Clinical trial NCT02181231
Conditions: Major Depressive Disorder Depression
Keywords: depression older adult buprenorphine Effexor XR treatment resistant venlafaxine Saint Louis late life major depression
Sponsor: Washington University School of Medicine
Start date: 2016-06-01; Completion date: 2018-04-30
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators are conducting a research study to learn about the safety and benefit of using a medication called buprenorphine for patients with difficult to treat depression. This research study is testing whether combining two medications will be effective in treating depression when initial treatment with just one antidepressant does not relieve the depressive symptoms; this is what is called "difficult to treat depression" or "treatment resistant depression". The two medications the investigators are using are: an anti-depressant medication called venlafaxine extended release (venlafaxine XR), which is the generic form of Effexor, and buprenorphine. Buprenorphine is a medication that is FDA approved for the treatment of opioid dependence. The investigators are testing whether adding buprenorphine to venlafaxine XR enhances treatment response.

Detailed description:
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 Participants meeting criteria for an incomplete response (those still feeling depressed or withdrawn), will be randomly assigned to receive either low-dose buprenorphine or placebo augmentation of venlafaxine xr for 8 weeks (Phase 2), with the goal of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.

Arms: arm 1: Drug: venlafaxine XR plus buprenorphine Dosage varies. Subject remains on antidepressant throughout the 32 week study. Will be randomized to buprenorphine or placebo for up to 16 weeks. 2 MRI sessions may occur before and during randomization. arm 2: Drug: venlafaxine XR plus placebo Dosage varies. Subject remains on antidepressant throughout the 32 week study. Will be randomized to buprenorphine or placebo for up to 16 weeks. 2 MRI sessions may occur before and during randomization.
Interventions: intervention 1: venlafaxine XR intervention 2: buprenorphine intervention 3: Placebo
Intervention descriptions: intervention 1: slow titration up to maximum dose of 300mg per day, will remain on venlafaxine XR for up to 32 weeks intervention 2: randomized to either buprenorphine or placebo, dose range from 0.2 mg/ qd to 2mg/ qd intervention 3: patients will remain on venlafaxine XR and be randomized to receive either placebo or buprenorphine for 8 weeks. at the end of the 8 weeks those who did not receive buprenorphine will be offered the opportunity to try it.

Protocol documents:
Prot_SAP_000.pdf: 
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RESEARCH PROTOCOL 
 
 
Incomplete Response in Late Life Depression: Getting to Remission with Buprenorphine 
 
 
Principal Investigator:  Eric J. Lenze, MD 
 
 
 
Professor of Psychiatry 
 
Washington University School of Medicine 
Department of Psychiatry 
660 S. Euclid Ave., Campus Box 8134 
St. Louis, MO 63110 
Voice: (314) 362-1671 
E-mail: lenzee@wustl.edu 
 
 
 
Collaborator:  Evan Kharasch, MD 
Vice Chancellor for Research 
Russell D. and Mary B. Shelden Professor of Anesthesiology 
Director, Division of Clinical and Translational Research 
Department of Anesthesiology 
Professor of Biochemistry and Molecular Biophysics 
Washington University in St. Louis 
660 S Euclid Ave, Campus Box 8054 
St. Louis, MO 63110-1093 
kharasch@wustl.edu 
T 314-362-8796 
F 314-362-8334 
 
Pilar Cristancho, MD 
Assistant Professor of Psychiatry 
660 S. Euclid Ave., Campus Box 8134 
St. Louis, MO 63110 
cristanp@psychiatry.wustl.edu 
314-362-2413 
 
 
Study Team Members: 
Julia Schweiger, CCRC – Project Manager, Psychiatry (314) 362-3153 
Marissa Rhea, MA, Clinical Research Coordinator, Psychiatry (314)-362-3797 
 
Washington University Human Research Protection Office 
Washington University in St. Louis 
660 S. Euclid Ave., Campus Box 8089 
St. Louis, MO 63110 
 
 
Sponsor:  National Institute of Mental Health 
 
 


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1. Synopsis: 
 
Study Title 
Incomplete Response in Late Life Depression: Getting to Remission with 
Buprenorphine 
Objective 
1) To test the efficacy of buprenorphine (BPN), 2) to examine safety and 
tolerability of buprenorphine (BPN). 
Study Period 
Planned enrollment duration: Approximately 3 years 
Planned study duration: Approximately 28 to 32 weeks per subject 
Number of 
Patients 
Enroll approximately 100 participants, aged 50 and older, of both sexes and 
all races 
Study Medication 
Administration 
Subjects will receive an approximate 12 week course of open-label 
venlafaxine XR.  Participants who remit on venlafaxine XR alone will exit the 
study. Participants meeting criteria for incomplete response will be randomly 
assigned (2:1) to receive either low-dose buprenorphine or placebo 
augmentation of venlafaxine for approximately 8 weeks (Phase 2).  At the 
conclusion of Phase 2, all participants can choose to continue into Phase 3.  
Those that were randomized to placebo in Phase 2 will be offered the 
chance to receive buprenorphine for approximately 8 weeks.  Those that 
were randomized to the buprenorphine can continue to receive it for Phase 
3.     
Study Design 
A randomized, placebo controlled, double blind parallel group comparison of 
venlafaxine XR + buprenorphine with venlafaxine XR + placebo for N=20 
participants with Treatment Resistant Late Life Depression (TRLLD). 
Inclusion and 
Exclusion 
Criteria 
 
Subject inclusion criteria 
     Age > to 50 years. 
     Major depressive disorder (MDD), single or recurrent, as 
diagnosed by the Structured Clinical Interview for DSM Axis I 
Disorders (SCID). 
     Montgomery Asberg Depression Rating Scale (MADRS) > to 15. 
     Has or agrees to establish a clinical relationship with primary 
care physician (PCP). 
     Availability of an informant (e.g., emergency contact). 
 
 
Subject exclusion criteria 
 
Inability to provide informed consent. 
 
Depressive symptoms not severe enough (i.e., Montgomery-
Asberg Depression Rating Scale (MADRS) < 15) at the baseline 
assessments). 
 
Dementia, as defined by Modified Mini-Mental State Exam (3MS) 
< 84 and clinical evidence of dementia (e.g., memory 
impairment, executive dysfunction, agnosia, apraxia, aphasia, 
with functional impairment). 
 
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 Axis I Disorders (SCID). 
 
Abuse of or dependence on alcohol or other substances within 
the past 3 months as determined by Structured Clinical Interview 
for DSM Axis I Disorders (SCID), and confirmed by study 


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physician interview. 
 
Drinking 15 or more drinks per week or consuming 5 or more 
drinks on any one occasion during the week. 
 
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. 
 
Contraindication to venlafaxine XR or buprenorphine (BPN) as 
determined by PCP and study physician including history of 
intolerance of either venlafaxine XR or buprenorphine (BPN) in 
the study target dosage range (venlafaxine XR at up to 300 
mg/day; buprenorphine (BPN) at up to 2 mg/day). 
 
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). 
 
Non-correctable clinically significant sensory impairment (i.e., 
cannot hear well enough to cooperate with interview). 
 
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. 
 
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). 
 
History of opioid abuse or dependence. 
 
Severe pain, defined as > 7 on 0-10 numeric rating scale for 
pain. 
 
Concomitant use of strong or moderate CYP3A4 inhibitor 
(indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, 
ketonazole, nefazodone, saquinovir, telithromycin, aprepitant, 
erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem). 
 
Refusal to stop all opioids (to avoid precipitating opioid 
withdrawal). 
 
Hepatic impairment (AST/ALT > 1.5 times upper normal). 
 
Estimated Glomerular Filtration Rate (GFR) < 20 ml/min. 
 
Inability/refusal to identify a person as an emergency contact. 
 
