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Late Life DepressionPhase 2D3NCT04469959

Dopaminergic Dysfunction in Late-Life Depression

A Phase 2 study testing L-Dopa in people with Late Life Depression and Cognitive Decline, run by Vanderbilt University Medical Center at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 60 years and olderHealthy volunteers can take part
What is being tested?
L-Dopa
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
79 participants
Where
2 sitesUnited States
Study dates
15 Feb 2021to 29 Apr 2026
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Age ≥ 60 years
  • Diagnostic and Statistical Manual-5 (DSM5) diagnosis of Major Depressive Disorder, Persistent Depressive Disorder, or Depression Not Otherwise Specified (NOS)
  • MADRS score ≥ 15
  • Decreased processing speed (0.5 SD below age-adjusted norms on the WAIS-IV Coding task or Trail Making Test, Part A) or decreased motor speed (gait speed/average walking speed on 15' course ≤ 1m/s, or 0.5 SD below age-, gender- and education-adjusted norms on the grooved pegboard test)
  • Capable of providing informed consent and adhering to study procedures

Who cannot join

  • Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) in the past 12 months
  • Other psychiatric disorders including a history of psychosis, psychotic disorder, mania, or bipolar disorder. Other comorbid psychiatric disorders are allowable if the depressive disorder diagnosis is considered to be the primary problem
  • Primary neurological disorder, including dementia, stroke, Parkinson's disease, epilepsy, etc
  • SBT > 10
  • MADRS suicide item > 4 or other indication of acute suicidality
  • History of inpatient psychiatric hospitalization in the last year;
Show all 15Show fewer
  • History of suicidal ideation in the last 6 months, operationalized as a 'yes' response to item 4 or 5 in the "Suicidal Ideation" section of the Columbia-Suicide Severity Rating Scale (CSSRS)
  • Any suicidal behavior in the last year (operationalized as a 'yes' response to any item in the "Suicidal Behavior" section of the CSSRS, including actual interrupted, aborted, or preparatory acts)
  • Current or recent (within the past 2 weeks) treatment with antipsychotics or mood stabilizers, or use of antidepressants where washout is not advisable
  • History of hypersensitivity, allergy, or intolerance to Carbidopa/levodopa
  • Any physical or intellectual disability adversely affecting ability to complete assessments
  • Unstable medical illness
  • Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, or history of joint replacement / spine surgery that limits mobility
  • Diagnosis of HIV
  • History of significant radioactivity exposure (nuclear medicine studies or occupational exposure).

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Vanderbilt Psychiatric Hospital

    Nashville, Tennessee, 37212

  • University of Pittsburgh Medical Center

    Pittsburgh, Pennsylvania, 15213

Other trials in United States

About this study

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 study, 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.

Read the 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, across collaborative sites, will enroll 100 evaluable elderly depressed outpatients who enter baseline study procedures and who exhibit evidence of dopaminergic dysfunction, characterized as either slowed processing speed or slowed gait speed. To disentangle depression effects from age-related changes, 70 never-depressed elders also will complete baseline evaluation. To achieve this goal, at Vanderbilt University Medical Center (VUMC) the investigators will enroll 80 depressed elders and 50 never-depressed elders who complete baseline study procedures. The University of Pittsburgh Medical Center will enroll an additional 20 depressed elders and 20 never-depressed elders who complete baseline study procedures.

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 the investigators to examine the contributions and interrelationships of dopamine-dependent processes in LLD and evaluate the responsivity of dopamine systems in LLD to pharmacological stimulation.

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 striatal [18F]-FDOPA relative influx rate, lower midbrain \& striatal [18F]-fallypride binding, and lower NM-MRI signal in the substantia nigra, pars compacta will predict lower performance across RDoC 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]-FDOPA relative influx rate, [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 RDoC domains in the crossover phase.

Being tested
L-Dopa, Placebo
Keywords
Antiparkinson agent, Levodopa, Elderly, Depressive Disorder, major
Medical subject headings
Cognitive Dysfunction, Depressive Disorder, Treatment-Resistant, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • L-DopaDrug

    Also called carbidopa/levodopa (Sinemet), 25/100 placebo capsules

    Generic 25/100mg carbidopa/levodopa (Sinemet)capsules will be administered in this study. Participants will begin randomized double blinded 3- week trial of Levodopa. Dose titration starting at 150 mg /daily to maximum of 450 mg daily three times a day for three weeks.

    After one week of taper participants 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.

  • PlaceboDrug

    Also called 25/100 placebo capsules

    Step 1 (3 weeks) Carbidopa/levodopa-matched placebo capsules 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.

