Buprenorphine for Treatment Resistant Depression

University of Pittsburgh13 enrolled

Overview

The purpose of this study is to compare the safety and efficacy of buprenorphine with placebo for adults with treatment resistant depression (TRD).

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Depression Depressive Disorder Depressive Disorder, Major

Interventions

BuprenorphineDRUG

low-dose buprenorphine (range 0.2 mg/day -- 1.6 mg/day)

PlaceboDRUG

matched placebo

Eligibility

Sex: ALLMin age: 21 Years

Medical Language ↔ Plain English

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.

Locations (1)

Western Psychiatric Institute and Clinic, University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Outcomes

Primary Outcomes

Montgomery Asberg Depression Rating Scale

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

Time frame: 6 weeks

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

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

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

Weight

Participant weight

Time frame: 6 weeks

Secondary Outcomes

Brief Symptom Inventory -- Anxiety Subscale

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

Time frame: 6 weeks

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

Data from ClinicalTrials.gov

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