Hepatitis C virus (HCV) infection is the most frequent. Original Research

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1 Original Research Annals of Internal Medicine Escitalopram for the Prevention of Peginterferon- 2a Associated Depression in Hepatitis C Virus Infected Patients Without Previous Psychiatric Disease A Randomized Trial 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; and Thomas Berg, MD Background: Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon- (IFN- ). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. Objective: To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN- in HCV-infected patients without a history of psychiatric disorders. Design: Randomized, multicenter, double-blind, prospective, placebocontrolled, parallel-group trial. (ClinicalTrials.gov registration number: NCT ) Setting: 10 university and 11 academic hospitals in Germany. Patients: 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December Intervention: Escitalopram, 10 mg/d (n ), or placebo (n 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. Measurements: 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. Results: 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). Limitations: 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. Conclusion: Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFNassociated depression in HCV-infected patients without previous psychiatric disease. Primary Funding Source: Roche Pharma and Lundbeck. Ann Intern Med. 2012;157: For author affiliations, see end of text. Hepatitis C virus (HCV) infection is the most frequent cause of chronic hepatitis and an important risk factor for cirrhosis and hepatocellular carcinoma. The standard treatment for chronic HCV infection is pegylated interferon- (PEG-IFN- ) combined with antivirals (1). Interferon- is used to treat several other chronic inflammatory or malignant disorders, such as hepatitis B virus infection, melanoma, hairy cell leukemia, and chronic myelogenous leukemia. However, psychiatric adverse effects, such as depression, fatigue, and insomnia, have been frequently observed during this therapy (2). See also: Print Summary for Patients....I- Up to % of HCV-infected patients treated with IFN- have been reported to have mild to moderate depressive syndromes (3 5), and 20% to % have major depression (5). Interferon-associated depression has a strong negative effect on quality of life and treatment adherence and is a risk factor for treatment failure (5 7). Suicide attempts represent the worst possible complication of IFN-induced depression (8). Preventing onset of depressive symptoms in patients is therefore an important goal. Recent trials addressing the prophylactic use of selective serotonin reuptake inhibitors (SSRIs) in HCV-infected patients have been limited by small sample sizes, and the contradictory results do not allow for substantial conclusions about daily clinical practice (4, 9 15). Although data support the view that prophylactic antidepressant treatment might decrease the incidence of depression in patients with comorbid psychiatric disorders, whether antidepressants should also be given to patients without previous American College of Physicians

2 Escitalopram for the Prevention of IFN- Induced Depression Original Research psychiatric disease remains unclear. We therefore designed a multicenter study to evaluate whether the antidepressant escitalopram can decrease the incidence or severity of IFNassociated depression in treatment-naive HCV-infected patients without a history of psychiatric disorders. METHODS Settings and Participants Patients were screened in the departments of hepatology of 10 university and 11 academic hospitals in different areas of Germany. Treatment-naive patients older than 18 years with chronic HCV infection and serum HCV RNA levels of 0 IU/mL or higher were eligible for the study. Psychiatric exclusion criteria were a lifetime diagnosis of an affective disorder; drug abuse in the past 12 months; treatment with antidepressants during the past 3 years; or a history of any other axis I disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (16). Medical exclusion criteria were pretreatment with IFN or immunotherapy, other chronic infection, or an autoimmune or severe somatic comorbid condition. The study protocol was approved by the ethics committee of Berlin and confirmed by local ethics committees. The study was conducted in accordance with the principles of the Declaration of Helsinki and local laws and regulations. All participants provided written informed consent. Randomization and Interventions This trial was a multicenter, double-blind, prospective, randomized, placebo-controlled, parallel-group, phase 3 study consisting of preobservation, treatment, and follow-up periods. An independent pharmacist at Charité Berlin was responsible for central block randomization by fax and dispensation of the study medication. Patients were stratified according to age, sex, and genotype. The escitalopram and placebo tablets (Lundbeck, Hamburg, Germany) were identical in appearance. Study personnel and participants were blinded to group assignment. In the preobservation period, patients were monitored for spontaneously developing symptoms of depression not related to antiviral therapy for 12 