Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02513485
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 57
• Location: 1
• Arms: 2
• Actual Duration (Months): 57.8
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: Levodopa+carbidopa; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• 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"
• Actual Study Start Date: Oct 9, 2015
• Actual Primary Completion Date: Feb 21, 2020
• Actual Study Completion Date: Aug 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. Change in Functional Corticostriatal Connectivity [Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)]

   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).

2. Correlation Coefficient Between Change in Corticostriatal Connectivity and Levels of Plasma C-reactive Protein and Other Immune Markers [Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)]

   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).

Secondary Outcome Measures

1. 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 Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial task used to objectively assess motivation. Possible results range between 0 to1 with 1 being a better outcome. Results show mean probability of hard (high effort) choice.

2. 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)]

   The Trail Making Test (TMT) is used to measure basic attention and psychomotor processing speed. Time taken to complete each task is recorded in seconds, whereby the greater the number of seconds, the slower the psychomotor speed.

3. 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)]

   The Digit Symbol Task was used to assess graphomotor speed, visual scanning and memory processing speed involving numbers and a corresponding blank box where subjects are asked to fill in matching symbol as fast as they can. Results show the average number of correct symbols completed in up to 100 boxes in 90 seconds.

4. 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)]

   The Finger Tapping Task (FTT) assesses motor speed and can detect subtle motor impairment. The test measures the average number of taps per 10 second trial. A greater number of taps reflects faster motor speed.

5. 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)]

   The reaction time test includes simple and choice reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses. The task provided distinction between reaction (or decision) time and movement latencies (milliseconds) based on touch responses made to a single (simple) or chosen from multiple (choice) stimuli flashed on a computer screen. Results show mean response latency in milliseconds.

6. Multidimensional Fatigue Inventory (MFI) Self-report Questionnaire [At baseline and Visit 1, Visit 2 (spaced by approximately 1 week)]

   The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure severity of fatigue based on five dimensions of fatigue, general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The total MFI scores range from 20 to 100 where high scores indicate greater fatigue.

7. Snaith-Hamilton Pleasure Scale (SHAPS) Self-report Questionnaire [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]

   The Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report scale with high psychometric validity for assessing the presence of anhedonia, was used to assess hedonic capacity. Participants rated how much they agreed or disagreed with the 14 items phrased as "I would enjoy __" based on their ability to experience pleasure. Of the four possible response categories (Definitely Agree, Agree, Disagree, and Strongly Disagree), either of the Disagree responses received a score of 1 and either of the Agree responses received a score of 0. The SHAPS score calculated as the sum of these 14 items ranged from 0 to 14, and higher SHAPS scores indicated greater anhedonia.

8. Inventory of Depressive Symptoms-Self Report (IDS-SR) Questionnaire [At baseline and Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)]

   The Inventory of Depressive Symptoms-Self Report (IDS-SR) is a 30-item self-report instrument with excellent psychometric properties for measuring symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that is widely used to measure depression severity in clinical trials. Response scores are summed and range from 0 to 84, with higher scores reflecting greater depression severity.

9. Beck Depression Inventory (BDI-II), Anhedonia Subscale Score [Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)]

   The Beck Depression Inventory-II (BDI-II) is a widely used self-report for measuring depression severity over the past two weeks and the anhedonia subscale is one of several validated subscales in the BDI-II. Responses are given on a 4-point scale where 0 = the symptom of depression has not been experienced and 3 = the symptom of depression is severe. The anhedonia subscale score is created by summing responses to four items of the BDI-II that assess loss of pleasure, loss of interest, loss of energy, loss of sex drive. The total score of the anhedonia subscale ranges from 0 to 12 where higher scores reflect greater severity of anhedonia symptoms.

10. Profile of Mood States (POMS) Scale [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]

    The Profile of Mood States (POMS) scale is a 30-item psychological rating scale used to assess transient, distinct mood states. Participants rate the extent to which they feel unhappy, blue, lonely, gloomy, and worthless on a scale from 0 (not at all) to 4 (extremely). Scores range from 0 to 120 with higher scores reflecting a more negative mood state.

11. State-Trait Anxiety Inventory (STAI) State Scale [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]

    The 20-item self-report State-Trait Anxiety Inventory (STAI) State scale was used to measure severity of anxiety symptoms. Total scores range from 20 to 80 with higher scores reflecting greater anxiety. Scores in the high 40s are considered clinically significant.

12. Change in Motivation and Pleasure (MAP) Scale Score [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]

    The motivation and pleasure (MAP) questionnaire is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. This scale was used to assess self-reported changes in symptoms of anhedonia before and after inflammation blockade. Respondents respond to statements about daily activities on a scale from 0 (no pleasure/not at all) to 4 (extreme pleasure/very often). Total scores range from 0 to 72 where higher scores indicate greater motivation and effort given to everyday situations.

