1/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study)

Growing evidence suggests that dopamine contributes to key cognitive, emotional, and motor functions across the lifespan. In Late-Life Depression (LLD), dysfunction in these areas is common, predicts poor outcomes, and manifests as difficulties in motivation and effort along with cognitive and gait impairment. While studies of dopamine function in early and midlife depression primarily focus on individuals' ability to feel pleasure and respond to rewards, they often exclude the cognitive and physical function domains relevant for older adults despite a recognized decline in dopamine function with normal aging. The objectives of this collaborative R01 proposal between Columbia University/New York State Psychiatric Institute and Vanderbilt University Medical Center are to: 1) characterize dopaminergic dysfunction in LLD across cognitive, emotional, and motor domains at several levels of analysis (cellular Positron Emission Tomography \[PET\], circuit Magnetic Resonance Imaging \[MRI\], and behavioral / self-report); and 2) examine the responsivity of dopamine-related circuits and behavior to stimulation with carbidopa/levodopa (L-DOPA).

Supported by pilot data, this project builds on past work demonstrating that dopamine function declines with aging, that dopaminergic dysfunction contributes to deficits in behavior, and that L-DOPA administration improves cognitive and motor performance. The long-term goal of this line of research is to determine how dopaminergic dysfunction contributes to clinical presentations of LLD, how responsive behavioral symptoms are to modulation of dopamine function, and to identify novel targets for future interventions. Investigator's approach is to enroll 30 psychiatrically healthy elders and 60 depressed elders at Columbia/NYSPI exhibiting either slowed processing speed or slowed gait speed. Participants will undergo thorough clinical evaluations and complete PET imaging measuring different aspects of the brain's dopamine system, neuromelanin-sensitive MRI measurement of longterm dopamine transmission, functional MRI focused on effort-based decision making and reward processing, a comprehensive neurocognitive evaluation, a physical performance evaluation, and measurement of inflammatory markers. To assess responsivity of the dopamine system to modulation, depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. In a second phase, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This proposal is significant and innovative, as no prior published study has comprehensively examined dopamine-dependent behaviors in LLD. This will inform treatment approaches focusing on facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation.

Eligibility Criteria:
Inclusion Criteria:

Depressed Subjects:

1. Age 60 years or older (female subjects will be post-menopausal by virtue of their age, but last menstrual period month and year will be documented in the study database)
2. Diagnosis and Statistical Manual (DSM-5) diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD)
3. Montgomery Asberg Depression Rating Scale Score (MADRS) \>=15
4. Decreased processing speed or decreased gait speed
5. Capable of providing informed consent and complying with study procedures
6. Alternative standard treatments for MDD or PDD have been discussed and the individual agrees to be involved in an experimental treatment

Psychiatrically Healthy Elders:

1. Age 60 years or older years old
2. MADRS \< 8
3. Capable of providing informed consent and complying with study procedures

Exclusion Criteria:

Depressed Subjects:

1. Diagnosis of Substance Use Disorder (excluding Tobacco Use Disorder) in the past 12 months
2. History of psychosis (except brief psychosis associated with transient medical conditions \[e.g., delirium, urinary tract infection, etc\], psychotic disorder, mania, or bipolar disorder.
3. Primary neurological disorder, including dementia, stroke, Parkinson's disease, or epilepsy.
4. Mini Mental State Examination (MMSE) \< 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. Acute, severe, or unstable medical illness
10. Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, or history of joint replacement or spine surgery that limits mobility
11. Contraindication to MRI scanning (Metal implants, pacemaker, metal prostheses, metal orthodontic appliances in the body unless there is confirmation that the substance is MRI compatible.)
12. History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)
13. Has a medical condition managed with medication and/or device and the managing physician considers the condition and/or its management a contraindication to the research use of L-DOPA in this participant

Psychiatrically Healthy Elders:

1. Any personal history of DSM-5 disorder
2. Family history of MDD in first-degree relative
3. Plus, Exclusion criteria 8-12 above