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Prophylactic SSRI during interferon alpha re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression
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Journal of Viral Hepatitis
Volume 12 Issue 1 Page 96 - January 2005
M. R. Kraus, A. Schäfer, O. Al-Taie and M. Scheurlen
Medizinische Poliklinik (Clinic for Internal Medicine), University of Würzburg, Klinikstrasse, Würzburg, Germany
Summary. Only limited data are available on selective serotonin re-uptake inhibitor (SSRI) prophylaxis for antiviral re-treatment in hepatitis C patients with previous interferon-induced major depressive episodes. Therefore, we investigated the efficacy and safety of secondary SSRI prophylaxis in these patients. In a prospective and longitudinal study, repeated psychometric testing (Hospital Anxiety and Depression Scale) was performed before, during, and after antiviral re-treatment. Chronic hepatitis C virus (HCV)-infected patients, who had been psychometrically monitored during an unsuccessful previous antiviral therapy, and had developed major depression were included. Interferon re-therapy with SSRI prophylaxis was started (n = 8). The reference group was comprised of HCV patients without a history of interferon-associated depression and also a group who were previously unsuccessfully treated with interferon and were re-treated without SSRI prophylaxis (n = 9). All patients receiving SSRI prophylaxis were able to complete interferon re-therapy as scheduled. As in the first therapeutic course, depression scores were significantly elevated during re-treatment also (P < 0.001). Depression scores were significantly lower (P =0.036) during interferon re-therapy with SSRI prophylaxis. Reference group subjects showed similar depression scores during first therapy and re-therapy (P > 0.05). In conclusion, hepatitis C patients with a history of interferon-induced major depression can be successfully re-treated with peginterferon/ribavirin and concomitant SSRI prophylaxis. In these patients, SSRI prophylaxis is safe and efficacious and should be considered, if antiviral re-therapy is indicated.
AUTHOR DISCUSSION
There is evidence that concomitant treatment with SSRIs may represent an effective strategy to reduce IFN alpha-induced depressive symptoms in patients with chronic hepatitis C [10,11,20-24]. The vast majority of the work published has either not focussed on the efficacy of SSRI medication in IFN-induced depressive symptoms, or dealt only with IFN treatment in malignant diseases/cancer [16,20,21,25]. However, systematic data on the efficacy and safety of prophylactic SSRI medication especially in pretreated/re-treated HCV patients are not available so far [15]. The consideration of re-treatment in these patients with previous therapy failure and an IFN-induced depression is of particular interest regarding the improved rates of sustained virological response with novel therapy regimens. Re-treatment should be specifically considered in cases with a high probability of reaching sustained virological response (genotype 2/3) or an urgent indication for therapy (e.g. cirrhosis). Therefore, we designed a novel study to provide systematic insight in the management of IFN-induced side-effects: patients with chronic hepatitis C and IFN-induced major depressive episodes during initial therapy were psychometrically monitored during re-therapy with peginterferon/ribavirin and SSRI prophylaxis.
We started prophylactic SSRI medication 3 weeks before initiation of antiviral re-therapy because IFN-induced major depression is unlikely to occur within the first 4 weeks of IFN therapy [12,22] and seems to respond particularly quickly to SSRI therapy [11]. Our data demonstrated that prophylactic SSRI medication prevented premature termination of antiviral therapy because of psychiatric toxicity in all the patients. We observed no relevant drug-induced side-effects or toxicities caused by the SSRI medication. During antiviral re-treatment and SSRI protection, depressive symptoms were significantly reduced when compared with previous therapy. There is convincing data that tolerability of conventional and pegylated IFN is similar [7,8]. Thus, it is unlikely that lower depressive scores during re-treatment, as observed in our study, are related to the application of the modified drug (peginterferon), contrary to the use of nonmodified IFN in the initial therapy course. Moreover, results in the reference group (re-treatment without SSRI prophylaxis) demonstrate that depression scores are not reduced by the use of peginterferon when compared with unmodified IFN alpha. The return of depressive symptoms to baseline levels after termination of antiviral therapy and simultaneous SSRI medication in seven of eight patients demonstrated that depression was specifically related to IFN therapy.
The results of our study are in accordance with data from Musselman et al. [15] who demonstrated the efficacy of prophylactic SSRI treatment in patients with malignant melanoma and high-dose administration of IFN-alpha. We provide evidence that SSRI prophylaxis is highly effective and safe in patients with HCV infection and peginterferon therapy, even if there is a history of IFN-induced depressive episodes. We do not, however, propose general SSRI prophylaxis in the treatment of chronic hepatitis C. If adequate monitoring of psychiatric symptoms is provided, it is safe and efficacious to start antidepressant SSRI medication only after the onset of depressive episodes in therapy-naïve patients [11,22].
