Dopaminergic Dysfunction in Late-Life Depression

NCT ID: NCT04469959

Last Updated: 2026-02-06

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-15
• Study Completion Date: 2026-07-30

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.

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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 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.

Group Type: EXPERIMENTAL

L-Dopa

Intervention Type: 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.

Placebo

Intervention Type: 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.

Placebo First / L-Dopa Second

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.

Group Type: PLACEBO_COMPARATOR

L-Dopa

Intervention Type: 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.

Placebo

Intervention Type: 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.

Interventions

L-Dopa

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.

Intervention Type: DRUG

Placebo

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.

Intervention Type: DRUG

Other Intervention Names

carbidopa/levodopa (Sinemet); 25/100 placebo capsules; 25/100 placebo capsules

Eligibility Criteria

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 score ≥ 15

4. 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)

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 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

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

4. SBT > 10

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

6. History of inpatient psychiatric hospitalization in the last year;

7. 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)

8. 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)

9. Current or recent (within the past 2 weeks) treatment with antipsychotics or mood stabilizers, or use of antidepressants where washout is not advisable

10. History of hypersensitivity, allergy, or intolerance to Carbidopa/levodopa

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

12. Unstable medical illness

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

14. Diagnosis of HIV

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Emory University

OTHER

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: collaborator

University of Pittsburgh Medical Center

OTHER

Sponsor Role: collaborator

Rutgers University

OTHER

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Warren Taylor

Professor of Psychiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Warren Taylor, MD,MHSc

Role: STUDY_DIRECTOR

Vanderbilt University Medical Center

Locations

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Vanderbilt Psychiatric Hospital

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 25251617 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22775583 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22721601 (View on PubMed)

Other Identifiers

201172

Identifier Type: -

Identifier Source: org_study_id