Major Depressive Disorder
Conditions
Keywords
depression, medication, antidepressant, chronic, recurrent
Brief summary
This study will compare whether a combination of antidepressant medications is better than one antidepressant medication alone when given as initial treatment for people with chronic or recurrent major depressive disorder.
Detailed description
The overall aim of Combining Medications to Enhance Depression Outcomes (CO-MED) is to enhance remission rates for outpatients with chronic or recurrent nonpsychotic major depressive disorder (MDD) as defined by DSM-IV TR, treated in primary or psychiatric care settings. Current evidence indicates that remission, the goal of treatment, is found in only about one-third of representative depressed outpatients treated for up to 14 weeks with an initial SSRI. In addition, even for those who do respond or remit, over one-third relapse in the subsequent 12 months. Combinations of antidepressants are used in practice at the second or subsequent steps when relapse occurs in the longer term, or, in some cases, even acutely as a first step when speed of effect is a clinical priority. Whether such combinations could potentially offer higher remission rates, lower attrition, or greater longer-term benefit if used as initial treatments as compared to monotherapy remains to be examined. CO-MED will test whether two different medications when given in combination as the first treatment step, compared to one medication, will enhance remission rates, increase speed of remission, be tolerable, and provide better sustained benefits in the longer term. Results of this study will inform practitioners in managing the treatment of patients with chronic or recurrent MDD.
Interventions
DRUGSSRI + placebo
Participants will take escitalopram (10 - 20 mg/day)+ placebo (1 to 3 pills per day). Medications taken orally. Participants will take escitalopram plus placebo for up to 28 weeks. Dosages were adjusted as need at each clinic visit.
DRUGEscitalopram + Bupropion SR
Participant will take Burpopion SR (150 to 450 mg/day) + Escitalopram (10 to 20 mg/day) for up to 28 weeks. Medications taken orally. Bupropion SR was blinded, and escitalopram was given open label. Dosages were adjusted as need at each clinic visit.
DRUGVenlafaxine XR + Mirtazapine
Participants will take Venlafaxine XR (75 to 225 mg/day) + Mirtazapine (15 to 45 mg/day) for up to 28 weeks. Medications taken orally. Venlafaxine XR was blinded, and mirtazapine was given open label. Dosages were adjusted as need at each clinic visit.
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Seeking treatment at the primary or specialty care site, and be planning to continue living in the area of that clinic for the duration of the study * Meets clinical criteria for nonpsychotic MDD, recurrent (with the current episode being at least 2 months in duration), or chronic (current episode greater than 2 years) as defined by a clinical interview and confirmed by the MINI International Neuropsychiatric Interview (MINI) * Screening 17 item HRSD score of 16 or greater * Treatment with antidepressant medication combinations is clinically acceptable * Patient with and without current suicidal ideation may be included in the study as long as outpatient treatment is clinically appropriate
Exclusion criteria
* Pregnant or breastfeeding * Plans to become pregnant over the ensuing 8 months following study entry or are sexually active and not using adequate birth control * History (lifetime) of psychotic depression, schizophrenia, bipolar (I, II, or NOS), schizoaffective, or other Axis I psychotic disorders * Current psychotic symptom(s) * History (within the last 2 years before study entry) of anorexia or bulimia * Current primary diagnosis of obsessive compulsive disorder * Current substance dependence that requires inpatient detoxification or inpatient treatment * Requiring immediate hospitalization for a psychiatric disorder * Definite history of intolerance or allergy (lifetime) to any protocol medication * History of clear nonresponse to an adequate trial of an FDA-approved monotherapy in the current MDE if recurrent, or during the last 2 years before study entry if chronic * History of clear nonresponse to an adequate trial of any study medication used as a monotherapy, or to one or more of the protocol combinations in the current or any prior MDE * Currently taking any of the study medications at any dose * Having taken Prozac (fluoxetine) or an MAOI in the 4 weeks before study entry * Presence of an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy less than 6 months after study entry) * Currently taking medications or have GMCs that contraindicate any study medications (e.g., seizure disorder) * Requiring medications for GMCs that contraindicate any study medication * Epilepsy or other conditions requiring an anticonvulsant * Lifetime history of having a seizure including febrile or withdrawal seizures * Receiving or have received vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or other somatic antidepressant treatments * Currently taking or having taken within the 7 days before study entry any of the following exclusionary medications: antipsychotic medications, anticonvulsant medications, mood stabilizers, or central nervous system stimulants (antidepressant medication used for the treatment of depression or other purposes such as smoking cessation or pain are excluded since these agents may interfere with the testing of the major hypotheses under study) * Uncontrolled narrow angle glaucoma * Taking thyroid medication for hypothyroidism may be included only if stable on the medication for 3 months * Using agents within the 7 days before study entry that are potential augmenting agents (e.g., T3 in the absence of thyroid disease, SAMe, St. John's Wort, lithium, buspirone) * Therapy that is depression-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quick Inventory of Depressive Symptoms | Measured at Month 7 | Percentage of patients that achieve remission, as defined as QIDS total score below 6 for last 2 study visits. QIDS depression scores range from 0 (normal) to 27 (very severe). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Inventory | Measured at Month 7 | The Quality of Life Inventory (QOLI) is a 32-item comprehensive self-report of satisfaction in 16 areas of life, such as love, work, and health. Each area is rated in terms of satisfaction and the relationship of that area to overall quality of life. It yields an overall raw score and satisfaction ratings for the 16 individual areas of life. The QOLI raw score is an average of weighted satisfaction ratings computed only over areas of life judged to be Important or Extremely Important to the respondent. Higher scores indicate higher reported quality of life. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from March 2008 through April of 2009, with the last subject completing the study in September 2009. Participants were recruited from six primary care and nine psychiatric care sites within the NIMH Depression Trials Network.