weeks before starting antidepressant therapy. After the preobservation period, patients received escitalopram, 10 mg/d (n ), or placebo (n 91) (Figure 1). After 2 weeks of antidepressant pretreatment, all patients began receiving antiviral therapy with PEG-IFN- 2a plus ribavirin (Roche, Grenzach-Wyhlen, Germany) with continuous concomitant administration of escitalopram or placebo. Patients with HCV genotype 1 or 4 received treatment for 48 weeks with PEG-IFN- 2a, 1 mcg weekly, and ribavirin, 0 mg/d (body weight, 75 kg) or 1200 mg/d (body weight, 75 kg). Patients with genotype 2 or 3 received PEG-IFN- 2a, 1 mcg weekly, and ribavirin, 0 mg/d, for 24 weeks. Antidepressant treatment was stopped at the end of antiviral therapy. Context Depression is a common adverse effect of interferon- (IFN- ) treatment for chronic hepatitis C virus infection. Whether escitalopram can prevent depression among patients without a history of psychiatric disease who require IFN- treatment is uncertain. Contribution Compared with placebo, continuous treatment with escitalopram starting 2 weeks before and during IFN- therapy decreased the number of patients who had depression. Caution Patients with a history of psychiatric disease were not studied. Implication Escitalopram may be useful for the prevention of depression when IFN- treatment is required for chronic hepatitis C virus infection. The Editors Psychiatric changes, adverse events, laboratory values, dose adjustments of the antiviral therapy, and possible pharmacologic adverse effects were systematically monitored throughout the study. Hepatitis C virus RNA levels were assessed at weeks 4, 12, and 24 and at week 48 in patients with HCV genotypes 1 and 4, as well as at the end of follow-up (that is, at week 48 in patients with HCV genotype 2 and 3 or at week 72 in patients with HCV genotype 1 and 4) to evaluate sustained virologic response. Serum HCV RNA levels were measured by using the High Pure System COBAS TaqMan HCV Monitor Test (Roche). Doses of ribavirin and PEG-IFN-2 were adjusted as needed. Adherence was assessed at each clinic visit by pill count. In cases of major depression, an experienced psychiatrist decided whether patients should receive open-label mirtazapine, to mg/d, as rescue medication in addition to the study medication (escitalopram or placebo), to which the patients remained blinded. Benzodiazepines were not allowed during the trial. Psychiatric Assessments and End Points Escitalopram or placebo pretreatment was started 2 weeks before antiviral therapy. Psychiatric assessments were performed 14, 8, and 2 weeks before antiviral therapy was started (that is, during the preobservation period), as well as after 2; 4; 12; 24; and, for patients with genotypes 1 and 4, 48 weeks of antiviral therapy (that is, during the treatment period) and 24 weeks after antiviral treatment (that is, during the follow-up period). In each participating center, 1 experienced psychiatrist performed the screening examination and psychiatric study visits. The Mini-International Neuropsychiatric Interview was used as systematic psychiatric screening to detect preexisting psychiatric disorders (17). The Structured Clinical 17 July 2012 Annals of Internal Medicine Volume 157 Number 2 95

3 Original Research Escitalopram for the Prevention of IFN- Induced Depression Figure 1. Study flow diagram. Patients assessed for eligibility (n = 0) Patients randomly assigned (n = 208) Excluded (n = 92) Did not meet inclusion criteria: 82 Declined to participate: 10 Psychiatric Preobservation Period Allocated to escitalopram (n = 108) Reasons for discontinuation Somatic complications: 1 Psychiatric reasons: 1 Declined participation: 7 Died: 1 Personal reasons: 8 Allocated to placebo (n = ) Reasons for discontinuation Somatic complications: 1 Psychiatric reasons: 1 Declined participation: 4 Personal reasons: 3 Antidepressant or Placebo Pretreatment* Received escitalopram (n = ) Plus PEG-IFN-α2a plus ribavirin Genotype 1: 54 Genotype 2: 9 Genotype 3: 19 Genotype 4: 8 Received placebo (n = 91) Plus PEG-IFN-α2a plus ribavirin Genotype 1: 59 Genotype 2: 5 Genotype 3: 21 Genotype 4: 6 Follow-up Intervention Plus Antiviral Treatment (n = 181) Therapy completed (n = 83) Reasons for early discontinuation HCV treatment failure: 12 Severe adverse events: 5 Nonadherence: 2 Lost to follow-up (n = 5) Therapy completed (n = 84) Reasons for early discontinuation HCV treatment failure: 17 Severe adverse events: 5 Other reasons: 2 Lost to follow-up (n = 4) Follow-up completed (n = 78) Follow-up completed (n = ) Included in the efficacy analysis: Included in the safety analysis: Included in the efficacy analysis: 91 Included in the safety analysis: 91 Most patients who discontinued treatment early withdrew for reasons associated with the antiviral therapy (e.g., nonresponse). HCV hepatitis C virus; PEG-IFN- 2a pegylated interferon- 2a. * During the 2-wk pretreatment period, antiviral therapy was not yet started. This patient died of causes unrelated to the study July 2012 Annals of Internal Medicine Volume 157 Number 2

