Martin Schaefer, MD; Rahul Sarkar, MD; Viola Knop, MD; Susanne Effenberger, MSc; Astrid Friebe, MD; Loni Heinze, MD; Ulrich Spengler, MD; Thomas Schlaepfer, MD; Jens Reimer, MD; Peter Buggisch, MD; Johann Ockenga, MD; Ralph Link, MD; Michael Rentrop, MD; Hans Weidenbach, MD; Gwendolyn Fromm, MD; Klaus Lieb, MD; Thomas F. Baumert, MD; Andreas Heinz, MD; Thomas Discher, MD; Konrad Neumann, PhD; Stefan Zeuzem, MD; Thomas Berg, MD
Acknowledgment: The authors thank U. Meyer, C. Mayr, B. Möller, B. Hintsche, R. Heyne, C. John, A. Jessen (Berlin); H. Schmidt (Münster); B. Ruf (Leipzig); M. Leuschner, S. Planz-Kuhlendahl (Offenbach); H. Jablonowsky (Salzgitter); C. Weber, W. Tacke (Königsstein); C. Gelbmann (Regensburg); C. Folwaczny, R. Zachoval, E. Schulte-Frohlinde, F. Schmidt (München); and J. Pausch (Kassel) for their help with recruiting patients.
Grant Support: The trial was supported in part by Roche Pharma, Grenzach-Whylen, Germany; Lundbeck, Hamburg, Germany (placebo medication and financial support); and the German Network of Competence on Viral Hepatitis.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2214.
Reproducible Research Statement:Study protocol: Available from Dr. Schaefer (e-mail, email@example.com). Statistical code and data set: Not available.
Requests for Single Reprints: Martin Schaefer, MD, Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Henricistr. 92, 45136 Essen, Germany; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Schaefer: Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Henricistr. 92, 45136 Essen, Germany.
Dr. Sarkar: Department of Psychiatry and Psychotherapy, Asklepios Westklinikum Hamburg, Suurheid 20, 22559 Hamburg, Germany.
Drs. Knop and Zeuzem: Department of Internal Medicine I, Klinikum der J. W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Ms. Effenberger and Drs. Heinze and Heinz: Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, 10117 Berlin, Germany.
Dr. Friebe: Department of Psychiatry and Psychotherapy, Universitätsklinik Bochum Alexandrinenstraße 1, 44791 Bochum, Germany.
Dr. Spengler: Department of Internal Medicine, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
Dr. Schlaepfer: Department of Psychiatry and Psychotherapy, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
Dr. Reimer: Department of Psychiatry and Psychotherapy, Interdisziplinäre Suchtforschung der Universität Hamburg, Martinistraße 52, 20246 Hamburg, Germany.
Dr. Buggisch: Institute of Interdisciplinary Medicine, Asklepiosklinikum St. Georg, Lohmühlenstraße 5, 20099 Hamburg, Germany.
Dr. Ockenga: Department of Internal Medicine, Klinikum Bremen-Mitte, St.-Jürgen-Straße 1, 28205 Bremen, Germany.
Dr. Link: Department of Internal Medicine, St. Josefsklinik, Weingartenstr. 70, 77654 Offenburg, Germany.
Dr. Rentrop: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar Ismaningerstraße 22, 81675 München, Germany.
Dr. Weidenbach: Department of Internal Medicine, Klinikum Mittelbaden, Balger Straße 50, 76532 Baden-Baden, Germany.
Dr. Fromm: Department of Psychiatry and Psychotherapy, Justus Liebig Universität Gießen, Am Steg 22, 35385 Giessen, Germany.
Dr. Lieb: Department of Psychiatry and Psychotherapy, Klinikum der Johannes Gutenberg-Universität Mainz, Untere Zahlbacher Straße 8, 55131 Mainz, Germany.
Dr. Baumert: Department of Internal Medicine, Hugstetterstrasse 55, 79106 Freiburg, Germany.
Dr. Discher: Department of Internal Medicine II, Universitätsklinikum Gießen Marburg, 35392 Gießen, Germany.
Dr. Neumann: Institute for Biostatistics and Clinical Epidemiology, Charité–Universitätsmedizin Berlin, Charite Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.
Dr. Berg: Section of Hepatology, Clinic and Policlinic for Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Liebigstraße 20, 04103 Leipzig, Germany.
Author Contributions: Conception and design: M. Schaefer, T. Berg.
Analysis and interpretation of the data: M. Schaefer, R. Sarkar, V. Knop, S. Effenberger, A. Friebe, J. Ockenga, K. Lieb, A. Heinz, K. Neumann, S. Zeuzem, T. Berg.
