Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, Major Depression, Depression, Geodon, Ziprasidone, SSRI Augmentation, Treatment Resistant Depression
Brief summary
The purpose of this study is to see if adding the study drug, ziprasidone, to an antidepressant medication helps improve symptoms of Major Depressive Disorder (MDD). We are studying the drug's effectiveness in treating depression, as well as its safety when it is added to another drug. Hypothesis A: There will be a difference in the percentage of responders in the two treatment conditions during phase 2; response rates will be higher for the ziprasidone group.
Detailed description
The proposed study involves three phases. The first phase is an 8-week, open-label trial of an SSRI for MDD. Patients who do not experience sufficient symptom improvement following this open-label trial will be enrolled in a 6-week, double-blind, placebo controlled trial of ziprasidone augmentation (second phase). Ziprasidone and placebo-remitters will then enter a 12-month, double-blind extension phase (third phase). We estimate that approximately 400 patients will enter phase 1 of the study so that a minimum of 180 subjects will enter double-blind treatment (phase 2) over 5 years. Each treatment arm during phase 2 will have 90 subjects. Hypothesis B1: During phase 2, there will be a difference between the two groups in the percentage of responders (50% or greater reduction in symptom severity) with regards to anxious symptoms of MDD as measured by the 14-item Hamilton Anxiety Rating Scale (HAM-A); response rates will be higher for the ziprasidone group. Hypothesis B2: During phase 2, there will be a difference between the two groups in the percentage of responders (50% or greater reduction in symptom severity) with regards to painful symptoms of MDD, as measured by the overall visual analogue pain (VAS-pain) scale scores; response rates will be higher for the ziprasidone group. Hypothesis C: The time to relapse during phase 3 will be shorter among adjunctive placebo- than ziprasidone-remitters.
Interventions
DRUGZiprasidone
20mg-80mg a day. Dose increases of 20mg per day may occur at three study visits as directed by clinician. Maximum; 80mg per day per patient.
DRUGPlacebo
0mg Placebo per day (1-4 tablets per day). Dose increases and dose decreases may occur, but patient will remain at 0mg placebo.
Sponsors
University of Alabama at Birmingham
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent. * Men or women, 18-65 years of age. * MDD, current, according to DSM-IV criteria and as diagnosed by the SCID- I/P during the screen and baseline visit of phase 1. * A HAM-D-17 score \> 14 during the screen and baseline visit of phase 1.
Exclusion criteria
* Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine * Device, tubal ligation, or partner with vasectomy). * Serious suicide or homicide risk, as assessed by evaluating clinician. * Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease or uncontrolled seizure disorder. * History of multiple adverse drug reactions or allergy to the study drug. * The following DSM-IV diagnoses: substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past). * Patients requiring excluded medications (see appendix 1 for details). * Psychotic features in the current episode or a history of psychotic features. * Prior course of ziprasidone, or intolerance to ziprasidone at any dose. * Any investigational psychotropic drug within the last 3 months. * Have failed more than 3 adequate antidepressant trials during the current MDE. Some examples of adequate dosage of an antidepressant trial include either \> 150 mg of imipramine (or its tricyclic equivalent), \> 60 mg of phenelzine (or its monoamine oxidase inhibitor equivalent), \> 20 mg of fluoxetine (or its SSRI-equivalent), \> 150mg of bupropion, \> 300mg of trazodone (or nefazodone), \>75 mg of venlafaxine, \>60mg of duloxetine, or \> 15mg of mirtazapine. A trial of adequate duration was defined as one during which the patient was on any given antidepressant at an adequate dose for a minimum of 6 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome Measure Will be Response Rates (50% Decrease in HAM-D-17 Scores) During Phase 2 | 8 Weeks | The primary outcome measure will be response rates (50% decrease in HAM-D-17 scores) during phase 2. A responder will be a patient who experiences a 50% or greater decrease in symptoms according to the HAM-D-17 during phase 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission Rates (HAM-D 17 Scores of Less Than 8) After Treatment Phase 2. | 8 weeks | A secondary outcome measure will be remission rates (HAM-D 17 scores of less than 8) after treatment phase 2.. A remitted will be a patient with a final score of 7 or less on the HAMD-17 during phase 2. |
| Comparing Scores on HAM-D 17 Baseline Visit to Phase 2 Final Visit at Week 8 | 8 weeks | This will involve looking at the change in HAM-D 17 scores during phase 2. For HAMD-17 the minimum is 0, the maximum is 52, and greater scores represent more symptoms. |
Countries
United States
Participant flow
Pre-assignment details
458 patients met eligibility criteria for the study and were enrolled in an 8-week, open-label, flexible dose trial of escitalopram. At the end of this open-label trial, 139 patients not responding to Escitalopram were randomized to receive adjunctive ziprasidone or adjunctive placebo.
