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Abstract

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

Aliment Pharmacol Ther 2011; 34: 1306–1317

Summary

Background  Treatment of hepatitis C with peginterferon and ribavirin is associated with psychiatric side-effects, frequently necessitating dose reduction or therapy cessation.

Aim  To assess the efficacy of prophylactic escitalopram to prevent psychiatric side-effects during peginterferon and ribavirin treatment in a randomised, double-blind, placebo-controlled trial.

Methods  Seventy-nine hepatitis C patients were treated with peginterferon and ribavirin. Patients received escitalopram (n = 40, 10 mg) or placebo (n = 39), which was initiated together with peginterferon and ribavirin. Primary outcomes were an increase of two points or more on the items reported sadness, inner tension and impaired concentration of the Montgomery-Asberg Depression Rating Scale, and hostile feelings of the Brief Anxiety Scale. Secondary outcome was the development of depression diagnosed by the Mini-International Neuropsychiatric Interview. Measurements were performed at baseline, week 4, 12 and 24 during anti-viral treatment, and 24 weeks thereafter.

Results  The incidence of psychiatric side-effects was significantly lower in patients treated with escitalopram compared with placebo for all primary and secondary outcomes, except for impaired concentration: reported sadness 27.5 vs. 48.7% (P = 0.052), inner tension 17.5 vs. 38.5% (P = 0.038), impaired concentration 55.0 vs. 66.7% (P = 0.288) and hostile feelings 22.5 vs. 43.6% (P = 0.046) (escitalopram vs. placebo, Chi-squared test). The sum scores of all four endpoints showed an overall beneficial effect of escitalopram (P = 0.009, Mann–Whitney U-test). Depression occurred in 12.5% of the patients in the escitalopram-group vs. 35.9% in the placebo-group (P = 0.015, Chi-squared test).

Conclusions  Prophylactic treatment with escitalopram is effective in the prevention of psychiatric side-effects during interferon-based treatment of hepatitis C.


Introduction

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

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma, and the most common indication for liver transplantation in Europe and the United States.1 The current standard therapy with peginterferon (PEG-IFN) and ribavirin (RBV) yields sustained virological response rates (SVR) of 50–80%.2–4 However, treatment with standard interferon or PEG-IFN is associated with the development of severe psychiatric side-effects, most notably depression. In addition, increased hostile feelings,5 feelings of malaise and fatigue,6 concentration difficulties7, 8 and anxiety 9, 10 are recognised psychiatric adverse effects.

The psychiatric side-effects negatively affect quality of life during treatment and lead to early dose reduction, treatment interruption or even treatment cessation. This threatens treatment success because continued use of at least 80% of the prescribed dosage for at least 80% of the planned treatment duration, is crucial to the achievement of a sustained viral response.11 A variety of case reports and open-label studies12 and one randomised controlled study,13 indicate that selective serotonin inhibitors (SSRIs) alleviate overt depression developed during PEG-IFN therapy. Consequently, one can adopt the strategy to closely monitor patients for the development of depression, and start subsequent antidepressant treatment. However, prophylactic treatment could also be considered because this might not only be effective against the development of a full-blown depressive disorder, but also against the development of subthreshold psychiatric symptoms (e.g. depressed mood without the presence of a full-blown depressive disorder or irritability per se). Both effects will potentially result in improved quality of life during treatment for all patients, improved treatment adherence and possibly improved response rates.

We designed a randomised, double-blind, placebo-controlled trial studying the effects of prophylactic SSRI treatment on the development of psychiatric side-effects of anti-viral therapy in HCV. The primary aim was to investigate whether prophylactic treatment with escitalopram during treatment with PEG-IFN and RBV was able to prevent psychiatric symptoms to a clinically significant degree (defined as an increase of two points on observer-based rating scales reflecting anxiety, loss of concentration, depression (MADRS: Montgomery and Asberg Depression Rating Scale) and hostile feelings (BAS: Brief Anxiety Scale). As secondary aim, we compared the incidence of syndromal depression (defined as major depression according to DSM-IV criteria) according to current classification14 between the two treatment groups.

