Conditions: Major Depressive Disorder Dysthymia Depression
Keywords: Depressive symptoms Cognitive problems Antidepressant non-response Dopamine system Older Adults Motor slowing
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
Individuals with Late Life Depression (LLD) often have cognitive problems, particularly problems with memory, attention, and problem solving, all of which contribute to antidepressant non-response. Our group and others have shown that decreased thinking speed is the central cause of functional problems in patients with LLD. Similarly, decreased walking speed is associated with depression and carries additional risk for falls, hospitalization, and death. Available evidence suggests that declining functionality in the brain's dopamine system contributes to age-related cognitive and motor slowing. The central hypothesis of this study is that by enhancing dopamine functioning in the brain and improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms in older adults.

Detailed description:
Enrolled participants were aged 60 and older with (1) a DSM 5 depressive disorder, (2) significant depressive symptoms, and (3) decreased thinking or walking speed will receive 8 weeks of treatment with L-DOPA up to 450mg. We will test whether L-DOPA increases brain dopamine release using neuroimaging and whether it speeds up thinking and walking speed. Data collected in the proposed studies may help identify a new treatment for LLD, which could have large public health ramifications given the prevalence, frequent treatment resistance, and chronicity characteristic of LLD. This project also will elucidate the neurobiology of slowing at molecular, structural, and functional levels of analysis, increasing our understanding of the interplay between these aging-associated processes and the pathophysiologic changes underlying late life neuropsychiatric disorders. Exploring patient characteristics that predict response to L-DOPA may provide useful information to guide differential therapeutics and develop personalized medicine for LLD.

Arms:
arm 1: Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose arm 2: Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study.

Interventions: intervention 1: L-DOPA intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: We will be using generic sinemet 25/100 tablets in this study. intervention 2: 25/100 placebo tablets

Protocol document:
ICF_002.pdf: 
Subject Consent Form 
IRB #7733 
v. 11/23/18 
 
1 
 
NEW YORK STATE PSYCHIATRIC INSTITUTE 
L-DOPA VS. PLACEBO FOR DEPRESSION AND PSYCHOMOTOR SLOWING 
IN OLDER ADULTS 
 
Overview 
Below is a summary of the study in which you are asked to participate. 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.  
 
Participation is Voluntary 
As with all research, this is a voluntary study, and you do not have to participate if 
you do not want to. Also, you may stop participating at any time. 
 
Alternatives 
You do not have to participate in this study to receive treatment for depression 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 medication classes are effective in the 
treatment of depression. Additionally, evidence based psychotherapies 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 
x
At the beginning of the study, you will be given a physical examination, an 
electrocardiogram (EKG), and have your blood drawn. 
x
Next you will have tests of your memory, concentration, and other thinking 
skills as well as a test of your walking speed. 
x
One third of subjects in this study will undergo two (2) magnetic resonance 
imaging (MRI) scans of the brain and two (2) positron emission 
tomography (PET) scans of the brain. You may be offered participation in 
the treatment portion of the study if you are not eligible or do not wish to 
have MRI and PET scans. 
x 
MRI scans use strong magnetic fields and radio waves to take pictures of  
your brain. 
x 
The PET scans require placement of an IV catheter and injection of a 
radioactive substance called [11C]-raclopride. [11C]-raclopride allows us to 


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2 
 
examine dopamine receptors in the brain which are important in some 
psychiatric diseases such as depression. 
x 
In the treatment part of the study, you will be randomly assigned to receive  
treatment with a medication called carbidopa/levodopa (Sinemet) or pill 
placebo (a sugar pill) for 8 weeks. 
x
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. 
x
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). These include the risk that your 
depression may worsen while you take an experimental medication such as 
carbidopa/levodopa or if 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 [11C]-raclopride 
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. 
 
 


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IRB #7733 
v. 11/23/18 
 
3 
 
PURPOSE OF STUDY 
The purpose of this research study is to test whether a medication called 
carbidopa/levodopa (Sinemet) is helpful for the treatment of depression in older adults. 
Carbidopa/levodopa is approved by the Food and Drug Administration for the treatment 
of Parkinson’s Disease. We are using carbidopa/levodopa off-label in this study to see 
whether it is capable of improving depressive symptoms as well as mental and physical 
slowing that occur as people age.  
 
In this study you may also be offered brain scans using magnetic resonance 
imaging (MRI) and positron emission tomography (PET). We are performing these scans 
to understand more about how Sinemet works in the brain. The PET scan involves the use 
of a radioactive investigational drug called [11C]-raclopride. It is an investigational drug 
that attaches to 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 
[11C]-raclopride. You will also be asked to take the drug carbidopa/levodopa so that the 
PET techniques can measure the impact of this drug on 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 included exercise programs and 
cognitive training. 
 


Subject Consent Form 
IRB #7733 
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4 
 
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 speed measured. 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 one hour to complete. The results of these tests are for 
research purposes only and will not be shared with you. 
 
Based on these tests, it will be determined whether you are eligible for the 
treatment portion of the study. If you are not eligible, you will be referred to appropriate 
options for further treatment. If you are eligible and continue to wish to participate, you 
will proceed with the next part of the study.  
 
MRI scans: Some of the participants in this study will be offered participation in 
brain imaging procedures. If you are otherwise eligible, you may participate in the 
treatment portion of the study if you are not eligible or do not wish to have MRI and PET 
scans. If you have brain imaging performed, you will have an MRI scan at the beginning 
of the study (before you receive any carbidopa/levodopa or placebo) and again at the end 
of the study (after you have taken carbidopa/levodopa or placebo for eight weeks). 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 60 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 scans: Individuals having brain imaging will also receive two PET scans, one 
at the beginning of the study (before you receive any carbidopa/levodopa or placebo) and 
again at the end of the study (after you have taken carbidopa/levodopa or placebo for eight 
weeks).  On the PET scan day, we will ask you not to eat from 6 am until the study is over. 


Subject Consent Form 
IRB #7733 
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5 
 
We will also ask you not to drink caffeinated beverages, such as coffee, tea, and soda, that 
day. 
 
For the PET scans, 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 both scans, we will ask you to lie on the 
narrow table. We will also position your head with a chin strap or a polyurethane 
headholder 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 [11C]-
raclopride through the catheter in your arm.  
 
Each 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. The 
second PET scan performed at the end of the study (eight weeks after the first PET scan) 
will be done identical to the first scan. However, approximately 90 minutes before we 
give the second [11C]-raclopride dose, we will ask you to take a pill by mouth. If you 
were assigned to receive carbidopa/levodopa in the clinical portion of the study, then this 
pill will contain carbidopa/levodopa. If you were assigned to receive placebo in the 
clinical portion of the study, then this pill will contain placebo. 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.   
 
Treatment study: In the treatment portion of the study, 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 treatment with the starting dose of 
carbidopa/levodopa (37.5mg/150mg). This dose will be increased over the course of 
approximately 3 weeks to the final dose of carbidopa/levodopa 112.5mg/450mg. This 
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. 
 
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.  


Subject Consent Form 
IRB #7733 
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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. During this week 8 
visit, you will again fill out some psychological tests and have your walking speed 
measured.  
 