Pregnancy 
 
Failure to meet inclusion criteria for imaging sub-study  
Measurements 
Pharmacogenetic collection, NIMH genetic sample and Safety Labs (CMP 
and CBC w/ diff), urine test, and EKG will be obtained at baseline.  All 
participants randomized will have biomarker collections done at the 
beginning and end of Phase 2.  Venlafaxine levels will be collected at the 
end of Phase 1.  Buprenorphine levels will be collected at the beginning and 


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end of Phase 2.  Depression outcomes measured using the Montgomery-
Asberg Depression Rating Scale (MADRS). Drug side-effects assessed with 
the Antidepressant Side-Effect Checklist (ASEC) and Frequency, Intensity, 
and Burden of Side Effects Rating (FIBSER). 
Statistical 
Methodology 
Our planned primary dichotomous outcomes are (1) remission rate (2) rate of 
serious adverse events, while our planned continuous outcomes are (1) 
Montgomery-Asberg Depression Rating Scale (MADRS) scores (2) side 
effect rating changes.  These analyses will be combined with other, 
secondary clinical outcome analyses of scales to address the primary 
question of whether there appears to be an efficacious and safe dose of 
buprenorphine (BPN) for LLD.  For each such analysis, both main effects and 
treatment interaction term will be examined.  Simple log-rank tests and Cox 
proportional hazard models will be the primary analytic approaches to 
compare time to remission among groups.  If the number of remissions is 
small, then exact tests of proportions will be performed.  Analyses will be 
conducted using the intent to treat (ITT) principle.  We will examine dropout 
attributable to adverse events, utilizing data from Phase 2, with survival 
analysis (with censoring at time of dropout or removal from the study).  This 
will include dropout due to patient decision as well as due to clinical decision. 
Mixed-effect models will be used to examine repeated Montgomery-Asberg 
Depression Rating Scale (MADRS) scores. 
 
2.  Study Protocol: 
2.1 Background and Significance 
Late-life treatment resistant depression (LL-TRD) is a large public health challenge: at least 50% of older 
people fail to respond adequately to antidepressant pharmacotherapy. Getting to and sustaining remission is 
the primary goal of treatment, yet there is a paucity of controlled studies of how best to manage LL-TRD. The 
development and testing of novel-mechanism pharmacotherapies is a public health priority embraced by 
NIMH. Table 1 lists some of the most devastating consequences of LL-TRD.   
LL-TRD is a common and potentially devastating condition, yet we have an 
extremely limited evidence basis for its management: clinicians do not have data 
to guide them regarding which augmentation agent to use, in whom, how, or with 
which risk/benefit ratio. This study will be the first placebo-controlled trial to 
examine a modern pharmacologic treatment for LL-TRD. If our hypotheses are 
supported, this study will establish a new approach to LL-TRD. It will also lead to 
a greater understanding of reasons for observed treatment resistance and thus 
ultimately to personalized treatment for LLD.   
 
Almost no data exists to guide the treatment of LL-TRD. The only published 
placebo-controlled pharmacotherapy trial for LL-TRD found that the monoamine 
oxidase inhibitor (MAOI) selegiline was efficacious.  However, in a recent 
randomized comparison of lithium augmentation and the MAOI phenelzine for LL-TRD, one-third of those 
receiving lithium remitted versus none receiving phenelzine; these two controlled studies suffer from small 
sample size, short duration, and inclusion of subjects with psychosis.  Our research group has open pilot data 
from 15 older adults with treatment-resistant depression who received low-dose buprenorphine (BPN).  (See 
Section 2.3)     
 
 
 
 
Table 1. 
Consequences of LL-
TRD 
Suicide 
Cardiac morbidity 
Hastened cognitive 
decline 
Worsened diabetes 
Worsened pain 
Higher caregiver burden 
Higher all-cause mortality 


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2.2 Objective 
The overall purpose is to examine the feasibility, safety, and tolerability of low-dose buprenorphine (BPN) as 
a novel treatment for late-life treatment resistant depression (LL-TRD) while also determining optimal dosing 
strategies to improve acceptability.  
Among the neuropeptidergic transmitters, opioids are known to modulate mood, and this system is often 
altered in patients with major depression.  Targeting the opiate system in LL-TRD may positively modulate a 
system in which there is age-associated imbalance. 1-4  Buprenorphine (BPN) is an antagonist at the kappa 
opiate receptor and a partial agonist at the mu opiate receptor.  Either, or both, of these pharmacodynamic 
actions may underlie its putative antidepressant effects.  In addition, since buprenorphine (BPN): 1) is 
available in sublingual formulation and 2) has a favorable safety and pharmacokinetic profile; it is an 
attractive candidate to use for LL-TRD.  Thus, the overarching aims of this project are to examine the 
feasibility, safety, tolerability and clinical effect of low-dose buprenorphine (BPN) as a novel treatment for 
LL-TRD. 
2.3 Approach: Preliminary Studies      
2.3.1 The opiate system modulates mood, reward behavior, and well-being.     
As mentioned above, among the neuropeptidergic transmitters, opioids are known to modulate mood.  Opiate 
receptors and endorphins are highly concentrated in the limbic and hypothalamic regions and interact with the 
monoaminergic system.5 Numerous studies have shown that opiate receptor neurotransmission is altered in 
patients diagnosed with major depressive disorder.6-9  Other studies have shown that when morphine is 
injected directly into the dorsal raphe nucleus, there is suppression of GABAergic-mediated inhibition of 
serotonin release.10  This results in a disinhibition of serotonergic neurons and the release of excess central 5-
HT in forebrain projection areas related with emotional integration, including the thalamus, nucleus 
accumbens, amygdala, frontal cortex, striatum, hypothalamus and ventral hippocampus.11   
 
Buprenorphine (BPN) is an antagonist at the kappa-OR and a partial agonist at the mu-OR; considerable 
evidence supports either, or both, of these pharmacodynamic actions as underlying the antidepressant effects 
of buprenorphine (BPN).  There is accumulating evidence that antagonism of the kappa-OR produces an 
antidepressant effect.  Antagonism of kappa-OR may produce an increase in monoaminergic signaling 
pathways, producing a functionally similar response to monoaminergic reuptake inhibitors.  However, it has 
also been observed for centuries that agonism of the µ-OR (e.g., “the opium cure”)12 leads to feelings of well-
being and anxiolysis.13,14  Given the feasibility and treatment development nature of this project, we will focus 
on both mu-OR and kappa-OR mechanisms in this study. We acknowledge that the delta-OR may have effects 
on mood15, but given the early phase of our work, we will focus on the two opiate receptor subtypes with the 
greatest support in the literature. 
 
2.3.2 Age-Related Changes in the Opiate System Support Our Focus on LL-TRD.   
While there is variability in the animal and human evidence supporting age-related changes in the opiate 
system, the human studies suggest age-associated increases in density and binding affinity for mu-OR.  
The majority of the animal aging studies indicate increased density and binding affinity for kappa-OR, in 
particular in the thalamus and amygdala. Increased density and binding affinity are consistent with work 
suggesting age-related decrease in endogenous opiates such as enkephalin and endorphin. 16,17 Targeting 
the opiate receptor system in LL-TRD may alter a system in which there is imbalance between circulating 
opiates and the density and affinity of mu-OR and kappa-OR. 
 
2.3.3 Buprenorphine is poised to be repurposed for treating LL-TRD.     Novel agents with unique 
mechanism of action and rapid onset require study when monoaminergic antidepressants are ineffective.  
Testing the efficacy and probing the mechanism of unique molecules is a focus of both personalized care and 
translational bench-to-bedside research, two priority aims of the NIMH strategic plan.18  As outlined in the 
NIMH Council monograph “From Discovery to Cure,” psychiatry must catch up with other fields of medicine, 


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such as cardiology, in the identification and testing of therapeutics that are mechanistically distinct.  In view of 
the general decline of psychiatric drug development by “big pharma”19, our repurposing of buprenorphine 
(BPN) (i.e., the application of buprenorphine for the different indication20 of LL-TRD) responds to this need. 
 
2.3.4 Buprenorphine may rapidly improve LL-TRD:  We recently completed an 8 week open-label clinical 
trial (n=15) using low dose buprenorphine (BPN) for LL-TRD patients (50 and older).21 The average age of 
these subjects was 60.7 (SD 5.6); 53.3% were female.  Twelve of the subjects received buprenorphine (BPN) 
as augmentation pharmacotherapy (vs. as monotherapy for 3).  The most commonly co-prescribed 
antidepressants were venlafaxine, citalopram, and duloxetine. 
  