Methods

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

Setting and participants

Patients between 18 and 70 years of age, with chronic hepatitis C as shown by detectable serum HCV-RNA, with hepatitis C genotype 1–4, with an indication for anti-viral therapy according to current clinical HCV guidelines, and who had provided written informed consent were considered eligible for the study. The following exclusion criteria were used: presence of contra-indications for anti-viral therapy, abnormal values for thyroid stimulating hormone, a concurrent psychiatric axis I diagnosis according to DSM-IV criteria (such as a major depressive episode, bipolar disorder or psychotic disorder), concurrent use of psychotropic drugs (such as monoamine-oxydase-inhibitors, St John’s wort, lithium, serotonin-agonists and anti-epileptics), a history or other evidence of severe illness or malignancy and any other condition which would make the patient, according to the opinion of the investigator, unsuitable for the study.

The human medical ethics committees of the participating centres approved the study, the trial was registered at http://www.clinicaltrials.gov (Identifier: NCT00133276) and the study was performed according to the Declaration of Helsinki and ICH-GCP guidelines. All patients were well aware that during the study, antidepressants could be given in the absence of concurrent psychiatric disease and/or absence of a psychiatric history.

Anti-viral treatment and follow-up

Anti-viral therapy consisted of peginterferon-alfa-2a (Pegasys; Roche Nederland B.V., Woerden, Netherlands) at a dose of 180 microgram weekly subcutaneously for 24 or 48 weeks depending on genotype and response to treatment together with RBV (Copegus, Roche Nederland B.V., Woerden, Netherlands). At the start of the trial, patients with genotype 2 and 3 were treated with standard 800 mg RBV per day, however, as the importance of RBV became more evident, patients with genotype 2 and 3 were also offered the same weight-based dose given to genotype 1 and 4 patients. Control visits during treatment were scheduled at week 0 (baseline), week 2, 4, 8, 12, 16, 20 and 24. Week 24 indicated the end of this study. Depending on genotype and virological response, treatment was continued according to international guidelines. Based on these guidelines, total treatment duration was 24 weeks in genotypes 2 and 3, and 48 weeks in genotypes 1 and 4. When, in genotype 1 and 4 patients, there was no early virological response at week 12 (<2 log drop) or when HCV-RNA was still positive at week 24, anti-viral treatment was stopped prematurely. The concomitant use of paracetamol, methadone and benzodiazepines was allowed. Twenty-four weeks after completion of anti-viral therapy, a follow-up visit was scheduled.

Randomisation and intervention

Patients were randomly assigned to use either escitalopram or placebo, for a period of 26 weeks, in identical looking tablets initiated together with anti-viral treatment (escitalopram and placebo were provided by Lundbeck). The dose of escitalopram was 5 mg daily during the first 2 weeks, 10 mg once daily until week 24 and thereafter, 5 mg during 2 weeks. A biostatistician made a randomisation list, yielding 50 numbers with placebo and 50 numbers with verum in blocks of four. The coded list remained at the pharmacy and the clinical research department during the course of the study. The study medication and placebo were stored at the Pharmacy Department of the Erasmus MC, Rotterdam, the Netherlands and delivered in blisters of 10 tablets. Patients, investigators and treating clinicians were blind to the use of escitalopram or placebo.

Outcomes and follow-up

The primary outcome measure was predefined as an increase at one of the time points during treatment of two points or more compared to baseline on the items reported sadness (depressed mood), inner tension and concentration difficulties of the Montgomery and Asberg Depression Rating Scale (MADRS) or on the item hostile feelings of the Brief Anxiety Scale (BAS). The secondary outcome measure was predefined as the presence of syndromal depression as diagnosed by the Mini-International Neuropsychiatric Interview (M.I.N.I). Patients were censored after achievement of the event.

Psychiatric evaluation took place at baseline and at 4, 12 and 24 weeks after the start of treatment, and at 24 weeks after completion of anti-viral therapy. No assessments took place in case PEG-IFN and RBV were stopped prematurely (e.g. because of viral nonresponse).

One of the investigators (GB) performed the psychiatric ratings after extensive training.

