Clinical trial NCT02513485: Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa
Official title: "Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa"; "Inflammation Effects on Corticostriatal Connectivity and Reward: Role of Dopamine"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Depression
Keywords: Inflammation
Anhedonia
Psychomotor retardation
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2015-07-31
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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 criteria: Inclusion Criteria:

* 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

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), 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
* 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
* 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
* Current obsessive-compulsive disorder (OCD), exclusionary only if impacting daily functioning, as assessed by clinical interview
* 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-cigarette 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

Primary outcomes:
measure: Change in Functional Corticostriatal Connectivity
timeFrame: Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
measure: Correlation Coefficient Between Change in Corticostriatal Connectivity and Levels of Plasma C-reactive Protein and Other Immune Markers
timeFrame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
Secondary outcomes:
measure: Effort-Expenditure for Rewards Task (EEfRT) Neurocognitive Test
timeFrame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
measure: The Trail Making Test (TMT) Neurocognitive Assessment
timeFrame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
measure: Digit Symbol Task Neurocognitive Test
timeFrame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
measure: Finger Tapping Task (FTT) Neurocognitive Test
timeFrame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
measure: Reaction Time Task (CANTAB) Neurocognitive Test
timeFrame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
measure: Multidimensional Fatigue Inventory (MFI) Self-report Questionnaire
timeFrame: At baseline and Visit 1, Visit 2 (spaced by approximately 1 week)
measure: Snaith-Hamilton Pleasure Scale (SHAPS) Self-report Questionnaire
timeFrame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo
measure: Inventory of Depressive Symptoms-Self Report (IDS-SR) Questionnaire
timeFrame: At baseline and Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)
measure: Beck Depression Inventory (BDI-II), Anhedonia Subscale Score
timeFrame: Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)
measure: Profile of Mood States (POMS) Scale
timeFrame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo
measure: State-Trait Anxiety Inventory (STAI) State Scale
timeFrame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo
measure: Change in Motivation and Pleasure (MAP) Scale Score
timeFrame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo
Other outcomes:
measure: Correlation Coefficient Between Change in Cerebral Blood Flow (CBF) and Change in Functional Connectivity
timeFrame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)
Locations:
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
Study officials:
affiliation: Emory University
name: Jennifer Felger, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.