As part of the study assessments, you will be asked to wear a wristband that keeps 
track of your physical activity levels (such as the number of steps you take per day, 
similar to a “Fitbit”). Members of the research team will download the activity logs from 
your wristband at each visit. At the end of the 8 week study, you will return the wristband 
monitor to the research staff. 
 
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 
 
The main risk to your participation in this study is that carbidopa/levodopa is an 
experimental treatment for depression, and it is not known yet whether it will be effective 
in treating symptoms of depression. In addition, there is a chance you will be assigned to 
receive placebo and will not receive actual 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. 
 
MRI risks: While there have been no reports of any harmful long-term effects 
caused by 3 Tesla (a measure of the magnetic field strength) magnets or magnets of even 
higher strength, the long-term effects of being placed in a magnet of this strength are 
unknown. Also, although there are no known risks associated with pregnancy, we will not 
scan someone who is pregnant. If you are a female in your childbearing years, you will be 
asked to take a pregnancy test to ensure that you are not pregnant. 
 


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IRB #7733 
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Some people have reported sensations during MRI scans with the 3T magnet, 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. With any MRI scan, 
on occasion, some people experience nervousness or discomfort due to the scanner's 
small space and the need to lie still. Except for pacemakers, some types of metallic 
implants, and medication patches, we are not aware of any other potentially dangerous 
interactions or hazards associated with the MRI scan. The MRI scanner also produces a 
loud noise; earplugs will be provided to reduce this discomfort. If you experience any 
discomfort and wish to stop the scan, you can tell the MRI technologist, and he or she 
will stop the scan immediately. In our experience, no one has had sensations from the 
MRI that did not stop when the scanning stopped. 
 
PET risks: This research study involves exposure to radiation from Positron 
Emission Tomography (PET). Please note that this radiation exposure is not necessary for 
your medical care and is for research purposes only. The radiation you will receive in this 
study is from two [11C]-raclopride scans and from CT transmission scans of your head 
used to help obtain the PET images. 
 
 The procedures involving radiation in this research study will expose you to a 
small amount (6.616 mSv) of radiation in addition to the amount that you might receive 
from your normal medical care. There may be an increase in the chances of your 
developing cancer many years after this study. The additional risk from this research 
study is less than 0.1%. At this very low level, scientists are uncertain as to the actual risk 
from research 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. 
 
Carbidopa/levodopa risks: 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.  
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. 


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IRB #7733 
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8 
 
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%.  
 
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 scan 
you may have as part of this study is for research purposes only. This means that the 
scans are not designed to provide clinical information that might be helpful to you or 
your doctor and they may not show problems that would normally be found in an MRI 
ordered to evaluate a specific medical problem. 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 and will only be available to the 
research staff and institutional personnel as part of routine audits. Representatives of the 
state and institutional regulatory personnel may review your records to ensure 
compliance with study design. There are legal advocacy organizations that have the 
authority under State Law to access otherwise confidential records, though they cannot be 
redisclosed without your consent. All records will be kept confidential to the extent 
permitted by law. Your name and other personal identifying information will be stored in 
an electronically secure database at New York State Psychiatric Institute. Electronically 
stored data will be accessible only by password known to the study investigators and 
research assistants. The results of your MRI scan also will be maintained in an 


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9 
 
electronically secure database at NYSPI and accessible only to the members of the 
research team. 
 
 
Data from this study may 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. 
 
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. We offer reasonable compensation for travel costs related to your 
study participation. You must bring in receipts for these costs, and compensation is 
limited to no more than $10 per week. 


Subject Consent Form 
IRB #7733 
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10 
 
 
To compensate you for the time required for each weekly study visit, we offer $15 
for each weekly study visit ($135 total if you attend all visits). 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 $50 for each 
MRI scan and $150 for each PET scan ($400 total if you attend all visits). 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 $135 for participants 
attending all study visits and not doing neuroimaging. The maximum compensation will 
be $535 for participants attending all study visits and all neuroimaging procedures. 
 
RESEARCH STANDARDS 
Federal regulations require that we inform participants about our institution's 
policy with regard to compensation and payment for treatment of research-related 
injuries.  
 
If you believe that you have sustained an injury as a result of participating in a 
research study, you may contact the Principal Investigator at 646-774-8660 so that you 
can review the matter and identify the medical resources that may be available to you. 
 
Please be aware that: 
1. 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 


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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
7733
Rutherford, Bret
Page 1 of 42
Protocol Title:
L-DOPA vs. Placebo for Depression and 
Psychomotor Slowing in Older Adults
Protocol Number:
7733
First Approval:
N/A
Expiration Date:
Not yet accepted
Version Date:
11/28/2018
Clinic:
Adult and Late Life Depression
Contact Principal Investigator:
Bret Rutherford, MD
Email: brr8@columbia.edu
Telephone: 646 774 8660
Co-Investigator(s):
Patrick Brown, PHD
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 Division/Department does the PI belong to?
Neurobiology and Therapeutics of Aging
Within the division/department, what Center or group are you affiliated with, if any? 
Neurobiology and Therapeutics of Aging
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.
Anissa Abi-Dargham, MD


Protocol Summary Form
7733
Rutherford, Bret
Page 2 of 42
Stony Brook University
Mark Slifstein, PhD
Stony Brook University
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
Off-label Use of Drug or Device
Population
Indicate which of the following populations will be included in this research
Adults over 50
Research Support/Funding
Will an existing internal account be used to support the project?
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 is currently funded
Source of Funding
Federal
Institute/Agency


Protocol Summary Form
7733
Rutherford, Bret
Page 3 of 42
NIMH
Grant Name
Targeting Dopaminergic Mechanisms of Slowing to Improve Late Life Depression
Grant Number
R61 MH110029
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
Stony Brook University
Study Location
Indicate if the research is/will be conducted at any of the following
NYSPI
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research
Lay Summary of Proposed Research
Individuals with Late Life Depression (LLD) often have cognitive problems, particularly problems with
memory, attention, and problem solving, all of which contribute to antidepressant non-response. Our group
and others have shown that decreased thinking speed is the central cause of functional problems in patients
with LLD. Similarly, decreased walking speed is associated with depression and carries additional risk for
falls, hospitalization, and death. Available evidence suggests that declining functionality in the brain's
dopamine system contributes to age-related cognitive and motor slowing. The central hypothesis of this
R61/R33 Phased Innovation Award is that by enhancing dopamine functioning in the brain and
improvingcognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve
depressive symptoms in older adults.
This IRB protocol pertains to the R33 Phase of this grant proposal (R61 Phase was approved under IRB
#7270). In the R33 Phase 90 adults aged > 60 years with (1) a DSM 5 depressive disorder, (2) significant
depressive symptoms, and (3) decreased thinking or walking speed will receive 8 weeks of treatment with


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L-DOPA up to 450mg. We will test whether L-DOPA increases brain dopamine release using neuroimaging 
and whether it speeds up thinking and walking speed. Data collected in the proposed studies may help 
identify a new treatment for LLD, which could have large public health ramifications given the prevalence, 
frequent treatment resistance, and chronicity characteristic
of LLD. This project also will elucidate the neurobiology of slowing at molecular, structural, and functional 
levels of analysis, increasing our understanding of the interplay between these aging-associated processes 
and the pathophysiologic changes underlying late life neuropsychiatric disorders. Exploring patient 
characteristics that predict response to L-DOPA may provide useful information to guide differential 
therapeutics and develop personalized medicine for LLD.
Background, Significance and Rationale
Background, Significance and Rationale
LLD affects 3% of community-dwelling adults over 60 years old (1), and 15% of older adults have
clinically significant depressive symptoms (2). LLD increases an older adult’s risk of disability by 67-73% 
over 6 year follow up (26), causes twice the functional impairment compared to those without LLD (27), 
increases mortality in patients with heart disease, and is associated with high rates of completed suicide in 
individuals over 65 (28-29). LLD is highly recurrent, can become chronic (30), and is often difficult to treat 
(31).
 
