Mechanisms of Antidepressant Non-Response in Late-Life Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: New York State Psychiatric Institute

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Version Date:
08/22/2019
Protocol Title:
Mechanisms of Antidepressant Non-
Response in Late-Life Depression
Protocol Number:
6836
Contact Principal Investigator:
Bret Rutherford, MD
Email: brr8@columbia.edu 
Telephone: 646 774 8660
Clinic:
Adult and Late Life Depression

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Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
Enrollment and research interventions have concluded. Data analysis is ongoing. Study recruitment met and 
exceeded expected enrollment (n=130), with one hundred thirty-eight subjects signing informed consent. 
The study progressed well, with neuropsychological testing, MRI scans, and other procedures tolerated well 
by participants. Overall, response and remission rates were consistent with antidepressant clinical trials in 
older adults. Many patients went on to receive follow-up treatment in CAAM and expressed appreciation for 
the high quality care we provide. Data has been well maintained and internally-monitored.
Overall Progress
Approved sample size
130
Total number of participants enrolled to date
138
Number of participants who have completed the study to date 
99
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 

Page 3 of 22
Sample Demographics
Older adults with diagnosis of Major Depressive Disorder Total number of participants enrolled from this 
population:138
Gender, Racial and Ethnic Breakdown Gender
Male: 51
Female: 87
Race:
American Indian/Alaska Native: 0
Asian: 2
Black/African-American: 30
Native Hawaiian/Pacific Islander: 0
White: 85
More than one: 7
 Don't Know: 11
Missing: 3
Ethnicity:
Not Hispanic/Latino: 112
Hipanic/Latino: 22
Missing: 4 
130
Total number of participants enrolled to date
138
Number of participants who have completed the study to date 
99
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 

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Procedures
   Psychiatric Assessment
   Neuropsychological Evaluation
   Medication Trial
   Use of Placebo or Sham Treatment
   MRI
   Medication-Free Period or Treatment Washout
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Non-English Speaking Participants

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Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
This project seeks to elucidate the mechanisms by which antidepressant medications have limited efficacy in 

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Late Life Depression (LLD) in order to develop new treatment interventions for this prevalent and disabling 
illness. We hypothesize that the presence of executive dysfunction (ED), which is common in depressed adults 
over 60, impairs the ability to form appropriate expectancies of improvement with antidepressant treatment. 
Greater expectancy has been shown to improve antidepressant treatment outcome and is hypothesized to be a 
primary mechanism of placebo effects. Moreover, white matter hyperintensities 
(WMH) on magnetic resonance imaging (MRI) are more prevalent in patients with LLD compared to healthy 
controls. It has been argued that WMH contribute to the pathogenesis of LLD with ED and decrease the 
efficacy of antidepressant medications by disrupting connections between prefrontal cortical (PFC) and 
subcortical structures. Vascular lesions to white matter tracts may also compromise the pathway by which 
expectancy-based placebo effects influence depressive symptoms. Expectancies reflect activation in PFC areas 
that may improve depressive symptoms by modulating the activity of subcortical regions subserving negative 
affective systems (i.e., amygdala) as well as those important in reward and hedonic capacity 
(nucleus accumbens and ventral striatum). Thus, LLD patients with ED and WMH may sustain a “double-hit” 
to their ability to experience placebo effects in antidepressant treatments: ED diminishes the ability to generate 
appropriate treatment expectancies, while WMH disrupt the physiologic pathways by which expectancies lead 
to improvement in depressive symptoms. 
To determine whether decreased antidepressant medication response in LLD patients with ED and WMH is 
caused by a loss of expectancy effects, we will evaluate 130 outpatients with LLD at baseline to determine their 
degree of ED (interference score on Stroop Color-Word Test), WMH burden (severity score on Fazekas 
modified Coffey Rating Scale derived from anatomical MRI), and white matter tract integrity 
(using diffusion tensor imaging [DTI]). Building on work from my K23 Award, we will manipulate 
participants’ expectancy of improvement in an 8-week duration antidepressant trial by randomizing them 
between open administration of escitalopram or duloxetine (i.e., high expectancy) and placebo-controlled 
administration of escitalopram or duloxetine (i.e., low expectancy). The difference in antidepressant response 
observed between open and placebo-controlled medication treatment is a measure of the expectancy 
contribution to outcome, which is substantial in younger depressed adults but we hypothesize will be 
diminished in LLD patients with ED and WMH.
Background, Significance and Rationale
Background, Significance and Rationale
Major Depressive Disorder (MDD) is a leading cause of disability, morbidity, and mortality across the lifespan 
but poses a particularly severe public health problem in late life.19-20 MDD affects 3% of community-dwelling 
adults over 60 years old,2 and 15% of older adults living in the community have clinically significant 
depressive symptoms.3 Diagnosis with MDD increases an older adult’s risk of disability by 67-73% over 6 year 
follow up,21 causes twice the functional impairment compared to those without MDD,22 increases the risk of 
mortality in patients with heart disease, and is associated with high rates of completed suicide in individuals 
over 65 (16.9/100,000 overall and 62/100,000 in white men).23-24 Late-life depression (LLD) is highly 
recurrent, can become chronic,25 and is often difficult to treat.1 Residual symptoms place patients at increased 
risk of suicide as well as cardiovascular morbidity and mortality.26-27
Available research on antidepressant non-response in older adults has focused on executive dysfunction 

