Major Depressive Disorder
Conditions
Brief summary
In this Phase 4 trial we will study the safety, tolerability and efficacy of mixed salts amphetamine (MSA), trade name Adderall, augmentation of antidepressant therapy for Major Depressive Disorder (MDD) in depressed outpatient adults who are taking an antidepressant but have not had complete resolution of their symptoms.
Detailed description
Forty adult outpatients with MDD who failed at least one adequate trial of antidepressant monotherapy will be consented in a 63-day, cross-sequential, multicenter study comprising two treatment phases of 21 days each. The time frame from consent to baseline is 7 days. Patients will receive placebo or MSA in Phase 1, and in Phase 2, participants will receive MSA. There will also be a two-week follow up visit after the completion of Phase 2. We hypothesize that MSA will be safe and well tolerated, and will improve the patient's response to their antidepressant and provide superior symptom relief to antidepressant alone. The primary outcome measure is the Massachusetts General Hospital Cognitive-Physical Function Questionnaire (MGH-CPFQ).
Interventions
DRUGmixed salts amphetamine
adjunctive to ADT
Sponsors
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female outpatients between the ages of 18-70. 2. Subject must meet criteria for single or recurrent, non-psychotic episode of MDD according to Diagnostic and Statistical Manual IV Text Revised (DSM-IV-TR) diagnosis, as determined by Structured Clinical Inventory of Depressive Symptoms (SCID) and confirmed by assessment of investigator. 3. Current depressive episode must be at least 8 weeks in duration. 4. Hamilton Depression Rating Scale 17 (HDRS-17) score ≥ 14 at both the screen and baseline visits. 5. Subject must have been receiving an adequate, stable dose of ADT, based on Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ). 6. Subject must be responding inadequately to his/her current monotherapy ADT in the current major depressive episode (MDE). 7. Subjects must be able to read and understand English and be able to provide written informed consent. 8. Subjects must be considered reliable, able to comply with protocol requirements and understand the risks and benefits, per the investigator's clinical judgment. 9. Female subjects of childbearing potential must agree to use adequate form of birth control throughout the course of the study. \-
Exclusion criteria
1. Inadequate response during the current episode to more than 3 adequate trials of an ADT, as defined by the MGH-ATRQ. 2. Psychiatric hospitalization within the last 6 months. 3. Presence of cognitive disorder(s), bipolar disorder, Axis II pathology or other condition that investigator believes would interfere with participation in the study. 4. Substance use disorder, current (as defined by DSM-IV-TR SCID) or positive results on urine drug screen or laboratory blood tests. 5. Risk to self or others. 6. The presence of any medical condition, current or past, stable or unstable, that contraindicates the use of antidepressant medication or mixed amphetamine salts medication as determined by clinician's judgment. 7. Clinically significant abnormal findings on physical exam, EKG or laboratory tests; current unstable, untreated hypertension in the opinion of the investigator; history of cerebrovascular accident (CVA) or seizure disorder (other than febrile childhood seizure). 8. Allergies and/or adverse drug reactions to MSA. 9. Failure to respond to an adequate trial of MSA adjunctive to ADT in the current episode. 10. Subjects taking narcotics, herbal/homeopathic remedies and/or other substance with psychotropic activity, based upon clinical judgment of study investigator. 11. Pregnant or breastfeeding women. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | Baseline (Visit 2); End Phase I (Visit 5, Week 3): End Phase II (Visit 8, Week 6) | The CPFQ is a seven-item self-administered questionnaire with higher scores indicating increased impairment in cognitive and physical functioning; score range being 7-42. