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DTA (Dopaminergic Therapy for Anhedonia) Study

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ClinicalTrials.gov Identifier: NCT04723147
Recruitment Status : Recruiting
First Posted : January 25, 2021
Last Update Posted : February 16, 2021
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Jennifer Felger, Emory University

Brief Summary:
The purpose of this 6-week, double-blind, placebo-controlled, crossover study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Thirty-five male and female participants with depression, between the ages of 25-55 years of age, will be randomized to two study tracks (A and B) to receive both placebo and three doses of L-DOPA, given in different orders. Increases or decreases in each dose will occur gradually over 6 weeks of the study. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing and functional MRI (fMRI) scans as part of the study. The total length of participation is about 2 months.

Condition or disease Intervention/treatment Phase
Depression Anhedonia Drug: Carbidopa Levodopa Drug: Placebo Phase 4

Detailed Description:

Depression is a widespread disorder (lifetime prevalence >20%). Current antidepressant medications are effective for many patients; however, more than 30% fail to respond. Of the patients that do respond to treatment, some continue to suffer with primary symptoms of depression like an inability to experience pleasure, called anhedonia. In this regard, one biological pathway that may contribute to symptoms of depression and particularly anhedonia is inflammation.

The purpose of this 6-week, double-blind, placebo-controlled, crossover study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Despite evidence of low dopamine function in patients with depression, the ability of existing dopaminergic therapies, like L-DOPA, to affect brain circuits in depression has yet to be explored. This study will help determine the best dose of an FDA-approved medication, Sinemet (L-DOPA) that might be used in the future to treat sub-groups of depressed individuals.

Forty male and female participants with depression, between the ages of 25-55 years of age, will be randomized to two study tracks (A and B) to receive both placebo and three doses of L-DOPA, given in different orders. Increases or decreases in each dose will occur gradually over 6 weeks of the study. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing and functional MRI (fMRI) scans as part of the study. The total length of participation is about 2 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Dopaminergic Therapy for Inflammation-Related Anhedonia in Depression
Actual Study Start Date : January 29, 2021
Estimated Primary Completion Date : November 2025
Estimated Study Completion Date : November 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Carbidopa Levodopa followed by Placebo
Participants will receive first Carbidopa Levodopa at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day; and then placebo.
Drug: Carbidopa Levodopa
Patients will receive L-DOPA at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA. Starting dose is 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day
Other Name: Sinemet, L-DOPA

Drug: Placebo
A placebo is a sugar pill that has no therapeutic effect and will be administered orally. Participants will receive 1 placebo tablet matching the Carbidopa Levodopa tablet.
Other Name: Placebo tablet

Experimental: Placebo followed by Carbidopa Levodopa
Participants will receive first placebo, and then Carbidopa Levodopa (L-DOPA) at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day.
Drug: Carbidopa Levodopa
Patients will receive L-DOPA at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA. Starting dose is 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day
Other Name: Sinemet, L-DOPA

Drug: Placebo
A placebo is a sugar pill that has no therapeutic effect and will be administered orally. Participants will receive 1 placebo tablet matching the Carbidopa Levodopa tablet.
Other Name: Placebo tablet




Primary Outcome Measures :
  1. Change in targeted ventral striatum to ventromedial prefrontal cortex (VS-vmPFC) connectivity [ Time Frame: Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA ]
    Patients will undergo resting-state and task-based functional magnetic resonance imaging (fMRI) to calculate functional connectivity (FC) between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC). FC is measured as continuous Z scores reflecting the correlation of activity between the brain regions. Higher FC Z scores reflect stronger connectivity.


Secondary Outcome Measures :
  1. Change in Effort-Expenditure for Rewards Task (EEfRT) [ Time Frame: Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA ]
    The EEfRT is a widely used, multi-trial task in which participants are given an opportunity on each trial to choose between two different task difficulty levels in order to obtain monetary rewards. EEfRT will be used as an objective measure of motivation and will be administered following MRI scans during the study. The EEfRT is reported as the percent of high effort trials selected. A higher percentage reflects higher motivation for effort expenditure.

