Major Depressive Disorder
Conditions
Keywords
depression, Major Depressive Disorder
Brief summary
This study will utilize a randomized double-blind design to evaluate whether initial treatment with two anti-depressant medications (escitalopram and bupropion) results in more rapid remission and greater over-all remission rates than either monotherapy in 240 depressed subjects.
Detailed description
Depression is a major public health problem due to its prevalence and accompanying dysfunction and costs. Depression is undertreated, but even when treatment is adequate and effective, sources of delay in current pharmacologic strategies include: mechanistic delays, those related to the physiologic and behavioral effects of antidepressants; dosing delays in identifying the effective dose; and programmatic delays in identifying an effective agent using sequential monotherapy. This study will randomize 240 patients with Diagnostic and Statistical Manual, 4th Edition (DSM-IV) Major Depressive Disorder (MDD) to 12 week double blind treatment with combined escitalopram and bupropion or each antidepressant administered alone to evaluate whether combined escitalopram and bupropion result in more rapid remission and greater over-all remission than monotherapy. Preclinical and clinical studies suggest that bupropion might prevent one mechanistic delay inherent in escitalopram monotherapy. Rapid dose escalation may counter dosing delays. The simultaneous use of two known antidepressant medications may alleviate programmatic delays inherent in usual sequential monotherapy. Six months follow up and careful assessment of adverse events will address tolerability, acceptability, sustainability, and pharmacoeconomic concerns. If successful, this study might have a significant impact on clinical practice, public health, and depression's cost consequences.
Interventions
DRUGescitalopram
10mg/d increasing by 10 mg/week to a maximum of 40 mg/d if tolerated and not remitted
DRUGbupropion extra long (XL)
150mg/d increasing to 300 mg/d after 1 week and 450 mg/d after 3 weeks, all increases if tolerated and not remitted
same dosing schedule as for monotherapy
Sponsors
University of Ottawa
National Institute of Mental Health (NIMH)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women ages 18-65 2. Major Depressive Disorder as primary diagnosis 3. Physically healthy 4. Signs informed consent 5. Montgomery Asberg Depression Rating Scale (MADRS) \>= 22
Exclusion criteria
1. Bipolar Disorder (ie, Bipolar I, Bipolar II, Bipolar NOS) 2. Life-time history of psychosis 3. Current (ie, last 6 months) drug or alcohol abuse or dependence (except nicotine) 4. Currently taking effective antidepressant medication 5. Prior adequate treatment in current depressive episode with a selective serotonin re-uptake inhibitor (SSRI), bupropion (BUP) or bupropion (BUP) + a selective serotonin re-uptake inhibitor (SSRI) (adequate is defined as \>= 4 weeks taking \>= 2/3 Physician's Desk Reference (PDR) maximal dose 6. Most recent antidepressant was within 5 weeks for fluoxetine and 1 week for all others 7. Currently taking a medication contraindicated with either study medication 8. Life time history of anorexia or bulimia 9. Life time history of seizure or known increased seizure risk (e.g., history of significant brain trauma, taking pro-convulsant medication, known anatomical brain lesion) 10. Currently taking psychoactive medication deemed to be necessary (including but not limited anticonvulsants, antidepressants, antipsychotics, steroids, and B-blockers); occasional use of hypnotics (ie, less than three times per week) will be allowed 11. Unstable medical condition (ie, condition not adequately stabilized for \>= 3 months) 12. Prior intolerance to escitalopram (ESC) or bupropion (BUP) 13. Inadequate understanding of English (for US site; Canadian site permits French fluency) 14. Currently pregnant or breast-feeding; fecund women not using adequate contraceptive methods
