L-DOPA vs. Placebo for Depression and Psychomotor Slowing in Older Adults

• ClinicalTrials.gov Identifier: NCT03761030
• Recruitment Status: Terminated
• First Posted: December 3, 2018
• Results First Posted: May 22, 2023
• Last Update Posted: May 22, 2023
• Sponsor: New York State Psychiatric Institute
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Bret Rutherford, New York State Psychiatric Institute

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Major Depressive Disorder; Dysthymia; Depression
• Interventions: Drug: L-DOPA; Drug: Placebo Oral Tablet
• Enrollment: 51

Participant Flow

Recruitment Details
Pre-assignment Details	In total, 51 subjects were enrolled. Of the 51 enrolled, 20 subjects were found to be ineligible or did not continue in the study after enrolling. Thus, 51 participants enrolled and 31 were assigned to a treatment group and began the study.

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Period Title: Overall Study
Started	15	16
Completed	13	12
Not Completed	2	4

Baseline Characteristics

Arm/Group Title		L-DOPA Arm	Placebo Arm	Total
Arm/Group Description		Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets	Total of all reporting groups
Overall Number of Baseline Participants		15	16	31
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	15 participants	16 participants	31 participants
		69.0 (7.3)	66.7 (6.1)	67.8 (6.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	16 participants	31 participants
	Female	9 60.0%	10 62.5%	19 61.3%
	Male	6 40.0%	6 37.5%	12 38.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	16 participants	31 participants
	Hispanic or Latino	1 6.7%	4 25.0%	5 16.1%
	Not Hispanic or Latino	13 86.7%	11 68.8%	24 77.4%
	Unknown or Not Reported	1 6.7%	1 6.3%	2 6.5%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	16 participants	31 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	1 6.3%	1 3.2%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	4 26.7%	3 18.8%	7 22.6%
	White	9 60.0%	10 62.5%	19 61.3%
	More than one race	2 13.3%	2 12.5%	4 12.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	15 participants	16 participants	31 participants
		15	16	31
Hamilton Rating Scale for Depression (24 item) [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	15 participants	16 participants	31 participants
		21.1 (4.7)	20.3 (3.9)	20.7 (4.3)
		[1] Measure Description: The Hamilton Rating Scale for Depression (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.
Clinical Global Impressions--Severity [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	15 participants	16 participants	31 participants
		3.7 (0.6)	4.3 (0.7)	4.0 (0.7)
		[1] Measure Description: The Clinical Global Impressions--Severity (CGI-S) scale measures the clinician's assessment of global illness severity. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Higher scores denote more severe illness.

Outcome Measures

1. Primary Outcome

Title	Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks)
Description	The Hamilton Rating Scale for Depression (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. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.
Time Frame	Change from Baseline to 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants with Week 8 data available were analyzed.

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description:	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Overall Number of Participants Analyzed	12	13
Mean (Standard Deviation); Unit of Measure: units on a scale
	-2.2 (6.4)	-3.6 (5.8)

2. Secondary Outcome

Title	Digit Symbol Test
Description	The Digit Symbol test is a neuropsychological test measuring information processing speed. It consists of 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 is measured. Score ranges from 0-133, with higher scores indicating higher information processing speed. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.
Time Frame	Change from Baseline to 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants with Week 8 data available were analyzed.

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description:	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Overall Number of Participants Analyzed	9	10
Mean (Standard Deviation); Unit of Measure: Number of items correctly completed
	2.8 (4.0)	5.0 (3.5)

3. Secondary Outcome

Title	Single Task Gait Speed
Description	Patients' gait was assessed as walking speed in cm/s on a 15' walking course. Patients walked 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 were completed, and gait speed was based on the average of 2 trials. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.
Time Frame	Change from Baseline to 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants with Week 8 data available were analyzed

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description:	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Overall Number of Participants Analyzed	10	9
Mean (Standard Deviation); Unit of Measure: cm/s
	3.7 (14.9)	-3.8 (14.7)

4. Secondary Outcome

Title	Inventory of Depressive Symptomatology--Self Report (IDS-SR)
Description	The Inventory of Depressive Symptomatology--Self Report (IDS-SR) is a rating scale for depressive symptoms based on standard diagnostic criteria for Major Depressive Disorder. The scale ranges from 0-84 with higher scores indicating more severe depression. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.
Time Frame	Change from Baseline to 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants with available Week 8 data were analyzed

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description:	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Overall Number of Participants Analyzed	10	10
Mean (Standard Deviation); Unit of Measure: units on a scale
	-9.8 (7.1)	-12.1 (15.0)

5. Secondary Outcome

Title	Pattern Comparison Test
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 reflect the number of correct items completed in 90 s, with scores ranging from a minimum of 0 to a maximum of 30. Items were designed to minimize the number of errors that were made. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.
Time Frame	Change from Baseline to 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants with available Week 8 data were analyzed

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description:	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Overall Number of Participants Analyzed	11	10
Mean (Standard Deviation); Unit of Measure: Number of items correctly completed
	0.6 (2.1)	1.2 (2.3)

6. Secondary Outcome

Title	Letter Comparison Test
Description	Subjects were 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. Scores range from 0 to 21, with the higher the number, the better the score. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.
Time Frame	Change from Baseline to 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants with available Week 8 data were analyzed

Arm/Group Title	L-DOPA Arm	Placebo Arm
Arm/Group Description:	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.	Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
Overall Number of Participants Analyzed	11	10
Mean (Standard Deviation); Unit of Measure: Number of items correctly completed
	1.2 (1.6)	0.7 (1.4)