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(ED) and white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI) scans 
as the variables prominently associated with poor treatment outcome. ED is common in older depressed 
patients5 and has been shown to predict poorer response to antidepressant medication and higher relapse 
rates during the continuation phase of treatment.28-29 Similarly, WMH are observed in the majority of 
older adults with MDD and are associated with a more chronic clinical course30 and poor response to 
antidepressants.31-32 To account for these data, the vascular depression model proposes that vascular 
lesions to deep white matter tracts disconnect prefrontal cortical (PFC) regions from striatal and limbic 
areas, disrupting reciprocal modulation between PFC and subcortical structures, and causing depressive 
symptoms as well as ED.9 It has been postulated that decreased observed antidepressant response in 
depressed patients with ED and WMH results from serotonergic medications being less efficacious in the 
setting of this structural brain pathology. 
While proposing ED and WMH as predictors of non-response to antidepressant medication is useful 
prognostically, the vascular depression model does not provide a physiologic mechanism explaining non-
response. The provision of such a mechanism would greatly advance our understanding of the pathogenesis 
of LLD as well as the biology of antidepressant response. It is not obvious why damage to frontostriatal 
tracts should block the effects of antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs). 
Their mechanisms of action appear to be related to salutary modulation of hyperactive limbic structures33 
as well as stimulation of neurogenesis,34 which would not necessarily be affected by deep WMH. 
Additionally, SSRIs are effective for the prevention35 and acute treatment36 of post-stroke depression and 
improve functional recovery following stroke.37 If SSRIs are effective in these contexts, it is unclear why 
they should also not be effective in treating LLD with ED and WMH. As has been the case with other 
developments in the history of psychopharmacology (e.g., understanding reserpine-induced depression 
leading to drugs targeting monoaminergic neurotransmitter systems), it is to be hoped that identifying the 
mechanism of antidepressant non-response in LLD would yield treatments based on rational designs 
targeting the pathophysiology. 
This project is designed to test the hypothesis that antidepressant response is lower in LLD patients with ED 
and WMH due to a loss of the component of medication response attributable to patient expectancy. Using a 
method of studying expectancy-based placebo effects emerging from my K23 Career Development 
Award,1,16,38 we will first assess participants at baseline using a neuropsychological test battery, 
anatomical MRI, and diffusion tensor imaging (DTI). Next, participants’ expectancy of improvement will be 
manipulated by randomizing them to different probabilities of receiving the same antidepressant medication. 
The high expectancy condition is open escitalopram (i.e., 100% chance of receiving active medication), 
while the low expectancy condition is placebo-controlled administration of escitalopram (which participants 
believe represents 50% chance of receiving active medication). The difference in antidepressant response 
observed between the open and placebo-controlled medication treatments is a measure of the expectancy 
contribution to outcome, which is substantial in younger depressed adults but we hypothesize will be 
diminished in older patients with ED and/or WMH. 
The finding that antidepressant non-response in LLD is caused by a disruption in expectancy effects would 
have several significant implications. Most importantly, understanding antidepressant non-response in LLD 
at the level of mechanism may permit the development of novel treatment interventions for patients with 
continued symptoms. For example, methods may be developed to restore the expectancy component of 
medication response through specific cognitive or manualized psychoeducational interventions aimed at 

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enhancing patients’ expectation of improvement with antidepressant treatment. Pairing such interventions 
with inexpensive and widely available first-line antidepressant medications (i.e., SSRIs) may be a safe, 
feasible, and effective way to enhance treatment response. More speculatively, somatic treatments aimed at 
promoting prefrontal-limbic and prefrontal-striatal connectivity may be promising therapeutic avenues to 
explore. Such treatments might include drugs that augment neurotransmitters supporting frontostriatal 
circuitry (e.g., dopamine, acetylcholine) or transcranial magnetic stimulation (TMS).
Specific Aims and Hypotheses
Specific Aims and Hypotheses
This project seeks to elucidate the mechanisms by which antidepressant medications have limited efficacy in 
Late Life Depression (LLD)1 in order to develop new treatment interventions for this prevalent and 
disabling illness.2-3 We hypothesize that the presence of executive dysfunction (ED), which is common in 
depressed adults over 60,4 impairs the ability to form appropriate expectancies of improvement with 
antidepressant treatment. Greater expectancy has been shown to improve antidepressant treatment outcome 
and is hypothesized to be a primary mechanism of placebo effects.5-7 Moreover, white matter 
hyperintensities (WMH) on magnetic resonance imaging (MRI) are more prevalent in patients with LLD 
compared to age-matched healthy controls.8 It has been argued that WMH contribute to the pathogenesis of 
LLD with ED and decrease the efficacy of antidepressant medications by disrupting connections between 
prefrontal cortical (PFC) and subcortical structures.9-10 Vascular lesions to white matter tracts may also 
compromise the pathway by which expectancy-based placebo effects influence depressive symptoms. 
Expectancies reflect activation in PFC areas that may improve depressive symptoms by modulating the 
activity of subcortical regions subserving negative affective systems (i.e., amygdala)11-12 as well as those 
important in reward and hedonic capacity (nucleus accumbens and ventral striatum).13-14 Thus, LLD 
patients with ED and WMH may sustain a “double-hit” to their ability to experience placebo effects in 
antidepressant treatments: ED diminishes the ability to generate appropriate treatment expectancies, while 
WMH disrupt the physiologic pathways by which expectancies lead to improvement in depressive 
symptoms. 
Consistent with the above model, cognitively intact patients with LLD appear to experience large 
expectancy effects during antidepressant treatment. We have shown that LLD patients enrolled in 
comparator-type studies, who are assured of receiving active medication for their condition, have 
medication response rates nearly double those of LLD patients enrolled in placebo-controlled studies, who 
are aware they may be receiving placebo.1 However, the ability to generate expectancy effects appears to be 
attenuated in LLD patients with significant WMH: we found in analyses of a large antidepressant trial for 
LLD that more severe WMH was associated with decreased response to placebo.15 In addition, a 
prospective study conducted preliminary to this application randomized depressed patients to receive the 
same antidepressant medication in “high expectancy” vs. “low expectancy” experimental conditions.16 
Randomization to the high as opposed to low expectancy condition resulted in increased expectancy of 
improvement and greater change in depressive symptoms over 8 weeks for patients < 60 years old. This was 
not true for patients ≥ 60 years old, who experienced little expectancy change and no treatment benefit in 
the high vs. low expectancy conditions. 
To determine whether decreased antidepressant medication response in LLD patients with ED and WMH is 

