<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04469959</url>
  </required_header>
  <id_info>
    <org_study_id>201172</org_study_id>
    <nct_id>NCT04469959</nct_id>
  </id_info>
  <brief_title>Dopaminergic Dysfunction in Late-Life Depression</brief_title>
  <acronym>D3</acronym>
  <official_title>Dopaminergic Dysfunction in Late-Life Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Late-Life Depression (LLD), or depression in older adults, often presents with motivational&#xD;
      deficits, deficits in performance in cognitive domains including processing speed and&#xD;
      executive dysfunction, and mobility impairments. This triad of findings implicate&#xD;
      dopaminergic dysfunction as a core pathophysiologic feature in depression, and may contribute&#xD;
      to cognitive decline and motor disability. Normal aging results in brain-wide dopamine&#xD;
      declines, decreased D1/D2 receptor density, and loss of dopamine transporters. Although brain&#xD;
      changes associated with depression and aging converge on dopamine circuits, the specific&#xD;
      disturbances in LLD and how responsive the system is to modulation remain unclear. In this&#xD;
      study, investigators are testing integrative model that aging, in concert with&#xD;
      pro-inflammatory shifts, decreases dopamine signaling. These signally changes affects&#xD;
      behaviors supported by these circuits, in the context of age-associated cortical atrophy and&#xD;
      ischemic microvascular changes, resulting in variable LLD phenotypes. Investigators propose a&#xD;
      primary pathway where dopaminergic dysfunction in depressed elders contributes to slowed&#xD;
      processing speed and mobility impairments that increase the effort cost associated with&#xD;
      voluntary behavior. The central hypothesis of this study is that late-life depression is&#xD;
      characterized by dysfunction in the dopamine system and, by enhancing dopamine functioning in&#xD;
      the brain. By improving cognitive and motor slowing, administration of carbidopa/levodopa&#xD;
      (L-DOPA) will improve depressive symptoms.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Late Life Depression (LLD) is a prevalent, disabling, and at times lethal condition for which&#xD;
      currently available treatments are often ineffective. No prior study has comprehensively&#xD;
      examined dopamine-dependent behaviors (i.e., reward processing, cognition, motor function) in&#xD;
      LLD, and none has integrated positron emission tomography (PET), multimodal magnetic&#xD;
      resonance imaging (MRI), neuropsychological evaluation, and mobility assessments. Should&#xD;
      cognitive and motor slowing result in altered effort-based decision making as researchers&#xD;
      hypothesize, treatment development may shift from addressing mood and hedonic responses&#xD;
      toward facilitating cognition and movement, reducing the effort cost of voluntary behavior,&#xD;
      and promoting behavioral activation.&#xD;
&#xD;
      This study at Vanderbilt University Medical Center (VUMC) will enroll 80 evaluable elderly&#xD;
      depressed outpatients with evidence of dopaminergic dysfunction, characterized as either&#xD;
      slowed processing speed, motor speed, or gait speed. To disentangle depression effects from&#xD;
      age-related changes, 50 never-depressed elders also will complete baseline evaluation.&#xD;
      Assessments include PET imaging of receptor density, neuromelanin-sensitive MRI (NM-MRI)&#xD;
      measurement of nigrostriatal status, task-based MRI focused on effort-based decision making&#xD;
      and reward processing, and comprehensive psychiatric, neurocognitive, and physical&#xD;
      performance evaluation. Depressed participants then will be randomized to levodopa (L-DOPA)&#xD;
      or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral&#xD;
      assessments. In a cross-over phase, participants will receive the opposite intervention for&#xD;
      an additional 3 weeks followed by clinical and cognitive assessments only. This mechanistic&#xD;
      probe allows us to examine the contributions and interrelationships of dopamine-dependent&#xD;
      processes in LLD and evaluate the responsivity of dopamine systems in LLD to pharmacological&#xD;
      stimulation.&#xD;
&#xD;
      AIM 1: To characterize dopaminergic dysfunction in LLD at molecular, circuit, and behavioral&#xD;
      levels.&#xD;
&#xD;
      Hyp 1: Compared to age- and gender-matched controls on baseline functional MRI (fMRI), LLD&#xD;
      participants will be less willing to expend effort for rewards and exhibit lower prefrontal&#xD;
      cortex and striatal activation on the Effort Expenditure for Rewards Task (EEfRT). Hyp 2:&#xD;