Pre-assignment details
Outpatient enrollees, 18-75 years old, met DSM-IV-TR criteria for either recurrent or chronic MDD. Eligible participants had to be in the index episode for at least two months and to score ≥16 on the 17-item HAM-D. Those with any history of psychotic illness or bipolar disorder, or in need of hospitalization were ineligible.
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram + Bupropion SR Participant takes Burpopion SR (150 to 450 mg/day)+ Escitalopram (10 to 20 mg/day) for up to 28 weeks. Medications taken orally. Bupropion SR was blinded, and escitalopram was given open label. Dosages were adjusted as need at each clinic visit. | 221 |
| Venlafaxine XR + Mirtazapine Participant takes Venlafaxine XR (75 to 225 mg/day) + Mirtazapine (15 to 45 mg/day) for up to 28 weeks. Medications taken orally. Venlafaxine XR was blinded, and mirtazapine was given open label. Dosages were adjusted as need at each clinic visit. | 220 |
| Escitalopram + Placebo Participants will take escitalopram (10 - 20 mg/day)+ placebo (1 to 3 pills per day). Medications taken orally. Participants will take escitalopram plus placebo for up to 28 weeks. Dosages were adjusted as need at each clinic visit. | 224 |
| Total | 665 |
Baseline characteristics
| Characteristic | Venlafaxine XR + Mirtazapine | Escitalopram + Placebo | Escitalopram + Bupropion SR | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 220 Participants | 224 Participants | 221 Participants | 665 Participants |
| Age, Continuous | 42.0 years STANDARD_DEVIATION 12.4 | 43.6 years STANDARD_DEVIATION 13.1 | 42.4 years STANDARD_DEVIATION 13.5 | 42.7 years STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 220 participants | 224 participants | 221 participants | 665 participants |
| Sex: Female, Male Female | 160 Participants | 143 Participants | 149 Participants | 452 Participants |
| Sex: Female, Male Male | 60 Participants | 81 Participants | 72 Participants | 213 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 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 12 / 221 | 16 / 220 | 13 / 224 |
Outcome results
Primary
Quick Inventory of Depressive Symptoms
Percentage of patients that achieve remission, as defined as QIDS total score below 6 for last 2 study visits. QIDS depression scores range from 0 (normal) to 27 (very severe).
Time frame: Measured at Month 7
Population: Remission = Last 2 QIDS \< 6. A chi-square test was used to compare the remission rates across the treatment groups. The Fisher's exact test was used when expected cell frequencies were \<5. For binary outcomes (e.g., remission), bivariate logistic regression models were fit to estimate the effect of treatment on outcome.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Escitalopram + Bupropion SR | Quick Inventory of Depressive Symptoms | 46.6 percentage of participants | 5.6 |
| Venlafaxine XR + Mirtazapine | Quick Inventory of Depressive Symptoms | 41.8 percentage of participants | — |
| Escitalopram + Placebo | Quick Inventory of Depressive Symptoms | 46.0 percentage of participants | 5.4 |
Secondary
Quality of Life Inventory
The Quality of Life Inventory (QOLI) is a 32-item comprehensive self-report of satisfaction in 16 areas of life, such as love, work, and health. Each area is rated in terms of satisfaction and the relationship of that area to overall quality of life. It yields an overall raw score and satisfaction ratings for the 16 individual areas of life. The QOLI raw score is an average of weighted satisfaction ratings computed only over areas of life judged to be Important or Extremely Important to the respondent. Higher scores indicate higher reported quality of life.
Time frame: Measured at Month 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram + Bupropion SR | Quality of Life Inventory | 0.6 units on a scale | Standard Deviation 2.1 |
| Venlafaxine XR + Mirtazapine | Quality of Life Inventory | 0.4 units on a scale | Standard Deviation 2.4 |
| Escitalopram + Placebo | Quality of Life Inventory | 0.4 units on a scale | Standard Deviation 2.6 |