Executive Dysfunction (ED) is common in patients with LLD, predicts poorer acute response to
antidepressants, and is associated with higher relapse rates during the continuation phase (5,32-33). Among 
the executive functions disturbed in LLD, decreased processing speed has been called “the core cognitive 
deficit (8,34).” Processing speed mediates performance on measures of verbal reasoning, fluency, and 
knowledge (35), and measures of working memory primarily depend upon speed of processing (36). 
Decreased processing speed has been repeatedly found in patients with LLD relative to healthy controls (8) 
and mediates the effects of depression and ED on daily functioning (7). The development of decreased 
processing speed places older individuals on a trajectory of poor outcomes, including increased risk of 
dementia (37), dependence in activities of daily living (ADL) (38), and driving cessation (39).
 
Less well recognized is the fact that depressed older adults also experience motor performance deficits,
including problems with coordination (14), slowed movement (15), and difficulties with balance and gait 
(16). Depressive symptoms lead to the development of decreased gait speed, and slowed gait speed leads to 
incident depression in older adults (12-13). Decreased gait speed has been associated with a greater risk of 
falls (40-42), disability (14), admission to the hospital (16,43), and all-cause as well as cardiovascular 
mortality (44-45). While LLD and decreased gait speed are each independent risk factors for adverse health 
outcomes, their comorbidity synergistically increases mortality risk in older adults (46). For these reasons 
gait speed has become a fifth “vital sign” to be monitored in older adults, and it merits increased attention 
by mental health specialists treating LLD.
 
Post-mortem experiments and in vivo neuroimaging studies have shown that aging is associated with
reduced dopamine levels, decreased D1/D2 receptor density, and loss of dopamine transporters (DAT) (17-
21). Mesolimbic dopaminergic tone modulates processing speed in both humans and animal models (47), 
and decreased striatal dopamine transmission has been associated with decreased motor speed (48), 


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deterioration in frontal functioning (23), and impaired balance (49). Cham et al (2008) examined gait speed 
and dopamine metabolism in healthy adults aged 21-85 years, finding that lower striatal DAT activity was 
associated with decreased gait speed and explained 23% of the variance in gait after controlling for other 
factors (50). These age-associated declines in dopaminergic functioning are topographically distinct from 
the denervation pattern typical of Parkinson’s disease (PD), being observed diffusely across the striatum 
rather than predominantly posterior putaminal in location (51-3). While subtle Parkinsonian-like phenomena 
may be observed with normal aging, the non-specific slowing associated with aging is clinically distinct 
from the signs and symptoms of PD. Thus, the hypodopaminergic state associated with aging and LLD has a 
distinct neurobiology from PD and appears to represent a parallel pathway to developing cognitive and 
motor deficits.
 
Pharmacologic augmentation of dopaminergic neurotransmission may ameliorate slowing and treat LLD. 
Studies in non-human primates as well as older adults with and without PD suggest that dopamine receptor 
agonism improves working memory (54), verbal fluency (55), problem-solving (56), and motor 
performance related to ADLs (57). Since slowed processing speed and gait predict the development of LLD 
and mediate a large portion of the disability associated with LLD, it is reasonable to hypothesize that 
improving slowing will positively impact LLD. Multiple case series from the 1960s onward report improved 
depressive symptoms (particularly psychomotor retardation) with levodopa (hereafter referred to as L-
DOPA) monotherapy or augmentation (58-61). L-DOPA is the immediate precursor of dopamine, is 
converted to dopamine in presynaptic dopaminergic nerve terminals, and enhances dopaminergic 
transmission in multiple brain regions. L-DOPA has been reported to relieve depressive symptoms in new 
onset PD, improving symptoms in 90.3% of patients (N=31) and resulting in a mean Hamilton Rating Scale 
for Depression (HRSD) decrease of 11.7 points in one study (62). Relatedly, augmentation with 
methylphenidate, which also increases synaptic dopamine levels, was recently shown to accelerate and 
enhance antidepressant response in depressed older adults (63).
 
Despite these promising results, negative studies of L-DOPA, stimulants, and dopamine agonists as
monotherapies and augmentation agents for depression also have been reported (64). One reason for these 
heterogeneous results is the different diagnostic criteria and experimental methodology used in older 
studies, which makes their results difficult to interpret. More importantly, no study examining dopamine 
augmentation as a treatment for depression selected subjects based upon the presence of decreased 
processing and gait speed. If the mechanism by which enhancing synaptic dopamine relieves depressive 
symptoms is by improving slowing, then including patients without slowing may contribute to negative 
results. By focusing on the subgroup of patients with LLD and slowing, we believe it will be possible to 
more clearly demonstrate the efficacy of dopaminergic agents and contribute to the development of 
personalized medicine for LLD.
 
Three types of interventions may be considered to enhance dopaminergic function and ameliorate slowing: 
dopamine receptor agonists (e.g., piribedil, pramipexole, ropinirole), stimulants (methylphenidate and 
amphetamine derivatives), and dopamine precursors such as L-DOPA. Among these options, L-DOPA 
enhances dopaminergic neurotransmission globally, including increasing vesicular storage, enhancing 
release, and stimulating post-synaptic receptors. In contrast, stimulants may not increase synaptic dopamine 
in individuals with diminished vesicular storage, and dopamine agonists may have reduced effects in older 
patients having fewer post-synaptic receptors. Moreover, a large literature shows beneficial effects of 
LDOPA on cognitive performance and gait in patients with PD (65-67), whereas the few available studies in 


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elderly patients show minimal effects of dopamine agonists (68-70) or stimulants (71) on cognition. 
LDOPA, especially at lower doses, is a safe and well-tolerated medication that is difficult to differentiate 
from placebo in terms of side effects (72). In contrast, a black box warning for adverse cardiac effects exists 
for stimulants, and even modest elevations in heart rate and blood pressure may significantly increase 
cardiac work in older patients. Similarly, dopamine agonists are associated with sleep attacks and increased 
impulsive behavior. For these reasons, this proposal focuses on L-DOPA as the safest, most promising 
pharmacologic agent for the treatment of slowing and LLD.
 