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caused by a loss of expectancy effects, we will evaluate 130 outpatients with LLD at baseline to determine 
their degree of ED (interference score on Stroop Color-Word Test17), WMH burden (severity score on 
Fazekas modified Coffey Rating Scale18 derived from anatomical MRI), and white matter tract integrity 
(using diffusion tensor imaging [DTI]). Building on work from my K23 Award, we will manipulate 
participants’ expectancy of improvement in an 8-week duration antidepressant trial by randomizing them 
between open administration of escitalopram or duloxetine (i.e., high expectancy) and placebo-controlled 
administration of escitalopram or duloxetine (i.e., low expectancy). The difference in antidepressant 
response observed between open and placebo-controlled medication treatment is a measure of the 
expectancy contribution to outcome, which is substantial in younger depressed adults16 but we hypothesize 
will be diminished in LLD patients with ED and WMH. 
Specific Aim 1: To determine whether ED and/or WMH moderate the difference in patient expectancy and 
antidepressant outcome between the open vs. placebo-controlled conditions. Hypothesis 1: Greater ED and 
WMH will be associated with smaller differences in expectancy and antidepressant outcome between 
conditions.
Specific Aim 2: To determine whether a loss of expectancy effects mediates the relationship between 
ED/WMH and poor antidepressant outcome. Hypothesis 2: ED and WMH will be associated with decreased 
change in depressive symptoms, and these associations will be mediated by a decreased contribution of 
expectancy to antidepressant outcome.
Exploratory Aim: To assess the integrity of frontostriatal and frontolimbic white matter tracts using DTI and 
explore whether specific damage to these pathways is associated with diminished expectancy effects in 
patients with LLD.
Substantiating this model would provide a mechanism explaining how ED and WMH predict non-response 
to antidepressant medications in LLD. Understanding the mechanisms of antidepressant non-response in 
LLD has the potential to yield treatments based on specific and rational designs that target the involved 
biological pathways. By combining inexpensive and widely available antidepressant medications with 
psychoeducational interventions or targeted psychotherapies to enhance expectancy, it may be possible to 
significantly improve antidepressant response rates in LLD patients.
Description of Subject Population
Sample #1
Specify subject population
N=130 outpatients with MDD
Number of completers required to accomplish study aims
90
Projected number of subjects who will be enrolled to obtain required number of completers
130
Age range of subject population

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60-90
Gender, Racial and Ethnic Breakdown
Gender: We anticipate the sample will be composed of approximately 60% women and 40% men. 
Racial/ethnic group: On the basis of previous depression studies conducted in the Adult and Late Life 
Depression Clinic, it is anticipated that the sample will be composed of approximately 75% Caucasian, 15% 
African American, and 10% Hispanic subjects.
Description of subject population
The proposed study will enroll 130 outpatients who are (1) men and women aged 60-90 years, (2) diagnosis 
with nonpsychotic Diagnostic and Statistical Manual (DSM) IV MDD, (3) 24-item Hamilton Rating Scale 
for Depression (HRSD) score ≥ 16, (4) willing to and capable of providing informed consent and complying 
with study procedures. Exclusion criteria are (1) current comorbid Axis I DSM IV disorder other than 
Nicotine Dependence, Adjustment Disorder, or Anxiety Disorder, (2) diagnosis of substance abuse or 
dependence (excluding Nicotine Dependence) within the past 12 months, (3) history of psychosis, psychotic 
disorder, mania, or bipolar disorder, (4) diagnosis of probable Alzheimer’s Disease, Vascular Dementia, or 
Parkinson’s Disease, (5) MMSE < 24, (6) HRSD suicide item > 2 or Clinical Global Impressions (CGI)-
Severity88 score of 7 at baseline, (7) history of allergic or adverse reaction to escitalopram and duloxetine, 
or non-response to adequate trial of escitalopram (at least 4 weeks at dose of 20mg) and duloxetine (at least 
4 weeks at dose of 60mg) during the current episode, (8) current treatment with psychotherapy, 
antidepressants, antipsychotics, or mood stabilizers, (9) having contraindication to MRI scanning (such as 
metal in body) or unable to tolerate the scanning procedures (i.e., severe obesity, claustrophobia) (for 
subjects undergoing MRI scanning only), and (10) acute, severe, or unstable medical or neurological illness.
Recruitment Procedures
Describe settings where recruitment will occur
Subjects will be recruited through radio and newspaper advertisements and referrals from other physicians.
How and by whom will subjects be approached and/or recruited? 
Individuals presenting to the Adult and Late Life Depression Research Clinic (ALLDRC) are evaluated 
under IRB #7284R, “Evaluation at the Adult and Late Life Depression Center.” Following this evaluation, 
one of the study psychiatrists authorized to obtain informed consent will discuss study participation with 
subjects.
How will the study be advertised/publicized? 
Newspaper and radio advertisements, flyers posted around CPMC, physician referrals.
Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT01931202

