Clinical trial NCT04493320
Conditions: Depression Cognitive Impairment Gait Impairment
Sponsor: New York State Psychiatric Institute
Start date: 2021-02-10; Completion date: 2021-10-27
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Growing evidence suggests that dopamine contributes to key cognitive, emotional, and motor functions across the lifespan. In Late-Life Depression (LLD), dysfunction in these areas is common, predicts poor outcomes, and manifests as difficulties in motivation and effort along with cognitive and gait impairment. While studies of dopamine function in early and midlife depression primarily focus on individuals' ability to feel pleasure and respond to rewards, they often exclude the cognitive and physical function domains relevant for older adults despite a recognized decline in dopamine function with normal aging. The objectives of this collaborative R01 proposal between Columbia University/New York State Psychiatric Institute and Vanderbilt University Medical Center are to: 1) characterize dopaminergic dysfunction in LLD across cognitive, emotional, and motor domains at several levels of analysis (cellular Positron Emission Tomography \[PET\], circuit Magnetic Resonance Imaging \[MRI\], and behavioral / self-report); and 2) examine the responsivity of dopamine-related circuits and behavior to stimulation with carbidopa/levodopa (L-DOPA).

Detailed description:
Supported by pilot data, this project builds on past work demonstrating that dopamine function declines with aging, that dopaminergic dysfunction contributes to deficits in behavior, and that L-DOPA administration improves cognitive and motor performance. The long-term goal of this line of research is to determine how dopaminergic dysfunction contributes to clinical presentations of LLD, how responsive behavioral symptoms are to modulation of dopamine function, and to identify novel targets for future interventions. Investigator's approach is to enroll 30 psychiatrically healthy elders and 60 depressed elders at Columbia/NYSPI exhibiting either slowed processing speed or slowed gait speed. Participants will undergo thorough clinical evaluations and complete PET imaging measuring different aspects of the brain's dopamine system, neuromelanin-sensitive MRI measurement of longterm dopamine transmission, functional MRI focused on effort-based decision making and reward processing, a comprehensive neurocognitive evaluation, a physical performance evaluation, and measurement of inflammatory markers. To assess responsivity of the dopamine system to modulation, depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. In a second phase, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This proposal is significant and innovative, as no prior published study has comprehensively examined dopamine-dependent behaviors in LLD. This will inform treatment approaches focusing on facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation.

Arms: arm 1: Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3.

Participants will then enter a 1 week taper period.

Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily.

Participants will then enter a 1-week taper period. arm 2: Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period.

Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3.

Participants will then enter a 1-week taper period.
Interventions: intervention 1: Carbidopa/levodopa intervention 2: Placebo
Intervention descriptions: intervention 1: 150-450mg carbidopa/levodopa 3 times daily intervention 2: Carbidopa/levodopa-matched placebo tablet 3 times daily

Protocol documents:
ICF_002.pdf: 
NEW YORK STATE PSYCHIATRIC INSTITUTE
DOPAMINERGIC DYSFUNCTION IN LATE LIFE DEPRESSION 
(THE D3 STUDY)
Overview
Below is a summary of the study in which you are asked to take part 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 study described is a double-blind placebo-
controlled study, which means that you will be randomly assigned (like the flip of a coin) 
to study medication or else placebo (a sugar pill). Neither you nor the study doctor will 
be informed whether you are receiving study medication or placebo until the end of the 
study.
Participation is 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 Irving Medical Center.
Alternatives
You do not have to participate in this study to receive treatment for depression or 
slowed thinking and movement. Food and Drug Administration (FDA)-approved 
antidepressant medications such as Selective Serotonin Reuptake Inhibitors (SSRIs, e.g., 
Prozac, Zoloft, etc.) or Serotonin Norepinephrine Reuptake Inhibitors (SNRIs, e.g., 
Effexor, Cymbalta, etc.), in addition to other types of medications are effective in the 
treatment of depression. Additionally, psychotherapies that are supported by research 
such as Interpersonal Psychotherapy and Cognitive Behavior Therapy are available 
outside of this study to treat depression. Finally, exercise programs and cognitive 
remediation may be helpful for slowed thinking and movement and also are available 
outside this research project.
Procedures
•
At the beginning of the study, you will be given a physical examination, an 
electrocardiogram (EKG), and have your blood drawn.
•
Next you will have tests of your memory, concentration, and other thinking skills 
as well as a test of your walking.
•
Subjects in this study will undergo two (2) magnetic resonance imaging (MRI) 
scans of the brain and one (1) positron emission tomography (PET) scan of the 
brain.


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•
MRI scans use strong magnetic fields and radio waves to take pictures of your 
brain.
•
The PET scans require placement of an IV catheter and injection of a radioactive 
substance called [18F]-DOPA. [18F]-DOPA allows us to examine the uptake of 
dopamine by cells in the brain, which are important in some psychiatric diseases 
such as depression.
•
In the medication part of the study, you will be randomly assigned to receive a
medication called carbidopa/levodopa (Sinemet) or pill placebo (a sugar pill). 
We are using carbidopa/levodopa “off-label” in this study, which means that 
it is not approved by the FDA for the treatment of depression. Half of study 
participants first will receive Sinemet for 3 weeks, then after a 1 week 
washout period, will be switched to receive a placebo for 3 weeks. The other 
half of participants first will receive placebo for 3 weeks, then after a 1 week 
washout period, will be switched to receive Sinemet for 3 weeks. All 
participants will receive placebo at some point in the study, either in Step 1 or 
Step 2.
•
You will be asked to return each week to see one of the study doctors, talk about 
how you are feeling and have tests of your thinking and walking speed.
•
The research study will end after 8 weeks. You will fill out some more thinking 
tests and have your walking speed tested again.
Risks
This study includes some risks and discomforts (please refer to the consent form
for further details and explanations of these risks). The main risk to you in this study is 
that carbidopa/levodopa is an experimental treatment, and it is not known yet whether it 
will be effective in treating low dopamine levels or symptoms of depression. Other risks 
are worsening of depression while you are assigned to receive placebo, side effects 
associated with carbidopa/levodopa (such as nausea, headache, abnormal movements of 
arms and legs, muscle stiffness, and vivid dreams), and radiation exposure from the [18F]-
DOPA tracer used in the PET scans.
Please alert study staff if you feel your depression is getting worse.
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.


Informed Consent for Participation in Research
DOPAMINERGIC DYSFUNCTION IN LATE LIFE DEPRESSION 
(THE D3 STUDY)
PURPOSE OF STUDY
The purpose of this research study is to better understand the brain’s dopamine 
system among older adults with depression. The dopamine system plays important roles 
in thinking, movement, motivation, and pleasurable or rewarding activities. In addition to 
performing brain scans and several different tests of your thinking and movement, we 
use a medication called carbidopa/levodopa (Sinemet) to investigate how the brain’s 
dopamine levels influence behavior. Carbidopa/levodopa is approved by the Food and 
Drug Administration (FDA) for the treatment of Parkinson’s Disease. We are using 
carbidopa/levodopa “off-label” in this study, which means that it is not approved by the 
FDA for the treatment of depression. We are interested in studying how 
carbidopa/levodopa affects the brain’s dopamine levels as well as the mental and 
physical slowing that occur as people age.
In this study you will have brain scans using magnetic resonance imaging (MRI) 
and positron emission tomography (PET). We are performing these scans to understand 
more about how the brain’s dopamine system may be different in older adults who are 
depressed. The MRI scans involve some parts where you will be asked to lie quietly in 
the scanner without doing anything and some parts where you will be asked to look at a 
screen and accomplish tasks by pressing buttons. The PET scan involves the use of a
radioactive investigational drug called [
18F]-DOPA. It is an investigational drug that is
taken up by parts of your brain that process dopamine. The drug contains a very small 
radioactive tracer that can be “seen” by the PET camera. The PET camera then takes 
“pictures” of the chemical activity in the brain by detecting the radioactive signal of 
[
18F]-DOPA. You will also be asked to take the drug carbidopa just before the PET scan 
so that the PET techniques can better measure the dopamine system in the brain.
This study is supported by a grant from the National Institute of Mental Health.
VOLUNTARY
Participation in this study is voluntary. If you do not wish to participate in this 
study or decide to discontinue your participation in this study later, you will not lose any 
benefits to which you are otherwise entitled, including current or future treatment at New 
York State Psychiatric Institute or Columbia University Medical Center. We will notify 
you of any significant new findings that may relate to your willingness to continue to 
participate.


ALTERNATIVE TREATMENT
You do not have to participate in this study. The alternative to participating in this 
study is to seek treatment outside the research project so that you would be certain of 
receiving a treatment approved for treatment of depression. Approved medications for 
depression are available (e.g., fluoxetine (Prozac), sertaline (Zoloft), etc.), and evidence 
based psychotherapies (Interpersonal Psychotherapy, Cognitive Behavior Therapy) also 
may be helpful with depression, whether on their own or combined with medication.
Although no treatments for mental and physical slowing have been formally 
approved by the FDA, other treatment approaches include exercise programs and 
cognitive training.
Information being collected is for research purposes only and is to learn more 
about changes in the brain’s dopamine system with aging, 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, 
complete some tests, and have your walking measured using a special mat. The total 
amount of blood taken at this study visit is about four tablespoons. Results of these blood 
tests will be available to you, should you request them. The tests measure thought 
processes such as memory, language, reasoning, and attention. These tests are paper-and-
pencil as well as computer-based and take about two hours 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 scans: You will have an MRI scan at the beginning of the study (before you 
receive any carbidopa/levodopa or placebo) and again after the first part of the 
medication study (after you have taken carbidopa/levodopa or placebo for three weeks). 
Some parts of the MRI scans involve completing tasks while you are lying in the scanner 
machine. You will be trained for about 1 hour before each scan in the performance of two 
computer tasks by one of the study’s research assistants. These tasks involve sitting at a 
desk, looking at pictures on a computer screen, and pressing buttons with your finger.
You then will be asked to undergo the MRI scans, each of which lasts approximately one 
and a half hours.


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. 
Before beginning the imaging procedure, we will determine whether you have a 
pacemaker or any unsafe metallic implants such as an aneurysm clip or heart valve and 
certain tattoos, and you will be asked to remove any metal or magnetized objects (such as 
keys, chains, jewelry, retainers, medication patches, hairpins and credit cards). You will 
be asked to lie flat on your back in the MRI scanner for about 90 minutes and to remain 
as still as possible. You will not feel anything, but you will hear a knocking noise. This is 
a normal sound produced by the MRI scanner and does not indicate that anything is 
wrong. If you feel nauseated during scanning, please immediately alert the MRI staff 
member. It could be dangerous to vomit while in the scanner due to a risk of aspiration.
PET scan: At the beginning of the study (before you receive any 
carbidopa/levodopa or placebo) you will also have a PET scan. The PET scan will likely 
happen after your first MRI scan and on a different day. On the PET scan day, we will 
ask you not to eat from 6 am until the study is over. We will also ask you not to drink 
caffeinated beverages, such as coffee, tea, and soda, that day.
For the PET scan, we will need to place an intravenous (IV) catheter in one of 
your veins, and we will inject the radioactive substance through it. After the catheter is 
inserted, we will begin the PET scan. For the scan, we will ask you to lie on the narrow 
table. We will also position your head with a chin strap or a polyurethane head holder 
that we will mold around your head to reduce head movement during the scan. Right 
before each PET scan we will perform a very short (~10-15 second) computerized 
tomography (CT, or “CAT”) scan of the brain, which helps us make sure the PET scan is 
positioned correctly. We will then inject the radioactive substance [18F]-DOPA through 
the catheter in your arm. Before this injection, you will be asked to take a pill containing 
carbidopa, which helps the [18F]-DOPA be absorbed better by your body.
The scan will last up to 1 hour. In addition, if you move your head during the PET 
scan we may do an additional CT position scan at the end of the PET scan. If you feel 
nauseated during scanning, please immediately alert the PET staff member. It could be 
dangerous to vomit while in the scanner due to a risk of aspiration. After the end of the 
last scan, we will remove the catheter and you will be evaluated.
Medication study: The medication part of the study has two parts, Step 1 and Step
2. In Step 1, you will be randomly assigned to one of two different treatment options (like 
by flipping a coin). If you are assigned to the first option, you will receive the starting 
dose of carbidopa/levodopa (37.5mg/150mg). This dose will be increased each week to 
the final dose of carbidopa/levodopa 112.5mg/450mg. Taking the medication in this 
study will involve taking three pills per day, one in the morning, one at lunchtime, and 
one at night. If you are assigned to the second option, then you will receive pill placebo.


