be treated with prophylactic antidepressant drugs cannot yet be defined. We recently found evidence that a specific polymorphism in the serotonin receptor gene (C-1019G of the HTR1A gene) predisposes to interferon-induced depression.28 These data demonstrate a link between interferon therapy, intracerebral serotonin metabolism and treatment-associated depression, thereby offering a rationale for prophylaxis or therapy with a serotonin reuptake inhibitor in this condition.
When and how to use an SSRI in interferon-induced depression has not, however, been evaluated in detail so far. The concept of primary prophylaxis has been addressed in a placebo-controlled study by Musselman et al16 in patients with malignant melanoma. They found a significantly lower rate of therapy-associated depression as well as discontinuation of treatment in the group of patients taking an SSRI compared with the placebo group. It has to be stressed that these data have been gathered during interferon treatment for malignant melanoma and as dosages and treatment regimens are different for antiviral HCV therapy, figures and results cannot directly be compared.
There is evidence suggesting that this kind of prophylaxis is also effective in the antiviral treatment of chronic HCV infection.29–32 As only a minority of hepatitis C patients on interferon therapy will actually become depressed, an alternative concept would be to use an SSRI only as a therapy and secondary prophylaxis in those patients who develop depressive symptoms and are at risk of terminating antiviral treatment prematurely. In the present study, we addressed for the first time in a randomised, double-blind, placebo-controlled design the question of whether it is an effective approach to treat with an SSRI only the subgroup of hepatitis C patients that actually become depressed during interferon therapy. We selected citalopram as an antidepressant, because pharmacokinetic studies have shown that the metabolism of this drug is no different in patients with hepatitis C without advanced cirrhosis compared with healthy individuals.20 21
As a psychometric instrument to measure depression and to select the patients for therapy with either SSRI or placebo (“study group”) the HADS questionnaire was chosen. The theoretical maximum HADS score in the subscale “depression” is 21 and a cutoff value of 9 was chosen, because validation of this test showed that values above this score describe clinically relevant depression.22 The suitability of this cutoff criterion has also been demonstrated in previously published studies involving HCV patients on interferon therapy.8 18 In our study, no patient with continuous HADS scores less than 9 had to stop therapy as a result of depressive symptoms, whereas five of 14 patients in the placebo group considered themselves unable to complete the antiviral treatment. This retrospective data inspection further supports the estimation that this cutoff value really characterises a group of patients who are at risk of terminating interferon therapy prematurely because of depression. All patients in the study group were closely followed up clinically and by repeated HADS testing. HADS scores were used as an outcome measure and to record the time course of the therapeutic effect. The decision to terminate the study and switch to the rescue medication after unblinding was, however, made clinically. The criterion was the patient’s statement to be unable to go on with the interferon therapy for the scheduled time as a result of continuing depression and an according assessment of the clinician (MRK, who was a hepatologist with a complete training in psychotherapy). Using this criterion instead of the results of consecutive HADS testing, we sought to imitate the “real-life” situation, when the decision to terminate a therapy as a result of an intolerable side effect is made in agreement by the patient and the doctor. Patients were encouraged to complete the antiviral therapy if possible, and an unblinding was performed only if both the patient and the doctor were convinced that this would not be feasible.
In total, 31% of the whole patient group met our criterion of relevant therapy-induced depression with a HADS score >8. We chose repeated evaluation of our patients using a standardised questionnaire designed to identify depression instead of relying on the clinical impression of the doctor or on psychiatric interviews. In our opinion, this approach would also be feasible in the management of HCV-infected patients treated by hepatologists. As according to our data, the cutoff value of 9 in the HADS depression subscale identified approximately 30% of our patient group as being at risk of relevant depression, the number of patients treated with an SSRI would be in the range of patients from other studies that became depressive. Our data from the subgroup of patients from the placebo group that became depressed and in whom interferon therapy was considered to be terminated indicate that alternatively the use of an SSRI and continuation of the antidepressant for the rest of the interferon therapy in only these patients is feasible. The data from our limited patient group indicate that by using this approach, approximately 10% of HCV patients treated with interferon would need an SSRI as a “rescue medication” to prevent premature termination of their antiviral therapy. (If none of the 28 patients with clinically relevant depression had received citalopram/SSRI we would have expected 10 (2 × 5) patients to need “rescue medication” in order to avoid premature therapy discontinuation—representing a rate of 10%.)
The limitations of our study comprise only a modest sample size; however, providing enough statistical power to detect a relevant treatment effect. Moreover, future confirmative studies should also include other SSRI and perhaps introduce additional evaluation time points in order to map the time course of depression more closely. Genotype 1 patients, in particular, needing antiviral treatment for more than 24 weeks should be more closely monitored, also after the first six months of interferon-alfa medication.
In our view, the most effective and elegant strategy would be to identify patients at risk of depression even before the start of antiviral therapy. As endogenous factors and a genetic predisposition seem to increase the risk of interferon-induced depression, the testing of patients for genetic markers may in the future help to select patients for whom concomitant SSRI therapy should be provided.28
In summary, our results suggest that citalopram is significantly more effective than placebo in the therapy of manifest interferon-induced depression and that this therapeutic effect occurs rapidly (within one to two weeks, in contrast to depressive disorders, in which approximately four weeks of therapy are usually needed). Therefore, a general and routinely performed citalopram prophylaxis in all hepatitis C patients receiving an interferon-based antiviral therapy is not necessary. Our data provide evidence for the strategy of awaiting the manifestation of depressive symptoms and starting citalopram medication only upon their occurrence, as has already been suggested by a number of uncontrolled observations.7 10 17–20 32 33 This strategy needs to be confirmed in future studies for other SSRI and classes of antidepressants. Awaiting the onset of clinically relevant depression, however, is not recommended in patients who have become depressed during a former therapeutic attempt and for whom prophylactic SSRI therapy has been shown to be justified.19
competing interests 57/4/531
Competing interests: MRK is a member of the Scientific Advisory Board of Essex Pharma, a subsidiary of Schering-Plough (Kenilworth, New Jersey, USA) and has served on speakers bureaus for Schering-Plough (Kenilworth, New Jersey, USA) and Essex Pharma (Munich, Germany). The other authors have no competing interests.
Funding: This study was supported in part by Essex Pharma (Munich, Germany), a subsidiary of Schering-Plough (Kenilworth, New Jersey, USA).
Ethics approval: Ethics approval was obtained.
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