Buprenorphine for Treatment Resistant Depression

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.

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.