Reported Sadness (MADRS - Q2)
Week
0
2
4
6
8
0
1
2
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4
 15
 15
 14
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 13
n:
Pessimistic Thoughts (MADRS - Q9)
Week
0
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0
1
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 15
 15
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n:
MADRS
Week
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8
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 15  15  15  14  14  11  13  13  13
n:
MADRS: Montgomery Asberg Depression Rating Scale
 
 
 
The average daily dose of buprenorphine (BPN) was 0.6 mg/day.  The Montgomery-Asberg Depression Rating 
Scale (MADRS) improved from average score of 27.0 (7.3) at baseline to 9.5 (9.5) at week 8, Cohen’s d=1.9 
(figure 1).  We observed the same magnitude of decrease in the depressed mood and pessimistic thoughts 
items, supporting benefits for core depressive symptoms.  The overall remission rate was 60% based on 
criteria of Montgomery-Asberg Depression Rating Scale (MADRS)<10 at week 8.   Weight and vital signs 
remained stable.  Although these data are from a relatively young TRD sample, stratification by age (based on 
a median age split of 62.5 years) revealed no difference between the “younger” and “older” groups.“  The 
subject who was 62.5 is included in the older group, since the groups are then < 60 and > 60.  Response rates 
(defined as MADRS < 10 at week 8) for the younger group was 83.3% (n=5/6) and 42.9 (n=3/7) for the older 
group (Fisher exact p = 0.27). 
 
Reasons for early termination included: 1) constipation and bloating (n=1) and 2) two subjects were removed 
from the study because of worsened pre-existing chronic suicidality (exacerbations directly linked with 
psychosocial stressors).  In addition to core depressive symptoms, participants also improved in anxiety (BSI 
anxiety subscale at baseline = 1.1 (0.7), week 8 = 0.6 (0.8)), sleep (PSQI at baseline = 9.9 (3.5), week 8 = 6.0 
(2.8)) and the positive affect subscale of the PANAS (baseline = 21.5 (8.6), week 8 = 29.4 (12.0)).  However, at 
week 16 (8 weeks after discontinuation of the buprenorphine (BPN)), the average MADRS score was 17.8 
(12.9; range=2-39), suggesting that buprenorphine (BPN) must be maintained long-term for continued 
antidepressant effect.  Of note, 3 subjects sought continued treatment with buprenorphine (BPN) to maintain 
depression remission after completing the protocol.  We also preliminarily examined buprenorphine (BPN)’s 
safety.  Improvements in memory and executive function (assessed with the Hopkins Verbal Learning Test and 
a computerized test of attention) from baseline to week 8 support the safety on cognition of buprenorphine 
(BPN) in this population.  We did not observe any symptoms of opiate withdrawal or craving, measured with 
the Clinical Opiate Withdrawal Scale (COWS),16 following the tapered discontinuation of buprenorphine (BPN).  
Further safety evaluation of buprenorphine (BPN) is a key component of this proposal and provides a rationale 
Figure 1.  Change in the Total MADRS Score and Depression-Specific Items During Open Exposure to BPN 


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for the neuropsychological testing.  In summary, this project indicates our success at recruiting and retaining 
very ill, treatment resistant patients into a protocol using buprenorphine (BPN). 
2.4 Patient Selection 
We will enroll approximately 100 participants, aged 50 and older, of both sexes and all races.  Participation 
may last approximately 32 weeks.  Previous participants in the “Incomplete Response in Late Life 
Depression: Getting to Remission”, (“IRL Grey”) multi-site R01, 201101816, who did not remit will be asked 
to participate.  Other participants will be recruited with the assistance of recruitment strategies utilized in 
previous studies (VFH, HealthStreet, PCP referrals…). Subjects will be screened with the Structured Clinical 
Interview for DSM Axis I Disorders (SCID) to determine eligibility.9 Structured Clinical Interview for DSM Axis 
I Disorders (SCID) assesses current and lifetime depression, as well as other psychiatric disorders, and is 
used to clarify psychiatric inclusion and exclusion criteria.  Participants must have current Major Depressive 
Disorder (MDD).  All risks and benefits will be explained, and subjects will sign an informed consent form.  
We will screen for ETOH abuse and dependence (using the Alcohol Use Disorders Identification Test – 
Consumption (AUDIT-C) and substance abuse and dependence section of the Structured Clinical Interview 
for DSM Axis I Disorders (SCID)). We will exclude anyone with evidence of active ETOH or substance 
abuse.  We will utilize a clinical trial that has 3 Phases.  In Phase 1 we will treat all 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" multi-site R01 for LL-TRD, and we have found it to be highly successful.  Participants 
who remit on venlafaxine XR alone will exit the study.   
Phase 2, RCT Overview: In the approximate 8-weeks of buprenorphine (BPN) vs. placebo, twenty subjects 
will be randomized (using permuted block randomization) 2:1 to receive venlafaxine XR (at the dose they 
reached and tolerated in the open-label lead-in) plus either buprenorphine (BPN) or placebo. The reasons 
for using a 2:1 random allocation include: 1) collection of data about plasma levels of buprenorphine (BPN), 
and 2) gaining further clinical experience with the molecule. Both of these reasons are consistent with the 
developmental nature of the R34 grant mechanism (the NIH grant mechanisms supporting this project). We 
will use independent evaluators (who are blind to treatment assignment) at the end of Phase 2 for the last 
two assessments to determine if the participant has met response. The reason for using independent 
evaluators at this pivotal time point is that clinicians may become unblinded because they are also 
assessing side effects.  Additionally, we will collect buprenorphine (BPN) plasma levels on all those 
randomized to explore a dose-effect relationship on treatment response.  The study will be posted on 
clinicaltrials.gov, once reviewed and approved by the Institutional Review Board (IRB). 
At the conclusion of Phase 2, the blind will be broken for all participants.   
Participants will undergo 2 MRI’s in Phase 2, unless it is unsafe for them to do so.  
Neuroimaging:  MRI   
The first MRI will take place before the administration of buprenorphine or placebo.  The second scan will 
occur at approximately week 8 after the administration of buprenorphine or placebo.  Scans will be performed 
at the CCIR.  The imaging protocol includes the following sequences:  1. Structural T1-weighted and T-2 
weighted lasting ~6 minutes each  2. Practice of behavioral task to record participant’s reaction time lasting 5 
minutes 3. Two resting state scans ~5 minutes each 4.BOLD image during performance of the behavioral task 
lasting 22 minutes (approximately 5- runs). The total scan time will be about 1 hour.  Subjects will be asked to 
lie still during the scan.  At the end of the task and outside the scanner subjects will undergo emotional ratings 
about how they felt while doing the task in each of the three types of trials this will take about 5 minutes.  
During each MRI subjects will perform the Monetary Incentive Delayed task ( MID) developed by Knutson et al 
(Neuroimage 2000, 12: 20-27). This task is designed to elicit neural responses to monetary incentive 
anticipation and outcomes.  This task activates brain regions including striatal and mesial forebrain structures 
(including insula, caudate, putamen, and mesial prefrontal cortex) during trials involving reward and 
punishment. It has been recently validated by NIMH-funded research as an fMRI task to measure functional 
opioidergic effects of KOR antagonists. 
 


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This task has three kinds of trials: reward, neutral and loss trials (punishment).  For reward trials subjects will 
be able to earn between $1.50 and $2.40 if they respond fast enough, for neutral trials the will not gain or lose 
any money and for loss trials, they will lose between $1.80 and $2.20 if they respond too slowly.  
 
At the onset of each trial subjects are presented with a visual cue (1.5 seconds) indicating a reinforcer 
associated with performance “+ $” for reward, “0 $” for neutral and “- $” for loss trials. After a variable inter-
stimulus interval ( 3, 4.5 or 6 seconds) participants will see a visual target ( a red square, 0.2 seconds) 
signaling they should press a button (on a key pad they hold on their hand ) as quickly as possible.  After they 
respond, visual feedback will be provided regarding gains, no change (for neutral trials) or losses; however no 
information about overall performance will be provided during performance of the task.  Prior to start the task 
subjects undergo practice inside the scanner to record their reaction times.  In this task gains are associated  
with successful performance in reward trials occurring when the participant’s reaction time (after they see the 
red square) is within the 70th percentile of those obtained in the previous run (for run 1, the practice run is used 
for this calculation).  
 
