Flavanol Augmentation for Antidepressant Non-Responsive Late Life Depression
Phase: NA
Conditions: Depression, Major Depressive Disorder
Sponsor: New York State Psychiatric Institute

Study Title: Flavanol Augmentation for Antidepressant Nonresponsive Late Life Depression 
NCT Number: 02943096 
Date of Document: 8/30/2017 

Signed copy on file at IRB 
v. 11/15/13 
New York State Psychiatric Institute 
Institutional Review Board 
August 30, 2017 
To: 
Dr. Bret Rutherford 
From: 
Dr. Edward Nunes, Co-Chairman 
Dr. Laurence Greenhill, Co-Chairman 
Subject: 
Approval Notice: CONTINUATION 
Your protocol # 7368 entitled: FLAVANOL AUGMENTATION FOR ANTIDEPRESSANT NON-
RESPONSIVE LATE LIFE DEPRESSION Protocol version date 08/30/2017 and consent forms have 
been approved by the New York State Psychiatric Institute - Columbia University Department of 
Psychiatry Institutional Review Board from September 12, 2017 to September 11, 2018. 
(Reviewed at the Full Board meeting on August 21, 2017.) 
Consent requirements: 
      Not applicable: 
√45CFR46.116 (d) waiver of consent for the telephone interview
√Signature by the person(s) obtaining consent is required to document the consent process
 Documentation of an independent assessment of the participant’s capacity to consent is also 
required. 
Approved for recruitment of subjects who lack capacity to consent: √ No  Yes   
Field Monitoring Requirements: √ Routine Special: ___________________ 
  Only copies of consent documents that are currently approved by the IRB may be used to obtain 
consent for participation in this study. 
  A progress report and application for continuing review is required 2 months prior to the 
expiration date of IRB approval. 
  Changes to this research may not be initiated without the review and approval of the IRB except 
when necessary to eliminate immediate hazards to participants.  
  All serious and/or unanticipated problems or events involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org for 
Adverse Event Reporting Procedures and additional reporting requirements.    
Cc: 
CU Business Office (internal acct, Briger); CUMC IRB 
Encl:  CF, MRI letters, recruitment, HIPAA 
EN/LG/alw 

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Protocol Title:
Flavanol Augmentation for Antidepressant 
Non-Responsive Late Life Depression
Protocol Number:
7368
First Approval:
09/22/2016
Expiration Date:
09/11/2018
Version Date:
08/30/2017
Clinic:
Adult and Late Life Depression
Contact Principal Investigator:
Bret Rutherford, MD
Email: brr8@columbia.edu
Telephone: 646 774 8660
Co-Investigator(s):
Scott Small
Richard Sloan, PHD
Adam Brickman, PHD
Research Chief:
Davangere Devanand, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation with modifications
Division & Personnel
Division
What Division/Department does the PI belong to?
geriatric psychiatry
Within the division/department, what Center or group are you affiliated with, if any? 
healthy aging and late life brain disorders
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.

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none
Amendment
Describe the change(s) being made 
The IRB protocol under which the subjects for this study are evaluated is being amended from IRB# 6395R 
to IRB# 7284R
Provide the rationale for the change(s) 
This change is being made to correct the evaluation protocol number. 
Comment on the extent to which the proposed change(s) alter or affect risks/benefits to subjects 
None
Comment on if the proposed change(s) require a modification to the Consent Form (CF)
None 
Application for Continuation of Research
Status
Current Status of Study: 
Subject enrollment 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.
Project goals are to establish the whether augmentation with flavanol supplements is beneficial for geriatric 
adults with depression and to examine the cognitive effects of flavanol supplementation. 
The participants have been completing the protocol as planned. Patients are evaluated in the Adult Late Life 
and Depression Clinic under IRB#7284R. They are then scheduled for a baseline visit and an MRI.
During these visits the patients complete a battery of neuropsych tests and undergo a gadolinium contrast 
MRI. The patients are then scheduled for follow up visits. These visits occur weekly until week 4. After 
week 4 biweekly visits are conducted until week 8. During these visits patients complete a short battery of 
depression ratings. On week 8 all measures taken at baseline are repeated along with the gadolinium 
contrast MRI. Patients are compensated $50 after the evaluation and after the completion of each MRI scan. 
 
Recruitment for the study has been slow due to studies with competing populations ALLDC and other 
clinics in the Columbia Medical Center offering similar treatment for the geriatric population. 
 
There are no new developments in the field that impact on the science or the risk/benefit balance of this 
protocol.

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Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 
No
Overall Progress
Approved sample size
50
Total number of participants enrolled to date
6
Number of participants who have completed the study to date 
5
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
Yes
Describe actions taken or planned to address these problems. 
Study recruitment has proved difficult due to competing studies recruiting a similar population of subjects. 
Therefore the target recruitment goals for this protocol have not been met. 
Comments / additional information 
None
Sample Demographics
Specify population
60 years and older

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Total number of participants enrolled from this population to date 
6
Gender, Racial and Ethnic Breakdown 
Male: 4
Female: 2
 
Black:1
White:5 
 
Not of Hispanic Descent: 6 
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
6
Number of participants currently enrolled
1
Did the investigator withdraw participants from the study? 
Yes
Circumstances of withdrawal:
The subject had no response to the augmentation and was feeling significantly worse after beginning the 
drug three weeks previously. 
Did participants decide to discontinue study involvement? 
No
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Neuropsychological Evaluation
   Collection of Biological Specimens
   Medication Trial
   Use of Placebo or Sham Treatment
   MRI
Population

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Indicate which of the following populations will be included in this research
   Adults over 50
Research Support/Funding
Will an existing internal account be used to support the project?
Yes
Describe internal account
The project will be funded by a donation from the Briger family for this purpose. These funds are currently 
in a CU acct under PI's name.
Is the project externally funded or is external funding planned?
No
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
   Other Columbia University Medical Center Facilities
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
The goal of this proposal is to conduct the first pilot study of whether consuming flavanol supplements will 
augment the cognitive and mood benefits of antidepressant medication in older adults with Late Life 
Depression (LLD). Flavanols represent a specific group of plant derived nutrients that are found in cocoa 
beans, grapes, tea, berries and various other fruits and vegetables. The specific flavanols investigated in this 
study come from cocoa. Currently available treatments for LLD (i.e., antidepressant medication) are limited 
in efficacy, especially in individuals who also suffer from cognitive impairment.  Recent studies performed 
at Columbia and elsewhere suggest that flavanols may induce beneficial brain changes that support 
cognitive functioning and elevate mood, but their precise clinical effects in older adults with combined 
depression and cognitive impairment remain to be evaluated.
 