Other Outcome Measures

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)]

   The cerebral blood flow (CBF) before and after Sinemet (250 mg levodopa/ 50mg carbidopa) or placebo administration was assessed by arterial spin labeling (ASL) fMRI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jennifer Felger, PhD, Emory University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 6, 2020
• Informed Consent Form - Jan 6, 2020

More Information

Publications

None provided.

• Responsible Party: Jennifer Felger, Associate Professor, Emory University
• ClinicalTrials.gov Identifier: NCT02513485
• Other Study ID Numbers: IRB00081486; R01MH109637
• First Posted: Jul 31, 2015
• Last Update Posted: May 17, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jennifer Felger, Associate Professor, Emory University: Inflammation; Anhedonia; Psychomotor retardation
• Additional relevant MeSH terms: Inflammation; Levodopa; Carbidopa

Study Results

Participant Flow

Recruitment Details	Participants were enrolled between October 2015 and February 2020.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	Subjects with major depression were 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 was given first followed by Sinemet at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.
Period Title: Overall Study
STARTED	28	29
COMPLETED	27	29
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet	Total
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	Subjects with major depression were 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 was given first followed by Sinemet at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	Total of all reporting groups
Overall Participants	27	29	56
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.1 (11.5)	38.7 (10.3)	37.5 (10.9)
Sex: Female, Male (Count of Participants)
Female	20 74.1%	21 72.4%	41 73.2%
Male	7 25.9%	8 27.6%	15 26.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.7%	5 17.2%	6 10.7%
Not Hispanic or Latino	26 96.3%	24 82.8%	50 89.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.7%	1 3.4%	2 3.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	15 55.6%	8 27.6%	23 41.1%
White	11 40.7%	20 69%	31 55.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	27 100%	29 100%	56 100%

Outcome Measures

1. Primary Outcome

Title	Change in Functional Corticostriatal Connectivity
Description	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).
Time Frame	Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

The number analyzed in one or more rows correspond to the number with available and analyzable resting fMRI scans both pre and post drug and placebo.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	21	19
Visit 1 resting corticostriatal connectivity response to drug/placebo (post minus pre)	0.10 (0.22)	0.04 (0.17)
Visit 2 resting corticostriatal connectivity response to drug/placebo (post minus pre)	0.07 (0.18)	0.00 (0.23)
Visit 1 resting corticostriatal connectivity post drug/placebo	0.22 (0.15)	0.24 (0.12)
Visit 2 resting corticostriatal connectivity post drug/placebo	0.24 (0.18)	0.17 (0.18)
Visit 1 task (reward anticipation) corticostriatal connectivity post drug/placebo	0.02 (0.16)	0.00 (0.15)
Visit 2 task (reward anticipation) corticostriatal connectivity post drug/placebo	-0.04 (0.19)	-0.03 (0.16)

2. Primary Outcome

Title	Correlation Coefficient Between Change in Corticostriatal Connectivity and Levels of Plasma C-reactive Protein and Other Immune Markers
Description	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).
Time Frame	Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

The number analyzed in each row correspond to the number available and analyzable with resting fMRI scans both pre and post drug and placebo.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	21	19
CRP mg/L and Visit 1 resting connectivity response to drug/placebo (post minus pre)	0.36	-0.15
CRP mg/L and Visit 2 resting connectivity response to drug/placebo (post minus pre)	-0.12	0.44
CRP mg/L and Visit 1 resting connectivity post drug/placebo	0.10	0.15
CRP mg/L and Visit 2 resting connectivity post drug/placebo	-0.10	0.41
CRP mg/L and Visit 1 task (reward anticipation) connectivity post drug/placebo	0.49	-0.31
CRP mg/L and Visit 2 task (reward anticipation) connectivity post drug/placebo	0.10	0.25
CRP > vs. < 2 mg/ and Visit 1 resting connectivity response to drug/placebo (post minus pre)	0.20	0.04
CRP > vs. < 2 mg/L and Visit 2 resting connectivity response to drug/placebo (post minus pre)	-0.33	0.52
CRP > vs. < 2 mg/L and Visit 1 resting connectivity post drug/placebo	0.12	0.17
CRP > vs. < 2 mg/L and Visit 2 resting connectivity post drug/placebo	-0.31	0.38
CRP > vs. < 2 mg/L and Visit 1 task (reward anticipation) connectivity post drug/placebo	0.22	-0.35
CRP > vs. < 2 mg/L and Visit 2 task (reward anticipation) connectivity post drug/placebo	-0.18	0.48
Sum of cytokine Z scores and Visit 1 resting connectivity response to drug/placebo (post minus pre)	0.40	-0.05
Sum of cytokine Z scores and Visit 2 resting connectivity response to drug/placebo (post minus pre)	-0.14	0.29
Sum of cytokine Z scores and Visit 1 resting connectivity post drug/placebo	0.15	-0.05
Sum of cytokine Z scores and Visit 2 resting connectivity post drug/placebo	-0.22	0.08
Sum of cytokine Z scores and Visit 1 task (reward anticipation) connectivity post drug/placebo	0.26	-0.34
Sum of cytokine Z scores and Visit 2 task (reward anticipation) connectivity post drug/placebo	0.04	-0.18

