A Study of L-DOPA for Depression and Slowing in Older Adults

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02744391
• Collaborator: (none)
• Enrollment: 47
• Location: 1
• Arm: 1
• Actual Duration (Months): 27.2
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

Individuals with Late Life Depression (LLD) often have cognitive problems, particularly problems with memory, attention, and problem solving, all of which contribute to antidepressant non-response. Our group and others have shown that decreased thinking speed is the central cause of functional problems in patients with LLD. Similarly, decreased walking speed is associated with depression and carries additional risk for falls, hospitalization, and death. Available evidence suggests that declining functionality in the brain's dopamine system contributes to age-related cognitive and motor slowing. The central hypothesis of this R61/R33 Phased Innovation Award is that by enhancing dopamine functioning in the brain and improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms in older adults.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder; Dysthymia; Depression Not Otherwise Specified; Decreased Processing Speed; Decreased Gait Speed	Drug: Levodopa	Phase 4

Detailed Description

This study will elucidate the neurobiology of slowing and LLD, identify a novel therapeutic target for depression, and contribute to the development of personalized treatment regimens for LLD. The multimodal neuroimaging methods detailed in this application will provide information about the neurobiology of aging-associated slowing and LLD at molecular, structural, and functional levels of analysis. These data will fill a crucial gap in our knowledge regarding what are the physiologic and functional consequences of dopamine depletion occurring across the lifespan in individuals without PD. Results from this project also will allow us to evaluate a novel therapeutic approach to LLD, which could have large public health ramifications given the prevalence, frequent treatment resistance, and chronicity characteristic of LLD. Even apart from patients with LLD, cognitive and motor slowing exact a large public health burden in terms of impaired functioning and increased morbidity and mortality, and this burden will only grow as the population ages. It is critical to develop treatments capable of altering the negative health trajectories associated with slowing in order to help older adults maintain independent functioning and live longer with an increased quality of life. Finally, while PET and MRI may prove critical to understand the neurobiology of slowing and LLD, their invasiveness and expense limit their roles in informing treatment decisions in clinical practice settings. For this reason the investigators are also assessing the influence of genetic moderators such as interleukin-6 (IL-6) and catechol-O-methyl-transferase (COMT) genotype on baseline dopamine functioning and response to L-DOPA. This may facilitate the identification of both high-risk individuals and those most likely to benefit from treatment interventions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study of L-DOPA for Depression and Slowing in Older Adults
• Actual Study Start Date: Aug 24, 2016
• Actual Primary Completion Date: Sep 14, 2018
• Actual Study Completion Date: Nov 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: L-DOPA Patients will receive titration of L-DOPA from 150 mg to 450 mg.	Drug: Levodopa; Other Names: L-Dopa

Outcome Measures

Primary Outcome Measures

1. Hamilton Rating Scale for Depression (24 Item) [Week 3]

   Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.

Secondary Outcome Measures

1. Digit Symbol Substitution Test [Screening]

   Digit symbol substitution test (DSST) is a neuropsychological test sensitive to brain damage, dementia, age and depression. The test is not sensitive to the location of brain-damage (except for damage comprising part of the visual field). It consists of (e.g. nine) digit-symbol pairs (e.g. 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 120 sec) is measured. The higher the number, the better the score.

2. Digit Symbol Substitution Test [Week 3]

   Digit symbol substitution test (DSST) is a neuropsychological test sensitive to brain damage, dementia, age and depression. The test is not sensitive to the location of brain-damage (except for damage comprising part of the visual field). It consists of (e.g. nine) digit-symbol pairs (e.g. 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 120 sec) is measured. The higher the number, the better the score.

3. Pattern Comparison [Screening]

   This test required participants to identify whether two visual patterns are the "same" or "not the same" (responses were made by pressing a "yes" or "no" button). Patterns were either identical or varied on one of three dimensions: color (all ages), adding/taking something away (all ages), or one versus many. Scores reflected the number of correct items (of a possible 130) completed in 90 s; items were designed to minimize the number of errors that were made.

4. Pattern Comparison [Week 3]

   This test required participants to identify whether two visual patterns are the "same" or "not the same" (responses were made by pressing a "yes" or "no" button). Patterns were either identical or varied on one of three dimensions: color (all ages), adding/taking something away (all ages), or one versus many. Scores reflected the number of correct items (of a possible 130) completed in 90 s; items were designed to minimize the number of errors that were made.

5. Letter Comparison [Screening]

   Subjects will be asked to determine whether two strings of letters are the same or different. There are 3 pages and the subject is given 30 seconds per page. Scoring is based on the number answered correctly. The higher the number, the better the score.

6. Letter Comparison [Week 3]

   Subjects will be asked to determine whether two strings of letters are the same or different. There are 3 pages and the subject is given 30 seconds per page. Scoring is based on the number answered correctly. The higher the number, the better the score.