The placebo looks like the other treatments/pills, but does not contain any medicine (it is 
sometimes called a “sugar pill”). Neither you nor the researchers will know if you are 
getting the placebo, but they can find out in an emergency. You will receive free 
medication or placebo for the duration of the study.
Step 1 lasts three weeks, and at the end you will have the number of pills you are 
taken gradually reduced and then stopped over the course of one week. This is called a 
“washout period.” After the washout period, you will begin Step 2, which has the same 
procedures as Step 1, except you will be assigned to the opposite pills to the ones you 
took in Step 1. If you were assigned to take carbidopa/levodopa in Step 1, then you will 
take pill placebo in Step 2. If you were assigned to take pill placebo in Step 1, then you 
will take carbidopa/levodopa in Step 2. The timing of the pill doses will be the same as 
Step 1, and the study will last three weeks followed by a one-week washout period.
In either Step, if you have trouble tolerating the study medication, we will lower 
your dose to one you previously tolerated. If you cannot tolerate any dose of the 
medication, 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 slowed thinking and walking.
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. 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—three weeks for 
Step 1, a one-week washout period, three weeks for Step 2, and a second washout period. 
At the end of Step 1, you will have your second MRI scan and complete the same tests 
that you performed at the beginning of the study. At the end of Step 2, you will again 
complete the tests you performed at the beginning of the study, but you will not have 
another MRI.
Following the study, you will still receive 3 months of free doctor visits in the 
clinic. The medication used in this study is available from pharmacies, so it is an option
to continue taking the medication following the study if you feel you have benefited from 
it. You will receive at least 1 month of free medication if you wish. 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. If you do not wish to continue the 
medication after the study, the dose will be gradually decreased over 3 days before 
stopping it.
RISKS
Carbidopa/levodopa risk: The main risk to your participation in this study is that 
carbidopa/levodopa is an experimental treatment, and it is not known yet whether it will


be effective in treating low dopamine levels or symptoms of depression. The most 
common side effects reported for carbidopa/levodopa are nausea, headache, and vivid 
dreams. You should be careful about drinking alcohol, since it may have a greater effect 
on you in combination with medication.
In addition, you will be assigned to receive placebo for three weeks during the 
study. Therefore, you will not receive Food and Drug Administration (FDA) approved 
medication for your condition until after the 8 week study is over. Therefore, there will 
be a delay of 8 weeks (the time you are doing the study) before you will receive a 
treatment that is known to be effective for the treatment of depression (e.g., 
antidepressant medication). There is a chance your depression may worsen during the 
time you are receiving carbidopa/levodopa or placebo in this study.
It is not fully known how the normal slowing down that occurs during aging 
relates to the type of slowing that occurs in patients with Parkinson’s disease. Some 
individuals who experience slowing with age may be at increased risk for Parkinson’s 
disease. L-DOPA is a treatment for Parkinson’s disease, but in patients with the illness it 
can be associated with increased risk for developing abnormal movements over time.
You do not have Parkinson’s disease right now. However, if you were to go on to 
develop Parkinson’s disease later on and need treatment with L-DOPA, there is a small 
possibility that your participation in this study could increase your risk of developing 
abnormal movements. It is difficult to know the exact chances of your needing L-DOPA 
in the future or your risk of abnormal movements, but we would estimate the chances of 
this study causing you problems in the future as less than 1%.
PET risks: This research study involves exposure to radiation. This radiation 
exposure is not required for your medical care and is for research purposes only. The 
radiation exposure is necessary to obtain the research information desired. The total 
amount of radiation that you may receive in this study is approximately 4.71 mSv. The 
additional cancer risk from this research study is estimated to be up to 0.02% (1/4405 
chance). At these low levels, scientists are uncertain as to the actual risk and there may be 
no risk at all.
Please tell your study doctor or other study personnel if you have taken part in 
other research studies at NYSPI or other places/hospitals that used radiation. This way we 
can make sure that you will not receive too much radiation. You should consider x-rays


taken in radiology departments, cardiac catheterization, and fluoroscopy as well as 
nuclear medicine scans in which radioactive materials were injected into your body. 
Before you take part in any future studies that use radiation, you should also tell those 
study doctors about your participation in this study.
The risk estimate is based on the subjects in the study population who are 
most sensitive to radiation exposure.
MRI risks: The long-term effects of being placed in a magnet of this strength (3 
Tesla) are unknown, but you should be aware that there have been no reports of any ill 
long=term effects caused by magnets of the same or even higher strength, either here or 
elsewhere. Also, although there are no known risks associated with pregnancy, we will 
not scan someone who is pregnant. Therefore, you should understand that if you are a 
woman in your childbearing years, pregnancy testing will be used to assure that you are 
not pregnant.
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 your body. If you experience sensations and 
feel that these are uncomfortable, you can tell the MRI technologist, and he or she will 
stop the scan immediately. Occasionally, some people experience nervousness or 
claustrophobic feelings due to the scanner’s small space. If you encounter any 
discomfort, you can tell the MR technologist, and he or she will stop the scan 
immediately. Despite these experiences, no one has ever had sensations from the 
scanning that did not stop as soon as the scanning stopped.
Except for pacemakers and some types of metallic implants, we know of no health 
hazard from the MRI scan. The MRI scan is not painful, but lying still on the scanning 
table may be slightly uncomfortable.
Other risks: When your blood is drawn, there is a small risk you may be left with a 
bruise that will resolve within a few days. Results of blood tests taken for research 
purposes will remain confidential.
BENEFITS
You may not benefit from this study, and no benefit is in any way guaranteed as a 
result of your participation.
RESULTS OF YOUR MRI
While MRI scans are sometimes done for clinical purposes, the kind of MRI scans 
you will 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. It is likely that the MRI scan will not have the 
quality of those done for clinical purposes.
However, within a month of the MRI scans, the scans will be read by a 
neuroradiologist for evidence of any obvious irregularities requiring your follow-up. You, 
or a physician whom you may designate, will be informed only when significant 
abnormalities are detected. If you wish, we can also inform you if there were no obvious 
findings. Given the nature of the scans, the absence of a finding does not mean that one is 
not present.
CONFIDENTIALITY
Your records will be stored in a locked file. Records will be available to research 
staff, and to Federal, State and Institutional regulatory personnel (who may review 
records as part of routine audits). 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.
Your MRI will be interpreted and the results will be shared with you or a 
physician who you may designate. Your MRI report will be maintained as part of the 
clinical database at the New York State Psychiatric Institute or the Columbia University 
Medical Center along with your name and will be accessible to clinicians at the Medical 
Center. Your psychiatric diagnosis will not be a part of the report.
The data obtained for this study and biospecimens could be used for future 
research studies or may be distributed to another investigator for future research studies, 
however all information including biospecimens will be de-identified (this means 
information cannot be linked back to you) and will not include whole genome sequencing 
(i.e., sequencing of a human germline or somatic specimen with the intent to generate the 
genome or exome sequence of that specimen). Biospecimens will not be used for 
commercial profit. Clinically relevant research results, including individual research 
results may be available to you at you request but such request will be granted under the 
discretion of the study doctor. You may be contacted in the future by the study team for
future studies.
Data from this study will be submitted to the National Institute of Mental Health 
Data Archive (NDA). NDA is a data repository run by the National Institute of Mental 
Health (NIMH) that allows researchers studying mental illness to collect and share de-


identified information with each other. A data repository is a large database where 
information from many studies is stored and managed. De-identified information 
means that all personal information about research participants such as name, address, 
and phone number is removed and replaced with a code number. With an easier way to 
share, researchers hope to learn new and important things about mental illnesses more 
quickly than before.
During and after the study, the researchers will send de-identified information 
about your health and behavior to NDA. Other researchers nationwide can then file an 
application with the NIMH to obtain access to your de-identified study data for research 
purposes. Experts at the NIMH who know how to protect health and science information 
will look at every request carefully to minimize risks to your privacy.
You may not benefit directly from allowing your information to be shared with 
NDA. The information provided to NDA may help researchers around the world treat 
future children and adults with mental illnesses so that they have better outcomes.
NIMH will also report to Congress and on its web site about the different studies that 
researchers are conducting using NDA data. However, you will not be contacted directly 
about the data you contributed to NDA.
You may decide now or later that you do not want to share your information using 
NDA. If so, contact the researchers who conducted this study, and they will tell NDA, 
which can stop sharing the research information. However, NDA cannot take back 
information that was shared before you changed your mind. If you would like more 
information about NDA, this is available on-line at http://data-archive.nimh.gov.
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. This means that the researchers cannot release or use information, 
documents, or samples that may identify you in any action or suit unless you say it is 
okay. They also cannot provide them as evidence unless you have agreed. This protection 
includes federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. An example would be a court subpoena.
There are some important things that you need to know. The Certificate DOES 
NOT stop reporting that federal, state or local laws require. Some examples are laws that 
require reporting of child or elder abuse, some communicable diseases, and threats to 
harm yourself or others. The Certificate CANNOT BE USED to stop a sponsoring United 
States federal or state government agency from checking records or evaluating programs. 
The Certificate DOES NOT stop disclosures required by the federal Food and Drug 
Administration (FDA). The Certificate also


DOES NOT prevent your information from being used for other research if allowed by 
federal regulations.
Researchers may release information about you when you say it is okay. For 
example, you may give them permission to release information to insurers, medical 
providers or any other persons not connected with the research. The Certificate of 
Confidentiality does not stop you from willingly releasing information about your 
involvement in this research. It also does not prevent you from having access to your own 
information
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
COMPENSATION AND ECONOMIC CONSIDERATIONS
You will not be charged for any procedures that are a part of this study, including 
the study medication.
To compensate you for the time required for each study visit, we offer $35 for 
your initial screening visit and $50 for each of your three main assessment sessions 
(beginning, after Step 1, after Step 2). This money will be paid by cash at the conclusion 
of each of these visits.
To compensate you for the time required for the brain scans, we offer $100 for 
each MRI scan and $200 for each PET scan ($400 total if you attend all scans). This 
money will be paid in 1 lump sum payment at the end of the study. Payments typically 
require 1-3 weeks to process and will be mailed in the form of a check.
Thus, the maximum compensation in this study will be $585 for participants 
attending all study visits and doing all neuroimaging procedures.
In Case of Injury
Federal regulations require that we inform participants about our institution's 
policy with regard to compensation and payment for treatment of research-related 
injuries.
In case of injury, New York State Psychiatric Institute will provide short term 
emergency medical treatment, which has been determined to be necessary by New York 
State Psychiatric Institute's doctors, and which is within the capability of New York 
State Psychiatric Institute to provide. In addition, we will provide assistance in arranging 
follow up care in such instances.


New York State Psychiatric Institute and Research Foundation for Mental 
Hygiene do not provide compensation or payment for treatment of research related 
injuries. However, you should be aware that you do not give up your legal right to seek 
such compensation through the court by participating in this research.
Please be aware that:
1. The Research Foundation for Mental Hygiene, The New York State Psychiatric 
Institute, Columbia University and New York Presbyterian Hospital will furnish 
that emergency medical care determined to be necessary by the medical staff of 
this hospital
2. You will be responsible for the cost of such care, either personally or through your 
medical insurance or other form of medical coverage.
3. No monetary compensation for wages lost as a result of injury will be paid to you 
by the New York State Psychiatric Institute, Columbia University or by New York 
Presbyterian Hospital.
4. By signing this consent form, you are not waiving any of your legal rights to seek 
compensation through the courts.
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 human subjects in 
research studies). You may call the IRB Main Office at (646) 774-7155 during regular 
office hours.
You will be given a copy of this consent form to keep.


DOCUMENTATION OF CONSENT
I have read the above and voluntarily agree to participate in the research study 
described above. To the best of my knowledge, I am not pregnant. I have been informed 
that my participation is voluntary, and that I can withdraw from the study at any time 
without penalty or loss of benefits to which I am otherwise entitled.
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: 

Prot_000.pdf: 
Protocol Summary Form
7976
Rutherford, Bret
Page 1 of 52
Protocol Title:
Dopaminergic Dysfunction in Late-Life 
Depression (The D3 Study)
Protocol Number:
7976
First Approval:
07/24/2020
Expiration Date:
05/03/2021
Version Date:
07/24/2020
Clinic:
Clinic for Aging, Anxiety, and Mood 
Disorders
Contact Principal Investigator:
Bret Rutherford, MD
Email: brr8@columbia.edu
Telephone: 646 774 8660
Research Chief:
Bret Rutherford, 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 a new protocol
Division & Personnel
Division
What Area Group does the PI belong to?
What Division/Department does the PI belong to?
Neurobiology and Therapeutics of Aging Division
Within the division/department, what Center or group are you affiliated with, if any? 
N/A
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.
Jennifer Felger, PhD
Emory University School of Medicine 


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Rutherford, Bret
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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
PET/SPECT Scan
MRI
Use of Investigational Drug or Device
Off-label Use of Drug or Device
Population
Indicate which of the following populations will be included in this research
Medically and Psychiatrically Healthy Subjects
Adults over 50
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol?
Yes
Select one of the following
The grant/contract application is a pending review or a funding decision
Source of Funding
Federal
Institute/Agency
NIMH
Grant Name


