Clinical trial NCT04650217
Conditions: Depressive Disorder
Keywords: slowed Information processing speed slowed gait speed
Sponsor: New York State Psychiatric Institute
Start date: 2021-10-07; Completion date: 2021-12-31
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this new research study, 80 adults aged \> 60 years with a significant depressive disorder and slowed processing and/or gait speed will be randomized to receive levodopa (L-DOPA; which the Candidate has previously shown to increase psychomotor speed and decrease depressive symptoms in older adults), aerobic exercise (itself an effective antidepressant treatment as monotherapy), or their combination in a 2x2 design incorporating placebo and a stretching/toning control. Participants will be evaluated before and after this 12-week duration study across cognitive domains, psychiatric symptoms, gait kinematics and mobility, and task-based magnetic resonance imaging (MRI) focused on effort-based decision making and reward processing. Data from this study will contribute toward the development of improved treatment and prevention strategies to maximize the functioning and active healthspan of older adults with neuropsychiatric disorders.

Detailed description:
Late-Life Depression \[LLD\]), is prevalent, disabling, and associated with high rates of completed suicide. Among the LLD patients at the highest risk of these adverse outcomes are those who manifest decreased processing speed and/or decreased gait speed. To develop urgently needed novel therapeutics for LLD, a reasonable approach is to target systems underlying the development and persistence of psychomotor slowing. One such approach has been to augment dopaminergic signaling since post-mortem experiments and in vivo neuroimaging studies have implicated age-related dopaminergic decline in the development of slowing. 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. As opposed to other dopaminergic interventions (i.e., dopamine receptor agonists and stimulants), a large literature shows beneficial effects of L-DOPA on cognitive performance and gait in patients with Parkinson's disease, all while being a safe and well-tolerated medication that is difficult to differentiate from placebo in terms of side effects.

A second therapeutic strategy that has been tested for LLD and is relevant to psychomotor slowing is aerobic exercise training. A number of reports and meta-analytic reviews suggest that exercise is an effective non-pharmacologic treatment for depression, including depression in older adults. The largest recent study found that progressive aerobic exercise conducted three times weekly for 30min over 24 weeks was effective for depression and was tolerated extremely well (14.3% drop-out rate, 70% intervention adherence). Exercise training may be effective for LLD by counteracting deleterious age-related changes related to its development and maintenance, such as by reducing pro-inflammatory cytokines, normalizing hypothalamic-pituitary-adrenal axis hyperactivity, and decreasing physical disability and social isolation. Exercise also appears to facilitate adaptive neuroplastic changes in the hippocampus, prefrontal cortex (PFC), and anterior cingulate cortex (ACC) as well as increased white matter connectivity.

While both dopaminergic augmentation and exercise are promising interventions, neither treatment alone may be sufficient to address the serious adverse medical and psychiatric outcomes associated with LLD and psychomotor slowing. In our preliminary study (NYSPI IRB# 7270), L-DOPA was associated with significant improvements in gait speed, but the effect size of this improvement was only moderate (d=0.4). L-DOPA failed to increase average gait speed in this study above the 1m/s threshold associated with functional disability and increased mortality risk in epidemiologic samples. While exercise has not been studied specifically in this patient population, meta-analyses of exercise interventions in older adults suggest overall effects on gait speed are modest (d=0.3) and perhaps not clinically significant. Thus, one goal of this study is to combine these interventions having complementary mechanisms of action to realize a greater therapeutic benefit.

This study includes task-based functional MRI that will allow us to probe the differential therapeutic mechanisms of L-DOPA and exercise and further elucidate the nature of effort-based decision making and reward deficits in LLD. Decision making about voluntary behavior requires weighing the benefit of potential rewards against the effort cost required to achieve them. This calculation is performed by separable populations of dopaminergic midbrain neurons whose signals for value and effort are integrated with the ventral striatum (VS). Anterior VS (AVS) consistently has been shown to encode subjective value, increasing with the probability of reward and decreasing with effort discounting, while recent work suggests dorsomedial VS (dmVS) activates during the initiation of effortful action. We hypothesize that older adults are biased toward inactivity (and thereby at risk for depression) on the basis of dopaminergic decline that diminishes subjective value estimates and increases the effort cost of action (i.e., by the development of slowing). Among PD patients, L-DOPA increases willingness to work independently of facilitating movement by increasing subjective value estimates. By increasing fitness and helping individuals learn about their increasing capacities, exercise may facilitate effort initiation. Below, we evaluate whether complementary effects on effortful behavior may be achievable via L-DOPA increasing subjective value and Exercise reducing effort cost.

Arms: arm 1: N=20 subjects assigned to L-DOPA + Exercise will receive L-DOPA three times daily for up to 450mg (L-DOPA) and also will receive exercise training 4 times a week (exercise) arm 2: N=20 subjects assigned to L-DOPA + Control will receive L-DOPA three times daily for up to 450mg (L-DOPA) and also will receive a stretching and toning regime (Control). arm 3: N=20 subjects assigned to Placebo + Exercise will receive placebo three times daily and also will receive exercise training 4 times a week (exercise). arm 4: N=20 subjects assigned to Placebo + Control will receive placebo three times daily and also will receive a stretching and toning regime (Control).
Interventions: intervention 1: Carbidopa/levodopa intervention 2: Placebo intervention 3: Exercise training intervention 4: Control
Intervention descriptions: intervention 1: 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. Subjects assigned to L-DOPA will begin with a Week 1 L-DOPA daily dosage of 150mg, or 1.5 25mg carbidopa/100mg levodopa tablets at 9am and placebo tablets at

1pm and 5pm. In Week 2 the L-DOPA daily dose will increase to 300mg (1.5 25mg carbidopa/100mg levodopa tablets at 9am and 5pm, with placebo at 1pm), followed by a Week 3 to 8 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets three times daily). Subjects assigned to placebo will take 1.5 placebo tablets three times daily for three weeks. Individuals will be instructed to maintain the same timing of doses throughout the study. Individuals unable to tolerate an increased dose will have their dosage reduced to the maximum previously tolerated dose. intervention 2: Carbidopa/levodopa matched placebo intervention 3: Subjects assigned t Exercise will exercise individually at their home on a program set each week by Dr. Sloan and the research assistant (RA) coach, who will work with the patient to ensure they train according to the program at the appropriate level of intensity. Subjects will select from a series of aerobic activities and for Weeks 1-2 will train at 55-65 percent of maximum HR as established during their qualifying CPET. In Weeks 3-4, they will increase exercise intensity to 65-75 percent of maximum HR, and in Weeks 5-12 they will train at 75 percent of maximum HR. intervention 4: Control will engage in a series of stretches and toning exercises designed to promote flexibility and improve core strength.

Protocol documents:
ICF_002.pdf: 
Subject Consent Form
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NEW YORK STATE PSYCHIATRIC INSTITUTE 
COMBINATION TREATMENT WITH L-DOPA AND 
EXERCISE FOR MOOD AND MOBILITY PROBLEMS IN 
LATER LIFE 
Overview 
Below is a summary of the study in which you are asked to take part in. This 
outline is meant to be a guide for you to use while considering the study and reading the 
consent form. It is not meant to replace the consent form, which you will have to sign if 
you decide to participate in the study. The study described is a double-blind placebo- 
controlled study, which means that you will be randomly assigned (like the flip of a coin) 
to study medication or else placebo (a sugar pill). You also will be assigned to one of 
two different types of physical training activities. Neither you nor the study doctor will 
be informed whether you are receiving study medication or placebo until the end of the 
study. 
Participation is Voluntary 
Participation in this research study is voluntary. If you decide not to participate, 
or if you later decide to stop participating, you will not lose any benefits to which you 
are otherwise entitled. A decision not to participate or withdraw your participation will 
not affect your current or future treatment at the New York State Psychiatric Institute or 
Columbia University Irving Medical Center. 
Alternatives 
You do not have to participate in this study to receive treatment for depression 
or slowed thinking and movement. Food and Drug Administration (FDA)-approved 
antidepressant medications such as Selective Serotonin Reuptake Inhibitors (SSRIs, 
e.g., Prozac, Zoloft, etc.) or Serotonin Norepinephrine Reuptake Inhibitors (SNRIs, e.g., 
Effexor, Cymbalta, etc.), in addition to other types of medications are effective in the 
treatment of depression. Additionally, psychotherapies that are supported by research 
such as Interpersonal Psychotherapy and Cognitive Behavior Therapy are available 
outside of this study to treat depression. Finally, exercise programs and cognitive 
remediation may be helpful for slowed thinking and movement and also are available 
outside this research project. 
Procedures 
•
At the beginning of the study, you will be given a physical examination, 
an electrocardiogram (EKG), and have your blood drawn. 
• Next you will have tests of your memory, concentration, and other thinking 
skills as well as a test of your walking. 
• Half of study participants will undergo two (2) magnetic resonance imaging 
(MRI) scans of the brain, one at the beginning and one at the end of the study. 


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• MRI scans use strong magnetic fields and radio waves to take pictures of your 
brain. 
• In the treatment part of the study, you will be randomly assigned to receive a 
medication called carbidopa/levodopa (Sinemet) or pill placebo (a sugar pill). 
We are using carbidopa/levodopa “off-label” in this study, which means that 
it is not approved by the FDA for the treatment of depression. 
• In addition to taking the study pills, you will be randomly assigned to 
participate in an aerobic exercise regimen or a stretching program. These are 
programs you will complete at home under the direction of our research staff. 
• You will be asked to speak to your study doctor, either in-person or remotely 
using the telephone or using WebEx, a Health Information Portability and 
Accountability Act (HIPAA) compliant video teleconferencing service, several 
times over the 12 weeks. You and the study doctors will talk about how you are 
feeling and have tests of your thinking and walking speed. 
• The research study will end after 12 weeks. You will fill out some more 
thinking tests and have your walking speed tested again. If you received an 
MRI scan at the beginning of the study, you will have another at the end. 
 
Risks 
This study includes some risks and discomforts (please refer to the consent form 
for further details and explanations of these risks). The main risk to you in this study is 
that carbidopa/levodopa is an experimental treatment, and it is not known yet whether it 
will be effective in treating low dopamine levels or symptoms of depression. Other risks 
are worsening of depression while you are assigned to receive placebo, side effects 
associated with carbidopa/levodopa (such as nausea, headache, abnormal movements of 
arms and legs, muscle stiffness, and vivid dreams), and potential physical injury during 
the exercise treatment.  There are also risks associated with COVID-19 and travel for 
research purposes. 
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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Informed Consent for Participation in Research 
COMBINATION TREATMENT WITH L-DOPA AND 
EXERCISE FOR MOOD AND MOBILITY PROBLEMS IN
LATER LIFE 
PURPOSE OF STUDY 
The purpose of this research study is to understand whether a combination of two 
different treatments can be helpful for older adults who struggle with depression and 
slowed thinking and/or movement. Participants in this study will receive two things—a pill 
(which will be either a medication called carbidopa/levodopa or placebo) and a physical 
training program (which will be either aerobic exercise or a stretching and toning program). 
Carbidopa/levodopa is approved by the Food and Drug Administration (FDA) for the 
treatment of Parkinson’s Disease. We are using carbidopa/levodopa “off-label” in this
study, which means that it is not approved by the FDA for the treatment of depression. We 
are interested in studying whether the addition of physical training may help the 
carbidopa/levodopa work better for people.  
Half of the people participating in this study will have brain scans using magnetic 
resonance imaging (MRI). We are performing these scans to understand more about how 
the brain’s dopamine system may be different in older adults who are depressed. The MRI 
scans involve some parts where you will be asked to lie quietly in the scanner without 
doing anything and some parts where you will be asked to look at a screen and accomplish 
tasks by pressing buttons 
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 


