A Study of L-DOPA for Depression and Slowing in Older Adults

Individuals with Late Life Depression (LLD) often have cognitive problems, particularly problems with memory, attention, and problem solving, all of which contribute to antidepressant non-response. Our group and others have shown that decreased thinking speed is the central cause of functional problems in patients with LLD. Similarly, decreased walking speed is associated with depression and carries additional risk for falls, hospitalization, and death. Available evidence suggests that declining functionality in the brain's dopamine system contributes to age-related cognitive and motor slowing. The central hypothesis of this R61/R33 Phased Innovation Award is that by enhancing dopamine functioning in the brain and improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms in older adults.

This study will elucidate the neurobiology of slowing and LLD, identify a novel therapeutic target for depression, and contribute to the development of personalized treatment regimens for LLD. The multimodal neuroimaging methods detailed in this application will provide information about the neurobiology of aging-associated slowing and LLD at molecular, structural, and functional levels of analysis. These data will fill a crucial gap in our knowledge regarding what are the physiologic and functional consequences of dopamine depletion occurring across the lifespan in individuals without PD. Results from this project also will allow us to evaluate a novel therapeutic approach to LLD, which could have large public health ramifications given the prevalence, frequent treatment resistance, and chronicity characteristic of LLD. Even apart from patients with LLD, cognitive and motor slowing exact a large public health burden in terms of impaired functioning and increased morbidity and mortality, and this burden will only grow as the population ages. It is critical to develop treatments capable of altering the negative health trajectories associated with slowing in order to help older adults maintain independent functioning and live longer with an increased quality of life. Finally, while PET and MRI may prove critical to understand the neurobiology of slowing and LLD, their invasiveness and expense limit their roles in informing treatment decisions in clinical practice settings. For this reason the investigators are also assessing the influence of genetic moderators such as interleukin-6 (IL-6) and catechol-O-methyl-transferase (COMT) genotype on baseline dopamine functioning and response to L-DOPA. This may facilitate the identification of both high-risk individuals and those most likely to benefit from treatment interventions.

Eligibility Criteria:
Inclusion Criteria:

* Age \>59 years
* DSM 5 non-psychotic Major Depressive Disorder, Dysthymia, or Depression Not Otherwise Specified
* Center for Epidemiological Studies Depression (CES-D) Rating Scale \> 9
* Decreased processing speed (defined as 0.5 SD below age-adjusted norms on the Digit Symbol Test) and decreased gait speed (defined as average walking speed over 15' course \< 1 m/s)
* Willing and capable of providing informed consent and complying with study procedures
* Prefer not to be treated with a standard treatment for MDD, Dysthymia, or Depression NOS (e.g., antidepressant medication or psychotherapy)

Exclusion Criteria:

* Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) within the past 12 months
* History of or current psychosis, psychotic disorder, mania, or bipolar disorder
* Diagnosis of probable Alzheimer's Disease, Vascular Dementia, or PD
* Mini Mental Status Exam (MMSE) \< 25
* HRSD ≥ 25 or the presence of significant suicide risk
* Current or recent (within the past 4 weeks) treatment with antidepressants, antipsychotics, dopaminergic agents, or mood stabilizers
* History of allergy, hypersensitivity reaction, or severe intolerance to LDOPA
* Acute, severe, or unstable medical or neurological illness
* Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, history of joint replacement surgery, or history of spine surgery
* Hypotension (SBP\<90), hypertension (SBP \>150 or DBP \> 90), past stroke causing sensory or movement deficits, cardiac arrhythmias, or any other severe or uncontrolled cardiovascular disease
* Having contraindication to MRI scanning (such as metal in body) or unable to tolerate the scanning procedures
* History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)
* Presence of a clinically significant brain abnormality, significant anemia, insulin dependent diabetes, a history of cardiovascular disease, or uncontrolled/untreated risk factors for coronary artery disease