Depression, Depressive Disorder, Depressive Disorder, Major
Conditions
Keywords
Buprenorphine, Receptors, opioid, Receptors, opioid, kappa
Brief summary
The purpose of this study is to compare the safety and efficacy of buprenorphine with placebo for adults with treatment resistant depression (TRD).
Detailed description
Rates of treatment resistant depression (TRD) in randomized controlled trials range from 50-80% using SSRIs and SNRIs. Innovative treatments are sorely needed. Modulation of the opiate system may be a novel treatment approach for TRD. Buprenorphine (BUP) is a partial agonist at mu-receptors, and also displays affinity for kappa and delta receptors. BUP has a favorable safety profile with low risk of respiratory depression, and the pharmacokinetics are not affected by advanced age or renal dysfunction. This combination of mu-agonism and kappa-antagonism produces less dysphoria than methadone, and animal studies suggest that kappa-antagonism may exert antidepressant effects. In this small proof of concept RCT (n=20), the investigators hypothesize that there will be differences between the group receiving buprenorphine and the group receiving placebo for the following: 1) depression, anxiety, and sleep, and 2)activation of the limbic system and brain structures rich in opiate receptors and critical to reward circuits. In addition, the investigators hypothesize that there will not be differences for measures of safety (vital signs, measures of memory and reaction time, and falls) between the two groups. This pilot project will provide compelling preliminary data to support a R01 application to test the efficacy of buprenorphine for these therapeutically challenging patients. Specific Aims: 1. Describe the relative safety of BUP in adults with TRD. The investigators hypothesize that there will be no differences in vital signs, measures of memory and reaction time, or falls between the two groups. 2. Describe the clinical effect of BUP in adults with TRD. The investigators hypothesize that depression, anxiety, sleep, and health-related quality of life, will improve to a greater extent among those receiving BUP. 3. Characterize the change in the phMRI responses to buprenorphine compared to placebo. The investigators will compare activation of the limbic system (rACC, insula, and amygdala) and brain structures rich in opiate receptors (periaqueductal grey) and critical to reward circuits (nucleus accumbens) before and immediately after administration of BUP or placebo. The investigators are recruiting 20 community-dwelling adults, age 21 and older, who have tried at least two FDA-approved antidepressant medications at therapeutic doses each for at least 6 weeks during this episode of depression, and are still depressed.
Interventions
DRUGBuprenorphine
low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)
DRUGPlacebo
matched placebo
Sponsors
National Alliance for Research on Schizophrenia and Depression
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 21 and older * Major depressive disorder * Non-responder to at least 2 FDA-approved antidepressants prescribed at a therapeutic dose, each for at least 6 weeks, or is a depression non-responder from an ongoing study of late-life depression at our research clinic. * For women of child-bearing age, must have negative pregnancy test and agree not to get pregnant while participating.
Exclusion criteria
* Concomitant use of strong or moderate CYP3A4 inhibitor. * Refusal to stop all opioids. * Refusal to discontinue all alcohol. * Refusal to discontinue benzodiazepines other than the equivalent of lorazepam 2 mg/day prescribed at a stable dose for at least the past 2 weeks. * Hepatic impairment (AST/ALT \> 1.5 times upper normal). * Lung disease requiring supplemental oxygen (CPAP for sleep apnea is acceptable). * Estimated creatinine clearance \<30 mL/min. * Inability to provide informed consent. * Depressive symptoms not severe enough (i.e., MADRS \< 10) at the baseline assessment. * Dementia, as defined by MMSE \< 24 and clinical evidence of dementia * Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms. * Abuse of or dependence on alcohol or other substances within the past 3 months. * Meets criteria for history of abuse or dependence upon opioids. * High risk for suicide. * Contraindication to buprenorphine. * Inability to communicate in English. * Non-correctable clinically significant sensory impairment. * Unstable medical illness. * Subjects taking psychotropic medications that cannot be safely tapered and discontinued prior to study initiation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Pressure | 6 weeks | Measure of systolic and diastolic blood pressure. 140/90 or lower is considered normal and indicates a better outcome. |
| Heart Rate | 6 weeks | Heart Rate (Beats per minute) 60-100 beats per minute is considered normal lower heart rate represent healthier outcome |
| Weight | 6 weeks | Participant weight |
| Montgomery Asberg Depression Rating Scale | 6 weeks | measure of depression severity Theoretical Range 0-60 lower values represent better outcome |
| UKU Side Effect Rating Scale | 6 weeks | measure of side effects 46 items with scores of 0,1,2,3 possible. Theoretical range 0-138 Lower scores indicate fewer side effects |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive and Negative Affect Scale | 6 weeks | Positive Affect Score: Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Score: Scores can range from 10 - 50, with lower scores representing lower levels of negative affect. |
| Brief Symptom Inventory -- Anxiety Subscale | 6 weeks | measure of anxiety Lower numbers indicate better outcome Theoretical Range 0-2.4 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Buprenorphine Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day) | 7 |
| Placebo Placebo: matched placebo | 6 |
| Total | 13 |
Baseline characteristics
| Characteristic | Total | Placebo | Buprenorphine |
|---|---|---|---|
| Age, Continuous | 59.66 years STANDARD_DEVIATION 12.17 | 64.59 years STANDARD_DEVIATION 5.01 | 53.92 years STANDARD_DEVIATION 15.88 |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 7 | 0 / 6 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 |
Outcome results
Primary
Blood Pressure
Measure of systolic and diastolic blood pressure. 140/90 or lower is considered normal and indicates a better outcome.