In case of emerging clinically significant psychiatric disorders, referral to the out-patient clinic of one of the psychiatric departments of the participating centres was arranged. In other instances, for example, when depressive disorder developed at the end of the anti-viral treatment and was expected to abate after cessation of anti-viral therapy, management was done by the treating clinicians. The study code was broken only when clinically deemed necessary by the participating and coordinating centre, for example, to treat with open-label antidepressant therapy. The investigator performing the psychiatric evaluations was blinded to the status of patients in which breaking the code was deemed necessary.

The presence of a major depressive episode was confirmed with the relevant module of the M.I.N.I., which is a short-structured diagnostic interview for DSM-IV-TR and ICD-10 15 psychiatric disorders and was designed to perform a short but accurate structured psychiatric interview.16 Depressive symptoms were assessed using the MADRS, a clinician-rated depression scale and one of the most commonly used symptom severity scales in depression,17 consisting of 10 items each of which is scored from 0 to 6. In addition, the BAS was used specifically for the item hostility to assess hostile feelings.18

For confirmation, as self-report questionnaires, the Beck Depression Inventory (BDI) and the Symptom Check List-90 (SCL-90) were used. The BDI is a well-validated and reliable 21-item self-report questionnaire designed to measure depressive symptoms.19 Five somatic items (e.g. measuring fatigue and loss of appetite) of the BDI were also recorded. The SCL-90 was used to assess if other domains of psychic functioning besides mood were affected. The SCL-90 is a well-validated, multidimensional self-report symptom inventory, designed to assess various dimensions of psychopathology, including hostile feelings.20

Statistical analysis

Based on literature of PEG-IFN-induced psychopathology, we estimated an incidence of the primary outcome measure of 50% in the placebo group.21, 22 A reduction to 30% due to prophylactic use of escitalopram was expected. The number of patients needed was calculated using two-sided Chi-squared test for equal proportions and equal group size (nQuery Advisor 4.0 software, Virginia Commonwealth University, Richmond, VA, USA). For a power of 0.80 at α = 0.05, 37 patients per arm were required. To account for potential nonevaluability, 80 patients were included.

Analysis was performed on intention-to-treat basis. The study population was defined as all patients in whom baseline psychiatric evaluation was performed and who received at least one dose of study medication in combination with one dose of PEG-IFN and RBV. Study groups were defined according to their initial assignment (placebo or escitalopram). Data from all different evaluation points of the two study groups were incorporated in the analysis as long as patients were still on anti-viral treatment at that point in time, irrespective if they were still using study medication, received open-label SSRI treatment or used no study medication or SSRI at all. In case of nonevaluability, the patient was censored at that time point.

To test for differences between patients with escitalopram or placebo, the Chi-squared test of the primary outcome measures was used. Furthermore, a total sum score of the four primary outcome measures was calculated and compared with the nonparametric Mann–Whitney U-test.

The relation between patient characteristics at baseline and the primary and secondary outcomes were examined by a univariate score test. The independence of these factors was assessed by multiple logistic regression analysis.

Mean differences of the crude observed item scores or sum scores of the BAS, MADRS, BDI and SCL-90 over the evaluation time points during treatment (week 4, 12, 24) were analysed with repeated measurement analysis using an unstructured covariance matrix of the time. At the time of follow-up, these scores were compared between the two treatment groups with Student’s t-test.

The level for statistical significance was set at P < 0.05.

Results

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

Study population

Eighty-five patients were screened and 80 patients met the eligibility criteria for the study and were randomised. Of the patients considered noneligible, one had a history of an antidepressant-induced manic episode, one had a current depressive episode according to the M.I.N.I., one was co-infected with Human Immunodeficiency Virus, one used prohibited medication and one reported severe psychosocial problems which were expected to hamper treatment adherence. After randomisation, one patient declined treatment, and so 79 patients participated in the study. Patients were enrolled between May 2005 and June 2007; 57 in Erasmus MC Rotterdam, 19 in Radboud University Nijmegen Medical Center and 3 in Academic Medical Center Amsterdam.