      Across all participants, lower midbrain &amp; striatal [18F]-fallypride binding, and lower NM-MRI&#xD;
      signal in the substantia nigra, pars compacta will predict lower performance across cognitive&#xD;
      domains: Positive Valence (impaired willingness to expend effort, decreased neural&#xD;
      activations on the EEfRT), Cognitive (slowed processing speed and executive dysfunction), and&#xD;
      Sensorimotor (slowed gait speed). Hyp 3: Across all participants, slowed processing and gait&#xD;
      speed likewise will predict lower willingness to expend effort on the EEfRT.&#xD;
&#xD;
      AIM 2: To examine responsivity of dopamine circuits in LLD to stimulation with L-DOPA.&#xD;
&#xD;
      Hyp 1: Compared to placebo, L-DOPA will result in greater normalization of neural activations&#xD;
      and improved behavioral performance in Positive Valence, Cognitive, and Sensorimotor domains.&#xD;
      Hyp 2: Baseline PET and NM-MRI measures will moderate L-DOPA effects. The greatest&#xD;
      improvements will be observed in those with the lowest baseline [18F]-fallypride binding, and&#xD;
      NM-MRI signal.&#xD;
&#xD;
      Exploratory Aims: 1) To investigate associations of baseline proinflammatory markers with&#xD;
      dopaminergic function across molecular, circuit, cognitive and behavioral levels of analysis.&#xD;
      2) To evaluate the durability of L-DOPA effects on cognitive domains in the crossover phase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 15, 2021</start_date>
  <completion_date type="Anticipated">June 30, 2026</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double Blinded</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in WAIS-R Coding Test Score</measure>
    <time_frame>Baseline, after week 3, and after week 6</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Pattern Comparison Test Score</measure>
    <time_frame>Baseline, after week 3, and after week 6</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Letter Comparison Test Score</measure>
    <time_frame>Baseline, after week 3, and after week 6</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in NIH EXAMINER Test Score</measure>
    <time_frame>Baseline, after week 3, and after week 6</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Gait pattern</measure>
    <time_frame>Baseline, after week 3, and after week 6</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Effort Expenditure for Rewards Task (EEfRT)</measure>
    <time_frame>Baseline to after week 3</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in NIH Toolbox Cognition Battery Scores</measure>
    <time_frame>Baseline, after week 3, and after week 6</time_frame>
    <description>This is a brief and psychometrically sound set of 7 computerized instruments providing an overall cognitive index from measures of 6 cognitive domains.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monetary Incentive Delay Task</measure>
    <time_frame>Baseline and after week 3</time_frame>
    <description>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 (&quot;Hit!&quot; or &quot;Miss!&quot;) 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in MADRS (Montgomery Asberg Depression Rating Scale) Score</measure>
    <time_frame>Baseline and weekly thereafter for 6 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in QIDS (Quick Inventory of Depressive Symptomatology) Score</measure>
    <time_frame>Baseline and weekly thereafter for 6 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Late Life Depression</condition>
  <condition>Cognitive Decline</condition>
  <condition>Depressive Disorder, Treatment-Resistant</condition>
  <condition>Levodopa</condition>
  <condition>Gait Impairment</condition>
  <arm_group>
    <arm_group_label>L-Dopa First / Placebo Second</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo First / L-Dopa Second</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>L-Dopa</intervention_name>
    <description>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.&#xD;
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.</description>
    <arm_group_label>L-Dopa First / Placebo Second</arm_group_label>
    <arm_group_label>Placebo First / L-Dopa Second</arm_group_label>
    <other_name>carbidopa/levodopa (Sinemet)</other_name>
    <other_name>25/100 placebo tablets</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>L-Dopa First / Placebo Second</arm_group_label>
    <arm_group_label>Placebo First / L-Dopa Second</arm_group_label>
    <other_name>25/100 placebo tablets</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 60 years&#xD;
&#xD;
          2. Diagnostic and Statistical Manual-5 (DSM5) diagnosis of Major Depressive Disorder,&#xD;
             Persistent Depressive Disorder, or Depression Not Otherwise Specified (NOS)&#xD;
&#xD;
          3. MADRS (116) score ≥ 15&#xD;
&#xD;