7. Single Task Gait Speed [Screening]

   Patients' gait will be assessed as walking speed in m/s on a 15' walking course. Patients are instructed to walk at their usual or normal speed for a total of 27' (starting and ending at a point 6 feet prior to and after the 15' course to eliminate acceleration and deceleration effects). Two trials will be completed, and gait speed will be based on the average of 2 trials.

8. Single Task Gait Speed [Week 3]

   Patients' gait will be assessed as walking speed in m/s on a 15' walking course. Patients are instructed to walk at their usual or normal speed for a total of 27' (starting and ending at a point 6 feet prior to and after the 15' course to eliminate acceleration and deceleration effects). Two trials will be completed, and gait speed will be based on the average of 2 trials.

9. Dual Task Gait Speed [Screening]

   For the Dual Task, patients are instructed to walk at their usual pace while simultaneously verbally listing as many animals as possible. In addition, a counting Dual Task will be used in which patients are instructed to walk at their usual pace while simultaneously performing serial subtractions by three starting at 100. Patients will start and end at a point 2 meters from the Gaitrite mat to eliminate acceleration and deceleration effects. Dual Task will be assessed two times with the average used in the analyses

10. Dual Task Gait Speed [Week 3]

    For the Dual Task, patients are instructed to walk at their usual pace while simultaneously verbally listing as many animals as possible. In addition, a counting Dual Task will be used in which patients are instructed to walk at their usual pace while simultaneously performing serial subtractions by three starting at 100. Patients will start and end at a point 2 meters from the Gaitrite mat to eliminate acceleration and deceleration effects. Dual Task will be assessed two times with the average used in the analyse.

11. Inventory of Depressive Symptomatology-Self Report [Screening]

    Rating scale for depressive symptoms based on Diagnostic and Statistical Manual of Mental Disorders (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 Diagnostic and Statistical Manual of Mental Disorders criteria. Patients will be asked to circle the one response to each item that best describes them for the past seven days. The answers range 0-84. The higher the score the greater the depressive symptoms.

12. Inventory of Depressive Symptomatology-Self Report [Week 3]

    Rating scale for depressive symptoms based on Diagnostic and Statistical Manual of Mental Disorders (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 Diagnostic and Statistical Manual of Mental Disorders criteria. Patients will be asked to circle the one response to each item that best describes them for the past seven days. The answers range 0-84. The higher the score the greater the depressive symptoms.

13. Pre-Treatment [11C]-Raclopride Binding Potential: Sensorimotor Striatum [Baseline]

    Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.

14. Post-Treatment [11C]-Raclopride Binding Potential: Sensorimotor Striatum [Week 3]

    Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.

15. Pre-Treatment [11C]-Raclopride Binding Potential: Limbic Striatum [Baseline]

    Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.

16. Post-Treatment [11C]-Raclopride Binding Potential: Limbic Striatum [Week 3]

    Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.

17. Pre-Treatment [11C]-Raclopride Binding Potential: Associative Striatum [Baseline]

    Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.

18. Post-Treatment [11C]-Raclopride Binding Potential: Associative Striatum [Week 3]

    Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age >59 years

• DSM 5 non-psychotic Major Depressive Disorder, Dysthymia, or Depression Not Otherwise Specified

• Center for Epidemiological Studies Depression (CES-D) Rating Scale > 9

• Decreased processing speed (defined as 0.5 SD below age-adjusted norms on the Digit Symbol Test) and decreased gait speed (defined as average walking speed over 15' course < 1 m/s)

• Willing and capable of providing informed consent and complying with study procedures

• Prefer not to be treated with a standard treatment for MDD, Dysthymia, or Depression NOS (e.g., antidepressant medication or psychotherapy)

Exclusion Criteria:

• Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) within the past 12 months

• History of or current psychosis, psychotic disorder, mania, or bipolar disorder

• Diagnosis of probable Alzheimer's Disease, Vascular Dementia, or PD

• Mini Mental Status Exam (MMSE) < 25

• HRSD ≥ 25 or the presence of significant suicide risk

• Current or recent (within the past 4 weeks) treatment with antidepressants, antipsychotics, dopaminergic agents, or mood stabilizers

• History of allergy, hypersensitivity reaction, or severe intolerance to LDOPA

• Acute, severe, or unstable medical or neurological illness

• Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, history of joint replacement surgery, or history of spine surgery

• Hypotension (SBP<90), hypertension (SBP >150 or DBP > 90), past stroke causing sensory or movement deficits, cardiac arrhythmias, or any other severe or uncontrolled cardiovascular disease

• Having contraindication to MRI scanning (such as metal in body) or unable to tolerate the scanning procedures

• History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)

• Presence of a clinically significant brain abnormality, significant anemia, insulin dependent diabetes, a history of cardiovascular disease, or uncontrolled/untreated risk factors for coronary artery disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute

Investigators

• Principal Investigator: Bret Rutherford, MD, New York State Psychiatric Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 8, 2019
• Informed Consent Form - Sep 20, 2017

More Information

Publications

None provided.

