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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background : Psychiatric side-effects may require dose reduction or premature discontinuation of interferon therapy in chronic hepatitis C. New strategies are needed in order to prevent the premature termination of interferon therapy.

Aim : To evaluate prospectively the efficacy and tolerability of antidepressant therapy (paroxetine, a selective serotonin reuptake inhibitor) in patients with chronic hepatitis C treated with interferon-α who have developed interferon-induced major depression.

Methods : A sub-group of 14 individuals from 121 consecutively treated hepatitis C patients developed substance-induced major depression without suicidal ideation during interferon-α treatment. The individuals in this sub-group received paroxetine after the occurrence of depression (20 mg daily until termination of interferon therapy). Diagnostic scores for depression (and anger–hostility) were obtained in a repeated measures design (Hospital Anxiety and Depression Scale and Symptom Checklist 90 Items Revised).

Results : Eleven of the 14 patients (78.6%) with interferon-induced major depression were able to complete interferon-α therapy as scheduled under concomitant paroxetine treatment (three dropouts: insufficient improvement of depression, occurrence of epileptic seizures, paroxetine-induced nausea/dizziness). Within 4 weeks after the start of paroxetine medication, depression scores declined significantly in all patients.

Conclusions : Our data suggest that concomitant therapy with paroxetine is an effective way to treat interferon-induced depression in patients with chronic hepatitis C.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Chronic hepatitis C is one of the most frequent infectious diseases world-wide and one of the most common causes of chronic liver disease. The number of people infected with hepatitis C virus (HCV) has been estimated to exceed 100 million world-wide.1 The mode of infection often remains unknown, but typical routes are blood transfusions and intravenous drug abuse.2, 3

When the disease is detected, approximately 20% of patients with chronic hepatitis C already have liver cirrhosis.4 As a consequence, chronic hepatitis C is now the leading indication for orthotopic liver transplantation in the USA and other Western countries.5, 6

Medical treatment for hepatitis C is still unsatisfactory, although at present about 50% of patients can reach a sustained loss of HCV by new therapeutic strategies (pegylated interferon-α in combination with ribavirin).7

However, interferon-α therapy is expensive and often poorly tolerated. An additional problem is the reduced quality of life8 and the high prevalence of important depression and anxiety,9 even in untreated patients with chronic hepatitis C. These symptoms may be aggravated to a serious degree by interferon-α therapy. In a study by McHutchison et al., 37% of patients treated with interferon-α monotherapy and 36% treated with a combination of interferon-α and ribavirin became depressed.10 Manns et al. reported depression in 31% of patients receiving combination therapy of pegylated interferon-α and ribavirin.11

These side-effects may become sufficiently serious to result in dose reduction or even premature discontinuation of therapy. The main psychiatric symptoms potentially leading to a reduction or cessation of therapy include depression (including suicidal ideation), irritability (anger–hostility, aggressiveness) and anxiety.

Owing to the high rate of morbidity and mortality associated with chronic hepatitis C, as well as its cost-intensive medical treatment, physicians (and patients) need to make every effort to optimize therapy. This includes issues such as patient compliance12 with therapy and the handling of physical side-effects.

However, most important in this context is the understanding, early recognition and effective treatment of psychiatric side-effects, especially interferon-induced major depression, in order to increase the chance of completing therapy with interferon-α in patients with chronic hepatitis C. In addition to a stable physician–patient relationship and other favourable therapy conditions (e.g. higher frequency of medical visits), medical treatment of interferon-induced depression might be a possible strategy to reduce the rate of premature termination of anti-viral therapy.

Several reports and case studies have indicated that antidepressant therapy might help to reduce interferon-induced psychiatric or depressive symptoms.13–18 In one prospective study, Musselman et al. showed that pre-treatment with paroxetine appeared to be an effective strategy for minimizing depression induced by interferon-α in patients with malignant melanoma.19 Surprisingly, however, until now, few data have been available on the effective use of antidepressants during interferon therapy in patients with chronic hepatitis C.