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | Baseline (Visit 2); End Phase I (Visit 5, Week 3): End Phase II (Visit 8, Week 6) | The group treated with mixed salt amphetamine (MSA) adjunctive to antidepressant therapy (ADT) will show a greater mean change from baseline to endpoint as compared to the group treated with placebo (PBO) adjunctive to ADT as measure by the change ion the MADRS scores. The MADRS is clinician-rated and consists of 10 items; each item is rated on a 0-6 scale, resulting in a maximum total score of 60 points, with higher scores indicative of greater depressive symptomology. The MADRS scoring instructions indicate that a total score ranging from 0 to 6 indicates that the patient is in the normal range (no depression), a score ranging from 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, a score of 35 and greater indicates severe depression. There is evidence that an improvement of two points or more on the MADRS is considered clinically relevant. |
| Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | Baseline (Visit 2); End Phase I (Visit 5, Week 3): End Phase II (Visit 8, Week 6) | The group with mixed salt amphetamine (MSA) adjunctive to antidepressant therapy (ADT) will show statistically significant improvement in core residual symptoms of major depressive disorder (MDD) extant on monotherapy ADT as measured by the Quick Inventory of Depressive Symptomatology Self Report 16. 16 items comprising 9 domains; each domain is scored from 0 to 3, with higher scores reflecting greater psychopathology. Total scores range from 0 to 27. Scoring procedure is to include ONLY the highest score on among the 4 sleep items (items 1 to 4); include ONLY the highest score among the 4 weight items (items 6 to 9); include ONLY the highest score on either of the 2 psychomotor items (15 and 16). The scores for these 3 domains are then added to the scores (0-3) for each of the 6 MDD symptom domains for a total score of 0-27. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1(A): Placebo/MSA Phase I (3 weeks) placebo adjunctive to Anti-Depressant Therapy (ADT). The total daily dosing of the concurrent ADT will be as follow: escitalopram 10-40 mg; Fluoxetine 20-80 mg; paroxetine CR (controlled release) 25-100 mg (paroxetine 20-80 mg may be substituted if paroxetine CR is not available); sertraline 100-400 mg; venlafaxine XR (extended release) 150-600 mg; desvenlafaxine 50-200 mg; citalopram 20-80 mg; or duloxetine 60-180 mg; buproprion 150-450 mg; mirtazapine 15-45 mg, tricyclics (standard dosing, individually per label instructions).
Phase II (3 weeks) mixed salts amphetamine adjunctive to ADT
mixed salts amphetamine: adjunctive to ADT | 21 |
| Group 2(B): MSA/MSA mixed salts amphetamine, adjunctive to Anti-Depressant Therapy (ADT). The total daily dosing of the concurrent ADT will be as follow: escitalopram 10-40 mg; Fluoxetine 20-80 mg; paroxetine CR (controlled release) 25-100 mg (paroxetine 20-80 mg may be substituted if paroxetine CR is not available); sertraline 100-400 mg; venlafaxine XR (extended release) 150-600 mg; desvenlafaxine 50-200 mg; citalopram 20-80 mg; or duloxetine 60-180 mg; buproprion 150-450 mg; mirtazapine 15-45 mg, tricyclics (standard dosing, individually per label instructions).
Phase II (3 weeks) mixed salts amphetamine adjunctive to ADT
mixed salts amphetamine: adjunctive to ADT | 20 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 | Adverse Event | 0 | 1 |
| Phase 1 | Lack of Efficacy | 1 | 0 |
| Phase 1 | Physician Decision | 1 | 1 |
| Phase 1 | Withdrawal by Subject | 3 | 2 |
| Phase 2 | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Group 1(A): Placebo/MSA | Group 2(B): MSA/MSA | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 19 Participants | 40 Participants |
| Region of Enrollment United States | 21 participants | 20 participants | 41 participants |
| Sex: Female, Male Female | 13 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 8 / 16 | 9 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ)
The CPFQ is a seven-item self-administered questionnaire with higher scores indicating increased impairment in cognitive and physical functioning; score range being 7-42.