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Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Subjects who meet criteria for this and other protocols in the ALLDC can participate in both protocols 
concurrently. These protocols are listed below:
-PHYSICAL AND MENTAL FATIGABILITY IN LATE LIFE CLINICAL POPULATIONS (PI Brown) -
IRB #7360
-MITOCHONDRIAL FUNCTION, FATIGUE, AND DEPRESSION IN LATER LIFE (PI Brown) IRB
#7379
The consent form for this study is separate from those for the above protocols. Participation in this study 
will not affect their participation in the other study. This is made explicit in the consent form for this study. 
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Depressed patients
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion criterion
Method of 
ascertainment 
(1) men and women aged 60-90 years
Clinical 
interview
(2) diagnosis with nonpsychotic Diagnostic and Statistical
Manual (DSM) IV MDD
Clinical 
interview, SCID
(3) 24-item Hamilton Rating Scale for Depression (HRSD)
score ≥ 16
 HRSD by 
trained rater
(4) willing to and capable of providing informed consent
and complying with study procedures
 Clinical 
interview
Create or insert table to describe the exclusion criteria and methods to ascertain them
 Exclusion criterion 
Method of 
ascertainment 
(1) current comorbid Axis I DSM IV disorder other than
Nicotine Dependence, Adjustment Disorder, or Anxiety
Disorder
 Clinical 
interview, 
SCID

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 (2) diagnosis of substance abuse or dependence (excluding 
Nicotine Dependence) within the past 12 months
 Clinical 
interview, 
SCID
 (3) history of psychosis, psychotic disorder, mania, or bipolar 
disorder
 Clinical 
interview, 
SCID
 (4) diagnosis of probable Alzheimer’s Disease, Vascular 
Dementia, or Parkinson’s Disease 
 Clinical 
interview
 (5) MMSE < 24
 MMSE
( 6) HRSD suicide item > 2 or Clinical Global Impressions 
(CGI)-Severity score of 6 or greater at baseline
 HRSD by 
trained rater, 
CGI by study 
physician
 (7) history of allergic or adverse reaction to escitalopram and 
duloxetine, or non-response to adequate trial of escitalopram 
(at least 4 weeks at dose of 20mg) and duloxetine (at least 4 
weeks at dose of 60mg) during the current episode 
 Clinical 
interview
 (8) current treatment with psychotherapy, antidepressants, 
antipsychotics, or mood stabilizers 
 Clinical 
interview
 (9) having contraindication to MRI scanning (such as metal 
in body) or unable to tolerate the scanning procedures (i.e., 
severe obesity, claustrophobia) (for subjects undergoing MRI 
scanning only)
  MRI safety 
screening 
form, 
Clinical 
interview
 (10) acute, severe, or unstable medical or neurological illness
 Clinical 
interview, 
blood tests, 
physical 
exam
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
No
Waiver of parental consent 

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No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
7284R
Describe Study Consent Procedures
When a patient arrives to be evaluated at the ALLDC, they must first sign the ALLDC evaluation consent 
form (IRB #7284R) and HIPAA consent form. The clinic coordinator or an ALLDC research assistant will 
then do the 30-item Mini-Mental State Exam to get a general idea of the patient’s global cognitive 
performance (this is especially important in older patients who may be experiencing cognitive/memory 
difficulties in addition to depression). The patient is then seen by one of the ALLDC psychiatrists. 
Following the MD evaluation, the doctor may ask for a SCID (Structured Clinical Interview for the DSM), a 
structured diagnostic interview, and HAM-D (Hamilton Rating Scale for Depression) to be performed by a 
qualified rater (Nancy Turret or trained research assistant). Based on the information from the MD 
evaluation, HAM-D score, and SCID diagnosis(es), the MD will decide if the patient is eligible for any of 
the ALLDC research protocols.
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Broft, Allegra, MD
Roose, Steven, MD
Rutherford, Bret, MD
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
Overview
 
The proposed 8-week antidepressant clinical trial design has been used to successfully manipulate patient 
expectancy and influence antidepressant outcome in pilot studies--the proposed design is nearly identical to 
that approved under IRB #6038. At baseline, subjects will be evaluated, and eligible individuals will be 
invited to participate in the study. Those signing informed consent will have physiologic tests conducted and 
will be scheduled for baseline neuropsychological testing and MRI scanning. Following baseline testing, 

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subjects will return for a Week 0 visit when continued symptoms will be confirmed and medication will be 
distributed, after which they will return for 8 weekly visits. Psychological assessments performed on study 
participants by a psychiatrist may also be performed by medical psychiatry interns (PGY-1) who come to 
our clinic for 4-week rotations. All medical interns will have completed NYSPI-specific CITI training for 
human subjects research (specifically the biomed or social/behavioral course). The interns will be 
supervised by our clinical team, which consists of Steven Roose, MD; Bret Rutherford, MD; Allegra Broft, 
MD; and Patrick Brown, PhD.
 
Evaluation and Screening
 
1. Patients will first undergo an initial evaluation comprising a psychiatric interview (MD), Mini Mental 
Status Exam (MMSE), as well as Structured Clinical Interview Diagnostic (SCID IV) and Hamilton Rating 
Scale for Depression (HRSD) by trained raters. 
2. All potentially eligible subjects will complete a screening questionnaire that includes questions regarding 
the presence of ferromagnetic implants. If the subject has any metallic implants (i.e. metal heart valve, aortic 
clips, etc.) that are unsuitable for the scanner, that subject will not be offered MRI scanning in this study. 
Further screening will be done by New York State Psychiatric Institute – Dept. of Psychiatry MRI Metal 
Screening Questionnaire. This is a 38-item questionnaire that was developed by Dr. Peterson (as Director of 
the MRI Unit) will be administered to every subject before they enter the MRI scanner. This questionnaire 
asks specifically about metallic implants and past experiences with metal to further ascertain any possible 
risks the person may incur by entering the scanner. If any metallic implants are detected that are unsuitable 
for the scanner, the subject will not undergo MRI scanning. Subjects who are otherwise eligible for the 
study and wish to participate will be offered participation in the clinical trial portion of the study only and 
will not have an MRI scan. 
3. The evaluating psychiatrist will review the consent form with eligible patients and invite them to 
participate.  
4. Patients who sign the consent form will complete the remainder of the baseline evaluation, including 
further paper measures, urine tests, blood tests, physical exam, and electrocardiogram (EKG) (RN or 
qualified research assistant). Lab results will be available to patients, should they request them. 
 