This study will elucidate the neurobiology of slowing and LLD, identify a novel therapeutic target for
depression, and contribute to the development of personalized treatment regimens for LLD. The multimodal 
neuroimaging methods detailed in this application will provide information about the neurobiology of 
aging-associated slowing and LLD at molecular, structural, and functional levels of analysis. These data will 
fill a crucial gap in our knowledge regarding what are the physiologic and functional consequences of 
dopamine depletion occurring across the lifespan in individuals without PD. Results from this project also 
will allow us to evaluate a novel therapeutic approach to LLD, which could have large public health 
ramifications given the prevalence, frequent treatment resistance, and chronicity characteristic of LLD. 
Even apart from patients with LLD, cognitive and motor slowing exact a large public health burden in terms 
of impaired functioning and increased morbidity and mortality, and this burden will only grow as the 
population ages. It is critical to develop treatments capable of altering the negative health trajectories 
associated with slowing in order to help older adults maintain independent functioning and live longer with 
an increased quality of life. Finally, while PET and MRI may prove critical to understand the neurobiology 
of slowing and LLD, their invasiveness and expense limit their roles in informing treatment decisions in 
clinical practice settings. For this reason we are also assessing the influence of genetic moderators such as 
interleukin-6 (IL-6) and catechol-O-methyl-transferase (COMT) genotype on baseline dopamine 
functioning and response to L-DOPA. This may facilitate the identification of both high-risk individuals and 
those most likely to benefit from treatment interventions.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
We hypothesize that treatment with levodopa (L-DOPA) will improve depressive symptoms in LLD by
enhancing striatal dopamine release and improving cognitive/motor slowing. In the R33 Phase, 90 adults 
aged > 60 years with (1) a DSM 5 depressive disorder, (2) significant depressive symptoms (CES-D > 10), 
and (3) decreased processing speed (0.5 SD below age-adjusted norms on the Digit Symbol Test or Trails 
A) or decreased gait speed (average walking speed over 15’ course < 1m/s) will be receive 8 weeks of 
treatment with LDOPA 450mg. Subjects will be tested for engagement of molecular target by determining 
whether subacute (8 week) treatment with L-DOPA displaces [11C]-raclopride on positron emission 
tomography (PET). 
 
R33 Phase. 
 
Aim 1: To determine whether L-DOPA improves depressive symptoms in older adults. 
 


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Hypothesis 1: Compared to placebo, L-DOPA administration will result in greater improvements in 
depressive symptoms (as measured by HRSD scores). 
 
Hypothesis 2: Greater post-L-DOPA decreases in [11C]-raclopride BP and increases in processing/gait 
speed will be associated with greater depressive symptom improvement. 
 
Exploratory aims: To explore the role of inflammatory markers and Catechol-O-methyl-transferase (COMT) 
genotype in moderating L-DOPA induced changes in slowing and depressive symptoms.
 
Description of Subject Population
Sample #1
Specify subject population
adults aged >59 years with a depressive disorder, decreased processing speed, or decreased gait speed
Number of completers required to accomplish study aims
68
Projected number of subjects who will be enrolled to obtain required number of completers
90
Age range of subject population
60 years or older
Gender, Racial and Ethnic Breakdown
On the basis of previous depression studies conducted in the Adult and Late Life Depression Research
Clinic, it is anticipated that the sample will be composed of 60% women and 40% men as well as
approximately 75% Caucasian, 15% African American, and 10% Hispanic subjects.
On the basis of previous depression studies conducted in the Adult and Late Life Depression Research 
Clinic, it is anticipated that the sample will be composed of 60% women and 40% men.
Description of subject population
This phase will enroll 90 outpatients who (1) are aged ≥ 60 years, (2) diagnosed with Diagnostic and
Statistical Manual (DSM) 5 (107) MDD, Dysthymia, or Depression Not Otherwise Specified (NOS), (3) 
have Center for Epidemiologic Studies-Depression Rating scale (CES-D) (108) score ≥ 10, (4) have 
decreased gait speed (defined as average walking speed over 15’ course < 1m/s) or decreased processing 
speed (defined as 1 SD below age-adjusted norms on the Digit Symbol Test), and (5) are willing to and 
capable of providing informed consent and complying with study procedures.
 
Exclusion criteria are (1) diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) 
within the past 12 months, (2) history of psychosis, psychotic disorder, mania, or bipolar disorder, (3) 
diagnosis of probable Alzheimer’s Disease, Vascular Dementia, or PD, (4) Mini Mental Status Examination 
(MMSE) ≤ 24 (109), (5) HRSD suicide item > 2 or Clinical Global Impressions (CGI)-Severity (110) score 


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of 7 at baseline, (6) current or recent (within the past 4 weeks) treatment with antidepressants, 
antipsychotics, or mood stabilizers, (7) history of allergy, hypersensitivity reaction, or severe intolerance to 
L-DOPA, (8) any physical or intellectual disability adversely affecting ability to complete assessments, (9) 
acute, severe, or unstable medical or neurological illness, (10) mobility limiting osteoarthritis of any lower 
extremity joints, symptomatic lumbar spine disease, mobility limiting history of joint replacement surgery, 
or history of spine surgery, (11) having contraindication to MRI scanning (such as metal in body) or unable 
to tolerate the scanning procedures, (12) history of significant radioactivity exposure (nuclear medicine 
studies or occupational exposure), and (13) presence of a clinically significant brain abnormality.
Recruitment Procedures
Describe settings where recruitment will occur
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, 
advertisements in local newspapers and on radio stations, information posted on departmental websites, and 
flyer mailings. 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? 
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? 
Advertisements will include research flyers and brochures posted around CUMC, advertisements in local
newspapers and on radio stations, and information posted on departmental websites. Advertisements will
also include research flyers mailed out individuals whom will primarily come from consumer marketing
databases, which are compiled using public information, surveys, subscription information, home owner
information, and phone directory information.
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.


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Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Subjects completing IRB #6836 (Rutherford PI) who meet the selection criteria for this study will be offered 
participation. Additionally, subjects who are currently participating in #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
Patients
Create or insert table to describe the inclusion criteria and methods to ascertain them
 Criterion
 Method of 
Ascertainment
1. Age >59 years 
 1. Interview
2. DSM 5 non-psychotic Major Depressive Disorder, 
Dysthymia, or Depression Not Otherwise Specified 
 2. Clinical 
interview and 
SCID
3. Center for Epidemiological Studies Depression (CES-D) 
Rating Scale >9 
 3. CES-D
4. decreased processing speed (defined as performance > 
0.5SD below age-adjusted norms on Digit Symbol 
Substitution Test or Trail Making Test Part A) OR 
decreased gait speed (defined as average walking speed 
over 15’ course < 1m/s) 
 4. Digit Symbol 
Substitution 
Test, Trails A, 
timing of 
walking speed
5. willing to and capable of providing informed consent 
and complying with study procedures 
 5. Clinical 
interview
6. Alternative standard treatments for MDD, 
Dysthymia, or Depression NOS (e.g., antidepressant 
medication or psychotherapy) 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
 Criterion
Method of Ascertainment 


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1. diagnosis of 
substance abuse
or dependence 
(excluding 
Tobacco Use
Disorder) within 
the past 12 
months 
 1. Clinical interview and SCID
2. history of or 
current 
psychosis, 
psychotic 
disorder, mania, 
or bipolar 
disorder 
 2. Clinical interview and SCID
3. diagnosis of 
probable 
Alzheimer’s 
Disease,
Vascular 
Dementia, or PD 
3. Clinical interview, MMSE for AD and VD. 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 the 
LLDC
(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), Dr. Nora Vanegas-Arroye (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 neurologic work up.  
4. Mini Mental 
Status Exam
(MMSE) < 25 
 4. MMSE
5. Total HRSD ≥ 
25, HRSD 
suicide item>2, 
or the
presence of 
significant
suicide risk as 
judged by 
clinician. 
pasting. HRSD 
suicide item > 2 
 5. Clinical interview, HRSD, CGI  