4 Escitalopram for the Prevention of IFN- Induced Depression Original Research Interview for DSM-IV Disorders was used to verify major depression before and during treatment (18). Although depression severity is an important characteristic of major depression, data are lacking about the validity of the DSM-IV definition of the severity of major depression (19). Thus, the severity of depressive symptoms was evaluated by using the interviewer-based Montgomery Asberg Depression Rating Scale (MADRS), which consists of 10 items (score range per item, 0 to 6) (20). The primary response criterion of depression was having a MADRS score of 13 or higher, and severe depression was defined as having a MADRS score of 25 or higher (20, 21). Health-related quality of life (HRQOL) was evaluated by using the Short Form-36. This short questionnaire consists of 36 items that measure 8 multi-item variables (physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, vitality, pain, and general health perception) and 2 summary scores for mental and physical health (22). For all subscales except health changes, a high score indicates a better state of health (0 worst possible health state; best possible health state). For health changes, lower scores indicate fewer negative health changes. Outcomes The primary end point was the incidence of depression, defined as a MADRS score of 13 or higher during antiviral therapy (up to 48 weeks, depending on genotype). Although no specific MADRS cutoff score exists to define major depression, evidence shows that patients with a MADRS score less than 12 did not have major depressive episodes and that a mean MADRS score of 13 (range, 10 to 16) was associated with mild to moderate depression according to the global clinical impression scale (21, 23). Thus, by choosing the MADRS cutoff of 13 or higher, we aimed to capture all patients with a clinically relevant depressive syndrome. Secondary end points were time to depression defined as a MADRS score of 13 or higher, incidence of major depression defined by DSM-IV criteria, severe depression defined as a MADRS score of 25 or higher, HRQOL, sustained virologic response, tolerability, and safety. Statistical Analysis Different trials using psychiatric rating scales showed a prevalence of depression during IFN treatment between % and % (5). On the basis of the assumption that the incidence of depression defined as a MADRS score of 13 or higher in the placebo group is % or more, a sample of 182 patients was needed for a statistical power of % to determine whether there was at least an absolute 20% lower rate of depression in the escitalopram group than in the placebo group (2-sided value, 0.05). The final analysis included only patients who received at least 1 dose of escitalopram or placebo. Between-group differences for the secondary outcome parameters (major depression, severe depression, sustained virologic response, and adverse events) were calculated with a chi-square test. Kaplan Meier survival analysis by using the Mantel Cox log-rank test was performed for group comparison of time to depression. For the primary end point (maximal MADRS score 13), we treated missing MADRS assessments by multiple imputation. We generated m 10 imputed samples by a linear model using all MADRS assessments, age, and body mass index (BMI). For each patient and sample, the maximum MADRS score was subsequently computed and dichotomized at a MADRS score of 13. For all imputed samples, differences between treatment groups were tested by a logistic model with the sole factor group. Combined point estimates and the covariance matrix of the model parameters were subsequently calculated by the Rubin rule. Finally, the combined P value, depression rates in both groups, and the difference of depression rates with 95% CIs were calculated by the delta method. The multiple imputation samples were generated by using SPSS, version (IBM SPSS, Chicago, Illinois). Patients without HCV RNA measurements at follow-up were considered nonresponders to antiviral treatment. Patients with missing data on major depressive disorder were categorized as nondepressed. A mixed-effects repeated measurement model was used to analyze group differences according to repeated measurements of depression severity (MADRS scores during antiviral treatment) and HRQOL (Short Form-36 scores). Mixed-effects repeated measurement is well-recognized in psychopharmacologic trials and has been shown to be more robust to biases from missing data compared with the last-observation-carried-forward method (24 27). Baseline covariates, such as sex, age and MADRS score (both dichotomized), HCV genotype (1 and 4 vs. 2 and 3), BMI, study site, and group-by-time interaction terms were included as fixed independent variables. The time variable was treated as a categorical variable with 3 (genotypes 2 and 3) and 4 (genotypes 1 and 4) levels. To allow for correlations of measurements from the same patient over time, an unstructured covariance matrix was specified within the SAS procedure MIXED (SAS Institute, Cary, North Carolina). Group-by-time contrasts were tested within the mixed-effects repeated measurement models, and P values were subjected to a Holm Bonferroni procedure for multiple testing. We used multiple logistic regression analysis to calculate odds ratios of the incidence of MADRS scores of 13 or higher between the 2 groups adjusted for sex, age, BMI, genotype (1 and 4 vs. 2 and 3), baseline MADRS score (median split at 1.42), and study site (4 major sites; all other small sites were combined in 1 category). Mean MADRS scores of the groups 6 months after treatment were compared by t test. The number needed to treat for benefit was calculated as the reciprocal of the between July 2012 Annals of Internal Medicine Volume 157 Number 2 97