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Rutherford, Bret
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1/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study)
Grant Number
R01 MH123660
Select one of the following
Single Site
Business Office
RFMH
Does the grant/contract involve a subcontract?
Yes
Subcontracted?
To
Name institution(s)
Columbia University
Emory University School of Medicine
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
Growing evidence suggests that dopamine contributes to key cognitive, emotional, and motor
functions across the lifespan. In Late-Life Depression (LLD), dysfunction in these areas is common,
predicts poor outcomes, and manifests as difficulties in motivation and effort along with cognitive and
gait impairment. While studies of dopamine function in early and midlife depression primarily focus
on individuals' ability to feel pleasure and respond to rewards, they often exclude the cognitive and
physical function domains relevant for older adults despite a recognized decline in dopamine function
with normal aging. The objectives of this collaborative R01 proposal between Columbia
University/New York State Psychiatric Institute and Vanderbilt University Medical Center are to: 1)
characterize dopaminergic dysfunction in LLD across cognitive, emotional, and motor domains at
several levels of analysis (cellular [PET], circuit [MRI], and behavioral / self-report); and 2) examine
the responsivity of dopamine-related circuits and behavior to stimulation with levodopa (L-DOPA).
Supported by pilot data, this project builds on our past work demonstrating that dopamine function
declines with aging, that dopaminergic dysfunction contributes to deficits in behavior, and that L-
DOPA administration improves cognitive and motor performance. The long-term goal of this line of


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research is to determine how dopaminergic dysfunction contributes to clinical presentations of LLD, 
how responsive behavioral symptoms are to modulation of dopamine function, and to identify novel 
targets for future interventions. Our approach is to enroll 30 psychiatrically healthy elders and 60 
depressed elders at Columbia/NYSPI exhibiting either slowed processing speed or slowed gait speed. 
Participants will undergo thorough clinical evaluations and complete PET imaging measuring 
different aspects of the brain's dopamine system, neuromelanin-sensitive MRI measurement of long-
term dopamine transmission, functional MRI focused on effort-based decision making and reward 
processing, a comprehensive neurocognitive evaluation, a physical performance evaluation, and 
measurement of inflammatory markers. To assess responsivity of the dopamine system to modulation, 
depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, followed by repeat 
multimodal MRI and cognitive/behavioral assessments. In a second phase, participants will receive 
the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments 
only. This proposal is significant and innovative, as no prior published study has comprehensively 
examined dopamine-dependent behaviors in LLD. This will inform treatment approaches focusing on 
facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting 
behavioral activation. 
Background, Significance and Rationale
Background, Significance and Rationale
A.1. Overview: Late-life depression (LLD) is a source of disability, risk for suicide, and elevated mortality 
in older adults (1). Differences from younger adult depression include more motivational impairment, 
cognitive deficits, and motor dysfunction. This triad of symptoms may be associated with age-related or 
accelerated declines in dopamine circuits that negatively affect the Positive Valence, Cognitive, and 
Sensorimotor RDoC domains. Better understanding of the molecular, circuit-level, and behavioral 
manifestations of dopaminergic decline and responsivity of the system to stimulation can inform 
therapeutics and guide personalized treatment.
A.2. Dopaminergic Circuits: Overview in Depression and Changes with Aging. Depressed patients 
exhibit motivation deficits, reduced willingness to commit effort to obtain rewarding stimuli (2), impaired 
reward-based decision making (3), and dysfunctional activation in neural circuits underlying approach 
behaviors (4). Most studies examining dopamine’s role in Major Depressive Disorder (MDD) primarily 
focus on aspects of reward processing as mediated by mesolimbic dopaminergic projections from the ventral 
tegmental area (VTA) to nucleus accumbens (NAC), ventral striatum (VS), hippocampus, and amygdala (5). 
Many data are consistent with a view of dopamine release in NAC influencing motivation and approach 
responses (6-8), but it has been challenging to precisely specify the nature of dopaminergic disturbances in 
MDD. Studies of D2/D3 receptor binding using SPECT or PET in MDD are mixed, with some finding 
receptor upregulation consistent with decreased dopaminergic activity (9-13), while others report no 
differences compared to controls (14-18). Functional MRI studies using reward tasks in patients with MDD 
report divergent results, though decreased striatal activation to rewards emerges as a consistent finding in 
recent meta-analyses (19,20). 
As dopaminergic function declines with aging, depressed older adults may be a specifically informative 
subgroup to test the links between dopamine and MDD. Post-mortem and in vivo neuroimaging studies 
demonstrate that aging is associated with decreased dopamine receptor binding potential and loss of 


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dopamine transporters (DAT) (21-23). Decreased dopamine synthesis and release may result from chronic, 
low-grade inflammation seen with aging (24), referred to as “inflammaging” (25). Declines in dopaminergic 
function amount to an average dopamine loss of 10% per decade from early adulthood, with some groups 
exhibiting greater declines (26). DAT PET studies show that 25% of older adults without Parkinson’s 
disease (PD) have a striatal DAT binding threshold ≥3 SD below that of younger subjects (27). Diminished 
dopaminergic tone has significant cognitive and motor effects in normal aging, including decreased 
processing speed (28), fine motor dysfunction (29), slowed gait and impaired balance (30,31). As dopamine 
circuits are implicated in the pathogenesis of MDD across the lifespan and as aging is associated with 
functionally significant dopaminergic decline, it is intuitive to hypothesize that dopaminergic dysfunction 
plays an important role in LLD. 
A.3. Positive Valence System: Motivation and Effort. Anhedonia is a core symptom of depression across 
the lifespan and has been proposed as a critical endophenotype with a distinct neurobiology (32,33). Often 
defined as “loss of pleasure,” anhedonia also encompasses diminished interest and anticipation, time spent 
in activities, and willingness to expend effort for rewards (34,35). Depressed adults exhibit impairment 
across many of these domains, prominently including deficient reward learning (36,37), reduced reward 
sensitivity (20,38), and decreased willingness to expend effort (2,39-41). All of these dimensions of reward 
processing are related to dopaminergic function (42-50). For example, using an amphetamine challenge 
combined with [18F] fallypride PET, changes in D2/D3 binding potential (BP) in the striatum and 
ventromedial prefrontal cortex (vmPFC) were associated with willingness to expend effort (48). Individuals 
with dopaminergic system dysfunction (e.g., those with PD) exhibit reward learning impairments that can be 
restored by dopamine replacement (51,52), while administration of levodopa (L-DOPA) to individuals 
performing a probabilistic learning task results in faster reward learning and enhanced VS representations of 
expected reward (53).
 
These findings are particularly germane for the treatment of patients with LLD, who are at risk of 
dopaminergic decline due to advanced age. While fMRI studies using the Monetary Incentive Delay Task 
(MIDT) suggest that behavioral and neural responses to the anticipation and receipt of rewards are similar 
between younger and older adults (54,55), aging is associated with greater perceived cost of effort (56) and 
reduced neural activity in relationship to a reward’s subjective value (57,58). Increased fatigability is a 
common complaint of many elders and predicts functional disability (59-61). In LLD, comorbid fatigability 
is associated with a doubling of mortality risk (62). We propose that decreased willingness to expend effort 
for rewards and impaired reward learning may result in older individuals failing to engage in pleasurable 
goal-directed behavior and becoming more withdrawn and isolated.
A.4. Cognitive Systems: Cognitive Control and Processing Speed. Executive dysfunction and cognitive 
control deficits are common in LLD and predict poorer acute antidepressant response and higher risk of 
relapse (63-66). In conjunction with executive deficits, decreased processing speed may be “the core 
cognitive deficit” in LLD (67,68) as it mediates working memory, verbal reasoning, fluency, and knowledge 
(69,70). Decreased processing speed is consistently reported in LLD (67,68,71), mediates the effects of 
depression on daily functioning (72), and places older individuals at risk of dementia (73) and disability 
(74). In aging adults, dopamine receptor density, DAT availability, and DA synthesis capacity are all 
associated with cognitive performance on tasks of processing speed, cognitive control, working memory, 
and episodic memory (75,76). Thus, decreased dopaminergic tone during aging may be an important 
neurochemical contributor for the cognitive slowing and executive dysfunction observed in LLD. 


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By increasing the time demands of instrumental tasks and worsening mental fatigability, cognitive slowing 
may predispose older adults to inactivity. Given the important modulatory roles of cognitive control circuits 
and hippocampal-striatal connections, dopamine-dependent cognitive deficits also may contribute to 
impairments in reward learning (77). Conversely, since motivation and effort are critical determinants of 
cognitive performance, Positive Valence System abnormalities may contribute to cognitive deficits in LLD. 
Decreased reward sensitivity and reduced motivation impairs performance of Cognitive Systems, 
particularly cognitive control (78,79) while using rewards as incentives during cognitive tasks leads to 
improved performance (80,81). Higher levels of motivation and effort are associated with better cognitive 
task performance in both younger and older adults (82), and in depressed groups (71,79,83,84). 
A.5. Sensorimotor Systems: Motor Function. Motor deficits are common with aging, including slowed 
movement, coordination deficits (85), and difficulties with balance and gait (86). Depressed older adults are 
at increased risk for such problems (87-89). This may be a bidirectional relationship, where depressive 
symptoms lead to the development of decreased gait speed while slowed gait speed leads to incident 
depression (90,91). Decreases in gait speed are associated with falls risk (92), disability (87), hospital 
admission and all-cause mortality (89,93,94). While LLD and decreased gait speed are each independent 
risk factors for adverse outcomes, their comorbidity synergistically increases mortality risk in older adults 
(95). 
Decreases in striatal dopamine transmission are associated with decreased motor speed (48), fine motor 
dysfunction (29), slowed gait and impaired balance (30,31). In healthy adults, lower striatal DAT binding is 
associated with poorer balance, postural control (30) and decreased gait speed, explaining 23% of the 
variance in gait (31). Diminished DAT binding is associated with exaggerated slips on a challenging 
walking course (96) and predicts recurrent falls in elderly subjects (97). These motor impairments 
reciprocally interact with the reward processing and cognitive deficits reviewed above. Increased incentives 
are associated with increased exertion on motor tasks (98,99), with motor cortex involved in integrating a 
reward’s subjective value with performance (98). Gait control is mediated by frontal subcortical circuits that 
also underlie executive functions and attention (100), and over half of cognitively impaired individuals also 
suffer from gait and postural impairments (101). 
A.6. Role of Inflammation. Although chronic, low grade increase of inflammatory markers is a 
fundamental aging process, its unchecked progression can trigger a deleterious cascade contributing to 
depression. Higher levels of circulating pro-inflammatory markers including c-reactive protein (CRP), 
tumor necrosis factor (TNF), and interleukin-6 (IL-6) are consistent immunological abnormalities observed 
in elders and predict the development of depression (102-104). In the aging brain, this pro-inflammatory 
shift is characterized by increased numbers of activated and primed microglia and decreases in anti-
inflammatory molecules (105). Chronic pro-inflammatory activation may lead to depression through 
multiple pathways including activation of the hypothalamus–pituitary–adrenal axis, decreased 
glucocorticoid sensitivity of immune cells, altered CNS neurotransmitter metabolism, and decreased 
neurogenesis and impaired neuroplasticity. Inflammaging (25) is associated with adverse structural and 
functional changes in the aging CNS, including increased white matter hyperintensity (WMH) burden and 
decreased hippocampal volumes (106). 
Pro-inflammatory cytokines reduce dopamine transmission by limiting tetrahydrobiopterin (BH4) 
availability and decreasing dopamine synthesis, impairing vesicular release of dopamine in presynaptic 
neurons by decreasing expression of vesicular monoamine transporter 2 (VMAT2), increasing dopamine 
transporter (DAT) reuptake of synaptic neurotransmitter, and decreasing glutamate-dependent dopamine 


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signaling (107). Higher levels of pro-inflammatory cytokines such as IL-6 are associated with cognitive 
impairment in elderly people (108,109) and higher risk of significant cognitive decline over 7 years (108). 
Inflammaging is similarly linked to poorer functional and mobility status, including gait slowing and faster 
decline in gait speed (110-113).
A.7. Integrative Model. A straightforward model integrating these data is that dopamine dysfunction 
contributes to alterations or deficits in these systems that combine and reciprocally interact in a pathway 
leading to behavioral deactivation and frank depressive symptoms (see Fig. 1). The severity of symptoms 
and specific LLD phenotype may depend on which dopamine circuits are most affected. In the primary 
pathway evaluated by our Specific Aims, decreased dopaminergic tone with increasing age leads to slowed 
processing speed with consequent 
executive dysfunction and slowed gait speed. Slowing results in increased effort costs, increases fatigability 
and results in decreased motivation to expend effort for a given reward value. Reward learning deficits 
secondary to dopaminergic decline compound this problem by impairing the ability of past rewarding 
experiences to influence future behavior. Alternatively, diminished motivation and effort may instead lead 
to cognitive deficits in LLD patients, and both reward processing and cognitive control may affect motor 
function. Our current proposal can examine both our primary hypotheses and alternative pathways in LLD. 
A.8. Overall Significance and Integration with NIMH Priorities. First, delineating how dopaminergic 
dysfunction contributes to LLD will help identify new treatment targets and inform development of novel or 
repurposed therapeutics. These may include pharmacologic means of restoring normative dopaminergic 
neurotransmission, such as L-DOPA. However, by linking behavioral features to dysfunction in RDoC 
Domains, these studies will inform a personalized treatment approach where therapeutic strategies can be 
deployed depending on the clinical presentation (e.g., behavioral activation psychotherapies for Positive 
Valence System dysfunction, cognitive remediation for Cognitive Systems impairment, and 
exercise/physical therapy for Sensorimotor Systems deficits). Second, deepening our understanding of 
RDoC Domains across multiple levels of analysis in older adults is of major significance. The current 
iteration of the RDoC matrices has been criticized for neglect of developmental factors (114), including 
senescence and aging (115). A significant outcome of this project would be to stimulate further study of 
aging & psychopathology interactions
Specific Aims and Hypotheses
Specific Aims and Hypotheses
The proposed study will enroll 60 elderly depressed outpatients who exhibit evidence of dopaminergic 
dysfunction, characterized as either slowed processing speed or slowed gait speed. To disentangle 
depression effects from age-related changes, 30 never-depressed elders also will complete baseline 
evaluation. Assessments include PET imaging of dopamine synthesis and receptor density, neuromelanin- 
sensitive MRI (NM-MRI) measurement of nigrostriatal status, task-based MRI focused on effort-based 
decision making and reward processing, and comprehensive psychiatric, neurocognitive, and physical 
performance evaluation. Depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, 
followed by repeat multimodal MRI and cognitive/behavioral assessments. In a cross-over phase, 


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participants will receive the opposite intervention for an additional 3 weeks followed by clinical and 
cognitive assessments only. This mechanistic probe allows us to examine the contributions and 
interrelationships of dopamine-dependent processes in LLD and evaluate the responsivity of dopamine 
systems to pharmacological stimulation.
 