The aim of this study was to assess the efficacy of the antidepressant paroxetine (a selective serotonin reuptake inhibitor, SSRI) in patients with chronic hepatitis C and interferon-induced major depression. In addition, the frequency of depression requiring medical treatment in an unselected group of interferon-treated hepatitis C patients was determined.

In contrast to previous studies or reports on this subject, this work was performed prospectively on a sufficiently homogeneous sample of hepatitis C patients using psychometric instruments and one antidepressant drug (paroxetine, SSRI) exclusively.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

One hundred and twenty-one consecutive patients were enrolled who had been given a diagnosis of chronic hepatitis C at the Medizinische Poliklinik, Würzburg University, or who had been referred there for interferon-α therapy of known chronic hepatitis C. At the Medizinische Poliklinik, Würzburg University, a multispecialist group of physicians (specialists in gastroenterology/hepatology and psychosomatic medicine) cares for patients from a wide geographical area on an out- and in-patient basis.

The time interval of patient recruitment ranged from November 1996 to April 2001. The latest data included in the present analysis are from December 2001.

Patients with documented antibody to HCV and serological confirmation of chronic hepatitis C [HCV-RNA: sensitive assay based on reverse-transcription polymerase chain reaction (Cobas-Amplicor HCV Monitor)] were included.

Patients were excluded from interferon-α treatment if they were under 18 years or over 65 years of age. Patients with co-infections, such as hepatitis B virus or human immunodeficiency virus, severe internal diseases (e.g. cancer, ischaemic heart disease, autoimmune disease), psychiatric illness (severe depression, psychosis, etc.), active intravenous drug or alcohol abuse, obvious intellectual impairment or insufficient knowledge of the German language were also excluded.

The more thoroughly monitored sub-sample of interest included patients who developed substance (interferon)-induced major depression according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edn. (DSM-IV).20 These patients were given paroxetine, 20 mg daily, for the remaining time of interferon-α therapy. According to the recommendations for the application of paroxetine in patients with liver diseases, we did not increase the dose during SSRI treatment. The frequency of monitoring was increased in these cases, but no specific psychological therapy was offered. Exact procedures and time intervals between evaluation points are described in the next section.

Study design and treatment schedule

This was a prospective, longitudinal study including one paroxetine treatment group monitored before, during and after therapy with interferon-α (one-factorial repeated measures design).

Subjects eligible for interferon treatment were patients in whom therapy with interferon-α was indicated and who gave written consent to this therapy and to study participation before enrolment. The study was approved by the Ethics Committee for Medical Research of Würzburg University in accordance with the Declaration of Helsinki.

According to the changing recommendations in Germany during the study period, patients were treated from November 1996 to August 1998 with interferon-α-2b monotherapy (n = 41/121). If effective (virological response), 5 MIU was given three times per week for up to 12 months. From September 1998, n = 44/121 patients received combination therapy for up to 12 months (interferon-α-2b, 3–5 MIU tiw; ribavirin, 1000–1200 mg daily). The remaining patients (n = 36/121) were treated with a combination of pegylated interferon-α (PegIntron, 80–150 µg/week) and ribavirin (800–1200 mg daily).

Before study entry, all eligible patients were given a manualized structured interview (Diagnostisches Interview bei Psychischen Störungen21) in order to exclude psychiatric illness according to the DSM-IV classification20 (psychotic disorders, major depressive disorder, anxiety disorders) and to explain the nature and aims of the study. Furthermore, a basic psychometric evaluation by the Hospital Anxiety and Depression Scale (HADS) and Symptom Checklist 90 Items Revised (SCL-90-R) was performed.

Data on the course of the disease and mode of infection were also obtained.