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buprenorphine | Blood Pressure | Systolic Blood Pressure | 138.4 mm Hg | Standard Deviation 22.71 |
| Buprenorphine | Blood Pressure | Diastolic Blood Pressure | 91 mm Hg | Standard Deviation 14.92 |
| Placebo | Blood Pressure | Systolic Blood Pressure | 117.2 mm Hg | Standard Deviation 28.1 |
| Placebo | Blood Pressure | Diastolic Blood Pressure | 71 mm Hg | Standard Deviation 15.92 |
Primary
Heart Rate
Heart Rate (Beats per minute) 60-100 beats per minute is considered normal lower heart rate represent healthier outcome
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine | Heart Rate | 87.25 Beats per minute | Standard Deviation 12.84 |
| Placebo | Heart Rate | 72.6 Beats per minute | Standard Deviation 19.73 |
Primary
Montgomery Asberg Depression Rating Scale
measure of depression severity Theoretical Range 0-60 lower values represent better outcome
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine | Montgomery Asberg Depression Rating Scale | 33.8 units on a scale | Standard Deviation 10.96 |
| Placebo | Montgomery Asberg Depression Rating Scale | 32.6 units on a scale | Standard Deviation 2.07 |
Primary
UKU Side Effect Rating Scale
measure of side effects 46 items with scores of 0,1,2,3 possible. Theoretical range 0-138 Lower scores indicate fewer side effects
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine | UKU Side Effect Rating Scale | 29.2 units on a scale | Standard Deviation 13.74 |
| Placebo | UKU Side Effect Rating Scale | 20.2 units on a scale | Standard Deviation 5.36 |
Primary
Weight
Participant weight
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine | Weight | 191.7 lbs | Standard Deviation 30.02 |
| Placebo | Weight | 203.7 lbs | Standard Deviation 12.99 |
Secondary
Brief Symptom Inventory -- Anxiety Subscale
measure of anxiety Lower numbers indicate better outcome Theoretical Range 0-2.4
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine | Brief Symptom Inventory -- Anxiety Subscale | 1.43 units on a scale | Standard Deviation 1.1 |
| Placebo | Brief Symptom Inventory -- Anxiety Subscale | 0.97 units on a scale | Standard Deviation 0.74 |
Secondary
Positive and Negative Affect Scale
Positive Affect Score: Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Score: Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.
Time frame: 6 weeks
Population: reduced sample size verified. This was secondary to administrative error.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buprenorphine | Positive and Negative Affect Scale | PANAS positive affect subscale | 13.75 units on a scale | Standard Deviation 0.96 |
| Buprenorphine | Positive and Negative Affect Scale | PANAS negative affect subscale | 22 units on a scale | Standard Deviation 11.4 |
| Placebo | Positive and Negative Affect Scale | PANAS positive affect subscale | 16.25 units on a scale | Standard Deviation 2.99 |
| Placebo | Positive and Negative Affect Scale | PANAS negative affect subscale | 20.5 units on a scale | Standard Deviation 1.73 |