Hepatitis C, Chronic, Major Depressive Disorder
Conditions
Keywords
Major depressive disorder, chemically induced., Peginterferon alfa-2a., Escitalopram., Chronic hepatitis C, psychology., Prophylactic treatment.
Brief summary
The purpose of this study is to determine whether the use of an antidepressant (escitalopram) can prevent depressive episodes that appear during the treatment with peg-interferon and ribavirin in patients with chronic hepatitis C.
Detailed description
Chronic hepatitis C is a prevalent condition, and the main cause of chronic liver diseases, including cirrhosis and cancer. Nowadays, interferon-alfa in combination with ribavirin is the main treatment option for this condition. In the last years, interferon molecule has been modified in order to improve tolerance into pegylated interferon. Interferon-alfa has been associated with a high prevalence of psychiatric side effects, especially major depression (up to 25% of the cases), which is one of the main concerns about using this treatment. In fact, major depression is one of the main reasons of treatment withdrawal and treatment failure. Major depression induced by interferon-alfa can be successfully treated with antidepressants, but we don't know if antidepressants can also prevent the development of major depression, and if this can be a safe intervention. In the literature, there is only one controlled trial about this issue, in cancer patients, and some open studies in hepatitis C. In order to evaluate the efficacy, and safety, of an antidepressant (escitalopram) for preventing peginterferon's induced depressive episodes in patients with chronic hepatitis C, we have designed this 14-weeks placebo-controlled, double-blind, randomized clinical trial. Study interventions will be started two weeks before peginterferon + ribavirin's treatment onset. Subjects included in the study will be patients with chronic hepatitis C who are going to be treated with peginterferon-alfa2a + ribavirin, and without mental disorders requiring active psychotropic treatment. The main variables studied will be the appearance of a major depressive episode, following Diagnostic & Statistical Manual of Mental Disorders (DSM-IV) criteria, and the total score on the Montgomery-Asberg Depression Rating Scale, along three assessment points at 4, 8 and 12 weeks of treatment with interferon. There will also be a follow-up period of up to 6 months after treatment with interferon is completed.
Interventions
DRUGEscitalopram
15 mg/day starting 2 weeks before and 12 weeks during interferon therapy
DRUGPlacebo
Placebo, 15 mg/day, starting 2 weeks before and for 12 weeks during interferon therapy.
Sponsors
Hoffmann-La Roche
H. Lundbeck A/S
Germans Trias i Pujol Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with chronic hepatitis C who are going to initiate treatment with peginterferon alfa2a + ribavirin. * Age 18-65 years. * Signed informed consent. * If female, they are not in fertile period or they use barrier contraceptives. * Patients able to understand and fill written questionnaires.
Exclusion criteria
* Hepatic cirrhosis or carcinoma. * Less than 4000/mm3 leucocytes, or less than 70000/mm3 platelets. * Hemoglobin less than 11 g/dL (females) or 12 (males). * Any risk factor for hemolysis. * Comorbid severe medical conditions (kidney, immune system, lung, heart, thyroid, etc). * Baseline mental disorders that require antidepressants (depressive disorders and anxiety disorders). * Other baseline mental disorders (delirium, substance use disorders). * Mental disorders at any time (dementia, psychotic disorders, bipolar disorders. * Contraindications of escitalopram (hypersensibility, diabetes, patients using serotoninergic agents, drugs that enhance the risk of bleeding, or monoamineoxidase inhibitors -MAOIs-).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Developed a Major Depressive Episode According to Diagnostic & Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) Criteria During the First 12 Weeks of Antiviral Treatment. | First three months of interferon treatment. | At least five of the symptoms have been present during the same 1-week period: depressed mood, loss of interest or pleasure, weight or appetite changes, insomnia, agitation or retardation, fatigue, feelings of worthlessness or guilt, diminished ability to think or concentrate, recurrent thoughts of death. At least one of the symptoms is either depressed mood or loss of interest. Diagnoses were made by a trained psychiatrist who applied the mood disorders module from the Structured Clinical Interview for DSM-IV Axis I Disorders, non-patient edition (SCID-I/NP) at each study evaluation. |
| Number of Participants With Sustained Hepatitis C Viral Response (Negativization of Serum Hepatitis C Virus Ribonucleic Acid). | Six months after the end of interferon treatment | Number of participants with negativization of serum hepatitis C Virus Ribonucleic Acid (HCV RNA) 6 months after concluding antiviral therapy (sustained viral response). Negativization was defined as the absence of detectable levels of serum HCV RNA using a polymerase chain reaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Score in the Montgomery-Asberg Depression Rating Scale | 12 weeks after interferon treatment onset | The MADRS is a 10-item scale, clinician-administered, which is sensitive to symptom change during antidepressant treatment. It has been frequently used to measure depressive symptoms during interferon-alpha therapy and exhibits improved internal consistency in patients with co-morbid medical conditions compared with other clinician-administered questionnaires. Items are rated on a scale of 0-6. Scores range from 0 to 60, higher scores meaning higher levels of depression. |
| Total Score in the Depression Subscale of the Hospital Anxiety and Depression Scale. | 12 weeks after interferon treatment onset | The Hospital Anxiety and Depression Scale (HADS) is 14-item scale, patient-administered, that allows two independent scores of depression and anxiety. It has been specially designed to apply in patients with comorbid medical conditions as it excludes somatic or vegetative symptoms from the depression subscale. We present data of de depression subscale. The seven-item Depression subscale yields a score of 0-21, with higher scores meaning higher levels of depressive symptoms. |
Countries
Spain
Participant flow
Recruitment details
Participants were recruited among chronic hepatitis C patients between 18 and 65 years old, referred by general practitioners between March 2005 and July 2006 to gastroenterology outpatient units in 15 academic general hospitals in Spain, who were suitable to initiate treatment with pegylated interferonalfa-2a and ribavirin.