Baseline characteristics of the 79 patients are summarised in Table 1. In the escitalopram group, slightly more females participated and less (substance-induced) depressive episodes were reported; otherwise, baseline characteristics were comparable. As diagnosed with the M.I.N.I., 24 (30%) patients had a history of one or more depressive episodes: 8 (20%) in the escitalopram-group, and 16 (41%) in the placebo-group (P = 0.042, Pearson’s Chi-squared test). Eleven patients (14%) reported having overdosed or attempted suicide. Twenty-nine patients (37%) reported a history of psychosis, mostly related to the use of illicit drugs, such as cocaine and amphetamines. None of them was actively psychotic at entrance of the study. Twenty-eight patients (35%) had been hospitalised in mental health and/or addiction centres. No recurrences of psychosis were observed during the study. At the time of inclusion, 22 (28%) patients had an ongoing contact with either mental health services or addiction services. Twelve (15%) patients were daily users of benzodiazepines and 10 (13%) were using methadone.

Table 1.   Characteristics of all patients: general characteristics at baseline, route of transmission and genotype of hepatitis C virus, and psychiatric history, current treatment and substance abuse
CharacteristicsEscitalopram (n = 40)Placebo (n = 39)Total (n = 79)
  1. BMI, body mass index; IVDU, intravenous drug use.

  2. * Statistically significant difference between escitalopram and placebo group (Chi-squared test): P ≤ 0.05.

General
 Mean (s.d.) age, years48.5 ± 9.744.6 ± 7.546.5 ± 8.8
 Mean (s.d.) body weight, kg79.1 ± 14.482.5 ± 14.380.8 ± 14.4
 Mean (s.d.) BMI26.1 ± 3.625.8 ± 4.326.0 ± 3.9
 Gender (% males)67.589.778.5
Route of transmission
 IVDU and/or tattoo192645
 Iatrogenic14923
 Sexual contact1 1
 Unknown6410
Genotype
 1 & 4181836
 2 & 3222143
Psychiatric history, current treatment and substance abuse
 One or more depressive episodes41014
 One or more depressive episodes including substance-induced8*16*24
 Suicides attempts/overdose5611
 Psychosis141529
 Admission to psychiatric hospital4711
 Admission to addiction facility111728
 Current contact with mental health or addiction service91322
 Daily use of: methadone or benzodiazepines9 (6 + 3)3 (2 + 1)12 (8 + 4)
 Daily use of: tobacco252954
 Last week use of: alcohol151530
 Last week use of: cannabis61016
 Last month use of non-iv hard drugs235

Of the whole group, 47 patients (59%) were born in the Netherlands, 40 patients (51%) were employed or housewife/househusband, 33 (42%) were on a form of social benefit, one was retired (1.3%) and 5 (6.3%) had no source of income. Fifty-four patients (68%) lived with a partner and/or with children, 17 (22%) were living single and 8 (10%) were hospitalised or detained.

Baseline results of the scores of the different items and sum scores of the MADRS, BAS, BDI and SCL-90 were comparable between the escitalopram and placebo groups, with the exception of the item loss of interest of the MADRS. For a comparison: SCL-90 sum scores (mean ± s.d.) at baseline were 130.64 ± 35.9 in the escitalopram-group and 136.53 ± 40.5 in the placebo-group; in the Dutch population, mean sum scores are 108–115 in men and 117–129 in females. The flow of patients according to treatment allocation is summarised in Figure 1.

image

Figure 1.  Trial profile.

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Outcome measures

The cumulative incidence of an increase of two points or more on the items reported sadness, inner tension of the MADRS and the item hostile feelings of the BAS and the incidence of a depressive episode according to the M.I.N.I. were all significantly more frequent (P < 0.05) in the placebo group compared to the escitalopram group (Figures 2 and 3, and Table 2).

image

Figure 2.  Cumulative incidence (%) of primary outcomes: reported sadness, inner tension, impaired concentration [Montgomery – Asberg Depression Rating Scale (MADRS)] and hostile feelings [Brief Anxiety Scale (BAS)].