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may be helpful with depression, whether on their own or combined with medication. 
Although no treatments for mental and physical slowing have been formally approved by 
the FDA, other treatment approaches include exercise programs and cognitive training. 
Information being collected is for research purposes only and is to learn more about 
changes in the brain’s dopamine system with aging, not about you. It is not necessary to
participate in this research study to have an MRI, and the MRI done as part of this study is 
not the same as one done for medical purposes. 
STUDY PROCEDURES 
This study will follow all applicable policies of the New York State Psychiatric 
Institute to ensure the safety of research participants and staff during the COVID-19 
pandemic. We have reduced in-person visits to the minimum needed. Some of your visits 
may be conducted remotely using the telephone or video teleconferencing. When it is 
necessary for your participation for you to come to the New York State Psychiatric 
Institute, research staff will ask screening questions about your health beforehand, and it is 
required that you wear a face covering when in the building. We offer transportation via 
car services to reduce risks inherent in public transportation. 
Evaluation: If you decide to participate in this study, you will have blood drawn, 
complete some tests, and have your walking measured using a special mat. The total 
amount of blood taken at this study visit is about four tablespoons. Results of these blood 
tests will be available to you, should you request them. The tests measure thought processes 
such as memory, language, reasoning, and attention. These tests are paper-and- pencil as 
well as computer-based and take about two hours to complete. The results of these tests are 
for research purposes only and will not be shared with you. 
Based on these tests, it will be determined whether you are eligible for the treatment 
portion of the study. If you are not eligible, you will be referred to appropriate options for 
further treatment. If you are eligible and continue to wish to participate, you will proceed 
with the next part of the study. 
MRI scans: Half of the participants in this study will be offered the opportunity to 
have an MRI scan at the beginning of the study (before you receive any carbidopa/levodopa 
or placebo) and again after the medication/physical training part of the study. You may still 
participate in the medication and exercise part of the study even if you are not eligible for 
or do not desire to do the MRI scan. Some parts of the MRI scans involve completing tasks 
while you are lying in the scanner machine. You will be trained for about 1 hour before 
each scan in the performance of two computer tasks by one of the study’s research
assistants. These tasks involve sitting at a desk, looking at pictures on a computer screen, 
and pressing buttons with your finger. You then will be asked to undergo the MRI scans, 


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each of which lasts approximately one hour. 
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. 
Medication portion: In the medication part 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 the starting dose of carbidopa/levodopa 
(37.5mg/150mg). This dose will be increased to the final dose of carbidopa/levodopa 
112.5mg/450mg. Taking the medication in this study will involve taking three pills per 
day, one in the morning, one at lunchtime, and one at night. If you are assigned to the 
second option, then you will receive pill placebo. The placebo looks like the other 
treatments/pills, but does not contain any medicine (it is sometimes called a “sugar pill”).
Neither you nor the researchers will know if you are getting the placebo, but they can find 
out in an emergency. You will receive free medication or placebo for the duration of the 
study. 
You will take the study pills for 12 weeks. 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. 
Exercise portion: At the beginning of the study, you will have an exercise test that 
will measure your exercise capacity and determine the proper heart rate range for you to 
target during aerobic exercise. You will then be assigned to participate in a four times per 
week home aerobic exercise program (using a manual walking treadmill) or else a regimen 
of stretching and muscle toning.  
 
 
 
 
 
 


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Manual Walking Treadmill 
 
 
 
 
You will be trained in the proper use of this equipment by a research staff member 
and then have the equipment delivered to your home. You will keep logs of your exercise 
and upload information from a heart rate monitor you will wear while doing the exercise. 
A research team member will serve as your “coach” and will review this information to 
ensure you are exercising safely and properly. You will be allowed to keep the exercise 
equipment following your participation in the study. 


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If you are assigned to the stretching and toning regimen, you will also be trained in 
the proper performance of the exercises, and a research “coach” will monitor your progress.
At the end of the 12 week study, you will again return to our clinic to have your exercise 
capacity re-tested. 
 
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 to our clinic several times to speak with the study doctor and have some tests. These 
appointments will last about 45 minutes. Between these visits you may have phone check 
ins with the study doctor and other research staff. The research study will end after 12 
weeks, when you will again complete the tests you performed at the beginning of the study 
and have another MRI (if you are in the MRI part of the study). 
Following the study, you will still receive 3 months of free doctor visits in the clinic. 
The medication used in this study is available from pharmacies, so it is an option to 
continue taking the medication following the study if you feel you have benefited from it. 
You will receive at least 1 month of free medication if you wish. Every effort will be made 
to provide free medication for 3 months total, but we cannot guarantee the availability of 
free medication beyond 1 month. If you do not wish to continue the medication after the 
study, the dose will be gradually decreased over 3 days before stopping it. 
RISKS 
Carbidopa/levodopa risk: The main risk to your participation in this study is that 
carbidopa/levodopa is an experimental treatment, and it is not known yet whether it will be 
effective in treating low dopamine levels or symptoms of depression. The most common 
side effects reported for carbidopa/levodopa are nausea, headache, and vivid dreams. You 
should be careful about drinking alcohol, since it may have a greater effect on you in 
combination with medication. 
In addition, you may be assigned to receive placebo for 12 weeks during the study. 
Therefore, you will not receive Food and Drug Administration (FDA) approved medication 
for your condition until after the 12 week study is over. There will be a delay of 12 weeks 
(the time you are doing the study) before you will receive a treatment that is known to be 
effective for the treatment of depression (e.g., antidepressant medication). There is a 
chance your depression may worsen during the time you are receiving carbidopa/levodopa 
or placebo in this study. 
It is not fully known how the normal slowing down that occurs during aging relates 
to the type of slowing that occurs in patients with Parkinson’s disease. Some individuals
who experience slowing with age may be at increased risk for Parkinson’s disease.
carbidopa/levodopa 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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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 carbidopa/levodopa, 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 
carbidopa/levodopa 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%. 
Exercise risks: You may experience physical injury, muscle soreness, and/or fatigue 
due to the study assessments of balance and gait as well as the increased physical activity 
if you are assigned to receive exercise. Most such injuries are minor and resolve on their 
own with time, but it is possible for more serious injuries to occur including broken bones 
or joint dysfunction. Additionally, an exercise-induced cardiovascular event (such as a 
stroke or heart attack) is a potential risk, although the study team seeks to minimize this 
risk by clearing your study participation with your primary doctor and not allowing 
individuals with serious cardiovascular problems to participate in the study. The study team 
will provide training on how to safely exercise or perform stretching movements, and we 
will closely monitor your heart rate during the study. 
 
MRI risks: The long-term effects of being placed in a magnet of this strength (3 
Tesla) are unknown, but you should be aware that there have been no reports of any ill 
long-term effects caused by magnets of the same or even higher strength, either here or 
elsewhere. Also, although there are no known risks associated with pregnancy, we will not 
scan someone who is pregnant. Therefore, you should understand that if you are a woman 
in your childbearing years, pregnancy testing will be used to assure that you are not 
pregnant. 
Some people have reported sensations during MRI scans, such as "tingling" or 
"twitching" (or, very rarely, a painful sensation), which are caused by changes in the 
magnetic field that can stimulate nerves in your body. If you experience sensations and feel 
that these are uncomfortable, you can tell the MRI technologist, and he or she will stop the 
scan immediately. Occasionally, some people experience nervousness or claustrophobic 
feelings due to the scanner’s small space. If you encounter any discomfort, you can tell the
MR technologist, and he or she will stop the scan immediately. Despite these experiences, 
no one has ever had sensations from the scanning that did not stop as soon as the scanning 
stopped. 
Except for pacemakers and some types of metallic implants, we know of no health 
hazard from the MRI scan. The MRI scan is not painful, but lying still on the scanning 
table may be slightly uncomfortable. 
Other risks: When your blood is drawn, there is a small risk you may be left with a 
bruise that will resolve within a few days. Results of blood tests taken for research purposes 
will remain confidential. 


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Furthermore, specifically for in person visits to NYSPI, individuals are at increased 
risk for exposure to COVID-19 both in transit to NYSPI as well as during their time at 
NYSPI. Procedures are in place to minimize this risk. We plan to offer car transportation 
subject to a maximum of $50 each way, which minimizes exposure to public transportation 
for those participants. At NYSPI, personal protective equipment such as masks will be 
utilized at all times both by staff and participants, and social distancing will be adhered to 
when possible (exceptions exist for procedures such as blood draws and EKGs). Screen 
shields between patient and staff will be used during neuropsychological testing to further 
minimize exposure risk.    
BENEFITS 
You may not benefit from this study, and no benefit is in any way guaranteed as a 
result of your participation. 
RESULTS OF YOUR MRI 
While MRI scans are sometimes done for clinical purposes, the kind of MRI scans 
you will have as part of this study is for research purposes only. This means that the scans 
are not designed to provide clinical information that might be helpful to you or your 
doctor and they may not show problems that would normally be found in an MRI ordered 
to evaluate a specific medical problem. It is likely that the MRI scan will not have the 
quality of those done for clinical purposes. 
However, within a month of the MRI scans, the scans will be read by a 
neuroradiologist for evidence of any obvious irregularities requiring your follow-up. You, 
or a physician whom you may designate, will be informed only when significant 
abnormalities are detected. If you wish, we can also inform you if there were no obvious 
findings. Given the nature of the scans, the absence of a finding does not mean that one is 
not present. 
CONFIDENTIALITY 
Your records will be stored in a locked file. Records will be available to research 
staff, and to Federal, State and Institutional regulatory personnel (who may review records 
as part of routine audits). There are legal advocacy organizations that have the authority 
under State Law to access otherwise confidential records, though they cannot be 
redisclosed without your consent. All records will be kept confidential to the extent 
permitted by law. Your name and other personal identifying information will be stored in 
an electronically secure database at New York State Psychiatric Institute. Electronically 
stored data will be accessible only by password known to the study investigators and 
research assistants. For participants with email access, self-report measures will be sent via 


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encrypted email. 
 
Your MRI will be interpreted and the results will be shared with you or a physician 
who you may designate. Your MRI report will be maintained as part of the clinical database 
at the New York State Psychiatric Institute or the Columbia University Medical Center 
along with your name and will be accessible to clinicians at the Medical Center. Your 
psychiatric diagnosis will not be a part of the report. 
The data obtained for this study and biospecimens could be used for future research 
studies or may be distributed to another investigator for future research studies, however 
all information including biospecimens will be de-identified (this means information 
cannot be linked back to you) and will not include whole genome sequencing (i.e., 
sequencing of a human germline or somatic specimen with the intent to generate the 
genome or exome sequence of that specimen). Biospecimens will not be used for 
commercial profit. Clinically relevant research results, including individual research 
results may be available to you at you request but such request will be granted under the 
discretion of the study doctor. You may be contacted in the future by the study team for 
future studies. 
Data from this study will be submitted to the National Institute of Mental Health 
Data Archive (NDA). NDA is a data repository run by the National Institute of Mental 
Health (NIMH) that allows researchers studying mental illness to collect and share de- 
identified information with each other. A data repository is a large database where 
information from many studies is stored and managed. De-identified information means 
that all personal information about research participants such as name, address, and phone 
number is removed and replaced with a code number. With an easier way to share, 
researchers hope to learn new and important things about mental illnesses more quickly 
than before. 
During and after the study, the researchers will send de-identified information about 
your health and behavior to NDA. Other researchers nationwide can then file an application 
with the NIMH to obtain access to your de-identified study data for research purposes. 
Experts at the NIMH who know how to protect health and science information will look at 
every request carefully to minimize risks to your privacy. 
You may not benefit directly from allowing your information to be shared with 
NDA. The information provided to NDA may help researchers around the world treat 
future children and adults with mental illnesses so that they have better outcomes. NIMH 
will also report to Congress and on its web site about the different studies that researchers 
are conducting using NDA data. However, you will not be contacted directly about the data 
you contributed to NDA. 


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You may decide now or later that you do not want to share your information using 
NDA. If so, contact the researchers who conducted this study, and they will tell NDA, 
which can stop sharing the research information. However, NDA cannot take back 
information that was shared before you changed your mind. If you would like more 
information about NDA, this is available on-line at http://data-archive.nimh.gov. 
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. This means that the researchers cannot release or use information, 
documents, or samples that may identify you in any action or suit unless you say it is okay. 
They also cannot provide them as evidence unless you have agreed. This protection 
includes federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. An example would be a court subpoena. 
There are some important things that you need to know. The Certificate DOES NOT 
stop reporting that federal, state or local laws require. Some examples are laws that require 
reporting of child or elder abuse, some communicable diseases, and threats to harm 
yourself or others. The Certificate CANNOT BE USED to stop a sponsoring United States 
federal or state government agency from checking records or evaluating programs. The 
Certificate DOES NOT stop disclosures required by the federal Food and Drug 
Administration (FDA). The Certificate also DOES NOT prevent your information from 
being used for other research if allowed by federal regulations. 
Researchers may release information about you when you say it is okay. For 
example, you may give them permission to release information to insurers, medical 
providers or any other persons not connected with the research. The Certificate of 
Confidentiality does not stop you from willingly releasing information about your 
involvement in this research. It also does not prevent you from having access to your own 
information 
A 
description 
of 
this 
clinical 
trial 
will 
be 
available 
on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time. 
COMPENSATION AND ECONOMIC CONSIDERATIONS 
You will not be charged for any procedures that are a part of this study, including 
the study medication or the exercise equipment and coaching. 
To compensate you for the time required for each study visit, we offer $35 for your 
initial screening visit and $100 for each of your two main assessment sessions (beginning 
and end of study). This money will be paid by cash at the conclusion of each of these visits. 