 MRI scanning
1. Patients will be scheduled for their MRI scan and neuropsychological assessment immediately after 
baseline assessment and prior to the first administration of study medication. It is possible that treatment 
may be delayed up to 1 week total due to scheduling these assessments, though we will make every effort 
not to delay treatment.
2. For the MRI procedures, the subject will be instructed to lie as still as possible within the magnet for 
approximately 90 minutes. When we position a subject in the scanner, head movement will be minimized 
through: (a) instructions to the participant; and (b) packing the head inside the head coil with a system of 
foam padding and pillows that we have found is well-tolerated by the participants, yet limits movement. All 
precautions and protections will be given to the participant to ensure that they are as safe and comfortable as 
possible. For the participant’s comfort within the scanner, they will lie on a padded table with a pillow to 
rest their heads on. A blanket will also be provided to keep subjects warm during the procedure. 
3. If the participant appears nervous or anxious, a trained member of the clinical staff will remain with them 
inside the scanning suite for the duration of the scan. The participant will be given a button box to terminate 

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the scan at any time. If they push the button, they will be removed from the scanner immediately All of the 
MRI procedures will be conducted on the 3-Tesla MRI scanner at the New York State Psychiatric Institute. 
Conducting these procedures will be an accredited Magnetic Resonance Technologist (B.M.R.) and a 
member of the research staff (Bachelor’s Level or Higher) trained in the acquisition of MR images by Dr. 
Peterson, as well as in procedures for testing human subjects. 
4. Although our MRI Scans are for research purposes, a radiologist will perform a clinical reading on every 
MRI within 1 month of scanning; if anything clinically significant is found, Dr. Rutherford will be notified 
immediately and he will provide an appropriate clinical referral to the participant.
5. At the start of the session, a 3-Plane localizer (scout) will be acquired to determine patient position. 
Subjects will then receive T1-weighted 3D SPGR (Spoiled Gradient Echo), T2 FLAIR, Dual FSE (Fast Spin 
Echo), and DTI (Diffusion Tensor Image) scans. While scanning parameters may change slightly, power-
monitoring software on the scanner will ensure total energy delivered to the subject will remain within FDA 
guidelines. Specifically, the specific absorption rate (SAR) will be not greater than: (1) 4 W/kg averaged 
over the whole body for any period of 15 minutes; (2) 3 W/kg averaged over the head for any period of 10 
minutes; (3) 8 W/kg in any gram of tissue in the head or torso; (4) 12 W/kg in any gram of tissue in the 
extremities, for any period of 5 minutes. These safety precautions are built into the MRI hardware, and are 
standard with every system.
6. We will rate the severity of White matter hyperintensities (WMH) on axial T2 FLAIR images using the 
Fazekas modified Coffey Rating Scale, which has been used extensively in vascular depression research. 
DWMH are scored as 0 (absent), 1 (punctate foci), 2 (beginning confluence of foci), and 3 (large confluent 
areas); subcortical gray matter HIs (basal ganglia) are scored as 0 (absent), 1 (punctate), 2 (multipunctate), 
and 3 (diffuse); periventricular HIs are scored as 0 (absent), 1 (caps), 2 (smooth halo), and 3 (irregular and 
extending into the deep white matter). Our primary measure of WMH burden will be DWMH score, which 
has been used to establish the only empirically validated diagnostic criteria for vascular depression. 
7. Regarding DTI, we will acquire the baseline image B0 and the diffusion weighted images (DWI) in 25 
directions. To isolate brain from non-brain tissue, we will apply the DTI software in the FSL analytic 
package (Analysis Group, FMRIB, Oxford, UK) to the B0 image and use the isolated brain as a mask to 
define the brain in DWIs. The images will be corrected for eddy current distortions, and then we will fit a 
diffusion tensor model to the DWI data at each voxel. The tensor model yields a voxel-wise map of 
1st/2nd/3rd eigenvectors and eigenvalues, fractional anisotropy (FA), and mean diffusivity across the entire 
brain. The DT images for all participants will be coregistered by applying affine transformation to a 
template brain using the B0 images, thereby permitting voxel-wise statistical analyses of the various DTI 
measures. In addition to the whole-brain voxel-wise statistical analyses, we will perform statistical analyses 
of the mean FA value within specified ROIs defined using regions of WMH in anatomical MR images for 
each participant. ROIs with significantly differing DTI measures will be associated with specific pathways 
in the brain by coregistering the template brain to a DTI atlas (LONI ICBM DTI atlas, cmrm.med.jhmi.edu), 
which parcellates the brain into 23 functionally meaningful anatomical regions, grouped by brainstem, 
projection fibers, association fibers, and commissural fibers (described in detail at cmrm.med.jhmi.edu). 
Finally, within the coordinate space of the template brain, we will perform diffusion tensor tractography 
from regions within prefrontal cortex to striatum and statistically analyze the various DTI measures at each 
voxel along these pathways. Statistically significant differences in the DTI measures along these pathways 
would indicate disruption of anatomical connectivity between regions in the prefrontal cortex and the 
striatum.
 
