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

Phase 4

Terminated

Conditions: Cognitive Impairment
Depression
Gait Impairment

Interventions: Drug: Carbidopa/levodopa
Drug: Placebo

Registration Number: NCT04493320

Lead Sponsor: New York State Psychiatric Institute

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).

Detailed Description: Supported by pilot data, this project builds on past work demonstrating that dopamine function declines with aging, that dopaminergic dysfunction contributes to deficits in behavior, and that L-DOPA administration improves cognitive and motor performance. The long-term goal of this line of research is to determine how dopaminergic dysfunction contributes to clinical presentations of LLD, how responsive behavioral symptoms are to modulation of dopamine function, and to identify novel targets for future interventions. Investigator's approach is to enroll 30 psychiatrically healthy elders and 60 depressed elders at Columbia/NYSPI exhibiting either slowed processing speed or slowed gait speed. Participants will undergo thorough clinical evaluations and complete PET imaging measuring different aspects of the brain's dopamine system, neuromelanin-sensitive MRI measurement of longterm dopamine transmission, functional MRI focused on effort-based decision making and reward processing, a comprehensive neurocognitive evaluation, a physical performance evaluation, and measurement of inflammatory markers. To assess responsivity of the dopamine system to modulation, depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. In a second phase, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This proposal is significant and innovative, as no prior published study has comprehensively examined dopamine-dependent behaviors in LLD. This will inform treatment approaches focusing on facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

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

Exclusion Criteria

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:

Any personal history of DSM-5 disorder
Family history of MDD in first-degree relative
Plus, Exclusion criteria 8-12 above

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
L-DOPA, Then Placebo	Placebo	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.
Placebo, Then L-DOPA	Placebo	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.
Placebo, Then L-DOPA	Carbidopa/levodopa	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.
L-DOPA, Then Placebo	Carbidopa/levodopa	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.

Primary Outcome Measures

Name	Time	Method
Change in Pattern Comparison Test Following Step 2	Change from Week 3 to Week 7 (post-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 in Effort Expenditure for Rewards Task (EEfRT) Following Step 1	Change from Baseline to 3 weeks (post 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 in Digit Symbol Test Following Step 1	Change from Baseline to 3 weeks (post 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 in Digit Symbol Test Following Step 2	Change from Week 3 to Week 7 (post-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 in Pattern Comparison Test Following Step 1	Change from Baseline to 3 weeks (post 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 in Single Task Gait Speed Test Following Step 1	Change from Baseline to 3 weeks (post 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 in Letter Comparison Test Following Step 1	Change from Baseline to 3 weeks (post 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 in Single Task Gait Speed Test Following Step 2	Change from Week 3 to Week 7 (post-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 in Letter Comparison Test Following Step 2	Change from Week 3 to Week 7 (post-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.
[18F]-FDOPA PET Measure in Striatal Region of Interest	Baseline (prior to LDOPA or placebo administration)	\[18F\]-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.

Secondary Outcome Measures

Name	Time	Method
Change in Montgomery Asberg Depression Rating Scale Following Step 2	Change from Week 4 to Week 7 (post-Step 2)	Secondary outcome measured by the total score of the clinician rated MADRS, a measure of depression severity. The MADRS total score range is 0-60, where higher scores indicate greater depression severity. In contrast to other measures, which were not available at Week 4, Week 4 was selected as the baseline for post-Step 2 change on the MADRS since it followed the taper period taking place between study Steps. 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 in Montgomery Asberg Depression Rating Scale Following Step 1	Change from Baseline to 3 weeks (post Step 1)	Secondary outcome measured by the total score of the clinician rated MADRS, a measure of depression severity. The MADRS total score range is 0-60, where higher scores indicate greater depression 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.
Change in Quick Inventory for Depressive Symptomatology (QIDS) Following Step 1	Change from Baseline to 3 weeks (post Step 1)	QIDS-16-item, a participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27, with higher scores indicative of 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.
Change in Quick Inventory for Depressive Symptomatology (QIDS) Following Step 2	Change from Week 4 to Week 7 (post-Step 2)	QIDS-16-item, a participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27, with higher scores indicative of greater severity. In contrast to other measures, which were not available at Week 4, Week 4 was selected as the baseline for post-Step 2 change on the QIDS since it followed the taper period taking place between study Steps. 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.