Depression
Conditions
Keywords
Pegasys-Induced depression
Brief summary
Primary end points * incidence of depression defined as a Montgomery Asberg Depression Scale Score (MADRS) of 13 or higher during antiviral therapy (up to 48 weeks, depending on genotype) * effect of an antidepressive pre-treatment over two weeks and a continuously concomitant treatment with Escitalopram (S-citalopram) on frequency and severity of depression in patients with chronic hepatitis C (HCV) treated with Peg-interferon alfa-2a (PEGASYS) and ribavirin, measured by the Montgomery Asberg Depression Scale Secondary end points * time to depression defined as a MADRS score of 13 or higher * incidence of major depression defined by Diagnostic and Statistical Manual IV (DSM-IV) criteria * severe depression according to MADRS scale (score 25 or higher) * Health related quality of life (HRQOL) measured by the Short Form 36 (SF-36) * sustained virologic response * tolerability * safety * changes/group differences in other psychiatric depression scales (Hamilton Depression Rating Scale, Beck Depression Inventory) Other investigations: * cognitive function, anxiety (word fluency test, trail making test part A and B, othe scales) * Predictive parameters for patients especially gaining from an antidepressive therapy (e.g. age, gender, weight, height, alanine aminotransferase (ALAT) quotient defined as median ALAT values before treatment divided by the upper standard value, HCV-RNA serum concentration level of fibrosis in liver histology, baseline values of the different psychometric scales) * alanine aminotransferase (ALAT), aspartate transaminase (ASAT), thyrotrophin (TSH) * biomarkers (genetic parameters, cytokines,...)
Interventions
DRUGEscitalopram
DRUGPlacebo
DRUGPeginterferon alfa-2a
Patients with HCV genotype 1 or 4 received treatment for 48 weeks with PEGinterferon-alfa2a, 180 mcg weekly. Patients with genotype 2 or 3 received PEGinterferon-alfa2a, 180 mcg weekly.
DRUGRibavirin
Patients with HCV genotype 1 or 4 received treatment for 48 weeks with ribavirin, 1000 mg per day (body weight 75 kg) or 1200 mg per day (body weight, 75 kg). Patients with HCV genotype 2 or 3 received ribavirin, 800 mg per day for 24 weeks.
Sponsors
Charite University, Berlin, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic hepatitis C infection defined as positive anti-HCV antibodies and serum HCV-RNA \>1000 IU/ml, naive to antiviral treatment * age \>18 years
Exclusion criteria
* Antidepressive treatment within the last 3 years * Psychiatric diseases including major depressive disorders in past medical history * Active substance abuse during the last 12 months * Pregnancy, lactation, wish to become pregnant * Hepatitis B (HBV)/HIV-coinfection * Decompensated liver disease, hepatocellular carcinoma, history of bleeding esophageal varices * Neutropenia (\<1500/ul), thrombocytopenia (\<70/nl), anemia (\<12g/dl in females, \<13g/dl in males) * History of autoimmune disease * History of organ transplantation, concomitant liver disease, severe cardiopulmonary disease, hemolytic anemia, malignant disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery Asberg Depression Scale (MADRS) With a Score of 13 or Higher | 50 weeks for genotypes 1 or 4 and 26 weeks for patients with genotype 2 or 3 | Clinically relevant depression (MADRS score of 13 or higher) during antiviral treatment presented as percentage of participants with MADRS scores \> 13 (entire time period: from starting study medication until end of antiviral treatment = 48 weeks in patients with genotype 1 or 4 and 24 weeks for patients with genotype 2 or 3) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Major Depression Defined by Diagnostic and Statistical Manual IV (DSM-IV) Criteria | major depression during 24 or 48 weeks of antiviral therapy | — |
| Severe Depression Defined as a MADRS Score of 25 or Higher | severe depression during 24 or 48 weeks of antiviral therapy | — |
| Health Related Quality of Life (HRQOL) Measured by the Short Form 36 (SF-36) | assessed 2,4,12,24 and 48 weeks of antiviral treatment | — |
| Proportion of Patients Without Depression (Defined as a MADRS Score of 13 or Higher) | Patients free of depression during 24 or 48 weeks of antiviral therapy | Number of patients who did not develop at any time of antiviral treatment (up to 48 weeks) a MADRS score of 13 or more as a sign of clinically relevant depression |
| Tolerability | assessed 2,4,12,24 and for genotype 1 and 4, 48 weeks of antiviral treatment | — |
| Safety | assessed 2,4,12,24 and for genotype 1 and 4, 48 weeks of antiviral treatment | — |
| Sustained Virologic Response | assessed 24 weeks after end of antiviral treatment | (negative Polymerase Chain Reaction (PCR) 6 months after the end of antiviral treatment) |
Countries
Germany
Participant flow
Recruitment details
A total of 208 of the 300 patients screened were enrolled between August 2004 and September 2008 in different centers in the pre-observation period. Overall 181 patients started the treatment period by taking escitalopram or placebo.