Time frame: Baseline (Visit 2); End Phase I (Visit 5, Week 3): End Phase II (Visit 8, Week 6)
Population: Subjects completing all seven visits and administered the CPFQ. Some subjects completing seven visits were not administered the CPFQ in error.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1(A): Placebo/MSA | Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | Baseline (V2) | 27.5 Scores on a scale | Standard Deviation 8.4896 |
| Group 1(A): Placebo/MSA | Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | End Phase I (V5; W3) | 22.6 Scores on a scale | Standard Deviation 7.78 |
| Group 1(A): Placebo/MSA | Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | End Phase II (V8; W6) | 16 Scores on a scale | Standard Deviation 4.69 |
| Group 2(B): MSA/MSA | Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | Baseline (V2) | 29 Scores on a scale | Standard Deviation 5.33 |
| Group 2(B): MSA/MSA | Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | End Phase I (V5; W3) | 25 Scores on a scale | Standard Deviation 6.45 |
| Group 2(B): MSA/MSA | Change in Scores on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) | End Phase II (V8; W6) | 21 Scores on a scale | Standard Deviation 5.73 |
Secondary
Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS)
The group treated with mixed salt amphetamine (MSA) adjunctive to antidepressant therapy (ADT) will show a greater mean change from baseline to endpoint as compared to the group treated with placebo (PBO) adjunctive to ADT as measure by the change ion the MADRS scores. The MADRS is clinician-rated and consists of 10 items; each item is rated on a 0-6 scale, resulting in a maximum total score of 60 points, with higher scores indicative of greater depressive symptomology. The MADRS scoring instructions indicate that a total score ranging from 0 to 6 indicates that the patient is in the normal range (no depression), a score ranging from 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, a score of 35 and greater indicates severe depression. There is evidence that an improvement of two points or more on the MADRS is considered clinically relevant.
Time frame: Baseline (Visit 2); End Phase I (Visit 5, Week 3): End Phase II (Visit 8, Week 6)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1(A): Placebo/MSA | Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | Baseline (V2) | 24.18 Scores on a scale | Standard Deviation 6.54 |
| Group 1(A): Placebo/MSA | Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | End of Phase I (V5; W3) | 11.55 Scores on a scale | Standard Deviation 7.67 |
| Group 1(A): Placebo/MSA | Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | End of Phase II (V8; W6) | 7.10 Scores on a scale | Standard Deviation 4.76 |
| Group 2(B): MSA/MSA | Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | Baseline (V2) | 27 Scores on a scale | Standard Deviation 6.2 |
| Group 2(B): MSA/MSA | Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | End of Phase I (V5; W3) | 18.31 Scores on a scale | Standard Deviation 10.24 |
| Group 2(B): MSA/MSA | Change in Scores of the Montgomery Asberg Depression Rating Scale (MADRS) | End of Phase II (V8; W6) | 10.17 Scores on a scale | Standard Deviation 8.33 |
Secondary
Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16)
The group with mixed salt amphetamine (MSA) adjunctive to antidepressant therapy (ADT) will show statistically significant improvement in core residual symptoms of major depressive disorder (MDD) extant on monotherapy ADT as measured by the Quick Inventory of Depressive Symptomatology Self Report 16. 16 items comprising 9 domains; each domain is scored from 0 to 3, with higher scores reflecting greater psychopathology. Total scores range from 0 to 27. Scoring procedure is to include ONLY the highest score on among the 4 sleep items (items 1 to 4); include ONLY the highest score among the 4 weight items (items 6 to 9); include ONLY the highest score on either of the 2 psychomotor items (15 and 16). The scores for these 3 domains are then added to the scores (0-3) for each of the 6 MDD symptom domains for a total score of 0-27.
Time frame: Baseline (Visit 2); End Phase I (Visit 5, Week 3): End Phase II (Visit 8, Week 6)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1(A): Placebo/MSA | Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | Baseline (V2; W1) | 12.5 Scores on a scale | Standard Deviation 3.8 |
| Group 1(A): Placebo/MSA | Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | End of Phase I (V5; W3) | 7.8 Scores on a scale | Standard Deviation 3.22 |
| Group 1(A): Placebo/MSA | Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | End of Phase II (V7; W6) | 5 Scores on a scale | Standard Deviation 2.2 |
| Group 2(B): MSA/MSA | Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | Baseline (V2; W1) | 14 Scores on a scale | Standard Deviation 4.5 |
| Group 2(B): MSA/MSA | Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | End of Phase I (V5; W3) | 8.7 Scores on a scale | Standard Deviation 5.6 |
| Group 2(B): MSA/MSA | Change in Scores on the Quick Inventory of Depressive Symptomatology Self Report 16 (QIDS-SR-16) | End of Phase II (V7; W6) | 5.3 Scores on a scale | Standard Deviation 4.4 |