Once the participant has finished the scan, study staff will provide feedback about how they did on the task 
and indicate how much they will receive. Subjects may receive up to $50 dollars cash for performing the 
task.  Based on experience using this task in depressed subjects provided by other investigators and based 
on calculations of the maximum wins and the maximum losses adjusted by the 70th percentile reaction time, 
we have determined to give a set amount of money close and up to $50 to each participant at the end of the 
task which will be assigned in a counterbalanced order 
 
Phase 3, open-label buprenorphine (BPN) plus venlafaxine:  We aim to collect data on the durability of 
clinical effect of buprenorphine (BPN).  All participants, regardless of their treatment assignment or response 
in Phase 2, can participate in Phase 3.  Those who had received BPN will continue to receive it, with further 
up-titration of the dose (maximum 1.2mg/d) as needed and tolerated.  Those who had received placebo in 
Phase 2 will start at 0.2mg/d with up-titration a needed and tolerated.  This Phase will last approximately 8 
weeks for all participants. We will carry out clinical ratings at each visit in order to follow symptoms and side 
effects of treatment. The Phase 3 variations will allow all participants a chance to experience the benefits of 
BPN.  Efficacy and tolerability data will provide a clinically informative estimate of benefits and risks of BPN 
augmentation for LL-TRD.     
 
2.5. Inclusion Criteria 
 
Subject inclusion criteria 
  Age > to 50 years. 
  Major depressive disorder (MDD), single or recurrent, as diagnosed by the Structured Clinical 
Interview for DSM Axis I Disorders (SCID). 
  Montgomery Asberg Depression Rating Scale (MADRS) > to 15. 
  Has or agrees to establish a clinical relationship with primary care physician (PCP). 
  Availability of an informant (e.g., emergency contact). 
 
Subject exclusion criteria 
 
Inability to provide informed consent. 
 
Depressive symptoms not severe enough (i.e., Montgomery-Asberg Depression Rating Scale 
(MADRS < 15) at the baseline assessments 
 
Dementia, as defined by 3MS < 80 and clinical evidence of dementia (e.g., memory impairment, 
executive dysfunction, agnosia, apraxia, aphasia, with functional impairment). 
 
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 Axis I Disorders (SCID). 


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 
Abuse of or dependence on alcohol or other substances within the past 3 months as determined 
by Structured Clinical Interview for DSM Axis I Disorders (SCID), and confirmed by study physician 
interview. 
 
Drinking 15 or more drinks per week or consuming 5 or more drinks on any one occasion during 
the past week. 
 
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. 
 
Contraindication to venlafaxine XR or buprenorphine (BPN) as determined by PCP and study 
physician including history of intolerance of either venlafaxine XR or buprenorphine (BPN) in the 
study target dosage range (venlafaxine XR at up to 300 mg/day; buprenorphine (BPN) at up to 2 
mg/day). 
 
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). 
 
Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to 
cooperate with interview). 
 
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. 
 
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). 
 
History of opioid abuse or dependence. 
 
Severe pain, defined as > 7 on 0-10 numeric rating scale for pain. 
 
Concomitant use of strong or moderate CYP3A4 inhibitor (indinavir, nelfinavir, ritonavir, 
clarithromycin, itraconazole, ketonazole, nefazodone, saquinovir, telithromycin, aprepitant, 
erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem). 
 
Refusal to stop all opioids (to avoid precipitating opioid withdrawal). 
 
Hepatic impairment (AST/ALT > 1.5 times upper normal). 
 
Estimated Glomerular Filtration Rate (GFR) < 20 ml/min. 
 
Inability/refusal to identify a person as an emergency contact. 
 
Pregnancy  
2.6 Design and Procedures 
2.6.1 Study Design 
The protocol is a  randomized, placebo controlled, double blind parallel group comparison of venlafaxine XR + 
buprenorphine with venlafaxine XR + placebo for N=20 participants with Treatment Resistant Late Life 
Depression (TRLLD).   Subjects will be studied for approximately 32 weeks: an approximate 12-16 week lead-
in phase of open-label venlafaxine XR, an approximate 8 week RCT of buprenorphine (BPN) vs. placebo as an 
augmentation to venlafaxine XR, and approximately 8 weeks open-label buprenorphine (BPN) plus venlafaxine 
phase.  Following the informative design of IRL GREY, participants will be aged 50 years and older, with MDD 
and a MADRS score > 15; they will be primarily recruited from previous studies.  The goal of treatment is 
remission, defined as a MADRS < 10 for at least two consecutive assessments.   
2.6.2 Open-label lead-in with venlafaxine XR:  We will prospectively determine treatment resistance by 
initially treating participants with a 12-16 week course of open-label venlafaxine XR (figure below).  


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Approximately 100 participants will start venlafaxine XR 37.5 mg daily and will rapidly (2 weeks) titrate to 150 
mg/d.  Then, at week 6, those who inadequately respond to this dose will have venlafaxine titrated (as 
tolerated) further, up to a maximum dose of 300 mg/day.  At the end of 12 weeks, those who achieve remission 
(Montgomery-Asberg Depression Rating Scale (MADRS) < 10 for 2 consecutive assessments) with 
venlafaxine will exit the study; non-remitters will be eligible for the RCT of buprenorphine (BPN) vs. placebo 
augmentation.  Visits and assessments during open-label lead-in are weekly for the first two weeks and then 
every other week.   
We have experience using this titration schedule for the 3-site IRL GREY clinical trial; our experience suggests 
this titration schedule optimally balances efficacy, safety, and tolerability.  The attrition rate for this study 
because of intolerable side effects is < 4% by week 12. This design confers the advantage of prospectively 
showing treatment resistance, instead of relying on historical data (which may be unreliable). 
2.6.3 Rationale for use of venlafaxine XR:  Prior studies by our research team and published guidelines 
have suggested that a switch to an SNRI is reasonable for LLD patients who do not respond to an SSRI.22-24 
We also chose venlafaxine XR as the sole agent for the open-label lead-in because: 1) it is approved for 
treating depression; 2) it lacks drug-drug interactions (including with buprenorphine (BPN)); 3) there is 
evidence for its use in older persons; and 4) we have successfully used this medication in prior studies of LLD 
and LL-TRD23,25 and in an ongoing trial across 3 sites.26  In addition, venlafaxine acts as an SSRI at lower 
doses and an SNRI at higher doses.27,28 Thus, based on our team’s experience, and published 
recommendations29, an initial 6-week period at 150 mg/d, followed by a second 6-week period at 300 mg/d, 
appears optimal in attaining remission with venlafaxine with the minimum likelihood of adverse effects and is, 
in a sense, two 6-week medication trials: one with low-dose venlafaxine as an SSRI, and one with high-dose 
venlafaxine as an SNRI. The primary reason for continuing venlafaxine during phase 2, even though 
subjects will be considered to be non-remitters, is to leverage any clinical improvements gained during 
phase 1.  Since the antidepressant effect of buprenorphine (BPN) is not established, it would be unethical to 
withdraw the venlafaxine in older patients with TRD who might have experienced some benefit from it.  
Even if there is no evidence of an antidepressant effect, there may be other benefits (e.g., reduced anxiety 
and anger, decreased suicidal ideation, improved sense of well-being) in which subjects may benefit from 
continued exposure to the medication.  Finally, adding buprenorphine (BPN) to the venlafaxine supports our 
testing of buprenorphine (BPN)  as an augmentation agent. 
2.6.4 RCT Overview:   
Phase 2, RCT Overview: In the approximate 8-weeks of buprenorphine (BPN) vs. placebo, twenty subjects will 
be randomized (using permuted block randomization) 2:1 to receive venlafaxine XR (at the dose they reached 
and tolerated in the open-label lead-in) plus either buprenorphine (BPN) or placebo. The reasons for using a 
2:1 random allocation include: 1) collection of more data about plasma levels of buprenorphine (BPN), and           
2) gaining further clinical experience with the molecule. Both of these reasons are consistent with the 
developmental nature of the R34 grant mechanism (the NIH grant mechanisms supporting this project). We will 
use independent evaluators (who are blind to treatment assignment) at the end of phase 2 for the last two 
assessments to determine if the participant has met response. The reason for using independent evaluators at 
this pivotal time point is that clinicians may become unblinded because they are also assessing side effects. 
 