3. Secondary Outcome

Title	Effort-Expenditure for Rewards Task (EEfRT) Neurocognitive Test
Description	The Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial task used to objectively assess motivation. Possible results range between 0 to1 with 1 being a better outcome. Results show mean probability of hard (high effort) choice.
Time Frame	At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment and had usable data. Two participants in each study arm did not complete this assessment at any time point. Two participants in the Placebo/Sinemet group had unusable data for the baseline assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	25	27
Baseline Visit (Task Practice)	0.29 (0.13)	0.39 (0.17)
Visit 1: 2-3 hrs post drug/placebo	0.28 (0.13)	0.34 (0.17)
Visit 2: 2-3 hrs post drug/placebo	0.30 (0.15)	0.34 (0.21)

4. Secondary Outcome

Title	The Trail Making Test (TMT) Neurocognitive Assessment
Description	The Trail Making Test (TMT) is used to measure basic attention and psychomotor processing speed. Time taken to complete each task is recorded in seconds, whereby the greater the number of seconds, the slower the psychomotor speed.
Time Frame	At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment and had usable data. One participant in the Sinemet/Placebo arm and two participants in the Placebo/Sinemet arm did not complete this assessment at any time point. Three participants in the Placebo/Sinemet group had unusable data for the baseline assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	26	27
Baseline Visit (Task Practice)	24.0 (10.0)	23.7 (4.7)
Visit 1: 2-3 hrs post drug/placebo	21.7 (8.8)	21.0 (5.2)
Visit 2: 2-3 hrs post drug/placebo	23.0 (13.8)	19.7 (4.6)

5. Secondary Outcome

Title	Digit Symbol Task Neurocognitive Test
Description	The Digit Symbol Task was used to assess graphomotor speed, visual scanning and memory processing speed involving numbers and a corresponding blank box where subjects are asked to fill in matching symbol as fast as they can. Results show the average number of correct symbols completed in up to 100 boxes in 90 seconds.
Time Frame	At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment and had usable data. One participant in the Placebo/Sinemet arm did not complete this assessment at any time point and one had unusable data for the baseline assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	27	28
Baseline Visit (Task Practice)	52.0 (8.8)	54.9 (11.3)
Visit 1: 2-3 hrs post drug/placebo	61.3 (11.3)	64.5 (10.2)
Visit 2: 2-3 hrs post drug/placebo	66.6 (11.7)	66.4 (11.6)

6. Secondary Outcome

Title	Finger Tapping Task (FTT) Neurocognitive Test
Description	The Finger Tapping Task (FTT) assesses motor speed and can detect subtle motor impairment. The test measures the average number of taps per 10 second trial. A greater number of taps reflects faster motor speed.
Time Frame	At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment and had usable data. One participant in the Placebo/Sinemet arm did not complete this assessment at any time point and one had unusable data for the baseline assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	27	28
Baseline Visit (Task Practice)	52.0 (8.8)	54.9 (11.3)
Visit 1: 2-3 hrs post drug/placebo	61.3 (11.3)	64.5 (10.2)
Visit 2: 2-3 hrs post drug/placebo	66.6 (11.7)	66.4 (11.6)