Drafting of the article: M. Schaefer, V. Knop, S. Effenberger, A. Friebe, T.F. Baumert, A. Heinz, K. Neumann, T. Berg.
Critical revision of the article for important intellectual content: M. Schaefer, R. Sarkar, V. Knop, U. Spengler, T. Schlaepfer, J. Reimer, K. Lieb, T.F. Baumert, A. Heinz, S. Zeuzem, T. Berg.
Final approval of the article: M. Schaefer, V. Knop, U. Spengler, T. Schlaepfer, P. Buggisch, J. Ockenga, R. Link, M. Rentrop, G. Fromm, K. Lieb, T.F. Baumert, A. Heinz, S. Zeuzem, T. Berg.
Provision of study materials or patients: M. Schaefer, V. Knop, T. Schlaepfer, J. Reimer, P. Buggisch, J. Ockenga, R. Link, H. Weidenbach, G. Fromm, K. Lieb, T.F. Baumert, S. Zeuzem, T. Berg.
Statistical expertise: M. Schaefer, V. Knop, S. Effenberger, K. Neumann, T. Berg.
Obtaining of funding: M. Schaefer, T. Berg.
Administrative, technical, or logistic support: M. Schaefer, R. Sarkar, V. Knop, S. Effenberger, L. Heinze, T.F. Baumert, A. Heinz, T. Berg.
Collection and assembly of data: M. Schaefer, R. Sarkar, V. Knop, S. Effenberger, A. Friebe, L. Heinze, U. Spengler, T. Schlaepfer, J. Reimer, P. Buggisch, J. Ockenga, R. Link, M. Rentrop, H. Weidenbach, G. Fromm, K. Lieb, T.F. Baumert, S. Zeuzem, T. Berg.
Schaefer M, Sarkar R, Knop V, Effenberger S, Friebe A, Heinze L, et al. Escitalopram for the Prevention of Peginterferon-α2a–Associated Depression in Hepatitis C Virus–Infected Patients Without Previous Psychiatric Disease: A Randomized Trial. Ann Intern Med. 2012;157:94-103. doi: 10.7326/0003-4819-157-2-201207170-00006
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Published: Ann Intern Med. 2012;157(2):94-103.
Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors.
To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders.
Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318)
10 university and 11 academic hospitals in Germany.
181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008.
Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy.
The primary end point was the incidence of depression, defined as a Montgomery–Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety.
32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21).
Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started.
Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease.
Roche Pharma and Lundbeck.
Depression is a common adverse effect of interferon-α (IFN-α) treatment for chronic hepatitis C virus infection. Whether escitalopram can prevent depression among patients without a history of psychiatric disease who require IFN-α treatment is uncertain.
Compared with placebo, continuous treatment with escitalopram starting 2 weeks before and during IFN-α therapy decreased the number of patients who had depression.
Patients with a history of psychiatric disease were not studied.
Escitalopram may be useful for the prevention of depression when IFN-α treatment is required for chronic hepatitis C virus infection.
Study flow diagram.
Most patients who discontinued treatment early withdrew for reasons associated with the antiviral therapy (e.g., nonresponse). HCV = hepatitis C virus; PEG-IFN-α2a = pegylated interferon-α2a.
* During the 2-wk pretreatment period, antiviral therapy was not yet started.
† This patient died of causes unrelated to the study.
Pretreatment Demographic and Clinical Characteristics
Cumulative Kaplan–Meier estimates of the time to first episode of depression during antiviral treatment.
More patients in the escitalopram pretreatment group remained depression-free (defined as a MADRS score ≥13) than those in the placebo group (hazard ratio, 0.43 [95% CI, 0.26 to 0.70]; log-rank test P < 0.001). MADRS = Montgomery–Asberg Depression Rating Scale.
Montgomery–Asberg Depression Rating Scale scores during hepatitis C virus therapy.
Significant group differences were seen at weeks 12 (P = 0.004), 24 (P = 0.002), and 48 (P = 0.001, genotypes 1 and 4).
* Only genotypes 1 and 4.
General health status assessed by using the SF-36.
For all subscales except for “health change,” a high score indicates a better state of health (0 = worst possible health state; 100 = best possible health state). For “health change,” lower scores indicate fewer negative health changes. Significant group differences during the first 24 wk of the trial were seen for the mental health summary score (P = 0.002) and within the domains of general health perception (P = 0.037), social functioning (P = 0.035), and mental health (P < 0.001). At 48 wk, additional group differences were found in patients with genotype 1 or 4 for general health perception (P = 0.047), mental health (P = 0.003), health change (P = 0.003), role limitations due to emotional problems (P = 0.003), social functioning (P = 0.025), and mental summary score (P = 0.003). SF-36 = Short Form-36.
