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Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

This study is currently recruiting participants.
Verified November 2017 by Jennifer Felger, Emory University
Sponsor:
ClinicalTrials.gov Identifier:
NCT02513485
First Posted: July 31, 2015
Last Update Posted: November 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Jennifer Felger, Emory University
  Purpose
The purpose of this study is to learn more about the changes that happen in the brain and the body when a person is depressed. This study will determine if the level of inflammation in the body is related to symptoms of depression, how well the person thinks, and how certain brain regions communicate.

Condition Intervention Phase
Depression Drug: Levodopa+carbidopa Drug: Placebo Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: "Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa"; "Inflammation Effects on Corticostriatal Connectivity and Reward: Role of Dopamine"

Resource links provided by NLM:


Further study details as provided by Jennifer Felger, Emory University:

Primary Outcome Measures:
  • Change in functional corticostriatal connectivity [ Time Frame: Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    Corticostriatal connectivity will be assessed by functional magnetic resonance imaging (fMRI). Resting-state and task-based (monetary incentive delay [MID]) fMRI scans will be conducted on a 3 Tesla Siemens Trio MRI scanner.

  • Correlation coefficient between change in corticostriatal connectivity and levels of plasma C-reactive protein and other immune markers [ Time Frame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    Peripheral blood samples will be analyzed for levels of immune markers like plasma C-reactive protein (CRP), interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), tumor necrosis factor (TNF) -alpha, soluble cytokine receptor2 (TNFR 2), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), interleukin 10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1).

  • Correlation coefficient between change in cerebral blood flow (CBF) and change in functional connectivity [ Time Frame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The cerebral blood flow (CBF) before and after Sinemet (250 mg levodopa/ 50mg carbidopa) or placebo administration will be assessed by arterial spin labeling (ASL) fMRI.


Secondary Outcome Measures:
  • Effort-Expenditure for Rewards Task (EEfRT) neurocognitive test [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial task that will be used to objectively assess motivation.

  • The Trail Making Test (TMT) neurocognitive assessment [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Trail Making Test (TMT) will be used to measure basic attention and psychomotor processing speed.

  • Digit Symbol Task neurocognitive test [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Digit Symbol Task will be used to assess graphomotor speed, visual scanning and memory.

  • Finger Tapping Task (FTT) neurocognitive test [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Finger Tapping Task (FTT) assesses motor speed and can detect subtle motor impairment.

  • Reaction Time Task (CANTAB) neurocognitive test [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The CANTAB reaction time tests, including simple and choice reaction time tasks, will be used.

  • Multidimensional Fatigue Inventory (MFI) self-report questionnaire [ Time Frame: At baseline and Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Multidimensional Fatigue Inventory (MFI) is a self-report, 20-item questionnaire that evaluates the presence and severity of fatigue.

  • Snaith-Hamilton Pleasure Scale (SHAPS) self-report questionnaire [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale used to assess present-state hedonic tone.

  • Inventory of Depressive Symptoms-Self Report (IDS-SR) questionnaire [ Time Frame: At baseline and Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Inventory of Depressive Symptoms-Self Report (IDS-SR) questionnaire is a 30-item self-report questionnaire to measure depressive symptom severity.

  • Beck Depression Inventory (BDI-II), Anhedonia Subscale questionnaire [ Time Frame: At baseline and Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Beck Depression Inventory (BDI-II), Anhedonia Subscale questionnaire is a subscale of the 21-item self-report measure of depressive symptoms.

  • Profile of Mood States (POMS) scale [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The Profile of Mood States (POMS) scale is a psychological rating scale used to assess transient, distinct mood states.

  • State-Trait Anxiety Inventory (STAI) State Scale [ Time Frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) ]
    The State-Trait Anxiety Inventory (STAI) State Scale is a 20-item self-report scale is used to measure current anxiety symptoms.


Estimated Enrollment: 80
Study Start Date: July 2015
Estimated Study Completion Date: June 2020
Estimated Primary Completion Date: June 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sinemet/Placebo
Subjects with major depression will be given Sinemet (a combination of 250 mg of levodopa and 50 mg of carbidopa) at one study visit and placebo at the other study visit. Sinemet will be given first followed by placebo at the subsequent visit.
Drug: Levodopa+carbidopa
Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet will be administered orally at Visit 1 or Visit 2.
Other Name: Sinemet
Drug: Placebo
A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Active Comparator: Placebo/Sinemet
Subjects with major depression will be given placebo at one study visit and Sinemet (a combination of 250 mg of levodopa and 50 mg of carbidopa) at the other study visit. Placebo will be given first followed by Sinemet at the subsequent visit.
Drug: Levodopa+carbidopa
Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet will be administered orally at Visit 1 or Visit 2.
Other Name: Sinemet
Drug: Placebo
A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.