5 Original Research Escitalopram for the Prevention of IFN- Induced Depression group risk difference, and the upper and lower 95% CIs were found by inverting the CIs for the risk difference. All tests and CIs were 2-sided, and the level of significance was an level of Statistical analyses were performed by using SAS 9.2; R, version (R Foundation for Statistical Computing, Vienna, Austria); and SPSS Statistics, version Role of the Funding Source This work was supported in part by Roche Pharma and Lundbeck. Lundbeck offered medication (escitalopram) and identical placebo pills. Roche was involved in part in the development of the study design by giving statistical support, including the preobservation period, and also gave support in organizing prestudy meetings and data presentation as posters on international scientific meetings. The funding source had no influence on any other aspects of the trial, including data collection, manuscript preparation, and the decision to submit the manuscript for publication. RESULTS A total of 208 of the 0 patients screened were enrolled between August 2004 and September Eightytwo patients did not meet the inclusion criteria. Twentyseven patients left the trial during the preobservation period after randomization but before starting antidepressant and antiviral therapy because of newly diagnosed somatic or psychiatric disorders or unexpected personal or job-related reasons (Figure 1). There were no apparent systematic differences in baseline characteristics between patients who withdrew before antiviral treatment and those who remained in the study. Baseline data of the remaining patients did not differ between the study groups (Table 1). During the preobservation period, 3 of the patients in the placebo group and 2 in the escitalopram group developed MADRS scores greater than 10. One patient in the placebo group had a transiently increased MADRS score of 16, but this had decreased to a score of 8 by the time antidepressant therapy was started. No patient had a MADRS score of 13 or higher. Depression According to a MADRS Score >13 On the basis of an analysis using multiple imputation to account for missing data, 32% (n 25 [CI, 21% to 43%]) of the escitalopram group and 59% (n 49 [CI, 48% to 69%]) of the placebo group developed MADRS scores of 13 or higher during antiviral therapy (absolute risk difference, 27 percentage points [CI, 12 to 42 percentage points]; number needed to treat, 3.7 [CI, 2.4 to 8.5]; P 0.001). Kaplan Meier curves for the cumulative incidence of depression defined as a MADRS score of 13 or higher differed by group (P 0.001) (Figure 2). In multivariable logistic regression analysis that accounted for escitalopram treatment, IFN-associated depression (MADRS score 13) was associated with female sex (P 0.027) and baseline MADRS score (P 0.001), Table 1. Pretreatment Demographic and Clinical Characteristics* Characteristic Placebo Group (n 91) Placebo Group, Withdrew During Preobservation Period (n 9) Escitalopram Group (n ) Escitalopram Group, Withdrew During Preobservation Period (n 18) Male sex, n (%) 48 (53) 4 (44) 48 (54) 7 (39) Age Mean (SD), y 48.5 (11) 43.9 (13) 46.2 (11) 48.1 (13) Range, y y, n (%) 22 (24) 3 (33) 25 (28) 6 (33) White ethnicity, n (%) (88) 6 (67) 81 () 13 (72) BMI Mean (SD), kg/m (8) 25.4 (4) 24.8 (3) 27.8 (6) Range, kg/m kg/m 2, n (%) 17 (19) 2 (22) 17 (19) 3 (17) kg/m 2, n (%) 9 (10) 0 (0) 8 (9) 3 (17) Mean HCV RNA, (SD), IU/mL (0.6) 5.6 (0.5) 5.6 (0.8) 5.6 (0.5) HCV viral load IU/mL, n (%) 26 (28) 1 (11) 20 (22) 2 (11) Genotype, n (%) 1 59 (65) 5 (56) 54 () 8 (44) 2 5 (5) 1 (11) 9 (10) 3 (17) 3 21 (23) 1 (11) 19 (21) 5 (28) 4 6 (7) 2 (22) 8 (9) 2 (11) MADRS score Mean (SD) 2.7 (3.9) 1.5 (2.3) 2.1 (2.6) 2.5 (2.7) Median Range BMI mass index; HCV hepatitis C virus; MADRS Montgomery Asberg Depression Rating Scale. * Data from randomization 12 wk before antidepressant treatment was started. Data are the mean scores of 3 measurements during the 12-wk preobservation period before antidepressant treatment was started. Six weeks after randomization, 1 patient in the placebo group developed a MADRS score of 16; however, this score had decreased to 8 by the time antidepressant therapy was started July 2012 Annals of Internal Medicine Volume 157 Number 2