If substance-related major depression without suicidal ideation occurred, as indicated by the diagnostic manualized structured interview and DSM-IV criteria and evaluated by psychometric assessment of the event, adjuvant antidepressant therapy (paroxetine, 20 mg daily) was started in agreement with the respective patient if two conditions were fulfilled: (i) the presence of a virological response (virus load below the detection limit or a significant decrease in the virus load by at least 2 logs); and (ii) absolute incapability of continuing interferon therapy without antidepressant therapy, as stated by both the physician and the patient. Once concomitant paroxetine treatment had started (n = 14/121), repetitive psychometric assessment was carried out in order to monitor intensively the time course of psychiatric (especially depressive) symptoms with interferon and adjuvant paroxetine medication. Psychometric data from the paroxetine-treated patients were obtained at seven time points: before therapy (t1), first occurrence of major depression (t2, event), 1 week (t3), 2 weeks (t4), 4 weeks (t5) and 3 months (t6, still on interferon-α) after the event, and last evaluation 4 weeks after termination of interferon-α therapy (t7).

Psychometric tests

Hospital Anxiety and Depression Scale.  Anxiety and depression were assessed by the well-validated Hospital Anxiety and Depression Scale (HADS, German version, as published by Herrmann et al.22). HADS is a 14-item questionnaire with dimensions of anxiety and depression. All items exclusively refer to the emotional state and do not reflect somatic symptoms. Recently, the cut-off values for clinically relevant depression and anxiety were set to ≥ 9 and ≥ 11, respectively.22

Symptom Checklist 90 Items Revised.  Anger–hostility and depression were assessed by the well-validated Symptom Checklist 90 Items Revised (SCL-90-R, Derogatis 1977, German version, as published by Franke23). SCL-90-R is a brief, multidimensional self-report inventory designed to screen for a broad range of psychological problems and symptoms of psychopathology. We focused exclusively on the evaluation of one questionnaire sub-scale (sub-scale no. 6: ‘anger–hostility’). According to the manual, the cut-off value for highly affected patients was set to ≥ 8.23

Laboratory tests and clinical and histological data

Blood samples were obtained repeatedly during the patients' medical visits in order to evaluate the following parameters: blood count, transaminases, anti-HCV antibodies and HCV-RNA. Genotype identification and liver biopsy (staging and grading: inflammation, fibrosis, cirrhosis) were performed once before the start of interferon-α therapy. However, a liver biopsy immediately before study entry/enrolment was not an inclusion criterion. Finally, the mode of infection was documented.

Evaluation of efficacy and statistical analysis

Data were registered and analysed using the Statistical Package for Social Sciences (SPSS for Windows,24 German version 10.0.7). All tests of significance were two-tailed. P < 0.05 was considered to be statistically significant. Because of the explorative character of the study, we did not consider α adjustment in multiple comparisons.

Descriptive analysis.  Data are expressed as the median or mean ± standard deviation (s.d.) for quantitative measures. Categorical variables are presented as counts and percentages.

Tests of significance.  The comparison of variables representing categorical data was performed using the chi-square statistic (CHISQUARE subcommand in SPSS).

The mean differences of continuous variables between patient sub-groups were examined either by t-tests for independent samples (comparison of two sub-groups) or by analysis of variance if more than two sub-groups were included [one-factorial anova with more than two factor categories; realized by general linear model (GLM) procedure].

Group means of dependent samples (e.g. time course of continuous variables) were compared by means of anova (repeated measures design, GLM procedure in SPSS for Windows 10.0.7).

Pearson's correlation was used where appropriate (assessment of associations between quantitative variables).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

Between November 1996 and April 2001, 121 consecutive patients with chronic hepatitis C were enrolled in the study. Fourteen (11.6%) developed substance (interferon)-induced major depression without suicidal ideation and therefore were concomitantly treated with paroxetine. The baseline characteristics of both sub-groups, with and without major depression (and adjuvant paroxetine treatment), are shown in Table 1. The groups had similar pre-treatment clinical, virological and histological data. Therefore, there is no statistically valid indication that the patient sub-sample which developed substance-induced major depression could be easily predicted by any baseline variables assessed in our study.