AIM 1: To characterize dopaminergic dysfunction in LLD at molecular, circuit, and behavioral levels. Hyp 
1: Compared to age- and gender-matched controls on baseline fMRI, LLD subjects will be less willing to 
expend effort for rewards and exhibit lower prefrontal cortex (PFC) and striatal activation on the Effort 
Expenditure for Rewards Task (EEfRT). Hyp 2: Across all subjects, lower striatal [18F]-FDOPA relative 
influx rate (Kocc), lower midbrain & striatal [18F]-fallypride binding, and lower NM-MRI signal in the 
substantia nigra, pars compacta (SNc) will predict lower performance across RDoC domains: Positive 
Valence (impaired willingness to expend effort, decreased neural activations on the EEfRT), Cognitive 
(slowed processing speed and executive dysfunction), and Sensorimotor (slowed gait speed). Hyp 3: Across 
all subjects, slowed processing and gait speed likewise will predict lower willingness to expend effort on the 
EEfRT.
 
AIM 2: To examine responsivity of dopamine circuits in LLD to stimulation with L-DOPA.
Hyp 1: Compared to placebo, L-DOPA will result in greater normalization of neural activations and 
improved behavioral performance in Positive Valence, Cognitive, and Sensorimotor domains. Hyp 2: 
Baseline PET and NM-MRI measures will moderate L-DOPA effects. The greatest improvements will be 
observed in those with the lowest baseline [18F]-FDOPA relative influx rate, [18F]-fallypride binding, and 
NM-MRI signal.
 
Exploratory Aims: 1) To investigate associations of baseline proinflammatory markers with dopaminergic 
function across molecular, circuit, cognitive and behavioral levels of analysis. 2) To evaluate the durability 
of L-DOPA effects on RDoC domains in the crossover phase.
Description of Subject Population
Sample #1
Specify subject population
Depressed subjects
Number of completers required to accomplish study aims
55
Projected number of subjects who will be enrolled to obtain required number of completers
60
Age range of subject population
60 and older
Sample #2
Specify subject population


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Never-depressed elders
Number of completers required to accomplish study aims
30
Projected number of subjects who will be enrolled to obtain required number of completers
30
Age range of subject population
60 and older
Gender, Racial and Ethnic Breakdown
We will recruit participants of all races and ethnic groups, to the extent possible within the local population 
demographics. We will make efforts to ensure a representative sample by working to boost minority 
enrollment to maintain sample consistency with population averages. 
On the basis of previous studies conducted at Columbia/NYSPI’s Clinic for Aging, Anxiety, and Mood 
Disorders (CAAM), it is anticipated that the sample at this site will be composed of approximately 75% 
Caucasian, 15% African American, and 10% Hispanic subjects. We will make every effort to recruit 
minority individuals in order to ensure the generalizability of the study’s findings to the overall population 
of individuals with Late-Life Depression (LLD). Given the increased prevalence of depression in women, 
we do not anticipate difficulty in women representing 60% of our sample. Previous samples in studies 
conducted in CAAM have been approximately 60% women and 40% men.
Description of subject population
The N=60 Depressed sample will enroll subjects who are 1) aged 60 years old or greater, 2) have DSM5 
diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder, 3) Montgomery-Asberg 
Depression Rating Scale (MADRS) > 15, 4) decreased processing speed (1 SD below age-adjusted norms 
on the Digit Symbol Test) OR decreased gait speed (average walking speed on 15’ course < 1m/s), and are 
5) capable of providing informed consent and adhering to study procedures. Subjects will be excluded for 1) 
diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) in the past 12 months, 2) 
history of psychosis, psychotic disorder, mania, or bipolar disorder, 3) primary neurological disorder, 
including dementia, stroke, Parkinson’s disease, epilepsy, etc., 4) MMSE < 24, 5) MADRS suicide item > 4 
or other indication of acute suicidality, 6) current or recent (within the past 2 weeks) treatment with 
antidepressants, antipsychotics, or mood stabilizers, 7) history of hypersensitivity, allergy, or intolerance to 
L-DOPA, 8) any physical or intellectual disability adversely affecting ability to complete assessments, 9) 
acute, severe, or unstable medical illness, 10) mobility limiting osteoarthritis of any lower extremity joints, 
symptomatic lumbar spine disease, or history of joint replacement / spine surgery that limits mobility, 11) 
contraindication to MRI scanning, or 12) history of significant radioactivity exposure (nuclear medicine 
studies or occupational exposure).
The N=30 sample of Never-Depressed Elders will enroll subjects who are 1) aged ≥ 60 years), 2) have 
MADRS < 8, and are 3) capable of providing consent and adhering to study procedures. Exclusion criteria 
are identical to the Depressed Subjects, plus: (1) Any history of DSM 5 disorder and (2) family history of 
MDD in first-degree relative.
Recruitment Procedures


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Describe settings where recruitment will occur
Patients will be recruited from around the general New York City/New York area and will present to the
Clinic for Aging, Anxiety, and Mood Disorders.
 
We will be specifically recruiting via advertisements for patients who feel depressed as well as slowed down 
physically and mentally. Advertisements will include research flyers and brochures posted around CUMC, 
NAMI website, Facebook advertisements, advertisements in local newspapers and on radio stations, 
information posted on departmental websites, flyer mailings, pharmacies, Craigslist, ResearchMatch.com, 
senior community centers, college campuses, and public talks and events. 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. We would also like to implement Columbia University's RecruitMe website as a 
recruitment method. 
 
How and by whom will subjects be approached and/or recruited? 
Recruitment in the Clinic for Aging, Anxiety, and Mood Disorders (CAAM) comes from clinician referrals, 
response to advertisements (radio, flyer, newspaper, online participant matching websites, Facebook), 
patients who have finished or are currently enrolled in other protocols in the CAAM, or word of mouth.
 
If the patient expresses a potential interest in participating, he/she will then be scheduled for a full 
evaluation with a study clinician. The nature of the study will be thoroughly reviewed with its risks, 
benefits, and alternatives to participation, and subjects’ questions regarding the study will be answered. 
Subjects will be notified that they may leave the study at any time. Informed consent will be obtained in a 
private research office. A study clinician will review study procedures and the consent form with each 
potential participant. Each individual may take as much time as they like to decide if they do or do not wish 
to participate. The consent form specifies (and the study coordinator emphasizes) that participation is 
voluntary and withdrawal after signing consent will not affect future care. Subjects will be given a copy of 
the consent form, and the original will become part of the clinical record. 
 
How will the study be advertised/publicized? 
The study will be advertised/publicized through clinician referrals and advertisements, Columbia's
RecruitMe website, Research Match website, Facebook, Clinical Connection website, Craigslist website, 
newspapers, recruitment flyers/brochures and mass mailers at community and senior centers, radio, the 
National Alliance on Mental Illness NYC Metro Research Studies Website, mass email campaigns from 
consumer marketing databases, which are compiled using public information, surveys, subscription 
information, home owner information, and phone directory information, pharmacies, senior community 
centers, college campuses, and public talks and events.  
 
All web based recruitment procedures have been previously approved by Chris Stanley for all of our 
approved studies.


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Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
YOU MUST REGISTER AT ClinicalTrials.gov IMMEDIATELY UPON RECEIPT OF IRB APPROVAL 
AND PRIOR TO ENROLLMENT OF THE FIRST SUBJECT. YOU WILL BE PROVIDED WITH A NCT 
REGISTRATION NUMBER ON REGISTRATION. PLEASE REVISE THIS SECTION OF THE 
PROTOCOL SUMMARY FORM TO INCLUDE THE NCT NUMBER AND RE-SUBMIT AS AN 
AMENDMENT TO THE IRB.
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Subjects who are currently participating in IRBs #7540, #7289R, #7409, #7360, #7489, and/or #7379 and 
meet the selection criteria for this study will be offered participation. Only an investigator not directly 
involved with an eligible subject’s care will approach the subject to describe this protocol and have an 
informed consent discussion.
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Depressed subjects
Create or insert table to describe the inclusion criteria and methods to ascertain them
 Inclusion criteria
 Methods of ascertainment
 1. Age 60 years or older
 1. Clinical interview
 2. DSM5 diagnosis of Major 
Depressive Disorder (MDD) or 
Persistent Depressive Disorder (PDD)
 2. SCID, clinical interview
 3. Montgomery Asberg Depression 
Rating Scale Score >=15
 3. MADRS
 4. Decreased processing speed or 
decreased gait speed
 4. 1 SD below age-adjusted norms 
on Digit Symbol Test (processing 
speed) or average walking speed on 
15 foot course <=1m/s (gait speed)
 5. Capable of providing informed 
consent and adhering to study 
procedures
 5. Clinical interview


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 6. Alternative standard treatments for 
MDD or PDD have been discussed 
and the individual agrees to be 
involved in an experimental treatment
 6. Clinical interview
Create or insert table to describe the exclusion criteria and methods to ascertain them
 Exclusion criteria  Methods of ascertainment
 1. Diagnosis of 
Substance Use  
Disorder 
(excluding 
Tobacco Use 
Disorder) in the 
past 12 months
 1. SCID, clinical interview
 2. History of 
psychosis (except 
brief psychosis 
associated with 
transient medical 
conditions [e.g., 
delirium, urinary 
tract infection, 
etc], psychotic 
disorder, mania, or 
bipolar disorder
 2. SCID, clinical interview
 3. Primary 
neurological 
disorder, including 
dementia, stroke, 
Parkinson's 
disease, or 
epilepsy
 3. Medical history, MMSE. PD will be ruled out by 
satisfying (1) and (2) and (3 or 4) below: (1) patient 
gives no history of PD during clinical interview, (2) 
patient's primary doctor gives no history of PD, (3) there 
are no signs of PD on physical exam in CAAM (e.g., 
absence of asymmetric resting tremor, decreased arm 
swing, soft voice, decreased facial expression, difficulty 
rising from chair, dystonia), (4) if a patient does have 
one or more signs of possible PD on exam as per (3), 
then Dr. Kimberly Kwei (study neurologist) will come 
examine the patient and comment on whether PD can be 
ruled out or whether PD is possible and patient needs 
further work up
 4. MMSE < 24
 4. MMSE
 5. MADRS 
suicide item >4 or 
other indication of 
 5, MADRS, clinical judgement, CGI


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acute suicidality
 6. Current or 
recent (within the 
past 2 weeks) 
treatment with 
antidepressants, 
antipsychotics, or 
mood stabilizers
6. Clinical interview 
 7. History of 
hypersensivity, 
allergy, or 
intolerance to 
LDOPA
 7. Clinical interview
 8. Any physical or 
intellectual 
disability 
adversely affecting 
ability to complete 
assessments
 8. Clinical interview 
 9. Acute, severe, 
or unstable 
medical illness
 9. Clinical interview, physical exam, medical history 
 10. Mobility 
limiting 
osteoarthritis of 
any lower 
extremity joints, 
symptomatic 
lumbar spine 
disease, or history 
of joint 
replacement or 
spine surgery that 
limits mobility
 10. Clinical interview, physical exam, medical history
 11. 
contraindication to 
MRI scanning
 11. MRI Safety Screening Form
 12. History of 
significant 
radioactivity 
exposure (nuclear 
medicine studies 
or occupational 
 12. Clinical interview, medical history


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exposure)
 13. Has a 
medical condition 
managed with 
medication 
and/or device and 
the managing 
physician 
considers the 
condition and/or 
its management a 
contraindication 
to the research 
use of L-DOPA in 
this participant
13. Clinical interview, medical history, discussion 
with participant's clinician
Inclusion/Exclusion Criteria #2
Name the subject group/sub sample
Never-Depressed Elders
Create or insert table to describe the inclusion criteria and methods to ascertain them 
 Inclusion criteria
 Methods of 
ascertainment
 1. Age 60 years or older
 1. Clinical 
interview 
 2. MADRS < 8
 2. MADRS
 3. Capable of providing informed consent and 
complying with study procedures
 3. Clinical 
interview
 