Subject Consent Form
IRB #8065
v. 12/28/2020
12
For those individuals doing MRI scans, we offer $50 for each MRI scan ($100 total 
if you attend both scans). This money will be paid in 1 lump sum payment at the end of the 
study. Payments typically require 1-3 weeks to process and will be mailed in the form of a 
check. 
Thus, the maximum compensation in this study will be $335 for participants 
attending all study visits and doing all neuroimaging procedures. 
IN CASE OF INJURY 
Federal regulations require that we inform participants about our institution's policy 
with regard to compensation and payment for treatment of research-related injuries. 
In case of injury, New York State Psychiatric Institute will provide short term 
emergency medical treatment, which has been determined to be necessary by New York 
State Psychiatric Institute's doctors, and which is within the capability of New York State 
Psychiatric Institute to provide. In addition, we will provide assistance in arranging follow 
up care in such instances. 
New York State Psychiatric Institute and Research Foundation for Mental Hygiene 
do not provide compensation or payment for treatment of research related injuries. 
However, you should be aware that you do not give up your legal right to seek such 
compensation through the court by participating in this research. 
Please be aware that: 
1. The Research Foundation for Mental Hygiene, The New York State Psychiatric 
Institute, Columbia University and New York Presbyterian Hospital will furnish that 
emergency medical care determined to be necessary by the medical staff of this hospital 
2. You will be responsible for the cost of such care, either personally or through 
your medical insurance or other form of medical coverage. 
3. No monetary compensation for wages lost as a result of injury will be paid to you 
by the New York State Psychiatric Institute, Columbia University or by New York 
Presbyterian Hospital. 
4. By signing this consent form, you are not waiving any of your legal rights to seek 
compensation through the courts. 
QUESTIONS 
If you have further questions about the research procedures, or about your response 
to the procedures research staff members are available to answer them to the best of their 
ability. You can reach Dr. Bret Rutherford at 646-774-8660 during general business hours. 


Subject Consent Form
IRB #8065
v. 12/28/2020
13
In an emergency, you may reach the on call doctor at 917-786-6940, 24 hours per day. If 
you have general questions, you may contact the research coordinator at 646-774-8664. 
We will notify you of any significant new findings that may relate to your willingness to 
continue to participate. 
If you have any questions about your rights as a research participant, want to provide 
feedback, or have a complaint, you may call the NYSPI Institutional Review Board (IRB). 
(An IRB is a committee that protects the rights of human subjects in research studies). You 
may call the IRB Main Office at (646) 774-7155 during regular office hours. 
You will be given a copy of this consent form to keep. 
DOCUMENTATION OF CONSENT 
I have read the above and voluntarily agree to participate in the research study 
described above. To the best of my knowledge, I am not pregnant. I have been informed 
that my participation is voluntary, and that I can withdraw from the study at any time 
without penalty or loss of benefits to which I am otherwise entitled. 
Print name:   _________________________ 
 
 
 
Signed:  
 _________________________ 
Date:    
_________________________ 
I have discussed the proposed research with this participant including the risks, benefits, 
and alternatives to participation (including the alternative of not participating in the 
research). The participant has had an opportunity to ask questions and in my opinion is 
capable of freely consenting to participate in this research. 
Print name:    _________________________ 
               Person Designated to Obtain Consent 
Signed:   
_________________________ 
Date:    
_________________________ 


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


Form #PP2: HIPAA Authorization for Research 4.1.14
Information has been disclosed to a third party which does not have to follow these laws (e.g., a drug company or the Sponsor
of the Research), it may no longer be protected under the HIPAA or NYS Mental Hygiene Law requirements but is subject to the
terms of the consent form and may be subject to other state or federal privacy laws or regulations.
4.
Please note that:
•
You do not have to sign this Authorization form, but if you do not, you may not be able to participate in the study or
receive study related care. You may change your mind at any time and for any reason. If you do so, you may no
longer be allowed to participate in the study. If you withdraw this Authorization the research staff and the Sponsor, if this
is sponsored research, may still use or disclose Health Information containing identifying information they already have
collected about you as needed to maintain the reliability of the research. Any request to withdraw this Authorization
must be made in writing to (enter name and contact information below):
•
While the Research is going on, you may not be allowed to review the Health Information in your clinical research
record that has been created or collected by NYSPI. When this research has been completed you may be allowed to see
this information. If it is needed for your care, your Health Information will be given to you or your Doctor.
5.
This Authorization does not have an end date.
6.
You will be given a copy of this form after you have signed it.
I agree to the use and disclosure of Health Information about me as described above:
__________________________________________
_____________________
Signature of Participant/ Legal Representative
Date
______________________________________
Printed Name of Participant
______________________________________
Relationship of Legal Representative to Participant (if applicable)
We also ask you or your legal representative to initial the statements below:
I have received a copy of the NYSPI/OMH Notice of Privacy Practices.
Bret R. Rutherford, MD
1051 Riverside Drive, Box 98
New York, New York 10032

Prot_000.pdf: 
Protocol Summary Form
8065
Rutherford, Bret
Page 1 of 43
Protocol Title:
Combination Treatment with L-DOPA and
Exercise for Mood and Mobility Problems
in Later Life
Protocol Number:
8065
First Approval:
10/21/2020
Expiration Date:
10/04/2022
Version Date:
10/06/2021
Contact Principal Investigator:
Bret Rutherford, MD
Email: brr8@columbia.edu
Telephone: 646 774 8660
Co-Investigator(s):
Richard Sloan, 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 an annual continuation with modifications
Department & Unaffiliated Personnel
Department
What Department does the PI belong to?
Brain Aging and Mental Health
Within the department, what Center or group are you affiliated with, if any?
Neurobiology and Therapeutics of Aging Division
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.


Protocol Summary Form
8065
Rutherford, Bret
Page 2 of 43
Michael Treadway, PhD
Emory University School of Medicine
Amendment
Describe the change(s) being made
Galit Sharon Marcus, NP is being removed as an individual designated to discuss and document consent, as
she no longer works in our clinic. Denise McClellan, NP is being added as an individual designated to
discuss and document consent, as she is joining our team.
Provide the rationale for the change(s)
Changes to our staff necessitate an update to the protocol's persons designated to discuss and document
consent.
Comment on the extent to which the proposed change(s) alter or affect risks/benefits to subjects
None - no alterations to risks/benefits to subjects.
Comment on if the proposed change(s) require a modification to the Consent Form (CF)
No - changes to the CF are not necessary.
Application for Continuation of Research
Status
Current Status of Study:
Subject enrollment is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and
procedures.
Although recruitment has been slower than expected (no subjects enrolled so far), CAAM has continued to
conduct evaluations assessing eligibility for enrollment. All study set-up procedures have been completed,
and the research staff are prepared for the first enrollment once a potential subject is identified.
Funding
Have there been any changes in funding status since the prior approval?
No
Have the principal investigator and other investigators made all required disclosures of financial interest in
the study sponsor/product?
Yes


Protocol Summary Form
8065
Rutherford, Bret
Page 3 of 43
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in
the past year which might affect the analysis of the safety, risks or benefits of study participation?
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to
subjects or others at this site which occured in the past year)?
No
Have all study staff with a significant role in the design or implementation of the human subject components
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality?
No
Overall Progress
Approved sample size
80
Total number of participants enrolled to date
0
Number of participants who have completed the study to date
0
Have there been any significant deviations from the anticipated study recruitment, retention or completion
estimates?
No
Comments / additional information
Sample Demographics
Specify population
Adults 60 years or older with a depressive disorder and decreased processing speed or decreased gait speed
Total number of participants enrolled from this population to date
0
Gender, Racial and Ethnic Breakdown
Gender:
Male: 0
Female: 0
Race:
American Indian/Alaska Native: 0
Asian: 0
Black/African-American: 0
Native Hawaiian/Pacific Islander: 0
White: 0


Protocol Summary Form
8065
Rutherford, Bret
Page 4 of 43
More than one: 0
Unknown: 0
Ethnicity:
Not Hispanic/Latino: 0
Hipanic/Latino: 0
Missing: 0
Summary of Current Year's Enrollment and Drop-out
Number of participants who signed consent in the past year
0
Number of participants currently enrolled
0
Did the investigator withdraw participants from the study?
No
Did participants decide to discontinue study involvement?
No
Procedures
To create the protocol summary form, first indicate if this research will include any of the following
procedures
Psychiatric Assessment
Neuropsychological Evaluation
Medication Trial
Use of Placebo or Sham Treatment
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


Protocol Summary Form
8065
Rutherford, Bret
Page 5 of 43
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol?
Yes
Select one of the following
The grant/contract application is a pending review or a funding decision
Source of Funding
Federal
Institute/Agency
NIMH
Grant Name
Mentoring to Develop Aging-Informed Patient Oriented Research in Neuropsychiatry
Grant Number
K24 MH122514
Select one of the following
Single Site
Business Office
CU
Does the grant/contract involve a subcontract?
No
Study Location
Indicate if the research is/will be conducted at any of the following
NYSPI
Other Columbia University Medical Center Facilities
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research
Lay Summary of Proposed Research
In this new research study, 80 adults aged > 60 years with a significant depressive disorder and slowed
processing and/or gait speed will be randomized to receive levodopa (L-DOPA; which the Candidate has
previously shown to increase psychomotor speed and decrease depressive symptoms in older adults),
aerobic exercise (itself an effective antidepressant treatment as monotherapy), or their combination in a 2x2
design incorporating placebo and a stretching/toning control. Participants will be evaluated before and after
this 12-week duration study across cognitive domains, psychiatric symptoms, gait kinematics and mobility,
and task-based magnetic resonance imaging (MRI) focused on effort-based decision making and reward


Protocol Summary Form
8065
Rutherford, Bret
Page 6 of 43
processing. Data from this study will contribute toward the development of improved treatment and
prevention strategies to maximize the functioning and active healthspan of older adults with
neuropsychiatric disorders.
Background, Significance and Rationale
Background, Significance and Rationale
Late Life Depression [LLD]), is prevalent (83-84), disabling (85-86), and associated with high rates of
completed suicide (87). Among the LLD patients at highest risk of these adverse outcomes are those who
manifest decreased processing speed and/or decreased gait speed. To develop urgently needed novel
therapeutics for LLD, a reasonable approach is to target systems underlying the development and
persistence of psychomotor slowing. One such approach has been to augment dopaminergic signaling, since
post-mortem experiments and in vivo neuroimaging studies have implicated age-related dopaminergic
decline in the development of slowing. 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. As opposed to other dopaminergic interventions (i.e., dopamine receptor agonists
and stimulants), a large literature shows beneficial effects of L-DOPA on cognitive performance and gait in
patients with Parkinson’s disease (88-89), all while being a safe and well-tolerated medication that is
difficult to differentiate from placebo in terms of side effects (90).
A second therapeutic strategy that has been tested for LLD and is relevant to psychomotor slowing is
aerobic exercise training. A number of reports and meta-analytic reviews suggest that exercise is an
effective non-pharmacologic treatment for depression, including depression in older adults (91). The largest
recent study found that progressive aerobic exercise conducted three times weekly for 30min over 24 weeks
was effective for depression and was tolerated extremely well (14.3% drop-out rate, 70% intervention
adherence) (55,92). Exercise training may be effective for LLD by counteracting deleterious age-related
changes related to its development and maintenance, such as by reducing pro-inflammatory cytokines (93),
normalizing hypothalamic-pituitary-adrenal axis hyperactivity (94), and decreasing physical disability and
social isolation (95). Exercise also appears to facilitate adaptive neuroplastic changes in the hippocampus,
prefrontal cortex (PFC), and anterior cingulate cortex (ACC) as well as increased white matter connectivity
(96-97).
While both dopaminergic augmentation and exercise are promising interventions, neither treatment alone
may be sufficient to address the serious adverse medical and psychiatric outcomes associated with LLD and
psychomotor slowing (34-35). In our preliminary study (NYSPI IRB# 7270), L-DOPA was associated with
significant improvements in gait speed, but the effect size of this improvement was only moderate (d=0.4)
(1). L-DOPA failed to increase average gait speed in this study above the 1m/s threshold associated with
functional disability and increased mortality risk in epidemiologic samples (98). While exercise has not
been studied specifically in this patient population, meta-analyses of exercise interventions in older adults
suggest overall effects on gait speed are modest (d=0.3) and perhaps not clinically significant (99). Thus,
one goal of this study is to combine these interventions having complementary mechanisms of action to
realize a greater therapeutic benefit.


