D3: Dopaminergic Dysfunction in Late-Life Depression

Sponsor
Vanderbilt University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT04469959
Collaborator
Columbia University (Other), Emory University (Other)
60
1
2
64.4
0.9

Study Details

Study Description

Brief Summary

Late-Life Depression (LLD), or depression in older adults, often presents with motivational deficits, deficits in performance in cognitive domains including processing speed and executive dysfunction, and mobility impairments. This triad of findings implicate dopaminergic dysfunction as a core pathophysiologic feature in depression, and may contribute to cognitive decline and motor disability. Normal aging results in brain-wide dopamine declines, decreased D1/D2 receptor density, and loss of dopamine transporters. Although brain changes associated with depression and aging converge on dopamine circuits, the specific disturbances in LLD and how responsive the system is to modulation remain unclear. In this collaborative study between Columbia University /New York State Psychiatric Institute and Vanderbilt University Medical Center, investigators are testing integrative model that aging, in concert with pro-inflammatory shifts, decreases dopamine signaling. These signally changes affects behaviors supported by these circuits, in the context of age-associated cortical atrophy and ischemic microvascular changes, resulting in variable LLD phenotypes. Investigators propose a primary pathway where dopaminergic dysfunction in depressed elders contributes to slowed processing speed and mobility impairments that increase the effort cost associated with voluntary behavior. The central hypothesis of this study is that late-life depression is characterized by dysfunction in the dopamine system and, by enhancing dopamine functioning in the brain. By improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Late Life Depression (LLD) is a prevalent, disabling, and at times lethal condition for which currently available treatments are often ineffective. No prior study has comprehensively examined dopamine-dependent behaviors (i.e., reward processing, cognition, motor function) in LLD, and none has integrated positron emission tomography (PET), multimodal magnetic resonance imaging (MRI), neuropsychological evaluation, and mobility assessments. Should cognitive and motor slowing result in altered effort-based decision making as researchers hypothesize, treatment development may shift from addressing mood and hedonic responses toward facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation.

This study at Vanderbilt University Medical Center (VUMC) will enroll 60 evaluable elderly depressed outpatients with evidence of dopaminergic dysfunction, characterized as either slowed processing speed or slowed gait speed. To disentangle depression effects from age-related changes, 30 never-depressed elders also will complete baseline evaluation. Assessments include PET imaging of receptor density, neuromelanin-sensitive MRI (NM-MRI) measurement of nigrostriatal status, task-based MRI focused on effort-based decision making and reward processing, and comprehensive psychiatric, neurocognitive, and physical performance evaluation. Depressed participants then will be randomized to levodopa (L-DOPA) or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. In a cross-over phase, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This mechanistic probe allows us to examine the contributions and interrelationships of dopamine-dependent processes in LLD and evaluate the responsivity of dopamine systems in LLD to pharmacological stimulation.

To maximize ability to detect drug effects, researchers will combine data gathered at VUMC with data gathered in a comparable sample enrolled at Columbia University. The sample enrolled at Columbia University will complete overlapping but not identical baseline assessments, including different PET imaging. Columbia University will complete a similar crossover trial of L-DOPA.

AIM 1: To characterize dopaminergic dysfunction in LLD at molecular, circuit, and behavioral levels.

Hyp 1: Compared to age- and gender-matched controls on baseline functional MRI (fMRI), LLD participants will be less willing to expend effort for rewards and exhibit lower prefrontal cortex and striatal activation on the Effort Expenditure for Rewards Task (EEfRT). Hyp 2: Across all participants, lower midbrain & striatal [18F]-fallypride binding, and lower NM-MRI signal in the substantia nigra, pars compacta will predict lower performance across cognitive domains: Positive Valence (impaired willingness to expend effort, decreased neural activations on the EEfRT), Cognitive (slowed processing speed and executive dysfunction), and Sensorimotor (slowed gait speed). Hyp 3: Across all participants, slowed processing and gait speed likewise will predict lower willingness to expend effort on the EEfRT.

AIM 2: To examine responsivity of dopamine circuits in LLD to stimulation with L-DOPA.

Hyp 1: Compared to placebo, L-DOPA will result in greater normalization of neural activations and improved behavioral performance in Positive Valence, Cognitive, and Sensorimotor domains. Hyp 2: Baseline PET and NM-MRI measures will moderate L-DOPA effects. The greatest improvements will be observed in those with the lowest baseline [18F]-fallypride binding, and NM-MRI signal.