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or Clinical 
Global 
Impressions 
(CGI)-Severity 
score of 7 at 
baseline.
6. current or 
recent (within
the past 4 
weeks) treatment 
with 
antidepressants,
antipsychotics, 
dopaminergic
agents, or mood 
stabilizers 
 6. Clinical interview
7. history of 
allergy,
hypersensitivity 
reaction, or
severe 
intolerance to L-
DOPA 
 7. Clinical interview
8. acute, severe, 
or unstable
medical or 
neurological
illness 
 8. Clinical interview, physical exam, EKG
9. mobility 
limiting 
osteoarthritis of 
any lower 
extremity joints, 
symptomatic 
lumbar spine
disease, mobility 
limiting history 
of joint 
replacement 
surgery, or 
history of spine 
surgery 
 9. Clinical interview, physical exam
 FOR 
SUBJECTS 
 


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RECEIVING 
PET/MRI 
SCANS ONLY:
10. having 
contraindication 
to MRI scanning 
(such as metal in 
body) or unable 
to tolerate the 
scanning 
procedures 
 10. MRI safety screening form
11. history of 
significant 
radioactivity 
exposure 
(nuclear 
medicine studies 
or occupational
exposure) 
 11. Clinical interview
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 the study screening procedures, a study clinician authorized to obtain patient consent will explain 


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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
Roose, Steven, MD
Rutherford, Bret, MD
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
Evaluation
1. Every subject evaluated for this protocol will receive a clinical interview by a psychiatrist or
psychologist. 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 a neurologist. Additional assessments will be administered by a
trained rater (BA, RN, or SW) in the LLDC, including the Center for Epidemiologic Studies Depression
Scale (CES-D) and the 24-item Hamilton Rating Scale for Depression (HRSD), and have a SCID performed
by a trained rater. If a subject has a diagnosis of Major Depressive Disorder (MDD) or Dysthymia, 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 and/or prefers to begin with an experimental treatment for slowing and
depression, he/she will be offered participation in the present study provided their HRSD < 25 and there is
no suicidal ideation present. Severe MDD (i.e., HRSD ≥25) and/or the presence of significant suicide risk
(e.g., HRSD suicide item > 2, clinician judgement that there is significant risk of suicide) are exclusions for
this study. Patients with Depression NOS will be educated that as yet, there are no FDA-approved
treatments for their condition. Based on the extant data supporting the efficacy of antidepressants for MDD
and Dysthymia, 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.


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2. Next, trained raters (BA, RN, or SW) in the LLDC will assess processing speed using Digit Symbol test 
from the WAIS-III, the Trail Making Test Part A, the Pattern Comparison Test, and the Letter Comparison 
Test. Previous research established that these tests were all reliable and valid (moderate to high loadings on 
the latent speed factor). Digit Symbol or Trails A will be used as a selection criterion, with patients included 
in this study if they scored 0.5 SD below the age-adjusted norms on Digit Symbol or Trails A. A latent 
factor (and subsequent factor score) will be extracted from the 3-test battery pre- and post-treatment and 
used as the main outcome in this pilot study. By extracting a latent factor and factor loadings we will utilize 
a more pure measure of processing speed for pre- post-testing than if we used the raw scores from an 
individual test or a sum total score from the three raw scores combined.
 
3. 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) (112) 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 (113).
 
5. Baseline markers of inflammatory status will be added to the serum assessments detailed above, 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”) (151). 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 (152). 
 
6. Other neuropsychological measures completed at baseline include trained study rater (BA, RN, SW) 
assessment of episodic memory functioning using the Wechsler Memory Scale Logical Memory Test I & II 
(153). Inclusion of this test will allow us to identify deficits in episodic memory functioning consistent with 
a classification of amnestic mild cognitive impairment (aMCI) (7). Executive function will be assessed 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. Confirmatory factor analysis supports both a one-factor model and 


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a three- factor model, and these models formed the basis for an Executive Composite score and subscales 
scores for Working Memory, Cognitive Control, and Fluency.
 
7.  Domains of function assessed by trained study raters (BA, RN, SW) at baseline include: the Short 
Physical Performance Battery (SPPB) (156), 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) (157). The self-report 38-item Measure of Everyday Cognition (ECog) is adapted from an 
informant-report version and measures impairment and change in domains of everyday/real-world 
functioning relevant to 7 specific neuropsychological domains (158). 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 (159-160).
 
8. Finally, aliquots of peripheral blood will be frozen for subsequent DNA isolation and determination of  
interleukin-6 (IL-6) and catechol-O-methyl-transferase (COMT) genotype. These genotypes will be 
analyzed in exploratory analyses to determine their effects on baseline dopamine functioning and response 
to L-DOPA. 
MRI Scanning
 
9. N=30 subjects of the total N=90 sample will undergo neuroimaging. The first 30 subjects who are 
eligible/safe for PET/MRI procedures and are willing to be scanned will be offered participation in these 
procedures. Subjects who are not willing or able to participate in the PET studies will be offered 
participation in the MRI studies. These subjects will undergo a pretreatment MRI and PET scan and a post-
treatment MRI and PET scan (i.e., 2 total MRIs, 2 total PET scans, separated by the 8 week clinical trial). 
Subjects who do not meet imaging selection criteria or who do not wish to undergo scanning will be allowed 
to participate in the clinical trial portion of the study only. MRI and PET scanning 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 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.
 
10. MRI of the brain will be acquired using a GE Premier 3.0T System. At the start of the session, a 3-Plane 
localizer (scout) will be acquired to determine patient position. Subjects will then receive T1-weighted 3D 
SPGR (Spoiled Gradient Echo), T2 FLAIR, and EPI scans. Acquisition parameters for the EPI scans will 
be: TE/TR (ms) 20/2000; Flip Angle (deg) 72o; in-plane resolution (voxels) 112x112; slice thickness/gap 
(mm) 3/0; slices 41.
 
11. For 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 60 minutes. 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


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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
12. The neuroimaging subset of depressed subjects will have 2 [11C]-raclopride PET scans: (1) pre-
treatment and (2) post-treatment (at the end of the 8 week duration trial).
13. 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.
14. 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. 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. Head will be positioned and a 
headholder will be used to decrease head movement during the scan.
15. Baseline scan: A low dose CT transmission scan is then obtained prior [11C] raclopride administration. 
At the end of the transmission scan, a maximum of 14 mCi of [11C] raclopride will be injected 
intravenously. The dose of [11C] raclopride, diluted in a 10 cc syringe, will be given as a single bolus over a 
period of 30 seconds. [11C] raclopride will be prepared by the central radio-ligand staff of the PET Center 
and will be administered by an approved Nuclear Medicine physician (Drs. Arif Sheikh, Esther Coronel, or 
Randy Yeh). Study physicians will be present for all radiotracer injections. All study physicians have New 
York State Medical license and have had extensive training and experience with these types of PET studies. 
[11C] raclopride will be synthesized and tested for purity and sterility according to our standard procedure. 
The injected dose of [11C]-raclopride for each scan will not
exceed 14 mCi, and lower amounts will be permitted. The study physician or Nuclear Medicine physician 
will evaluate the reconstructed PET image in order to ensure tracer uptake in the brain and will inform the 
radiochemist if there is a lack of expected uptake in the brain. All subjects will be monitored by the study 
physician at the time of injection and a study physician or nurse will be present in the PET suite.
16. Post-treatment scan: As close to the end of the 8 week study as possible (based on PET scheduling),
subjects will undergo their post treatment scan. We will follow standard procedures for measuring LDOPA-
induced changes in synaptic dopamine levels set forth in PET studies of PD patients. Subjects will be given 
75mg carbidopa/300mg L-DOPA approximately 1.5 hours before scanning. Subjects in week 8 of the 