7. Secondary Outcome

Title	Reaction Time Task (CANTAB) Neurocognitive Test
Description	The reaction time test includes simple and choice reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses. The task provided distinction between reaction (or decision) time and movement latencies (milliseconds) based on touch responses made to a single (simple) or chosen from multiple (choice) stimuli flashed on a computer screen. Results show mean response latency in milliseconds.
Time Frame	At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment and had usable data. Seven participants in the Sinemet/Placebo arm and 8 participants in the Placebo/Sinemet arm did not complete this assessment at any time point. One participant in each study arm had unusable data for the baseline assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	20	21
Baseline Simple Motor Time	266.92 (59.55)	276.12 (94.35)
Baseline Choice Motor Time	286.82 (50.47)	299.57 (89.33)
Baseline Simple Reaction Time	360.84 (38.38)	356.53 (42.11)
Baseline Choice Reaction Time	397.60 (46.74)	394.82 (31.31)
Visit 1: 2-3 hrs post drug/placebo Simple Motor Time	240.62 (55.50)	258.53 (89.29)
Visit 1: 2-3 hrs post drug/placebo Choice Motor Time	268.69 (52.17)	284.94 (75.16)
Visit 1: 2-3 hrs post drug/placebo Simple Reaction Time	256.99 (35.69)	348.93 (26.14)
Visit 1: 2-3 hrs post drug/placebo Choice Reaction Time	397.07 (39.50)	385.03 (22.59)
Visit 2: 2-3 hrs post drug/placebo Simple Motor Time	241.28 (46.34)	268.37 (93.51)
Visit 2: 2-3 hrs post drug/placebo Choice Motor Time	260.47 (42.43)	296.94 (83.62)
Visit 2: 2-3 hrs post drug/placebo Simple Reaction Time	358.59 (35.87)	361.76 (47.55)
Visit 2: 2-3 hrs post drug/placebo Choice Reaction Time	395.22 (33.75)	396.68 (38.93)

8. Secondary Outcome

Title	Multidimensional Fatigue Inventory (MFI) Self-report Questionnaire
Description	The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure severity of fatigue based on five dimensions of fatigue, general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The total MFI scores range from 20 to 100 where high scores indicate greater fatigue.
Time Frame	At baseline and Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	27	29
Baseline	74.7 (10.9)	72.7 (13.5)
Visit 1: Pre drug/placebo	76.7 (10.7)	74.2 (15.05)
Visit 2: Pre drug/placebo	75.7 (10.5)	74.1 (14.9)

9. Secondary Outcome

Title	Snaith-Hamilton Pleasure Scale (SHAPS) Self-report Questionnaire
Description	The Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report scale with high psychometric validity for assessing the presence of anhedonia, was used to assess hedonic capacity. Participants rated how much they agreed or disagreed with the 14 items phrased as "I would enjoy __" based on their ability to experience pleasure. Of the four possible response categories (Definitely Agree, Agree, Disagree, and Strongly Disagree), either of the Disagree responses received a score of 1 and either of the Agree responses received a score of 0. The SHAPS score calculated as the sum of these 14 items ranged from 0 to 14, and higher SHAPS scores indicated greater anhedonia.
Time Frame	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

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	27	28
Visit 1: Pre drug/placebo	4.7 (3.5)	5.8 (3.7)
Visit 1: 1-2 hrs post drug/placebo	4.3 (4.0)	4.6 (3.7)
Visit 2: Pre drug/placebo	4.2 (3.9)	4.9 (4.2)
Visit 2: 1-2 hrs post drug/placebo	4.2 (4.4)	3.9 (4.2)

10. Secondary Outcome

Title	Inventory of Depressive Symptoms-Self Report (IDS-SR) Questionnaire
Description	The Inventory of Depressive Symptoms-Self Report (IDS-SR) is a 30-item self-report instrument with excellent psychometric properties for measuring symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that is widely used to measure depression severity in clinical trials. Response scores are summed and range from 0 to 84, with higher scores reflecting greater depression severity.
Time Frame	At baseline and Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

Three participants in the Sinemet/Placebo arm and four participants in the Placebo/Sinemet arm had unusable data for the baseline assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	27	29
Baseline	37.9 (65)	35.0 (10.8)
Visit 1: Pre drug/placebo	37.6 (6.3)	31.8 (10.7)
Visit 2: Pre drug/placebo	34.7 (8.6)	32.0 (11.1)

11. Secondary Outcome

Title	Beck Depression Inventory (BDI-II), Anhedonia Subscale Score
Description	The Beck Depression Inventory-II (BDI-II) is a widely used self-report for measuring depression severity over the past two weeks and the anhedonia subscale is one of several validated subscales in the BDI-II. Responses are given on a 4-point scale where 0 = the symptom of depression has not been experienced and 3 = the symptom of depression is severe. The anhedonia subscale score is created by summing responses to four items of the BDI-II that assess loss of pleasure, loss of interest, loss of energy, loss of sex drive. The total score of the anhedonia subscale ranges from 0 to 12 where higher scores reflect greater severity of anhedonia symptoms.
Time Frame	Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	27	29
Visit 1: Pre drug/placebo	6.4 (2.4)	5.9 (2.5)
Visit 2: Pre drug/placebo	5.7 (2.9)	5.9 (2.8)