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram Patients treated with 15 mg/day of Escitalopram since 2 weeks before starting pegylated interferon and ribavirin until week 12 of antiviral treatment | 67 |
| Placebo Patients treated with placebo since 2 weeks before starting pegylated interferon and ribavirin until week 12 of antiviral treatment | 66 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Escitalopram | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 46.7 years STANDARD_DEVIATION 10.6 | 44.8 years STANDARD_DEVIATION 10.8 | 45.8 years STANDARD_DEVIATION 10.7 |
| Age, Customized Between 18 and 65 years | 67 participants | 66 participants | 133 participants |
| Region of Enrollment Spain | 67 participants | 66 participants | 133 participants |
| Sex: Female, Male Female | 28 Participants | 25 Participants | 53 Participants |
| Sex: Female, Male Male | 39 Participants | 41 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 66 | 58 / 66 |
| serious Total, serious adverse events | 0 / 66 | 0 / 63 |
Outcome results
Primary
Number of Participants Who Developed a Major Depressive Episode According to Diagnostic & Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) Criteria During the First 12 Weeks of Antiviral Treatment.
At least five of the symptoms have been present during the same 1-week period: depressed mood, loss of interest or pleasure, weight or appetite changes, insomnia, agitation or retardation, fatigue, feelings of worthlessness or guilt, diminished ability to think or concentrate, recurrent thoughts of death. At least one of the symptoms is either depressed mood or loss of interest. Diagnoses were made by a trained psychiatrist who applied the mood disorders module from the Structured Clinical Interview for DSM-IV Axis I Disorders, non-patient edition (SCID-I/NP) at each study evaluation.
Time frame: First three months of interferon treatment.
Population: One of 67 patients allocated to the escitalopram group and 3 of 66 in placebo did not receive the first dose of study medications. Consequently, 66 patients treated with escitalopram and 63 with placebo were included in the intention to treat analysis, with a procedure of last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Number of Participants Who Developed a Major Depressive Episode According to Diagnostic & Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) Criteria During the First 12 Weeks of Antiviral Treatment. | 5 Participants |
| Placebo | Number of Participants Who Developed a Major Depressive Episode According to Diagnostic & Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) Criteria During the First 12 Weeks of Antiviral Treatment. | 2 Participants |
p-value: 0.44195% CI: [0.075, 2.141]Fisher Exact
Primary
Number of Participants With Sustained Hepatitis C Viral Response (Negativization of Serum Hepatitis C Virus Ribonucleic Acid).
Number of participants with negativization of serum hepatitis C Virus Ribonucleic Acid (HCV RNA) 6 months after concluding antiviral therapy (sustained viral response). Negativization was defined as the absence of detectable levels of serum HCV RNA using a polymerase chain reaction.
Time frame: Six months after the end of interferon treatment
Population: Patients with available data for viral response 6 months after completion of interferon treatment were compared between treatment groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Number of Participants With Sustained Hepatitis C Viral Response (Negativization of Serum Hepatitis C Virus Ribonucleic Acid). | 36 Participants |
| Placebo | Number of Participants With Sustained Hepatitis C Viral Response (Negativization of Serum Hepatitis C Virus Ribonucleic Acid). | 38 Participants |
p-value: >0.05Chi-squared
Secondary
Total Score in the Depression Subscale of the Hospital Anxiety and Depression Scale.
The Hospital Anxiety and Depression Scale (HADS) is 14-item scale, patient-administered, that allows two independent scores of depression and anxiety. It has been specially designed to apply in patients with comorbid medical conditions as it excludes somatic or vegetative symptoms from the depression subscale. We present data of de depression subscale. The seven-item Depression subscale yields a score of 0-21, with higher scores meaning higher levels of depressive symptoms.
Time frame: 12 weeks after interferon treatment onset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram | Total Score in the Depression Subscale of the Hospital Anxiety and Depression Scale. | 2.25 Scores on a Scale | Standard Error 0.34 |
| Placebo | Total Score in the Depression Subscale of the Hospital Anxiety and Depression Scale. | 2.13 Scores on a Scale | Standard Error 0.33 |
p-value: 0.93ANOVA
Secondary
Total Score in the Montgomery-Asberg Depression Rating Scale
The MADRS is a 10-item scale, clinician-administered, which is sensitive to symptom change during antidepressant treatment. It has been frequently used to measure depressive symptoms during interferon-alpha therapy and exhibits improved internal consistency in patients with co-morbid medical conditions compared with other clinician-administered questionnaires. Items are rated on a scale of 0-6. Scores range from 0 to 60, higher scores meaning higher levels of depression.
Time frame: 12 weeks after interferon treatment onset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram | Total Score in the Montgomery-Asberg Depression Rating Scale | 3.82 Scores on a scale | Standard Error 0.57 |
| Placebo | Total Score in the Montgomery-Asberg Depression Rating Scale | 4.38 Scores on a scale | Standard Error 0.63 |
p-value: 0.443ANOVA