          4. Decreased processing speed (0.5 SD below age-adjusted norms on the WAIS-IV Coding task&#xD;
             or Trail Making Test, Part A) or decreased motor speed (gait speed/average walking&#xD;
             speed on 15' course ≤ 1m/s, or 0.5 SD below age-, gender- and education-adjusted norms&#xD;
             on the grooved pegboard test)&#xD;
&#xD;
          5. Capable of providing informed consent and adhering to study procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) in the&#xD;
             past 12 months&#xD;
&#xD;
          2. Other psychiatric disorders including a history of psychosis, psychotic disorder,&#xD;
             mania, or bipolar disorder. Other comorbid psychiatric disorders are allowable if the&#xD;
             depressive disorder diagnosis is considered to be the primary problem&#xD;
&#xD;
          3. Primary neurological disorder, including dementia, stroke, Parkinson's disease,&#xD;
             epilepsy, etc&#xD;
&#xD;
          4. SBT &gt; 10&#xD;
&#xD;
          5. MADRS suicide item &gt; 4 or other indication of acute suicidality&#xD;
&#xD;
          6. Current or recent (within the past 2 weeks) treatment with antipsychotics or mood&#xD;
             stabilizers, or use of antidepressants where washout is not advisable&#xD;
&#xD;
          7. History of hypersensitivity, allergy, or intolerance to L-DOPA;&#xD;
&#xD;
          8. Any physical or intellectual disability adversely affecting ability to complete&#xD;
             assessments&#xD;
&#xD;
          9. Unstable medical illness&#xD;
&#xD;
         10. Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar&#xD;
             spine disease, or history of joint replacement / spine surgery that limits mobility&#xD;
&#xD;
         11. Diagnosis of HIV&#xD;
&#xD;
         12. History of significant radioactivity exposure (nuclear medicine studies or&#xD;
             occupational exposure).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Warren Taylor, MD,MHSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Warren Taylor, MD,MHSc</last_name>
    <phone>615-322-1073</phone>
    <email>warren.d.taylor@vumc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Carrie Williams</last_name>
    <phone>(615) 936-2162</phone>
    <email>carrie.e.williams@vumc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Vanderbilt Psychiatric Hospital</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carrie Williams</last_name>
      <phone>615-936-2162</phone>
      <email>carrie.e.williams@vumc.org</email>
    </contact>
    <investigator>
      <last_name>Warren Taylor, MD,MHSc</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Taylor WD. Clinical practice. Depression in the elderly. N Engl J Med. 2014 Sep 25;371(13):1228-36. doi: 10.1056/NEJMcp1402180. No abstract available.</citation>
    <PMID>25251617</PMID>
  </reference>
  <reference>
    <citation>Treadway MT, Bossaller NA, Shelton RC, Zald DH. Effort-based decision-making in major depressive disorder: a translational model of motivational anhedonia. J Abnorm Psychol. 2012 Aug;121(3):553-8. doi: 10.1037/a0028813. Epub 2012 Jul 9.</citation>
    <PMID>22775583</PMID>
  </reference>
  <reference>
    <citation>Kunisato Y, Okamoto Y, Ueda K, Onoda K, Okada G, Yoshimura S, Suzuki S, Samejima K, Yamawaki S. Effects of depression on reward-based decision making and variability of action in probabilistic learning. J Behav Ther Exp Psychiatry. 2012 Dec;43(4):1088-94. doi: 10.1016/j.jbtep.2012.05.007. Epub 2012 May 31.</citation>
    <PMID>22721601</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>March 9, 2023</last_update_submitted>
  <last_update_submitted_qc>March 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Warren Taylor</investigator_full_name>
    <investigator_title>Professor of Psychiatry</investigator_title>
  </responsible_party>
  <keyword>Antiparkinson agent</keyword>
  <keyword>Levodopa</keyword>
  <keyword>Elderly</keyword>
  <keyword>Depressive Disorder, major</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
    <mesh_term>Depressive Disorder, Treatment-Resistant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levodopa</mesh_term>
    <mesh_term>Carbidopa</mesh_term>
    <mesh_term>Carbidopa, levodopa drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>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.</ipd_time_frame>
    <ipd_access_criteria>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.</ipd_access_criteria>
    <ipd_url>https://nda.nih.gov</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04469959
org study id: 201172
nct id: NCT04469959
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Double Blinded
measure: Change in WAIS-R Coding Test Score
time frame: Baseline, after week 3, and after week 6
description: 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.