 
Create or insert table to describe the exclusion criteria and methods to ascertain them 
Never-Depressed Elders will meet all exclusion criteria specified for Depressed Subjects, plus:
 
 Additional Exclusion criteria
 Methods of ascertainment
 1. Any personal history of DSM5 disorder
 1. SCID, clinical 
interview
 2. Family history of MDD in first-degree 
relative
 2. Clinical interview
 


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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
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB #
6395R
Describe Study Consent Procedures
Following clinical evaluation and screening procedures, a study clinician 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 clinician will then leave the room while the potential
subject reads the consent form and return to answer any questions the subject has. During the consent
discussion, individuals will be offered the option to take the consent home to discuss with family and/or
physician prior to signing it. 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
Marcus, Galit
Miller, Jeffrey, MD
Roose, Steven, MD
Rutherford, Bret, MD


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Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
Overview
 
The overarching goal of this project is to characterize the influence of dopaminergic system dysfunction on 
the clinical presentation of late-life depression (LLD) across multiple Research Domain Criteria (RDoC) 
domains (Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems) at several levels of 
analysis (cellular [PET], structure / circuit [MRI], and functional / self-report). This IRB pertains to 
procedures completed at Columbia/NYSPI. A companion grant in this Collaborative R01 project takes place 
at Vanderbilt University Medical Center and utilizes similar, but not identical procedures (e.g., the PET 
scanning at Vanderbilt utilizes a different radiotracer). Thus, we have opted to have separate IRB protocols 
for this project. At Columbia/NYSPI we will enroll 60 elderly depressed outpatients who exhibit behavioral 
evidence of dopaminergic dysfunction, defined as either slowed processing speed or slowed gait speed. To 
disentangle the effects of depression from age-related changes, 30 psychiatrically healthy elders also will 
complete baseline evaluation. After determination of eligibility, baseline assessments include PET imaging 
measurements of dopamine synthesis and receptor density, neuromelanin-sensitive MRI measurement of 
long-term nigrostriatal dopamine transmission, task positive MRI focused on effort-based decision making 
and reward processing, and a comprehensive psychiatric, neurocognitive, and physical performance 
evaluation. To examine responsivity of the dopamine system to dopamine supplementation with L-DOPA, 
the 60 depressed subjects (ONLY) then will be randomized to L-DOPA or placebo for 3 weeks, followed by 
repeat multimodal MRI, neurocognitive and behavioral assessments. In a cross-over design, participants will 
then receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive 
assessments only. 
 
Evaluation
 
1. Every subject (both potential Depressed participants and Never-Depressed participants) evaluated for this 
protocol will receive a clinical interview by a psychiatrist or psychologist. A psychiatrist or other qualified 
physician will see participants to evaluate medical aspects of eligibility, including screening for signs or 
symptoms of Parkinson’s Disease (PD). If there is any concern, they will be referred to the study neurologist 
(Dr. Kimberly Kwei at Columbia). Additional assessments will be administered by a trained rater (BA, RN, 
or SW) in CAAM, including the Montgomery Asberg Depression Rating Scale (MADRS) and a SCID 
performed by a trained rater. Never-Depressed Elders will be selected for participation based on this initial 
assessment and clinical interview, while potential Depressed subjects will be further assessed as below.
 
2. If a subject has a diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder 
(PDD), he/she will be informed of this and educated about the availability of treatments for depression. If a 
subject is not interested in depression treatment during the 6-8 weeks of study participation and/or prefers to 
begin with an experimental treatment for slowing and depression, he/she will be offered participation in the 
present study provided there is no suicidal ideation present. Based on the extant data supporting the efficacy 


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of antidepressants for MDD and PDD, they will be informed that antidepressant treatment would be a very 
reasonable option for their condition. These potential subjects will be offered the option of being referred 
out for depression treatment, and it will be clarified that L-DOPA is not as yet a treatment for MDD. Thus, 
all potential participants in this study must state their preference not to be treated with a standard treatment 
for depression.
 
3. Next, trained raters (BA, RN, or SW) in CAAM will assess processing speed using the Digit Symbol test 
from the WAIS-III and the Trail-Making Test Part A. Digit Symbol or Trails A will be used as a selection 
criterion, with patients included in this study if they score 0.5 SD below the age-adjusted norms on Digit 
Symbol or Trails A. Patients’ gait will be assessed by trained raters as walking speed in m/s on a Gaitrite 
walkway system. Patients are instructed to walk at their usual or normal speed starting and ending at a point 
6 feet prior to and after the walkway course to eliminate acceleration and deceleration effects. Two trials 
will be completed, and gait speed will be based on the average of 2 trials. Gait speed will be used as a 
selection criterion, with patients included in this study if they have a gait speed < 1 m/s.
 
4. If subjects are eligible for the study after review of their processing speed and gait speed and decide to 
participate by signing informed consent, then they will complete the remainder of the baseline assessment. 
This includes recording of each subject’s chief complaint, referral source, age of onset of mood and/or 
cognitive decline, number prior depressive episodes, age, sex, marital status, race and ethnicity, years of 
education, employment status and income, years of education, family history. We also will document 
medical history, physical exam, urine drug screen, CBC, chemistries and electrolytes, thyroid profile, 
vitamin B12 and folate levels, urine analysis, and ECG. Vital signs will be measured at baseline and 
monitored weekly throughout the study. The Cumulative Illness Rating Scale-Geriatric (CIRS-G) will be 
filled out at baseline to measure chronic medical illness burden. Subjects’ current physical pain will be 
assessed weekly using a 100mm Pain Visual Analog Scale (VAS) and used as a covariate in analyses of gait 
speed.
 
5. Additional plasma will be separated and pipetted into tubes to be transferred to Dr. Jennifer Felger's 
laboratory at Emory University for measurement of baseline markers of inflammatory status, including C-
reactive protein (CRP), IL-6, and Tumor Necrosis Factor α (TNFα). The rationale for inflammatory marker 
measurement is evidence that dopaminergic dysfunction in older adults may be caused by the chronic, low-
grade inflammatory process concomitant with aging (“inflammaging”). Pro- inflammatory cytokines such as 
IL-6 may reduce dopaminergic transmission in multiple ways, including decreasing dopamine synthesis by 
limiting tetrahydrobiopterin (BH4) availability, impairing vesicular release of dopamine in presynaptic 
neurons by decreasing expression of vesicular monoamine transporter 2 (VMAT2), increasing DAT 
reuptake of synaptic neurotransmitter, and decreasing glutamate-dependent dopamine signaling.
 
6. In the situation where a potential participant is taking medication and/or has a device to stabilize or 
manage a medical condition, the research physician will, without exception, contact the physician 
managing the condition to describe the possible research use of L-DOPA, to discuss any possible risks, 
and to obtain the managing physician’s opinion as to whether the participant’s condition and/or it’s 
management is a contraindication to the research use of L-DOPA in this participant. This discussion 
and its outcome will be documented in the research chart.
 


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7. Otherwise eligible subjects who are currently taking an ineffective antidepressant medication (i.e., 
the individual is symptomatic at a level meeting inclusion criteria) will be offered participation as 
above after a discussion of the risks, benefits, and alternatives. No patients will be taken off of 
effective antidepressant medications solely for the purpose of research. Should an individual taking 
an ineffective antidepressant medication wish to participate and sign consent, their psychiatric care 
will be taken over by a CAAM study clinician after a discussion with their prescribing physician. 
Such participants will be tapered off of the ineffective medication as per standard clinical practice 
(depending on the medication) and be followed closely in CAAM, likely through weekly visits. Should 
a participant be unable to tolerate the medication taper due to increasing depressive symptoms, they 
will be withdrawn from the study and entered into the 3 month open treatment period directly. Once 
participants are washed off of the medication they will proceed with the study assessment described in 
points 8-10 immediately below. Subjects must be off medication for 2 weeks prior to neuroimaging 
procedures and beginning the L-DOPA study medication.
 
8. Other neuropsychological measures completed at baseline include trained study rater (BA, RN, SW) 
assessment of processing speed using the Pattern and Letter Comparison Tests, broad cognitive evaluation 
with the NIH Toolbox, and evaluation of executive function via the NIH-EXAMINER battery designed to 
assess executive functions reliably, comprehensively, and efficiently (154-155). This battery examines 
working memory, inhibition, set shifting, fluency, insight, planning, social cognition and behavior. We also 
include the supplemental NIH Toolbox Auditory Verbal Learning (Rey) Test for a robust assessment of 
episodic memory and allow for classification of amnestic mild cognitive impairment.
 
9. Domains of function assessed by trained study raters (BA, RN, SW) at baseline include: the Short 
Physical Performance Battery (SPPB), a performance measure of gait, balance, and lower extremity strength 
sensitive to meaningful change. The 36-item self-report World Health Organization Disability Assessment 
Schedule 2.0 (WHODAS2) provides a global measure of disability and 7 domain-specific scores based on 
the conceptual framework of the International Classification of Functioning, Disability, and Health (ICF). 
The Falls Efficacy Scale-International will assess subjects’ fear of falling weekly using a 16-item scale 
rating respondents’ confidence (1 not at all concerned—4 very concerned) in doing daily tasks without 
falling.
10. Finally, additional clinical measures include the Antidepressant History Form (ATHF), the Daily 
Inventory of Stressful Events, the Preceived Stress Scale, and the Duke Social Support Index. Depressive 
symptoms will be measured with the MADRS in addition to the Inventory of Depressive Symptoms--Self 
Report (IDS-SR).
 
MRI Scanning
 
11. All of the N=60 Depressed subjects and N=30 Never-Depressed subjects will undergo neuroimaging, 
but the Depressed subjects will undergo a pre-treatment MRI and a post-treatment MRI following Step 1 (3 
week duration) of the LDOPA study, whereas Never-Depressed Elders will have a baseline scan only 
(because they will not participate in below LDOPA study). MRI and PET scanning (see below) may occur 
on the same day if this can be scheduled (MRI occurring first, followed by PET scan). However, due to the 
tightness of scheduling for these scanners, it is more likely that the MRI and PET scans will occur on 


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different days--one day for MRI scan and one day for the PET scan. Typically the MRI scanning day will 
come before the PET scanning day.
 
12. MRI of the brain will be acquired using a GE Premier 3.0T System. For PET / fMRI coregistration and 
region of interest determination we will use a sagittal, whole-brainT1-weighted 3D sequence (MPRAGE) 
with TR/TI/TE = 2400/ 1000/ 2.22ms, flip angle (FA) 8, field of view (FOV) 240x256, 0.8mm isotropic 
resolution (no slice gap), and parallel imaging acceleration factor of 2 (Philips SENSE, GE ARC/ASSET). 
For assessment of white matter hyperintensities (WMH) we will use an axial, whole-brain T2 FLAIR 
sequence with TR/TI/TE = 9690/2500/91ms, FA 136, FOV 240x256, 0.8x0.8x1.6mm resolution (no slice 
gap), and parallel acceleration factor of 2.
 
13. For the BOLD functional MRI, we will use an axial, whole-brain gradient-echo echoplanar imaging 
(EPI) sequence: TR/TE = 1000/30ms, FA 45, FOV 220x220, 2.3mm isotropic resolution (no slice gap). 
Multiband and parallel imaging acceleration factors will be tuned for each scanner to obtain the specified 
TR/TE/voxel size. The most inferior functional slice will be inferior to the most inferior aspect of the 
temporal lobes. Prior to functional image acquisition, an axial, whole-brain field map is collected to correct 
for distortions caused by magnetic field inhomogeneities with TR/TE1/TE2 = 590/4.92/ 7.38ms, FA 60, 
FOV 220x220, 2.3mm isotropic resolution. We will also collect a pair of single volume spin-echo EPI with 
opposite phase encoding direction to provide an alternative method for field map computation. 
 
14. Two tasks will be undertaken in the scanner. The first is the Effort Expenditure for Rewards task 
(EEfRT). On each EEfRT trial, participants decide whether to work harder for a larger reward (high number 
of finger presses with their pinky), or expend less energy (low number of presses with a dominant index 
finger) for a lesser reward, with lower rewards being $1 dollar and higher rewards ranging from $1.20 to $5. 
Participants receive information about the probability of winning on each trial regardless of their pick and 
one trial from each run is randomly selected for payout. Computational modelling of the EEfRT allows an 
estimation of the effort level at which people begin to discount rewards, and the rate of discounting once 
they start discounting. Because these models are more accurate with at least 3 levels of effort, the modified 
EEfRT offers subjects choices between high and low effort, low and medium effort, and medium and high 
effort (one third of trials each). The level of effort is manipulated using the number of finger presses and 
which finger on the nondominant or dominant hand is utilized. The number of button presses (required in a 
10s response window) will be calculated as a percentage of each participant’s maximum sustained button 
press rate in order to control for differences in ability level. The response rate (20% index dominant, 50% 
middle finger nondominant, 80% pinky nondominant) and time span for the responses have been calibrated 
for this population in order to limit floor effects seen in some participants in past EEfRT studies. 
Participants will complete three 320-s runs for a total of 60 trials. The following equation will be fit to the 
data utilizing in-house computational modelling scripts in MATLAB: SV= M -kCp, where SV= subjective 
value, M = monetary value of the chosen reward, k= the discount rate, C = the effort level of the option, and 
p determines the inflection point at which participants begin to discount. We will further examine traditional 
measures of the proportion of high-effort choices made during the session (primary outcome), and the 
relative influence of reward magnitude on making a high-effort choices (reward magnitude beta derived 
from a generalized estimating equation (GEE), as a weakening of reward magnitude sensitivity in decision 
making has been seen in our past studies with depressed patients .
 


