Dopaminergic Dysfunction in Late-Life Depression

201172

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.

2021-02-15

2025-04-30

2026-06-30

Recruiting

Early phase I

100

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. Current or recent (within the past 2 weeks) treatment with antipsychotics or mood stabilizers, or use of antidepressants where washout is not advisable 7. History of hypersensitivity, allergy, or intolerance to Carbidopa/levodopa 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. Diagnosis of HIV 12. History of significant radioactivity exposure (nuclear medicine studies or occupational exposure).

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2024-03-15