BUP-TRD: Buprenorphine for Treatment Resistant Depression

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Completed
• CT.gov ID: NCT01407575
• Collaborator: National Alliance for Research on Schizophrenia and Depression (Other)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Depression; Depressive Disorder; Depressive Disorder, Major	Drug: Buprenorphine; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Buprenorphine For Treatment Resistant Depression
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Buprenorphine 0.2 to 1.6mg of buprenorphine sublingual over the course of 8 weeks	Drug: Buprenorphine; low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day); Other Names: suboxone buprenex temgesic subutex
Placebo Comparator: Placebo matching placebo- sublingual- over the course of 8 weeks	Drug: Placebo; matched placebo

Outcome Measures

Primary Outcome Measures

1. Montgomery Asberg Depression Rating Scale [6 weeks]

   measure of depression severity Theoretical Range 0-60 lower values represent better outcome

2. Blood Pressure [6 weeks]

   Measure of systolic and diastolic blood pressure. 140/90 or lower is considered normal and indicates a better outcome.

3. 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

4. Heart Rate [6 weeks]

   Heart Rate (Beats per minute) 60-100 beats per minute is considered normal lower heart rate represent healthier outcome

5. Weight [6 weeks]

   Participant weight

Secondary Outcome Measures

1. Brief Symptom Inventory -- Anxiety Subscale [6 weeks]

   measure of anxiety Lower numbers indicate better outcome Theoretical Range 0-2.4

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Western Psychiatric Institute and Clinic, University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• University of Pittsburgh
• National Alliance for Research on Schizophrenia and Depression

Investigators

• Principal Investigator: Jordan F Karp, M.D., University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jordan F. Karp, MD, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01407575
• Other Study ID Numbers: BUP-TRD
• First Posted: Aug 2, 2011
• Last Update Posted: Mar 9, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jordan F. Karp, MD, University of Pittsburgh: Buprenorphine; Receptors, opioid; Receptors, opioid, kappa
• Additional relevant MeSH terms: Disease; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major; Buprenorphine

Study Results

Participant Flow

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Period Title: Overall Study
STARTED	7	6
COMPLETED	5	5
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Buprenorphine	Placebo	Total
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo	Total of all reporting groups
Overall Participants	7	6	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.92 (15.88)	64.59 (5.01)	59.66 (12.17)
Sex: Female, Male (Count of Participants)
Female	2 28.6%	3 50%	5 38.5%
Male	5 71.4%	3 50%	8 61.5%

Outcome Measures

1. Primary Outcome

Title	Montgomery Asberg Depression Rating Scale
Description	measure of depression severity Theoretical Range 0-60 lower values represent better outcome
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	33.8 (10.96)	32.6 (2.07)

2. Primary Outcome

Title	Blood Pressure
Description	Measure of systolic and diastolic blood pressure. 140/90 or lower is considered normal and indicates a better outcome.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Measure Participants	5	5
Systolic Blood Pressure	138.4 (22.71)	117.2 (28.1)
Diastolic Blood Pressure	91 (14.92)	71 (15.92)

3. Primary Outcome

Title	UKU Side Effect Rating Scale
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	29.2 (13.74)	20.2 (5.36)

4. Secondary Outcome

Title	Brief Symptom Inventory -- Anxiety Subscale
Description	measure of anxiety Lower numbers indicate better outcome Theoretical Range 0-2.4
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	1.43 (1.1)	0.97 (0.74)

5. Secondary Outcome

Title	Positive and Negative Affect Scale
Description	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

Outcome Measure Data

Analysis Population Description

reduced sample size verified. This was secondary to administrative error.

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Measure Participants	4	4
PANAS positive affect subscale	13.75 (0.96)	16.25 (2.99)
PANAS negative affect subscale	22 (11.4)	20.5 (1.73)

6. Primary Outcome

Title	Heart Rate
Description	Heart Rate (Beats per minute) 60-100 beats per minute is considered normal lower heart rate represent healthier outcome
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	0.2 to 1.6mg of buprenorphine sublingual over the course of 8 weeks Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	matching placebo- sublingual- over the course of 8 weeks Placebo: matched placebo
Measure Participants	5	5
Mean (Standard Deviation) [Beats per minute]	87.25 (12.84)	72.6 (19.73)

7. Primary Outcome

Title	Weight
Description	Participant weight
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)	Placebo: matched placebo
Measure Participants	5	5
Mean (Standard Deviation) [lbs]	191.7 (30.02)	203.7 (12.99)

Adverse Events

Arm/Group Title	Buprenorphine		Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)		Placebo: matched placebo
All Cause Mortality
	Buprenorphine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Buprenorphine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Buprenorphine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.