6 Escitalopram for the Prevention of IFN- Induced Depression Original Research Figure 2. Cumulative Kaplan Meier estimates of the time to first episode of depression during antiviral treatment. Proportion of Patients Free of Depression (MADRS Score 13) 20 Escitalopram Placebo to Incidence of Any Depression (MADRS Score 13) Escitalopram, n Placebo, n 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.]; log-rank test P 0.001). MADRS Montgomery Asberg Depression Rating Scale. whereas no association was seen for BMI (P 0.055), genotype (P 0.24), age (P 0.195), and study site (P 0.28). Under a sensitivity analysis where patients with missing data were assumed not to have a MADRS score of 13 or higher, 28% of the escitalopram group versus 54% of the placebo group developed a MADRS score of 13 or higher (absolute risk difference, 26 percentage points [CI, 16 to 36 percentage points]; P 0.001). Incidence of Major Depression and Severe Depression The incidence of major depression as defined by the DSM-IV and diagnosed by an experienced psychiatrist was 8% (n 7 [CI, 4% to 15%]) in the escitalopram group and 19% (n 17 [CI, 12% to 28%]) in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P 0.031). Severe depression defined as a MADRS score of 25 or higher was found in 1% of the escitalopram group (n 1 [CI, 0.3% to 6%]) compared with 12% of the placebo group (n 11 [CI, 7% to 21%]). Course and Risk Factors for Depressive Symptoms Montgomery Asberg Depression Rating Scale scores increased during IFN treatment (weeks 4, 12, and 24) compared with the preobservation period in the escitalopram and placebo groups. Overall, patients in the escitalopram group had lower mean MADRS scores at week 12 (mean difference, 2.8 [CI, 0.9 to 4.7]; P 0.004), week 24 (mean difference, 3.1 [CI, 1.1 to 5.1]; P 0.002), and week 48 (mean difference, 5.2 [CI, 2.1 to 8.4]; P 0.001) of antiviral treatment (Figure 3). The treatment effect did not vary by week of antiviral therapy (P 0.154). Mean MADRS scores 6 months after treatment returned to normal and did not differ between the placebo group (MADRS score, 4.0 [CI, 2.8 to 5.2]) and the escitalopram group (MADRS score, 2.6 [CI, 1.6 to 3.6]; P 0.081) and if compared with baseline scores. Health-Related Quality of Life During the first 24 weeks of the trial, escitalopram therapy resulted in overall better mental health summary scores, as well as scores within the domains of general health perception, social functioning, and mental health, compared with placebo (Figure 4). No overall differences were seen in the physical health summary score or in the other Short Form-36 HRQOL domains. In addition to the differences during the first 24 weeks, patients with genotype 1 or 4 who received antidepressant pretreatment had better scores for general health perception, mental health, role limitations due to emotional problems, social functioning, health change, and mental summary score after 48 weeks of antiviral therapy. Sustained Virologic Response Sustained virologic response was achieved in 42 patients (46% [CI, 37% to 57%]) in the placebo group (genotypes 1 or 4, 35% [CI, 25% to 48%]; genotypes 2 or 3, 86% [CI, 72% to 96%]) and in patients (56% [CI, 46% to 66%]) in the escitalopram group (genotype 1 or 4, 42% [CI, 31% to 55%]; genotype 2 or 3, 73% [CI, 56% to 88%]; P 0.21). Safety and Tolerability Three patients (3% [CI, 1.2% to 9.4%]) in the escitalopram group and 16 (18% [CI, 11% to 27%]) in the placebo group received mirtazapine as a rescue medication (P 0.004). No suicidal syndromes or suicide attempts were reported. Seventy-eight out of patients in the escitalopram group (87%) and out of 91 patients in the placebo group (88%) finished antiviral therapy according to protocol. Figure 3. Montgomery Asberg Depression Rating Scale scores during hepatitis C virus therapy. Estimated Mean MADRS Placebo Escitalopram Escitalopram, n Placebo, n 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 July 2012 Annals of Internal Medicine Volume 157 Number 2 99

7 Original Research Escitalopram for the Prevention of IFN- Induced Depression Figure 4. General health status assessed by using the SF-36. A. SF-36 Physical Functioning B. SF-36 Role Limitations due to Physical Problems C. SF-36 Bodily Pain D. SF-36 General Health Perception E. SF-36 Vitality F. SF-36 Social Functioning G. SF-36 Mental Health H. SF-36 Role Limitations due to Emotional Problems I. SF-36 Health Change J. SF-36 Physical Health Summary Score K. SF-36 Mental Summary Score Placebo Escitalopram For all subscales except for health change, a high score indicates a better state of health (0 worst possible health state; 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. * Only genotypes 1 and 4. The number of patients who discontinued treatment early did not differ between the groups. Ten patients (6%) discontinued treatment early because of severe adverse events: 5 (6%) in the placebo group and 5 (6%) in the escitalopram group (P 0.99). In 5 out of 10 patients, psychiatric events were responsible for treatment failure. Three patients in the placebo group had severe depression, and 2 patients in the escitalopram group reported drug abuse or self-harming behavior. Five patients were withdrawn because of somatic complications: 2 in the placebo group because of retinopathy or glioblastoma and 3 in the escitalopram group because of renal failure, cerebral tumor, or jaundice. Two patients in the escitalopram group withdrew because of nonadherence. The overall incidence of adverse effects, including possible adverse events of escitalopram or PEG-IFN-2 and ribavirin, was higher in the placebo group (87%) than in the escitalopram group (74%) (absolute risk difference, 13 percentage points [CI, 4 to 22 percentage points]; P 0.022). No group differences were found regarding specific adverse effects of escitalopram (Table 2). However, significantly fewer patients in the escitalopram group had fatigue (P 0.0) or insomnia (P 0.015), which were both frequently observed during IFN treatment. Laboratory test data, such as levels of alanine and aspartate aminotransferase, -glutamyltransferase (Table 2), serum creatinine, hemoglobin, neutrophil granulocytes, and thrombocytes (data not shown), did not differ between treatment groups before, during, or after treatment. Dose reduction of PEG-IFN-2 was necessary for 19% of patients in both groups. Ribavirin dose was decreased in 29% of the placebo group and 24% of the escitalopram group. 17 July 2012 Annals of Internal Medicine Volume 157 Number 2