Protocol Summary Form
8065
Rutherford, Bret
Page 7 of 43
This study includes task-based functional MRI that will allow us to probe the differential therapeutic
mechanisms of L-DOPA and exercise and further elucidate the nature of effort-based decision making and
reward deficits in LLD. Decision making about voluntary behavior requires weighing the benefit of
potential rewards against the effort cost required to achieve them (100-102). This calculation is performed
by separable populations of dopaminergic midbrain neurons whose signals for value and effort are
integrated in the ventral striatum (VS) (103). Anterior VS (aVS) consistently has been shown to encode
subjective value, increasing with the probability of reward and decreasing with effort discounting (32),
while recent work suggests dorsomedial VS (dmVS) activates during the initiation of effortful action (33).
We hypothesize that older adults are biased toward inactivity (and thereby at risk for depression) on the
basis of dopaminergic decline that diminishes subjective value estimates and increases the effort cost of
action (i.e., by the development of slowing). Among PD patients, L-DOPA increases willingness to work
independent of facilitating movement by increasing subjective value estimates (104). By increasing fitness
and helping individuals learn about their increasing capacities, exercise may facilitate effort initiation.
Below, we evaluate whether complementary effects on effortful behavior may be achievable via L-DOPA
increasing subjective value and Exercise reducing effort cost
Specific Aims and Hypotheses
Specific Aims and Hypotheses
AIM 1: To measure individual and combined effects of L-DOPA and Exercise (Ex) on cognitive,
psychiatric, and physical performance measures in depressed older adults with psychomotor slowing.
Hyp 1: L-DOPA and Ex individually will be associated with significant main effects on processing
speed, gait speed, and depressive symptoms.
Hyp 2: An L-DOPA x Ex interaction will be observed on these outcomes, such that the greatest
improvements will occur among participants randomized to L-DOPA + Ex.
AIM 2: To investigate responsivity of reward-related dopamine circuits to L-DOPA and Ex.
Hyp 3: In an effort-based decision making (EBDM) task, L-DOPA and Ex each will be associated with
increased willingness to work (right-shift in subjective value discounting curve) and changes in associated
neural activations (ventromedial prefrontal cortex [vmPFC] and dorsal anterior cingulate [dACC]).
Hyp 4: In a virtual reality maze-navigation (VRMN) task, L-DOPA will be associated with increased
neural responses to subjective value (anterior VS [aVS]), while Ex will be associated with increased
dorsomedial ventral striatum (dmVS) activation during effort initiation.
Exploratory aims: We will explore correlations between real-world physical functioning metrics (i.e., gait
speed, fatigability, physical activity) and behavioral/neural responses on the EBDM and VRMN tasks in the
scanner. Differences in L-DOPA and Ex acceptability, side effects, and attrition will be compared.


Protocol Summary Form
8065
Rutherford, Bret
Page 8 of 43
Description of Subject Population
Sample #1
Specify subject population
Older depressed subjects
Number of completers required to accomplish study aims
72
Projected number of subjects who will be enrolled to obtain required number of completers
80
Age range of subject population
>= 60 years old
Gender, Racial and Ethnic Breakdown
We will recruit participants of all races and ethnic groups, to the extent possible within the local
population demographics. We will make efforts to ensure a representative sample by working to boost
minority enrollment to maintain sample consistency with population averages.
On the basis of previous studies conducted at Columbia/NYSPI’s Clinic for Aging, Anxiety, and Mood
Disorders (CAAM), it is anticipated that the sample at this site will be composed of approximately 75%
Caucasian, 15% African American, and 10% Hispanic subjects. We will make every effort to recruit
minority individuals in order to ensure the generalizability of the study’s findings to the overall population
of individuals with Late-Life Depression (LLD). Given the increased prevalence of depression in women,
we do not anticipate difficulty in women representing 60% of our sample. Previous samples in studies
conducted in CAAM have been approximately 60% women and 40% men.
Description of subject population
The N=80 Depressed sample will enroll subjects who are 1) aged 60 years old or greater, 2) have DSM5
diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder, 3) Montgomery-
Asberg Depression Rating Scale (MADRS) >= 15, 4) decreased processing speed (0.5 SD below age-
adjusted norms on the Digit Symbol Test or Trails A) OR decreased gait speed (average walking speed of
0.5 SD below age-adjusted norms), and are 5) capable of providing informed consent and adhering to
study procedures. Subjects will be excluded for 1) diagnosis of substance abuse or dependence (excluding
Tobacco Use Disorder) in the past 12 months, 2) history of psychosis, psychotic disorder, mania, or bipolar
disorder, 3) primary neurological disorder, including dementia, stroke, Parkinson’s disease, epilepsy, etc., 4)
MMSE < 24, 5) MADRS suicide item > 4 or other indication of acute suicidality, 6) current or recent
(within the past 2 weeks) treatment with antidepressants, antipsychotics, or mood stabilizers, 7) history of
hypersensitivity, allergy, or intolerance to L-DOPA, 8) any physical or intellectual disability adversely
affecting ability to complete assessments, 9) acute, severe, or unstable medical illness, 10) mobility limiting
osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, or history of joint
replacement / spine surgery that limits mobility, or 11) contraindication to MRI scanning.


Protocol Summary Form
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Rutherford, Bret
Page 9 of 43
Recruitment Procedures
Describe settings where recruitment will occur
Patients will be recruited from around the general New York City/New York area and will present to the
Clinic for Aging, Anxiety, and Mood Disorders.
We will be specifically recruiting via advertisements for patients who feel depressed as well as slowed down
physically and mentally. Advertisements will include research flyers and brochures posted around CUMC,
NAMI website, Facebook advertisements, advertisements in local newspapers and on radio stations,
information posted on departmental websites, flyer mailings, pharmacies, Craigslist, ResearchMatch.com,
senior community centers, college campuses, and public talks and events. For direct clinical or research
referrals, a clinical staff member known to the patient will approach him/her and raise the possibility of
study participation. We would also like to implement Columbia University's RecruitMe website as a
recruitment method.
How and by whom will subjects be approached and/or recruited?
Recruitment in the Clinic for Aging, Anxiety, and Mood Disorders (CAAM) comes from clinician
referrals, response to advertisements (radio, flyer, newspaper, online participant matching websites,
Facebook), patients who have finished or are currently enrolled in other protocols in the CAAM, or word of
mouth.
How will the study be advertised/publicized?
The study will be advertised/publicized through clinician referrals and advertisements, Columbia's
RecruitMe website, Research Match website, Facebook, Clinical Connection website, Craigslist website,
newspapers, recruitment flyers/brochures and mass mailers at community and senior centers, radio, the
National Alliance on Mental Illness NYC Metro Research Studies Website, mass email campaigns from
consumer marketing databases, which are compiled using public information, surveys, subscription
information, home owner information, and phone directory information, pharmacies, senior community
centers, college campuses, and public talks and events.
All web based recruitment procedures have been previously approved by Chris Stanley for all of our
approved studies.
Do you have ads/recruitment material requiring review at this time?
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT04650217
Concurrent Research Studies


Protocol Summary Form
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Rutherford, Bret
Page 10 of 43
Will subjects in this study participate in or be recruited from other studies?
Yes
Describe concurrent research involvement
Subjects who are currently participating in or have recently completed IRBs #7540, #7289R, #7409, #7360,
#7489, #7976, #7733, and/or #7379 and meet the selection criteria for this study may be offered
participation. Only an investigator not directly involved with an eligible subject’s care will approach the
subject to describe this protocol and have an informed consent discussion.
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Depressed older adults
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion criterion
Method of ascertainment
1. Age >= 60 years old
1. Clinical interview
2. DSM5 diagnosis of Major
Depressive Disorder (MDD) or
Persistent Depressive Disorder
2. SCID, clinical interview
3. Montgomery-Asberg Depression
Rating Scale (MADRS) >= 15
3. MADRS
4. Decreased processing speed (0.5
SD below age-adjusted norms on
the Digit Symbol Test or Trails A)
OR decreased gait speed (0.5 SD
below age-adjusted norms)
4. 0.5 SD below age-adjusted norms
on Digit Symbol Test or Trails A
(processing
speed) or average walking speed on
15 feet course 0.5 SD below age-
adjusted norms (gait speed)
5. Capable of providing informed
consent and adhering to study
procedures
5. Clinical interview
Create or insert table to describe the exclusion criteria and methods to ascertain them
Exclusion
criterion
Method of ascertainment
1. Diagnosis of
substance abuse or
dependence
(excluding
Tobacco Use
Disorder) in the
past 12 months
1. SCID, clinical interview


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Rutherford, Bret
Page 11 of 43
2. History of
psychosis,
psychotic disorder,
mania, or bipolar
disorder
2. SCID, clinical interview
3. Primary
neurological
disorder, including
dementia, stroke,
Parkinson’s
disease, epilepsy,
etc.
3. Medical history, MMSE. Parkinson's disease (PD)
will be ruled out by
satisfying (1) and (2) and (3 or 4) below: (1) patient
gives no history of PD during clinical interview, (2)
patient's primary doctor gives no history of PD, (3) there
are no signs of PD on physical exam in CAAM (e.g.,
absence of asymmetric resting tremor, decreased arm
swing, soft voice, decreased facial expression, difficulty
rising from chair, dystonia), (4) if a patient does have
one or more signs of possible PD on exam as per (3),
then Dr. Kimberly Kwei (study neurologist) will come
examine the patient and comment on whether PD can be
ruled out or whether PD is possible and patient needs
further work up
4. MMSE < 24
4. MMSE
5. MADRS
suicide item > 4 or
other indication of
acute suicidality
5. MADRS, clinical judgement, CGI
6. Current or
recent (within the
past 2 weeks)
treatment with
antidepressants,
antipsychotics, or
mood stabilizers
6. Clinical interview
7. History of
hypersensitivity,
allergy, or
intolerance to L-
DOPA; exposure
to LDOPA in the
past 30 days
7. Clinical interview
8. Any physical or
intellectual
disability
adversely affecting
ability to complete
8. Clinical interview, physical exam, Falls Efficacy
Scale, Short Physical Performance Battery


Protocol Summary Form
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Page 12 of 43
assessments or
exercise training,
including
significant risk of
falling or fear of
falling during
home exercise as
measured by Falls
Efficacy Scale >27
or SPPB < 7
9. Acute, severe,
or unstable
medical illness or
in the opinion of
primary medical
doctor (PMD) not
safe to participate
in exercise
program
9. Clinical interview, physical exam, history from PMD
10. Mobility
limiting
osteoarthritis of
any lower
extremity joints,
symptomatic
lumbar spine
disease, or history
of joint
replacement /
spine surgery that
limits mobility
10. Clinical interview, physical exam, medical history
11. Has a medical
condition managed
with
medication and/or
device and the
managing
physician
considers the
condition and/or
its management a
contraindication to
the research
use of L-DOPA in
11. Clinical interview, medical history, discussion
with participant's clinician


Protocol Summary Form
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Rutherford, Bret
Page 13 of 43
this participant
For participants
undergoing MRI
scanning
procedures only
(N=40;
participants may
participate in
clinical portion of
study-only if they
are ineligible for
MRI scanning):
12.
Contraindication
to MRI scanning
12. Clinical interview, MRI Safety Screening Form
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of
Authorization)
No
Waiver or alteration of consent
No
Waiver of documentation of consent
No
Waiver of parental consent
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB #
6395R
Describe Study Consent Procedures
Following clinical evaluation and screening procedures, a study clinician authorized to obtain patient
consent will explain the study procedures along with the attendant risks, benefits, and alternatives,
including the anticipated outcome of doing nothing. The study clinician will then leave the room while the
potential subject reads the consent form and return to answer any questions the subject has. During the


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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
Brewster, Katharine
Broft, Allegra, MD
McClellan, Denise
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
Study Overview
Briefly, following baseline screening and eligibility determination, subjects who decide to participate by
signing informed consent will undergo testing of baseline aerobic capacity in Mentor Dr. Richard Sloan's
laboratory in the Division of Behavioral Medicine at Columbia/New York State Psychiatric Institute
(NYSPI). Half of all subjects (N=10 per group, N=40 total) will undergo baseline magnetic resonance
imaging (MRI) including structural scanning and functional imaging with an effort-based decision making
(EBDM) and virtual reality maze navigation (VRMN) tasks. All subjects will have comprehensive cognitive
assessment, including specific tests focused on processing speed and executive function, and a motor
evaluation (including gait speed and kinematics using the GaitRite walkway) will be performed. Next,
participants will be randomized in double-blind fashion to receive carbidopa/levodopa (L-DOPA) or
placebo tablets three times daily (9am, 1pm, 5pm). Also at Week 0, participants will be randomized to
exercise training 4 times weekly (Exercise) or a stretching and toning control (Control). This will result in
four treatment groups: L-DOPA + Exercise (N=20), L-DOPA + Control (N=20), Placebo + Exercise
(N=20), and Placebo + Control (N=20). Subjects assigned to Exercise training will exercise individually at
their home on a program set each week by Dr. Sloan and the research assistant (RA) coach, who will work
with the patient to ensure they train according to the program at the appropriate level of intensity.
Participants assigned to the Control condition will engage in a series of stretches and toning exercises
designed to promote flexibility and improve core strength. All subjects will have follow up clinic visits for
12 weeks in order to monitor their depressive symptoms as well as assess compliance and tolerability of L-
DOPA/Placebo and Exercise/Control interventions. Baseline assessments, including structural and task-
based MRI scanning, will be repeated at Week 12 to measure the effects of the interventions. Please see Fig.
1 for a graphic depiction of the design.