For this study, we plan to recruit 50 adults aged ≥60 years who have Major Depressive Disorder, meet a 
minimum depressive symptom threshold despite currently receiving an adequate trial of an antidepressant, 
and have a significant cognitive complaints without a diagnosis of dementia. Subjects will be randomized to 
receive 8 weeks of augmentation treatment with flavanol capsules (in addition to continuing their 
antidepressant) vs. capsules not containing flavanols. Pre- and post-treatment MRI scanning of the brain will 
be conducted, and comprehensive pre- and post-treatment neuropsychological assessment will be 

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performed. Results from this project will allow us to evaluate a novel therapeutic approach to LLD, which 
could have large public health ramifications given the prevalence, frequent treatment resistance, and 
chronicity characteristic of LLD.
Background, Significance and Rationale
Background, Significance and Rationale
The goal of this proposal is to conduct the first pilot study of whether consuming a diet high in flavanols 
will augment the cognitive and mood benefits of antidepressant medication in older adults with Late Life 
Depression (LLD). LLD affects 3% of community-dwelling adults over 60 years old, and 15% of older 
adults living in the community have clinically significant depressive symptoms. Diagnosis with LLD 
increases an older adult’s risk of disability by 67-73% over 6 year follow up, causes twice the functional 
impairment compared to those without LLD, and is associated with high rates of completed suicide in 
individuals over 65. Currently available treatments for LLD (i.e., antidepressant medication) are limited in 
efficacy, leading to high rates of recurrence and frequent development of chronicity. Cognitive impairment, 
which is commonly associated with LLD, predicts poor acute response to antidepressants, leads to higher 
relapse rates during the continuation phase of treatment, and is associated with the development of adverse 
age-related health outcomes, including increased risk of dementia, dependence in activities of daily living 
(ADL), and driving cessation.
Novel treatments addressing LLD’s underlying neurobiology are critically needed, particularly therapies 
that may also have beneficial effects on the cognitive components of LLD. The most extensively studied 
brain region to be implicated in both the depressive and cognitive aspects of LLD has been the 
hippocampus. Decreased hippocampal volumes are found in depressed patients compared to controls, and 
this finding appears to be particularly pronounced in individuals with recurrent depressive illness. Among 
the subregions comprising the hippocampus, evidence suggests that it is decreased neurogenesis within the 
dentate gyrus (DG) specifically that may contribute to the development of depression, and it appears that 
part of the mechanism of action of antidepressants is to enhance neurogenesis in the DG. As the DG is also 
a critical contributor to the cognitive functions of the hippocampus, it stands out as a highly significant brain 
region that may be involved with both the mood and cognitive components of LLD.
These considerations suggest that targeting the DG may be a valuable therapeutic strategy to explore in the 
treatment of LLD. Recently, flavanols were shown in mice to result in a selective increase in dendritic spine 
and capillary density within the DG. A subsequent study of healthy elders performed by Scott Small and 
colleagues at Columbia found that following a cocoa-flavanol enhanced diet for three months resulted in 
improved functioning on a DG-dependent cognitive task and increased cerebral blood flow (CBV) in the 
DG. Since Dr. Small’s group previously showed that increased CBV on high-resolution functional magnetic 
resonance imaging (fMRI) correlates with increased neurogenesis, these findings suggest that consuming a 
flavanol supplements may enhance DG-dependent cognitive functioning by selectively inducing DG 
neurogenesis. In terms of effects on mood symptoms, it has been speculated since the 1980s that cocoa-
flavanols have antidepressant effects, and more recently multiple groups have reported antidepressant 
effects of plant-derived flavonoids in animal models of depression. Thus, it appears that flavanols may 
induce beneficial structural brain changes that support cognitive functioning and elevate mood, but their 
precise clinical effects in older adults with combined depression and cognitive impairment remain to be 

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evaluated.
We propose to conduct the first study of whether consuming flavanol supplements will augment the benefits 
of antidepressant medication treatment in older adults with LLD. Our guiding hypotheses are that older 
adults receiving antidepressant medication plus flavanol supplementation will experience greater depressive 
symptom improvement, greater improvements in cognitive functioning, and increased blood flow in the DG 
on CBV-fMRI compared to older adults receiving antidepressant medication alone. To test these 
hypotheses, we plan to recruit 50 adults aged ≥60 years who meet DSM 5 criteria for Major Depressive 
Disorder, meet a minimum depressive symptom threshold despite currently receiving an adequate trial of an 
antidepressant, and have a significant cognitive complaints without a diagnosis of dementia. Subjects will be 
randomized to receive 8 weeks of augmentation treatment with flavanols (in addition to continuing their 
antidepressant) or augmentation with capsules not containing flavanols. Pre- and post-treatment CBV-fMRI 
will be conducted, and comprehensive pre- and post-treatment neuropsychological assessment will be 
performed testing diverse domains of cognitive functioning (including cognitive tasks previously shown to 
be DG-dependent).
Results from this project will allow us to evaluate a novel therapeutic approach to LLD, which could have 
large public health ramifications given the prevalence, frequent treatment resistance, and chronicity 
characteristic of LLD. Even apart from the potential benefits for mood symptoms, cognitive impairment in 
older adults exacts a large public health burden in terms of impaired functioning and increased morbidity 
and mortality, and this burden will only grow as the population ages. Flavanols may represent a safe and 
effective means to help older adults maintain a healthy aging trajectory, maintain independent functioning, 
and live longer with an increased quality of life.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
Aim 1. To determine whether augmentation with flavanol supplements is helpful for depression.
 
Hypothesis 1. Subjects randomized to the flavanol intervention will have greater depressive symptom 
improvement compared to subjects not receiving flavanols.
Aim 2. To examine the cognitive effects of flavanol supplementation.
 
Hypothesis 2. Subjects randomized to the flavanol group will have greater improvement on pattern 
separation performance (MST and ModBent) compared to subjects not receiving flavanols. Improvement in 
pattern separation performance will occur in the setting of general unchanged cognitive functioning in other 
domains (e.g., processing speed, EF).
Aim 3. To examine the relationship between cognitive improvement and depressive symptom improvement 
in patients receiving flavanol augmentation.
 

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Hypothesis 3: Improvement in pattern separation performance will mediate the group difference in 
depressive symptom reduction.
 
Description of Subject Population
Sample #1
Specify subject population
Depressed older adults
Number of completers required to accomplish study aims
40
Projected number of subjects who will be enrolled to obtain required number of completers
50
Age range of subject population
60 and older
Gender, Racial and Ethnic Breakdown
On the basis of previous studies conducted in the Late Life Depression Research Clinic at the New York 
State Psychiatric Institute (NYSPI) and Columbia University, it is anticipated that the sample will be 
composed of approximately 75% Caucasian, 15% African American, and 10% Hispanic subjects. It is 
anticipated that the sample recruited from these sites will be composed of 60% women and 40% men.
Description of subject population
Community-ascertained outpatients with antidepressant non-responsive depressive disorders
Recruitment Procedures
Describe settings where recruitment will occur
We will recruit subjects via advertisements for patients who feel depressed, through the RecruitMe online 
platform, as well as clinical referrals from colleagues around CUMC. Advertisements will include research 
flyers and brochures posted around CUMC, advertisements in local newspapers and on radio stations, and 
information posted on departmental websites. For direct clinical or research referrals, a clinical staff 
member known to the patient will approach him/her and raise the possibility of study participation.
How and by whom will subjects be approached and/or recruited? 
If the patient expresses a potential interest in participating, he/she will then be scheduled for a full
evaluation with a study clinician.
How will the study be advertised/publicized? 
Advertisements will include research flyers and brochures posted around CUMC, advertisements in local
newspapers and on radio stations, and information posted on departmental websites and the RecruitMe web 
recruitment platform.
Do you have ads/recruitment material requiring review at this time? 