8 Escitalopram for the Prevention of IFN- Induced Depression Original Research DISCUSSION To our knowledge, this is the first trial that demonstrates that preemptive and concomitant therapy with escitalopram significantly decreases the incidence and severity of PEG-IFN- associated depression in patients without preexisting psychiatric risk factors. Escitalopram treatment was safe and did not negatively influence sustained virologic response to antiviral therapy, which corroborates the findings of trials showing good safety and tolerability of antidepressants in patients with HCV infection during antiviral therapy (4, 10, 11, 15, 24, 25). We consequently aimed to exclude patients with any history of psychiatric disorders to avoid spontaneous depression independent of antiviral therapy and to assess the real capability of SSRIs to protect patients from IFNassociated depressive mood changes. Although patients with preexisting psychiatric conditions were excluded, 18% of the placebo group developed major depression and 58% developed IFN- induced clinically relevant depressive episodes with a MADRS score of 13 or higher. Most trials reported a 10% to % incidence of major depression during antiviral therapy (5). Some trials that did not exclude patients with preexisting psychiatric conditions found up to a % incidence of depression (3, 4). Thus, our results corroborate these data and those of recent trials showing that patients without psychiatric risk factors have a similar risk for depression during antiviral therapy with IFN- as patients with psychiatric disorders (24, 25). Interferon- associated depression has been related to a serotonergic deficit, and changes in serotonin signaling prove the rationale for therapeutic use of SSRIs (2, 26, 27). Indeed, in a prospective, controlled trial, acute treatment with the SSRI citalopram was shown to significantly decrease IFN-associated depressive symptoms (28). However, whether a prophylactic antidepressant therapy offers an advantage over a treat-as-needed strategy is uncertain. Considering our trial s high efficacy in preventing depressive symptoms, as well as the good tolerability of escitalopram, our findings show good reasons to favor a preventive strategy for IFN-associated depression. The diagnosis of major depressive episodes is often missed, because patients with HCV infection are not regularly seen by a psychiatric specialist. According to a recent study, only 32% of patients with a major depressive episode are correctly diagnosed during routine medical interviews (6). Thus, the treat-as-needed strategy might lead to a significant delay in antidepressant therapy with an increased risk for worsening depressive symptoms, nonresponse, treatment discontinuation, or suicide attempts (29). Depression that is especially severe may be associated with major complications (for example, suicidal thoughts and treatment discontinuation). In our trial, antidepressant pretreatment significantly decreased the incidence of IFNassociated severe depressive episodes. Table 2. Safety Data for Escitalopram and Placebo* Variable Placebo Group (n 91) Escitalopram Group (n ) Serious adverse events requiring 5 (5.5) 5 (5.6) treatment discontinuation, n (%) Psychiatric 3 (3.3) 2 (2.2) Somatic 2 (2.2) 3 (3.4) Adverse events, n (%) 73.6 (67) 87 (78) Adverse events possibly associated with antiviral treatment/ escitalopram, n (%) Fatigue 55 (61.1) 44 (48.0) Insomnia 48 (53.3) 34 (37.7) Irritability 12 (13.3) 6 (6.6) Mania 1 (1.1) 0 (0.0) Sexual dysfunction 2 (2.2) 4 (4.4) Nausea 35 (38.8) 28 (31.1) Diarrhea 14 (15.5) 22 (24.2) Headache 33 (36.6) 31 (34.4) Dizziness 12 (13.3) 21 (23.3) Nervousness 6 (6.6) 4 (4.4) Absence of appetite 17 (18.8) 10 (11.1) Weight 4 (4.4) 5 (5.5) Other psychiatric symptoms 7 (7.7) 8 (8.8) Thrombocytopenia 2 (2.2) 7 (7.7) Other adverse events, n (%) Cognitive dysfunction Concentration 5 (5.5) 4 (4.4) Memory 0 (0.0) 1 (1.1) Neurologic symptoms 15 (16.6) 9 (9.9) Influenza-like illness (44.4) 33 (36.6) Musculoskeletal pain 42 (46.6) (44.4) Allergic reaction 2 (2.2) 3 (3.3) Rash 44 (48.8) 37 (41.1) Pruritus 23 (25.5) 22 (24.4) Cough 20 (22.2) 15 (16.6) Neutropenia 8 (8.8) 8 (8.8) Anemia 14 (15.5) 18 (20) Thyroid dysfunction 5 (5.5) 7 (7.7) Alopecia 21 (23.3) 21 (23.3) Dyspnea 23 (25.5) 15 (16.6) Cardiac conditions 7 (7.7) 4 (4.4) Mean laboratory data (treatment week 24) (SD) Alanine aminotransferase, U/L 38.1 (42) 43.6 (38) Aspartate aminotransferase, U/L.2 (36).1 (25) -Glutamyltransferase, U/L 44.3 (37) 56.4 (57) Thyroid-stimulating hormone, miu/l 3.2 (10.1) 2.4 (7.0) * Data include all adverse events during antiviral treatment with pegylated interferon- 2a and ribavirin and study medication. Escitalopram vs. placebo, P 0.0. Escitalopram vs. placebo, P Psychiatric adverse events of IFN- treatment significantly decrease patients quality of life (). We prospectively investigated HRQOL for the first time in patients receiving a prophylactic antidepressant during antiviral therapy. Escitalopram pretreatment was associated with a better mental health summary score during the course of the study. Other psychiatric adverse effects of IFN- that are important risk factors for depression, such as sleep dis July 2012 Annals of Internal Medicine Volume 157 Number 2 101