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Remission, Defined by the Week of Onset of Persistent Hamilton Rating Scale for Depression (HAM-D 17) <= 7, With no Subsequent HAM-D 17 > 7 | 12 weeks | Life Table Survival Analysis run twice, once comparing Dual Therapy (i.e., Bupropion + Escitalopram) to Bupropion alone (i.e., Bupropion + Placebo) and once comparing Dual Therapy to Escitalopram alone (i.e., Escitalopram + Placebo). Because both analyses must significantly favor Dual Therapy, each individual analysis must reach a critical alpha = .0916 in order to reach an over-all alpha = .05. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12 | 12 weeks | Chi square comparison of rates of persistent remission (i.e., no subsequent Hamilton Rating Scale for Depression, 17 items \[HAMD-D 17\] \> 7 once HAMD-D 17 \<= 7); Dual rate vs. Escitalopram only rate and Dual rate vs. Bupropion only rate. |
| Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17) | 12 weeks | Last summary score rating on the 17-item Hamilton Rating Scale for Depression Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. Range 0-58. 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression |
| Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score | 12 weeks | Social adjustment was measured using the Social Adjustment Scale (SAS). The SAS is a self-report scale that assesses depressive symptoms and functioning in nine social and work-related domains generating a total score that is indicative of a subject's overall level of social adjustment. Subjects rate their own social functioning over times on a 5-point scale on items covering work for pay, housework, extended family, parenting, marital status, social activity and leisure, family unit and student status (sub-scales). Mean values of all the sub-scales are used, with a range from 0-5. Higher score = worse outcome … worse functioning |
| Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF) | 12 weeks | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) intends to measure quality of life in 16 domains. A summary score is computed by adding the scores and dividing by 16 (or the number of answered items if some are not answered). The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70. Higher score means more satisfaction. |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment dates: August, 2007 to August 2011 Locations: 4 outpatient research clinics in two countries (US and Canada)
Pre-assignment details
All patients had to be psychoactive drug-free for at least two weeks (five weeks for fluoxetine) prior to randomization and had to continue to meet study entry criteria at point of randomization
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram + Bupropion escitalopram plus bupropion XL | 78 |
| Escitalopram escitalopram monotherapy | 84 |
| Bupropion bupropion XL monotherapy | 83 |
| Total | 245 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 | 10 |
| Overall Study | Lost to Follow-up | 7 | 7 | 6 |
| Overall Study | unstated | 1 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 3 | 7 |
Baseline characteristics
| Characteristic | Escitalopram + Bupropion | Total | Bupropion | Escitalopram |
|---|---|---|---|---|
| Age, Continuous Age | 40 years STANDARD_DEVIATION 10 | 40 years STANDARD_DEVIATION 11 | 40 years STANDARD_DEVIATION 11 | 41 years STANDARD_DEVIATION 11 |
| Region of Enrollment Canada | 41 participants | 125 participants | 42 participants | 42 participants |
| Region of Enrollment United States | 37 participants | 120 participants | 41 participants | 42 participants |
| Sex: Female, Male Female | 52 Participants | 163 Participants | 49 Participants | 62 Participants |
| Sex: Female, Male Male | 26 Participants | 82 Participants | 34 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 71 / 78 | 80 / 84 | 71 / 83 |
| serious Total, serious adverse events | 0 / 78 | 0 / 84 | 0 / 83 |
Outcome results
Primary
Time to Remission, Defined by the Week of Onset of Persistent Hamilton Rating Scale for Depression (HAM-D 17) <= 7, With no Subsequent HAM-D 17 > 7
Life Table Survival Analysis run twice, once comparing Dual Therapy (i.e., Bupropion + Escitalopram) to Bupropion alone (i.e., Bupropion + Placebo) and once comparing Dual Therapy to Escitalopram alone (i.e., Escitalopram + Placebo). Because both analyses must significantly favor Dual Therapy, each individual analysis must reach a critical alpha = .0916 in order to reach an over-all alpha = .05.