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Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT02943096
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Subjects completing IRB 6836 (Rutherford PI) or 6470 (Brown PI) who meet the selection criteria for this 
study will be offered participation.
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Depressed older adult sample
Create or insert table to describe the inclusion criteria and methods to ascertain them
 Criterion
 Method of 
Ascertainmen
t
 1. Men and women aged ≥60 years
 1. Clinical 
interview
 2. DSM 5 diagnosis of Major Depressive Disorder
 2. SCID, 
clinical 
interview
 3. Subjective report of memory or thinking problems
 3. Clinical 
interview
 4. 24-item Hamilton Rating Scale for Depression ≥16
 4. HRSD
 5. Failure of depressive symptoms to remit following an 
adequate trial of an antidepressant (defined as at least 8 
weeks of treatment, with 4 weeks of at least half PDR 
maximum dose, of an FDA approved antidepressant)
 5. Clinical 
interview
 6. Capable of providing informed consent and complying 
with the study procedures
 6. Clinical 
interview
Create or insert table to describe the exclusion criteria and methods to ascertain them
 Criterion
 Method of 

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Ascertainment
 1. Diagnosis of Substance Use Disorder within the past 
12 months (excluding Tobacco)
 1. SCID, clinical 
interview
 2. History of psychosis, psychotic disorder, mania, or 
bipolar disorder
 2. SCID, clinical 
interview
3. HRSD suicide item > 2 or CGI =7 at baseline
 3. HRSD, CGI
 4. Diagnosis of probable or definite dementia 
(Alzheimer’s Disease, Vascular Dementia, Parkinson’s 
disease, etc.)
 4. SCID, clinical 
interview, MMSE
 5. MMSE ≤24
 5. MMSE
 6. Physical or intellectual disability adversely affecting 
ability to complete assessments
 6. Clinical 
interview
 7. History of allergy, hypersensitivity, or intolerance to 
cocoa flavanols
 7. Clinical 
interview
 8. Contraindication to MRI scanning or unable to 
tolerate scanning procedures
 8. Clinical 
interview
 9. Allergic or adverse reaction to gadolinium, 2 or 
more prior scans with gadolinium, or creatinine 
clearance < 50
 9. Clinical 
interview, blood 
draw
 10. Daily consumers of dietary or herbal supplements, 
including Gingko, flavonoid, and dietary herbal or plant 
extracts
 10. clinical 
interview
 11. Diabetes or acute, severe, or unstable medical or 
neurologic condition
 11. clinical 
interview, physical 
exam, EKG
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 
No

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Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
7284R
Describe Study Consent Procedures
Following the study screening procedures, a study physician (only MDs will obtain consent in this study) 
authorized to obtain patient consent will explain the study procedures along with the attendant risks, 
benefits, and alternatives, including the anticipated outcome of doing nothing. The study physician will then 
leave the room while the potential subject reads the consent form and return to answer any questions the 
subject has. Subjects who wish to participate will sign the consent form, while those who do not wish to 
participate will receive appropriate referrals.
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
Evaluation 
 
1. Every subject evaluated for this protocol will receive a clinical interview by a psychiatrist or
psychologist, be administered the 24-item Hamilton Rating Scale for Depression (HRSD) and 
Antidepressant Treatment History Form, and have a SCID performed by a trained rater. During the consent 
process, subjects will be educated about the availability of appropriate treatments for depression (switch or 
augment antidepressant medication, evidence based psychotherapy). If a subject is not interested in these 
depression treatments and/or prefers to try an experimental treatment for depression, he/she will be offered 
participation in the present study provided there is no suicidal ideation present.
 
2. Those signing informed consent will have physiologic tests conducted (including EKG) and will be 
scheduled for baseline neuropsychological testing and MRI scanning. Other baseline tests include measures 
of frailty (Pittsburgh Fatigability Scale, Grip Strength, Gait speed, Minnesota Leisure Time Physical 

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Activity Questionnaire, Short Physical Performance Battery),the Mnemonic Similarity Task (MST), and the 
Trail Making Test Parts A and B, all which will be repeated at week 8
 
Neuropsychological testing
1. 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.
 
2. We will also use a specific cognitive task shown to be dentate gyrus-dependent in order to provide a
functional assessment of DG to go along with our anatomic MRI assessments of DG and other hippocampal 
subregions. The Benton Visual Retention Test (BVRT) was developed to evaluate patients with severe 
impairment. It contains only a limited number of items that are not sufficiently challenging for healthy 
subjects, and therefore typically leads to a ‘ceiling’ effect. Accordingly, we (Dr. Brickman) developed a 
computerized modification of the BVRT, which is more appropriate for use among individuals without 
frank impairment across the lifespan. We call this task the ‘Modified Benton’ (ModBent). The ModBent is 
an object recognition task with immediate matching trials and delayed recognition trials. The stimuli used in 
the ModBent are intersecting sinusoidal curves designed parametrically to be similar to each other in order 
to evoke the pattern separation cognitive operation. During the immediate matching trials, participants view 
a single complex stimulus for 10 seconds; following a 1 second delay they are asked to select which one of 
two objects is identical to the studied stimulus. Following 41 matching trials, participants are shown serially 
individual complex objects and asked to indicate whether the object is identical to any of the target stimuli 
studied during the immediate matching trials. There are 82 recognition trials, which include 41 targets and 
41 foils. The primary dependent variable for the ModBent is the mean reaction time (ms) for correct 
rejections of foil stimuli on the delayed recognition trials. Given our previous observation that performance 
on the BVRT is selectively correlated with functioning of the DG and that the putative role of DG in pattern 
separation, the ModBent was designed specifically to maximize the cognitive operation of pattern separation 
and tap DG functioning.
 
3. NP testing is for research purposes only and the results of these tests will not be interpreted clinically or 
shared with the patient.
CBV-fMRI
1. For the MRI procedures, the subject will be instructed to lie as still as possible within the magnet for
approximately 30 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 

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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.
 
2. 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 
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, as well 
as in procedures for testing human subjects.
3.The CBV-fMRI procedure involves the acquisition of a T1-weighted MRI scan before and after the
administration of a contrast agent, which in this case is a macrocylic called Dotarem. Evidence has shown 
this compound does not remain in the brains of patients in post-mortem studies. After the pre-contrast image 
is obtained, Dotarem (gadoterate meglumine) at a dose of 0.2mL/kg will be infused through a peripheral IV 
site. After a 4-minute delay, the second, post-contrast, image will be acquired. Participants are able to 
communicate with research staff by means of button press for any reason during the MRI procedures. The 
injection is conducted by a registered nurse or physician, who is on premises throughout each MRI study. 
This procedure results in the creation of whole brain and regional CBV maps by subtracting a T1-weighted 
MRI scan from a gadolinium-enhanced T1-weighted MRI image and then normalizing the values by a 
measure of 100% blood taken from a large sinus. The resulting image provides a measure of blood volume 
with the high spatial resolution of T1-weighted imaging. Either region-of-interest analysis or voxel-based 
analyses can be applied to interrogate functional neuroanatomy with submillimeter resolution.
 