measure: Change in Pattern Comparison Test Score
time frame: Baseline, after week 3, and after week 6
description: 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.
measure: Change in Letter Comparison Test Score
time frame: Baseline, after week 3, and after week 6
description: 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.
measure: Change in NIH EXAMINER Test Score
time frame: Baseline, after week 3, and after week 6
description: 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.
measure: Change in Gait pattern
time frame: Baseline, after week 3, and after week 6
description: 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.
measure: Change in Effort Expenditure for Rewards Task (EEfRT)
time frame: Baseline to after week 3
description: 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.
measure: Change in NIH Toolbox Cognition Battery Scores
time frame: Baseline, after week 3, and after week 6
description: This is a brief and psychometrically sound set of 7 computerized instruments providing an overall cognitive index from measures of 6 cognitive domains.
measure: Monetary Incentive Delay Task
time frame: Baseline and after week 3
description: 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.
measure: Change in MADRS (Montgomery Asberg Depression Rating Scale) Score
time frame: Baseline and weekly thereafter for 6 weeks
description: 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.
measure: Change in QIDS (Quick Inventory of Depressive Symptomatology) Score
time frame: Baseline and weekly thereafter for 6 weeks
description: 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.
arm group label: L-Dopa First / Placebo Second
arm group type: Experimental
description: 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.
arm group label: Placebo First / L-Dopa Second
arm group type: Placebo Comparator
description: 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.
intervention type: Drug
intervention name: L-Dopa
description: 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.
arm group label: L-Dopa First / Placebo Second
arm group label: Placebo First / L-Dopa Second
other name: carbidopa/levodopa (Sinemet)
other name: 25/100 placebo tablets
intervention type: Drug
intervention name: Placebo
description: 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.
arm group label: L-Dopa First / Placebo Second
arm group label: Placebo First / L-Dopa Second
other name: 25/100 placebo tablets
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Warren Taylor, MD,MHSc
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
last name: Warren Taylor, MD,MHSc
phone: 615-322-1073
email: warren.d.taylor@vumc.org
last name: Carrie Williams
phone: (615) 936-2162
email: carrie.e.williams@vumc.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
citation: Taylor WD. Clinical practice. Depression in the elderly. N Engl J Med. 2014 Sep 25;371(13):1228-36. doi: 10.1056/NEJMcp1402180. No abstract available.
PMID: 25251617
citation: Treadway MT, Bossaller NA, Shelton RC, Zald DH. Effort-based decision-making in major depressive disorder: a translational model of motivational anhedonia. J Abnorm Psychol. 2012 Aug;121(3):553-8. doi: 10.1037/a0028813. Epub 2012 Jul 9.
PMID: 22775583
citation: Kunisato Y, Okamoto Y, Ueda K, Onoda K, Okada G, Yoshimura S, Suzuki S, Samejima K, Yamawaki S. Effects of depression on reward-based decision making and variability of action in probabilistic learning. J Behav Ther Exp Psychiatry. 2012 Dec;43(4):1088-94. doi: 10.1016/j.jbtep.2012.05.007. Epub 2012 May 31.
PMID: 22721601
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Warren Taylor
investigator title: Professor of Psychiatry
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Cognitive Dysfunction
mesh term: Depressive Disorder, Treatment-Resistant
mesh term: Levodopa
mesh term: Carbidopa
mesh term: Carbidopa, levodopa drug combination
sharing ipd: Yes
ipd description: 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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: 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.
ipd access criteria: 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.
ipd url: https://nda.nih.gov