Time frame: 12 weeks
Population: age 18-65 with Major Depressive Disorder (MDD), non-bipolar, non-psychotic, non-substance abusing, without intolerance to study drugs or adequate selective serotonin re-uptake inhibitor (SSRI) and/or bupropion treatment in current episode; physically healthy without contraindications to bupropion or escitalopram.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram + Bupropion | Time to Remission, Defined by the Week of Onset of Persistent Hamilton Rating Scale for Depression (HAM-D 17) <= 7, With no Subsequent HAM-D 17 > 7 | 8 weeks | Standard Deviation 7 |
| Escitalopram | Time to Remission, Defined by the Week of Onset of Persistent Hamilton Rating Scale for Depression (HAM-D 17) <= 7, With no Subsequent HAM-D 17 > 7 | 9 weeks | Standard Deviation 7 |
| Bupropion | Time to Remission, Defined by the Week of Onset of Persistent Hamilton Rating Scale for Depression (HAM-D 17) <= 7, With no Subsequent HAM-D 17 > 7 | 10 weeks | Standard Deviation 7 |
Comparison: Hypothesis: Dual Treatment (escitalopram + bupropion) will result in greater improvement over 12 weeks than either monotherapy (i.e., two analyses: 1) dual treatment will outperform escitalopram monotherapy; 2) dual treatment will outperform bupropion monotherapy). Therefore each analysis will be done twice and it will be required that both analyses be significant to declare the over-all study significant.p-value: 0.05Cochran-Mantel-Haenszel
Secondary
Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score
Social adjustment was measured using the Social Adjustment Scale (SAS). The SAS is a self-report scale that assesses depressive symptoms and functioning in nine social and work-related domains generating a total score that is indicative of a subject's overall level of social adjustment. Subjects rate their own social functioning over times on a 5-point scale on items covering work for pay, housework, extended family, parenting, marital status, social activity and leisure, family unit and student status (sub-scales). Mean values of all the sub-scales are used, with a range from 0-5. Higher score = worse outcome … worse functioning
Time frame: 12 weeks
Population: All randomized patients; latest available Total SAS score used if week 12 score not available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram + Bupropion | Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score | 2.65 units on the SAS scale | Standard Deviation 0.69 |
| Escitalopram | Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score | 2.63 units on the SAS scale | Standard Deviation 0.69 |
| Bupropion | Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score | 2.74 units on the SAS scale | Standard Deviation 0.71 |
Secondary
Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF)
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) intends to measure quality of life in 16 domains. A summary score is computed by adding the scores and dividing by 16 (or the number of answered items if some are not answered). The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70. Higher score means more satisfaction.
Time frame: 12 weeks
Population: All Randomized Subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram + Bupropion | Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF) | 3.0 units on the Q-LES-Q scale | Standard Deviation 0.82 |
| Escitalopram | Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF) | 3.0 units on the Q-LES-Q scale | Standard Deviation 0.76 |
| Bupropion | Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF) | 3.1 units on the Q-LES-Q scale | Standard Deviation 0.74 |
Secondary
Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12
Chi square comparison of rates of persistent remission (i.e., no subsequent Hamilton Rating Scale for Depression, 17 items \[HAMD-D 17\] \> 7 once HAMD-D 17 \<= 7); Dual rate vs. Escitalopram only rate and Dual rate vs. Bupropion only rate.
Time frame: 12 weeks
Population: age 18-65 with MDD, non-bipolar, non-psychotic, non-substance abusing, without intolerance to study drugs or adequate SSRI/bupropion treatment in current episode; physically healthy without contraindications to bupropion or escitalopram.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram + Bupropion | Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12 | 52 percentage of participants |
| Escitalopram | Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12 | 46 percentage of participants |
| Bupropion | Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12 | 34 percentage of participants |
Secondary
Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17)
Last summary score rating on the 17-item Hamilton Rating Scale for Depression Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. Range 0-58. 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression
Time frame: 12 weeks
Population: age 18-65 with MDD, non-bipolar, non-psychotic, non-substance abusing, without intolerance to study drugs or adequate SSRI/bupropion treatment in current episode; physically healthy without contraindications to bupropion or escitalopram.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram + Bupropion | Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17) | 10 units on Hamilton Rating Scale for Depre | Standard Deviation 8 |
| Escitalopram | Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17) | 9 units on Hamilton Rating Scale for Depre | Standard Deviation 7 |
| Bupropion | Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17) | 12 units on Hamilton Rating Scale for Depre | Standard Deviation 8 |
Comparison: To test the hypothesis that escitalopram + bupropion would have superior efficacy relative to each monotherapy, the group receiving both medications was separately compared to each monotherapy group, covarying for baseline score and countryp-value: 0.0916ANCOVA