Nashville,
Tennessee
37212
Purpose:
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.
Study summary:
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.
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 (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).