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. 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. Subjects will receive 2 MRI scans in this protocol: immediately before treatment begins and after 8 weeks 
of high vs. low flavanol diet augmentation.
 
Clinical trial
 
1.  Subjects will be continued on their baseline dose of antidepressant medication for the duration of the 
protocol and will be randomized to augmentation with  flavanol capsules (500mg per day) or placebo. 
Placebo is being purchased from the NYSPI pharmacy, and flavanols are being purchased commercially in 

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the form of CocoVia supplements. We selected the 500mg dose in collaboration with colleagues who have 
performed previous flavanol studies (Drs. Small and Sloan) and on the literature. A 500mg dose of cocoa 
flavanols has previously been associated with cognitive benefits (Mastroiacavo et al, Am J Clin Nutrition 
2014).
 
2. Following baseline testing, 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 visits at weeks 1,2,3,4,6,8. 
Patients will receive clinical management (MD) and complete assessment measures conducted by raters 
blinded to condition assignment. Measures performed at each visit will include HRSD, Quick Inventory of 
Depressive Symptomatology (QIDS), Hamilton Anxiety Rating Scale, CGI—Severity and Improvement, 
and Treatment Emergent Side Effect Scale.
3. We do not anticipate any tolerability problems with flavanol supplementation, but if a patient 
discontinues medication due to tolerability problems, ineffectiveness, patient preference, or other reasons, 
the patient will continue follow up appointments as scheduled. Appropriate medication options will be 
discussed with the patient based on their symptoms and history. A patient will not be considered a drop out 
unless they decide to discontinue follow up appointments in the study or are lost to follow up.
 
4. 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.
5. The blind will be broken at the end of the 8 week study period.Following the 8 week duration treatment 
study, endpoint assessments will be made. Patients will enter 3 month open treatment period provided free 
of charge as described below.
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
The risk of non-response or adverse events to flavanol supplementation during the study period is addressed 
by having close clinical follow up of study subjects and stringent withdrawal criteria. These criteria are (1) 
participant withdraws his or her consent; (2) significant clinical worsening as defined by a slowing 
assessment rating using the CGI-Improvement scale of 6 (worse) or 7 (much worse) for 2 consecutive visits; 
or (3) development of significant side effects or an adverse event. Any subjects meeting any of these criteria 
will be withdrawn from the study and treated clinically. In addition, a CGI of 6 or 7 after one week will 
trigger a clinical evaluation and then clinical judgment as to whether the patient should be discontinued. 
Furthermore, subjects may be withdrawn if they repeatedly miss scheduled appointments or clinical 
worsening necessitates more intensive treatment. Withdrawn patients will be followed in the open treatment 
period and offered appropriate psychiatric treatments if they have any conditions requiring treatment (e.g., 
depression).

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Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
A 20cc blood sample will be drawn at baseline. General medical tests will be performed, such as CBC,
Chem 7, LFTs, TSH, cholesterol, B12, and folate.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
1.Frailty assessment: weight loss (patient report of 10 lb loss unintentionally in last year), weak grip
strength (via hand dynamometer; stratified by gender and body mass index), slow walking speed, (15 feet 
speed stratified by gender and height), low energy expenditure (Short version of the Minnesota Leisure 
Time Activity questionnaire, kcals per week expended are calculated using standardized algorithm and 
stratified by gender), Short Physical Performance Battery--15 min
2. Hamilton Rating Scale for Depression (HSRD)--15min
3. Quick Inventory of Depressive Symptomatology (QIDS)--5min
4. Clinical Global Impression (CGI)--1min
5. Measure of Everyday Cognition (ECog)--10min
6. Wechsler Test of Adult Reading (WTAR)--5 min
7. Mini Mental State Examination (MMSE) -- 8 min
8. Stroop COlor Word Test (Stroop) -- 5 min
9. Mattis DRS- I/P subset -- 10 min
10. Digit Symbol Subtest of the WAIS III -- 2 min
11. Logical Memory Test (WMS III) -- 10min 
12. Modified Benton Visual Retention Test (ModBent)--30 min
13. Mnemonic Similarity Task (MST) -- 15 min 
14. Trail Making Test part A and part B   
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 
There is a possible delay in treatment of up to 8 weeks since an experimental agent is being investigated for 
the treatment of depression, and it may not be effective.

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Maximum duration of delay to standard care or treatment of known efficacy
8 weeks
Treatment to be provided at the end of the study
We will provide 3 months of additional free clinic visits following the end of this project. At the conclusion 
of the 8 week study, a non-study clinician in our research clinic will be given the data on the subject’s 
response to flavanol augmentation. This clinician will discuss with each subject on a case-by-case basis the 
risks and benefits of continuing flavanol treatment as well as other treatment options if warranted. Those 
who have benefited from the treatment and have not had significant side effects may elect to continue 
receiving flavanols after receiving an explanation of the potential risks of chronic administration. If they do 
not want to continue flavanols, it will be discontinued after a 3 day step-down withdrawal. Transferring 
after-study care to a non-study clinician protects against the development of bias in the study clinicians and 
offers optimal clinical care to the subjects at the study conclusion.
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
1. Interview, emergencies, and possible suicidal ideation. Subjects may experience discomfort during the 
clinical interview and evaluations when discussing symptoms and current life events. The study
coordinators are experienced and skilled in interviewing depressed subjects. Half-way through the initial 
assessment, the coordinator will ask the subject if they would like to take a break, and this will be provided 
if desired. A study clinician will be available during all aspects of the assessment if there are any questions 
or problems. In addition, should the subject express suicidal ideation at any time during the interview, the 
study clinician will be contacted immediately to assess the subject and to determine the appropriate course 
of action. Options for addressing suicidal ideation will include contacting the individual’s mental health 
caregiver, referring for urgent (same day) evaluation and treatment in an outpatient clinic, or emergency 
room evaluation and hospitalization. Similar practices will be used for other emergencies, including but not 
limited to psychosis, homicidal or violent thoughts, or an acute change in a subject’s physical status. 
 
2. Magnetic resonance imaging (MRI). 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 60 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, 

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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. 
 
Regarding gadolinium-based MRI scanning specifically, gadolinium compounds do have side effects. We 
use Dotarem (Gadoterate Meglumine). Side effects of Dotarem include nausea, headache, injection site 
pain, injection site coldness and burning sensation observed in fewer than 1 people out of every 100 injected 
(0.2% estimate). Adverse reactions that occurred with a frequency <0.2% in patients
who received Dotarem include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, 
paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, orophrayngeal discomfort, 
serum creatinine increased and injection site reactions, including site inflammation, extraversion, pruritus, 
and warmth. All of these side effects resolve within 20 minutes to several hours. A trained physician or 
licensed nurse will inject the gadolinium and remain with the patient for the entire duration and for 15 
minutes after the scanning session is complete. 
 