12. Secondary Outcome

Title	Profile of Mood States (POMS) Scale
Description	The Profile of Mood States (POMS) scale is a 30-item psychological rating scale used to assess transient, distinct mood states. Participants rate the extent to which they feel unhappy, blue, lonely, gloomy, and worthless on a scale from 0 (not at all) to 4 (extremely). Scores range from 0 to 120 with higher scores reflecting a more negative mood state.
Time Frame	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

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	25	26
Visit 1: Pre drug/placebo	60.2 (17.6)	57.0 (14.6)
Visit 1: 1-2 hrs post drug/placebo	54.0 (15.1)	51.5 (11.8)
Visit 2: Pre drug/placebo	53.0 (12.7)	56.2 (14.3)
Visit 2: 1-2 hrs post drug/placebo	48.5 (14.3)	51.0 (11.5)

13. Secondary Outcome

Title	State-Trait Anxiety Inventory (STAI) State Scale
Description	The 20-item self-report State-Trait Anxiety Inventory (STAI) State scale was used to measure severity of anxiety symptoms. Total scores range from 20 to 80 with higher scores reflecting greater anxiety. Scores in the high 40s are considered clinically significant.
Time Frame	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

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	14	16
Visit 1: Pre drug/placebo	52.1 (12.3)	46.5 (10.6)
Visit 1: 1-2 hrs post drug/placebo	49.2 (9.3)	42.2 (9.3)
Visit 2: Pre drug/placebo	51.3 (9.9)	45.9 (14.0)
Visit 2: 1-2 hrs post drug/placebo	43.4 (12.0)	43.0 (9.9)

14. Secondary Outcome

Title	Change in Motivation and Pleasure (MAP) Scale Score
Description	The motivation and pleasure (MAP) questionnaire is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. This scale was used to assess self-reported changes in symptoms of anhedonia before and after inflammation blockade. Respondents respond to statements about daily activities on a scale from 0 (no pleasure/not at all) to 4 (extreme pleasure/very often). Total scores range from 0 to 72 where higher scores indicate greater motivation and effort given to everyday situations.
Time Frame	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

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment.

Arm/Group Title	Sinemet/Placebo	Placebo/Sinemet
Arm/Group Description	Subjects with major depression were 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 was given first followed by placebo at the subsequent visit. Levodopa+carbidopa: Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally at Visit 1 or Visit 2. Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally at Visit 1 or Visit 2.	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. 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. Placebo: A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.
Measure Participants	10	7
Visit 1: Pre drug/placebo	25.5 (11.5)	26.6 (13.8)
Visit 1: 1-2 hrs post drug/placebo	26.9 (11.1)	25.4 (16.1)
Visit 2: Pre drug/placebo	28.9 (13.6)	25.1 (22.0)
Visit 2: 1-2 hrs post drug/placebo	29.2 (13.7)	25.1 (21.3)

15. Other Pre-specified Outcome

Title	Correlation Coefficient Between Change in Cerebral Blood Flow (CBF) and Change in Functional Connectivity
Description	The cerebral blood flow (CBF) before and after Sinemet (250 mg levodopa/ 50mg carbidopa) or placebo administration was assessed by arterial spin labeling (ASL) fMRI.
Time Frame	Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From time of consent until follow up (up to 2 weeks).
Adverse Event Reporting Description	The population analyzed includes all subjects who were randomized and had taken at least one dose of the medication.
Arm/Group Title	Sinemet		Placebo
Arm/Group Description	Levodopa+carbidopa (Sinemet) is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet was administered orally either at Visit 1 if the subject was in the Sinemet/Placebo group or, at Visit 2 if the subject was in the Placebo/Sinemet group.		Placebo: A placebo is a sugar pill that has no therapeutic effect and was administered orally either at Visit 1 if the subject was in the Placebo/Sinemet group or, at Visit 2 if the subject was in the Sinemet/Placebo group.
All Cause Mortality
	Sinemet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/57 (0%)		0/56 (0%)
Serious Adverse Events
	Sinemet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/57 (0%)		0/56 (0%)
Other (Not Including Serious) Adverse Events
	Sinemet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/57 (87.7%)		11/56 (19.6%)
Gastrointestinal disorders
Vomiting	8/57 (14%)	9	1/56 (1.8%)	1
Nausea	22/57 (38.6%)	27	3/56 (5.4%)	3
General disorders
Lightheadedness	5/57 (8.8%)	5	0/56 (0%)	0
Feeling Hot	3/57 (5.3%)	3	0/56 (0%)	0
Nervous system disorders
Headache	6/57 (10.5%)	6	5/56 (8.9%)	5
Dizziness	6/57 (10.5%)	6	2/56 (3.6%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.