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 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 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.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder; Dysthymia; Depression	Drug: L-DOPA; Drug: Placebo Oral Tablet	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double Blind
• Primary Purpose: Treatment
• Official Title: Targeting Dopaminergic Mechanisms of Slowing to Improve Late Life Depression
• Actual Study Start Date: January 9, 2019
• Actual Primary Completion Date: September 8, 2021
• Actual Study Completion Date: September 8, 2021

Arms and Interventions

Arm	Intervention/treatment
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	Drug: L-DOPA; We will be using generic sinemet 25/100 tablets in this study.; Other Name: carbidopa/levodopa (Sinemet)
Placebo Comparator: Placebo Arm; Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study.	Drug: Placebo Oral Tablet; 25/100 placebo tablets; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Eligibility Criteria

• Ages Eligible for Study: 60 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

United States, New York

New York State Psychiatric Institute

New York, New York, United States, 10032

Sponsors and Collaborators

New York State Psychiatric Institute

National Institute of Mental Health (NIMH)

Investigators

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

  Study Documents (Full-Text)

Documents provided by Bret Rutherford, New York State Psychiatric Institute:

Study Protocol  [PDF] November 28, 2018

Statistical Analysis Plan  [PDF] July 24, 2015

Informed Consent Form  [PDF] November 28, 2018

More Information

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

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Bret Rutherford, New York State Psychiatric Institute:

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

Additional relevant MeSH terms:

Depression; Depressive Disorder; Depressive Disorder, Major; Dysthymic Disorder; Behavioral Symptoms; Mood Disorders; Mental Disorders; Levodopa; Carbidopa; Carbidopa, levodopa drug combination; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Aromatic Amino Acid Decarboxylase Inhibitors; Enzyme Inhibitors; Adjuvants, Immunologic; Immunologic Factors; Dopamine Agonists