Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, Cognitive Impairment, Partial Response, Residual Symptoms
Brief summary
This study aims to test the effect of a newly-approved stimulant medication, lisdexamfetamine dimesylate (Vyvanse), on specific residual symptoms of depression found in some patients who are undergoing treatment with, but have only partially responded to, a selective-serotonin reuptake inhibitor (SSRI) or selective-norepinephrine reuptake inhibitor (SNRI) antidepressant. Specifically, the investigators hypothesize that symptoms potentially related to deficient dopaminergic activity, such as lassitude, apathy, reduced positive affect and impaired executive function, in particular, will improve. This protocol is designed to test the hypothesis that this cluster of co-occurring residual symptoms sometimes found in treated depression will respond as a group to adjunctive psychostimulant therapy. The investigators propose to demonstrate this cluster of residual depressive symptoms and to measure the effect of stimulant therapy on it. The investigators hope to better understand the specific symptoms in this clinical population that are likely to improve with stimulant therapy.
Detailed description
This protocol is designed to test the hypothesis that a cluster of co-occurring residual symptoms sometimes found in treated depression will respond as a group to psychostimulant therapy. This cluster includes apathy, reduced drive, fatigue, impaired executive function and other cognitive measures, and low positive affect. We propose to measure this cluster of symptoms in a population of residually depressed subjects demonstrating them, and then to measure the effect of stimulant therapy on this cluster, and each constituent symptom, as well as to measure its effect on subjects' overall functional impairment, and to document treatment emergent adverse effects. The goal is to gather data about the response of these residual symptoms to stimulant therapy. Since each subject will be exposed to active treatment and matched placebo, a benefit to individual participants will be to learn if their specific symptom burden is ameliorated by stimulant therapy, and what adverse effects may emerge for them. We hope to develop an understanding of the specific symptoms in this clinical population that are likely to improve with stimulant therapy. We also hope to be able to characterize the side effect burden of stimulant therapy in this clinical population.
Interventions
DRUGLisdexamfetamine Dimesylate (Vyvanse)
Lisdexamfetamine Dimesylate (Vyvanse) capsules dose ranging from 20mg to 50 mg.
DRUGPlacebo
Lisdexamfetamine Dimesylate (Vyvanse)-matched placebo capsules.
Sponsors
Shire
Mclean Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Both the study participant and the study investigators making evaluations are blinded to which treatment arm the participants are assigned to (i.e., whether they are receiving placebo or Vyvanse at any given point). Placebo and active medication capsules look identical.
Intervention model description
This is a double-blind, placebo-controlled, crossover study in which each subject will act as their own control after being randomly assigned to placebo or Lisdexamfetamine Dimesylate (Vyvanse) for the first 4 weeks of study treatment, then receiving the other for the second 4 weeks of treatment. The two 4-week treatment periods are separated by a washout of 2 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Meeting diagnostic criteria for major depression during the present episode of illness, currently with at least mild improvement by report (CGI-I ≥3) but with continuing residual symptoms. 2. A score of ≥10 on MADRS items 1,2,6,7 and 8, (the MADRS Dysphoric Apathy/Retardation factor, Parker et al., 2003) at screening and randomization. These 5 items are: Apparent sadness, Reported sadness, Concentration difficulties, Lassitude, and Inability to feel. A score of ≥3 will be required for at least 2 of these items. 3. A score of 3 or 4 on the Clinical Global Impression of Severity (CGI-S) at screening and randomization. 4. At randomization subjects must have received therapeutic dosages of approved SSRI or SNRI agents for at least 8 weeks, with the last 4 weeks at a constant dosage. 5. Females of Child-bearing Potential (FOCP) must have a negative serum beta Human Chorionic Gonadotropin (B-hCG) pregnancy test at the screening visit and a negative urine pregnancy test at the baseline visit, and agree to use one of the following methods of birth control: oral contraceptives, contraceptive implants, injectable contraceptives, IUDs, double-barrier contraception, sexual abstinence or vasectomized partner(s).