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image

Figure 3.  Cumulative incidence (%) of secondary outcome: MINI (Mini-International Neuropsychiatric Interview) depression according to Diagnostic & Statistical Manual-IV criteria.

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Table 2.   The occurrence of psychiatric side-effects during anti-viral therapy with peginterferon and ribavirin: the effects of prophylactic treatment with escitalopram or placebo
 Escitalopram: Events (%) n = 40Placebo: Events (%) n = 39P-value (χ2)
  1. BAS, Brief Anxiety Scale; MADRS, Montgomery and Asberg Depression Rating Scale; MINI, Mini International Neuropsychiatric Interview.

Increase of at least two points of:
 MADRSReported sadness11 (27.5)19 (48.7)0.052
Inner tension7 (17.5)15 (38.5)0.038
Impaired concentration22 (55.0)26 (66.7)0.288
 BASHostile feelings9 (22.5)17 (43.6)0.046
Occurrence of depression
 MINIDepression5 (12.5)14 (35.9)0.015

The use of one sum score of the four primary endpoints revealed an overall significant effect of escitalopram (P = 0.009, Mann–Whitney U-test); the mean number of times a patient had an increase of two points or more on one of the four primary outcome measures (scoring range 0–4) was 1.23 in the escitalopram-group and 1.97 in the placebo-group. In addition, 15 patients in the escitalopram group did not have any increase (score 0) compared to four patients in the placebo-group. In 11 patients, it was considered necessary to break the study code: in four patients in the escitalopram group and in seven patients in the placebo group.

Some patient characteristics (Table 1) were associated with the primary and secondary outcomes at baseline. The recent use of cannabis or hard drugs was associated with an impaired concentration (both P = 0.02) at baseline, admission to an addiction facility was associated with reported sadness at baseline (P = 0.01) and one or more depressive episodes prior to treatment was associated with the development of a depression during treatment (P < 0.001). However, after correction of these covariates with logistic regression modelling, the treatment effects of escitalopram and placebo remained similar.

In addition, we looked for efficacy of escitalopram in patients with and without a psychiatric history, in particular, the previous development of a depressive syndrome and/or psychosis. From the total study population, 55 patients had never developed a depressive syndrome or psychosis: 2 of 32 (6.3%) patients randomised to escitalopram developed a depressive syndrome vs. 4 of 23 (17.4%) randomised to placebo (Fisher’s exact test P = 0.223). There were 23 patients who had a depressive syndrome in their past medical history: 3 of 8 (37.5%) patients randomised to escitalopram developed a depressive syndrome during the study vs. 10 of 15 (66.7%) patients randomised to placebo (P = 0.221). Hence, although due to small numbers statistical significance is lost, when looking at absolute numbers, escitalopram seems to be effective in both patients without and with a psychiatric history in the past.

Additional analyses

The descriptive of the crude observed scores are given in Table 3. At week 4, 12 and 24, patients treated with escitalopram had significant lower total scores on the MADRS and lower scores on the item hostile feelings of the BAS. Specifically at week 4 and 24, the scores on the item inner tension of the MADRS were lower in the escitalopram group; there were also significant differences between escitalopram and placebo at the sleep item at week 4 and the appetite item at week 12 and 24, in favour of the escitalopram group (data not shown).

Table 3.   Mean scores with standard deviation of the different rating scales in the escitalopram and placebo group (at baseline, during anti-viral therapy and during follow-up)
 BaselineWeek 4Week 12Week 24Treatment effect over timeFollow-up
EscitalopramPlaceboEscitalopramPlaceboEscitalopramPlaceboEscitalopramPlaceboEscitalopramPlacebo
n = 40n = 39n = 39n = 38n = 38n = 38n = 33n = 34n = 28n = 34
  1. BDI, Beck Depression Inventory; MADRS, Montgomery and Asberg Depression Rating Scale; SCL-90, Symptom Check List-90.

  2. All patients were asked to fill in the questionnaires, including those in whom the study code was broken. Incomplete questionnaires (administrative failure) were not taken into consideration.

  3. Treatment effect over time was obtained using repeated measurement analysis using an unstructured covariance matrix of the time.

