BUILD: Buprenorphine for Late-Life Treatment Resistant Depression

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Completed
• CT.gov ID: NCT01071538
• Collaborator: National Institutes of Health (NIH) (NIH), Reckitt Benckiser LLC (Industry), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The goals of this pilot study are to gather data about the safety and clinical effect of low-dose buprenorphine in older adults with treatment resistant depression.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: Buprenorphine	Phase 2

Detailed Description

We are recruiting 20 participants for this pilot study. Subjects are recruited from either:

1. An ongoing study of Late-Life Depression(MH083660; PI: Reynolds) who did not meet research response criteria; and 2) community-dwelling individuals, at least 50 years old, who have tried at least two FDA-approved antidepressant medications at therapeutic doses each for at least 6 weeks, and who are currently in an episode of major depression.

Overview of intervention: To guide future placebo-controlled work, at this preliminary stage of research we will collect data about both buprenorphine (BUP) 1) augmentation pharmacotherapy, and 2) monotherapy. Subjects recruited from the community will have the buprenorphine prescribed as augmentation to any currently prescribed antidepressant medication.

BUP 0.2 mg will be used for the first week. The first dose will be administered at the clinic under the supervision of the PI. Because peak plasma levels occur 60 minutes after ingestion, subjects will be re-assessed after 1 hour for safety. Participants will be seen weekly for eight weeks to assess progress and monitor intervention-emergent side effects. Dosing increases will be guided by antidepressant response (e.g., continued MADRS scores > 10 will trigger an increase dose of BUP) and our protocolized use of the Frequency, Intensity, and Burden of Side Effect Rating (FIBSER) Scale score. For example, a score of 5 to 7 on the FIBSER will trigger additional assessment of side effects and require justification for increasing the dose, while a score of > 7 will signal no increase in dose, although specific side effects should be reviewed in detail before a final determination, including review if the UKU Side Effects Rating Scale.

We will increase the dose by 0.2 mg/week up to 1.6 mg/day based on MADRS and FIBSER scores. Every time the dose is increased, the first ingestion of the higher dose will be monitored in the clinic as described above.

Subjects will participate in the project at the Late-Life Depression Clinic on the 7th Floor of Bellefield Tower. Subjects will complete paper and pencil and clinician-administered psychiatric assessments before receiving the first dose of buprenorphine and at all subsequent visits. After the first ingestion and all subsequent first ingestions of higher doses of BUP, subjects will remain in the clinic for 60 minutes after ingestion and be re-assessed for the emergence of side effects and have vital signs re-checked. The duration of the first visit will be approximately 2.5 hours. If subsequent visits require observed ingestion of buprenorphine, they will last about 1.75 hours. If subsequent visits do not require observed ingestion of buprenorphine, these visits will last 30-45 minutes.

Prior to the first ingestion, the first ingestion of subsequent higher doses, and at study end, subjects will complete a 15 minute battery of computerized neuropsychological tests assessing reaction time and attention. These tests will be repeated 60 minutes after the ingestion. Prior to the first ingestion and after discontinuation of the buprenorphine, memory will be assessed with the Hopkins Verbal Learning Test (HVLT). The HVLT takes about 10 minutes to complete.

The discontinuation phase will occur during weeks 9-12. To minimize the risk of withdrawal symptoms, we will discontinue the buprenorphine slowly by reducing the dose to 0.4 mg/day for 7 days, then 0.2 mg/day every other day for 7 days, and then stop the buprenorphine. We will see subjects weekly over these four weeks.

The final visit will occur at week 16. This will be a telephone check in of mood and functioning. This call will take about 15-20 minutes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Buprenorphine for Late-Life Treatment Resistant Depression
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Buprenorphine Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12.	Drug: Buprenorphine; Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.

