Incomplete Response in Late-Life Depression: Getting to Remission With Buprenorphine

1. Age >/= to 50 years.
2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the Structured Clinical Interview for the DSM IV (SCID-IV).
3. Montgomery-Åsberg 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.,Montgomery-Åsberg Depression Rating Scale ( MADRS) \< 15 at the baseline assessments.
3. Dementia, as defined by The Modified Mini-Mental State (3MS) examination \< 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 Structured Clinical Interview for DSM (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. Alcohol use amounting to 15 or more drinks per week or drinking 5 or more drinks on one occasion during any given week.
7. High risk for suicide (e.g., active suicidal ideation (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 extended release (XR) or BPN as determined by 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, 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. Sodium and glucose levels done in the past 6 months are also reviewed before a subject begins study medication to determine if an illness is stable or uncontrolled. Individual lab parameters may deviate from normal without any associated pathophysiology or negative clinical affect; therefore we will follow the guide below before beginning starting any study medication.

    Sodium value of 135 but asymptomatic= consider to be normal and proceed without further testing.

    Sodium value of 134= repeat sodium. If value continues to be at 134 or higher and subject is asymptomatic, continue study participation but recheck sodium level after one week of exposure to study medication to confirm it has stayed stable.

    Sodium value of 133 or less= will evaluate subject's medication list to suggest possibly removing other medications which may be contributing to low sodium (in collaboration with their PCP), suggest fluid restriction and require repeat sodium that is normal range prior to commencing study.

    Glucose \< 275 and asymptomatic= stable to proceed but will communicate value to PCP with participants permission.

    (see exclusion #17 for information on hepatic function lab parameters)

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 opiate 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, ketonazole, nefazodone, saquinovir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem)
16. Refusal to stop all opioids (to avoid precipitating opioid withdrawal).
17. Hepatic impairment- aspartate aminotransferase (AST) /alanine aminotransferase (ALT) > 1.5 times upper normal. If AST and ALT are within 1.5 times the upper limit, and subjects are asymptomatic, they will be considered medically stable to participate
18. Estimated Glomerular Filtration Rate (GFR) \< 20 ml/min.
19. Inability/refusal to identify a person as an emergency contact.
20. Pregnancy
21. Contraindications to MRI