9 Original Research Escitalopram for the Prevention of IFN- Induced Depression turbance and fatigue (31), also occurred less frequently when escitalopram was given as a prophylactic treatment. So far, a systematic English-language MEDLINE search to December 2011 yielded 5 randomized, controlled trials investigating prophylactic antidepressant therapy for HCV-infected patients receiving antiviral therapy with IFN- and ribavirin (9, 10, 13 15). Four trials showed no significant effects of an antidepressant pretreatment on the incidence of depression or depression severity (10, 13 15). Two different small trials of the same group did not find significant effects of a prophylactic treatment with either paroxetine (n 33) (13) or citalopram (n 39) (14). Another trial with a small sample size (n 52) that showed no general significant benefit demonstrated at least a decrease of depressive symptoms in a subgroup of patients with higher MADRS scores at baseline (15). The fourth negative study included 133 patients who received antidepressant pretreatment with escitalopram (10). However, depression was monitored only in the first 12 weeks of antiviral therapy; furthermore, patients were allowed to continue benzodiazepines or sleep medication, which might explain the overall very low incidence of depression in this trial (31). Finally, a very recently published trial (n 79) also using escitalopram for antidepressant pretreatment found a significant reduction of single-symptom items in the MADRS scale and the incidence of depression (9), whereas mean MADRS scores or the incidence of major depression according to the DSM-IV criteria was not specifically assessed. Most trials available so far have limited power owing to small sample sizes, high withdrawal rates, or a low incidence of depression. On the basis of their data, Raison and colleagues (15) calculated that at least 1 patients would be required for sufficient power, a number that so far has been realized only in our trial. Furthermore, in contrast to the other trials, we excluded patients with a history of psychiatric disorders or substance abuse in the past 12 months. In addition, IFN-associated depression was assessed and verified with different instruments for up to 84 weeks during and after antiviral treatment. Our trial has some limitations. Random assignment of patients before the preobservation period followed by patient withdrawal from the trial independent of antidepressant treatment weakens the strength of the randomization. However, the groups were balanced once antidepressant treatment was started. The overall observation period of 24 to 48 weeks depending on genotype was associated with a decreased number of cases available at week 48. Thus, the trial was not powered to detect group differences for sustained virologic response. Data about the outcome of acute antidepressant rescue treatment are not available. Finally, our results do not allow conclusions about the preventive effects of antidepressants in patients with drug addiction or psychiatric comorbid conditions. Future trials should evaluate different antidepressants and possible additional effects on other psychiatric symptoms (such as fatigue and sleep disturbances) and on sustained virologic response. Moreover, more information is needed about new antivirals used in combination with IFN- and ribavirin and about possible drug drug interactions between the new antivirals and antidepressants and benzodiazepines (32 35). In conclusion, our study shows that preemptive treatment with escitalopram is effective in reducing the incidence and severity of depressive symptoms associated with antiviral therapy for chronic HCV infection in patients without psychiatric risk factors. Given the current and future treatment options for PEG-IFN- in gastroenterology, dermatology, and oncology and the burden of treatment-associated depression, our study s findings are highly relevant for improving and optimizing the safety and tolerability of IFN- treatment. From Charité Universitätsmedizin Berlin, Campus Charité Mitte, Berlin; Kliniken Essen-Mitte, Essen; Asklepios Westklinikum Hamburg, Hamburg; Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin; Medizinische Klinik I, Goethe Universität, Frankfurt am Main; Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin; LWL- Klinik, Ruhr-Universität, Bochum; Universitätsklinikum Bonn, Bonn; Centre for Interdisciplinary Addiction Research, Universität Hamburg, Hamburg; Institute for Interdisciplinary Medicine, Asklepios-Clinic, St. Georg, Hamburg; Medizinische Klinik II, Klinikum Bremen-Mitte, Bremen; St. Josephsklinik, Offenburg; Technische Universität München, München; Klinikum Mittelbaden, Baden-Baden; Universitätsklinikum Gießen Marburg, Marburg; Universitätsmedizin Mainz, Mainz; Medizinische Universitätsklinik Freiburg, Freiburg; Institute for Biometry and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin; and Section of Hepatology, Clinic and Policlinic for Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Leipzig, Germany. 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 M Reproducible Research Statement: Study protocol: Available from Dr. Schaefer ( , m.schaefer@kliniken-essen-mitte.de). 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, Essen, Germany; , m.schaefer@kliniken-essen -mitte.de July 2012 Annals of Internal Medicine Volume 157 Number 2

