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

Inclusion Criteria: 1. Age \> 50 years 2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV (or SCID-5 if available) 3. MADRS \> 15 4. Has or agrees to establish a clinical relationship with primary care physician (PCP). 5. Availability of an informant (e.g., emergency contact) is encouraged but not required for study participation 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 3MS \< 80 and clinical evidence of dementia 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 score of \> 8 on AUDIT-C and confirmed by study physician interview 6. 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 7. Contraindication to venlafaxine or buprenorphine as determined by PCP and study physician including history of intolerance of either venlafaxine or buprenorphine in the study target dosage range (venlafaxine at up to 300 mg/day; buprenorphine at up to 1.2 mg/day) 8. 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) 9. Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview) 10. 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 11. 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 32 -36 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) 12. History of opiate abuse or dependence 13. Severe pain, defined as \> 7 on 0-10 numeric rating scale for pain 14. Concomitant use of strong or moderate CYP3A4 inhibitor (indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketonazole, nefazodone, saquinovir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem) 15. Refusal to stop all opioids (to avoid precipitating opioid withdrawal) 16. Refusal to discontinue all alcohol (to reduce the risk of respiratory depression) 17. Hepatic impairment (AST/ALT \> 1.5 times upper normal) 18. Estimated Glomerular Filtration Rate (GFR) \< 20 ml/min 19. Inability/refusal to identify a person as an emergency contact \-