Buprenorphine Used With Treatment Resistant Depression in Older Adults

We will consent approximately 100 participants, aged 50 and older, of both sexes and all
races. Participation may last up to 32 weeks. We will utilize a clinical trial that has 3
Phases. In Phase 1 we will treat participants with an approximate 12 week course of
open-label venlafaxine XR. This is the same lead-in treatment as in our ongoing "IRL Grey"
("Incomplete Response in Late Life Depression: Getting to Remission") multi-site R01 for
late-life treatment resistant depression (LL-TRD), and we have found it to be highly
successful. Participants who find relief from their depressive symptoms on venlafaxine XR
alone will exit the study. Participants meeting criteria for an incomplete response (those
still feeling depressed or withdrawn), will be randomly assigned to receive either low-dose
buprenorphine or placebo augmentation of venlafaxine xr for 8 weeks (Phase 2), with the goal
of achieving remission. Subjects will start at 0.2mg and titrate up as needed to 1.2mg.
Subjects may undergo up to 2 MRI scans at the beginning and end of Phase 2 as well as
cognitive testing at the same time points. At the conclusion of Phase 2, the blind will be
broken for all participants. The participants who were on placebo will be able to begin
taking buprenorphine immediately for Phase 3 (approximately 8 weeks). The participants who
were already on buprenorphine in Phase 2 can continue to take it during Phase 3.
Buprenorphine (BPN) will be tapered upon exiting the study, under the guidance of the P.I.
The Phase 3 variations will allow all participants a chance to experience the benefits of
buprenorphine (BPN). Efficacy and tolerability data will provide a clinically informative
estimate of benefits and risks of buprenorphine augmentation for late-life treatment
resistant depression (LL-TRD). We will randomize approximately 20 subjects into Phase 2.
Additionally, we will collect buprenorphine (BPN) plasma levels on all those randomized to
explore a dose-effect relationship on treatment response.

A small pilot study (ages 21 and up) of up to 15 healthy control subjects will be studied
over an approximate 2 week period in order to ensure all of our procedures are working and to
determine that there are clinical effects from buprenorphine. Control subjects will undergo a
baseline PET/MRI before taking buprenorphine. At least 24 hours after the imaging, control
subjects will receive a small dose of BPN starting at 0.2 mg/day and will titrate up as
tolerated to 1.2 mg/day for the first week. Each subject will remain at approximately 1.2
mg/day for the duration of the study. At the end of the study, subjects will undergo a second
PET/MRI.

Inclusion Criteria for Main Study:

1. Age > or = to 50 years.

2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the Structured
Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders
(SCID-IV).

3. Montgomery Asberg Depression Rating Scale (MADRS) >/= to 15.

4. Has or agrees to establish a clinical relationship with primary care physician (PCP).

5. Availability of an informant (e.g., emergency contact).

Exclusion Criteria:

1. Inability to provide informed consent.

2. Depressive symptoms not severe enough (i.e., MADRS < 15) at the baseline assessments

3. Dementia, as defined by Mini Mental State Exam (3MS) < 84 and clinical evidence of
dementia (e.g., memory impairment, executive dysfunction, agnosia, apraxia, aphasia,
with functional impairment).

4. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective
disorder, schizophreniform disorder, delusional disorder, or current psychotic
symptoms, as diagnosed by the SCID.

5. Abuse of or dependence on alcohol or other substances within the past 3 months as
determined by SCID, and confirmed by study physician interview.

6. Drinking 15 or more drinks per week or consuming 5 or more drinks on any one occasion
in the past week.

7. High risk for suicide (e.g., active SI and/or current/recent intent or plan) and
unable to be managed safely in the clinical trial (e.g., unwilling to be
hospitalized). Urgent psychiatric referral will be made in these cases.

8. Contraindication to venlafaxine XR or BPN as determined by PCP and study physician
including history of intolerance of either venlafaxine XR or BPN in the study target
dosage range (venlafaxine XR at up to 300 mg/day; BPN at up to 2 mg/day).

9. Inability to communicate in English (i.e., interview cannot be conducted without an
interpreter; subject largely unable to understand questions and cannot respond in
English).

10. Non-correctable clinically significant sensory impairment (i.e., cannot hear well
enough to cooperate with interview).

11. Unstable medical illness, including delirium, uncontrolled diabetes mellitus,
hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that
are not under medical management. This will be determined based on information from
the patient's personal physician and study physician's clinical judgment. Referral to
the patient's personal physician or to a general practitioner will be made in these
cases.

12. Subjects taking psychotropic medications that cannot be safely tapered and
discontinued prior to study initiation. The following exceptions are allowed if they
have been taken at a stable dose for at least 4 weeks prior to study entry and there
is not a plan to change the dose during the next 28 weeks: benzodiazepines up to 2
mg/d lorazepam equivalent; other sedative-hypnotics (e.g., zolpidem, zaleplon,
eszopiclone); gabapentin if prescribed for non-psychiatric indication (e.g.,
neuropathy).

13. History of opioid abuse or dependence.

14. Severe pain, defined as > 7 on 0-10 numeric rating scale for pain.

15. Concomitant use of strong or moderate CYP3A4 inhibitor (indinavir, nelfinavir,
ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir,
telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil,
diltiazem).

16. Refusal to stop all opioids (to avoid precipitating opioid withdrawal).

17. Hepatic impairment

18. Estimated Glomerular Filtration Rate (GFR) < 20 ml/min.

19. Inability/refusal to identify a person as an emergency contact.

20. Pregnancy