Detailed Description:
Cytokines released by an activated immune system have been associated with decreased brain dopamine and the development of depression. Biomarkers of inflammation, such as inflammatory cytokines and acute-phase proteins like C-reactive protein (CRP), are elevated in a significant proportion of patients with mood and psychiatric disorders. The investigators will study if administration of Levodopa (L- 3,4-dihydroxyphenylalanine [DOPA]-carbidopa, 250/25mg) to depressed patients with high inflammation will 1) increase corticostriatal functional connectivity, and 2) improve objective measures of motivation compared to placebo.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects have signed a current version of the Informed Consent and HIPAA documents prior to initiation of study procedures
  • Diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV major depression and currently off antidepressant medication, unless otherwise approved by the PI or PI's designee
  • Hamilton Depression Rating Scale (HDRS) 17 > 20, unless otherwise approved by the PI, or PI's designee
  • Negative pregnancy test for women of childbearing potential
  • Not breast feeding

Exclusion Criteria:

  • Evidence of untreated or poorly controlled endocrine, cardiovascular, pulmonary, hematological, renal, or neurological disease
  • History of central nervous system (CNS) trauma or active seizure disorder requiring medication unless otherwise approved by principal investigator, or PI's designee
  • Current or history of migraines, glaucoma, melanoma, or bleeding disorder of any kind
  • Autoimmune or inflammatory disorder of any kind
  • Embedded metallic objects, prosthetics made of paramagnetic metals, aneurysmal clips and/or a history of claustrophobia
  • Chronic infection (e.g. hepatitis B or C or Human Immunodeficiency Virus infection)
  • Chronic use of agents known to affect the immune system including glucocorticoid therapy within the past 6 months, methotrexate within the past 1 year, chemotherapy of any kind (past or present), immunotherapy of any kind (past or present), aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) (within the past 2 weeks), statins (within the past 1 month), vaccinations (within the past 2 weeks), topical steroids (within the past 2 weeks), and antibiotics (within the past two weeks) unless otherwise approved by principal investigator or PI's designee.
  • Suicide attempt within six months of screening, or active suicidal intent or plan, or score >2 on Hamilton Depression Rating Scale (HDRS) Suicide Item, unless otherwise approved by the PI or PI's designee
  • A positive pregnancy test
  • Organ transplants
  • Current or history of cancer within the past five years besides basal cell carcinoma, unless otherwise approved by the PI or PI's designee
  • A score of <28 on the Mini Mental Status Exam (MMSE), unless otherwise approved by the PI or PI's designee
  • Wide Range Achievement Test (WRAT-3) score indicating less than 8th grade reading level, unless otherwise approved by the PI or PI's designee
  • History of the following: schizophrenia, schizoaffective disorder, other (non mood disorder) psychosis, depression secondary to a medical condition, mental retardation, dementia, or delirium
  • Substance dependence [or abuse within the past year (except nicotine)], unless otherwise approved by the PI or PI's designee
  • Body Mass Index >40 to limit the impact of morbid obesity on the results, unless otherwise approved by the principal investigator or PI's designee
  • Active suicidal intent or plan and a score >2 on the Hamilton Depression Rating Scale suicide item (item #3).
  • Antisocial personality disorder diagnosis as assessed during clinical interview, as well as a history of hospitalization and/or recurrent suicidal behavior judged to be directly due to the personality disorder
  • Current eating disorder (except binge eating related to depression) unless approved by PI or PI's designee
  • Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with participating in or completing the protocol
  • Smoking more than 1/2 pack a day or e-cig equivalent, unless approved by the PI or PI's designee
  • Initiation of any of the following medications, unless otherwise approved by the PI or PI's designee: Aspirin or Aspirin-like compounds, Ibuprofen or Naproxen Sodium, Cholesterol medications, Antibiotics, Herbal Medications, Psychiatric or Psychotropic Medications, Omega-3 supplements, Topical Steroids, Vaccinations
  • Currently on antidepressant medication, unless otherwise approved by the PI or PI's designee
  Contacts and Locations
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): NCT02513485


Contacts
Contact: Behavioral Immunology Program Screening Center 404-727-8229 behavioral.immunology@emory.edu
Contact: Bobbi Woolwine, CCRC 404-712-9620 bwoolwi@emory.edu

Locations
United States, Georgia
Emory University Hospital Recruiting
Atlanta, Georgia, United States, 30322
Contact: Behavioral Immunology Program Screening Center    404-727-8229    behavioral.immunology@emory.edu   
Contact: Bobbi Woolwine, CCRC    404-712-9620    bwoolwi@emory.edu   
Sponsors and Collaborators
Emory University
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Jennifer Felger, PhD Emory University
  More Information

Responsible Party: Jennifer Felger, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT02513485     History of Changes
Other Study ID Numbers: IRB00081486
R01MH109637 ( U.S. NIH Grant/Contract )
First Submitted: July 29, 2015
First Posted: July 31, 2015
Last Update Posted: November 30, 2017
Last Verified: November 2017

Keywords provided by Jennifer Felger, Emory University:
Inflammation
Anhedonia
Psychomotor retardation

Additional relevant MeSH terms:
Inflammation
Pathologic Processes
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