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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.
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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.
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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.