Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

NCT02513485 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: IRB00081486R01MH109637
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Depression

Keywords

Inflammation; Anhedonia; Psychomotor retardation

Outcome Measures

Primary Outcomes (2)

• Change in Functional Corticostriatal Connectivity

  Corticostriatal connectivity was assessed by functional magnetic resonance imaging (fMRI). Resting-state and task-based (monetary incentive delay \[MID\]) fMRI scans were conducted on a 3 Tesla Siemens Trio MRI scanner. Subject-level correlations for degree of cortical and striatal functional connectivity were Fisher's Z transformed {Z(R)=0.5ln\[(1+R)/(1-R)\]}, a standard method for calculating fMRI functional connectivity. Greater Fisher's Z-scores reflected stronger correlated fMRI activity (i.e., higher corticostriatal connectivity).

  Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

• Correlation Coefficient Between Change in Corticostriatal Connectivity and Levels of Plasma C-reactive Protein and Other Immune Markers

  Peripheral blood samples were 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).

  Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Secondary Outcomes (12)

• Effort-Expenditure for Rewards Task (EEfRT) Neurocognitive Test

  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) Neurocognitive Assessment

  At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

• Digit Symbol Task Neurocognitive Test

  At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

• Finger Tapping Task (FTT) Neurocognitive Test

  At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

• Reaction Time Task (CANTAB) Neurocognitive Test

  At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Other Outcomes (1)

• Correlation Coefficient Between Change in Cerebral Blood Flow (CBF) and Change in Functional Connectivity

  Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Study Arms (2)

Sinemet/Placebo

ACTIVE COMPARATOR

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; Drug: Placebo

Placebo/Sinemet

ACTIVE COMPARATOR

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; Drug: Placebo

Interventions

Levodopa+carbidopa DRUG

Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet will be administered orally at Visit 1 or Visit 2.

Also known as: Sinemet

Placebo/Sinemet; Sinemet/Placebo

Placebo DRUG

A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.

Placebo/Sinemet; Sinemet/Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects have signed a current version of the Informed Consent and HIPAA documents prior to initiation of study procedures
• Able to comprehend English
• Diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM)-V major depression and currently off antidepressant medication, unless otherwise approved by the PI or PI's designee
• Depression as the primary axis I disorder
• Negative pregnancy test for women of childbearing potential
• Not breast feeding
• At least two CRP tests conducted to establish reliability

You may not qualify if:

• 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), or Quick Inventory of Depressive Symptomatology Self-Report (QIDS) or Patient Health Questionnaire (PHQ-9) 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
• Either QIDS \<14 or PHQ-9 \<15, or HDRS \<18, unless otherwise approved by the principal investigator 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

Sponsors & Collaborators

• Emory University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Emory University Hospital

Atlanta, Georgia, 30322, United States

Location

Related Publications (1)

• Bekhbat M, Li Z, Mehta ND, Treadway MT, Lucido MJ, Woolwine BJ, Haroon E, Miller AH, Felger JC. Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study. Mol Psychiatry. 2022 Oct;27(10):4113-4121. doi: 10.1038/s41380-022-01715-3. Epub 2022 Aug 4.

  PMID: 35927580 RESULT

MeSH Terms

Conditions

Depression; Inflammation; Anhedonia; Psychomotor Disorders

Interventions

carbidopa, levodopa drug combination

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms

Results Point of Contact

• Title: Dr. Jennifer Felger
• Organization: Emory University

jfelger@emory.edu

404-727-3987

Study Officials

• Jennifer Felger, PhD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 29, 2015
• First Posted: July 31, 2015
• Study Start: October 9, 2015
• Primary Completion: February 21, 2020
• Study Completion: August 1, 2020
• Last Updated: September 19, 2022
• Results First Posted: May 17, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)