Table 1.  Sociodemographic and biomedical characteristics of the study sample. The most relevant patient characteristics of the study sample are presented (total and stratified for patients with and without interferon-induced major depression). P values were obtained by t-test for independent samples (age) or chi-squared statistics (remaining variables)
Sociodemographic and biomedical factorsTotal sample (n = 121)Paroxetine group (n = 14)Patients without major depression (n = 107)P value
  1. IVDU, intravenous drug use.

Age (min.–max.)41.2 ± 8.9 (18–65)41.1 ± 6.8 (27–53)41.2 ± 9.2 (18–65)0.970
Females49 (40.5%)8 (57.1%)41 (38.3%)0.177
Males72 (59.5%)6 (42.9%)66 (61.7%) 
Acquisition mode
 Unknown37 (30.6%)2 (14.3%)35 (32.7%)0.353
 IVDU60 (49.6%)9 (64.3%)51 (47.7%) 
 Post-transfusion24 (19.8%)3 (21.4%)21 (19.6%) 
Virus genotype
 Genotype 169 (57.0%)5 (35.7%)64 (59.8%)0.173
 Genotype 212 (9.9%)1 (7.2%)11 (10.3%) 
 Genotype 338 (31.4%)8 (57.1%)30 (28.0%) 
 Genotype 4 2 (1.7%)0 (0.0%) 2 (1.9%) 
Liver biopsy/liver damage
 Hepatitis only61 (52.1%)6 (46.1%)55 (52.9%)0.622
 Fibrosis32 (27.4%)3 (23.1%)29 (27.9%) 
 Cirrhosis24 (20.5%)4 (30.8%)20 (19.2%) 

As our goal was to monitor and evaluate the efficacy and tolerability of antidepressant medication during interferon therapy, the rest of the results in this section exclusively refer to the sub-sample of patients who received paroxetine (Table 1).

The mean age of the 14 patients was 41.1 years (s.d. 6.8 years), ranging from 27 to 53 years. In the sub-group of patients with interferon-induced major depression, there were eight females and six males. With regard to the virus genotype, there were eight patients with genotype 3, five patients with genotype 1 and one patient with genotype 2. In nine patients, the mode of acquisition was intravenous drug abuse. The cases of interferon-induced major depression were not significantly associated with the mode of interferon therapy [interferon monotherapy, three patients (expected, 4.7); interferon-α and ribavirin, seven patients (expected, 5.1); pegylated interferon-α and ribavirin, four patients (expected, 4.2)]. In all patients, no dose reduction of interferon-α was performed during the remaining treatment period.

Tolerability to paroxetine and response rate

In one patient, depressive symptoms and anorexia continued to worsen during the 14 days following the start of paroxetine treatment, and interferon therapy had to be stopped. Another patient had to discontinue paroxetine and interferon treatment due to adverse events (nausea, dizziness) caused by the antidepressant. A third patient was obliged to stop both medications after the occurrence of a presumably interferon-associated epileptic grand mal seizure. Additionally, the relapse of this reformed alcohol abuser may have triggered this neurological event. Overall, 11 of 14 patients (78.6% response rate to paroxetine treatment without further complications) were able to complete interferon therapy as scheduled with adjuvant paroxetine medication. The longitudinal statistical analysis in the next section refers to these 11 patients with complete data sets: t1 to t7.

Time course of depression scores

Figure 1 shows the time course of the mean depression scores (HADS) in the paroxetine-treated group of hepatitis C patients. Anova analysis revealed a significant decrease in depression score after the initiation of paroxetine treatment [P < 0.001; time points t2 (event) to t6 (3 months of paroxetine)]. Nevertheless, before and after the end of interferon treatment, depression scores were at a markedly lower level than those during concomitant treatment with interferon and paroxetine.

image

Figure 1. Time course of depression scores (Hospital Anxiety and Depression Scale, HADS) during adjuvant paroxetine therapy. Mean depression scores (HADS) in the sub-group of patients with interferon-induced major depression are displayed for the seven evaluation time points t1–t7 (n = 11).

