1/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study)

NCT04493320 | Terminated Phase 4 Results DMC FDA Drug

• 2 other identifiers: 7976R01MH123660-01
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

Growing evidence suggests that dopamine contributes to key cognitive, emotional, and motor functions across the lifespan. In Late-Life Depression (LLD), dysfunction in these areas is common, predicts poor outcomes, and manifests as difficulties in motivation and effort along with cognitive and gait impairment. While studies of dopamine function in early and midlife depression primarily focus on individuals' ability to feel pleasure and respond to rewards, they often exclude the cognitive and physical function domains relevant for older adults despite a recognized decline in dopamine function with normal aging. The objectives of this collaborative R01 proposal between Columbia University/New York State Psychiatric Institute and Vanderbilt University Medical Center are to: 1) characterize dopaminergic dysfunction in LLD across cognitive, emotional, and motor domains at several levels of analysis (cellular Positron Emission Tomography \[PET\], circuit Magnetic Resonance Imaging \[MRI\], and behavioral / self-report); and 2) examine the responsivity of dopamine-related circuits and behavior to stimulation with carbidopa/levodopa (L-DOPA).

Conditions

Depression; Cognitive Impairment; Gait Impairment

Outcome Measures

Primary Outcomes (10)

• Change in Effort Expenditure for Rewards Task (EEfRT) Following Step 1

  In this task participants decide whether to work harder for a larger reward (high number of finger presses with their pinky) or expend less energy (low number of presses with a dominant index finger) for a lesser reward, with lower rewards being $1 dollar and higher rewards ranging from $1.20 to $5. Participants receive information about the probability of winning on each trial regardless of their pick and one trial from each run is randomly picked for payout. The primary output on this task is the percentage of time participants choose the high cost / high reward option on the EEfRT. 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. This task was not completed following Step 2 of the study, so there are no EEfRT data reported for change in task performance following Step 2.

  Change from Baseline to 3 weeks (post Step 1)

• Change in Digit Symbol Test Following Step 1

  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.

  Change from Baseline to 3 weeks (post Step 1)

• Change in Digit Symbol Test Following Step 2

  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.

  Change from Week 3 to Week 7 (post-Step 2)

• Change in Pattern Comparison Test Following Step 1

  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.

  Change from Baseline to 3 weeks (post Step 1)

• Change in Pattern Comparison Test Following Step 2

  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.

  Change from Week 3 to Week 7 (post-Step 2)

• Change in Letter Comparison Test Following Step 1

  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.

  Change from Baseline to 3 weeks (post Step 1)

• Change in Letter Comparison Test Following Step 2

  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.

  Change from Week 3 to Week 7 (post-Step 2)

• Change in Single Task Gait Speed Test Following Step 1

  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.

  Change from Baseline to 3 weeks (post Step 1)

• Change in Single Task Gait Speed Test Following Step 2

  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.

  Change from Week 3 to Week 7 (post-Step 2)

• [18F]-FDOPA PET Measure in Striatal Region of Interest

  \[18F\]-FDOPA PET quantifies dopamine synthesis capacity in specific brain regions. Lower \[18F\]-FDOPA uptake in the striatum has been associated with increased depression severity and worse cognitive and motor function in patients. Because \[18F\]-FDOPA uptake may be sensitive to deficits in dopamine synthesis capacity in older depressed patients, in this study depressed participants at baseline underwent a PET scan to quantify relative \[18F\]-FDOPA influx rate in the nucleus accumbens bilaterally. Time activity curves (TACs) were extracted within the nucleus accumbens region of interest (ROI) as the average radioactivity in the ROI over time. The occipital lobe, which has the lowest dopamine concentration in the brain, was used as the "reference region" to yield the Kocc measure of \[18F\]-FDOPA influx rate. Higher \[18F\]-FDOPA influx rate (kocc) numbers indicate greater relative influx rate and therefore greater dopamine synthesis capacity.