• Responsible Party: Bret Rutherford, Assistant Professor of Clinical Psychiatry, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT02744391
• Other Study ID Numbers: 7270
• First Posted: Apr 20, 2016
• Last Update Posted: Jul 5, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Dysthymic Disorder; Levodopa

Study Results

Participant Flow

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Period Title: Overall Study
STARTED	47
COMPLETED	33
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Overall Participants	47
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 10.6%
>=65 years	42 89.4%
Sex: Female, Male (Count of Participants)
Female	30 63.8%
Male	17 36.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 17%
Not Hispanic or Latino	39 83%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	17 36.2%
White	26 55.3%
More than one race	0 0%
Unknown or Not Reported	3 6.4%
Region of Enrollment (Count of Participants)
United States	47 100%
Hamilton Rating Scale for Depression (24 item) (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	15.53 (6.04)

Outcome Measures

1. Primary Outcome

Title	Hamilton Rating Scale for Depression (24 Item)
Description	Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [Units on a Scale]	10.94 (6.87)

2. Secondary Outcome

Title	Digit Symbol Substitution Test
Description	Digit symbol substitution test (DSST) is a neuropsychological test sensitive to brain damage, dementia, age and depression. The test is not sensitive to the location of brain-damage (except for damage comprising part of the visual field). It consists of (e.g. nine) digit-symbol pairs (e.g. 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 120 sec) is measured. The higher the number, the better the score.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [total score]	31.86 (9.69)

3. Secondary Outcome

Title	Digit Symbol Substitution Test
Description	Digit symbol substitution test (DSST) is a neuropsychological test sensitive to brain damage, dementia, age and depression. The test is not sensitive to the location of brain-damage (except for damage comprising part of the visual field). It consists of (e.g. nine) digit-symbol pairs (e.g. 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 120 sec) is measured. The higher the number, the better the score.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [total score]	41.42 (9.56)

4. Secondary Outcome

Title	Pattern Comparison
Description	This test required participants to identify whether two visual patterns are the "same" or "not the same" (responses were made by pressing a "yes" or "no" button). Patterns were either identical or varied on one of three dimensions: color (all ages), adding/taking something away (all ages), or one versus many. Scores reflected the number of correct items (of a possible 130) completed in 90 s; items were designed to minimize the number of errors that were made.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [total score]	24.72 (5.42)

5. Secondary Outcome

Title	Pattern Comparison
Description	This test required participants to identify whether two visual patterns are the "same" or "not the same" (responses were made by pressing a "yes" or "no" button). Patterns were either identical or varied on one of three dimensions: color (all ages), adding/taking something away (all ages), or one versus many. Scores reflected the number of correct items (of a possible 130) completed in 90 s; items were designed to minimize the number of errors that were made.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [total score]	27.61 (4.95)

6. Secondary Outcome

Title	Letter Comparison
Description	Subjects will be asked to determine whether two strings of letters are the same or different. There are 3 pages and the subject is given 30 seconds per page. Scoring is based on the number answered correctly. The higher the number, the better the score.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [Total Correct]	14.36 (4.73)

7. Secondary Outcome

Title	Letter Comparison
Description	Subjects will be asked to determine whether two strings of letters are the same or different. There are 3 pages and the subject is given 30 seconds per page. Scoring is based on the number answered correctly. The higher the number, the better the score.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [Total Correct]	15.69 (4.54)

8. Secondary Outcome

Title	Single Task Gait Speed
Description	Patients' gait will be assessed as walking speed in m/s on a 15' walking course. Patients are instructed to walk at their usual or normal speed for a total of 27' (starting and ending at a point 6 feet prior to and after the 15' course to eliminate acceleration and deceleration effects). Two trials will be completed, and gait speed will be based on the average of 2 trials.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [m/s]	0.80 (0.18)

9. Secondary Outcome

Title	Single Task Gait Speed
Description	Patients' gait will be assessed as walking speed in m/s on a 15' walking course. Patients are instructed to walk at their usual or normal speed for a total of 27' (starting and ending at a point 6 feet prior to and after the 15' course to eliminate acceleration and deceleration effects). Two trials will be completed, and gait speed will be based on the average of 2 trials.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [m/s]	.92 (.21)

10. Secondary Outcome

Title	Dual Task Gait Speed
Description	For the Dual Task, patients are instructed to walk at their usual pace while simultaneously verbally listing as many animals as possible. In addition, a counting Dual Task will be used in which patients are instructed to walk at their usual pace while simultaneously performing serial subtractions by three starting at 100. Patients will start and end at a point 2 meters from the Gaitrite mat to eliminate acceleration and deceleration effects. Dual Task will be assessed two times with the average used in the analyses
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [m/s]	0.69 (.23)