  4. At follow-up, escitalopram and placebo groups were compared using Student’s t-test.

  5. * Denotes significant differences (P ≤ 0.05).

MADRS
Sum score4.58 ± 3.94.69 ± 4.76.69 ± 5.410.29 ± 7.38.26 ± 7.210.92 ± 6.67.39 ± 6.112.00 ± 6.0P = 0.00245.04 ± 6.97.24 ± 7.0
BAS
Hostile feelings0.83 ± 1.00.95 ± 1.00.79 ± 1.21.24 ± 1.11.03 ± 1.41.71 ± 1.00.91 ± 1.21.56 ± 1.3P = 0.00950.61 ± 1.00.94 ± 1.3
 n = 40n = 38n = 38n = 38n = 37n = 38n = 32n = 34 n = 28n = 32
BDI
Sum score9.05 ± 7.98.21 ± 7.78.87 ± 7.713.53 ± 10.110.76 ± 9.614.66 ± 9.28.09 ± 6.714.56 ± 8.8P = 0.00426.89 ± 8.69.59 ± 8.0
Somatic items3.25 ± 2.52.82 ± 2.84.08 ± 2.75.71 ± 3.74.57 ± 3.16.42 ± 3.53.91 ± 2.96.50 ± 3.4P = 0.00442.21 ± 2.14.34 ± 4.1
 n = 39n = 38n = 37n = 38n = 37n = 38n = 32n = 33 n = 28n = 32
SCL
Sum score130.64 ± 35.9136.53 ± 40.5124.74 ± 29.2156.37 ± 56.3131.57 ± 40.9158.97 ± 50.0125.59 ± 33.4160.61 ± 50.1P = 0.0004119.71 ± 34.8*149.78 ± 55.6*
Depression24.79 ± 9.325.74 ± 8.623.79 ± 8.029.24 ± 11.625.41 ± 10.430.26 ± 1.223.94 ± 7.930.36 ± 10.8P = 0.004323.11 ± 11.127.75 ± 11.6
Anxiety14.51 ± 5.114.82 ± 5.512.63 ± 3.416.66 ± 7.113.84 ± 4.016.95 ± 6.513.00 ± 4.217.09 ± 6.7P = 0.000712.71 ± 3.416.38 ± 6.6
Insufficiency14.92 ± 5.115.50 ± 5.014.24 ± 4.918.42 ± 7.015.59 ± 6.819.47 ± 7.015.16 ± 5.719.52 ± 6.9P = 0.001713.50 ± 5.5*17.88 ± 7.4 *
Hostility8.49 ± 3.68.08 ± 2.47.21 ± 2.09.63 ± 4.68.19 ± 2.99.76 ± 3.48.13 ± 3.29.85 ± 3.5P = 0.00287.46 ± 1.88.78 ± 3.8
Somatic18.33 ± 5.619.58 ± 6.720.92 ± 6.525.32 ± 9.421.22 ± 6.924.76 ± 9.119.72 ± 8.125.21 ± 9.6P = 0.01717.14 ± 4.621.75 ± 9.5

At week 4, 12 and 24, patients treated with escitalopram had lower scores on the BDI total score, BDI-somatic items, SCL total score, SCL-depression, SCL-anxiety, SCL-insufficiency in thinking and acting and SCL-hostility (Table 3). No differences at week 4 and 12 were observed between the two groups on the item SCL-somatic complaints.

24 weeks post-anti-viral treatment

At 24 weeks post-treatment, the MADRS-, BDI- and SCL-90-sum scores and BAS-hostile feelings score all returned to baseline in patients treated with escitalopram. In contrast, among the placebo-treated patients, the BAS-hostile feelings score but not the MADRS-, BDI- and SCL-90-sums cores returned to baseline (Table 3).

Safety and tolerability

Three serious adverse events (SAE’s) were observed during the study period. A 35-year-old female developed a severe, persistent trombocytopenia; after cessation of all medication the trombocytopenia resolved. A 49-year-old male, with as risk factor smoking, developed bilateral pulmonary embolism. A 53-year-old female with recompensated liver cirrhosis had a new episode of decompensated liver disease with ascites. These SAE’s occurred all in the escitalopram group, but none was considered to be related to the use of escitalopram. No dose reductions of PEG-IFN or RBV were necessary due to psychopathology, also because of the possibility to break the study code and start open-label treatment with antidepressants.