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Evaluation
1. Every subject evaluated for this protocol will receive a clinical interview by a psychiatrist, psychologist,
or nurse practitioner. A psychiatrist or other qualified physician will see participants to evaluate medical
aspects of eligibility, including screening for signs or symptoms of Parkinson’s Disease (PD). If there is any
concern, they will be referred to the study neurologist (Dr. Kimberly Kwei at Columbia). Additional
assessments will be administered by a trained rater (BA, RN, or SW) in CAAM, including the Montgomery
Asberg Depression Rating Scale (MADRS) and a SCID performed by a trained rater. Raters in CAAM
receive their initial training from Nancy Turret, SW who has been administering these tools in CAAM for
many years. The training involves a combination of in person didactics, videotaped interview viewing,
shadowing an experienced rater, and conducting a number of supervised interviews. Supervision occurs by
Ms. Turret as well as study clinicians (MDs and NP) in weekly CAAM meetings and on an ongoing basis as
needed.
2. If a subject has a diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder
(PDD), he/she will be informed of this and educated about the availability of treatments for depression. If
a subject is not interested in depression treatment during the 12 weeks of study participation and/or prefers
to begin with an experimental treatment for slowing and depression, he/she will be offered participation in
the present study provided there is no suicidal ideation present. Based on the extant data supporting the
efficacy of antidepressants for MDD and PDD, they will be informed that antidepressant treatment would be
a very reasonable option for their condition. These potential subjects will be offered the option of being
referred out for depression treatment, and it will be clarified that L-DOPA is not as yet a treatment for
MDD. Thus, all potential participants in this study must state their preference not to be treated with a
standard treatment for depression.
3. Next, trained raters (BA, RN, or SW) in CAAM will assess processing speed using the Digit Symbol
test from the WAIS-III and the Trail-Making Test Part A. Digit Symbol or Trails A will be used as a
selection criterion, with patients included in this study if they score 0.5 SD below the age-adjusted norms on
Digit Symbol or Trails A. Patients’ gait will be assessed by trained raters as walking speed in m/s on a
Gaitrite walkway system. Patients are instructed to walk at their usual or normal speed starting and ending at
a point 6 feet prior to and after the walkway course to eliminate acceleration and deceleration effects. Two
trials will be completed, and gait speed will be based on the average of 2 trials. Gait speed will be used as
a selection criterion, with patients included in this study if they have a gait speed of 0.5 standard
deviations below age-adjusted norms.
4. If subjects are eligible for the study after review of their processing speed and gait speed and decide to
participate by signing informed consent, then they will complete the remainder of the baseline assessment.
This includes recording of each subject’s chief complaint, referral source, age of onset of mood and/or
cognitive decline, number prior depressive episodes, age, sex, marital status, race and ethnicity, years of
education, employment status and income, years of education, family history. We also will document
medical history, physical exam, urine drug screen, CBC, chemistries and electrolytes, thyroid profile,
vitamin B12 and folate levels, urine analysis, and ECG. Vital signs will be measured at baseline and
monitored weekly throughout the study. The Cumulative Illness Rating Scale-Geriatric (CIRS-G) will be
filled out at baseline to measure chronic medical illness burden. Subjects’ current physical pain will be


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assessed weekly using a 100mm Pain Visual Analog Scale (VAS) and used as a covariate in analyses of
gait speed.
5. In the situation where a potential participant is taking medication and/or has a device to stabilize or
manage a medical condition, the research physician will, without exception, contact the physician
managing the condition to describe the possible research use of L-DOPA, to discuss any possible risks,
and to obtain the managing physician’s opinion as to whether the participant’s condition and/or it’s
management is a contraindication to the research use of L-DOPA in this participant. This discussion
and its outcome will be documented in the research chart.
6. Otherwise eligible subjects who are currently taking an ineffective antidepressant medication (i.e.,
the individual is symptomatic at a level meeting inclusion criteria) will be offered participation as
above after a discussion of the risks, benefits, and alternatives. No patients will be taken off of
effective antidepressant medications solely for the purpose of research. Should an individual taking
an ineffective antidepressant medication wish to participate and sign consent, their psychiatric care
will be taken over by a CAAM study clinician after a discussion with their prescribing physician.
Such participants will be tapered off of the ineffective medication as per standard clinical practice
(depending on the medication) and be followed closely in CAAM, likely through weekly visits. Should
a participant be unable to tolerate the medication taper due to increasing depressive symptoms, they
will be withdrawn from the study and entered into the 3 month open treatment period directly. Once
participants are washed off of the medication they will proceed with the study assessment described in
points 7-9 immediately below. Subjects must be off medication for 2 weeks prior to neuroimaging
procedures and beginning the L-DOPA study medication.
7. We will assess episodic memory using the Wechsler Memory Scale Logical Memory Test I & II (119).
Inclusion of this test will allow us to identify deficits in episodic memory functioning consistent with
amnestic mild cognitive impairment (aMCI). Executive function will be assessed via the NIH-EXAMINER
battery designed to assess executive functions reliably, comprehensively, and efficiently (120-121).
Domains of physical function assessed at baseline and Week 12 include the Short Physical Performance
Battery (SPPB) (122), a performance measure of gait, balance, and lower extremity strength sensitive to
meaningful change and the Pittsburgh Fatigability Scale (PFS) (123). The Falls Efficacy Scale-International
will assess subjects’ fear of falling (124-125), and weekly physical activity will be measured with the 7-Day
Physical Activity Recall questionnaire (126). The 36-item self-report World Health Organization Disability
Assessment Schedule 2.0 (WHODAS2) provides a global measure of disability, and the self-report Measure
of Everyday Cognition (ECog) will measure change in functioning relevant to 7 specific cognitive domains
(127). These measures will be repeated at study endpoint.
8. Baseline aerobic capacity of all subjects will be assessed prior to randomization in the Behavioral
Medicine Division at CUMC (Co-Inv Sloan) using a sub-maximal stress that correlated highly with the
results of a full-maximal stress test (128). The tests will be conducted by Vincenzo Lauriola, who has a
master’s degree in exercise physiology and is a PhD candidate in the exercise physiology program at
Teachers College. The RA coaches are all college graduates who have been trained by Vincenzo. This is the
arrangement used for many of the Behavioral Medicine Division's IRB approved exercise studies. This test
comprises walking on a treadmill at progressively increasing rates. If the participant’s heart rate (HR) at the
end of a stage, measured by telemetry (Model RS400, Polar Electro OY, Finland) is less than 85% of that


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predicted by the maximal heart rate equation (220-age), the participant will complete the next stage. Each
participant’s V̇O2max is estimated from the exercise HR at the end of the test according to established
equations, and the results are used to establish target HR for the 12-week training period. Following the 12-
week treatment program, these procedures will be repeated to determine change in aerobic capacity.
9. To minimize any risks of COVID transmission during assessments in Dr. Sloan's Laboratory, all NYSPI
and Columbia safety procedures will be followed, including the pre-screening of participants for COVID
symptoms prior to their appointments and screening on the day of appointments. All participants will be
required to wear a face covering when they come on site. The minimum number of staff necessary to
conduct the testing in the Sloan Lab will be present, and these staff will be wearing N95 masks and face
shields during the entire time the participant is onsite. Participants will not wear face coverings during the
submaximal exercise tests at baseline and endpoint. We will minimize the risk of COVID transmission in
three ways. First, no more than one subject per day will be assessed in the Sloan Lab, which will allow time
for sufficient air turnover in the space. Second, we have consulted with Dr. Rochelle Goldsmith, Director of
the Exercise Physiology Laboratory at Columbia, who has researched the best methods to disinfect the air in
exercise laboratories. Following her recommendation (which mirrors procedures currently being used at the
Mayo Clinics), will purchase a Model SS-400 portable air cleaner from Sentry Air Systems (please see
specs for this device in attachments). This industrial grade fume extractor will run during the time
participants are in the Sloan Lab and for 3 hours afterward. Third, we will follow relevant procedures for
wiping down surfaces and minimizing infection risk as implemented in the dentistry department at
Columbia (please see summary of procedures that we have obtained from the Dentistry Dept. attached).
10. Finally, additional clinical measures include the Antidepressant History Form (ATHF) and the Inventory
of Depressive Symptoms--Self Report (IDS-SR).
MRI Scanning
10. All of the N=80 Depressed subjects will undergo MRI scanning on NYSPI's 3T GE Premier
system before and after 12 weeks of treatment with L-DOPA and/or Exercise. For structural imaging, we
will acquire a high resolution 3D T1 weighed image using a MPRAGE sequence with TI=1060ms, flip
angle=8º, voxel size=1x1x1mm, and 208 contiguous slices (6 min). For task-based fMRI, we will use a
multi-band (or Simultaneous Multi-Slice) EPI sequence with multiband acceleration factor 6,
TE/TR=30/800ms, flip angle=52°, matrix=90x90, 60 slices, and voxel size=2.4x2.4x2.4 mm (EBDM 2 runs
at 9 min/run; VRMN 2 runs at 11 min/run). Thus, total scan time will be approximately 1 hour. All scanning
RAs have undergone MRI safety training and are experienced with the preparation of research subjects in
the MRI scanner. RAs have been trained in the performance of fMRI tasks via didactics with the Principal
Investigator and ongoing supervision provided in biweekly scientific meetings of the larger
Columbia/Vanderbilt neuroimaging team.
11. As previously implemented in Dr. Michael Treadway’s Lab (Mentor and collaborator on this K24
project), the Effort-based Decision Making (EBDM) task requires participants to make binary choices given
information about the dollar amount of a reward and the required amount of physical effort to obtain that
reward. Individuals opt to receive $1.00 for no work or to complete an effortful task (button pressing) for a
larger reward of varying amounts (32). In the Virtual Reality Maze Navigation (VRMN) task, participants
undertake first-person navigation through a single-path virtual maze in pursuit of monetary rewards. Trial


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types include a High-Effort condition requiring repeated button presses to advance through the maze,
a Low-Effort condition allowing participants to advance through the maze by simply holding down buttons,
a Passive-Motion condition in which participants view moving through the maze without making any
action, and a No-Motion condition where participants wait for the approximate duration of the maze and are
then teleported to the goal (33). Each trial is associated with one of 4 reward magnitudes from which an
amount is randomly selected.
12. For all of the MRI procedures, participants are instructed to lie as still as possible within the magnet.
The MRI scan is completed in one session, and lasts for a total of approximately 60 minutes, including
time for positioning subjects in the scanner. All precautions and protections are given to the participant to
ensure that they are as safe and as comfortable as possible. For participants’ comfort within the scanner,
they lie on a padded table with a pillow to rest their heads on. A blanket is also provided to keep participants
warm during the procedure. If the participant appears nervous or anxious, a trained member of the research
staff remains with them inside the scanning suite for the duration of the scan. The participant is given a
squeeze ball to terminate the scan at any time. If he/she squeezes the ball, he/she will be removed from the
scanner immediately. Participants may decline the MRI scans at any time. If the participant chooses not to
be scanned, his/her participation in the study will not be affected. 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, Brewster, Roose, or Broft, present.
Clinical treatment
13. Participants will be randomized to receive either active L-DOPA or matching placebo as well as
Exercise or a stretching/toning control based on a block design using R Statistical Software version 3.4.3 (R
Foundation for Statistical Computing, Vienna, Austria). Participants, physicians and research staff will be
blinded to L-DOPA vs. placebo group assignment but given the nature of the intervention will be aware of
assignment to Exercise or stretching/toning control. The NYSPI Pharmacy will maintain the randomization
key for each site and can unblind individual subjects in emergencies. The medication blind will not be
broken until study completion. Following the 12 week duration trial participants will have repeat MRI
scanning and cognitive/behavioral testing.
14. Subjects will take active or placebo tablets three times daily (9am, 1pm, 5pm). Those assigned to L-
DOPA will begin with a Week 1 L-DOPA daily dosage of 150mg, or 1.5 25mg carbidopa/100mg
levodopa tablets at 9am and placebo tablets at 1pm and 5pm. In Week 2 the L-DOPA daily dose will
increase to 300mg (1.5 25mg carbidopa/100mg levodopa tablets at 9am and 5pm, with placebo at 1pm),
followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets three
times daily). This dose will then be continued for the remainder of the 12 week duration study. Subjects
assigned to placebo will take 1.5 placebo tablets three times daily for three weeks. Individuals will be
instructed to maintain the same timing of doses throughout the study. Individuals unable to tolerate
an increased dose will have their dosage reduced to the maximum previously tolerated dose.
15. At each weekly visit, subjects will meet with a psychiatrist or study physician. Both in our Pilot study
and the literature overall, L-DOPA is an extremely well tolerated medication at doses < 600mg, which is
substantially less than the doses often reached in the treatment of Parkinson’s disease (900-1200mg).