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15. The second task is the Monetary Incentive Delay task (MIDT). On each trial, participants are presented 
with a 2000msec cue indicating that trial’s reward value ($0, $1, or $5). After the cue, a 2000-2500 msec 
delay period ensues as the participant waits for the target. Participants press a button as quickly as possible 
when the target is visible. After another delay lasting from 950 to 2800 msec, a feedback screen lasting 
2500msec appears indicating the outcome (“Hit!” or “Miss!”) for each trial, with a brief ISI before the next 
trial and an average trial length of 8 s. Target duration is continually adjusted during the session based on 
individual performance to keep success rate at 60%. Participants will complete 96 trials over three five-
minute runs, for a total of 32 trials with each cue. Participants receive the money they win from the run with 
the greatest earnings. We include only gain trials to maximize the number of trials per condition to improve 
statistical power. This task distinguishes between reward anticipation and notification of reward receipt, and 
for modeling responses to the presence or absence of reward and responses to the magnitude of rewards. 
Modeling will use our past approach with the primary contrast being reward anticipation (Potential Win 
Anticipation > No Change Anticipation) and secondarily reward response (contrast Win Feedback > No 
Change Feedback). Post-hoc tests will examine the relationship between discounting behavior by reward 
magnitude and BOLD signal, contrasting responses to the three reward values ($0, $1, or $5.
 
16. Finally, neuromelanin-sensitive MRI (NM-MRI) will be conducted, which has been successfully 
implemented by Co-Inv Horga at NYSPI in several studies. NM-MRI consists of 2D gradient echo (GRE) 
images with magnetization transfer (MT) contrast of the midbrain (2D-GRE-MT, 0.39 mm2 in-plane 
resolution, 1.5mm slice thickness, 20 slices, FOV=162×200 mm, FA=40°, TR= 260 ms, TE=2.68 ms, MT 
frequency offset=1200 Hz, AC-PC alignment). To ensure imaging of the substantia nigra (SN), the image 
stack will be manually positioned by trained research staff according to anatomical landmarks on the high-
resolution T1w scan, a protocol that yields excellent test-retest reliability for voxelwise analysis (median 
ICC=0.91).
 
17. For all of the MRI procedures, participants are instructed to lie as still as possible within the magnet.
The MRI scan is completed in one session, and lasts for a total of approximately 90 minutes, including time 
for positioning subjects in the scanner. All precautions and protections are given to the participant to ensure 
that they are as safe and as comfortable as possible. For participants’ comfort within the scanner, they lie on 
a padded table with a pillow to rest their heads on. A blanket is also provided to keep participants warm 
during the procedure. If the participant appears nervous or anxious, a trained member of the research staff 
remains with them inside the scanning suite for the duration of the scan. The participant is given a squeeze 
ball to terminate the scan at any time. If he/she squeezes the ball, he/she will be removed from the scanner 
immediately. Participants may decline the MRI scans at any time. If the participant chooses not to be 
scanned, his/her participation in the study will not be affected. Of course, a structural MRI scan would 
be required to participate in the PET scans. Any subject who cannot have at least a structural MRI scan 
would not be able to participate in this protocol. All of the MRI procedures are conducted on the 3-Tesla 
MRI scanner at the New York State Psychiatric Institute. Conducting these procedures will be an accredited 
Magnetic Resonance Technologist and one member of the research staff (Bachelor’s Level or Higher), or Dr 
Rutherford or Broft, present.
 
PET Scanning
18. The N=60 Depressed subjects and N=30 Never-Depressed subjects will undergo a single [18F]DOPA 
PET scan at baseline.


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19. PET experiments will be conducted with the mCT scanner in the PET Suite on the R1 level of the Public 
Health Building. Subjects participating in the study will be escorted on PET scan day by a research staff 
member to the R1 level of the Public Health Building where the PET scanner is located. A research staff 
person will stay with the subject throughout the procedure. The preparation of the subject will include the 
placement of a venous catheter.
 
20. The radiochemistry laboratory and PET suite staff will be in frequent communication regarding the 
status of preparation of the research subject (such as placement of venous line) and the progress of the 
radiotracer synthesis. [18F]-FDOPA will be produced at the on-site radiochemistry facility. After fasting 
overnight, participants are pretreated with 150 mg of carbidopa 120 minutes prior to [18F]-FDOPA 
injection to increase brain bioavailability. As scan time approaches, the subject will be placed in a supine 
position on the camera table and will have vital signs (blood pressure and heart rate) obtained. Each person's 
head will be positioned, and a headholder will be used to decrease head movement during the scan. Similar 
to previous studies, participants will be injected with [18F]-FDOPA (maximum dose of 5 mCi). The 
emission scan will be initiated with injection and data obtained for 90 minutes. At the completion of the 
scan the IV catheter will be removed, and the subject will be evaluated (including mental status and vital 
signs) by a study physician. Vital signs will be performed prior to discharge from the PET suite. A new IND 
application to the FDA is underway by the PI (Dr. Rutherford) to cover the baseline PET scan in this study 
and will be added to this application when received.
 
21. PET data will be reconstructed into images using the appropriate reconstruction protocols and
filters. PET images will be coregistered to the MRI and regional time activity curves will be measured. Data 
will be fitted to pharmacokinetic models, and relevant pharmacokinetic parameters, including
the percent of receptors engaged by dopamine, will be estimated based on the model fitting procedures.
 
22. Drs. Miller, Zanderigo, and Lan in the MIND Division at NYSPI are Co-Investigators who will lead 
analyses of neuroimaging data. In terms of on-site execution of PET and MRI scans, these are supervised by 
the study PI (Bret Rutherford) and/or Dr. Allegra Broft, who works with the PI as a study clinician and has a 
research background in PET neuroimaging.
 
Clinical treatment
 
23. For the mechanistic probe of dopaminergic functioning using LDOPA, a crossover trial will be 
conducted. In Step 1, participants will be randomized to initially receive either active L-DOPA or matching 
placebo based on a block design using R Statistical Software version 3.4.3 (R Foundation for Statistical 
Computing, Vienna, Austria). Participants, physicians and research staff will be blinded to group 
assignment. The NYSPI Pharmacy will maintain the randomization key for each site and can unblind 
individual subjects in emergencies. The blind will not be broken until study completion. Following Step 1, 
participants will have repeat MRI scanning and cognitive/behavioral testing, then undergo a 1 week taper 
and wash out period before being crossed over to the opposite treatment (Step 2). Repeat cognitive and 
behavioral testing will occur after Step 2 but there will be no further neuroimaging.
 
24. Subjects will take active or placebo tablets three times daily (9am, 1pm, 5pm). Those assigned to L-
DOPA will begin with a Week 1 L-DOPA daily dosage of 150mg, or 1.5 25mg carbidopa/100mg levodopa 


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tablets at 9am and placebo tablets at 1pm and 5pm. In Week 2 the L-DOPA daily dose will increase to 
300mg (1.5 25mg carbidopa/100mg levodopa tablets at 9am and 5pm, with placebo at 1pm), followed by a 
Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets three times daily). 
Subjects assigned to placebo will take 1.5 placebo tablets three times daily for three weeks. Individuals will 
be instructed to maintain the same timing of doses throughout the study. Individuals unable to tolerate an 
increased dose will have their dosage reduced to the maximum previously tolerated dose. 
 
25. Following the three-week Step 1 Phase, there will be a one-week taper period. Subjects will be 
instructed to decrease their dosage to 1.5 tablets twice daily for 3 days, followed by 1.5 tablets once daily 
for three days, then discontinue tablets. Subjects will then restart an identical dosing regimen while being 
crossed over to the opposite treatment assignment for Step 2.
 
26. At each weekly visit, subjects will meet with a psychiatrist of study physician. Both in our Pilot study 
and the literature overall, L-DOPA is an extremely well tolerated medication at doses < 600mg, which is 
substantially less than the doses often reached in the treatment of Parkinson’s disease (900-1200mg). L-
DOPA has been administered to healthy subjects in single dose studies and found to be well-tolerated. In 
Parkinson’s disease, a recent clinical trial published in the New England Journal of Medicine randomized 
patients to receive 150mg, 300mg, or 600mg L-DOPA for 40 weeks. No dyskinesias or other 
neuropsychiatric effects were observed that were greater than the placebo group.
 
27. Participants will be given the option to receive medication reminders via text messages three times daily 
(morning 9am, midday 12pm, evening 5pm) adhering to the study medication schedule. Text messages will 
be automatically sent out by service provider www.remindercall.com. Participants will be able to opt-in and 
opt-out of this service at any time during the study by either replying “STOP” to any text message or by 
contacting the study coordinator. 
26. At the conclusion of Step 2, participants will undergo another 1 week washout phase and then enter 
post-protocol open treatment, which will be offered for 3 months. Appropriate medication treatment options 
for depression will be discussed with each participant, which may include continued off-label use of 
LDOPA as discussed below. 
Assessments
 
29. Subjects are expected to have a screening/evaluation visit, pre-treatment PET/MRI scanning day(s), and 
weekly visits during Steps 1 and 2 of the crossover trial (i.e., Weeks 0-3 [Step 1], 4 [taper], 5-8 [Step 2], 9 
[taper]). At each clinic visit, depression severity measured using the MADRS and adverse events assessed. 
The presence of any suicidal thoughts will be assessed at every contact. Vital signs (weight, heart rate, blood 
pressure) will also be measured.
 
30. Cognitive assessments will be performed at baseline and after each step of the crossover trial. To obtain 
a broad assessment of cognitive function, we will administer the NIH Toolbox Cognition Battery that 
measures 6 ability subdomains and assess episodic memory functioning supplemental NIH Toolbox 
Auditory Verbal Learning (Rey) Test. Our primary outcome is processing speed, assessed using Coding 
from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) and the Pattern and Letter Comparison tests 
(secondary outcomes). To assess executive function, we will supplement the NIH Toolbox with the NIH-


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EXAMINER battery, which measures working memory, inhibition, set shifting, fluency, insight, planning, 
social cognition and behavior (secondary outcomes).
 
31. Gait will be assessed at baseline and after each step of the crossover trial as both a single and dual tasks 
(ST, DT) using the GaitRite system (Sparta, NJ), which assesses gait parameters in real time (gait speed, 
cadence, stride length). For the ST (primary gait outcome), participants are instructed to walk at their usual 
or normal speed over the 15’ walking course. For the DT (secondary outcome), participants are instructed to 
walk at their usual pace while simultaneously verbally listing as many animals as possible (fluency DT). In 
addition, a counting DT will be used in which participants are instructed to walk at their usual pace while 
simultaneously performing serial subtractions by threes starting at 100. 
 
32. Other clinical assessments collected each visit include the CGI Severity and Improvement (provide a 
clinical assessment of subjects at each visit and help maintain safety by identifying clinical worsening), 
Inventory of Depressive Symptoms—Self Report (IDS-SR) (provide a self-report measure for depressive 
symptoms), Structured Pill Count Interview (to assess study medication compliance), and the Treatment 
Emergent Side Effect Scale (TESS) to monitor side effects associated with medication treatment. We will 
utilize the Unified Parkinson’s Disease Rating Scale (UPDRS) to identify any dyskinesias caused by L-
DOPA, although based on our previous studies we are not expecting to observe motor side effects with the 
L-DOPA doses and duration being used in this study.
 
End of study procedures
 
33. Following the 8 week (in total) duration crossover study, endpoint assessments of psychiatric symptoms, 
cognition, and motor functioning will be made. Once post-treatment research procedures are completed, 
patients will enter 3 month open treatment period provided free of charge as described below.
You can upload charts or diagrams if any
Figures.pdf
Dosimetry chart for [18F]DOPA.pdf
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
The risk of non-response or adverse events to L-DOPA 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 (in any aspect, including motoric 
function or depressive symptoms) as defined by a 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. Furthermore, 
subjects may be withdrawn if they repeatedly miss scheduled appointments or clinical worsening 
necessitates more intensive treatment. No treatment is currently available for slowing, so there is not a 
standard of care treatment to offer patients withdrawn from the study. Thus, withdrawn patients will be 
followed in the open treatment period, offered appropriate psychiatric treatments if they have any conditions 
requiring treatment (e.g., depression), and be referred to their internist for close medical follow up.


