Major Depressive Disorder
Conditions
Keywords
Depression, Neuroimaging, Aripiprazole, Mood disorder, PET Scan, fMRI
Brief summary
Aripiprazole has been approved by the FDA for augmenting ineffective/partially effective oral antidepressant therapy in patients suffering from major depression. The mechanism by which this augmentation is achieved is not known. This study has been designed to test the hypothesis that the primary mechanism of action of aripiprazole (ARP) antidepressant augmentation is through the dopaminergic pathway. Two positron emission tomography (PET) scan procedures and a functional magnetic resonance imaging (fMRI) scan will be used to test this hypothesis.
Detailed description
This study is designed to help understand the mechanism of action of ARP in major depressive disorder (MDD) augmentation. Subjects will undergo exposure to an existing antidepressant (Lexapro 10-20mg) for 10 weeks; subjects failing to completely respond to the monotherapy antidepressant treatment will receive augmentation with ARP for six weeks. Two placebo phases are included in which the subjects will receive one placebo along with the Lexapro for the first 6 weeks and a second placebo along with Lexapro for the next two weeks. A baseline brain imaging series (MRI and 2 PET/CT scans) will be obtained at week 10, prior to starting the aripiprazole, on subjects not responding to Lexapro. A second series of images will be obtained at the end of the six weeks of ARP augmentation. The neuroimaging will consist of fMRI, a raclopride PET scan, and a fluoro-dopa PET scan. Ten normal control subjects will not receive any treatment. They will be age and gender matched to study subjects and undergo one set of scans (fMRI,raclopride and FOPA PET scans) to use as comparison group for quality control on a non-depressed population and not for data analysis.
Interventions
DRUGEscitalopram
All subjects will begin on escitalopram and placebo for 8 weeks
DRUGAripiprazole
Subjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.
DRUGPlacebo Capsule
All subjects will begin on escitalopram and placebo capsule for 8 weeks.
DRUGPlacebo Tablet
After 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.
Sponsors
Bristol-Myers Squibb
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Subject)
Intervention model description
This study is designed to help understand the mechanism of action of aripiprazole in MDD augmentation. Subjects will undergo exposure to en an existing antidepressant (Lexapro 10-20mg) for 10 weeks; subjects failing to completely respond to the monotherapy antidepressant treatment will receive augmentation with aripiprazole for six weeks. We have included two placebo phases to the study in which the subjects received one placebo along with the Lexapro for the first 6 weeks and a second placebo along with Lexapro for the next two weeks (weeks 7 and 8). This double placebo design is to ensure that subjects receiving aripiprazole augmentation have a legitimate response (non-placebo) to the aripiprazole augmentation. Since the N of this study is small and a small % of patients with placebo response could skew the imaging data significantly, the use of a double placebo prior to the start of the true aripiprazole augmentation should reduce or eliminate a placebo response.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Treatment Group Inclusion Criteria: 1. Subjects with known history of MDD verified using the Mini International Neuropsychiatric Interview and a Hamilton Depression Rating Scale 17-item score of at least 18 2. Subjects must have failed to respond to one previous adequate dose-duration trial of antidepressant therapy 3. Must complete the MRI screening tool and demonstrate ability to receive an MRI 4. For entry into the ARP augmentation phase the subject must be a non-responder to the escitalopram phase as demonstrated by a MADRS score at week 10, that is not reduced by greater than 50% from baseline.
Exclusion criteria
1. Subjects cannot be smokers 2. No significant history of anxiety disorder 3. Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception 4. The following DSM-IV diagnoses are excluded: Organic mental disorder; substance abuse/dependence, including alcohol, active within the last year; schizophrenia, paranoid or delusional disorders; other psychotic disorders; panic disorder; generalized anxiety disorder; obsessive-compulsive disorder, or post-traumatic stress disorder; bipolar disorder; bulimia nervosa; anorexia nervosa 5. Subjects with serious suicidal risks 6. Subjects who have taken any antidepressant medication other than escitalopram within 5 half lives, of the most recent antidepressant taken 7. Subjects involved in any other form of treatment for depression 8. Subjects who have demonstrated any previous inadequate antidepressant response to electroconvulsive therapy (ECT) 9. Subjects who have received ECT for the current depression episode 10. Subjects who have been hospitalized within 4 weeks of the study 11. Subjects who have received treatment with a monoaminoxidase inhibitor within 2 weeks of enrollment 12. Subjects with a known allergy, hypersensitivity, or previous unresponsiveness to aripiprazole or known intolerance to any study medications 13. Subjects with a history of participation in any investigational medication trial in the past month 14. A positive drug screen or substance use disorder in the past 12 months 15. History of any thyroid pathology 16. History of serotonin syndrome or neuroleptic malignant syndrome 17. History of seizure disorder 18. Subjects who have participated in a trial using PET scans in the past 12 months and in any trial in the past 30 days. Control Group Inclusion Criteria: 1. Ages 18-55 matched to a study subject 2. Must be a healthy subject with no significant medical history 3. Must complete the MRI screening tool and demonstrate ability to receive an MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders | Week 10 and Week 16 (6 weeks of combined therapy) | A ratio of the image derived radioactivity concentration and the whole body concentration of the injected radioactivity specifically in a cluster within the right medial caudate (see data below). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders. | Week 10 and Week 16 (6 weeks of combined therapy) | Montgomery-Åsberg Depression Rating (MADRS) Scale scores compared between the 6 week Aripiprazole augmentation groups (responds vs. non-responders). Total range of the MADRS is 0 to 60, with a score of greater than 34 indicating severe depression, 20-34 indicating moderate depression, 7-19 mild depression, and 0-6 normal or absent of symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Depressed Participants Subjects with treatment-resistant depression (TRD) will receive escitalopram combined with an adjunctive placebo capsule for 8 weeks.