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protocol are taking 450mg LDOPA per day (150mg three times daily), so the 300mg administered prior to 
the post-treatment PET scan will constitute 300mg of their usual 450mg daily dose on the scan day. A low 
dose CT transmission scan is obtained prior to intravenous administration of 14mCi [11C] raclopride (or 
less). The start of tracer injection will be timed to coincide with the time of onset of L-DOPA effects 
(approximately 60-90 minutes following oral dose). Thus, the 60 minute PET scanning session will occur 
from 90 minutes to 150 minutes following L-DOPA dosing in all subjects. 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, and physical exam will be performed prior to discharge from the PET suite.
17. Since nausea is a known side effect of L-DOPA, we will be particularly vigilant about
monitoring for it. When nausea occurs patients generally feel warm and sick to their stomachs. It will likely 
occur after PET scanning, but if vomiting were necessary, the MD would remove the subject from the 
scanner so that vomiting does not occur while supine. Removal from the scanner can occur immediately.
18. 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.
16. Drs. Abi-Dargham and Slifstein continue to be Co-Investigators responsible for neuroimaging as part of 
a subcontract executed between RFMH and SUNY-Stony Brook. They 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
 
19. At each weekly visit, subjects will meet with a psychiatrist of study physician. At Week 0, subjects 
will be randomized to L-DOPA vs. placebo according to a blocked randomization schedule developed by 
the study statisticians and supplied to the NYSPI pharmacy. Raters, clinicians, and participants will be 
blinded to treatment assignment, though clinicians will be able to break the blind in case of clinical 
emergency. Treatment allocation will be concealed by over-encapsulation of 25/100 sinemet tablets or 
placebo tablets, such that all study pills will appear identical. All subjects will take 1 pill three times daily 
regardless of their treatment assignment. Those assigned to L-DOPA will begin taking 37.5mg 
carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg 
carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one 
week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa 
three times daily and no placebo) for the final six weeks. Subjects assigned to placebo will take placebo 
three times daily throughout the study. The 1.5 25/100 sinemet pills that are needed to make up a dose of 
150mg levodopa will be installed a single, overencapsulated pill by the pharmacy.
 
20. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate 
higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose. We 
chose 450mg as the target dose based on its being the dose that met the target progression criteria in the R61 


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Phase of this project (increased dopamine release in the striatum and increased processing/gait speed) and 
was highly tolerable to subjects. 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.
 
Assessments
21. Subjects are expected to have a screening/evaluation visit, pre-treatment PET/MRI scanning day(s) (for 
those receiving imaging), and weekly visits from Week 0-8.
 
22. The following measures will be collected weekly throughout the study: 24-item HRSD, CGI Severity 
and Improvement, Structured Pill Count Interview, Unified Parkinson’s Disease Rating Scale (UPDRS) 
(questions 32 and 33 will be used in this study to assess the duration and disability of dyskinesias caused by 
L-DOPA), Treatment Emergent Side Effect Scale, and Inventory of Depressive Symptoms—Self Report 
(IDS-SR).
23. In addition, baseline processing and gait speed assessments will be repeated after Weeks 1, 2, 5, and 8 
at 1pm to control for time of day effects and the duration since the last morning L-DOPA dose (anticipated 
to be 4 hours). Processing speed will be assessed using the Digit Symbol test from the Wechsler Adult 
Intelligence Scale-III (WAISIII) (119) and the Pattern and Letter Comparison tests (120). These tests are all 
reliable and valid, with moderate to high loadings on the latent speed factor. A latent factor (and subsequent 
factor score) will be extracted from the 3-test battery pre- and post-treatment and used as the main outcome 
in the R61. By extracting a latent factor and factor loadings we will utilize a more pure measure of 
processing speed than if we used the raw scores from an individual test or a sum total score from the three 
raw scores combined (121-124).
24. Gait will be assessed as both a single and dual task (ST, DT) on a Gaitrite walkway system in the LLDC. 
For the ST, patients are instructed to walk at their usual or normal speed over the 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 (125). Patients 
will start and end at a point 2 meters from beginning of the course to eliminate acceleration and deceleration 
effects. Each ST and DT will be assessed two times with the average used in the analyses.
 
25. Activity levels will be monitored in real time throughout the 8 week duration study using the GT3X+ 
Activity Monitors from Actigraph and the ActiLife Enterprise Software. We will analyze the average energy 
expenditure level (total counts in kcal per day assessed over 8 days with partial first day and last day 
assessments discarded) recorded in the week prior to baseline and the week prior to the Week 8 visit. A 60-
second epoch will be used, and the percentage of time spent as sedentary vs. moderately active will also be 
explored. The combination of the Work-Energy Theorem and the Freedson Equation to adjust for lower 


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caloric expenditures if necessary. We will purchase 10 GT3X+ Activity Monitors for repeated use by all of 
the R33 Phase subjects.
 
End of study procedures
26. Following the 8 week duration treatment study, endpoint assessments of depressive symptoms, 
processing speed, and gait speed will be made. Subjects will undergo endpoint neuropsychological testing 
and post-L-DOPA MRI and PET scanning.
 
27. 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
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 as defined by a slowing assessment rating 
using the CGI-Improvement scale of 6 (worse) or 7 (much worse) for 2 consecutive visits; or (3) 
development of significant side effects or an adverse event. Any subjects meeting any of these criteria will 
be withdrawn from the study and treated clinically. 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.
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
A 20cc blood sample will be drawn at baseline. General medical tests will be performed, such as CBC,
Chem 7, LFTs, TSH, cholesterol, B12, and folate. Also, tubes of whole blood will be aliquoted and frozen 
for subsequent measurement of (1) serum inflammatory markers and (2) IL-6 and COMT genotypes.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment


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Structured Clinical Interview Diagnostic for DSM 5 (SCID) (114): this semi-structured diagnostic interview 
will allow determination of whether subjects meet selection criteria.
 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) (112) 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 (113).
 
Center for Epidemiologic Studies—Depression Scale (CES-D): depression screening measure chosen given 
its ease of administration and wide use in epidemiological studies.
 
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.
 
24-item HRSD (115): standard measure of depression severity that measures changes in depressive
symptoms, though L-DOPA effects on depression are not the focus of the R61 Phase.
 
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) (116): standardized, reliable, and valid instrument for 
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) (117): 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 (118).
 
Processing speed will be assessed using the Digit Symbol test from the Wechsler Adult Intelligence Scale-
III (WAIS-III) (119) and the Pattern and Letter Comparison tests (120). These tests are all reliable and valid, 
with moderate to high loadings on the latent speed factor. 