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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 from all depressed (N=60) and healthy (N=30) subjects baseline. 
General medical tests will be performed as safety screens for Depressed subjects, such as CBC, Chem 7, 
LFTs, TSH, cholesterol, B12, and folate. Also, plasma samples from all subjects (Depressed and Never-
Depressed) will be isolated by centrifugation at 1000 x g for 10 minutes at 4C, aliquoted into siliconized 
polypropylene tubes and stored at -80C until batch assay. Samples will be shipped to Co-Inv Jennifer 
Felger’s laboratory at Emory University in batches by a staff member at each site who is certified to ship 
biospecimens using standard procedures for shipping samples on dry ice and with arrival the next day before 
10am via Fedex.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Structured Clinical Interview Diagnostic for DSM 5 (SCID): this semi-structured diagnostic interview will 
allow determination of whether subjects meet selection criteria.
 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) will be filled out at baseline to measure chronic 
medical illness burden.
 
Subjects’ current physical pain will be assessed weekly using a 100mm Pain Visual Analog Scale (VAS) 
and used as a covariate in analyses of gait speed.
 
MMSE: standard means of assessing global cognition. The SCID, CES-D, and MMSE will be measured at 
baseline for the purpose of subject selection, while the following measures will be collected weekly 
throughout the study.
Montgomery Asberg Depression Rating Scale: standard measure of depression severity that measures 
changes in depressive symptoms.
CGI Severity and Improvement: scales measuring the clinician’s view of subjects’ global functioning that 
will provide a clinical assessment of subjects at each visit and help maintain safety by identifying clinical 
worsening.
Structured Pill Count Interview: assessment of study medication compliance accounting for each dose of 
prescribed study medication during the study period.
Blind Assessments rate clinician’s and patient’s guesses as to study drug assignment.
Unified Parkinson’s Disease Rating Scale (UPDRS): standardized, reliable, and valid instrument for 


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assessing the severity of the clinical features of PD; questions 32 and 33 will be used in this study to assess 
the duration and disability of dyskinesias caused by L-DOPA. While we include this measure, we are not 
expecting to observe dyskinesias in healthy subjects or at the L-DOPA doses being used in this study. 
Typically, such L-DOPA side effects emerge only in patients who have had Parkinson’s disease for a 
number of years and then only if the LDOPA dose is raised to 600 mg or more.
Treatment Emergent Side Effect Scale: standardized general checklist used in our clinic for monitoring side 
effects associated with medication treatment.
Inventory of Depressive Symptoms—Self Report (IDS-SR): rating scale for depressive symptoms based on 
DSM criteria that has been increasingly used in antidepressant studies due to its equivalent weightings for 
each item, understandable anchor points, and inclusion of all DSM criteria.
Processing speed will be assessed using the Digit Symbol test from the Wechsler Adult Intelligence Scale- 
III (WAIS-III) and the Pattern and Letter Comparison tests. These tests are all reliable and valid, with 
moderate to high loadings on the latent speed factor.
 
To broadly assess cognitive function, we will administer the NIH Toolbox Cognition Battery, a brief and 
psychometrically sound set of 7 computerized instruments providing an overall cognitive index from 
measures of 6 cognitive domains . We also include the supplemental NIH Toolbox Auditory Verbal 
Learning (Rey) Test for a robust assessment of episodic memory and allow for classification of amnestic 
mild cognitive impairment. 
Executive function will be assessed via the NIH-EXAMINER battery designed to assess executive functions 
reliably, comprehensively, and efficiently. This battery examines working memory, inhibition, set shifting, 
fluency, insight, planning, social cognition and behavior.
 
Gait will be assessed as both a single and dual task (ST, DT) using the GaitRite system (Sparta, NJ), which 
assesses gait parameters in real time (gait speed, cadence, stride length). For the ST, patients are instructed 
to walk at their usual or normal speed over the 15’ walking course. For the DT, patients are instructed to 
walk at their usual pace while simultaneously verbally listing as many animals as possible (fluency DT). In 
addition, a counting DT will be used in which patients are instructed to walk at their usual pace while 
simultaneously performing serial subtractions by threes starting at 100. Patients will start and end at a point 
2 meters from the GaitRite mat to eliminate acceleration and deceleration effects. Each ST and DT will be 
assessed two times with the average used in the analyses. The ST assessment of walking speed in m/s will 
be the primary gait outcome measure for this study. 
Pittsburgh Fatigability Scale (PFS) will assess mental and physical fatigability.
 
Short Physical Performance Battery (SPPB) provides a performance measure of gait, balance, and lower 
extremity strength. 
 
The Falls Efficacy Scale-International will assess subjects’ fear of falling using a 16-item scale rating 
respondents’ confidence (1 not at all concerned—4 very concerned) in doing daily tasks without falling.


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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
Drug
Radiolabeled drug/compound
Select the number of drugs used in this study
1
Drug #1
Name of the drug
Sinemet (carbidopa/levodopa)
Manufacturer and other information
We will be using generic carbidopa/levodopa (L-DOPA) 25/100 tablets in this study. We will purchase them
through the New York State Psychiatric Institute (NYSPI) pharmacy, using the generic manufacturer
recommended. L-DOPA is currently approved by the Food and Drug Administration (FDA) for the
treatment of the symptoms of idiopathic Parkinson's disease, post-encephalitic parkinsonism, and
symptomatic parkinsonism. This project proposes off-label use of L-DOPA in individuals with significant
cognitive/motor slowing.
Approval Status
No IND is required
Choose one of the following options
FDA has determined that IND is not required
Off label and investigational use of radiolabeled drugs/compounds
Radiolabeled Drug/Compound #1
Name of the radiolabeled drug/compound
[18F]DOPA
Manufacturer and other information
[18F]-FDOPA quantifies dopamine synthesis capacity in the striatum, although it is also used for
quantification in the cortex. Striatal [18F]-FDOPA uptake has been inversely related to depression severity
and cognitive and motor function in PD. Moreover, striatal [18F]-FDOPA uptake was decreased in a group
of patients with MDD who exhibited psychomotor retardation and affective flattening as compared to a
second MDD cohort characterized by impulsivity and anxiety and a group of healthy volunteers. These data


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suggest that this tracer may be sensitive to deficits in dopamine synthesis capacity that we hypothesize to 
mediate pathological processes in LLD.
Approval Status
IND is approved
IND#
151595
Who holds the IND/IND sponsor?
IND is held by PI/CU Investigator
Rutherford, Bret, MD
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
None.
Maximum duration of delay to standard care or treatment of known efficacy
Since patients will be assigned to placebo for one phase of the crossover study and the effects of L-DOPA 
on depression in this population are currently unknown, there will be an 8-week duration delay to receiving 
an agent of known efficacy to treat depression posed by subjects' participation in this study.
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 3 week study, a non-study clinician in our research clinic will be given the data on the subject’s 
response to L-DOPA. This clinician will discuss with each subject on a case-by-case basis the risks and 
benefits of continuing L-DOPA 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 
LDOPA after receiving an explanation of the potential risks of chronic administration. If they do not want to 
continue L-DOPA, it will be discontinued after a 3 day step-down withdrawal of the drug. 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


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1. L-DOPA Side Effects: Side effects will be assessed at each planned visit and as needed through 
additional or unscheduled contacts. We will attempt to minimize side effects by slow dosage titration and 
allowance for dose reduction if needed. We will withdraw subjects from the study if they cannot tolerate the 
lowest dose of carbidopa/levodopa (L-DOPA) 37.5mg/150mg daily. L-DOPA is a well-tolerated medication 
at the doses we will be using in this study. In healthy controls, the only available studies are single-dose 
experiments, in which the sole reported side effect has been nausea. No serious adverse events or side 
effects due to an effect on the nigrostriatal dopamine system have been observed in these studies. There are 
many studies of chronic L-DOPA administration for the treatment of Parkinson’s disease (PD), since this 
drug has been used since the 1960s. Perhaps the most relevant study was a clinical trial published in the 
New England Journal of Medicine in 2004. In this study 361 patients with PD were randomized to receive 
150mg, 300mg, or 600mg L-DOPA for 40 weeks. In the 150mg and 300mg L-DOPA treatment groups, the 
only side effects observed that were different from placebo were headache and nausea. No dyskinesias or 
other neuropsychiatric effects were observed that were greater than the placebo group, and this study lasted 
40 weeks as opposed to 4 weeks (3 week dose titration, with 1 week taper) in this study.
In our preliminary work at NYSPI, a series of depressed older adult outpatients (N=36 subjects aged 75.3 ± 
7.5 years, 44.4% male) were treated with open L-DOPA for three weeks (one week each of 150mg, 300mg, 
and 450mg). The overall drop-out rate was 8.3%, with 5.6% subjects dropping out due to adverse effects of 
L-DOPA. Thirty of the total N=36 analyzed subjects reached the final L-DOPA dose of 450mg. Nausea 
was the most frequently reported treatment-emergent side effect, and the frequency of subjects 
reporting nausea decreased over the course of the trial, from 19.4% of subjects reported for 150mg L-
DOPA, to 17.1% for 300mg L-DOPA, and 9.1% for 450mg L-DOPA. The only other side effects reported 
by more than one subject were insomnia and headache. The emergence of dyskinesias during L-DOPA 
treatment was evaluated using items 32 and 33 of the UPDRS, and no significant change from baseline was 
observed on either these items. Mean scores were 0.0 at Week 3 for both items. No significant adverse 
events (SAEs) attributable to study medication were noted during the project. Since we found the greatest 
effects on processing/gait speed at 450mg without no decrease in tolerability relative to 150mg and 300mg 
doses, we selected 450mg as the target dose for the mechanistic probe in the present study. In our pilot 
work, L-DOPA 450mg was associated with increased dopaminergic availability in the sensorimotor and 
associative striatum.
a. L-DOPA common side effects: In patients taking L-DOPA for the management of bradykinesia and 
freezing associated with PD, the most common side effects are dyskinesias (i.e., choreiform, dystonic, and 
other involuntary movements) and nausea.
b. Other L-DOPA side effects: blood pressure changes, orthostasis, anorexia, dyspepsia, constipation, 
psychotic episodes (e.g., delusions, hallucinations), vivid dreams, and nightmares.
c. Discontinuation Syndrome: A neuroleptic malignant-like syndrome (fever, akinetic crisis, rigidity, 
autonomic disturbances) has been reported following withdrawal of levodopa in patients with PD.
2. [18F]-FDOPA PET Imaging Specific Risks: Risks associated with [18F]-FDOPA PET scans are (a) 
radiation exposure, (b) toxicology, (c) venous catheter, and (d) discomfort during scanning. To limit the 
risks of radiation exposure, participants with radiation exposure in a research study in the previous year will 


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only be included if the injected dose and dosimetry of the radiotracer are known and the cumulative annual 
exposure of the previous study and this study is lower than the annual limit for research subjects defined by 
the FDA (21 CFR 361.1, see below). The critical organ is the bladder for [18F]-FDOPA. The exposure to 
the critical organs after a single injection of [18F]-FDOPA is below the 21CFR361 single dose limits for 
research subjects, of 5 rads (50 mGy) for dose-limiting organs and 3 rads (30 mGy) for testes. The total 
annual dose is also below the limit for research subjects of 15 rads (150 mGy) for dose-limiting organs and 
5 rads (50 mGy) for testes. Further protections are that, before scanning, participants are interviewed about 
past radiation exposure to ensure that limits are not being exceeded. In order to further limit radiation 
exposure, after the PET scan, participants are asked to empty their bladders following scanning and to drink 
extra fluids in order to decrease radiation exposure to the bladder wall. Persons exposed to radiation in the 
work place or to nuclear medicine research procedures during the previous year are excluded from 
participation.
A low dose attenuation CT scan will be needed before each PET scan acquisition is started. If the subject 
needs to leave the scanner to use the restroom during the scan, the CT scan will need to be repeated. The 
effective dose per administration will be 0.044 mGy, so the total potential effective dose per study/protocol 
will be 0.088 mGy. The total effective dose for all procedures in the study will therefore be 4.71 mGy. 
These doses are below the dose limits for research studies under FDA 21CFR 361. Since only trace amounts 
of the radiotracer will be present, the procedure presents no risks in terms of toxicity. L-DOPA is an 
approved medication for Parkinson Disease at much higher doses. The use of [18F]-FDOPA for PET 
imaging is approved in the European Union for clinical nuclear medicine use in the field of oncology. 
Nevertheless, a physician will be present during each injection of the radiotracer in case of an idiosyncratic 
response.
 