Download figure to PowerPoint

The graph (Figure 1) clearly demonstrates that a marked response to paroxetine does not take place before t4 (2 weeks of paroxetine). However, after this evaluation time point, the response to paroxetine is strong and persisting. Post hoc tests show that the decrease up to 1 week after the start of paroxetine therapy is not statistically significant [P = 0.241, paired t-test, event (t2) vs. 1 week (t3)].

Figure 2 displays the course of the SCL-90-R depression scores. The results correspond to those of the HADS scores. Therefore, both instruments seem to be suitable for the assessment of the effects of adjuvant paroxetine treatment on interferon-induced psychiatric/depressive symptoms.

image

Figure 2. Time course of depression scores (Symptom Checklist 90 Items Revised, SCL-90-R) during adjuvant paroxetine therapy. Mean depression scores (SCL-90-R) in the sub-group of patients with interferon-induced major depression who completed interferon therapy (n = 11) are displayed for the seven evaluation time points t1–t7.

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Time course of anger–hostility scores

Clinical practice and previous studies have suggested that irritability (anger or hostility) also belongs to the spectrum of interferon-induced psychiatric symptoms. We were interested to determine if and how hostility scores (sub-scale of SCL-90-R) are affected by antidepressant therapy with paroxetine.

One striking finding was the fact that, when the major depression event took place (t2), scores for anger–hostility were clearly increased compared to baseline values. However, changes in depression and anger–hostility were not actually parallel to each other (r = 0.26).

As shown in Figure 3, SCL-90-R scores for anger–hostility decrease as a result of paroxetine treatment. According to our data, this trend is statistically significant (anova, P = 0.025), but not before 2 weeks after the onset of antidepressant treatment. The strongest improvement with the SSRI paroxetine is observed between t3 and t4 (Figure 3).

image

Figure 3. Time course of anger–hostility scores (Symptom Checklist 90 Items Revised, SCL-90-R) during adjuvant paroxetine therapy. Mean anger–hostility scores (SCL-90-R) in the sub-group of patients with interferon-induced major depression who completed interferon therapy (n = 11) are displayed for the seven evaluation time points t1–t7.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Psychiatric symptoms, such as depression, are a frequent co-morbid condition in patients with chronic hepatitis C.9, 25 Additionally, the aggravation or development of severe psychiatric problems, such as depression, anxiety, irritability and, rarely, even suicidal ideation, during interferon therapy may lead to the premature termination of anti-viral treatment. The recognition, appropriate management and effective treatment of these possible interferon-associated psychiatric complications may increase the chance of completing therapy with interferon, attaining a sustained virological response and raising the cost efficiency of therapy. Since the first report in 1993 of the successful application of an antidepressant medication (fluoxetine) in patients with chronic hepatitis C treated with interferon,26 several case studies on the use of various antidepressant drugs in interferon-associated psychiatric complications have been published.13–18

Previous research on this subject has been hampered by several methodical shortcomings (e.g. case reports with only one or very few patients, retrospective studies without baseline values for depression, and assessment of psychiatric symptoms without the use of validated psychiatric instruments or structured interviews). Therefore, in this study, we measured SSRI efficacy using a prospective, careful, longitudinal assessment of psychiatric symptoms before, during and after treatment with paroxetine in patients with chronic hepatitis C and interferon-induced major depression. A placebo-controlled study design was not applicable in the treatment of substance (interferon)-induced major depression, because interferon therapy would have had to be discontinued without antidepressant intervention in the control group.

Different possible mechanisms for interferon-α-induced depression include the depletion of serotonin by the effect of interferon on serotonin transporter transcription27 or on the serotonin precursor tryptophan,28 possible direct neurotoxicity by interferon, or a cascade of secondary cytokine activation and neuroendocrine changes.29, 30 The suggested central role of serotonergic transmission in interferon-induced psychiatric adverse effects is underlined by an elevated rate of anger–hostility during therapy with interferon-α.14

As current evidence suggests that the decrease in central serotonergic transmission associated with depression is reversed by SSRIs,31, 32 and that interferon-induced depression is a homogeneous condition specifically involving depleted serotonergic transmission, we chose to investigate the effect of the SSRI paroxetine.