2.6.5 Titration schedule of buprenorphine (BPN):  buprenorphine (BPN) will be started at 0.2 mg/d and will 
be titrated weekly by 0.2 mg, based on tolerability (assessed with the FIBSER) and depression severity 
(assessed with Montgomery-Asberg Depression Rating Scale (MADRS). The minimum target dose is 0.6 mg/d 
(based on our pilot work) with an allowed maximum of 1.2 mg/d. The primary outcome will be remission at the 
end of the Phase 2. 
 
Since the analgesic effects of buprenorphine (BPN) may obscure the antidepressant effects, we will exclude 
subjects with severe pain. This will be defined as a score of > 7 on a 0-10 Numeric Rating Scale for Pain. The 
time assessed for pain will be the previous month (note: we are not trying to diagnose a chronic pain 
syndrome, but exclude those with recent clinically significant pain). We have decided to not exclude all 


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individuals who endorse pain, since they represent the majority of older adults with depression. Therefore, we 
will include pain levels < 7.   
 
Consistent with the developmental aim to learn more about dosing ranges and plasma levels, we will extend 
Phase 2 to approximately eight weeks with a maximum dose of 1.2 mg/d. This is a complicated dosing regimen 
(with up to a 6-fold variability of doses). With this approach, we expect to clarify the range of efficacious and 
tolerable doses for buprenorphine (BPN), ultimately resulting in a more parsimonious dose titration schedule. 
This is of great importance, as the appropriate dose range is not yet established. In order to ensure that 
subjects do not experience withdrawal, we will taper the study drug at the end of the study for all participants. 
The study drug will be tapered by 20% every 3 days until discontinued.  We will use the Clinical Opiate 
Withdrawal Scale (COWS) to assess any symptoms of withdrawal and adjust the discontinuation as needed to 
assure a comfortable discontinuation for subjects.  In our pilot work, we have not encountered ANY 
discontinuation symptoms during the cessation of buprenorphine (BPN). 
 
2.6.6 Open label buprenorphine (BPN) plus venlafaxine XR:   
Phase 3, Assessing durability of clinical response:  While a relapse prevention study would require a different 
design, we aim to collect data on the durability of clinical effect.  The blind will be broken for all participants at 
the end of Phase 2.  All are welcome to continue into Phase 3 of the study.  Phase 3 allows those who did not 
receive BPN a chance to titrate to the highest, most beneficial dose offered through this clinical trial.  Those 
who did receive BPN but did not reach remission are offered an additional 8 weeks to titrate to a higher dose, 
possible more beneficial dose as tolerated.  And those who did receive BPN and found it beneficial are offered 
8 more weeks at this remission dose.  At the end of Phase 3, BPN will be tapered as described above.  
 
     
 
 
 
 
 
 
 
 
                                                                  
 
 
2.7  Assessments:  
2.7.1 Assessments and Primary Outcomes 
Subjects will be evaluated with the following measures: 
 
Structured Clinical Interview for DSM-IV (or DSM-5, depending on when the new DSM is published) disorders 
(SCID).  The SCID will involve the collection of information from the consenting individual alone.  We will not 
require an outside source to provide information or validate information supplied by the consenting individual.   
 
The Montgomery-Asberg Depression Rating Scale (MADRS) will be our main depression outcome measure.  A 
MADRS score >15 at baseline will establish study eligibility. 
 
Comorbid physical illness will be measured with the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), 
which we have validated and frequently used to quantify total medical burden. 
 
Documentation of Previous Treatment Resistance: Treatment history will be assessed with the Antidepressant 
Treatment History Form (ATHF) to further characterize the sample. 
 
 
 
BPN (N=15) 
PBO (N=5) 
N=20 
randomized  
First dose of BPN 0.2mg 
First dose of placebo 
 Phase 3:  8 
weeks open 
label BPN 
0.2-1.2mg 
8 week trial of BPN 0.2-1.2mg 
8 week trial of placebo 


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Since pain of various etiologies is highly prevalent in late-life has been shown to moderate treatment outcome 
and may be improved with buprenorphine (BPN), we will assess pain with a Numeric Scale of 0-10 (NRS-P). 
 
Sleep quality is a critical covariate of depression onset and response. We will assess sleep quality with the 
Insomnia Severity Index (ISI). 
 
To address the aim of tolerability and safety, we will assess vital signs and weight at approximately every visit. 
 
The experience of euphoria (or a feeling of being “high”) will be assessed with two 0-10 visual analog scales. 
 
Side effects will be assessed with the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) and 
the Antidepressant Side Effect Checklist (ASEC) at every visit. 
 
Symptoms of withdrawal after study medication taper and discontinuation will be assessed with the Clinical 
Opiate Withdrawal Scale (COWS). 
 
Scale for Suicide Ideation (SSI). It has been shown to predict completed suicide 30,31 and has moderately high 
internal consistency with Cronbach’s alphas ranging from 0.84 to 0.89 and good inter-rater reliability 32,33. To 
reduce participant burden, 5 screening items are administered; if any are endorsed, the participant completes 
items 6-19. The full SSI takes 10 minutes to administer. For every enrolled participant, we also utilize a 
checklist of suicide risk and suicide protective factors.  
 
Alcohol Use Disorders Identification Test – Consumption (AUDIT-C)34: The theoretical range of scores for the 
AUDIT-C is 12. Patients who report drinking 4 or more (women) or 5 or more (men) drinks in a day during the 
interval period on the single-item screening question are considered to have unhealthy use of alcohol. If 
subjects have an AUDIT-C score > 8, we will evaluate them with the substance use disorder section of the 
Structured Clinical Interview for DSM Axis I Disorders (SCID) to further refine their clinical state and to help us 
decide if it is safe for them to remain in the study and/or if they require referral for specialty alcohol use 
treatment. 
 
Brief Symptom Inventory (BSI-anxiety) will be used to measure general anxiety symptoms.  We have reported 
that the BSI-anxiety scale has good internal consistency in LLD subjects (Cronbach's alpha = 0.84) and a 
score >1.0 predicts decreased response in LLD and increased recurrence rate during maintenance treatment. 
It will be our primary outcome measure of anxiety because of its low burden and our group’s experience with it. 
 
Patient Global Impression of Change (P-GIC) will also be utilized. This self-report scale is used to measure a 
subject's individual perception of change or no change in terms of how they are feeling. 
 
Adherence Form will be administered at every visit (with the exception of screening/ baseline) to monitor 
medication adherence as well as alcohol and substance use. 
  
Suicide History Form will be administered once at screening/ baseline to gather historical suicidal thoughts and 
behaviors.  We will not require an outside source to provide information or validate information supplied by the 
consenting individual. 
 
2.7.2 Neuropsychological functioning will be assessed with the following: 
3MS (Modified Mini-Mental State Exam).  This cognitive screening test, which is an expanded version of the 
Mini-Mental Status Exam, has a score range of 0-100. In addition to providing a broader variety of cognitive 
functioning and a wider range of difficulty, the original MMSE score can be extracted.  A score of at least 80 is 
required to enter the study, as scores below this may indicate dementia. 
 
Trail Making Test (parts A & B) (Halstead, 1947). Part A consists of 25 circles numbered 1 through 25 


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distributed over a page. The subject is instructed to connect the circles with a pencil line as quickly as possible 
in ascending numerical order. Part B also consists of 25 circles, but these circles contain numbers (1 through 
13) or letters (A through L). The subject must connect the circles while alternating between numbers and 
letters in ascending order. The subject's performance is based on the time required to complete each part and 
by the number of errors. Both parts A and B require visuomotor and perceptual scanning skills, but part B also 
requires flexibility in shifting from number to letter sets while under time pressure.  
 