3. Delay in Antidepressant Treatment Initiation: As specified in the above selection criteria, participants in 
this study will have a DSM 5 depressive disorder and MADRS ≥ 15, but current treatment with 
antidepressant medication is an exclusion criterion. Otherwise eligible subjects who are currently taking an 
ineffective antidepressant medication (i.e., the individual is symptomatic at a level meeting inclusion 
criteria) will be offered participation after a discussion of the risks, benefits, and alternatives. Those wishing 
to participate will undergo a medication washout following standard clinical practice and be closely 
followed by study clinicians until they are eligible to begin the study. The maximum duration of delay of 
treatment for depression with an agent of known efficacy will be 8 weeks. No patients will be taken off of 
effective antidepressant medications solely for the purpose of research, and patients will be withdrawn from 
the study and treated if clinically indicated and desired by the patient.
A number of precautions have been taken to safely maintain participants antidepressant-free for the duration 
of the proposed study. First, our selection criteria exclude individuals who are judged to be at high risk of 
suicide (MADRS suicide item > 4). Second, we have stringent criteria for early discontinuation and 
initiation of appropriate open clinical treatment. These criteria are (1) participant withdraws his or her 
consent; (2) significant clinical worsening in the judgment of the study clinician; (3) a CGI-Improvement 
rating of 6 (worse) or 7 (much worse) for 2 consecutive visits, or (4) development of significant side effects 
or an adverse event. Any subjects meeting any of these criteria will be withdrawn from the study and treated 
as clinically indicated. Furthermore, subjects may be withdrawn if they repeatedly miss scheduled 
appointments or clinical worsening necessitates more intensive treatment. Finally, following the study, 


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subjects are offered state-of-the-art clinical visits at no cost to them or their insurer for 3 months, although 
they will be responsible for the cost of any antidepressant medications.
4. 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.
 
5. L-DOPA treatment—End of Study Procedures: We will provide up to 3 months of additional free clinic 
visits following the end of this project to facilitate the return to clinical care. A non-study clinician in our 
research clinic will be given the data on each subject’s response to L-DOPA. This clinician will discuss with 
each subject on a case-by-case basis the risks and benefits of continuing L-DOPA treatment as well as other 
options for the treatment of depression. Those who have benefited from the treatment and have not had 
significant side effects may elect to continue receiving L-DOPA after receiving an explanation of the 
potential risks of chronic administration. If they do not want to continue L-DOPA, it will be discontinued 
after a 3-day step-down withdrawal of the drug. 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.
6. Gait speed assessment: During the gait speed assessment and other physical performance measures, 
patients may feel unsteady and their risk of falls may increase. To mitigate these risks, patients are 
accompanied by research coordinators and/or doctors during each of the performance-based assessments 
(including the gait assessment, balance test, and chair stand, the latter two components of the Short Physical 
Performance Battery). Coordinators walk slightly behind and alongside the patients during the gait 
assessment, providing support for the patients should they become unsteady during the procedure.
7. Breach of confidentiality: There is the potential risk of breach of confidentiality of clinical and laboratory 
information. PIs Rutherford and Taylor have extensive experience as clinical investigators in dealing with 
sensitive information and assuring that data is adequately protected. Safeguards to protect confidentiality 
include locked records and firewalls around password-protected electronic data, and all study data being 
coded, with the key linking the code with a subject’s identity being kept in a separate, locked file. Please 
refer to Human Subjects section 3.3 for a discussion of data management, security, and monitoring.
 
8. PET and MR scanner environments. The physical confinement and isolation produced by the scanner 
could cause mild to moderate emotional distress, although in our extensive past experience, subjects 
generally have tolerated the procedures well. To protect against this risk, subjects will be acclimated to the 
MRI and its noise with training sessions in a mock scanner on the morning of the scan. Relaxation training 
will be used to help calm anxious subjects and to reduce motion. Frequent praise and reminders to remain 
still, along with an inflation pillow and taping of the subject’s forehead, will help to acquire motion-free 


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images. In the past dozen years, our groups at Columbia/NYSPI and Vanderbilt have acquired superb, 
motion-free structural and functional scans in 1000s of adults affected by a variety of neuropsychiatric 
illnesses. All subjects will be able to communicate directly with technologists and study staff to report any 
emotional or physical distress during the scanning procedure. If they wish, the scan will be terminated 
immediately, and the subject will be removed from the scanner.
9. Magnetic Resonance Imaging: Although this procedure is generally low-risk, there are particular 
concerns. Individuals will be screened for the presence of implanted metal (including but not limited to 
medical devices, shrapnel, tattoos or permanent makeup). Those who screen positive will be excluded from 
the study. Claustrophobia is also an issue for many potential subjects. During the MRI, subjects will have 
voice contact with a radiology technician, and they may request the scan be stopped at any time.
10. Incidental Findings: Magnetic Resonance Imaging: Another risk is the occurrence of incidental findings 
on MRI. All scans are reviewed at time of acquisition and concerning findings are discussed with an 
attending neuroradiologist. Should any concerning findings be seen, the site PI will convey these findings to 
the subject along with recommendations for further evaluation, and facilitate referrals for such evaluation 
and treatment.
11. Risks of blood draw: When obtaining a 20 cc blood sample, patients can experience side effects that 
include pain, fainting, bruising, light-headedness, and, on rare occasions, infection. 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.
Describe procedures for minimizing risks
1. Side effects will be assessed at each planned visit and if needed through additional or unscheduled 
contacts. We will attempt to minimize side effects by slow dosage titration and allowance for dose reduction 
if needed. We will withdraw subjects from the study if they cannot tolerate the lowest dose of 
carbidopa/levodopa (L-DOPA) 37.5mg/150mg daily.
 
2.  The dose of radiation will be approved by the JRSC, as we will submit an application to cover 
[18F]DOPA scanning. All scans will be done in the presence of medical supervision and trained nursing 
staff in an imaging center specifically designed to support imaging studies. In the event of serious medical 
complications, the PET scan facilities have immediate access to a consultation with specialized medical 
units at New York Presbyterian Hospital. Preparation of radiopharmaceuticals and performance of PET 
scans will be by radiochemists, physicians, and technologists of the Department of Radiology at Columbia. 
These professionals are qualified by training and experience in the safe use and handling of 
radiopharmaceuticals. Subjects will be asked about their previous radiation exposure and those who have 
had research exposure within the past year will be excluded if their cumulative annual exposure (including 
the present study) exceeds FDA limits. The information on the previous radiation exposure of study subjects 
will be notified to the study doctor.
3. In terms of [18F]DOPA pharmacologic effects, we do not anticipate any pharmacological effects from the 
radiotracer used in the proposed studies. As with any drug, the possibility of idiosyncratic reaction exists 
and is mentioned in the consent forms. A physician is present at each experiment.
 


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4.  The staff will take every precaution to avoid difficulties with gait speed assessments. Patients are 
accompanied by research coordinators and/or doctors during the test of gait speed. Coordinators walk 
slightly behind and alongside the patients during the gait assessment, providing support for the patients 
should they become unsteady during the procedure.
 
5.  Dr. Rutherford has extensive experience as a clinical investigator in dealing with sensitive information 
and assuring that data is adequately protected. Safeguards to protect confidentiality include locked records 
and firewalls around password-protected electronic data, and all study data being coded, with the key 
linking the code with a subject’s identity being kept in a separate, locked file.
 
6. The study coordinators are experienced and skilled in interviewing subjects with a variety of mental 
health issues. 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.
7. To minimize MRI risks, each subject will fill out the MRI Safety Questionnaire before the study. Only 
subjects who fulfill the criteria by this questionnaire will be eligible for the study. In addition, subjects will 
remove all metal (watch, hair pins, jewelry) before entering the MRI room. If the subject has any metallic 
prostheses/implants they will be excluded from the study. If a subject becomes anxious during the scan they 
can request that the MRI scan be stopped. 
8. Risks of bruising, clotting, and infection during IV placement and blood draw will be minimized by 
having venipuncture performed by trained and experienced personnel under sterile conditions. To avoid 
injury due to fainting, the antecubital vein catheter will be inserted when the subjects are recumbent.
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.
 


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The data obtained for this study and biospecimens could be used for future research studies or may be 
distributed to another investigator for future research studies, however all information including 
biospecimens will be de-identified and will not include whole genome sequencing (i.e., sequencing of a 
human germline or somatic specimen with the intent to generate the genome or exome sequence of 
that specimen). Biospecimens will not be used for commercial profit. Clinically relevant research results, 
including individual research results may be available to participants at their request but such request will be 
granted under the discretion of the study doctor. Participants may be contacted in the future by the study 
team for future studies. 
 
Data shared with the National Institute of Mental Health Data Archive (NDA) will maintain patient 
confidentiality by ensuring exclusion of all 18 identifiers (outlined by HIPAA) prior to data sharing.
Will the study be conducted under a certificate of confidentiality?
Yes, we have already received a Certificate of Confidentiality
Direct Benefits to Subjects  
Direct Benefits to Subjects
There is no direct benefit to subjects. If L-DOPA treatment is effective in ameliorating slowing, subjects 
may experience improved quality of life and decreased of falls and other sequelae of slowing.
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.
All subjects who complete a screening visit will be reimbursed $35. 
 
Eligible depressed subjects (N=60), will be reimbursed $150 for cognitive/motor assessment sessions, paid 
cash at the end of each visit. 
$100 per MRI (2 MRI scan), and $200 per [18F]-FDOPA PET scan. This equates to $585 per depressed 
participant. This money will be paid in 1 lump sum payment at the end of the study. Payments 
typically require 1-3 weeks to process and will be mailed in the form of a check.
 
Eligible Non-depressed control subjects (N=30) will be reimbursed $50 for cognitive/motor assessment 
session, paid cash at the end of each visit.
$100 for MRI (1 MRI), and $200 for [18F]-FDOPA PET scan. This equates to $385 per control 
participant. This money will be paid in 1 lump sum payment at the end of the study. Payments 
typically require 1-3 weeks to process and will be mailed in the form of a check.


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SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan 
1/2 - Dopaminergic Dysfunction in Late-Life Depression (The D3 Study) 
IRB #7976 
NCT #04493320 
Date: 10/03/19 
 
 


C.11. DATA ANALYSES: We will examine variables for illegitimate values and outliers. The 
distribution of demographic variables and baseline characteristics will be examined across LLD 
(N=120) and never-depressed elder (NDE) subjects (N=60) as means, standard deviations, 
proportions, and 95% confidence intervals. As a precaution, indications of inequality between 
diagnostic groups (Aim 1) or the L-DOPA and placebo groups (Aim 2) in specific features (despite 
randomization) will trigger examination of whether differences in primary outcome measures may 
be attributed to group imbalances on background characteristics. For all analyses, significance 
tests will be reported after Benjamin-Hochberg adjustment controlling for FDR at level 0.05. 
 
Analyses for Aim 1: By design the LLD and NDE subjects will be age and gender distribution 
matched. All analyses will control for site (2 sites). Hyp 1: The EEfRT analytic procedures will 
output data on the proportion of high-effort choices made, the relative influence of reward 
magnitude on making high-effort choices, and neural activations in the PFC and striatal ROIs. 
Depressed and never-depressed groups will be compared on these measures using linear 
regression models with group membership (LLD vs. NDE) as the primary predictor. In sensitivity 
analyses, NDE participants will be categorized as slowed (gait speed <1m/s) or non-slowed, and 
between-group comparisons will be performed to test LLD subjects vs. NDE-slow and NDE-non-
slow groups. Hyp 2: Combining data from both LLD and NDE subjects, linear regression will 
assess associations between dopamine measures (specifically [18F]-FDOPA relative influx rate 
[Kocc in striatal ROI], [18F]-fallypride binding [BPND in midbrain and striatal ROIs], and mean NM-
MRI signal intensity in the SNc) and primary RDoC outcome measures (behavioral/neural 
activation measures from the EEfRT, the processing speed latent factor, the NIH-EXAMINER 
Executive Composite score, and ST gait speed). Separate regressions will be fit for each of the 
RDoC outcome measures, including the different dopamine imaging measures as simultaneous 
predictors while controlling for demographics, site, and group status. Similar regression analyses 
will examine associations between the dopamine imaging measures and the first-level MIDT 
measures (i.e., neural activations on the anticipation and receipt of monetary reward contrasts 
in a priori ROIs), secondary cognitive outcomes, and secondary physical performance outcomes. 
Hyp 3: To further assess the degree to which slowing is a key pathway leading to the LLD 
phenotype, linear regression will test associations between the processing speed latent factor, 
NIH-EXAMINER Executive Composite score, ST gait speed, and the probability of choosing the 
HC/HR option on the EEfRT.  
Analyses for Aim 2: Randomization in Aim 2 will be stratified by site, and analyses will adjust 
for site effects. Analyses will occur on an intention-to-treat basis. Dropouts and Missing 
Data/Imputation: Based on the preliminary studies, we expect that missingness will be minimum. 
Nonetheless, missing data will be imputed using multiple imputation. We will conduct sensitivity 
analyses to explore the impact of missing data via pattern mixture models (e.g., by investigating 
robustness of results to perturbations of assumed values for missing data within implausible 
clinical ranges). Hyp 1: ANCOVA models will test for treatment group differences in the change 
in each outcome between baseline and Week 3. Outcomes include behavioral data and neural 
activations from fMRI tasks as above, cognitive measures, and motor function tests. Hyp 2: We 
will use linear regression to estimate and test the effect modification of baseline PET/NM-MRI 
measurements ([18F]-FDOPA relative influx rate, [18F]-fallypride binding, and NM-MRI CNR in 
SNc) on L-DOPA’s effect on each outcome. Specifically, the change in each outcome measure 
will be regressed on treatment group, baseline value of the outcome, each baseline PET/NM-MRI 


measurement, and the interaction of treatment and each PET/NM-MRI measurement. The 
modification effect will be tested by the significance of the interaction effect.