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

Tracking Information

• First Submitted Date: November 29, 2018
• First Posted Date: December 3, 2018
• Results First Submitted Date: May 2, 2023
• Results First Posted Date: May 22, 2023
• Last Update Posted Date: May 22, 2023
• Actual Study Start Date: January 9, 2019
• Actual Primary Completion Date: September 8, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 2, 2023)

Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 29, 2018)

Hamilton Depression Rating Scale (HAM-D) [ Time Frame: 8 Weeks ]

A multiple item questionnaire used to provide an indication of depression, and as a guide to evaluate recovery. Our target is depressive symptomatology as measured by the HAM-D.

Current Secondary Outcome Measures (submitted: May 17, 2023)

• Digit Symbol Test [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: L-DOPA vs. Placebo for Depression and Psychomotor Slowing in Older Adults
• Official Title: Targeting Dopaminergic Mechanisms of Slowing to Improve Late Life Depression
• 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.
• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double Blind

Primary Purpose: Treatment

Condition

• Major Depressive Disorder
• Dysthymia
• Depression

Intervention

• Drug: L-DOPA
  We will be using generic sinemet 25/100 tablets in this study.
  Other Name: carbidopa/levodopa (Sinemet)
• Drug: Placebo Oral Tablet
  25/100 placebo tablets
  Other Name: Placebo

Study Arms

• Experimental: 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
  Intervention: Drug: L-DOPA
• Placebo Comparator: Placebo Arm
  Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study.
  Intervention: Drug: Placebo Oral Tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 2, 2023): 51
• Original Estimated Enrollment (submitted: November 29, 2018): 90
• Actual Study Completion Date: September 8, 2021
• Actual Primary Completion Date: September 8, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03761030
• Other Study ID Numbers: 7733; 4R33MH110029-03 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Bret Rutherford, New York State Psychiatric Institute
• Original Responsible Party: Bret Rutherford, New York State Psychiatric Institute, Associate Professor
• Current Study Sponsor: New York State Psychiatric Institute
• Original Study Sponsor: Same as current
• Collaborators: National Institute of Mental Health (NIMH)

Investigators

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

• PRS Account: New York State Psychiatric Institute
• Verification Date: May 2023