Some patients with acute renal failure or end-stage renal disease have developed a serious medical
condition known as nephrogenic systemic fibrosis (NSF) after the use of gadolinium for MRI. The
primary concern regarding risks to renal function from gadolinium-based contrast agents (GBCAs)
is specific to this population of patients who have end-stage renal disease (ESRD) on
hemodialysis, or acute, florid, clinical renal failure, and then are exposed to gadolinium. This
population of patients is by definition excluded from this study by virtue of medical history and
general review of systems. Renal dysfunction as a result of gadolinium in a population without
history of end-stage renal disease or acute renal failure has not been described in the medical
literature. In a retrospective study conducted at two large medical centers, 74,124 patients were
injected with a standard dose of gadolinium (0.1mmol/kg, the same dose used in our research
studies) who had no screening for renal function, with a rate of 0/74124 cases of renal
complications (e.g., NSF or other renal dysfunction) post injection. All 15 cases of NSF that were
found in this retrospective study had severe, clinical renal failure at the time of gadolinium injection.
No cases of NSF have been identified in persons with normal renal function or with moderate renal
dysfunction.
 
According to a recent report by the FDA, while gadolinium is mostly eliminated from
the body after administration, recent studies have shown trace amounts of gadolinium in the brains
of patients who have undergone four or more gadolinium-enhanced MRI scans. While there have
been no adverse health effects associated with this finding, in order to safeguard against the
potential for gadolinium accumulation, we utilize Dotarem (gadoterate meglumine) instead of Multihance 
(gadoebnate dimeglumine). Dotarem is a macrocylic, a class of gadolinium contrast agents, which has not 
been shown to remain in the body in the post-mortem studies which prompted the FDA warning. By using 
this macrocylic, we avoid the possibility of gadolinium accumulation. Despite the
overwhelming evidence that macrocylics do not pose the same risk as other gadolinium-contrast
agents, we will exclude participants who have had a history of 2 or more gado-enhanced MRI.
 

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3. Blood draw. In the placement of a peripheral IV and the obtaining a 20 cc blood sample (3), patients can 
experience side effects that include pain, fainting, bruising, light-headedness, and, on rare occasions, 
infection.
 
4. Flavanol augmentation. Although we are currently unaware of any risks, there may be possible risks to 
the dietary intervention, such as previously unknown allergies. 
 
5. Maintenance of antidepressant dosage: Because antidepressant medications cannot be adjusted during 
study participation, there is a risk that participants will not improve or will worsen. 
Describe procedures for minimizing risks
Please see above for procedures to minimize risks of CBV-fMRI and contrast administration, which are
discussed in the context of each individual potential risk.
 
Regarding the risks during the assessment procedures, if patients become upset during the assessment of 
their cognition or functioning, they are not obliged to answer the questions; if they wish to discontinue 
participation in the treatment protocol, they can withdraw their participation at anytime without effecting 
their participation in any other study protocol.
 
Regarding the risk associated with blood draw, the staff will take every precaution to avoid these
difficulties. The staff members are all certified at the hospital to be drawing blood from patients, and are
instructed to keep the comfort and welfare of our patients as their primary priority. 
 
Regarding the risk of worsening associated with antidepressant medication dosage not being adjusted, we 
have implemented stringent criteria for early discontinuation as well as criteria for discussing whether 
participants should be discontinued.
 
 Finally, we will mitigate risks associated with the generally increased medical problems occurring in older 
adults by doing a careful interview to detect an unstable, severe, or acute medical problem and obtain 
parallel history from the subject's primary medical doctor. 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. All data collected will be kept confidential and used for professional purposes 
only.
 

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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
There is no direct benefit to subjects. If flavanol treatment is effective in improving cognition and 
ameliorating depressive symptoms, subjects may experience improved quality of life.
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 a total of $150 for completion of all study assessments, neuropsychological testing,
and MRI scans. The payment schedule will be that they will receive $50 after completion of blood draws 
and psychological tests, $50 after first MRI scan, and an additional $50 for completion of the week 8 MRI 
scan. Given that subjects may incur travel expenses and are expected to spend several hours in the LLDC 
and MRI scanner completing the study procedures, we judge that this amount is reasonable.
References
References
NIH Consensus Conference. Diagnosis and treatment of depression in late life. JAMA 1992; 268:1018–
1024.
Rothschild AJ. The diagnosis and treatment of late-life depression. J Clin Psychiatry 1996; 57:5–11.
World Health Organization. The World Health Report 2004: Changing history, Annex Table 3: Burden of 
disease in DALYs by cause, sex, and mortality stratum in WHO regions, estimates for 2002. Geneva: WHO, 
2004.
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS. The 
epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication 

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(NCS-R). JAMA 2003; 289:3095-105.
Penninx B, Leveille S, Ferrucci L, van Eijk J, Guralnik J. Exploring the effect of depression on physical 
disability: longitudinal evidence from the Established Populations for Epidemiologic Studies of the Elderly. 
Am J Publ Health 1999; 89:1346–1352.
Callahan CM, Wolinsky FD, Stump TE, Nienaber NA, Hui SL, Tierney WM. Mortality, symptoms, and 
functional impairment in late-life depression. J Gen Intern Med 1998; 13:746–752.
Blazer D, Bachar J, Manton K. Suicide in late life: review and commentary. J Am Geriatr Soc1986; 34:519–
526.
Conwell Y, Lyness J, Duberstein P, Cox C, Seidlitz L, DiGiorgio A. Completed suicide among older 
patients in primary care practices: a controlled study. J Am Geriatr Soc 2000; 48:23–29.
Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Feder M, Einhorn A, Rosedahl E. Recovery in 
geriatric depression. Arch Gen Psychiatr 1996; 53:305–312.
Sneed JR, Rutherford BR, Rindskopf D, Roose SP. Design makes a difference: antidepressant response rates 
in placebo-controlled versus comparator trials in late life depression. Am J Geri Psychiatry 2008; 16:65-73.
Alexopoulos GS, Meyers BS, Young RC, et al. Executive dysfunction and long-term outcomes of geriatric 
depression. Arch Gen Psychiatry 2000; 57:285–290.
Butters MA, Whyte E, Nebes RD, et al. The nature and determinants of neuropsychological functioning in 
late-life depression. Arch Gen Psychiatry 2004; 61:587-595.
Pimontel MA, Culang-Reinlieb ME, Morimoto SS, Sneed JR. Executive dysfunction and treatment response 
in late life depression. Int J Geriatr Psychiatry 2012; 27:893-899.
Rapp MA, Reischies FM. Attention and executive control predict Alzheimer disease in late life: results from 
the Berlin Aging Study (BASE). Am J Geriatr Psychiatry 2005; 13:134-141.
Iwasa H, Gondo Y, Yoshida Y, et al. Cognitive performance as a predictor of functional decline among the 
non-disabled elderly dwelling in a Japanese community: A 4-year population-based prospective cohort 
study. Arch Gerontol Geriatr 2008; 47:139-149.
Edwards JD, Bart E, O’Connor ML, Cissell G. Ten years down the road: Predictors of driving cessation. 
Gerontologist 2000; 50:393–399.
Alexopoulos GS, Meyers BS, Young RC, et al. Executive Dysfunction and Long-term Outcomes of 
Geriatric Depression. JAMA Psychiatry 2000; 57:285-290.
Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA. A pathophysiological framework of 
hippocampal dysfunction in ageing and disease. Nat Neurosci Rev 2011; 12:585-601.
Schmaal L, Veltman DJ, Van Erp TGM, et al. Subcortical brain alterations in major depressive disorder: 
findings from the ENIGMA Major Depressive Disorder working group. Molec Pyshciatry 2015; advance 
online publication.
Duman, R.S., Malberg, J., Nakagawa, S. and D’sa, C. (2000) Neuronal plasticity and survival in mood 
disorders. Biol. Psychiatry, 48: 732–739.
Jacobs, B.L., Praag, H. and Gage, F.H. (2000) Adult brain neurogenesis and psychiatry: a novel theory of 
depression. Mol. Psychiatry, 5: 262–269.
van Praag, H. et al. Plant-derived flavanol (−)epicatechin enhances angiogenesis and retention of spatial 
memory in mice. J Neurosci 2007; 27:5869–5878.
Brickman AM, Khan UA, Provenzano FA, et al. Enhancing dentate gyrus function with dietary flavanols 
improves cognition in older adults. Nat Neurosci 2014; 17:1798-1806.
Pereira AC, Huddleston DE, Brickman AM, et al. An in vivo correlate of exercise-induced neurogenesis in 
the adult dentate gyrus, Proc Natl Acad Sci USA 2007; 104:5638-5643.
Liebowitz MR, Klein D. Hysteroid dysphoria. Psychiatr Clin North Am 1979; 2:555-575.