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LDOPA 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.
16. After a training visit in Dr. Sloan's laboratory, during which subjects are taught the proper use of the
equipment, how to monitor HR, and maintain training logs, subjects assigned to Exercise will complete 4
training sessions per week at their homes on the equipment of their choosing (either an Exerpeutic 900XL
Extended Capacity Recumbent Bike with Pulse or Sunny Folding Climbing Stepper). Exercise equipment
will be provided to participants at no cost to them by the study. Proper home assembly and initial working
of the exercise equipment will be verified with the participant, including visually through the use of
teleconferencing, prior to the initiation of the treatment portion of the study. Subjects will
exercise individually at their home on a program set each week by Dr. Sloan and the research assistant (RA)
coach assigned to him/him, who will work with the patient to ensure they train according to the program at
the appropriate level of intensity. Additionally, we will gather information on support people available at
home for each participant and invite them, if the participant so desires and grants permission, to be involved
with the exercise regimen and help ensure that the participant is following the proper regimen. Adherence
to the training programs is documented by weekly logs and data from HR monitors used during each
training session. Subjects are contacted on a weekly basis by their coaches to monitor their progress. If the
performance of participants in the aerobic training condition falls out of range, they will be contacted more
frequently until they return to prescribed training levels. All training sessions will comprise 10-15 minutes
of warm-up and cool down and 30-40 minutes of workout. Subjects will select from a series of aerobic
activities and for Weeks 1-2 will train at 55-65 percent of maximum HR as established during their
qualifying CPET. In Weeks 3-4, they will increase exercise intensity to 65-75 percent of maximum HR, and
in Weeks 5-12 they will train at 75 percent of maximum HR. To exercise at their target HR, participants will
wear a Polar Electro model s610i heart rate monitor during each training session, which provides a digital
display of HR and recorded HR throughout the training session. At the end of each session, participants
upload their training data so that coaches may verify their compliance with exercise program.
17. Subjects assigned to the Exercise control condition will participate in a prescribed stretching and toning
regimen. Under the guidance of their trainers and coaches, participants in this condition will engage in a
series of stretches and toning exercises designed to promote flexibility and improve core strength. All upper
body and lower body major muscle groups will be included. Core strengthening exercises will include
abdominal, back, and pelvic muscles. Like subjects in the exercise condition, they will wear Polar HR
monitors to assure that they will not improve in aerobic capacity.
Assessments
18. Subjects are expected to have a screening/evaluation visit, Week 0/pre-treatment MRI scanning day,
and monitoring visits at Weeks 2, 4, 8, and 12. Participants will have telephone contacts with study
physician and research staff at Weeks 6 and 10 and will be offered more frequent in-person visits if
indicated. At each contact, depression severity is measured using the MADRS and adverse events are
assessed. The presence of any suicidal thoughts will be assessed at every contact. Vital signs (weight, heart
rate, blood pressure) will also be measured.


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19. Cognitive assessments will be performed at baseline and Week 12. Gait will be assessed at baseline and
Week 12 with both single and dual tasks (ST, DT) using the GaitRite system (Sparta, NJ), which assesses
gait parameters in real time (gait speed, cadence, stride length). For the ST (primary gait outcome),
participants are instructed to walk at their usual or normal speed over the 15’ walking course. For the DT
(secondary outcome), participants are instructed to walk at their usual pace while simultaneously verbally
listing as many animals as possible (fluency DT). In addition, a counting DT will be used in which
participants are instructed to walk at their usual pace while simultaneously performing serial subtractions by
threes starting at 100.
20. Other clinical assessments collected each visit include the CGI Severity and Improvement (provide a
clinical assessment of subjects at each visit and help maintain safety by identifying clinical worsening),
Inventory of Depressive Symptoms—Self Report (IDS-SR) (provide a self-report measure for depressive
symptoms), Structured Pill Count Interview (to assess study medication compliance), and the Treatment
Emergent Side Effect Scale (TESS) to monitor side effects associated with medication treatment. We will
utilize the Unified Parkinson’s Disease Rating Scale (UPDRS) to identify any dyskinesias caused by
LDOPA, although based on our previous studies we are not expecting to observe motor side effects with
the L-DOPA doses and duration being used in this study.
End of study procedures
21. Following the 12 week duration study, endpoint assessments of psychiatric symptoms,
cognition, and motor functioning will be made and post-treatment MRI will be conducted. Once post-
treatment research procedures are completed, patients will enter 3 month open treatment period provided
free of charge as described below.
Attestations
As both Area Leader and Principal Ivestigator of this study, I attest to follow the COVID-19 Safety
Guidelines for Columbia Psychiatry and NYSPI Re-Entry outlined in the NYSPI Director’s June 1st memo,
which include but are not limited to:
•Infection Control/PPE – Guidelines
•Research participants will only come on-site if absolutely necessary (e.g., for procedures).
•No volunteers/externs on-site.
•Clinical research teams will screen their participants for COVID symptoms (night before and day of onsite
visit, documenting this in the chart), and escort them in and out of the building. •COVID/COVID-like
symptoms in participants will be reported to IRB via PRISM.
You can upload charts or diagrams if any
Criteria for Early Discontinuation


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Criteria for Early Discontinuation
The risk of non-response or adverse events to L-DOPA and/or Exercise during the study period is addressed
by having close clinical follow up of study subjects and stringent withdrawal criteria. These criteria are (1)
participant withdraws his or her consent; (2) significant clinical worsening (in any aspect, including
motoric function or depressive symptoms) as defined by a CGI-Improvement scale of 6 (worse) or 7
(much worse) for 2 consecutive visits; or (3) development of significant side effects or an adverse event.
Any subjects meeting any of these criteria will be withdrawn from the study and treated clinically.
Furthermore, subjects may be withdrawn if they repeatedly miss scheduled appointments or clinical
worsening necessitates more intensive treatment. No treatment is currently available for slowing, so there is
not a standard of care treatment to offer patients withdrawn from the study. Thus, withdrawn patients will
be followed in the open treatment period, offered appropriate psychiatric treatments if they have any
conditions requiring treatment (e.g., depression), and be referred to their internist for close medical follow
up.
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
A 20cc blood sample will be drawn from all depressed subjects at baseline. General medical tests will be
performed as safety screens for Depressed subjects, such as CBC, Chem 7, LFTs, TSH, cholesterol, B12,
and folate.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Structured Clinical Interview Diagnostic for DSM 5 (SCID): this semi-structured diagnostic interview will
allow determination of whether subjects meet selection criteria.
Cumulative Illness Rating Scale-Geriatric (CIRS-G) will be filled out at baseline to measure chronic
medical illness burden.
Subjects’ current physical pain will be assessed weekly using a 100mm Pain Visual Analog Scale (VAS)
and used as a covariate in analyses of gait speed.
MMSE: standard means of assessing global cognition. The SCID, CES-D, and MMSE will be measured at
baseline for the purpose of subject selection, while the following measures will be collected weekly
throughout the study.
Montgomery Asberg Depression Rating Scale: standard measure of depression severity that measures
changes in depressive symptoms.
CGI Severity and Improvement: scales measuring the clinician’s view of subjects’ global functioning that
will provide a clinical assessment of subjects at each visit and help maintain safety by identifying clinical
worsening.


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Structured Pill Count Interview: assessment of study medication compliance accounting for each dose of
prescribed study medication during the study period.
Blind Assessments rate clinician’s and patient’s guesses as to study drug assignment.
Unified Parkinson’s Disease Rating Scale (UPDRS): standardized, reliable, and valid instrument
for assessing the severity of the clinical features of PD; questions 32 and 33 will be used in this study to
assess the duration and disability of dyskinesias caused by L-DOPA. While we include this measure, we are
not expecting to observe dyskinesias in healthy subjects or at the L-DOPA doses being used in this
study. Typically, such L-DOPA side effects emerge only in patients who have had Parkinson’s disease for a
number of years and then only if the LDOPA dose is raised to 600 mg or more.
Treatment Emergent Side Effect Scale: standardized general checklist used in our clinic for monitoring
side effects associated with medication treatment.
Inventory of Depressive Symptoms—Self Report (IDS-SR): rating scale for depressive symptoms based
on DSM criteria that has been increasingly used in antidepressant studies due to its equivalent weightings
for each item, understandable anchor points, and inclusion of all DSM criteria.
Processing speed will be assessed using the Digit Symbol test from the Wechsler Adult Intelligence Scale-
III (WAIS-III) and the Pattern and Letter Comparison tests. These tests are all reliable and valid, with
moderate to high loadings on the latent speed factor.
We will assess episodic memory using the Wechsler Memory Scale Logical Memory Test I & II. Inclusion
of this test will allow us to identify deficits in episodic memory functioning consistent with amnestic mild
cognitive impairment (aMCI).
Executive function will be assessed via the NIH-EXAMINER battery designed to assess executive functions
reliably, comprehensively, and efficiently.
Domains of physical function assessed at baseline and Week 12 include the Short Physical Performance
Battery (SPPB), a performance measure of gait, balance, and lower extremity strength sensitive to
meaningful change and the Pittsburgh Fatigability Scale (PFS).
The Falls Efficacy Scale-International will assess subjects’ fear of falling, and weekly physical activity will
be measured with the 7-Day Physical Activity Recall questionnaire.
The 36-item self-report World Health Organization Disability Assessment Schedule 2.0 (WHODAS2)
provides a global measure of disability, and the self-report Measure of Everyday Cognition (ECog) will
measure change in functioning relevant to 7 specific cognitive domains.
Gait will be assessed as both a single and dual task (ST, DT) using the GaitRite system (Sparta, NJ), which
assesses gait parameters in real time (gait speed, cadence, stride length). For the ST, patients are instructed
to walk at their usual or normal speed over the 15’ walking course. For the DT, patients are instructed to
walk at their usual pace while simultaneously verbally listing as many animals as possible (fluency DT). In


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addition, a counting DT will be used in which patients are instructed to walk at their usual pace while
simultaneously performing serial subtractions by threes starting at 100. Patients will start and end at a
point 2 meters from the GaitRite mat to eliminate acceleration and deceleration effects. Each ST and DT
will be assessed two times with the average used in the analyses. The ST assessment of walking speed in
m/s will be the primary gait outcome measure for this study.
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
Select the number of drugs used in this study
1
Drug #1
Name of the drug
carbidopa/levodopa
Manufacturer and other information
We will be using generic carbidopa/levodopa (L-DOPA) 25/100 tablets in this study. We will purchase
them through the New York State Psychiatric Institute (NYSPI) pharmacy, using the generic manufacturer
recommended. L-DOPA is currently approved by the Food and Drug Administration (FDA) for the
treatment of the symptoms of idiopathic Parkinson's disease, post-encephalitic parkinsonism, and
symptomatic parkinsonism. This project proposes off-label use of L-DOPA in individuals with significant
cognitive/motor slowing.
Approval Status
No IND is required
Choose one of the following options
FDA conditions are met (see 'Rules')
Explain
The proposed use of L-DOPA is below or within the usual range, and we are not seeking an FDA indication
for its use in this condition. Our prior communications with Frank Lutterodt (Senior Regulatory Health
Project Manager) in connection with IRBs 7270, 7733, and 7976 have confirmed this.
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