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Episodic memory functioning will be assessed using the Wechsler Memory Scale Logical Memory Test I &
II (153). Inclusion of this test will allow us to identify deficits in episodic memory functioning consistent
with a classification of amnestic mild cognitive impairment (aMCI) (7).
Executive function will be assessed 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.
The Short Physical Performance Battery (SPPB) (156), 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) (157).
The self-report 38-item Measure of Everyday Cognition (ECog) is adapted from an informant-report version
and measures impairment and change in domains of everyday/real-world functioning relevant to 7 specific
neuropsychological domains (158).
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 (159-160).
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
carbidopa/levodopa (Sinemet)
Manufacturer and other information
We will be using generic sinemet 25/100 tablets in this study. We will purchase them through the pharmacy,
using whichever generic manufacturer is recommended by the NYSPI pharmacy.
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


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parkinsonism. This project proposes off-label use of L-DOPA in individuals with significant
cognitive/motor slowing. When we submitted an NIMH grant application Oct 2014 for this study, we
contacted the Division of Neurology Products at the FDA to inquire whether an IND was required for
LDOPA use in this project. We had a phone conversation with Cathleen Michaloski (Sr. Regulatory Project 
Manager, Division of Neurology Products), during which she listened to our description of the study 
methods and stated that an IND was not required. She later sent us an email after discussion with Dr. David 
Podskalny (Team Leader, Division of Neurology Products) confirming that in their assessment an IND was 
not needed for a project such as this. 
 
Text of email follows:
 
Dear Dr. Brown [Co-Investigator on submission],
 
Thank you for your time by phone. As we discussed by phone and after consulting with our Team Leader, 
Dr. Dave Podskalny, believes an IND is not required (unless your IRB stipulates otherwise). The 
information provided in your email suggests that the indication is covered in labeling. Also, as you may 
know we do not regulate off label, “practice of medicine” usage.
 
Thank you.
 
Cathleen Michaloski, BSN, MPH, RAC
Sr. Regulatory Project Manager
Division of Neurology Products
FDA / CDER / OND / ODEI /DNP
White Oak Building 22 room 4342
301-796-1123
Cathleen.michaloski@fda.hhs.gov
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
[11C] raclopride
Manufacturer and other information
[11C]raclopride or
[C-11]-(S)-3,5-dichloro-N-(1-ethyl-pyrrolidin-2-yl-methyl)-2-hydroxy-6-methoxy-benzamide)
[11C]raclopride is manufactured onsite in the Radioligand lab
Approval Status


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IND is approved
IND#
141742
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 may be assigned to placebo 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
1. Interview, emergencies, and possible suicidal ideation. Subjects may experience discomfort during the 
clinical interview and evaluations when discussing symptoms and current life events. The study
coordinators are experienced and skilled in interviewing depressed subjects. Half-way through the initial 
assessment, the coordinator will ask the subject if they would like to take a break, and this will be provided 


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if desired. A study clinician will be available during all aspects of the assessment if there are any questions 
or problems. In addition, should the subject express suicidal ideation at any time during the interview, the 
study clinician will be contacted immediately to assess the subject and to determine the appropriate course 
of action. Options for addressing suicidal ideation will include contacting the individual’s mental health 
caregiver, referring for urgent (same day) evaluation and treatment in an outpatient clinic, or emergency 
room evaluation and hospitalization. Similar practices will be used for other emergencies, including but not 
limited to psychosis, homicidal or violent thoughts, or an acute change in a subject’s physical status.
 
2. L-DOPA Side Effects: 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. L-DOPA is a well-tolerated medication at the 
doses we will be using in this study. Older (i.e., 1960s-70s era) case studies report administering L-DOPA 
doses of 400-1200mg and in some cases much higher to depressed, non-PD patients over subacute time 
periods (4-12 weeks). Variable clinical results were observed, but few side effects were reported and no 
dyskinesias. More recently, a double-blind study (conducted by Co-Investigator Yaakov Stern and 
colleagues) of a single dose of L-DOPA 200mg vs. placebo investigated the role of dopamine in the 
impaired interval timing abilities observed in older adults. Thirty two healthy aged participants aged 71.2 ± 
7.6 years were trained to produce two target time intervals
(6 and 17 seconds in duration) in separate blocks corresponding to drug/placebo administration. Of the 16 
elderly subjects who took 200mg L-DOPA, no severe side effects were noted, and no individuals
discontinued participation in the study. Forty-four percent reported mild nausea at some point during the
experiment, which was the only side effect noted. There are sporadic other reports in the literature
examining the effects of single-dose 200mg L-DOPA on cognitive outcomes in healthy controls (e.g., Rihet 
et al, Psychopharmacology 2002; Hasbroucq et al, Psychopharmacology 2003), but no other recent (i.e., 
post 2000) studies have been performed of subacute L-DOPA dosing in healthy controls.
There are many studies of chronic L-DOPA administration for the treatment of PD, since this drug has been 
used since the 1960s. Perhaps the most relevant recent study was a clinical trial published in the New 
England Journal of Medicine in 2004 (72). In this study 361 patients with PD were randomized 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, and this study lasted 40 weeks as opposed to 8 weeks in 
the R33 Phase of this study. Despite these reassuring data, and recognizing that we include a different 
patient population, we will carefully assess subjects with new complaints to determine if they may be 
related to study drug and if there is a need for closer monitoring or change in study drug dosing.
 
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: Case studies of a neuroleptic malignant-like syndrome (fever, akinetic crisis, 
rigidity, autonomic disturbances) have been reported following withdrawal of levodopa in patients with PD. 
Retrospective analyses suggest NMS syndromes appear to occur in approximately 2% of PD patients, and 


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levodopa discontinuation may be a risk factor in approximately half of these instances (1% of PD patients) 
(Hashimoto et al, Parkinsonism and Related Disorders, 2003). Controlled studies measuring NMS incidence 
following levodopa withdrawal have not been performed.
 
d. Sensitization to L-DOPA: 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. It is difficult to estimate the risk of sensitizing 
healthy participants to L-DOPA in this study as there are no studies in which participants without PD 
were given L-DOPA, then followed for many years to see whether they developed PD and whether, if 
so, they had increased rates of motor complications. However, even if subjects later on develop PD, 
the likelihood of developing dyskinesias is reliant on well described factors such as disease duration 
and high doses of L-DOPA. Thus a short exposure to L-DOPA before disease diagnosis appears less 
likely to have play a role in the development of motor complications with L-DOPA treatments in non 
PD patients. If we were to conservatively estimate that <10% of individuals treated with 450mg L-
DOPA for 40 weeks (much longer than the duration in this study) will develop a dyskinesia and <5% 
of individuals with significant age-related slowing in our study will go on to develop PD and require 
future L-DOPA treatment, then the risk of sensitizing patients in our study such that their later PD 
treatment would be compromised should be 0.5%.
 
