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

Targeting Dopaminergic Mechanisms of Slowing to Improve Late Life Depression

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03761030

Enrollment

Registered

2018-12-03

Start date

2019-01-09

Completion date

2021-09-08

Last updated

2023-05-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Major Depressive Disorder, Dysthymia, Depression

Keywords

Depressive symptoms, Cognitive problems, Antidepressant non-response, Dopamine system, Older Adults, Motor slowing

Brief summary

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

Detailed description

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

Interventions

DRUGL-DOPA

We will be using generic sinemet 25/100 tablets in this study.

DRUGPlacebo Oral Tablet

25/100 placebo tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Double Blind

Eligibility

Sex/Gender

ALL

Age

60 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Aged 60 years and older 2. DSM 5 non-psychotic Major Depressive Disorder, Dysthymia, or Depression Not Otherwise Specified 3. Hamilton Rating Scale for Depression (HRSD) \> 15 4. Decreased processing speed (defined as performance \> 0.5SD below age-adjusted norms on Digit Symbol Substitution Test or Trail Making Test Part A) OR decreased gait speed (defined as average walking speed over 15' course \< 1m/s) 5. Willing to and capable of providing informed consent and complying with study procedures 6. Alternative standard treatments for MDD, Dysthymia, or Depression NOS (e.g., antidepressant medication or psychotherapy) have been discussed and the individual agrees to be involved in an experimental treatment.

Exclusion criteria

1. Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) within the past 12 months. 2. History of or current psychosis, psychotic disorder, mania, or bipolar disorder 3. Diagnosis of probable Alzheimer's Disease, Vascular Dementia, or Parkinson's Disease (PD) 4. Mini Mental Status Exam (MMSE) \< 25 5. HRSD ≥ 28; HRSD suicide item \> 2 or the presence of significant suicide risk as judged by clinician or Clinical Global Impressions (CGI)-Severity score of 7 at baseline. 6. Current or recent (within the past 4 weeks) treatment with antidepressants, antipsychotics, dopaminergic agents, or mood stabilizers. 7. History of allergy, hypersensitivity reaction, or severe intolerance to L-DOPA 8. Acute, severe, or unstable medical or neurological illness 9. Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, mobility limiting history of joint replacement surgery, or history of spine surgery FOR SUBJECTS RECEIVING PET/MRI SCANS ONLY: 10. Having contraindication to MRI scanning (such as metal in body) or unable to tolerate the scanning procedures 11. History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks)	Change from Baseline to 8 Weeks	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.

Secondary

Measure	Time frame	Description
Digit Symbol Test	Change from Baseline to 8 Weeks	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.
Single Task Gait Speed	Change from Baseline to 8 Weeks	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.
Inventory of Depressive Symptomatology--Self Report (IDS-SR)	Change from Baseline to 8 Weeks	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.
Pattern Comparison Test	Change from Baseline to 8 Weeks	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.
Letter Comparison Test	Change from Baseline to 8 Weeks	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.

Countries

United States

Participant flow

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.

Participants by arm

Arm	Count
L-DOPA Arm 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.	15
Placebo Arm Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study. Placebo Oral Tablet: 25/100 placebo tablets	16
Total	31

Baseline characteristics

Characteristic	L-DOPA Arm	Placebo Arm	Total
Age, Continuous	69.0 years STANDARD_DEVIATION 7.3	66.7 years STANDARD_DEVIATION 6.1	67.8 years STANDARD_DEVIATION 6.7
Clinical Global Impressions--Severity	3.7 units on a scale STANDARD_DEVIATION 0.6	4.3 units on a scale STANDARD_DEVIATION 0.7	4.0 units on a scale STANDARD_DEVIATION 0.7
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	4 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants	11 Participants	24 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	2 Participants
Hamilton Rating Scale for Depression (24 item)	21.1 units on a scale STANDARD_DEVIATION 4.7	20.3 units on a scale STANDARD_DEVIATION 3.9	20.7 units on a scale STANDARD_DEVIATION 4.3
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	4 Participants	3 Participants	7 Participants
Race (NIH/OMB) More than one race	2 Participants	2 Participants	4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	9 Participants	10 Participants	19 Participants
Region of Enrollment United States	15 participants	16 participants	31 participants
Sex: Female, Male Female	9 Participants	10 Participants	19 Participants
Sex: Female, Male Male	6 Participants	6 Participants	12 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 15	1 / 16
other Total, other adverse events	14 / 15	15 / 16
serious Total, serious adverse events	0 / 15	2 / 16

Outcome results

Primary

Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks)

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.