Study groups in NCT04469959
Study groupRoleWhat they receive
L-Dopa First / Placebo SecondExperimentalSTEP 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 capsules) at 9am. Week 2 will increase to a L-DOPA daily dose of 300mg (1.5 25mg carbidopa/100mg levodopa capsules) at 9am and 5pm, followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa capsules) 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 capsules daily. Participants take placebo capusles once daily during week 1 (9am), twice daily during week 2 (9am, 5pm), and three times daily during week 3 (9am, 1pm, 5pm) over three weeks. Following post-trial assessments, participants then enter a 1-week taper period and study drug is withdrawn.
Receives: Drug: L-Dopa; Drug: Placebo
Placebo First / L-Dopa SecondPlacebo comparatorStep 1 (3 Weeks): Participants will receive matching placebo capsules daily. Participants take placebo capsules once daily during week 1 (9am), twice daily during week 2 (9am, 5pm), and three times daily during week 3 (9am, 1pm, 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 capsules) at 9am. Week 2 will increase to a L-DOPA daily dose of 300mg (1.5 25mg carbidopa/100mg levodopa capsules) at 9am and 5pm, followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa capsules) three times daily. After completing post-trial assessments, participants then enter a 1 week taper period and study drug will be discontinued.
Receives: Drug: L-Dopa; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in WAIS-R Digit Symbol Task Score

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

    Measured: Baseline, after week 3, and after week 6

  2. Change in Pattern Comparison Test Score

    Pattern Comparison Test score will be used to measure processing speed. A composite score is derived with two other test scores of WAIS-R by extracting latent fact and factor loadings, creating a purer measure of processing speed. Higher scores indicate better performance.

    Measured: Baseline, after week 3, and after week 6

  3. Change in Letter Comparison Test Score

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

    Measured: Baseline, after week 3, and after week 6

  4. Change in NIH EXAMINER Test Score

    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.

    Measured: Baseline, after week 3, and after week 6

  5. Change in Gait pattern

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

    Measured: Baseline, after week 3, and after week 6

  6. Change in Effort Expenditure for Rewards Task (EEfRT)

    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.

    Measured: Baseline to after week 3

Secondary outcomes (4)

  1. Change in NIH Toolbox Cognition Battery Scores

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

    Measured: Baseline, after week 3, and after week 6

  2. Monetary Incentive Delay Task

    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.

    Measured: Baseline and after week 3

  3. Change in MADRS (Montgomery Asberg Depression Rating Scale) Score

    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.

    Measured: Baseline and weekly thereafter for 6 weeks

  4. Change in QIDS (Quick Inventory of Depressive Symptomatology) Score

    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.

    Measured: Baseline and weekly thereafter for 6 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jul 2020
  2. Study start15 Feb 2021
  3. Primary completion29 Apr 2026
  4. Study completion29 Apr 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
79 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04469959
Sponsor's protocol ID
201172
Acronym
D3
Status last verified
Aug 2026
First submitted
2 Jul 2020
Last updated
6 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: This study will include clinical, cognitive, and neuroimaging data from older depressed subjects. The final dataset will include clinical information about subject psychiatric diagnoses, psychiatric and medical history, cognitive data, and response to L-dopa . The investigators will share data via the National Database for Clinical Trials related to Mental Illness (NDCT). NDCT provides a secure platform for data-sharing allowing for communication of research data, tools, and supporting documents. As required by NDCT, the investigators will obtain a Global Unique Identifier (GUID) for each participant. The investigators will additionally follow NDCT requirements to certify and review data, as well as timeline requirements for data submission and data sharing. Sharing of neuroimaging data will also be facilitated by an XNAT system (xnat.org). XNAT is an open-source informatics software platform that assists in the management and archiving of imaging data.

Publications

  • Taylor WD. Clinical practice. Depression in the elderly. N Engl J Med. 2014 Sep 25;371(13):1228-36. doi: 10.1056/NEJMcp1402180. No abstract available.

    PubMed 25251617

  • Treadway MT, Bossaller NA, Shelton RC, Zald DH. Effort-based decision-making in major depressive disorder: a translational model of motivational anhedonia. J Abnorm Psychol. 2012 Aug;121(3):553-8. doi: 10.1037/a0028813. Epub 2012 Jul 9.

    PubMed 22775583

  • Kunisato Y, Okamoto Y, Ueda K, Onoda K, Okada G, Yoshimura S, Suzuki S, Samejima K, Yamawaki S. Effects of depression on reward-based decision making and variability of action in probabilistic learning. J Behav Ther Exp Psychiatry. 2012 Dec;43(4):1088-94. doi: 10.1016/j.jbtep.2012.05.007. Epub 2012 May 31.

    PubMed 22721601

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing L-Dopa in people with Late Life Depression and Cognitive Decline, run by Vanderbilt University Medical Center at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in WAIS-R Digit Symbol Task Score (time frame: Baseline, after week 3, and after week 6). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04469959, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2026.

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