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Yi LT, Li J, Li HC, et al. Antidepressant-like behavioral, neurochemical and neuroendocrine effects of 
naringenin in the mouse repeated tail suspension test. Prog Neuropsychopharmacol Biol Psychiatry 2012; 
39(1):175-81.
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Upload any additional documents that may be related to this study
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ACAR Stipulations Memo 8-23-17.pdf

Patient Consent Form 
IRB# 7368 
v. 10/12/16
NEW YORK STATE PSYCHIATRIC INSTITUTE 
FLAVANOL AUGMENTATION FOR LATE LIFE DEPRESSION 
Overview 
Below is a summary of the study that you are asked to participate in.  This outline is meant to be a guide 
for you to use while considering the study and reading the consent form.  It is not meant to replace the consent 
form, which you will have to sign if you decide to participate in the study.  The consent form contains detailed 
information about the study and about the risks which you will need to consider before making your decision.  
Read the consent form carefully and discuss it with others before deciding to take part.  And remember that, 
even if you agree to participate, you can change your mind at any time. 
Purpose of Study 
The purpose of this study is to examine the effect of a nutritional supplement containing flavanols on 
depression and brain activity. Flavanols represent a specific group of plant derived nutrients that are found in 
cocoa beans, grapes, tea, berries and various other fruits and vegetables.  
Participation is Voluntary 
As with all research, this is a voluntary study, and you do not have to participate if you do not want to. 
Also, you may stop participating at any time. 
Alternatives 
You do not have to participate in this study to receive treatment for depression. Medications, 
psychotherapy, and their combination may be helpful for treating depression, and they are available outside this 
research project. 
Procedures 
•
The study consists of blood tests and psychological tests conducted at the beginning, a magnetic
resonance imaging (MRI) scan conducted at the beginning and end, and the consumption of pills 
containing flavanols derived from cocoa. 
•
MRI scans use strong magnetic fields and radio waves to take pictures of your brain. The MRI scans
performed in this study also use a gadolinium contrast agent called Dotarem that will be administered to 
you through a catheter inserted into a vein. The psychological tests are paper and pencil and 
computerized tasks that will take about 2 hours to complete. 
•
For 8 weeks, you will be asked to consume cocoa flavanols in the form of 4 capsules daily or else
placebo. A placebo is a sugar pill that is not specifically effective for treating depression. 
Risks 
This study includes some risks and discomforts (please refer to the consent form for further details and 
explanations of these risks).  These include side effects associated with the MRI contrast agent Dotarem (such as 
nausea, headache, and coldness or burning at the catheter site), frustration caused by the memory and thinking 
tasks you will perform, cocoa flavanol intake problems, and discomfort associated with the MRI scan and 
psychological tests. 
Benefits 
This research study is not meant to benefit you directly. You may contact the study doctor, Dr. Bret 
Rutherford at 646-774-8660 with any questions. 
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Patient Consent Form 
IRB# 7368 
v. 10/12/16
NEW YORK STATE PSYCHIATRIC INSTITUTE 
FLAVANOL AUGMENTATION FOR LATE LIFE DEPRESSION 
PURPOSE OF STUDY 
You are being asked to participate in this study because you are an adult, aged 60 years 
or older, who has been diagnosed with Major Depressive Disorder (known in older patients as 
Late Life Depression) and is currently taking an antidepressant medication that has not fully 
treated your symptoms. We are studying whether adding a nutritional supplement containing 
flavanols to your current antidepressant medication helps with depression and influences brain 
activity linked to depression. Flavanols represent a specific group of plant derived nutrients 
that are found in cocoa beans, grapes, tea, berries and various other fruits and vegetables. The 
specific flavanols investigated in this study come from cocoa. 
This research study is supported by a private philanthropic gift to Columbia University. 
VOLUNTARY 
Participation in this research study is voluntary.  If you decide not to participate, or if 
you later decide to stop participating, you will not lose any benefits to which you are otherwise 
entitled.  A decision not to participate or withdraw your participation will not affect your 
current or future treatment at the New York State Psychiatric Institute or Columbia University. 
ALTERNATIVE TREATMENT 
You do not have to participate in this study. This is a study of an experimental 
nutritional supplement to help depression, but there are treatments for depression which are 
known to be effective. The alternative to participating in this study is to seek treatment outside 
the research project so that you would be certain of receiving a medication approved for 
treatment of depression. Approved medications for depression are available (e.g., fluoxetine 
(Prozac), sertaline (Zoloft), etc), and psychotherapy also may be helpful with depression, 
whether on its own or combined with medication. 
Information being collected is for research purposes only and is to learn more about the 
effects of flavanols on depression and the brain, not about you. It is not necessary to participate 
in this research study to have an MRI, and the MRI done as part of this study is not the same as 
one done for medical purposes. 
STUDY PROCEDURES 
Evaluation: If you decide to participate in this study, you will have blood drawn and 
complete some psychological tests. The total amount of blood taken at this study visit is about 
2 