In conclusion, these data demonstrate that patients with a history of IFN-induced major depression (relative contraindication for IFN re-therapy) may be safely re-treated with peginterferon/ribavirin under SSRI prophylaxis. This is especially important for patients with sufficient probability of sustained virological response or an urgent indication for further therapy.
Results
Study population
Table 1 shows the characteristics of all patients included in the final analysis.
In the SSRI group, genotype 2 or 3 infections (6/8 patients; 75.0%) were significantly more frequent. Four of the eight patients (50%) had liver cirrhosis (Table 1). All patients in the reference group were infected with virus genotype 1.
The mean time interval between the first and the second therapeutic phases was 2.6 years (SD 1.8) for the SSRI group, and 2.8 years (SD 1.6) in the reference group. In all cases, antiviral re-treatment consisted of peginterferon alpha-2b and ribavirin.
Depression during previous antiviral therapy
During initial IFN therapy, all eight patients had developed signs of a 'major depressive episode' according to DSM-IV criteria (inclusion criterion). Seven of the eight patients reached HADS depression scores of at least 12 (cut-off: >=9). Despite the small sample size, the increase of depression scores during the initial treatment phase was highly significant (P < 0.001) (Fig. 1). Initial IFN therapy had to be stopped prematurely because of adverse events of depression in three of eight patients. None of the patients achieved sustained virological response (inclusion criterion).
Re-treatment with pegylated IFN-alpha-2b plus ribavirin and SSRI prophylaxis
With concomitant SSRI treatment, seven of eight patients were able to complete peginterferon re-therapy as scheduled. As a result of a lack of sustained virological response, peginterferon therapy was continued for a long term in one patient.
None of the patients had to stop re-treatment prematurely because of psychiatric side-effects. Sustained virological response subsequent to antiviral re-treatment was observed in five of eight patients.
HADS depression scores rose also during re-treatment with peginterferon and prophylactic SSRI medication with maximum levels at t4. However, depression score increments were significantly reduced when compared with initial treatment. (Increase of HADS depression scores during re-treatment: P = 0.012.)
Repeated-measures anova (time course x prophylaxis) revealed a significant effect of SSRI prophylaxis (P = 0.036), reflecting lower depression scores during re-treatment within the prophylaxis group. Testing of contrasts revealed that depression scores during antiviral treatment were significantly reduced by concomitant SSRI treatment. This reduction of IFN-associated depressive symptoms reached statistical significance despite the small sample size (difference at time point t3: effect size d = 2.6).
In the reference-group subjects, repeated-measures anova did not reveal any significant difference between both therapy regimens (main effect therapy attempt/mode: P > 0.05). Mean depression scores were even higher during and after re-treatment with peginterferon alpha and ribavirin.
METHODS
Patients
Seventeen patients in two groups were included in the study. The prophylaxis group consisted of eight patients who had been treated for chronic HCV infection at least once before without sustained virological response, and developed an IFN-associated major depressive episode. The indication for re-treatment with a combination of peginterferon alpha-2b and ribavirin was advanced liver damage (cirrhosis) in four patients, cryoglobulinemic vasculitis in one patient, a favourable genotype (3) in two patients, and the explicit wish to be treated again in one patient.
The reference group consisted of nine patients who had also been treated unsuccessfully for chronic HCV infection, but without developing IFN-associated depressive symptoms. In these patients, the main indication for re-therapy was the explicit wish to be re-treated for their chronic hepatitis C.
All patients had detectable levels of antibodies to HCV and displayed circulating HCV-RNA as measured by reverse transcription-polymerase chain reaction (Cobas Amplicor HCV Monitor® test, Roche Diagnostics, F. Hoffmann-LaRoche Ltd, Basel, Switzerland). Patients were recruited from August 1998 to August 2002. Patients were excluded if they were of an age below 18 or above 65 years, were co-infected with hepatitis B virus (HBV) or human immunodeficiency virus (HIV), had severe internal diseases (e.g. cancer, ischaemic heart disease, autoimmune disease), were active alcohol or intravenous drug abusers, or had obvious intellectual impairment or insufficient knowledge of the German language. If liver cirrhosis was present, it had to be well compensated (child A).
All patients gave written consent to participation in the study before enrollment. The study protocol was in accordance with the ethical guidelines of the Declaration of Helsinki.
Study design and procedures
The study was a prospective controlled longitudinal single-centre trial analysing two within-subject (repeated measures) factors [time course of antiviral therapy and re-treatment (with or without SSRI prophylaxis)] and one between-subject factor (prophylaxis vs reference group).
SSRI prophylaxis group
Ten patients fulfilled the inclusion criteria of the study and were offered antiviral re-treatment. One patient denied re-therapy with peginterferon and ribavirin because of fear of depressive symptoms. One patient withdrew his consent to participation in the study after 4 weeks of therapy with peginterferon-alpha 2b and concomitant SSRI prophylaxis (dropout rate 11.1%). Overall, eight of nine (88.9%) patients were included in the final evaluation and statistical analysis.