Hopkins Verbal Learning Test- Revised (Brandt & Benedict, 2001). The HVLT-R offers six alternate forms. 
Each form contains 12 nouns, four words each from one of three semantic categories (e.g., precious gems, 
articles of clothing, vegetables, etc.), to be learned over the course of three learning trials. Approximately 20-25 
min later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of 
any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 
false-positives, 6 semantically related, and 6 semantically unrelated. This is a test of verbal learning and 
episodic memory. 
 
Letter-Number Sequencing from the WAIS-4 (Wechsler, 2008). Examiner presents combinations of letters and 
numbers, from 2 to 9 letter-number combinations. Examinee must repeat each series by first repeating the 
numbers in ascending order, then the letters in alphabetical order (e.g., 9-L-2-A; correct response is 2-9-A-L). 
This task measures "working memory," the ability to simultaneously recall and organize stimuli of different, 
similar types.  
 
Nebes' computerized Reaction Time Tasks (Jennings et al., 2011). These two computerized tasks with 
repeatable conditions measure basic attention, psychomotor speed, and inhibition. The tasks include a Choice 
Reaction Time Task and a Congruous vs. Incongruous Conditions Reaction Time Task. The simple Choice 
Reaction Time Task involves pressing a button held in the dominant hand as soon as a 1 cm dot appears in 
the center of the computer screen. The interstimulus interval is preset and varies randomly between 1.5 and 3 
seconds so that the participant cannot anticipate stimulus onset. 
 
The Congruous vs. Incongruous Conditions Reaction Time Task, consists of trials in which a right- or left-
pointing arrow appears 8.5 cm to the right or left of the central fixation. The participant is instructed to press the 
button on the side toward which the arrow pointed. There were two conditions: Congruous and Incongruous. In 
the Congruous condition, the spatial location of the arrow (i.e., the side of the screen on which it appeared) is 
the same as the direction the arrow is pointing (e.g., a left-pointing arrow appears to the left of fixation). In the 
Incongruous condition, the location of the arrow conflicts with the direction in which it is pointing (e.g., a right 
pointing arrow appears to the left of fixation). In this condition, the participant has to inhibit processing the 
arrow's location, focusing only on the direction it is pointing. There are 40 congruous and 40 incongruous trials 
randomly intermixed. Prior to this experimental block, a block of unscored trials reinforced the prepotent spatial 
response: subjects respond to a rectangle on the left or right of the screen on the spatially congruent key.  
 
Computerized Reward Response Task (Pechtel, 2013): This probabilistic reward task (PRT), uses a differential 
reinforcement schedule of monetary feedback to examine reward responsiveness.  The task uses monetary 
incentives (“Correct! You won 5 cents”) as reward feedback. The 15-20 min task is presented on a 1700 PC 
monitor using E-Prime software (Version 1.1.; Psychology Software Tools Inc., Pittsburgh, Pennsylvania). 
Participants complete three blocks of 100 trials (monetary reward) to induce a response bias towards the more 
frequently rewarded stimulus (RICH) compared to the less frequent rewarded stimulus (LEAN). Reward 
feedback is provided three times more often for the RICH than the LEAN stimulus. Participants are instructed 
that the goal of the task was to win as much money as possible and are informed that not every correct 
response will lead to a reward feedback. In each block, a pseudo-random sequence of 50% long and 50% 
short mouths are presented. Each trial consisted of a fixation cross (jittered 750-900 ms) followed by a mouth-
less line drawing of a face (500 ms), after which either a short (11.5 mm) or a long (13 mm) mouth appears on 
the face (100 ms). Participants are instructed to press one of two keyboard keys to indicate whether the mouth 
was long or short. Reward feedback is displayed on the computer screen (1500 ms). Keys and conditions (long 


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or short mouth as RICH stimulus) are counterbalanced across participants. Participants complete a short 
series of practice trials to ensure they understand the instructions. 
 
3.  Data Collection, Management, and Analysis: 
Before major analyses, we will examine all variables descriptively using cross-tabulations, histograms, and 
tests for normalcy (with corrective actions, such as data transformation, as necessary).  We will also examine 
for patterns of missing data and dropout.   
 
Baseline demographic and clinical characteristics will be compared for the buprenorphine (BPN) and placebo 
groups, using tests for differences in proportions (e.g., chi squared) and t-tests for continuous measures.  If 
normality assumptions for continuous variables are not met even after appropriate data transformations, 
Wilcoxon rank sum tests will be used.  These analyses will be employed to describe the study sample and 
also, to determine whether the randomization effectively balanced the two treatment groups with regard to 
baseline characteristics.  If imbalances are found, it may be necessary to adjust for significant baseline 
differences when testing study hypotheses.  Simple log-rank tests and Cox proportional hazard models will 
be the primary analytic approaches to compare time to remission among groups.  If the number of remissions 
is small, then exact tests of proportions will be performed.  Analyses will be conducted using the intent to 
treat (ITT) principle. We will examine dropout attributable to adverse events, utilizing data from Phase 2, with 
survival analysis (with censoring at time of dropout or removal from the study).  This will include dropout due 
to patient decision as well as due to clinical decision. Mixed-effect models will be used to examine repeated 
Montgomery-Asberg Depression Rating Scale (MADRS)  scores.  Although a treatment development study is 
by definition not a formal test of efficacy hypotheses, it is consistent with the R34 mechanism for a pilot RCT 
to examine outcome data using appropriate statistical methods.  Therefore, for dichotomous outcomes, 
treatment differences will be evaluated using logistic regression allowing for both unadjusted and adjusted 
analyses.  Methods using generalized estimating equations (GEE) will be employed to test repeatedly 
measured discrete outcomes.  For continuous outcomes, mixed effects models with site as a fixed effect will 
be performed to test for trajectory over time.   
 
Our planned primary dichotomous outcomes are (1) remission rate (2) rate of serious adverse events, while 
our planned continuous outcomes are (1) Montgomery-Asberg Depression Rating Scale (MADRS) scores (2) 
side effect rating changes.  We hypothesize that:  1) buprenorphine (BPN) will improve depressive 
symptoms, as compared to those assigned placebo, 2) buprenorphine (BPN) will be associated with low 
rates of side effects. 
 
For the MRI data, we will use descriptive and inferential statistics. Comparison of data sets will include 
standard statistical analysis using a within subjects factorial ANOVA, T-test or multiple regression.  All data 
points will be included. 
3.1 Pharmacokinetics and Genetics involved in LL-TRD 
Drug Level Monitoring:  Pharmacokinetic changes associated with aging result in higher and more variable 
drug concentrations.  Variability in treatment outcomes (efficacy or tolerability/safety) due to any cause 
(clinical or genetic) is more interpretable when also accounting for variable drug exposure. Thus, plasma 
levels will be collected for both venlafaxine and buprenorphine (BPN) at specific time points. Buprenorphine 
levels will be tested at beginning and end of Phase 2 for those randomized.   
 
We will be collaborating with Evan Kharasch, M.D., a pharmacologist with expertise in buprenorphine 
pharmacokinetics. His lab will carry out buprenorphine blood level analysis.  
 
 
4. Interventions and Risks: 
4.1  Venlafaxine side effects 


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Infrequent to common: sustained hypertension, dizziness, vasodilatation, nausea, anorexia, weight loss, 
constipation, diarrhea, sexual dysfunction, excessive sweating, somnolence, insomnia, nervousness, tremor, dry 
mouth, and asthenia.  In premarketing depression studies, 3% of subjects receiving venlafaxine XR, up to doses of 
375 mg/d, developed sustained increase in blood pressure (defined as treatment emergent supine diastolic blood 
pressure >90 mg Hg and >10 mm Hg above baseline for three consecutive on-therapy visits). In premarketing 
depression studies, the mean increase of supine diastolic pressure in subjects receiving venlafaxine XR 75 mg/d to 
225 mg/d was 1.2 mm Hg.  
Rare: increased heart rate and hyponatremia. 
 