Neuropsychological testing

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 1. The baseline neuropsychological test battery assembled for this study meets five important criteria that 
we were striving to achieve (see Table 4): 1) it is short and well tolerated by the elderly (total administration 
time approximately 40 minutes), 2) it is a reasonably comprehensive assessment of executive functioning, 3) 
the measures are capable of tapping a range of abilities (minimizes floor and ceiling effects), 4) it comprises 
standard tests, and 5) it allows for reliable administration by trained technicians. 
2. Neuropsychological testing will include assessment of global cognitive functioning, IQ, attention, 
memory, language, executive functions, reaction time, and visuospatial processing. The 30-item Mini-
Mental State Examination (MMSE) will be used to measure general cognitive impairment. The Wechsler 
Test of Adult Reading (WTAR) will be used in conjunction with demographic variables to estimate IQ. 
Memory will be assessed using the Logical Memory Test (WMS III). We will use two standard measures to 
assess executive functioning. The Stroop Color Word Interference Test (Stroop) is a measure of attention, 
concentration, and behavioral inhibition under distracting conditions that is sensitive to frontal lobe 
dysfunction. The Mattis Dementia Rating Scale Initiation and Perseveration subtest (DRS I/P) measures a) 
verbal initiation and perseveration (e.g., naming supermarket items over 1 minute), b) performing 
alternating movements, and c) reproducing graphomotor designs (e.g., XOXO). Attention will be assessed 
using the wechler adult intelligence scale (WAIS-III) Digit Symbol Test.
3. NP testing is for research purposes only and the results of these tests will not be interpreted clinically or 
shared with the patient.
 
Clinical study
 
 1. Patients will then be randomized to an Open Group or a Placebo Controlled Group (please see attached 
for flow chart).
a. Subjects in the Open Group will be informed: “You have been randomly assigned to the open group of 
the study. This means that there is a 100% chance you will receive the antidepressant medication 
escitalopram [or duloxetine] for the duration of the study. Escitalopram  [or duloxetine] has been proven 
effective for the treatment of depression in patients like you. You will not be receiving any placebo pills for 
the duration of the study. While you are aware that you are receiving actual antidepressant medication and 
not placebo, some of the staff members seeing you do not know whether you are taking escitalopram [or 
duloxetine] or placebo. If it can be avoided, please do not reveal to anyone in the study what group you have 
been assigned to.” At the time of their entry into the study, patients will be started on escitalopram 10mg per 
day, which will be continued for four weeks. If at the end of that time patients do not meet remission criteria 
(HRSD < 11) or the patient continues to report depressive symptoms, is tolerating the medication well, and 
wishes to try a higher dose, the dose will be increased to 20mg escitalopram for the remainder of the study. 
Subjects who have previously not responded to or not tolerated escitalopram will be allowed to receive 
duloxetine. Subjects will receive duloxetine 30mg for 1 week, then if they do not meet remission criteria or 
the patient continues to report depressive symptoms, is tolerating the medication well, and wishes to try a 
higher dose, will increase to 60mg for 4 weeks, and then if they still do not meet remission criteria or the 
patient continues to report depressive symptoms, is tolerating the medication well, and wishes to try a higher 
dose, will increase to 90mg for final 3 weeks. The first choice is for subjects to receive escitalopram, and 
they will only receive duloxetine if they have previously failed or not tolerated escitalopram.
b. Subjects in the Placebo-controlled Group will be randomized unequally (6:1) to escitalopram [or 
duloxetine] vs placebo. They will be informed: “You have been randomly assigned to the placebo-
controlled group of the study. This means that there is a chance you will receive the antidepressant 

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medication escitalopram [or duloxetine] for the duration of the study. Escitalopram [or duloxetine] has been 
proven effective for the treatment of depression in patients like you. There is also a chance you will receive 
placebo for the duration of the study. A placebo is a sugar pill that is not specifically effective for 
depression. Neither you, nor your doctors, will know whether you are receiving escitalopram [or duloxetine] 
or placebo. If it can be avoided, please do not reveal to anyone in the study what group you have been 
assigned to.” Patients will receive 1 pill (10mg escitalopram or placebo) per day for four weeks. If at the end 
of that time patients do not meet remission criteria (HRSD < 11) or the patient continues to report 
depressive symptoms, is tolerating the medication well, and wishes to try a higher dose, the dose will be 
increased to 2 pills per day (20mg escitalopram or placebo) for the remainder of the study. Subjects who 
have previously not responded to or not tolerated escitalopram will be allowed to receive duloxetine. 
Subjects will receive 1 pill (duloxetine 30mg or placebo) for 1 week, then if they do not meet remission 
criteria or the patient continues to report depressive symptoms, is tolerating the medication well, and wishes 
to try a higher dose, will increase to 1 pill of 60mg duloxetine or placebo for 4 weeks. Then if they still do 
not meet remission criteria or the patient continues to report depressive symptoms, is tolerating the 
medication well, and wishes to try a higher dose, will increase to 2 pills (totaling 90mg duloxetine or 
placebo) for final 3 weeks. The first choice is for subjects to receive escitalopram, and they will only receive 
duloxetine if they have previously failed or not tolerated escitalopram.
2. Should a subject ask about the specific chances of being assigned to placebo or escitalopram [or 
duloxetine] in the Placebo Controlled Group, we will respond: “For the purpose of maintaining the study 
integrity, certain details of the study must be temporarily withheld from you. These details include your 
exact chances of receiving placebo or escitalopram [or duloxetine]. However, we can tell you that your 
chances of receiving placebo in this study are no greater than 50%. Also, following the conclusion of your 
participation in the study, we will provide you with the complete details of the study design if you so wish.” 
This approach allows the patient sufficient information to judge whether they wish to continue participating 
in the study while ensuring that the data produced are informative. Of course, subjects may choose to 
withdraw informed consent and not participate in the study if they are not comfortable with this level of 
specificity.
3. Patients will return to the LLDRC for weekly visits, at which they will receive clinical
management (MD) and complete assessment measures conducted by raters blinded to condition assignment. 
Weekly measures will include HRSD, Hamilton Anxiety Scale (HARS), Clinical Global Impressions 
(CGI)—Improvement, Credibility and Expectancy Scale (CES), and Quick Inventory for Depressive 
Symptomatology (QIDS) (MD, RN, or MSW). 
4. If a patient discontinues medication due to tolerability problems, ineffectiveness, patient preference, or 
other reasons, the patient will be dropped out of the study and enter the 3 month long open treatment phase. 
Appropriate medication options will be discussed with the patient based on their symptoms and history. If 
the patient wishes, they will be provided referrals for psychotherapy or treatment options outside of our 
research clinic. No further research measures will be conducted once a patient enters the open treatment 
phase.
5. Patients in all treatment cells will be discontinued from the acute treatment phase if there is there is a 
rating of 6 (much worse) or 7 (very much worse) on the CGI—I for 2 consecutive weeks. Patients receiving 
medication may continue receiving the same medication if clinically indicated after being dropped from the 
study. No further research measures will be performed on patient dropped from the study.
6. The blind will be broken at the end of the 8 week study period. Remitters (HRSD < 11) will be continued 
on the same medication. Responders to placebo will be followed off of medication. Placebo non-responders 