Patient Consent Form 
IRB# 7368 
v. 10/12/16
two tablespoons. Results of these blood tests will be available to you, should you request them. 
The psychological tests measure thought processes such as memory, language, reasoning, and 
attention. These tests are paper-and-pencil as well as on the computer, and they take about one 
hour to complete. The results of these tests are for research purposes only and will not be 
shared with you. 
Based on these tests, it will be determined whether you are eligible for the treatment 
portion of the study. If you are not eligible, you will be referred to appropriate options for 
further treatment. If you are eligible and continue to wish to participate, you will proceed with 
the next part of the study.  
MRI scan: You will also have 2 MRI scans as part of the study—one before treatment 
begins and the second one 8 weeks later, after treatment has ended. The MRI uses strong 
magnetic fields and radio waves to take pictures of your brain. MRI involves lying on a table 
that slides into a large magnet shaped like a cylinder. You will be asked to lie flat on your back 
in the MRI scanner for about 30 minutes and to remain as still as possible. Before the scan, a 
catheter will be placed in one of your veins (usually in your arm near the elbow) so that we 
may administer to you a gadolinium-based contrast agent known as Dotarem during the MRI 
scan. These contrast agents help parts of the brain that are of interest to researchers show up 
better.  
While in the scanner, you will hear a knocking noise. This is a normal sound produced 
by the MRI scanner and does not indicate that anything is wrong. The technologist operating 
the scanner and a member of the research team will be able to see you, and voice contact will 
be maintained throughout the scan. You may ask to stop the scan at any time if you feel 
uncomfortable. Your MRI scans will be reviewed by a radiologist within 1 month of the scan 
and the results will be shared with you and your physician. 
Treatment study: After the first MRI scan, you will then begin an 8-week period 
during which you will be randomly assigned (like flipping a coin) to consume flavanol-
containing capsules once a day with breakfast or pill placebo. A placebo is a sugar pill 
that is not specifically effective for depression. You will take the capsules for 8 weeks and 
neither you nor the investigators will know which capsules you are receiving. The flavanol 
capsules contain alkalized cocoa powder and other ingredients including theobromine and 
caffeine that are naturally found in chocolate. Your diet will not be changed in this study. 
If you cannot tolerate the flavanol supplements, your participation in the study will 
be discontinued. If the study doctor feels your condition worsens significantly, the current 
treatment will be stopped, and you will be offered different treatments for your depression. 
The study doctor may stop your participation in the study at any time without your consent 
if you do not comply with the study procedures or for other reasons.  
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Patient Consent Form 
IRB# 7368 
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During the study, you will continue taking the same dose of your antidepressant 
medication that you were taking prior to the study. Your dosage of antidepressant 
medication may not be adjusted for the duration of the 8-week study. You may continue to 
receive this medication from your pharmacy, or, if you do not have the ability to get your 
medication, medication will be provided by the study. You will return each week to speak 
with the study doctor and have some tests. These appointments will last about 45 minutes. 
The research study will end after 8 weeks. During each visit, you will again fill out some 
psychological tests and have your depressive symptoms measured.  
Following the study, you will still receive 3 months of free doctor visits in the clinic. 
The flavanols used in this study are available commercially, so it is an option to continue 
taking them following the study if you feel you have benefited. If you do not wish to 
continue the flavanols after the study, it will be discontinued. 
RISKS 
Regarding gadolinium-based MRI scanning, gadolinium compounds do have side 
effects. The gadolinium compound we use is Dotarem (Gadoterate Meglumine). Side effects of 
Dotarem include nausea, headache, and injection site pain. Fewer than 1 out of every 100 
people injected (0.2% estimate) may experience injection site coldness and burning sensation. 
Side effects that occurred with a frequency less than 0.2% in patients who received Dotarem 
include: feeling cold, rash, feeling sleepy and fatigued, dizziness, vomiting, itching, sensation 
changes, pain in extremity, anxiety, elevated blood pressure, rapid or pounding heart beat, and 
swelling or redness around the catheter site.  All of these side effects go away within 20 
minutes to several hours. A trained physician or licensed nurse will administer the gadolinium 
through the intravenous catheter and remain with you for the entire duration of the MRI scan 
and for 15 minutes after the scanning session is complete. 
Some patients with severe kidney problems or end-stage kidney disease have developed 
a serious medical condition known as nephrogenic systemic fibrosis (NSF) after the use of 
gadolinium for MRI. Only patients who have end-stage renal disease (ESRD) requiring 
hemodialysis, or current, severe kidney failure that causes significant symptoms and apparent 
illness have developed NSF after exposed to gadolinium. Individuals with these severe types of 
kidney problems will not be offered participation in this study.  
The Food and Drug Administration (FDA) is currently investigating a possible risk of 
health problems caused by repeated use of gadolinium for MRI. Though the FDA has not 
reached a conclusion at this time, you should not participate in this study if you have 
previously had more than 2 MRI scans with gadolinium. 
There are some potential risks associated with MRI in general. While there have been 
no reports of harmful long-term effects caused by a 3T (a measure of the magnetic field 
4 

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IRB# 7368 
v. 10/12/16
strength) magnet, the long-term effects of being placed in a magnet of this strength are not 
known. Some people may experience nervousness or discomfort due to the scanner’s small 
space and the need to lie still during the scans, but we are not aware of any other potentially 
dangerous effects of the MRI scan. We do not allow people with pacemakers, some types of 
metallic implants, and medication patches to do the MRI scans, since this may be dangerous. 
Since the MRI scanner produces loud knocking noises, participants will be provided 
with earplugs for comfort. If you experience any discomfort and wish to stop the scan, you can 
inform the MRI technologist through a microphone within the scanner and he or she will stop 
the scan immediately. 
When your blood is drawn or the catheter is placed in your vein, there is a small risk of 
infection, bleeding, discomfort, and that you may be left with a bruise that will resolve within a 
few days. Blood taken for research purposes will remain confidential. Additionally, some of 
the memory and thinking tasks you will be performing may be frustrating. 
Although we are currently unaware of any risks of the flavanol capsules, there may be 
possible risks of the intervention, such as previously unknown allergies. Because your 
antidepressant medication dosage cannot be adjusted during your participation in this study, 
there is a chance that your depressive symptoms will not improve or will worsen. 
RESULTS OF YOUR MRI 
You also should know that while MRI scans are sometimes done for clinical purposes, 
the kind of MRI scan you may have as part of this study is for research purposes only. This 
means that the scans are not designed to provide clinical information that might be helpful to 
you or your doctor and they may not show problems that would normally be found in an MRI 
ordered to evaluate a specific medical problem. However, within a month of each MRI, the 
scan will be read by a neuroradiologist for evidence of any obvious irregularities requiring 
your follow-up. We will contact you, or a physician whom you may designate, via telephone or 
letter with information about the results of your scan. Given the nature of the scans, the 
absence of a finding does not mean that one is not present. 
BENEFITS 
You may not benefit from this study, and no benefit is in any way guaranteed as a result 
of your participation. The main benefit of your participation in this research is that it may lead 
to a better understanding of how the brain changes in depression and what may be potential 
new treatments for depression in older adults.  
CONFIDENTIALITY 
5 