11. Secondary Outcome

Title	Dual Task Gait Speed
Description	For the Dual Task, patients are instructed to walk at their usual pace while simultaneously verbally listing as many animals as possible. In addition, a counting Dual Task will be used in which patients are instructed to walk at their usual pace while simultaneously performing serial subtractions by three starting at 100. Patients will start and end at a point 2 meters from the Gaitrite mat to eliminate acceleration and deceleration effects. Dual Task will be assessed two times with the average used in the analyse.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [m/s]	0.82 (.24)

12. Secondary Outcome

Title	Inventory of Depressive Symptomatology-Self Report
Description	Rating scale for depressive symptoms based on Diagnostic and Statistical Manual of Mental Disorders (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 Diagnostic and Statistical Manual of Mental Disorders criteria. Patients will be asked to circle the one response to each item that best describes them for the past seven days. The answers range 0-84. The higher the score the greater the depressive symptoms.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [total score]	26.42 (12.57)

13. Secondary Outcome

Title	Inventory of Depressive Symptomatology-Self Report
Description	Rating scale for depressive symptoms based on Diagnostic and Statistical Manual of Mental Disorders (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 Diagnostic and Statistical Manual of Mental Disorders criteria. Patients will be asked to circle the one response to each item that best describes them for the past seven days. The answers range 0-84. The higher the score the greater the depressive symptoms.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	36
Mean (Standard Deviation) [total score]	15.09 (10.64)

14. Secondary Outcome

Title	Pre-Treatment [11C]-Raclopride Binding Potential: Sensorimotor Striatum
Description	Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	10
Mean (Standard Deviation) [mCi/ ml]	2.43 (0.25)

15. Secondary Outcome

Title	Post-Treatment [11C]-Raclopride Binding Potential: Sensorimotor Striatum
Description	Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis. Only 10 subjects were scanned in this study.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	10
Mean (Standard Deviation) [mCi/ ml]	2.19 (0.29)

16. Secondary Outcome

Title	Pre-Treatment [11C]-Raclopride Binding Potential: Limbic Striatum
Description	Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis. Only 10 subjects were scanned in this study.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	10
Mean (Standard Deviation) [mCi/ ml]	2.04 (0.18)

17. Secondary Outcome

Title	Post-Treatment [11C]-Raclopride Binding Potential: Limbic Striatum
Description	Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis. Only 10 subjects were scanned in this study.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	10
Mean (Standard Deviation) [mCi/ ml]	2.04 (0.15)

18. Secondary Outcome

Title	Pre-Treatment [11C]-Raclopride Binding Potential: Associative Striatum
Description	Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis. Only 10 subjects were scanned in this study.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	10
Mean (Standard Deviation) [mCi/ ml]	2.17 (0.26)

19. Secondary Outcome

Title	Post-Treatment [11C]-Raclopride Binding Potential: Associative Striatum
Description	Subjects received 2 [11C]-raclopride positron emission tomography (PET) scans: baseline and post-L-DOPA treatment. High resolution anatomical T1-weighted MRI scans were acquired for each subject and PET data were co-registered to the MRIs using maximization of mutual information (SPM12, Wellcome Centre for Human Neuroimaging). Regions of interest (ROIs) were applied to the MRIs and transferred to the PET data and included the sensorimotor striatum (post-commissural putamen, SMST), associative striatum (whole caudate and pre-commissural putamen, AST) and the limbic striatum (nucleus accumbens and the most ventral aspects of the pre-commissural caudate and putamen, LST). Additionally, an ROI was drawn on cerebellum as a reference tissue. ROI time activity curves were derived as the average activity in each ROI in each frame. The primary outcome measure was BPND, the binding potential with respect to the non-displaceable compartment, derived by the simplified reference tissue model.
Time Frame	Week 3

Outcome Measure Data

Analysis Population Description

47 patients were enrolled and 36 patients were analyzed according to the intent to treat analysis. Only 10 subjects were scanned in this study.

Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
Measure Participants	10
Mean (Standard Deviation) [mCi/ ml]	2.05 (0.26)

Adverse Events

Time Frame	3 Weeks
Arm/Group Title	L-DOPA
Arm/Group Description	Patients will receive titration of L-DOPA from 150 mg to 450 mg. Levodopa
All Cause Mortality
	L-DOPA
	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)
Serious Adverse Events
	L-DOPA
	Affected / at Risk (%)	# Events
Total	0/47 (0%)
Other (Not Including Serious) Adverse Events
	L-DOPA
	Affected / at Risk (%)	# Events
Total	0/47 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.