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will be treated openly with escitalopram [or duloxetine], while escitalopram [or duloxetine] non-responders 
will be treated as clinically indicated with augmentation or switch in class of antidepressants.
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
If a patient discontinues medication due to tolerability problems, ineffectiveness, patient
preference, or other reasons, the patient will be dropped out of the study and enter the 3 month long open 
treatment phase. Appropriate medication options will be discussed with the patient based on their symptoms 
and history. If the patient wishes, they will be provided referrals for psychotherapy or treatment options 
outside of our research clinic. No further research measures will be conducted once a patient enters the open 
treatment phase.
Patients in all treatment cells will be discontinued from the acute treatment phase if there is there is a rating 
of 6 (much worse) or 7 (very much worse) on the CGI—I for 2 consecutive weeks. Patients may also be 
discontinued from the study if this is indicated in the clinical judgement of the study physician and/or 
principal investigator. Patients receiving escitalopram/duloxetine may continue receiving the same 
medication if clinically indicated after being dropped from the study. No further research measures will be 
performed on patient dropped from the study. 
Patients will be informed that should they experience a crisis or acute symptom worsening between 
scheduled weekly appointments, they should call their study clinician via the clinic office/research 
coordinator or the 24 hr doctor on call pager for the LLDC. The study physician will evaluate the patient 
and make appropriate follow up arrangements, which may include activating EMS, calling the relevant 
mobile crisis team, or scheduling pt for immediate outpatient appointment in the LLDC. Patients in crisis 
will be assessed immediately and appropriate clinical action taken as above (i.e., those meeting criteria for 
early discontinuation will be dropped from the study and treated openly).
Blood and other Biological Samples
 CBC, blood chemistries, and electrolytes will be drawn before initiating escitalopram/duloxetine or 
placebo. The total amount of blood drawn should be no greater than 20cc.
Assessment Instruments

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Clinical measures
1. SCID IV -- 30 minutes
2. HRSD --15 minutes
3. QIDS -- SR 10 minutes
4. CES -- 5 minutes
5. CGI-I -- 1 minute
6. Blind assessment -- Patient guess -- 1 minute
7. Blind assessment -- Doctor guess -- 1 minute
8. TESS -- 3 minutes
9. ATHF -- 5 minutes
10. Credibility and Expectancy Scale  -- 5 minute
11. HARS -- 15 minutes
12. UCLA Revised Loneliness Scale -- SR -- 1 minute
Neoruopsychological tests
1. Wechsler Test of Adult Reading (WTAR)--5 min
2. Mini Mental State Examination (MMSE) -- 8 min
3. Stroop Color Word Test (Stroop) -- 5 min
4. Mattis DRS- I/P subset -- 10 min
5. Digit Symbol Subtest of the WAIS III -- 2 min
6. Logical Memory Test (WMS III) -- 10min
Please attach copies, unless standard instruments are used
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
It is possible that treatment may be delayed due to scheduling study MRI scans and neuropsychological 
testing, though we will make every effort not to delay treatment. If there are scheduling difficulties, 
treatment will not be delayed more than 1 week.
Maximum duration of delay to standard care or treatment of known efficacy
There will also be a delay of 8 weeks for 10/130 of patients (those assigned to receive placebo). 
Justification: In this study 10 subjects will be randomized to placebo in place of antidepressant treatment 
with escitalopram/duloxetine, which is not so toxic that patients routinely refuse treatment. The use of 
placebo rather than escitalopram/duloxetine could result in longer exposure to depressive symptoms, so the 