According to therapy recommendations in Germany during the study period, all the eight patients received peginterferon alpha-2b (80-150 mu g; 1.5 mu g/kg b.w. once weekly subcutaneously) and oral ribavirin (800-1200 mg daily). Previous therapy had been undertaken with nonpegylated IFN alpha-2b in all patients.
All patients received prophylactic SSRI treatment (20 mg daily: six patients received paroxetine; two patients received citalopram), starting 3 weeks before the start of peginterferon/ribavirin therapy. Termination of antiviral therapy and SSRI medication was at the same time.
Reference group
All nine patients received an antiviral re-treatment regimen as described above, except SSRI prophylaxis. All previous therapy attempts included nonpegylated IFN alpha-2b.
Monitoring and evaluation of dependent variables in all patients followed the same schedule with respect to previous IFN treatment and peginterferon re-treatment: in all patients, psychometric scores (depression, anxiety, anger/hostility) were obtained before therapy (t1), after 4 weeks (t2), 3-4 months (t3) and 6-8 months (t4) of treatment as well as 4-6 weeks (t5) after termination of therapy.
Blood samples were obtained at the patients' medical visits at time points t1 to t5 for analysis of blood count, liver transaminases, and HCV-RNA. Genotype identification, measurement of serum anti-HCV antibodies, and liver biopsy (staging and grading: inflammation, fibrosis, cirrhosis) were performed once before initial therapy.
Psychometric instruments
HADS
Depression was assessed by the German version of the Hospital Anxiety and Depression Scale (HADS), as published by Herrmann et al. [17,18]). HADS is a 14-item questionnaire with the dimensions, anxiety and depression. All items exclusively refer to the emotional state and do not reflect somatic symptoms. The cut-off value for clinically relevant depressive symptoms was set to >8 and for anxiety >10 on the appropriate subscale [17].
Statistical analysis
Data were registered and analysed using the Statistical Package for Social Sciences (SPSS for Windows, German version 10.0.7 [19]). P-values of <0.05 were considered statistically significant.
Descriptive analysis.
Results of quantitative measures are expressed as median or mean ± standard deviation or standard error as indicated. Qualitative variables are presented as counts and percentages.
Tests of significance.
Comparison of variables representing categorical data was performed using the chi-squared test. Mean differences of continuous variables between patient subgroups were examined either by Student's t-test for independent samples or anova if more than two subgroups were included.
Group means of dependent samples (e.g. time course of continuous variables before, during and after IFN-alpha therapy, or comparison of initial therapy vs re-therapy) were compared by anova (repeated-measures design, GLM procedure [19]. Corresponding contrasts were tested using Student's t-tests for dependent samples.
INTRODUCTION
Hepatitis C virus (HCV) infection is one of the most frequent infectious diseases worldwide, with a global prevalence of 1-2% [1]. It has been estimated that approximately 170 million people are infected with HCV [2-5]. Chronic disease occurs in approximately 85% of patients following HCV infection. Of these up to 20% develop liver cirrhosis [1,4-6].
The primary aim of antiviral treatment in chronic HCV infection is sustained virological response. With the present therapeutic standard (combination therapy with peginterferon and ribavirin), this is achieved in >50% of the patients [7,8]. However, medical treatment of HCV infection is still unsatisfactory because it is expensive and frequently not well tolerated. One obstacle for therapy is the high prevalence of relevant depression and anxiety found even in untreated patients with chronic hepatitis C [9]. Psychiatric symptoms may be aggravated by interferon (IFN)-alpha therapy [10-14] and may require dose reduction or even premature discontinuation of therapy. The main psychiatric symptoms requiring reduction or cessation of therapy include depression, suicidal tendencies, irritability and anxiety.
In this context, the understanding, early recognition and effective treatment of psychiatric side-effects, in particular those of IFN-induced major depression, is of key importance, as this may increase the probability of a successful antiviral therapy. Selective serotonin re-uptake inhibitor (SSRI) treatment of active IFN-induced depression has been shown to be an effective strategy to avoid premature termination of antiviral therapy [10,11].
In contrast to IFN treatment in cancer patients [15], the efficacy of antidepressant SSRI medication in secondary prophylaxis has not yet been tested in patients with chronic hepatitis C [16]. Moreover, no adequate clinical approach has been established to reduce or prevent psychiatric symptoms in IFN-treated patients with a history of IFN-induced major depression during initial therapy. Secondary IFN treatment of patients with previous therapy failure is of particular interest given the improved rates of sustained virological response with newer therapy regimens. Therefore, we conducted a study including HCV chronically infected patients without sustained virological response upon previous IFN therapy who had already been psychometrically monitored. All of them had developed IFN-induced major depression. Secondary IFN therapy was started with concomitant SSRI medication. Therapeutic efficacy and safety of SSRI prophylaxis during IFN re-therapy was analysed.
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