Buprenorphine for Late-Life Treatment Resistant Depression

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.

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.