The use of escitalopram had no influence on either haematological or biochemical parameters (liver enzymes).

Response to anti-viral treatment

The response to anti-viral treatment in the escitalopram and in the placebo group was similar. The respective SVRs forescitalopram and placebo were, 46% and 50% for genotype 1, 83% and 80% for genotype 2 and 73% and 86% for genotype 3 respectively. None of the five patients with genotype 4 reached SVR.

Concomitant use of benzodiazepines

The concomitant use of paracetamol and benzodiazepines was allowed. Before and after the start of anti-viral therapy, the use of benzodiazepines was similar among both groups. At baseline, three patients in the escitalopram-group and one patient in the placebo-group already used benzodiazepines. After anti-viral therapy was started, 10 additional patients in the escitalopram-group and 13 in the placebo-group had benzodiazepines prescribed.

Patient withdrawal and patients lost to follow-up during the study

Patient withdrawal was higher in the escitalopram-group (12 out of 40) than in the placebo-group (5 out of 39). The difference was not statistically significant (P = 0.1 Fisher’s exact test). There were several reasons for patient withdrawal: occurrence of side-effects (escitalopram three, placebo zero), viral nonresponse (escitalopram two, placebo two) and no obvious reason (escitalopram two, placebo zero). In two patients (one escitalopram, one placebo), data were not complete (administrative failure). Six patients were lost to follow-up (four escitalopram, two placebo).

Discussion

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

In this randomised double-blind placebo-controlled study, we demonstrated the efficacy of prophylactic escitalopram in the prevention of psychiatric side-effects during anti-viral therapy for chronic hepatitis C. When started concomitantly with PEG-IFN and RBV, escitalopram not only reduced the number of psychiatric events (increases to a clinically significant degree in depressed mood (reported sadness), anxiety (inner tension), concentration difficulties and in hostile feelings), but also the occurrence of a depressive syndrome. The study was designed such that the risk of premature discontinuation of anti-viral treatment was minimised. When judged clinically necessary by the treating physician, the study code was broken and the patient was started on open-label psychopharmacological treatment when indicated. Adherence to anti-viral therapy was considered more important than to address the question whether prophylactic escitalopram treatment itself would improve adherence and SVR. The concomitant use of escitalopram was safe and the SVR rates were similar in the two treatment groups. It is important to note that apart from observing a beneficial effect of escitalopram on three of the four pre-defined observer-based outcome measures (symptom level), and on depression (syndromal level), these findings were corroborated with the use of self-administered questionnaires.

In agreement with the literature,7, 21–23 a substantial percentage of patients treated with placebo developed clinically relevant psychiatric side-effects. Escitalopram had a beneficial effect on both the occurrence and the intensity of these side-effects, such that the incidence of psychiatric side-effects was approximately halved compared to placebo. During follow-up, no late adverse events related to escitalopram were observed; in contrary, although not being the aim of study, the beneficial effects of escitalopram seemed to be sustained 24 weeks after the end of anti-viral therapy.

Results from three small open-label studies on the prophylactic treatment with antidepressants suggest that SSRIs are capable of preventing depression during PEG-IFN-based treatment for HCV infection.24–26 In the first study, eight patients underwent successful anti-viral re-treatment with concomitant SSRI prophylaxis with lower depression scores compared to those during the initial PEG-IFN and RBV treatment.24 In the second study, 11 patients who were scheduled for IFN-based treatment and who were considered to have a clinical indication for antidepressant treatment, received SSRI prophylaxis. A comparison was made with 11 patients with a comparable psychiatric history and with 11 patients without such a history. In the prophylaxis group, less depression occurred.25 In the third study, 10 patients with a past history of but no current depression, were treated with escitalopram during anti-viral treatment. Depression could be prevented in 9 of 10 patients.26