Safety Data for Escitalopram and Placebo
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Gijs W. D. Landman, MD
Diabetes cCntre, Isala Clinics, Zwolle
August 8, 2012
Primary Outcome Measure Needed
Schaefer et al. performed an industry sponsored trial investigating whether preemptive antidepressive medication could potentially decrease the incidence of moderate to severe depressions in patients treated with a pegylated IFN-a containing regimen in HCV infected patients without a history of depressive symptoms . They found a significant reduction in both moderate and severe depression in the escitalopram group. The incidence of depressive disorders was measured using the MADRS score with a cutoff value of 13 for moderate depressions.
With regard to the definition of a depressive disorder I have 2 concerns. Firstly, the original study protocol (available at clinicaltrials.gov) clearly states that the primary end-point, the incidence of moderate to severe depressions, was originally planned to be evaluated with the Hamilton Depression Rating Scale at week 24 after starting interferon. Secondly, the authors used a cutoff value of 13 for diagnosing moderate depression and 25 for severe depression. However, the cutoff value of 13 is used for defining remission after depression . Cut-off values of 19 and 32 are considered standard for diagnosing moderate and severe depression [3,4]. Using these lower cutoff values is not in accordance with previous studies and could lead to considerable over diagnosing of depressions and could possibly lead to inflation of effect of escitalopram.
To avoid the suggestion of a potential conflict, could the authors provide the primary outcome measured according to the incidence of depressions after 24 weeks of treatment in both the treatment and placebo group according to the Hamilton Depression Scale and also using the MADRS cutoff values of 19 and 32.
1.Schaefer M, Sarkar R, Knop V, Effenberger S, Friebe A, Heinze L, at al. Escitalopram for the Prevention of Peginterferon-α2a-Associated Depression in Hepatitis C Virus-Infected Patients Without Previous Psychiatric Disease: A Randomized Trial. Ann Intern Med. 2012;157:94-103
2.Zimmerman M, Posternak MA, Chelminski I. Implications of using different cut-offs on symptom severity scales to define remission from depression. Int Clin Psychopharmacol. 2004;19:215-20
3.Müller MJ, Himmerich H, Kienzle B, Szegedi A Differentiating moderate and severe depression using the Montgomery-Asberg depression rating scale (MADRS). J Affect Disord. 2003;77:255-60
4.Einarson TR. Evidence based review of escitalopram in treating major depressive disorder in primary care. Int Clin Psychopharmacol. 2004;19:305-10
Martin Schaefer 1,2, Susanne Sarkar 2, Thomas Berg 3
1. Dept of Psychiatry, Psychotherapy and Addiction Medicine, Essen, Germany, Dept of Psychiatry and Psychotherapy. 2. Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, G
September 21, 2012
In his letter Dr. Landmann raises two queries concerning our use of the MADRS depression scale with a cutoff value of 13 for a moderate depression and also asks why the Hamilton Depressing Rating Scale (HAMD) was not further evaluated by us as initially planned. He suggests to present results using the HAMD scale as well as MADRS cut-off values of 19 and 32.
Here we can show that in our study neither the used depression scale nor the definition of the cut-off score had any influence on group differences regarding the effect of antidepressant pre-treatment on the incidence of depression. Fewer patients suffered from depression in the escitalopram group compared to the placebo group with a MADRS cut-off of ≥19 [7.8% (N=7) vs. 24.2% (n=22), Chi square =9.043, df=1, p=0.003] or a MADRS cut-off of ≥32 [1.1% (N=1) vs. 5.5% (N=5), Chi square =2.0713, df=1, p=0.10]. By choosing the HAMD with a cut-off score of 18 (1), escitalopram pre-treatment significantly reduced the incidence of depression until week 24 of IFN-α therapy [9.2% (N=7) vs. 1.3% (n=1), Chi square =4.832, df=1, p=0.028]. A HAMD score ≥10 (a cut-off comparable to MADRS ≥13) was found in 27.8% (N=25) of patients treated with escitalopram and 48.4% (n=44) with placebo [Chi square =8.119, df=1, p=0.004]. Similar to other groups we finally decided to use the MADRS scale for primary evaluation of IFN-associated depressive mood changes (2;3), because the HAMD scale was considered to include too many items concerning sleep disturbance and somatic problems, which are common side effects of IFN-α treatment but not specific to depressive syndromes (protocol available from the authors). We did not choose a moderate to high MADRS score as primary endpoint because this score may underrepresent patients suffering from mild to moderate depressive mood changes. While only a MADRS scores ≤4 indicate a mood state without depressive symptoms, it has been shown that patients with a MADRS score ≥13 might fulfill the diagnostic criteria for a major depression, which was therefore defined as cut-off for a clinically relevant depression in our trial (4;5).