Exploratory Aims: 1) To investigate associations of baseline proinflammatory markers with dopaminergic function across molecular, circuit, cognitive and behavioral levels of analysis. 2) To evaluate the durability of L-DOPA effects on cognitive domains in the crossover phase.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
60 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double Blinded
Primary Purpose:
Treatment
Official Title:
Dopaminergic Dysfunction in Late-Life Depression
Actual Study Start Date :
Feb 15, 2021
Anticipated Primary Completion Date :
Apr 30, 2025
Anticipated Study Completion Date :
Jun 30, 2026

Arms and Interventions

Arm Intervention/Treatment
Experimental: L-Dopa First / Placebo Second

STEP 1(3 weeks): Participants initially assigned to L-DOPA will begin with a Week 1 L-DOPA daily dosage of 150mg, (1.5 25mg carbidopa/100mg levodopa tablets) at 9am and placebo tablets at 1pm and 5pm. Week 2 will increase to a L-DOPA daily dose of 300mg (1.5 25mg carbidopa/100mg levodopa tablets) at 9am and 5pm, with placebo at 1pm, followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets) three times daily. After completing post-trial assessments, participants then enter a 1 week taper period before proceeding to Step 2. Step 2 (3 Weeks): Participants will receive matching placebo tablets daily. Participants take placebo tablets at 9am, 1pm, and 5pm over three weeks. Following post-trial assessments, participants then enter a 1-week taper period and study drug is withdrawn.

Drug: L-Dopa
Generic 25/100mg carbidopa/levodopa (Sinemet)tablets will be administered in this study. Participants will begin randomized double blinded 3- week trial of Levodopa. Dose titration starting at150 mg /daily to maximum of 450 mg patch/daily three times a day for three weeks. After one week of taper they will enter step 2 phase of study where carbidopa/levodopa matched placebo will be administered for 3 weeks afterwards dose will be slowly tapered over next 7 days.
Other Names:
  • carbidopa/levodopa (Sinemet)
  • 25/100 placebo tablets
  • Drug: Placebo
    Step 1(3weeks) Carbidopa/levodopa-matched placebo tablet 3 times. Followed by 1 week of taper Step2(3 weeks):150-450mg carbidopa/levodopa 3 times daily for three weeks .Followed by 1 week of taper.
    Other Names:
  • 25/100 placebo tablets
  • Placebo Comparator: Placebo First / L-Dopa Second

    Step 1 (3 Weeks): Participants will receive matching placebo tablets daily. Participants take placebo tablets at 9am, 1pm, and 5pm over three weeks. Following post-trial assessments, participants then enter a 1-week taper period before proceeding to Step 2. Step 2 (3 Weeks): Participants will begin with a Week 1 L-DOPA daily dosage of 150mg, (1.5 25mg carbidopa/100mg levodopa tablets) at 9am and placebo tablets at 1pm and 5pm. Week 2 will increase to a L-DOPA daily dose of 300mg (1.5 25mg carbidopa/100mg levodopa tablets) at 9am and 5pm, with placebo at 1pm, followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets) three times daily. After completing post-trial assessments, participants then enter a 1 week taper period and study drug will be discontinued.

    Drug: L-Dopa
    Generic 25/100mg carbidopa/levodopa (Sinemet)tablets will be administered in this study. Participants will begin randomized double blinded 3- week trial of Levodopa. Dose titration starting at150 mg /daily to maximum of 450 mg patch/daily three times a day for three weeks. After one week of taper they will enter step 2 phase of study where carbidopa/levodopa matched placebo will be administered for 3 weeks afterwards dose will be slowly tapered over next 7 days.
    Other Names:
  • carbidopa/levodopa (Sinemet)
  • 25/100 placebo tablets
  • Drug: Placebo
    Step 1(3weeks) Carbidopa/levodopa-matched placebo tablet 3 times. Followed by 1 week of taper Step2(3 weeks):150-450mg carbidopa/levodopa 3 times daily for three weeks .Followed by 1 week of taper.
    Other Names:
  • 25/100 placebo tablets
  • Outcome Measures

    Primary Outcome Measures

    1. Change in WAIS-IV Coding Test Score [Baseline, after week 3, and after week 6]

      Wechsler Adult Intelligence Scale(WAIS-IV) Coding test score will be used to measure the processing speed .A composite score is derived with two other test scores of WAIS-IV by extracting latent fact and factor loadings, creating a purer measure of processing speed. Higher scores indicate better performance.

    2. Change in WAIS-IV Pattern Comparison Test Score [Baseline, after week 3, and after week 6]

      Wechsler Adult Intelligence Scale(WAIS-IV) Comparison Test score will be used to measure the processing speed. A composite score is derived with two other test scores of WAIS-IV by extracting latent fact and factor loadings, creating a purer measure of processing speed. Higher scores indicate better performance.

