Dopaminergic Dysfunction in Late-Life Depression

  • STATUS
    Recruiting
  • End date
    Jun 30, 2026
  • participants needed
    60
  • sponsor
    Vanderbilt University Medical Center
Updated on 24 February 2021

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.

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.

Details
Condition Levodopa, Cognitive Impairment, Cognitive Dysfunction, Cognitive Decline, Cognitive Impairments, Late Life Depression, Mental Deterioration, Gait Impairment, l-dopa, l-3,4-dihydroxyphenylalanine, neurocognitive disturbance, Depressive Disorder, Treatment-Resistant, Depressive Disorder, Treatment-Resistant
Treatment Placebo, L-Dopa
Clinical Study IdentifierNCT04469959
SponsorVanderbilt University Medical Center
Last Modified on24 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Age 60 years
Diagnostic and Statistical Manual-5 (DSM5) diagnosis of Major Depressive Disorder, Persistent Depressive Disorder, or Depression Not Otherwise Specified (NOS)
MADRS (116) score 15
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)
Capable of providing informed consent and adhering to study procedures

Exclusion Criteria

Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) in the past 12 months
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)
Primary neurological disorder, including dementia, stroke, Parkinson's disease, epilepsy, etc
Mini-Mental State Exam score (117) < 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
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
Contraindication to MRI
History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)
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