  Baseline (prior to LDOPA or placebo administration)

Secondary Outcomes (4)

• Change in Montgomery Asberg Depression Rating Scale Following Step 1

  Change from Baseline to 3 weeks (post Step 1)

• Change in Montgomery Asberg Depression Rating Scale Following Step 2

  Change from Week 4 to Week 7 (post-Step 2)

• Change in Quick Inventory for Depressive Symptomatology (QIDS) Following Step 1

  Change from Baseline to 3 weeks (post Step 1)

• Change in Quick Inventory for Depressive Symptomatology (QIDS) Following Step 2

  Change from Week 4 to Week 7 (post-Step 2)

Study Arms (2)

L-DOPA, Then Placebo

EXPERIMENTAL

Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period.

Drug: Carbidopa/levodopa; Drug: Placebo

Placebo, Then L-DOPA

EXPERIMENTAL

Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period.

Drug: Carbidopa/levodopa; Drug: Placebo

Interventions

Carbidopa/levodopa DRUG

150-450mg carbidopa/levodopa 3 times daily

Also known as: L-DOPA, Sinemet

L-DOPA, Then Placebo; Placebo, Then L-DOPA

Placebo DRUG

Carbidopa/levodopa-matched placebo tablet 3 times daily

Also known as: Placebo tablet

L-DOPA, Then Placebo; Placebo, Then L-DOPA

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Depressed Subjects:
• Age 60 years or older (female subjects will be post-menopausal by virtue of their age, but last menstrual period month and year will be documented in the study database)
• Diagnosis and Statistical Manual (DSM-5) diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD)
• Montgomery Asberg Depression Rating Scale Score (MADRS) \>=15
• Decreased processing speed or decreased gait speed
• Capable of providing informed consent and complying with study procedures
• Alternative standard treatments for MDD or PDD have been discussed and the individual agrees to be involved in an experimental treatment
• Psychiatrically Healthy Elders:
• Age 60 years or older years old
• MADRS \< 8
• Capable of providing informed consent and complying with study procedures

You may not qualify if:

• Depressed Subjects:
• Diagnosis of Substance Use Disorder (excluding Tobacco Use Disorder) in the past 12 months
• History of psychosis (except brief psychosis associated with transient medical conditions \[e.g., delirium, urinary tract infection, etc\], psychotic disorder, mania, or bipolar disorder.
• Primary neurological disorder, including dementia, stroke, Parkinson's disease, or epilepsy.
• Mini Mental State Examination (MMSE) \< 24
• MADRS suicide item \>4 or other indication of acute suicidality
• Current or recent (within the past 2 weeks) treatment with antidepressants, antipsychotics, or mood stabilizers
• History of hypersensitivity, allergy, or intolerance to L-DOPA
• Any physical or intellectual disability adversely affecting ability to complete assessments.
• Acute, severe, or unstable medical illness
• Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, or history of joint replacement or spine surgery that limits mobility
• Contraindication to MRI scanning (Metal implants, pacemaker, metal prostheses, metal orthodontic appliances in the body unless there is confirmation that the substance is MRI compatible.)
• History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)
• Has a medical condition managed with medication and/or device and the managing physician considers the condition and/or its management a contraindication to the research use of L-DOPA in this participant
• Psychiatrically Healthy Elders:

Sponsors & Collaborators

• New York State Psychiatric Institute: lead
• National Institute of Mental Health (NIMH): collaborator
• Vanderbilt University Medical Center: collaborator
• Columbia University: collaborator
• Emory University: collaborator

Study Sites (1)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Depression; Cognitive Dysfunction

Interventions

carbidopa, levodopa drug combination; Levodopa

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Dihydroxyphenylalanine; Catecholamines; Amines; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Tyrosine

Limitations and Caveats

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

Results Point of Contact

• Title: Dr. Bret Rutherford
• Organization: New York State Psychiatric Institute

bret.rutherford@nyspi.columbia.edu

646 774 8660

Study Officials

• Bret R Rutherford, MD

  New York State Psychiatric Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Clinical Psychiatry

Model Details: Double blind crossover study

Study Record Dates

• First Submitted: July 27, 2020
• First Posted: July 30, 2020
• Study Start: February 10, 2021
• Primary Completion: October 27, 2021
• Study Completion: October 27, 2021
• Last Updated: May 22, 2023
• Results First Posted: May 22, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)