    3. Change in WAIS-IV Letter Comparison Test Score [Baseline, after week 3, and after week 6]

      Wechsler Adult Intelligence Scale(WAIS-IV) Letter Comparison Test score will be used to measure the processing speed . A composite score is derived with two other test scores of WAIS-IV by extracting latent fact and factor loadings, creating a purer measure of processing speed .Higher scores indicate better performance.

    4. Change in NIH EXAMINER Test Score [Baseline, after week 3, and after week 6]

      This neuropsychological test battery assesses a range of executive functions. Tasks measuring working memory, inhibition, set shifting, fluency, insight, and planning and 3 self-report questionnaires rating social cognition and behavior . Higher scores indicate better performance.

    5. Change in Gait pattern [Baseline, after week 3, and after week 6]

      Gait will be assessed with a single and dual task (ST, DT) using the GaitRite system, which assesses gait parameters in real time (gait speed, cadence, stride length).Changes in these parameters will reflect changes in gait slowness.

    6. Change in Effort Expenditure for Rewards Task (EEfRT) [Baseline to after week 3]

      In this functional Magnetic Resonance Imaging 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 outputs on this task are the percentage of time participants choose the high cost / high reward option on the EEfRT and associated neural activation patterns in prefrontal cortex (PFC) and striatum.

    Secondary Outcome Measures

    1. Change in NIH Toolbox Cognition Battery Scores [Baseline, after week 3, and after week 6]

      This is a brief and psychometrically sound set of 7 computerized instruments providing an overall cognitive index from measures of 6 cognitive domains.

    2. Monetary Incentive Delay Task [Baseline and after week 3]

      This functional Magnetic Resonance Imaging task assesses neural response during reward anticipation and receipt. On each trial, participants are presented with a 2000msec cue indicating that trial's reward value ($0, $1, or $5). After the cue, a 2000-2500 msec delay period ensues as the participant waits for the target. Participants press a button as quickly as possible when the target is visible. After another delay lasting from 950 to 2800 msec, a feedback screen lasting 2500msec appears indicating the outcome ("Hit!" or "Miss!") for each trial, with a brief interval before the next trial. the primary contrast for analyses is the contrast of Cue $5 - Cue $0 to brain activation during reward anticipation. The contrast of Hit vs. Miss on both $5 and $1 trials is the primary index of reward receipt.

    3. Change in MADRS (Montgomery Asberg Depression Rating Scale) Score [Baseline and weekly thereafter for 6 weeks]

      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.

    4. Change in QIDS (Quick Inventory of Depressive Symptomatology) Score [Baseline and weekly thereafter for 6 weeks]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    60 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Age ≥ 60 years

    2. Diagnostic and Statistical Manual-5 (DSM5) diagnosis of Major Depressive Disorder, Persistent Depressive Disorder, or Depression Not Otherwise Specified (NOS)

    3. MADRS (116) score ≥ 15

    4. Decreased processing speed (1 standard deviation below age-adjusted norms on the Digit Symbol test) or decreased gait speed (average walking speed on 15' course < 1m/s)

    5. Capable of providing informed consent and adhering to study procedures

    Exclusion Criteria:
    1. Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) in the past 12 months

    2. Other Axis I psychiatric disorders including a history of psychosis, psychotic disorder, mania, or bipolar, except for simple phobia or anxiety disorders present during the depressive episode (e.g., generalized anxiety disorder (GAD) or panic disorder symptoms)

    3. Primary neurological disorder, including dementia, stroke, Parkinson's disease, epilepsy, etc

    4. Mini-Mental State Exam score (117) < 24

    5. MADRS suicide item > 4 or other indication of acute suicidality

    6. Current or recent (within the past 2 weeks) treatment with antidepressants, antipsychotics, or mood stabilizers

    7. History of hypersensitivity, allergy, or intolerance to L-DOPA;

    8. Any physical or intellectual disability adversely affecting ability to complete assessments

    9. Unstable medical illness

    10. Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, or history of joint replacement / spine surgery that limits mobility

    11. Contraindication to MRI

    12. History of significant radioactivity exposure (nuclear medicine studies or occupational exposure).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Vanderbilt Psychiatric Hospital Nashville Tennessee United States 37212

    Sponsors and Collaborators

    • Vanderbilt University Medical Center
    • Columbia University
    • Emory University

    Investigators

    • Principal Investigator: Warren Taylor, MD,MHSc, Vanderbilt University Medical Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Warren Taylor, Professor of Psychiatry, Vanderbilt University Medical Center
    ClinicalTrials.gov Identifier:
    NCT04469959
    Other Study ID Numbers:
    • 201172
    First Posted:
    Jul 14, 2020
    Last Update Posted:
    Feb 24, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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 Warren Taylor, Professor of Psychiatry, Vanderbilt University Medical Center
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 24, 2022