 
4.2  Buprenorphine (BPN) side effects (experienced in a 16 week study at dose ~ 2 mg/day) 
Common: (> 10%):    asthenia, headache, diarrhea, insomnia, rhinitis, sweating. 
Infrequent: (4-9%): chills, constipation, nausea, nervousness, runny eyes. 
Rare: (</= 3%): dyspepsia, dizziness, and somnolence. 
 
These buprenorphine (BPN) side effects are taken from the package insert and are from participants receiving 
buprenorphine (BPN) who were younger and receiving treatment for opioid dependence.  This population is very 
different from our proposed sample of older adults who are not taking opioids.  In general, we have observed that 
low-dose buprenorphine (BPN) is well-tolerated.  The most common side effects we have observed are 
constipation, bloating, sedation, falls, confusion, G.I. upset, and in one instance, possible minor exacerbation of 
already present lower extremity edema.   
 
Chronic exposure to opioids may negatively affect testosterone levels in men.  The effect on sex hormones in 
women is inconclusive.  Given the low dose (up to 1.2 mg/d) and relatively short duration of exposure to 
buprenorphine (BPN) (up to 16 weeks) in this project, we do not plan to monitor endocrine status.  In future studies 
of buprenorphine (BPN) of longer duration, we plan to assess whether exposure of low dose buprenorphine (BPN) 
leads to alterations in endocrine status (e.g., testosterone and prolactin).   
 
4.3 Risks of MRI: 
Likely risks: There are no known physical risks to participants undergoing MRI scans who meet study inclusion 
and exclusion criteria.  However, during scan and behavioral task procedures, patients may experience 
boredom or get tired.  
 
Less likely risks: Because patients are asked to lie still during the scan they may experience mild muscle aches 
and pains.  Participants are offered cushions to place at pressure points or beneath the knees to reduce 
discomfort.  Participants will be exposed to the MRI scanner acoustic noise.  They will be provided with 
earplugs to dampen the noise.  Participants may feel anxious or even experience claustrophobia (fear of being 
in closed spaces) while in the scan.  Participants are able to communicate with staff throughout the scan and 
are encouraged to tell the staff if they feel anxious and whether they want to interrupt or stop the scan.  
 
Rare risks: Because the scanner uses a high strength magnet, subjects with ferro-magnetic metallic objects 
inside their bodies are at substantial risk. Metallic objects can be pulled by the magnetic field and cause 
physical harm.  The following medical devices and body implants can be affected by the MRI field or be 
potentially hazardous in the MRI environment: cardiac pacemaker, implanted cardioverted defibrillator (ICD),  
aneurysm clip, implanted insulin/drug pump, neurostimulator (TENS unit), biostimulator/bone growth stimulator, 
hearing aid/cochlear implant, Gianturco coil (embolus coil), vascular clip, surgical clip or staples, heart valve 
prosthesis, Greenfield Vena Cava filter, middle ear implant, penile prosthesis, shrapnel or bullets, wire sutures, 
tattooed eye liner, body piercing jewelry, permanent contraceptive implants such as diaphragm/ UID and 
pessaries, intraventricular shunts, wire mesh, artificial limb or joint, any orthopedic item that is ferro-conductive 


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(ei, pins, rods, screws, nails, clips, plates, wire etc) dentures, any type of dental item held in place by a 
magnet, dental braces or any type of removable dental item, any other implanted item not mentioned. There 
may be unknown risks to the unborn fetus during pregnancy.  Prior to the MRI, each subject will be carefully 
screened for the presence of any of these devices or implants. 
 
 
 
4.4 Risk of precipitating substance abuse:   
What is known and how will this be minimized?  Buprenorphine is controlled as a Schedule III narcotic under 
the Controlled Substances Act.  Buprenorphine is a partial agonist at the mu-opioid receptor.  Chronic use 
may produce dependence as well as withdrawal symptoms.  In our pilot work, we have seen no evidence of 
abuse/dependence or withdrawal effects. 
 
During our pilot work, patients have not described euphoria, drug craving, or physical or psychological difficulty with 
stopping the medication after completing the study.  A benefit of studying older adults is that most opioid-abuse 
disorders have been declared by old age, and we will  exclude subjects with a history of opioid dependence, serially 
assess subjects for euphoria, closely monitor all prescribed study medication, and require that unused tablets be 
returned to the pharmacy for destruction (to minimize the risk of diversion).  However, there is still a risk of 
precipitating a de novo abuse/dependence diathesis.  We have observed that 22.4% of patients with LL-TRD have 
a history of alcohol mis-use.  These subjects may be at increased risk of opioid mis-use.  For all subjects, we will 
closely monitor for the emergence of change in alcohol use.  We will use the Alcohol Use Disorders Identification 
Test (AUDIT) as deemed clinically necessary to assure there is not a clinically significant change in alcohol use.   
The euphoria measure will be administered at a number of time points.  If subjects endorse euphoria, the dose of 
study medication will be decreased.  At the end of the study, the study medication will be tapered approximately 
20% every 3 days until it is discontinued.  Subjects will be monitored by telephone for the week following 
discontinuation using the Clinical Opiate Withdrawal Scale (COWS) to assess for symptoms of withdrawal.  They 
will also be encouraged to contact the research staff/ P.I. if they experience symptoms of withdrawal (about which 
they will be counseled).  If symptoms emerge, we will then restart the study medication at the last dose and begin 
another slowed taper.  All subjects will be monitored for at least one week after discontinuation of the study 
medication to assure they are comfortably off the medicine.  Aftercare resources will be determined on a case-by-
case basis with the subject.  All subjects will be counseled during the informed consent process about the low but 
possible risk of becoming dependent upon the study medication during their participation.  Our DSMB will help us 
monitor the emergence of such problems. 
 
One of our primary aims is to evaluate the acceptability of the augmentation of venlafaxine XR with buprenorphine 
(BPN), and we will closely monitor all subjects for any serious adverse events (SAE).  Thus, we believe that 
subjects treated under the controlled conditions of the proposed protocol will actually be safer than subjects 
receiving many augmentation strategies in the community under usual care conditions. The potential risks 
associated with participation (including the risk of the augmentation and the risk of receiving an ineffective 
treatment) will be clearly described to all the potential subjects as part of the informed consent process. 
 
4.5 Suicide:   
Patients who are identified as being acutely suicidal will be excluded from the study.  Nevertheless, since the 
rate of completed suicide in the USA remains high (i.e., about twice the rate of homicide) and most Americans 
who commit suicide suffer from depression, all subjects eligible to participate in this study are statistically at a 
relatively higher risk for suicide than the general population.  However, the subjects’ absolute risk for 
completing suicide during this brief study remains very low (i.e., about 1 in 3,000 to 10,000) and participation in 
the study does not create or increase the risk of completed suicide.  Actually, most experts believe that one of 
the most efficient ways to decrease suicidal risk in older depressed individuals is to treat their depression. 
Even though we predict that the depression of subjects randomized to buprenorphine (BPN) is more likely to 
resolve than the depression of those randomized to placebo, this hypothesis still needs to be confirmed, which 
is beyond the scope of this developmental trial.   
 


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As discussed in the Assessments section, at each assessment point, the trained raters will probe for passive 
death wish, and suicidal ideation, intent or plan when they administer the Montgomery-Asberg Depression 
Rating Scale (MADRS) and the Scale for Suicidal Ideation (SSI).  If a subject endorses suicidal ideation, intent, 
or plan, the rater will be trained to follow an operationalized protocol that has been developed to manage high-
risk subjects in other studies of depressed subjects potentially at risk for suicide.  This protocol has already 
been used successfully by investigators to manage several acutely suicidal patients and it has been 
published.35  Briefly, the protocol entails a specific determination of the suicidal risk and prescribes a set of 
actions.  For instance, when a subject is determined to be at high and immediate risks, the rater is instructed to 
stay with the subject until he or she has contacted a study psychiatrist to discuss the situation and to devise a 
plan. For this reason, raters will have cell phones and at least one study psychiatrist will be reachable at all 
times.  In case of extreme emergency, raters are instructed to call their hospital security team or 911 for 
immediate help and to initiate commitment proceedings.   
 