Participants by arm
| Arm | Count |
|---|---|
| Ziprasidone + Escitalopram Patients in group 1 will receive Ziprasidone added to Escitalopram for the full 8 weeks of Phase 2.
Ziprasidone: 20mg-80mg a day. Dose increases of 20mg per day may occur at three study visits as directed by clinician. Maximum; 80mg per day per patient. | 71 |
| Placebo + Escitalopram Patients in group 2 will receive Placebo added to Escitalopram for the full 8 weeks of Phase 2.
Placebo: 0mg Placebo per day (1-4 tablets per day). Dose increases and dose decreases may occur, but patient will remain at 0mg placebo. | 68 |
| Total | 139 |
Baseline characteristics
| Characteristic | Ziprasidone + Escitalopram | Placebo + Escitalopram | Total |
|---|---|---|---|
| Age, Continuous | 44.7 Years STANDARD_DEVIATION 13.8 | 44.2 Years STANDARD_DEVIATION 11 | 44.5 Years STANDARD_DEVIATION 12.9 |
| Region of Enrollment United States | 71 participants | 68 participants | 139 participants |
| Sex: Female, Male Female | 49 Participants | 49 Participants | 98 Participants |
| Sex: Female, Male Male | 22 Participants | 19 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 71 | 42 / 68 |
| serious Total, serious adverse events | 0 / 71 | 0 / 68 |
Outcome results
Primary
The Primary Outcome Measure Will be Response Rates (50% Decrease in HAM-D-17 Scores) During Phase 2
The primary outcome measure will be response rates (50% decrease in HAM-D-17 scores) during phase 2. A responder will be a patient who experiences a 50% or greater decrease in symptoms according to the HAM-D-17 during phase 2.
Time frame: 8 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ziprasidone + Escitalopram | The Primary Outcome Measure Will be Response Rates (50% Decrease in HAM-D-17 Scores) During Phase 2 | 35.2 Percentage of patients |
| Placebo + Escitalopram | The Primary Outcome Measure Will be Response Rates (50% Decrease in HAM-D-17 Scores) During Phase 2 | 20.5 Percentage of patients |
Secondary
Comparing Scores on HAM-D 17 Baseline Visit to Phase 2 Final Visit at Week 8
This will involve looking at the change in HAM-D 17 scores during phase 2. For HAMD-17 the minimum is 0, the maximum is 52, and greater scores represent more symptoms.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone + Escitalopram | Comparing Scores on HAM-D 17 Baseline Visit to Phase 2 Final Visit at Week 8 | -6.4 units on a scale | Standard Deviation 6.4 |
| Placebo + Escitalopram | Comparing Scores on HAM-D 17 Baseline Visit to Phase 2 Final Visit at Week 8 | -3.3 units on a scale | Standard Deviation 6.2 |
Secondary
Remission Rates (HAM-D 17 Scores of Less Than 8) After Treatment Phase 2.
A secondary outcome measure will be remission rates (HAM-D 17 scores of less than 8) after treatment phase 2.. A remitted will be a patient with a final score of 7 or less on the HAMD-17 during phase 2.
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ziprasidone + Escitalopram | Remission Rates (HAM-D 17 Scores of Less Than 8) After Treatment Phase 2. | 38 Percentage of patients |
| Placebo + Escitalopram | Remission Rates (HAM-D 17 Scores of Less Than 8) After Treatment Phase 2. | 30 Percentage of patients |