Finally we wish to point out that our trial was an investigator sponsored trial supported only in part by industry, which had no influence on our data management or publication strategy.
(1) Morasco BJ, Rifai MA, Loftis JM, Indest DW, Moles JK, Hauser P. A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C. J Affect Disord. 2007;103:83-90.
(2) de Knegt RJ, Bezemer G, Van Gool AR, Drenth JP, Hansen BE, Droogleever Fortuyn HA et al. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C. Aliment Pharmacol Ther. 2011;34:1306-17.
(3) Diez-Quevedo C, Masnou H, Planas R, Castellvi P, Gimenez D, Morillas RM et al. Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72:522-28.
(4) Zimmerman M, Chelminski I, Posternak M. A review of studies of the Montgomery-Asberg Depression Rating Scale in controls: implications for the definition of remission in treatment studies of depression. Int Clin Psychopharmacol. 2004;19:1-7.
(5) Riedel M, Moller HJ, Obermeier M, Schennach-Wolff R, Bauer M, Adli M et al. Response and remission criteria in major depression--a validation of current practice. J Psychiatr Res. 2010;44:1063-68.
Martin Schaefer, MD, 1,2, Susanne Sarkar, MD,2, Thomas Berg, MD3
1:Dept of Psych/Psychother & Addiction Med, Kliniken Essen-Mitte, Germany. 2: Dept of Psych/Psychother, Charité–Univ Berlin.3:Div of Hepat, Clinic/Policlinic for Gastro/Rheum, Leipzig
November 20, 2012
Based on the comments of Dr. Landman, we noticed, that our primary entry in the database clinicaltrial.gov was not updated with details of the final protocol and indeed included a mistake: The Hamilton depression scale (HAM-D) was listed as the instrument for the primary outcome measurement instead of the MADRS-scale. This has been communicated to the ClinicalTrials.gov registry so that a correction can be posted. Nevertheless, we have to emphasize that the MADRS-scale and not the HAM-D was defined as primary outcome before any patient was included in our final study protocol, which was approved by the responsible ethic committee of the Charité Berlin and by the local ethic committees of the participating centers.
In order to demonstrate that the results in our trial are robust and independent from the finally chosen depression scale, we calculated a group comparison as in our original paper with the HAM-D scale (cut-offs ≥10 for mild to moderate and ≥18 for moderate to severe depression) using multiple imputations for missing data. Overall, 33% (95% CI, 23% to 45%) of the patients in the escitalopram group developed a HAM-D score of ≥10 compared with 54% (95% CI, 43% to 64%) in the placebo group (absolute difference, 20 % points [95% CI, 5 to 35 % points]; p=0.012). 6% (95% CI, 2% to 13%) of the patients in the escitalopram group developed a HAM-D score of ≥ 18 compared with 24% (95% CI, 16% to 34%) in the placebo group (absolute difference, 18% points [95% CI, 7% to 28% points]; p=0.003). Longitudinal analysis of continuous HAM-D scores using a mixed-effects repeated measurement model confirmed lower mean HAM-D scores in the escitalopram group at week 4 (estimated means 4.7 [95% CI, 3.6 to 5.9] vs. 6.3 [95% CI, 5.2 to 7.5], P=0.010), week 12 (estimated means 5.6 [95% CI, 4.3 to 6.9] vs. 7.8 [95% CI, 6.5 to 9.1]; p < 0.001), week 24 (estimated means 5.3 [95% CI, 3.8 to 6.7] vs. 8.6 [95% CI, 7.2 to 10.1]; p = 0.032), and week 48 (estimated means 4.4 [95% CI, 2.7 to 6.2] vs. 7.8 [95% CI, 6.0 to 9.5]; p=0.004) of antiviral treatment if compared to controls (P=0.001 for group difference all weeks combined).
Finally in our trial group differences are also independent from the MARDS cut-off score. Fewer patients suffered from depression in the escitalopram group compared to the placebo group with a MADRS cut-off of ≥19 (estimated means 11% [95% CI, 6 to 21] vs. 28% [95% CI, 20 to 39]; p=0.018) or a MADRS cut-off of ≥32 (estimated means 1% [95% CI, 0 to 8] vs. 6% [95% CI, 3 to 14]; p=0.13).
In conclusion, escitalopram pre-treatment significantly reduced incidence and severity of depression evaluated with the HAM-D or MADRS scales independent from the chosen cut-off score. Both the MADRS and the HAM-D scale are equally effective to monitor depressive mood changes during interferon treatment in patients with hepatitis C.
1 Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
2 Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
3 Division of Hepatology, Clinic and Policlinic for Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Germany
Gastroenterology/Hepatology, Infectious Disease, Viral Hepatitis.
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