Outcome Measures

Primary Outcome Measures

1. Montgomery Asberg Depression Rating Scale [8 weeks]

   measure of depression severity theoretical scale range 0-60 Lower values represent better outcome

2. Blood Pressure [8 weeks]

   Blood Pressure- systolic and diastolic 140/90 or lower is considered normal and indicates a better outcome.

3. UKU Side Effect Rating Scale [8 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 [8 weeks]

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

Secondary Outcome Measures

1. Brief Symptom Inventory -- Anxiety Subscale [8 weeks]

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

2. Positive and Negative Affect Scale [8 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.

3. Pain Numeric Rating Scale (20 Item) [8 weeks]

   measure of average physical pain score range 0-20 Higher scores indicate worse outcome

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age >/= 50 years

• 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.

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.

• 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.

• 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 Clinica, University of Pittsburgh School of Medicine	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• University of Pittsburgh
• National Institutes of Health (NIH)
• Reckitt Benckiser LLC
• National Center for Research Resources (NCRR)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Information about buprenorphine
• This link describes our other work with late-life depression at our NIH-funded research clinic in Pittsburgh, PA

Publications

• Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995 Feb;15(1):49-57.
• Emrich HM, Vogt P, Herz A. Possible antidepressive effects of opioids: action of buprenorphine. Ann N Y Acad Sci. 1982;398:108-12.
• Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC Jr, Jones RM, Portoghese PS, Carlezon WA Jr. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003 Apr;305(1):323-30.
• Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy. J Clin Psychopharmacol. 2008 Oct;28(5):593-5. doi: 10.1097/JCP.0b013e31818638a4.

• Responsible Party: Jordan F. Karp, Associate Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01071538
• Other Study ID Numbers: BUILD; KL2RR024154
• First Posted: Feb 19, 2010
• 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, Associate Professor, University of Pittsburgh: Depressive Disorder, Major; Late-Life Depression; Geriatrics; Buprenorphine
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Buprenorphine

Study Results

Participant Flow

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Period Title: Overall Study
STARTED	15
COMPLETED	13
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Overall Participants	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.7 (5.6)
Sex: Female, Male (Count of Participants)
Female	8 53.3%
Male	7 46.7%

Outcome Measures

1. Primary Outcome

Title	Montgomery Asberg Depression Rating Scale
Description	measure of depression severity theoretical scale range 0-60 Lower values represent better outcome
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	15
Mean (Standard Deviation) [units on a scale]	9.5 (9.5)

2. Primary Outcome

Title	Blood Pressure
Description	Blood Pressure- systolic and diastolic 140/90 or lower is considered normal and indicates a better outcome.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	13
systolic blood pressure	122.5 (23.0)
diastolic blood pressure	70.5 (12.1)

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	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	13
Mean (Standard Deviation) [units on a scale]	6.2 (3.5)

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	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	13
Mean (Standard Deviation) [units on a scale]	0.6 (0.8)

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	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	13
Positive affect subscale	29.4 (12.0)
Negative affect subscale	15.5 (6.7)

6. Secondary Outcome

Title	Pain Numeric Rating Scale (20 Item)
Description	measure of average physical pain score range 0-20 Higher scores indicate worse outcome
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	13
Mean (Standard Deviation) [units on a scale]	4.6 (5.2)

7. 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	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
Measure Participants	13
Mean (Standard Deviation) [beats per minute]	72.7 (9.9)

Adverse Events

Arm/Group Title	Buprenorphine
Arm/Group Description	Older adults with treatment resistant depression will receive buprenorphine up to 1.6 mg/day for 8 weeks. Discontinuation of the buprenorphine will occur during weeks 9-12. Buprenorphine: Sublingual buprenorphine 0.2 mg will be used for the first week. The dose will be increased by 0.2 mg/week based on safety and clinical response up to a maximal dose of 1.6 mg/day.
All Cause Mortality
	Buprenorphine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Buprenorphine
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Buprenorphine
	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)
Gastrointestinal disorders
constipation	1/15 (6.7%)	1

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.