  2. Change in Inventory of Depressive Symptomatology- Self-Report (IDS-SR) [ Time Frame: Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA ]
    Anhedonia will be assessed from a subscale of the Inventory of Depressive Symptomatology- Self-Report (IDS-SR). Scores on this 3-question scale range from 0-9 with higher scores reflecting greater anhedonia.

  3. Change in Snaith-Hamilton Pleasure Scale-Clinician (SHAPS-C ) [ Time Frame: Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA ]
    The Snaith-Hamilton Pleasure Scale-Clinician (SHAPS-C) is a clinician administered tool to assess symptoms of anhedonia. The SHAPS-C uses 14 question each rated on a Likert scale of 1-4, with higher scores reflecting greater pathology.

  4. Change in Motivation and Pleasure-Self-Report (MAP-SR) [ Time Frame: Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA ]
    The Motivation and Pleasure-Self-Report (MAP-SR) will be used to capture self-reported aspects of anhedonia and reduced motivation. The scale uses 18 question each rated on a Likert scale of 0-4, with higher scores reflecting greater pathology.

  5. Change in Hamilton Depression Rating Scale (HAM-D) [ Time Frame: Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA ]
    The anhedonia and motivation-related item from the clinician administered Hamilton Depression Rating Scale (HAM-D) (item #7: work and activities) will be used to measure anhedonia. This item is rated on a scale of 0-4 with higher scores reflecting greater pathology



Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • willing and able to give written informed consent;
  • men or women, 25-55 years of age
  • a primary diagnosis of DSM-V MD, current, as diagnosed by the SCID-I;
  • score >10 on the Patient Health Questionnaire [PHQ]-9
  • off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, anxiolytics, and sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for fluoxetine)
  • CRP ≥2 mg/L
  • Score >/=2 on the anhedonia question of Patient Health Questionnaire [PHQ]-9

Exclusion Criteria:

  • history or evidence (clinical or laboratory) of an autoimmune disorder ;
  • history or evidence (clinical or laboratory) of hepatitis B or C infection or human immunodeficiency virus infection; - history of any type of cancer requiring treatment with more than minor surgery;
  • unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination, EKG and laboratory testing);
  • history of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; history or current bipolar disorder; history or current gambling disorder; substance abuse/dependence within 6 months of study entry (as determined by SCID);
  • active suicidal plan as determined by a score >3 on item #3 on the HAM-D; g. an active eating disorder (except for patients with binge eating disorder in whom binging is clearly associated with worsening of mood symptoms) ;
  • a history of a cognitive disorder
  • pregnancy or lactation;
  • chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications or statins;
  • use of NSAIDS, glucocorticoids, or statins at any time during the study;
  • urine toxicology screen is positive for drugs of abuse,
  • any contraindication for MRI scanning; n. intolerance, sensitivity or contraindication to carbidopa-levodopa (including history of narrow-angle glaucoma, melanoma, gastric and/or duodenal ulcers, bleeding disorders, or frequent migraines).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04723147


Contacts
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Contact: Jennifer Felger, PhD 404-727-3987 jfelger@emory.edu
Contact: Bobbi Woolwine, CCRC 4047129620 bwoolwi@emory.edu

Locations
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United States, Georgia
Emory University Hospital Recruiting
Atlanta, Georgia, United States, 30322
Contact: Bobbi Woolwine    404-712-9620    bwoolwi@emory.edu   
Sponsors and Collaborators
Emory University
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Jennifer Felger, PhD Emory University
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Responsible Party: Jennifer Felger, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT04723147    
Other Study ID Numbers: STUDY00000361
1R61MH121625-01A1 ( U.S. NIH Grant/Contract )
First Posted: January 25, 2021    Key Record Dates
Last Update Posted: February 16, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Only the data - raw and analyzed, or both, depending on the items. Statistical plans an additional information may be shared within the data base but it is not required as the data will be linked to the publications.
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: After publication, within one year of the end of the project.
Access Criteria: Must be NIH investigators and they have to submit an application, including analysis plan, in order to be granted access.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Jennifer Felger, Emory University:
Depression
Anhedonia
Additional relevant MeSH terms:
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Anhedonia
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Levodopa
Carbidopa
Carbidopa, levodopa drug combination
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors
Adjuvants, Immunologic
Immunologic Factors
Dopamine Agonists