By now, five randomised controlled trials on prophylaxis with SSRIs have been performed. In oncology patients treated with high-dose IFN, paroxetine successfully attenuated depression.27 However, no beneficial effect could be demonstrated in the four trials in HCV patients. The first HCV-trial enrolled only 33 patients and different formulations of anti-viral therapy were used.28 The second trial, performed by the same investigators but now using PEG-IFN-based therapy only, did also not show a beneficial effect of paroxetine over placebo. However, this study had to be concluded prematurely because of recruitment difficulties.29 The third study was also closed prematurely due to a slow inclusion and had a very high drop-out rate [29 out of 61 patients).30 The fourth study was the largest, studying the effects of 14 weeks escitalopram vs. placebo in 129 patients with hepatitis C treated with PEG-IFN plus RBV.31 In comparison with other studies, the occurrence of depression was low. No beneficial effect of escitalopram could be demonstrated. With the appropriate sample size and power and 24-week treatment duration, we could demonstrate a significant beneficial effect of prophylactic treatment with escitalopram. A strong point of this study is the fact that those separate individual items considered to represent the most important types of IFN-induced psychopathology (reported sadness (i.e. mood lowering), inner tension (i.e. anxiety), concentration difficulties and aggression) were used as primary outcomes instead of only total composite scores or the occurrence of a full-blown depression.32–35 The study design was practically oriented with the use of a fixed dose of escitalopram, the permitted use of psychotropic medication, such as methadone and benzodiazepines, the concomitant start of escitalopram and anti-viral therapy, and with demographic characteristics of the participating HCV patients fitting well into everyday practice of Western hospitals.

Although no official data is available, in Dutch clinical practice many HCV patients have a history of intravenous drug use and/or tattoo. For a comparison, US-veterans with HCV show an increased prevalence of psychiatric history and/or use of antidepressants,36 and a major part of these patients has been infected via intravenous drugs. But also HCV itself may induce psychopathological symptoms, suggested by a study showing increased presence of neuropsychiatric symptoms and impaired mood (depression and anxiety) in HCV patients without a background of drug abuse and with a stable social background.37 This might explain the high prevalence of a previous psychiatric history among our participating patients.

A weak point of the study might be the fact that patients with genotype 1 and 4 were treated for 48 weeks with peginterferon and RBV but received escitalopram or placebo for 26 weeks only. However, it is known that the occurrence of most psychiatric side-effects is within the first 24 weeks of anti-viral therapy and is relatively rare thereafter.9, 31, 38 One could also argue that as no lead in period with escitalopram was used, the SSRI might not have been fully active in the first weeks of anti-viral therapy; consequently, the effect of prophylactic SSRI treatment might have been even greater. In addition, one might argue that despite an adequate randomisation procedure, the placebo group displayed a greater vulnerability to the development of IFN-induced psychiatric disturbance, as shown by a tendency to have a history of more depressive episodes in the past and more admissions in psychiatric and addiction facilities. This might also explain why the scores of self-administered questionnaires did not return to baseline at 24 weeks post-treatment in the placebo-group.

In conclusion, the substantial reduction of psychiatric side-effects in combination with the safety of escitalopram, suggests that prophylactic escitalopram treatment could be considered in hepatitis C patients treated with PEG-IFN and RBV.

Acknowledgements

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

Declaration of personal interests: Robert J. de Knegt has served as a speaker and an advisory board member for Roche and Merck, and has received research funding from Roche and Merck. Arthur R. Van Gool has served as an advisory board member for Merck and Lundbeck. Harry L. A. Janssen has served as a speaker and an advisory board member for Roche, Novartis, Gilead, Merck and Bristol-Myers Squibb, and has received research funding from Roche, Merck, Gilead and Bristol-Myers Squibb. Declaration of funding interests: The sponsor of this study was the Rotterdam Foundation for Liver Research (SLO). Financial support was given by Roche Netherlands BV. The medication – escitalopram and placebo – were kindly delivered by Lundbeck Denmark. Data collection and data management at the trial coordinating centre was supported by Elke Verheij, Clinical Research Bureau, Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

References

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