Adverse Events

Time Frame	Subjects were monitored over a period of 8 weeks.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	L-DOPA Arm		Placebo Arm
Arm/Group Description	Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose L-DOPA: We will be using generic sinemet 25/100 tablets in this study.		Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets
All-Cause Mortality
	L-DOPA Arm		Placebo Arm
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/15 (0.00%)		1/16 (6.25%)
Serious Adverse Events
	L-DOPA Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0.00%)		2/16 (12.50%)
Infections and infestations
Hospitalization for infection †	0/15 (0.00%)	0	1/16 (6.25%)	1
Psychiatric disorders
Death by suicide †	0/15 (0.00%)	0	1/16 (6.25%)	1
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	L-DOPA Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/15 (93.33%)		15/16 (93.75%)
Eye disorders
Blurred vision †	2/15 (13.33%)	2	2/16 (12.50%)	2
Gastrointestinal disorders
Nausea †	5/15 (33.33%)	8	3/16 (18.75%)	3
Dry mouth †	5/15 (33.33%)	5	4/16 (25.00%)	4
Diarrhea †	3/15 (20.00%)	3	2/16 (12.50%)	2
Constipation †	2/15 (13.33%)	2	2/16 (12.50%)	3
Stomach/throat discomfort †	2/15 (13.33%)	2	1/16 (6.25%)	1
Increased appetite †	1/15 (6.67%)	1	0/16 (0.00%)	0
Weight loss †	1/15 (6.67%)	1	0/16 (0.00%)	0
Decreased appetite †	0/15 (0.00%)	0	4/16 (25.00%)	4
Diverticulitis †	0/15 (0.00%)	0	1/16 (6.25%)	1
General disorders
Hot flashes †	2/15 (13.33%)	2	0/16 (0.00%)	0
Malaise/weakness †	1/15 (6.67%)	1	2/16 (12.50%)	2
Poor balance †	1/15 (6.67%)	1	1/16 (6.25%)	1
Fall †	0/15 (0.00%)	0	1/16 (6.25%)	1
Musculoskeletal and connective tissue disorders
Toe fracture †	0/15 (0.00%)	0	1/16 (6.25%)	1
Neck/back pain †	5/15 (33.33%)	6	1/16 (6.25%)	1
Joint/limb pain †	4/15 (26.67%)	4	0/16 (0.00%)	0
Leg/ankle swelling †	2/15 (13.33%)	2	0/16 (0.00%)	0
Muscle tightness/rigidity †	1/15 (6.67%)	1	3/16 (18.75%)	3
Bursitis †	0/15 (0.00%)	0	1/16 (6.25%)	1
Nervous system disorders
Incidental MRI finding †	2/15 (13.33%)	2	0/16 (0.00%)	0
Headache †	4/15 (26.67%)	4	5/16 (31.25%)	5
Numbness †	1/15 (6.67%)	1	0/16 (0.00%)	0
Word finding difficulty †	0/15 (0.00%)	0	1/16 (6.25%)	1
Psychiatric disorders
Anxiety during neuroimaging †	0/15 (0.00%)	0	2/16 (12.50%)	2
Insomnia †	6/15 (40.00%)	7	6/16 (37.50%)	7
Drowsiness †	5/15 (33.33%)	6	2/16 (12.50%)	2
Excitement †	2/15 (13.33%)	2	0/16 (0.00%)	0
Vivid dreams †	1/15 (6.67%)	1	3/16 (18.75%)	3
Irritability †	1/15 (6.67%)	1	0/16 (0.00%)	0
Forgetfulness †	0/15 (0.00%)	0	1/16 (6.25%)	1
Suicidal ideation †	0/15 (0.00%)	0	1/16 (6.25%)	1
Panic †	0/15 (0.00%)	0	1/16 (6.25%)	1
Renal and urinary disorders
Increased urination †	2/15 (13.33%)	2	1/16 (6.25%)	1
Urinary tract infection †	1/15 (6.67%)	1	0/16 (0.00%)	0
Cloudy urine †	1/15 (6.67%)	1	0/16 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Sighing †	1/15 (6.67%)	1	0/16 (0.00%)	0
Nasal congestion †	0/15 (0.00%)	0	1/16 (6.25%)	1
Hyperventilation †	0/15 (0.00%)	0	1/16 (6.25%)	1
Skin and subcutaneous tissue disorders
Itching †	2/15 (13.33%)	2	0/16 (0.00%)	0
Increased sweating †	0/15 (0.00%)	0	1/16 (6.25%)	1
Vascular disorders
Dizziness †	6/15 (40.00%)	6	4/16 (25.00%)	4
Increased heart rate †	2/15 (13.33%)	2	0/16 (0.00%)	0
Decreased heart rate †	1/15 (6.67%)	1	1/16 (6.25%)	1
Abnormal heart rhythm †	1/15 (6.67%)	1	0/16 (0.00%)	0
Palpitations †	0/15 (0.00%)	0	2/16 (12.50%)	2
† Indicates events were collected by systematic assessment

Limitations and Caveats

Data collected in the trial have been presented as required but are considered unreliable.

More Information

Certain Agreements

Principal Investigators are NOT 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.

Results Point of Contact

• Name/Title: Dr. Bret Rutherford
• Organization: New York State Psychiatric Institute
• Phone: 646 774 8660
• EMail: bret.rutherford@nyspi.columbia.edu

• Responsible Party: Bret Rutherford, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT03761030
• Other Study ID Numbers: 7733; 4R33MH110029-03 ( U.S. NIH Grant/Contract )
• First Submitted: November 29, 2018
• First Posted: December 3, 2018
• Results First Submitted: May 2, 2023
• Results First Posted: May 22, 2023
• Last Update Posted: May 22, 2023