The ethical ground for the use of a “placebo” condition in studies involving depressed subjects who are at risk 
for suicide has been reviewed.36  Furthermore, all participants will be formally assessed weekly during the 
study. We have a 24/7/365 on-call system with geriatric psychiatry back-up.  If the study personnel identify that 
a subject has become acutely suicidal, this subject will be referred to a mental health professional for further 
evaluation and treatment. This may lead to a clinical intervention that is lifesaving and may not have occurred 
had the subject not been participating in the study.  Continued use of venlafaxine during phase 2 of the study 
may also provide protection from suicide, as antidepressants have been shown to decrease the risk of suicide 
in older adults.37 
 
4.6 Procedures to Minimize Risk:  The PI will have primary responsibility for the monitoring of subjects during 
the entire time they participate in the study.  Subjects will be reviewed at baseline by the PI; exclusion criteria 
will reduce the risk to subjects.  The study will have a 24-hour answering service with physician backup.  The 
study investigators, study coordinators, and other study staff will meet weekly to review accrued data, data 
confidentiality, adherence to protocol design, recruitment, and subject complaints.  During this meeting, all 
subjects will be clinically reviewed, including discussion of clinical presentation, changes in clinical symptoms, 
side effects, any possible adverse events, and intercurrent medical conditions.  During these discussions, any 
possible changes to the risk-benefit level will be discussed.  
 
The first dose of study medication (buprenorphine (BPN) or placebo) will be taken at home.  Participants will be 
encouraged to not use alcohol during participation in the project, minimize driving or the operation of heavy 
machinery for the day of and immediately following dose escalations, and to keep the study medication in a secure 
and/or locked place.   
 
4.7 Procedures to Minimize Risk of MRI: 
To minimize the risk of boredom, tiredness, muscle aches and anxiety, participants may take breaks as 
needed throughout the study.  They will also be told they can take breaks.  Participants are offered pillows and 
blankets to alleviate discomfort in the scanner.  Participants will be able to communicate with study staff at all 
times during the scan and will be told they can stop the scan at any time for any reason.  Earplugs will be 
offered to decrease the exposure to the scanner’s acoustic noise. 
 
Participants will be screened at the time of the phone screener and again before the MRI scan for any 
contraindications to the MRI, including the presence of implanted devices that pose a substantial risk.  The 
scanning bay on the CCIR is located inside the hospital thus facilitating access to the hospital emergency 
personnel should a medical emergency arise.    
 
4.8 Discomfort With Answering Questionnaires: With respect to minimizing the discomfort that may result 
from the interview, raters have been or will be selected on the basis of personal attributes and interpersonal 


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skills as well as substantive knowledge.  They will be further trained and periodically observed to ensure that 
they are respectful and sensitive to the needs and feelings of the subjects.  Furthermore, they are trained to 
recognize signs of significant stress or irritability and will be instructed that they should gently terminate the 
interview whenever distress is observed. 
 
4.9 Side Effects and Adverse Events:  Regular assessments for side effects including sedation, falls, 
constipation, and mental slowing will be routinely conducted.  If present, they will be assessed by a physician. 
Regular feedback will be provided to the subjects and their treating physicians. At any time during the study if a 
subject is judged to be experiencing serious side effects by the treating or research physician, he or she will be 
withdrawn from the study and the appropriate referral will be recommended. 
 
4.10 Data Integrity and Confidentiality:  Subjects will be interviewed specifically to obtain research data.  In 
addition to training and close supervision of research staff described above, a formal quality control 
mechanism will provide a systematic check on the quality of interview data.  Specific procedures to protect 
subjects’ confidentiality, and formal mechanisms limiting access to information that can link data to individual 
subjects include:  Data forms that include identifying information will be kept in locked cabinets. Only the 
unique ID number, assigned by the research coordinator at the time consent is signed, will represent subjects 
during data entry, data transfer, data analysis, or other file management procedures. To facilitate tracking, a 
password-protected computer file will be maintained containing the identity of subjects, their ID numbers, and 
information about how they can be reached. This file, however, will contain no clinical data. Only members of 
the investigative group will have access to secured files or to master lists for subject code numbers and will be 
well-informed regarding the protection of patients’ rights to confidentiality. Identities of participants will not be 
revealed in the publication or presentation of any results from this project. 
 
Clinical information obtained at initial evaluation, and clinical treatment notes, will become part of subjects’ 
medical records. Modern medical record facilities are maintained that provide adequate safeguards for the 
protection of confidentiality of medical records.  
 
Research team members will enter study data via a secure Web site into a SQL/Server relational database. At 
point-of-entry, data values will undergo consistency edits (e.g., ID validation, range verification, duplicate 
detection) and personnel will be required to correct errors. RedCap will be used to create reports, also via the 
Web-based program.  
 
4.11 Risks in Relation to the Anticipated Benefits 
All subjects participating in this study will receive a comprehensive assessment performed at the time of 
initiation of the study.  In addition, subjects will be assessed at regular intervals.  As discussed above, these 
research assessments may reveal conditions that had not been identified (e.g., suicidality, psychosis, or 
mania), leading to critical clinical intervention that would not have occurred otherwise.  All subjects will be 
treated openly with venlafaxine and some will be randomized to buprenorphine (BPN) or placebo.  They may 
benefit from these interventions if indeed they are effective.  Regardless of whether the main hypotheses are 
supported, the results of this study should be useful in determining the safety and clinical effect of venlafaxine 
plus buprenorphine (BPN) for the treatment of LL-TRD.  These results will guide the use of this combination in 
clinical settings.  If it is shown to be dangerous or ineffective, knowledge derived from this project could help to 
reduce its use.  Conversely, if it is shown to be safe and effective, this knowledge will support the treatment of 
older patients with LL-TRD and thus, contribute to reduce the significant public health burden associated with 
LL-TRD.  Moreover, subsequent studies can then compare the relative effectiveness, tolerability, and 
acceptability of this intervention and other pharmacotherapies or psychotherapies.  Finally, comparative 
studies can lead to additional research investigating the use of venlafaxine plus buprenorphine (BPN) in other 
“complicated” forms of late-life depression (e.g., bipolar depression, psychotic depression). As the overall risks 
involved in participating in this study are deemed relatively small because of the protections described above, 
the risk to benefit ratio for this project is perceived to be low and justifies its implementation. 
 


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Adverse events, assessment of changes to the risk/benefit ratio, acceptability of study continuation, breaches 
in confidentiality, and subject complaints will be reviewed by the principal investigator and reported to the IRB 
in accordance with guidelines.  Any change in risk-to-benefit ratio will be provided to currently active subjects, 
and once a modified consent form is approved by the IRB, active subjects will be re-consented if they decide to 
continue, and any new subjects will be consented with the new consent form. 
  
Data and Safety Monitoring Plan 
A summary of the data and safety monitoring frequency and outcome will be submitted yearly to the IRB at 
time of obtaining renewal approval. Adverse events, assessment of changes to the risk/benefit ratio, 
acceptability of study continuation, breaches in confidentiality, and subject complaints will be reviewed by the 
principal investigator and reported to the IRB in accordance with IRB reporting guidelines. Any change in risk-
to-benefit ratio will be provided to currently active subjects and once a modified consent form is approved by 
the IRB, active subjects will be re-consented if they decide to continue, and any new subjects will be consented 
with the new consent form. 
 
Briefly, major depression is a serious disorder that can lead to suicide and other significant adverse 
consequences. We also recognize that our interventions could expose some subjects to risks that have not 
been identified thus far. Therefore, the presence of an independent DSMB is critical. The DSMB will include 
experts in late-life depression, substance abuse/ dependence, and a biostatistician. The functions of the DSMB 
have been designed to ensure the safe and effective conduct of research projects and to recommend 
conclusion of a trial when significant benefits or risks are identified, or if it becomes unlikely that the trial can be 
concluded successfully. The DSMB will assure that the investigators submit reports of all unexpected adverse 
events and of all serious adverse events to the IRB and to the DSMB itself. The DSMB will in turn inform the 
IRB of its relevant deliberations and the final determination. The DSMB will also decide when adverse events 
require reporting to the NIH. If applicable, the DSMB will also send to the IRB copies of all communications 
with the NIH. 
 


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