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currently not proven, there will be a 12-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 12 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 L-DOPA after receiving an explanation of the potential risks of chronic administration. If they do
not want to continue L-DOPA, it will be discontinued after a 3 day step-down withdrawal of the drug.
Transferring after-study care to a non-study clinician protects against the development of bias in the study
clinicians and offers optimal clinical care to the subjects at the study conclusion.
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. L-DOPA Side Effects: Side effects will be assessed at each planned visit and as needed through
additional or unscheduled contacts. We will attempt to minimize side effects by slow dosage titration and
allowance for dose reduction if needed. We will withdraw subjects from the study if they cannot tolerate
the lowest dose of carbidopa/levodopa (L-DOPA) 37.5mg/150mg daily. L-DOPA is a well-tolerated
medication at the doses we will be using in this study. In healthy controls, the only available studies are
single-dose experiments, in which the sole reported side effect has been nausea. No serious adverse events
or side effects due to an effect on the nigrostriatal dopamine system have been observed in these studies.
There are many studies of chronic L-DOPA administration for the treatment of Parkinson’s disease (PD),
since this drug has been used since the 1960s. Perhaps the most relevant study was a clinical trial published
in the New England Journal of Medicine in 2004. In this study 361 patients with PD were randomized to
receive 150mg, 300mg, or 600mg L-DOPA for 40 weeks. In the 150mg and 300mg L-DOPA treatment
groups, the only side effects observed that were different from placebo were headache and nausea. No
dyskinesias or other neuropsychiatric effects were observed that were greater than the placebo group, and
this study lasted 40 weeks as opposed to 4 weeks (3 week dose titration, with 1 week taper) in this study.
In our preliminary work at NYSPI (IRB 7270), a series of depressed older adult outpatients (N=36 subjects
aged 75.3 ± 7.5 years, 44.4% male) were treated with open L-DOPA for three weeks (one week each of
150mg, 300mg, and 450mg). The overall drop-out rate was 8.3%, with 5.6% subjects dropping out due to
adverse effects of L-DOPA. Thirty of the total N=36 analyzed subjects reached the final L-DOPA dose of
450mg. Nausea was the most frequently reported treatment-emergent side effect, and the frequency of
subjects reporting nausea decreased over the course of the trial, from 19.4% of subjects reported for 150mg


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LDOPA, to 17.1% for 300mg L-DOPA, and 9.1% for 450mg L-DOPA. The only other side effects
reported by more than one subject were insomnia and headache. The emergence of dyskinesias during L-
DOPA treatment was evaluated using items 32 and 33 of the UPDRS, and no significant change from
baseline was observed on either these items. Mean scores were 0.0 at Week 3 for both items. No significant
adverse events (SAEs) attributable to study medication were noted during the project. Since we found the
greatest effects on processing/gait speed at 450mg without no decrease in tolerability relative to 150mg and
300mg doses, we selected 450mg as the target dose for the mechanistic probe in the present study. In our
pilot work, L-DOPA 450mg was associated with increased dopaminergic availability in the sensorimotor
and associative striatum.
a. L-DOPA common side effects: In patients taking L-DOPA for the management of bradykinesia and
freezing associated with PD, the most common side effects are dyskinesias (i.e., choreiform, dystonic, and
other involuntary movements) and nausea.
b. Other L-DOPA side effects: blood pressure changes, orthostasis, anorexia, dyspepsia, constipation,
psychotic episodes (e.g., delusions, hallucinations), vivid dreams, and nightmares.
c. Discontinuation Syndrome: A neuroleptic malignant-like syndrome (fever, akinetic crisis, rigidity,
autonomic disturbances) has been reported following withdrawal of levodopa in patients with PD.
2. Exercise Intervention: Another potential risk is associated with the exercise trial in older patients, and
specifically in adults with LLD and psychomotor slowing. Individuals can experience physical injury,
muscle soreness, and fatigue due to assessments of balance and gait and increased physical activity due to
exercise. Most will be self-limiting, though it is possible for more serious injuries to occur including broken
bones or joint dysfunction. Although an exercise-induced cardiovascular event is a potential risk, risk is
minimized by excluding patients with acute and unstable medical illnesses (e.g., severe aortic stenosis, or
severe congestive heart failure) and receiving verbal approval from the patient’s PMD prior to
randomization. All baseline and endpoint assessment sessions will be conducted in the Behavioral Medicine
Division here at Columbia University Medical Center. Center staff is trained in CPR and the facility is
equipped with an automated external defibrillator. In the event of a medical emergency, a team from the
hospital responds immediately. While we respect these risks associated with exercise, steps have been taken
to mitigate these risks:
a) Evaluation: Patients will undergo a medical and psychiatric assessment during their initial evaluation at
CAAM.
b) Pre-enrollment: Communication between the patients’ PMD and the study psychiatrist prior to study
enrollment and throughout the study will allow for any safety concerns from the PMD or from the research
staff to be discussed and addressed in a timely manner.
c) Exercise Protocol: The design of the intervention itself minimizes risk of physical injury. It is a
progressive, sequential design with built-in parameters to assess the progress each patient is making prior to
graduating to the next component of the exercise intervention. The exercise sessions are carefully designed
each week by the study team and communicated to the patient at the start of each week. These designs will
include warm-up, stretching, and cool-down components utilized to minimize injuries. Stretching exercises


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will consist of arm circles, neck rotations, toe reach, gluteal stretches, lateral leg swings, Achilles stretch
and ankle rolls. If a patient develops a significant illness requiring mobility restriction, surgery or
hospitalization, the PI, Dr. Sloan (who is experienced in the conduction of exercise protocols), and the study
psychiatrist will be informed and will contact the participant’s PMD to gauge as a team the preferred time
for his/her return to the exercise program. If adverse events develop during participation in the exercise
intervention, the adverse event will be reported and a one-week hiatus will be enforced. During this time the
patient will perform gentle, static stretching exercises and communicate his/her condition with the PI, Dr.
Sloan, study psychiatrist, and/or PMD, and, in accordance with this conference, will be slowly reintroduced
to the exercise program following the hiatus. Every precaution will be taken to ensure each patient’s
comfort, safety and security including the provision of fluids and rest as needed. For those individuals who
are extremely deconditioned, frequent rest periods and exercise in a seated position (stationary bike) will be
offered.
3. Exercise training—Risk of Dropout: Virtually all exercise-training programs suffer from substantial
attrition. Based on experience in several training programs and on the exercise literature, we have devised a
series of activities that maximize participant retention. The activities that are included to improve adherence
and monitor the safety of the patients throughout the 12-week protocol include:
a) Baseline Assessment and Training: Subjects will come to the Behavioral Medicine Division at the
Columbia University Irving Medical Center (CUIMC) for baseline assessment. They will undergo an
aerobic capacity assessment to determine the progressive nature of the exercise protocol they will undertake.
During this period, subjects will be trained on the general safety issues in exercising, instruction and
practice in the use of the heart rate monitor system and the exercise apparatus that they choose for their
program.
b) Home-based exercise program: Given that both exercise interventions and research studies in depressed
samples are met with issues of adherence, we determined that a home based exercise program with built-in
monitoring would be ideal for this patient population and geographic location (given weather issues in the
northeast in particular during the winter season, a home based program would allow for continued
adherence without the risk of falls due to icy or snowy conditions). Currently, this model is being
implemented for the treatment of individuals with social anxiety disorder at CUIMC on which Dr. Sloan is a
Co-I.
c) Exercise Logs: Subjects will complete detailed logs of their activity during each exercise session. These
logs will contain information on the date and duration of exercise training and the activities of each training
session. These logs will be collected at CAAM during their weekly visits in the antidepressant medication
portion of the trial and reviewed regularly to inform coaching phone calls.
d) HR Monitoring during all exercise sessions: Subjects will wear heart rate monitors that record HR
throughout the session and upload the data into a cloud-based system. These data provide rigorous
documentation of training intensity levels and determine the progressive nature of the subsequent exercise
routines. These data are monitored by Dr. Sloan’s lab, and the study research assistant and both the coaching
phone calls and the following week’s activities are devised based on these data and input from the patient.
e) Coach: An essential component of our training program is the research assistant coach assigned to each


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participant after consent has been obtained. The research assistant coach is trained in several behavioral
techniques. These include: phone contact two x per week (or more as needed), with email contact to
acknowledge good attendance and HR compliance, or encourage improvement if needed; answer exercisers’
reasons for noncompliance using positive suggestions and reframing to help the exerciser see feasible
solutions for overcoming compliance obstacles, and setting obtainable goals that aim for improvement over
time (e.g. exercise 2 times this week then aim for 3 times next week). The research assistant-coach is not
responsible for teaching exercise techniques; Dr. Sloan and the staff at the Behavioral Medicine Division at
CUIMC is responsible for communicating training and ongoing oversight of participants if needed for the
study. Coaches will follow all subjects, letting them know when it is time to schedule testing sessions and
begin training. The coaches also make motivation/reminder calls at a minimum two x per week. These calls
are intended to “cheerlead” subjects through their exercise programs. They also are intended to inform
subjects of any adherence issues (e.g., not exercising in their target heart rate range, not exercising
frequently enough). Coaches will review exercise logs collected during the patients’ visits to CAAM for
antidepressant medication management and enter these data into the study database. We have found that the
addition of coaches to our training programs substantially improves adherence.
f) Incentive: We offer an incentive for substantial adherence to the training: patients may keep both the
exercise apparatus that they chose to use during the exercise training and the HR monitor. In past studies,
virtually all of our subjects who completed the training sessions took advantage of this incentive.
g) Exercise Supervision: The entire program is monitored, with HR data and exercise logs monitored
throughout the 12-week intervention and patients’ physical health monitored during weekly visits to CAAM
as part of the medication management component of the trial. This monitoring will help mitigate risk of
injury. During the patient’s weekly visit to CAAM, clinicians will be instructed to be vigilant for the
emergence of “red flag” symptoms such as angina, shortness of breath, or hypotension. Participants will be
instructed to discontinue exercise if they experience significant pain, weakness, or joint swelling during or
after exercise.
4. Delay in Antidepressant Treatment Initiation: As specified in the above selection criteria, participants in
this study will have a DSM 5 depressive disorder and MADRS ≥15, but current treatment with
antidepressant medication is an exclusion criterion. Otherwise eligible subjects who are currently taking
an ineffective antidepressant medication (i.e., the individual is symptomatic at a level meeting inclusion
criteria) will be offered participation after a discussion of the risks, benefits, and alternatives. Those
wishing to participate will undergo a medication washout following standard clinical practice and be
closely followed by study clinicians until they are eligible to begin the study. The maximum duration of
delay of treatment for depression with an agent of known efficacy will be 12 weeks. No patients will be
taken off of effective antidepressant medications solely for the purpose of research, and patients will be
withdrawn from the study and treated if clinically indicated and desired by the patient.
A number of precautions have been taken to safely maintain participants antidepressant-free for the
duration of the proposed study. First, our selection criteria exclude individuals who are judged to be at high
risk of suicide (MADRS suicide item > 4). Second, we have stringent criteria for early discontinuation
and initiation of appropriate open clinical treatment. These criteria are (1) participant withdraws his or
her consent; (2) significant clinical worsening in the judgment of the study clinician; (3) a CGI-
Improvement rating of 6 (worse) or 7 (much worse) for 2 consecutive visits, or (4) development of