Patient Consent Form 
IRB# 7368 
v. 10/12/16
Your records will be stored in a locked file and will only be available to the research 
staff and institutional personnel as part of routine audits. Representatives of the state and 
institutional regulatory personnel may review your records to ensure compliance with study 
design. There are legal advocacy organizations that have the authority under State Law to 
access otherwise confidential records, though they cannot be redisclosed without your consent. 
All records will be kept confidential to the extent permitted by law. Your name and other 
personal identifying information will be stored in an electronically secure database at New 
York State Psychiatric Institute. Electronically stored data will be accessible only by password 
known to the study investigators and research assistants. 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.  
COMPENSATION AND ECONOMIC CONSIDERATIONS 
You will not be charged for any procedures that are a part of this study, including the 
MRI scans. To compensate you for your time, you will be paid $150 if you complete all 
procedures in this study, including the blood draw, psychological tests, and MRI scans. 
Payment will take place in the form of a check mailed to your home and may take three to four 
weeks to process. If you complete part of the study procedures but not all, you will receive 
partial compensation for the portion of the study you completed. 
RESEARCH STANDARDS 
     Federal regulations require that we inform participants about our institution's policy with 
regard to compensation and payment for treatment of research-related injuries.  
     If you believe that you have sustained an injury as a result of participating in a research 
study, you may contact the Principal Investigator at 646-774-8660 so that you can review the 
matter and identify the medical resources that may be available to you.   
     In case of injury, New York State Psychiatric Institute, Columbia University and New York 
Presbyterian Hospital will furnish that emergency medical determined to be necessary by the 
medical staff of this hospital. Please be aware that you will be responsible for the cost of such 
care, either personally or through your medical insurance or other form of medical coverage.  
     No monetary compensation for wages lost as a result of injury will be paid to you by 
Research Foundation for Mental Hygiene, the New York State Psychiatric Institute, Columbia 
University or by New York Presbyterian Hospital. However, you should be aware that by 
signing this consent form, you are not waiving any of your legal rights to seek compensation 
through the courts. 
6 

Patient Consent Form 
IRB# 7368 
v. 10/12/16
QUESTIONS 
If you have further questions about the research procedures, or about your response to 
the procedures research staff members are available to answer them to the best of their ability. 
You can reach Dr. Bret Rutherford at 646-774-8660 during general business hours. In an 
emergency, you may reach the on call doctor at 917 786 6940, 24 hours per day. If you have 
general questions, you may contact the research coordinator at 646-774-8664. We will notify 
you of any significant new findings that may relate to your willingness to continue to 
participate. 
If you have any questions about your rights as a research participant, want to provide 
feedback, or have a complaint, you may call the NYSPI Institutional Review Board (IRB). (An 
IRB is a committee that protects the rights of participants in research studies). You may call 
the IRB Main Office at (646)774-7155 during regular office hours. A copy of this consent form 
will be provided to you. 
DOCUMENTATION OF CONSENT 
I voluntarily agree to participate in the research study described above. 
Print name: __________________ 
Signed: _____________________ 
Date: _______________________ 
I have discussed the proposed research with this participant including the risks, benefits, 
and alternatives to participation (including the alternative of not participating in the research).  
The participant has had an opportunity to ask questions and in my opinion is capable of freely 
consenting to participate in this research.  
Print name: ________________ 
Person Designated to Obtain Consent 
Signed: ___________________ 
Date: _____________________ 
7 

Form #PP2: HIPAA Authorization for Research 4.14.14 
New York State Psychiatric Institute (NYSPI) 
Authorization to Use or Disclose Health Information during a Research Study 
Protocol Number: 
Principal Investigator: 
Name of Study: 
Before researchers can use or share any identifiable health information (“Health Information”) about you as part of the 
above study (the “Research”), the New York State Psychiatric Institute (NYSPI) is required to obtain your authorization. You agree 
to allow the following individuals and entities to use and disclose Health Information about you as described below: 
•
New York State Psychiatric Institute (NYSPI), your doctors and other health care providers, if any, and
•
The Principal Investigator and his/her staff (together “Researchers”).   Researchers may include staff of NYSPI, the New York
State Office of Mental Health (OMH), Research Foundation for Mental Hygiene, Inc. (RFMH), and Columbia University (CU),
provided such staff is a part of the study, and
•
Providers of services for the Research at CU, NYSPI and/or RFMH, such as MRI or PET, or  Central Reference Laboratories
(NKI), if indicated in the consent form.
1.
The Health Information that may be used and/or disclosed for this Research includes:
All information collected during the Research as told to you in the Informed Consent Form.   
Health Information in your clinical research record which includes the results of physical exams, medical and 
psychiatric history, laboratory or diagnostic tests, or Health Information relating to a particular condition that is related  to 
the Research. 
Additional information may include: 
2.
The Health Information listed above may be disclosed to:
Researchers and their staff at the following organizations involved with this Research: 
The Sponsor of the Research, 
and its agents and contractors (together, “Sponsor”); and  
Representatives of regulatory and government agencies, institutional review boards, representatives of the Researchers 
and their institutions to the level needed to carry out their responsibilities related to the conduct of the research.   
Private laboratories and other persons and organizations that analyze your health information in connection with 
this study 
Other (family members or significant others, study buddies, outside agencies etc.) Specify: 
3.
By giving permission to release your Health Information as described above, you understand that your Health
Information may be disclosed to individuals or entities which are not required to comply with the federal and state privacy laws
which govern the use and disclosure of personal Health Information by NYSPI.   This means that once your Health
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NYSPI
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MRI PET scans
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Flavanol Augmentation for Late Life Depression
Bret Rutherford, MD
7368

Form #PP2: HIPAA Authorization for Research 4.1.14 
Information has been disclosed to a third party which does not have to follow these laws (e.g., a drug company or the Sponsor 
of the Research), it may no longer be protected under the HIPAA or NYS Mental Hygiene Law requirements but is subject to the 
terms of the consent form and may be subject to other state or federal privacy laws or regulations.  
4.
Please note that:
•
You do not have to sign this Authorization form, but if you do not, you may not be able to participate in the study or
receive study related care.  You may change your mind at any time and for any reason. If you do so, you may no
longer be allowed to participate in the study.  If you withdraw this Authorization the research staff and the Sponsor, if this
is sponsored research, may still use or disclose Health Information containing identifying information they already have
collected about you as needed to maintain the reliability of the research.  Any request to withdraw this Authorization
must be made in writing to (enter name and contact information below):
•
While the Research is going on, you may not be allowed to review the Health Information in your clinical research
record that has been created or collected by NYSPI.   When this research has been completed you may be allowed to see
this information.  If it is needed for your care, your Health Information will be given to you or your Doctor.
5.
This Authorization does not have an end date.
6.
You will be given a copy of this form after you have signed it.
I agree to the use and disclosure of Health Information about me as described above: 
__________________________________________                _____________________ 
Signature of Participant/ Legal Representative    
Date 
______________________________________ 
Printed Name of Participant 
______________________________________ 
Relationship of Legal Representative to Participant (if applicable) 
We also ask you or your legal representative to initial the statements below: 
I have received a copy of the NYSPI/OMH Notice of Privacy Practices. 
Bret Rutherford, MD
1051 Riverside Dr
New York, NY  10032

Statistical Analysis plan 
 
Descriptive statistics are expressed as means and standard deviations or percentages. Chi-square 
analyses and independent samples t-tests were used to compare subjects assigned to flavanol vs. 
placebo augmentation on categorical and continuous depression outcomes, respectively.