Subjects who fail to respond will continue to receive escitalopram and additionally change to receive a placebo tablet resembling the active augmentation agent Aripiprazole (ARP) for 2 weeks.
Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP.
Subjects will have 3 neuroimaging scans: F-DOPA PET, raclopride PET, and functional MRI conducted after 10 weeks of treatment and repeated after 6 weeks of ARP treatment. | 37 |
| Control Participants Non-depressed, age- and sex-matched subjects without a DSM-IV Axis I diagnosis will serve as controls. They will not receive antidepressant, ARP, or any drug augmentation and will be used to compare the pre-ARP and post-ARP treatment brain images to draw conclusions about the pre-treatment state (depression) and post-treatment state (depression responders). | 6 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1: 8 Weeks Escitalopram + Placebo | Adverse Event | 1 | 0 |
| Phase 1: 8 Weeks Escitalopram + Placebo | Lost to Follow-up | 3 | 0 |
| Phase 1: 8 Weeks Escitalopram + Placebo | Pregnancy | 1 | 0 |
| Phase 1: 8 Weeks Escitalopram + Placebo | Screen failures | 6 | 0 |
| Phase 1: 8 Weeks Escitalopram + Placebo | Withdrawal by Subject | 2 | 0 |
| Phase 2: 2 Weeks Escitalopram + Placebo | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | Depressed Participants | Control Participants | Total |
|---|---|---|---|
| Age, Continuous | 41.69 years | 45.67 years | 42.27 years |
| Region of Enrollment United States | 37 participants | 6 participants | 43 participants |
| Sex: Female, Male Female | 27 Participants | 5 Participants | 32 Participants |
| Sex: Female, Male Male | 10 Participants | 1 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 37 | 0 / 6 |
| serious Total, serious adverse events | 2 / 37 | 0 / 6 |
Outcome results
Primary
Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders
A ratio of the image derived radioactivity concentration and the whole body concentration of the injected radioactivity specifically in a cluster within the right medial caudate (see data below).
Time frame: Week 10 and Week 16 (6 weeks of combined therapy)
Population: The outcome purpose was to examine mechanism of action of aripiprazole in responders versus nonresponders. Control subjects were age and gender matched to study subjects and underwent one set of scans (fMRI, raclopride and FOPA PET scans) for use as a comparison group for quality control on a non-depressed population and not for data analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARP Responders | Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders | Week 10 | 1.297 FDOPA ratio in the right medial caudate | Standard Deviation 0.176 |
| ARP Responders | Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders | Week 16 | 1.333 FDOPA ratio in the right medial caudate | Standard Deviation 0.175 |
| ARP Non-Responders | Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders | Week 10 | 1.363 FDOPA ratio in the right medial caudate | Standard Deviation 0.18 |
| ARP Non-Responders | Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders | Week 16 | 1.350 FDOPA ratio in the right medial caudate | Standard Deviation 0.252 |
Comparison: A region of increased relative Fluorodopa (FDOPA) uptake in the right medial caudate was anticipated for the aripiprazole augmentation responders over the 6 weeks of augmentation treatment (Weeks 10-16).p-value: 0.029t-test, 1 sided
Secondary
Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders.
Montgomery-Åsberg Depression Rating (MADRS) Scale scores compared between the 6 week Aripiprazole augmentation groups (responds vs. non-responders). Total range of the MADRS is 0 to 60, with a score of greater than 34 indicating severe depression, 20-34 indicating moderate depression, 7-19 mild depression, and 0-6 normal or absent of symptoms.
Time frame: Week 10 and Week 16 (6 weeks of combined therapy)
Population: MADRS score comparison between ARP responders and nonresponders.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARP Responders | Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders. | Week 10 | 27.9 score on the MADRS scale | Standard Deviation 5.6 |
| ARP Responders | Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders. | Week 16 | 6.5 score on the MADRS scale | Standard Deviation 3 |
| ARP Non-Responders | Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders. | Week 10 | 31.7 score on the MADRS scale | Standard Deviation 12.7 |
| ARP Non-Responders | Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders. | Week 16 | 25.3 score on the MADRS scale | Standard Deviation 5.5 |
p-value: <0.001t-test, 2 sided
p-value: 0.366t-test, 2 sided