Dopaminergic Dysfunction in Late-Life Depression (D3)

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.

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 80 evaluable elderly depressed outpatients with evidence of dopaminergic dysfunction, characterized as either slowed processing speed, motor speed, or gait speed. To disentangle depression effects from age-related changes, 50 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. 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.

Late Life Depression, Cognitive Decline, Depressive Disorder, Treatment-Resistant, Levodopa, Gait Impairment

STEP 1(3 weeks): Participants initially assigned to L-DOPA will begin with a Week 1 L-DOPA daily dosage of 150mg, (1.5 25mg carbidopa/100mg levodopa tablets) at 9am. Week 2 will increase to a L-DOPA daily dose of 300mg (1.5 25mg carbidopa/100mg levodopa tablets) at 9am and 5pm, followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets) three times daily. After completing post-trial assessments, participants then enter a 1 week taper period before proceeding to Step 2. Step 2 (3 Weeks): Participants will receive matching placebo tablets daily. Participants take placebo tablets once daily during week 1 (9am), twice daily during week 2 (9am, 5pm), and three times daily during week 3 (9am, 1pm, 5pm) over three weeks. Following post-trial assessments, participants then enter a 1-week taper period and study drug is withdrawn.

Step 1 (3 Weeks): Participants will receive matching placebo tablets daily. Participants take placebo tablets once daily during week 1 (9am), twice daily during week 2 (9am, 5pm), and three times daily during week 3 (9am, 1pm, 5pm) over three weeks. Following post-trial assessments, participants then enter a 1-week taper period before proceeding to Step 2. Step 2 (3 Weeks): Participants will begin with a Week 1 L-DOPA daily dosage of 150mg, (1.5 25mg carbidopa/100mg levodopa tablets) at 9am. Week 2 will increase to a L-DOPA daily dose of 300mg (1.5 25mg carbidopa/100mg levodopa tablets) at 9am and 5pm, followed by a Week 3 L-DOPA daily dose of 450mg (1.5 25mg carbidopa/100mg levodopa tablets) three times daily. After completing post-trial assessments, participants then enter a 1 week taper period and study drug will be discontinued.

Generic 25/100mg carbidopa/levodopa (Sinemet)tablets will be administered in this study. Participants will begin randomized double blinded 3- week trial of Levodopa. Dose titration starting at150 mg /daily to maximum of 450 mg patch/daily three times a day for three weeks. After one week of taper they will enter step 2 phase of study where carbidopa/levodopa matched placebo will be administered for 3 weeks afterwards dose will be slowly tapered over next 7 days.

Step 1(3weeks) Carbidopa/levodopa-matched placebo tablet 3 times. Followed by 1 week of taper Step2(3 weeks):150-450mg carbidopa/levodopa 3 times daily for three weeks .Followed by 1 week of taper.

Wechsler Adult Intelligence Scale(WAIS-R) Coding test score will be used to measure processing speed. A composite score is derived with two other test scores of WAIS-R Pattern Comparison Test Score by extracting latent fact and factor loadings, creating a purer measure of processing speed. Higher scores indicate better performance.

Pattern Comparison Test score will be used to measure processing speed. A composite score is derived with two other test scores of WAIS-R by extracting latent fact and factor loadings, creating a purer measure of processing speed. Higher scores indicate better performance.

Letter Comparison Test score will be used to measure the processing speed. A composite score is derived with two other test scores of WAIS-R by extracting latent fact and factor loadings, creating a purer measure of processing speed. Higher scores indicate better performance.

This neuropsychological test battery assesses a range of executive functions. Tasks measuring working memory, inhibition, set shifting, fluency, insight, and planning and 3 self-report questionnaires rating social cognition and behavior . Higher scores indicate better performance.

Gait will be assessed with a single and dual task (ST, DT) using the GaitRite system, which assesses gait parameters in real time (gait speed, cadence, stride length).Changes in these parameters will reflect changes in gait slowness.

In this functional Magnetic Resonance Imaging task, participants decide whether to work harder for a larger reward (high number of finger presses with their pinky) or expend less energy (low number of presses with a dominant index finger) for a lesser reward, with lower rewards being $1 dollar and higher rewards ranging from $1.20 to $5. Participants receive information about the probability of winning on each trial regardless of their pick and one trial from each run is randomly picked for payout. The primary outputs on this task are the percentage of time participants choose the high cost / high reward option on the EEfRT and associated neural activation patterns in prefrontal cortex (PFC) and striatum.

This is a brief and psychometrically sound set of 7 computerized instruments providing an overall cognitive index from measures of 6 cognitive domains.

This functional Magnetic Resonance Imaging task assesses neural response during reward anticipation and receipt. On each trial, participants are presented with a 2000msec cue indicating that trial's reward value ($0, $1, or $5). After the cue, a 2000-2500 msec delay period ensues as the participant waits for the target. Participants press a button as quickly as possible when the target is visible. After another delay lasting from 950 to 2800 msec, a feedback screen lasting 2500msec appears indicating the outcome ("Hit!" or "Miss!") for each trial, with a brief interval before the next trial. the primary contrast for analyses is the contrast of Cue $5 - Cue $0 to brain activation during reward anticipation. The contrast of Hit vs. Miss on both $5 and $1 trials is the primary index of reward receipt.

Secondary outcome measured by the total score of the clinician rated MADRS, a measure of depression severity. The MADRS total score range is 0-60, where higher scores indicate greater depression severity.

QIDS-16-item, a participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27, with higher scores indicative of greater severity.

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 (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) 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 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 Primary neurological disorder, including dementia, stroke, Parkinson's disease, epilepsy, etc SBT > 10 MADRS suicide item > 4 or other indication of acute suicidality Current or recent (within the past 2 weeks) treatment with antipsychotics or mood stabilizers, or use of antidepressants where washout is not advisable 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 Diagnosis of HIV History of significant radioactivity exposure (nuclear medicine studies or occupational exposure).

This study will include clinical, cognitive, and neuroimaging data from older depressed subjects. The final dataset will include clinical information about subject psychiatric diagnoses, psychiatric and medical history, cognitive data, and response to L-dopa . We will share data via the National Database for Clinical Trials related to Mental Illness (NDCT). NDCT provides a secure platform for data-sharing allowing for communication of research data, tools, and supporting documents. As required by NDCT, we will obtain a Global Unique Identifier (GUID) for each participant. We will additionally follow NDCT requirements to certify and review data, as well as timeline requirements for data submission and data sharing. Sharing of neuroimaging data will also be facilitated by an XNAT system (xnat.org). XNAT is an open-source informatics software platform that assists in the management and archiving of imaging data.

Data will be shared according to policies from the NDCT and NDA (NIMH Data Archive). Descriptive data, outcome measures and analyzed data will be shared will be shared within 4 months of when a publication is accepted. Study data will be shared through the NDCT indefinitely.

The NIH will provide access to scientific investigators for research purposes. Qualified researchers who have completed a Data Use Certification and received approval from the NDA Data Access Committee (DAC) may be approved to access broadly shared data. A separate request process exists for access to data in federated sources. Additionally, the DAC and support staff at NIH have access to NDA shared data.

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