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significant side effects or an adverse event. Any subjects meeting any of these criteria will be withdrawn
from the study and treated as clinically indicated. Furthermore, subjects may be withdrawn if they
repeatedly miss scheduled appointments or clinical worsening necessitates more intensive treatment.
Finally, following the study, subjects are offered state-of-the-art clinical visits at no cost to them or their
insurer for 3 months, although they will be responsible for the cost of any antidepressant medications.
5. Interview, emergencies, and possible suicidal ideation: Subjects may experience discomfort during the
clinical interview and evaluations when discussing symptoms and current life events. The study
coordinators are experienced and skilled in interviewing depressed subjects. Half-way through the initial
assessment, the coordinator will ask the subject if they would like to take a break, and this will be
provided if desired. A study clinician will be available during all aspects of the assessment if there are any
questions or problems. In addition, should the subject express suicidal ideation at any time during the
interview, the study clinician will be contacted immediately to assess the subject and to determine the
appropriate course of action. Options for addressing suicidal ideation will include contacting the
individual’s mental health caregiver, referring for urgent (same day) evaluation and treatment in an
outpatient clinic, or emergency room evaluation and hospitalization. Similar practices will be used for other
emergencies, including but not limited to psychosis, homicidal or violent thoughts, or an acute change in a
subject’s physical status.
6. L-DOPA treatment—End of Study Procedures: We will provide up to 3 months of additional free clinic
visits following the end of this project to facilitate the return to clinical care. A non-study clinician in our
research clinic will be given the data on each subject’s response to L-DOPA. This clinician will discuss
with each subject on a case-by-case basis the risks and benefits of continuing L-DOPA treatment as well as
other options for the treatment of depression. Those who have benefited from the treatment and have not
had significant side effects may elect to continue receiving L-DOPA after receiving an explanation of the
potential risks of chronic administration. If they do not want to continue L-DOPA, it will be discontinued
after a 3-day step-down withdrawal of the drug. Transferring after-study care to a non-study clinician
protects against the development of bias in the study clinicians and offers optimal clinical care to the
subjects at the study conclusion.
7. Gait speed assessment: During the gait speed assessment and other physical performance measures,
patients may feel unsteady and their risk of falls may increase. To mitigate these risks, patients are
accompanied by research coordinators and/or doctors during each of the performance-based assessments
(including the gait assessment, balance test, and chair stand, the latter two components of the Short
Physical Performance Battery). Coordinators walk slightly behind and alongside the patients during the
gait assessment, providing support for the patients should they become unsteady during the procedure.
8. Breach of confidentiality: There is the potential risk of breach of confidentiality of clinical and
laboratory information. PI 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.
9. MR scanner environments. The physical confinement and isolation produced by the scanner
could cause mild to moderate emotional distress, although in our extensive past experience, subjects


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generally have tolerated the procedures well. To protect against this risk, subjects will be acclimated to the
MRI and its noise with training sessions in a mock scanner on the morning of the scan. Relaxation training
will be used to help calm anxious subjects and to reduce motion. Frequent praise and reminders to remain
still, along with an inflation pillow and taping of the subject’s forehead, will help to acquire motion-
free images. In the past dozen years, our group at Columbia/NYSPI has acquired superb,
motion-free structural and functional scans in 100s of adults affected by a variety of neuropsychiatric
illnesses. All subjects will be able to communicate directly with technologists and study staff to report any
emotional or physical distress during the scanning procedure. If they wish, the scan will be terminated
immediately, and the subject will be removed from the scanner.
10. 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.
11. 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.
12. Risks of blood draw: When obtaining a 20 cc blood sample, patients can experience side effects that
include pain, fainting, bruising, light-headedness, and, on rare occasions, infection. The staff will take
every precaution to avoid these difficulties. The staff members are all certified at the hospital to be drawing
blood from patients and are instructed to keep the comfort and welfare of our patients as their primary
priority.
Describe procedures for minimizing risks
Most procedures for minimizing risks are discussed in the context of the risks themselves above. Additional
procedures follow below:
1. Side effects will be assessed at each planned visit and if needed through additional or unscheduled
contacts. We will attempt to minimize side effects by slow dosage titration and allowance for dose
reduction if needed. We will withdraw subjects from the study if they cannot tolerate the lowest dose of
carbidopa/levodopa (L-DOPA) 37.5mg/150mg daily.
2. The 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.
3. 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


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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.
4. 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.
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 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. Risks of bruising, clotting, and infection during blood draw will be minimized by having venipuncture
performed by trained and experienced personnel under sterile conditions. To avoid
injury due to fainting, the butterfly needle will be inserted when the subjects are recumbent.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
All records of the participating subjects will be kept in a locked room with access provided only to staff
members. Patients’ names will be linked with code numbers in a password protected file to which only the
research assistant has access. Only these code numbers will appear on all pill bottles and paper measures
collected during study. All data collected will be kept confidential and used for professional purposes only.
Publications using these data will be done in a manner that protects the subjects’ anonymity. All
electronically stored data will be accessible by password known only to the principal investigator and
research assistants for the study.
Data shared with the National Institute of Mental Health Data Archive (NDA) will maintain patient
confidentiality by ensuring exclusion of all 18 identifiers (outlined by HIPAA) prior to data sharing.
Will the study be conducted under a certificate of confidentiality?
Yes, we have already received a Certificate of Confidentiality


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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. Subjects may
also experience physical functioning benefits from the aerobic exercise treatment or the stretching and
toning control condition.
Compensation and/or Reimbursement
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s).
Include justification for compensation amounts and indicate if there are bonus payments.
All subjects who complete a screening visit will be reimbursed $35.
Each subject will be compensated for the time spent conducting the cognitive, psychiatric, and aerobic
capacity assessments at both baseline and Week 12 ($100 each, totaling $200 per subject).
In addition, the subset of subjects undergoing neuroimaging procedures will receive an additional $50 per
scan ($100 total).
References
References
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Y, Bailey V, Valente E, Roose SP. Effects of L-DOPA Monotherapy on Psychomotor Speed and
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BR. Neural Mechanisms of Expectancy-Based Placebo Effects in Antidepressant Clinical Trials. J Psychiatr
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Response in Depression: A Meta-Analytic Review. J Psychiatr Res 2012, 46:697-702.
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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
Combination Treatment with L-DOPA and Exercise for Mood and Mobility Problems in Later Life 
IRB# 8065 
NCT#04650217 
Date: 10/22/2020 
 
 


 
Statistical Design and Power 
 
Overview: The primary aims of the study are to (1) measure individual and combined effects of L-DOPA and 
Exercise on cognitive, psychiatric, and physical performance measures in depressed older adults with 
psychomotor slowing and (2) investigate responsivity of reward-related dopamine circuits to L-DOPA and 
exercise. Exploratory aims are to evaluate correlations between real-world physical functioning metrics (i.e., gait 
speed, fatigability, physical activity) and behavioral/neural responses on the effort-based decision making 
(EBDM) and virtual reality maze navigation (VRMN) tasks in the scanner as well as compare differences in L-
DOPA and exercise acceptability, side effects, and attrition. As outlined in Human Subjects 4.3.,  the primary 
psychiatric/behavioral measure is the Hamilton Rating Scale for Depression (HRSD), the primary cognitive 
measure is the processing speed latent factor extracted from the Digit Symbol and Pattern/Letter Comparison 
Tests, and the primary physical functioning measure is gait speed measured on the Gaitrite walkway. The 
primary neuroimaging measures on the EBDM task are each participant’s subjective value discounting curve, 
the parameter k=the discount rate, and p=the inflection point at which participants begin to discount, and neural 
activations in ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC). For the VRMN 
paradigm, the primary measures are dorsomedial ventral striatum (dmVS) activation associated with effort (High-
Effort>Low-Effort) and action (Low-Effort>Passive-Motion) during the Cue and Navigation Start phases as well 
as anterior VS (aVS) activation associated with the effect of reward (Reward>No-Reward, across all conditions) 
and magnitude of reward (in parametric models) during the Reward phase. 
 
Before the specific techniques are applied, we will examine all variables at all time points for illegitimate values, 
outliers, and inconsistencies. The distribution of demographic variables and baseline clinical characteristics will 
be examined and described across the depressed subjects (N=80 total, 20 randomized to each group) in terms 
of means, standard deviations, proportions, and 95% confidence intervals. As a precaution, 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 
analysis will be implemented for all estimation and testing. All tests for main effects will be performed at two-
tailed significance 5%. 
 
Analyses for Specific Aim 1: Hyp 1: Analysis of covariance (ANCOVA) models will be used to determine 
whether there are significant main effects of L-DOPA and Exercise (as compared to Placebo and 
Stretching/Toning Control, respectively) on change in processing speed, gait speed, and depressive symptoms 
from baseline to 12-week follow-up. The change from baseline in (1) each of the three processing speed 
measures (Digit Symbol, Pattern and Letter Comparison tests) and also for the factor score obtained from a one-
factor confirmatory factor analysis model, (2) the continuous gait speed (m/s) measure (single and dual task), 
and (3) 24-item HRSD each will be analyzed as a function of treatment group and baseline values of the outcome. 
Contrasts of treatment difference in each variable will be formed and tested. Hyp 2: The L-DOPA x Exercise 
interaction will be evaluated by extending the ANCOVA model to include a 4-category treatment group variable 
and testing the contrast that the L-DOPA + Ex group shows the greatest improvement compared to Placebo + 
Control. 
 
Analysis for Specific Aim 2: Hyp 3: Outputs from the first-level analyses of functional MRI data described in 
Research Strategy C.7. will be entered into ANCOVA models similar to Aim 1. These will test for main effects 
of L-DOPA and Exercise (as compared to Placebo and Stretching/Toning Control, respectively) on behavioral 
and neural activation measures derived from the EBDM task (Hyp 3) and the VRMN task (Hyp 4). 
 
Exploratory aims: Correlations between each physical performance measure (e.g., single and dual task gait 
speed, fatigability scores on the Pittsburgh Fatigability Scale [PFS], Short Physical Performance Battery [SPPB] 
scores) with behavioral and neural activation measures derived from the EBDM and VRMN tasks will be 
examined at baseline and 12 weeks across all treatment groups. Correlations between change scores will also 
be examined. Linear and logistic regression will be used to examine differences in acceptability, side effects, 
and attrition across the 4 randomized conditions.  
 


Approach to Dropouts and Missing Data: The aims will be analyzed using intent-to-treat (ITT) sample on all 
randomized subjects. We will account for unobserved data by using inverse probability weighting by building a 
model with baseline predictors of drop-out (156). This weighting method is appropriate under the missing ‘at 
random’ assumption.   We also plan to perform sensitivity analyses using various models of missingness and 
assess the effect of the assumption of missing ‘at random’ on the inference (157-160). 
 
Power Analysis: For Aim 1, the analysis will include N=80 (N=20 per group) depressed subjects in a 
randomized, blinded, placebo-controlled mechanistic trial of L-DOPA and Exercise for between-group 
comparisons on cognitive, motor, and behavioral assessments. For Aim 2, we will evaluate the N=40 subject 
sub-sample (N=10 per group) for between-group comparisons on behavioral and neural activation data from the 
effort-based reward tasks. Based on our past pilot data (1), we anticipate a minimal dropout rate of approximately 
8%. 
 
Power for Aim 1: Hyp 1 examines differences between treatment groups (L-DOPA + Exercise, L-DOPA + 
Control, Placebo + Exercise, Placebo + Control) on change in cognitive processing speed, gait speed, and 
depressive symptoms. With N=74 LLD subjects providing follow-up data (approximately 37 receiving L-DOPA 
and 37 receiving Exercise), we will have at least 80% power to detect effect size differences of Cohen’s d = 0.63 
for the independent main effects of L-DOPA and Exercise, at a fixed significance level of 5%. Such a medium to 
large effect size would be clinically meaningful in LLD patients and is in a range of what has been observed in 
prior L-DOPA (1) and exercise studies (55,92). Hyp 2 evaluates whether an L-DOPA x Exercise interaction is 
present on these outcomes, such that the greatest improvements occur among participants randomized to L-
DOPA + EX. Based on simulations, with N=20 depressed subjects in each of the four groups, we will have >80% 
power to detect an interaction corresponding to an effect size of Cohen’s d=1.28. 
 
Power for Aim 2: Aim 2 will be evaluated using a mechanistic probe of dopaminergic function with a trial of 
L-DOPA and/or Exercise. We anticipate a low drop-out rate of 8% based on our pilot study of L-DOPA in N=36 
depressed adults very similar to the population to be enrolled here and assume roughly equivalent drop-out 
between groups (1). Hyp 3-4 examine between-group differences on our neuroimaging outcomes of interest after 
the acute 12 week across the two tasks (effort-based decision making [EBDM] task and virtual reality maze-
navigation [VRMN] task). We will have at least 80% power to detect effect size differences of Cohen’s d=0.96 
for the main effects of L-DOPA and Exercise on task responses (each participant’s subjective value discounting 
curve, the parameter k=the discount rate, p=the inflection point at which participants begin to discount, and 
neural activations in vmPFC, dACC, dmVS, and aVS ROIs). K24 Mentor Dr. Treadway’s previous studies 
examining between-group differences in willingness to expend effort using similar fMRI tasks have reported 
between-group effect sizes in this range (24).