Pre-assignment details
A total of 208 of the 300 patients screened were enrolled between August 2004 and September 2008. 92 patients did not meet the inclusion criteria, had exclusion criteria or did not want to participate in the trial.27 patients stopped the trial during the preobservation period before the trial started by taking antidepressant or placebo therapy.
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram After the preobservation period,patients received escitalopram, 10 mg per day. During treatment period, all patients began receiving antiviral therapy with PEG-interferon plus ribavirin with continuous concomitant administration of escitalopram.
Peginterferon alfa-2a :
Escitalopram :
Ribavirin : | 90 |
| Placebo After the preobservation period, patients received placebo. After 2 weeks of antidepressant pretreatment, all patients began receiving antiviral therapy with PEG-interferon plus ribavirin with continuous concomitant administration of placebo.
Peginterferon alfa-2a :
Placebo :
Ribavirin : | 91 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Escitalopram | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 84 Participants | 84 Participants | 168 Participants |
| Age Continuous | 48.5 years STANDARD_DEVIATION 11 | 46.2 years STANDARD_DEVIATION 11 | 47.4 years STANDARD_DEVIATION 11 |
| Region of Enrollment Germany | 91 participants | 90 participants | 181 participants |
| Sex: Female, Male Female | 43 Participants | 42 Participants | 85 Participants |
| Sex: Female, Male Male | 48 Participants | 48 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 90 | 78 / 91 |
| serious Total, serious adverse events | 5 / 90 | 5 / 91 |
Outcome results
Primary
Montgomery Asberg Depression Scale (MADRS) With a Score of 13 or Higher
Clinically relevant depression (MADRS score of 13 or higher) during antiviral treatment presented as percentage of participants with MADRS scores \> 13 (entire time period: from starting study medication until end of antiviral treatment = 48 weeks in patients with genotype 1 or 4 and 24 weeks for patients with genotype 2 or 3)
Time frame: 50 weeks for genotypes 1 or 4 and 26 weeks for patients with genotype 2 or 3
Population: The final analysis included only patients who received at least one of escitalopram or placebo. Between group differences for the primary outcome parameters were calculated with a chi-square test. For the primary end point (MADRS score of 13 or higher), we treated missing MADRS assessments by multiple imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Montgomery Asberg Depression Scale (MADRS) With a Score of 13 or Higher | 32 percentage of participants |
| Placebo | Montgomery Asberg Depression Scale (MADRS) With a Score of 13 or Higher | 59 percentage of participants |
Secondary
Health Related Quality of Life (HRQOL) Measured by the Short Form 36 (SF-36)
Time frame: assessed 2,4,12,24 and 48 weeks of antiviral treatment
Secondary
Incidence of Major Depression Defined by Diagnostic and Statistical Manual IV (DSM-IV) Criteria
Time frame: major depression during 24 or 48 weeks of antiviral therapy
Population: The final analysis included only patients who received at least 1 dose of escitalopram or placebo. Between-group differences for the secondary outcome parameters were calculated with a chi-square test.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Incidence of Major Depression Defined by Diagnostic and Statistical Manual IV (DSM-IV) Criteria | 8 percentage of participants |
| Placebo | Incidence of Major Depression Defined by Diagnostic and Statistical Manual IV (DSM-IV) Criteria | 17 percentage of participants |
Secondary
Proportion of Patients Without Depression (Defined as a MADRS Score of 13 or Higher)
Number of patients who did not develop at any time of antiviral treatment (up to 48 weeks) a MADRS score of 13 or more as a sign of clinically relevant depression
Time frame: Patients free of depression during 24 or 48 weeks of antiviral therapy
Population: Number of patients per group who did not develop any depressive episode during 48 weeks of antiviral therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Proportion of Patients Without Depression (Defined as a MADRS Score of 13 or Higher) | 60 participants |
| Placebo | Proportion of Patients Without Depression (Defined as a MADRS Score of 13 or Higher) | 40 participants |
Secondary
Safety
Time frame: assessed 2,4,12,24 and for genotype 1 and 4, 48 weeks of antiviral treatment
Secondary
Severe Depression Defined as a MADRS Score of 25 or Higher
Time frame: severe depression during 24 or 48 weeks of antiviral therapy
Population: The final analysis included only patients who received at least 1 dose of escitalopram or placebo. Between-group differences for the secondary outcome parameters were calculated with a chi-square test.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Severe Depression Defined as a MADRS Score of 25 or Higher | 1 percentage of participants |
| Placebo | Severe Depression Defined as a MADRS Score of 25 or Higher | 12 percentage of participants |
Secondary
Sustained Virologic Response
(negative Polymerase Chain Reaction (PCR) 6 months after the end of antiviral treatment)
Time frame: assessed 24 weeks after end of antiviral treatment
Population: The final analysis included only patients who received at least 1 dose of escitalopram or placebo. Between-group differences for the secondary outcome parameters were calculated with a chi-square test.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Sustained Virologic Response | 56 percentage of participants |
| Placebo | Sustained Virologic Response | 46 percentage of participants |
Secondary
Tolerability
Time frame: assessed 2,4,12,24 and for genotype 1 and 4, 48 weeks of antiviral treatment