3. PET imaging—Radiation Exposure: The dose of radiation will be submitted for approval to the
Columbia University Medical Center Joint Radiation Safety Committee (JRSC). All scans will be done in 
the presence of medical supervision and trained nursing staff in an institution specifically designed to
support imaging studies. In the event of serious medical complications, the PET scan facilities have
immediate access to, or consultation with, specialized medical units at the Columbia University Medical
Center (CUMC). Preparation of radiopharmaceuticals and performance of PET scans will be by
radiochemists, physicians, and technologists of the Department of Radiology, Columbia University Medical 
Center. 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 study doctor will be informed regarding subjects’ previous 
radiation exposure. Dose estimates indicate that the maximum, permissible single study dosage of [11C]-
raclopride in human subjects, to remain below the CFR 361.1 dose limits for research subjects, is 42.8 mCi 
(i.e., calculation based upon gallbladder as the critical organ; 5 rads per single study limit and 0.117 rads per 
mCi to the gallbladder). Thus, a dose of max 14 mCi per injection, and the dose associated with 
participation to this study (2 injections: 28 mCi) will be within this limit. Subjects will be instructed not to 
participate in any other research studies that include radiation exposure during the year starting on the day 
of the first study. Subjects exposed to radiation in the work place are excluded, as well as subjects exposed 
to nuclear medicine procedures during the previous year, including research protocols.
 
4. PET imaging—The dose of raclopride used in this study is negligible (equal or below 6.94 μg per
administration) and is expected to induce less than 5% occupancy of D2 receptors. [11C]raclopride is a
radiotracer that has been extensively used to measure striatal D2 receptors both in the US and in
Europe. Side effects have never been reported at the tracer doses used in PET studies. In


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addition, unlabeled raclopride has been tested at pharmacological doses in humans, as a potential
antipsychotic drug. Its safety and tolerability have been well characterized (Farde et al., 1989;
Farde et al., 1988; Cookson et al., 1989; The British Isles Raclopride Study Group, 1992) Therefore, 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.
 
5. 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.
 
6. 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.
 
7. Breach of confidentiality: There is the potential risk of breach of confidentiality of clinical, genetic, and 
laboratory information. 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.
 
8. a. Risks of placing an intra-venous catheter. Drawing blood from and inserting an intravenous line (IV) 
into an arm vein are safe and standard medical procedures. Sometimes a bruise will occur at the puncture 
site and rarely a blood clot or infection will occur in the vein. Certain individuals may feel light-headed 
during venipuncture. The volume of blood collected during this study, include screening laboratories, will 
be approximately 2-3 tablespoons. These are not expected to have any serious negative effects on the study 
participants. 
 
b. Risks of blood draw: In the 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.
9. Gait speed assessment: During the gait speed assessment, patients may feel unsteady and as such 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. Coordinators walk slightly behind and alongside 
the patients during the gait assessment, providing support for the patients should they become unsteady 
during the procedure. 
 


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10.  Patients assigned to placebo may experience continued symptoms or clinical worsening. As noted 
above, this risk is mitigated by the fact that there are currently no treatments available for psychomotor 
slowing. Slowing also is a negative prognostic factor for antidepressant response in patients who are both 
slowed and depressed, and there are currently no evidence based treatments specifically aimed at this 
subgroup. The risk of harm to subjects in this study will be minimized by restricting the study to moderately 
depressed, nonsuicidal patients, following them closely, and dropping them from the study for signs of 
clinical deterioration.
Describe procedures for minimizing risks
1. 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.
 
2. 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.
 
3. The dose of radiation was approved by the JRSC for the R61 Phase of this project (IRB 7270), and we 
will resubmit an additional application to cover this R33 Phase. No changes have been made to the PET 
scanning procedures for this R33 Phase. 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.
 
4. In terms of raclopride 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.
 
5. 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


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Page 28 of 42
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. 6. 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.
 
7. 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.
 
8. 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.
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.
 
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?
No
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 


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Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Subjects will receive reasonable reimbursement for transportation related costs associated with study
involvement as long as they provide receipts.
 
Subjects will receive $15 for each weekly study visit (Weeks 0-8) attended. This money will be paid by cash 
at the conclusion of each of these visits for a total of $135 if all study visits are attended.
 
Subjects will receive $50 for each MRI scan ($100 total for the MRI) and $150 for completing each PET
scan ($300 total for PET). Of note, subjects will be compensated for scheduled scans if they are brought to
the MRI or PET suites and the scans are not completed that day due to chemistry failure or other similar
issues.
 
Thus, subjects undergoing neuroimaging may earn $400 in this study, which will be a lump sum payment
mailed in the form of a check at the conclusion of the study, plus an additional $135 cash ($15 cash at the
end of each weekly visit) if all weekly study visits are also completed. If a subject does not complete the
study, payment is pro-rated to portions completed. Subjects are advised to allow 1-3 weeks for receipt of
payment for neuroimaging.
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Targeting Dopaminergic Mechanisms of Slowing to Improve Late-Life Depression 
 
IRB #7733 
 
NCT #03761030 
 
Date: 07/24/15 
 
 
 
 


Overview: All variables at all time points will be examined for illegitimate values, outliers, and inconsistencies. 
The distribution of demographic variables and baseline clinical characteristics will be examined and described 
across the two randomized patient groups (N=45 each) in terms of means, standard deviations, proportions, 
and 95% confidence intervals. Indications of inequality between groups in specific features (despite 
randomization) will trigger examination of whether differences in primary outcome measures can be attributed 
to an imbalance in group assignment. Intent-to-treat will be used for analyses including all participants who are 
randomized and have at least one post-baseline HRSD score. Tests will be two-sided and statistical 
significance determined at p-value < 0.05.  
 
Missing data: We will make every effort to obtain all data. The longitudinal mixed modeling described below is 
valid if missing data are missing at random (MAR). MAR assumptions cannot be verified. A 2010 national 
expert panel (166) recommended sensitivity analyses for the impact of missing data via pattern mixture models 
(167), which we will conduct (e.g., by investigating robustness of results to perturbations of assumed values for 
missing data within clinically plausibly ranges). 
 
Analyses for Aim 3: Aim 3.1: To determine whether L-DOPA administration results in greater improvements in 
depressive symptoms on the HRSD, a longitudinal mixed effects model will be used to analyze group 
differences using SAS Proc Mixed Version 9.3. The change in 24-item HRSD from baseline will be analyzed as 
a function of time, treatment group, the interaction between time and treatment, and baseline HRSD. Contrasts 
of mean difference in HRSD at each week will be formed and tested. Aim 3.2: To determine whether greater 
increases in processing and gait speed are associated with greater HRSD improvement, change scores from 
baseline to 8 weeks will be calculated for both processing and gait speed. Pearson correlation among all 
change scores, including change in HRSD will be examined, and two-sample t-tests will be used to assess 
treatment group differences. Multivariate linear regression models will be fit with change in HRSD as the 
outcome predicted by treatment, processing and gait speed change scores, and baseline values of processing 
and gait speed. 
 
Exploratory aims: Inflammatory markers and COMT genotype will be tested as moderators of the L-DOPA 
effect on HRSD change by including their interactions with treatment in the Aim 3 analyses. 
 
Power analysis: Aim 3.1: With N=45 per treatment group, and assuming a drop out of 15%, using two-sided 
test with α=0.05, we have >80% power to detect treatment group differences with ES = 0.60 or greater. Given 
expected SD=5 points based on similar previously conducted studies in the LLDRC, this ES would correspond 
to a change in HRSD of 3 points, which is smaller than the 4 point change considered meaningful. Aim 3.2: 
With N=90, assuming a drop out of 15%, we would be able to detect correlations >0.31. Thus, we have 
adequate power to detect a moderate to large correlations between change in HRSD and change in 
processing and gait speed.