10 Escitalopram for the Prevention of IFN- Induced Depression Original Research Current author addresses and author contributions are available at References 1. Nelson DR. The role of triple therapy with protease inhibitors in hepatitis C virus genotype 1 naïve patients. Liver Int. 2011;31 Suppl 1:53-7. [PMID: ] 2. Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Schmidt F, et al. Interferon alpha (IFNalpha) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26: [PMID: ] 3. Reichenberg A, Gorman JM, Dieterich DT. Interferon-induced depression and cognitive impairment in hepatitis C virus patients: a 72 week prospective study. AIDS. 2005;19 Suppl 3:S [PMID: ] 4. Schaefer M, Schwaiger M, Garkisch AS, Pich M, Hinzpeter A, Uebelhack R, et al. Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol. 2005;42: [PMID: ] 5. Schäfer A, Wittchen HU, Seufert J, Kraus MR. 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Boston: The Health Institute; 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-. [PMID: ] 24. Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology. 2003;37: [PMID: ] 25. Schaefer M, Hinzpeter A, Mohmand A, Janssen G, Pich M, Schwaiger M, et al. Hepatitis C treatment in difficult-to-treat psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects. Hepatology. 2007;46: [PMID: ] 26. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26: [PMID: ] 27. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;1: [PMID: ] 28. Kraus MR, Schäfer A, Schöttker K, Keicher C, Weissbrich B, Hofbauer I, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut. 2008;57: [PMID: ] 29. Mann JJ. The medical management of depression. N Engl J Med. 2005;353: [PMID: ]. Younossi Z, Kallman J, Kincaid J. The effects of HCV infection and management on health-related quality of life. Hepatology. 2007;45:6-16. [PMID: ] 31. Sockalingam S, Abbey SE, Alosaimi F, Novak M. A review of sleep disturbance in hepatitis C. J Clin Gastroenterol. 2010;44: [PMID: ] 32. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: [PMID: ] 33. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364: [PMID: ] 34. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: [PMID: ] 35. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al; REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364: [PMID: ] 17 July 2012 Annals of Internal Medicine Volume 157 Number 2 103

11 Annals of Internal Medicine Current Author Addresses: Dr. Schaefer: Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Henricistr. 92, Essen, Germany. Dr. Sarkar: Department of Psychiatry and Psychotherapy, Asklepios Westklinikum Hamburg, Suurheid 20, Hamburg, Germany. Drs. Knop and Zeuzem: Department of Internal Medicine I, Klinikum der J. W. Goethe-Universität, Theodor-Stern-Kai 7, 5 Frankfurt am Main, Germany. Ms. Effenberger and Drs. Heinze and Heinz: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany. Dr. Friebe: Department of Psychiatry and Psychotherapy, Universitätsklinik Bochum Alexandrinenstraße 1, Bochum, Germany. Dr. Spengler: Department of Internal Medicine, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, Bonn, Germany. Dr. Schlaepfer: Department of Psychiatry and Psychotherapy, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, Bonn, Germany. Dr. Reimer: Department of Psychiatry and Psychotherapy, Interdisziplinäre Suchtforschung der Universität Hamburg, Martinistraße 52, Hamburg, Germany. Dr. Buggisch: Institute of Interdisciplinary Medicine, Asklepiosklinikum St. Georg, Lohmühlenstraße 5, Hamburg, Germany. Dr. Ockenga: Department of Internal Medicine, Klinikum Bremen- Mitte, St.-Jürgen-Straße 1, Bremen, Germany. Dr. Link: Department of Internal Medicine, St. Josefsklinik, Weingartenstr., Offenburg, Germany. Dr. Rentrop: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar Ismaningerstraße 22, München, Germany. Dr. Weidenbach: Department of Internal Medicine, Klinikum Mittelbaden, Balger Straße, Baden-Baden, Germany. Dr. Fromm: Department of Psychiatry and Psychotherapy, Justus Liebig Universität Gießen, Am Steg 22, Giessen, Germany. Dr. Lieb: Department of Psychiatry and Psychotherapy, Klinikum der Johannes Gutenberg-Universität Mainz, Untere Zahlbacher Straße 8, Mainz, Germany. Dr. Baumert: Department of Internal Medicine, Hugstetterstrasse 55, Freiburg, Germany. Dr. Discher: Department of Internal Medicine II, Universitätsklinikum Gießen Marburg, Gießen, Germany. Dr. Neumann: Institute for Biostatistics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Charite Campus Benjamin Franklin, Hindenburgdamm, Berlin, Germany. Dr. Berg: Section of Hepatology, Clinic and Policlinic for Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Liebigstraße 20, 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. W July 2012 Annals of Internal Medicine Volume 157 Number 2