Exclusion criteria
1. Treatment within 4 weeks of randomization with any non-SSRI/SNRI antidepressant (trazodone is permitted up to 100 mg at night for sleep); any antipsychotic agent; any mood stabilizer; any standing benzodiazepine regimen other than at low doses for sleep (≤ 1 mg lorazepam HS or the equivalent); or a standing regimen of any other agent that may affect cognitive function (e.g., psychostimulants, including modafinil or R-modafinil). 2. Any current or past psychotic disorder, Bipolar I or II disorder, Current panic disorder, History of ADHD, Antisocial Personality Disorder or Borderline Personality Disorder, Mental retardation or any dementing disorder. 3. Covi Anxiety Scale score greater than Raskin Depression Scale score at Screening, to exclude subjects with more prominent anxiety than depression 4. MADRS Sleep (item 4), or Appetite (item 5) \>3 at screening or randomization 5. Initial insomnia at screening that is not adequately controlled by sleep medication (trazodone up to 100 mg HS for sleep and/or ≤ 1 mg lorazepam HS or the equivalent). 6. Medical conditions that might be exacerbated by Vyvanse treatment, such as uncontrolled hypertension or angina; or conditions that would make study findings hard to interpret, such as hyperthyroidism 7. History of seizure (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or family history of Tourette's Disorder. 8. Known cardiac structural abnormality or any other condition that may affect cardiac performance 9. Any clinically significant ECG or laboratory abnormality at Screening 10. Current abnormal thyroid function, as defined by abnormal TSH at Screening (Treatment with a stable dose of thyroid medication for at least 3 months is permitted if TSH is normal at screening). 11. Suicide attempt within the past 2 years or a history of any homicidal behavior. 12. MADRS Suicidal thoughts (item 10) \>4 at any study visit, or if a patient is considered by the investigator to be at clinical risk of suicide at any time in the course of the study. 13. resting sitting systolic blood pressure \>149mmHg or diastolic blood pressure \> 95mmHg. Subjects may be on monotherapy with anti-hypertensive medication. 14. documented allergy, hypersensitivity, intolerance, or non-responsivity to methylphenidate or amphetamines. 15. Subject has a history of a substance use disorder (abuse or dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, within 6 months prior to screening. 16. Subject has glaucoma 17. Subject is taking other medications that have central nervous system (CNS) effects or affect performance, such as sedating antihistamines and decongestant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Baseline to 4 weeks of treatment | The Montgomery-Asberg Depression Rating Scale Dysphoric Apathy Retardation subfactor (MDAR) is a 5-item subscale of the clinician-administered 10-item Montgomery-Asberg Depression Rating Scale (MADRS). MDAR score can range from 0-30 with a higher score representing a greater severity of depressive symptoms. |
Countries
United States
Participant flow
Recruitment details
35 potential subjects were screened for eligibility between September 2010 and April 2014 at McLean Hospital in Belmont, MA.
Pre-assignment details
Of the 35 subjects screened, 29 were randomized. Of the 6 not randomized, 3 did not meet inclusion criteria, 1 withdrew consent, and 2 were lost to follow post screening. Of the 29 randomized, 28 completed both parts of the study. One subject was lost to follow after 3 weeks in the first half. Data were analyzed for the 28 completers only.
Participants by arm
| Arm | Count |
|---|---|
| Placebo, Then Vyvanse Participants first received Placebo capsule (matching Lisdexamfetamine Dimesylate(Vyvanse) 20-50 mg capsule) each morning for 4 weeks. After a washout period of 2 weeks, they then received Lisdexamfetamine Dimesylate capsule each morning for 4 weeks.
Lisdexamfetamine Dimesylate (Vyvanse): Lisdexamfetamine Dimesylate (Vyvanse) capsules dose ranging from 20mg to 50 mg.
Placebo: Lisdexamfetamine Dimesylate (Vyvanse)-matched placebo capsules. | 13 |
| Vyvanse, Then Placebo Participants first received Lisdexamfetamine Dimesylate 20-50 mg capsule each morning for 4 weeks. After a washout period of 2 weeks, they then received Placebo capsule (matching Lisdexamfetamine Dimesylate (Vyvanse) capsule) each morning for 4 weeks.
Lisdexamfetamine Dimesylate (Vyvanse): Lisdexamfetamine Dimesylate (Vyvanse) capsules dose ranging from 20mg to 50 mg.
Placebo: Lisdexamfetamine Dimesylate (Vyvanse)-matched placebo capsules. | 16 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo, Then Vyvanse | Vyvanse, Then Placebo | Total |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 10.6 | 48.9 years STANDARD_DEVIATION 11.4 | 50.6 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 13 Participants | 16 Participants | 29 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 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 / 28 | 0 / 28 |
| other Total, other adverse events | 23 / 28 | 18 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks.
The Montgomery-Asberg Depression Rating Scale Dysphoric Apathy Retardation subfactor (MDAR) is a 5-item subscale of the clinician-administered 10-item Montgomery-Asberg Depression Rating Scale (MADRS). MDAR score can range from 0-30 with a higher score representing a greater severity of depressive symptoms.
Time frame: Baseline to 4 weeks of treatment
Population: All participants who completed all 4 weeks on both treatments (i.e., Placebo and Vyvanse) were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Adjunct | Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Baseline Mean MDAR score | 12.57 scores on a scale | Standard Deviation 3.98 |
| Placebo Adjunct | Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Week 4 Mean MDAR score | 9.08 scores on a scale | Standard Deviation 5.51 |
| Placebo Adjunct | Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Change from BL in mean MDAR score | -3.49 scores on a scale | Standard Deviation 4.66 |
| Lisdexamfetamine Dimesylate (Vyvanse) | Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Baseline Mean MDAR score | 13.46 scores on a scale | Standard Deviation 3.94 |
| Lisdexamfetamine Dimesylate (Vyvanse) | Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Week 4 Mean MDAR score | 6.36 scores on a scale | Standard Deviation 5.54 |
| Lisdexamfetamine Dimesylate (Vyvanse) | Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks. | Change from BL in mean MDAR score | -7.08 scores on a scale | Standard Deviation 5.03 |
Comparison: The statistical analysis represents a within-subject comparison of change under treatment with Vyvanse versus change under treatment with placebo, using paired t-tests with each subject as their own control. All tests reported are two-tailed.p-value: <0.05t-test, 2 sided