Paroxetine is a well-established and tolerated antidepressant that can be used safely if there is no evidence of severe liver dysfunction33 (which was an exclusion criterion in our study, see above). Side-effects associated with paroxetine (most commonly nausea) are generally mild, transient and easily managed.34–36 Animal data and clinical experience suggest that paroxetine is considerably safer and better tolerated than tricyclic antidepressant drugs, and therefore more suitable for the treatment of depression in out-patients.35–37 Compared with other common SSRIs (e.g. fluoxetine, sertraline, nefazodone), efficacy measures and rates of adverse effects are in a similar range with paroxetine.38–40

The results of our study suggest that the SSRI paroxetine can efficiently improve interferon-induced depressive symptoms as well as irritability. Thus, 78.6% (11/14) of our patients with interferon-induced major depression completed anti-viral therapy as scheduled. This response rate is higher than that reported for the treatment of depressive disorders in general (58–77%).37, 38, 41

One explanation could be the homogeneous pathophysiological mechanisms during interferon therapy (e.g. specific serotonergic neurotransmitter pathways), in contrast to the broad range of possible aetiological factors in general depressive disorders. The unusually early onset of the paroxetine response, with a significant improvement of depression and irritability within 2 weeks, can be explained in a similar manner.

With regard to the tolerability to paroxetine, only one patient (7.1%) discontinued medication due to adverse events (nausea, dizziness). Although seizures have been described as a very rare side-effect of paroxetine, we believe that, in the single patient with grand mal seizure in our study, the predominant factor was the combination of interferon therapy and excessive alcohol intake. In general, withdrawal rates during paroxetine treatment have been reported to range from 13% to 17%.37, 40

Despite the first report of possible negative immunoregulatory effects of antidepressants in vitro,42 54.5% of patients (n = 6/11) with an improvement of depressive symptoms during adjuvant paroxetine therapy reached a sustained virological response after termination of interferon medication. This comparably high response rate may be due to the fact that four of the patients with a virological response had genotype 2 or 3.

Similar to the results of Schramm et al.,14 the time from the onset of interferon-α medication to the occurrence of depression ranged from 5 to 22 weeks (mean, 10.4 weeks). In contrast to another published report,13 with the onset of interferon-induced depression during the first 8 weeks in all cases, we observed a much broader range. In our opinion, interferon-induced major depression after only 1 or 2 weeks of application is very unusual. It is more likely that the reported symptoms are associated with early ‘flu-like’ side-effects.

In conclusion, we recommend that patients who develop substance (interferon)-induced major depression with or without irritability should be considered as candidates for treatment with an SSRI before presumably successful interferon-α therapy is reduced or stopped prematurely. However, if patients show suicidal ideation, interferon-α therapy should be discontinued immediately. Although our patient group might be highly pre-selected, we believe that the initiation of antidepressant therapy only after interferon-induced depression has developed is a sufficient and efficacious strategy, and that general prophylactic treatment with paroxetine in patients with hepatitis C is not necessary. In the case of high-dose interferon therapy, however (e.g. in malignant melanoma), with a much higher incidence of interferon-induced depression as well as disease-associated depression, prophylactic treatment with antidepressants may be indicated.19

Basic conditions for this adjuvant therapy include frequent professional monitoring of the patient's mental state and the immediate termination of interferon-α therapy if the depressive mood worsens, psychosis develops or suicide becomes a significant risk. Clearly (with respect to the limited sample size and the more or less explorative character of the statistical analysis), more prospective studies with larger patient groups are needed.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This work was supported in part by Essex-Pharma (Germany), a subsidiary of Schering-Plough (Kenilworth, NJ, USA).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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