Dopaminergic Dysfunction in Late-Life Depression

NCT04469959 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 201172
• Study Type: interventional
• Target: 79
• Locations: 1 country
• Sites: 2

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 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.

Conditions

Cognitive Decline; Levodopa; Late Life Depression; Depressive Disorder, Treatment-Resistant; Gait Impairment

Keywords

Antiparkinson agent; Levodopa; Elderly; Depressive Disorder, major

Outcome Measures

Primary Outcomes (6)

• 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.

  Baseline, after week 3, and after week 6

• 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.

  Baseline, after week 3, and after week 6

• 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.

  Baseline, after week 3, and after week 6

• 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.

  Baseline, after week 3, and after week 6

• 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.

  Baseline, after week 3, and after week 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.

  Baseline to after week 3

Secondary Outcomes (4)

• Change in NIH Toolbox Cognition Battery Scores

  Baseline, after week 3, and after week 6

• Monetary Incentive Delay Task

  Baseline and after week 3

• Change in MADRS (Montgomery Asberg Depression Rating Scale) Score

  Baseline and weekly thereafter for 6 weeks

• Change in QIDS (Quick Inventory of Depressive Symptomatology) Score

  Baseline and weekly thereafter for 6 weeks

Study Arms (2)

L-Dopa First / Placebo Second

EXPERIMENTAL

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 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.

Drug: L-Dopa; Drug: Placebo

Placebo First / L-Dopa Second

PLACEBO COMPARATOR

Step 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.

Drug: L-Dopa; Drug: Placebo

Interventions

L-Dopa DRUG

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.

Also known as: carbidopa/levodopa (Sinemet), 25/100 placebo capsules

L-Dopa First / Placebo Second; Placebo First / L-Dopa Second

Placebo DRUG

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.

Also known as: 25/100 placebo capsules

L-Dopa First / Placebo Second; Placebo First / L-Dopa Second

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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;
• 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).

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• Emory University: collaborator
• University of Pittsburgh: collaborator
• University of Pittsburgh Medical Center: collaborator
• Rutgers University: collaborator
• University of North Carolina, Chapel Hill: collaborator

Study Sites (2)

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt Psychiatric Hospital

Nashville, Tennessee, 37212, United States

Location

Related Publications (3)

• 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.

  PMID: 25251617 BACKGROUND

• 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.

  PMID: 22775583 BACKGROUND

• 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.

  PMID: 22721601 BACKGROUND

MeSH Terms

Conditions

Cognitive Dysfunction; Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major

Interventions

Levodopa; Carbidopa; carbidopa, levodopa drug combination

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Depressive Disorder; Mood 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; Methyldopa; Hydrazines

Study Officials

• Warren Taylor, MD,MHSc

  Vanderbilt University Medical Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double Blinded
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Study Record Dates

• First Submitted: July 2, 2020
• First Posted: July 14, 2020
• Study Start: February 15, 2021
• Primary Completion: April 29, 2026
• Study Completion: April 29, 2026
• Last Updated: June 11, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be shared according to policies from the NDCT and NDA (NIMH Data Archive). Descriptive data, outcome measures and analyzed data will be shared will be shared within 4 months of when a publication is accepted. Study data will be shared through the NDCT indefinitely.
• Access Criteria: The NIH will provide access to scientific investigators for research purposes. Qualified researchers who have completed a Data Use Certification and received approval from the NDA Data Access Committee (DAC) may be approved to access broadly shared data. A separate request process exists for access to data in federated sources. Additionally, the DAC and support staff at NIH have access to NDA shared data.

Locations

US (2)