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IRB algorithm would seem to judge the risk of placebo as high. This risk is mitigated since there are not 
large differences between antidepressant medications and placebos in most clinical trials. Typical 
antidepressant response rates in placebo controlled trials are 40-45%, while placebo response rates are 30-
35%. If 10 subjects in this study are assigned to placebo rather than escitalopram/duloxetine, then based on 
these estimated rates only 1 subject would fail to respond to placebo who may have responded to 
escitalopram/duloxetine. That being said, continuing with the IRB algorithm, it is not possible to accurately 
predict placebo response in a single study (placebo response ranged widely between 13-52% in the Walsh et 
al 2002 meta-analysis). Finally, the potential benefit of understanding the cognitive and neural pathways by 
which placebo and expectancy effects cause improvement in depressive symptoms is substantial. Therefore, 
according to the algorithm provided by the IRB, the use of placebo in this study is ethical.
Treatment to be provided at the end of the study
At the end of the acute treatment protocol, appropriate treatment (medication continuation, change in 
medication, and/or follow-up) will be provided free for 3 months. Subjects will receive 3 months of free 
doctor visits in the clinic and at least 1 month of free medication. Every effort will be made to provide free 
medication for 3 months total, but we cannot guarantee the availability of free medication beyond 1 month. 
At the end of the three month period, patients will be referred out for further psychiatric follow up.
Clinical Treatment Alternatives
Clinical treatment alternatives
The alternative to participating in this study is to seek treatment outside the research project. Patients who 
would rather receive treatment elsewhere will be given referrals to appropriate and affordable care.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
The main risks in this study are (1) patients may not respond to the medication treatment, (2) patients 
assigned to placebo may experience continued symptoms or clinical worsening, (3) side effects of the 
medication, (4) risks related to MRI, and (5) specific risks associated with being a participant aged over 60 
years (such as having a comorbid medical condition, or being cognitively impaired). There are also minimal 
risks associated with the blood draws, but there is no greater risk in this protocol for this procedure than in 
any standard clinical setting.
Describe procedures for minimizing risks
Regarding (1), treatment with SSRIs and SSNRIs are accepted first line treatments for depression. Reliable 
evidence does not exist for the superiority of another medication or psychotherapy to escitalopram in 
depressed patients. Patients will be seen weekly to have their symptoms assessed, and patients who exhibit 
clinical worsening (as described in above procedures) will be dropped from the study and receive clinical 
treatment. Regarding (2), it is the case that patients in the Placebo Controlled Group will not receive a 
proven effective treatment for their condition if they are assigned to placebo. However, the risk of 
permanent harm to subjects will be minimized by restricting the study to depressed, nonsuicidal patients, 
following them closely, and dropping them from the study for signs of clinical deterioration. Regarding (3), 
commonly observed side effects associated with escitalopram and duloxetine are diaphoresis, diarrhea, 
nausea, insomnia, somnolence, disorder of ejaculation, impotence, and fatigue. The FDA has also placed a 

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black box warning in the package insert for all SSRIs warning of increased suicidal ideation and behavior. 
Side effects of the medication will be assessed at each visit. If the side effects represent an intolerable 
burden in the assessment of the patient or the treating clinician, the medication will be discontinued. 
Regarding (4), the Magnetic Resonance (MR) scanner uses strong magnetic fields and radio waves to take 
measurements in the brain. MRI involves lying on a table that slides into a large magnet shaped like a 
cylinder. Before beginning the procedure, we will determine that patients do not have a pacemaker or any 
unsafe metallic implants such as an aneurysm clip or heart valve and certain tattoos, and they will be asked 
to remove any metal or magnetized objects (such as keys, chains, jewelry, retainers, medication patches, 
hairpins or credit cards). They will be asked to lie flat on the back in the MRI scanner for approximately 90 
minutes and to remain as still as possible. Some people have reported sensations during MRI scans, such as 
"tingling" or "twitching" (or, very rarely, a painful sensation), which are caused by changes in the magnetic 
field that can stimulate nerves in the body. With any MRI scan, on occasion, some people experience 
nervousness or types of metallic implants, and medication patches, we are not aware of any other potentially 
dangerous interactions or hazards associated with the MRI scan. The MRI scanner also produces a loud 
noise; earplugs will be provided to reduce this discomfort. If a patient experience any discomfort and wish 
to stop the scan, he/she can tell the MRI technologist who will stop the scan immediately. In our experience, 
no one has had sensations from the MRI that did not stop when the scanning stopped. Finally, we will 
mitigate the risks associated with increased medical problems in older adults by doing a careful physical 
examination and blood tests to detect an unstable, severe, or acute medical problem. Since cognitive 
impairment is a condition impacting older adults, we will measure a MMSE and exclude subjects with a 
score lower than 24.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
All records of the participating subjects will be kept in a locked room with access provided only to staff 
members. Patients’ names will be linked with code numbers in a password protected file to which only the 
research assistant has access. Only these code numbers will appear on all pill bottles and paper measures 
collected during study. All data collected will be kept confidential and used for professional purposes only. 
Publications using these data will be done in a manner that protects the subjects’ anonymity. All 
electronically stored data will be accessible by password known only to the principal investigator and 
research assistants for the study. All MRI scans and
related data will be kept on the secure, password protected, MRI server. MRI scan reports will be provided 
to the clinic by the MRI scanner, and kept in a locked file.
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
Patients who are not currently in treatment and are experiencing depressive symptoms may receive a 
medication proven effective for their condition. Therefore, the major benefit is that patients will achieve 

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remission from the depression as a result of participating in the study.
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Subjects will receive reasonable reimbursement for transportation related costs associated with study 
involvement as long as they provide receipts. Reimbursement is limited to no more than $10 per week. To 
compensate subjects for the time required for the MRI scan, subjects will be compensated $100 for the scan.
References
References
NIH Consensus Conference. Diagnosis and treatment of depression in late life. JAMA 1992; 268:1018–
1024.
Alexopoulos GS. Role of executive dysfunction in late-life depression. J Clin Psychiatry 2003; 64:18-23.
Rutherford BR, Sneed JR, Roose SP. Does study design affect outcome? The effects of placebo control and 
treatment duration in antidepressant trials. Psychother and Psychosom 2009; 78:172-181.
Rutherford BR, Roose SP. A model of placebo effects in antidepressant clinical trials. Am J Psychiatry, 
advance online publication, doi: 10.1176/appi.ajp.2012.12040474.
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