We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

Dynamics of Inflammation and Its Blockade on Motivational Circuitry in Depression

This study is currently recruiting participants.
Verified September 2017 by Michael Treadway, Emory University
Sponsor:
ClinicalTrials.gov Identifier:
NCT03006393
First Posted: December 30, 2016
Last Update Posted: September 25, 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.
Information provided by (Responsible Party):
Michael Treadway, Emory University
  Purpose

The main purpose of this study is to examine the effects of infliximab on measures related to depression symptoms. Infliximab is also known by its brand name Remicade. Infliximab, or Remicade, is given to by an intravenous (IV) needle and is currently used to treat rheumatoid arthritis and Crohn's disease. Infliximab is thought to help these conditions because it reduces inflammation in the body. Infliximab (Remicade) reduces inflammation by blocking a chemical in the body called tumor necrosis factor (TNF)-alpha. This chemical produces inflammation. Inflammatory chemicals in the body like TNF-alpha appear to be increased in some people with major depression. Researchers believe that a drug like infliximab, which blocks TNF-alpha, may be helpful in treating depression.

This is a double-blind, placebo-controlled study in which participants will be randomized to receive one infusion of infliximab or placebo. The study will assess neuroimaging measures of corticostriatal circuitry before and after a placebo-controlled pharmacologic blockade of inflammation in 80 depressed patients.


Condition Intervention Phase
Depression Drug: Infliximab Other: Placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Dynamics of Inflammation and Its Blockade on Motivational Circuitry in Depression

Resource links provided by NLM:


Further study details as provided by Michael Treadway, Emory University:

Primary Outcome Measures:
  • Change in Reward Motivation assessed by the Behavioral Effort-Expenditure for Rewards Task (behEEfRT) Score [ Time Frame: Baseline, Day 14 ]
    Assessment of reward motivation will be accomplished using an fMRI-adapted version of the EEfRT task.The behEEfRT task is a multi-trial game in which participants are given an opportunity on each trial to choose between two different task difficulty levels in order to obtain monetary rewards. The higher the reward, the more motivation the participant expresses.


Secondary Outcome Measures:
  • Change in the Columbia Suicide Severity Rating Scale (C-SSR) Score [ Time Frame: Baseline, Day 14 ]
    The C-SSR is a suicidal ideation rating scale created to evaluate suicidality in children ages 12 and up. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The scale identifies behaviors which may be indicative of an individual's intent to commit suicide. An individual exhibiting even a single behavior identified by the scale was 8 to 10 times more likely to commit suicide.

  • Change in the Multidimensional Fatigue Inventory (MFI) Score [ Time Frame: Baseline, Day 14 ]
    The MFI is a 20-item self-report instrument designed to measure fatigue, covering the dimensions General Fatigue (GF), Physical Fatigue (PF), Mental Fatigue (MF), Reduced Motivation (RM) and Reduced Activity (RA). A higher total score indicates more fatigue.

  • Change in Inventory of Depressive Symptoms Self-Report (IDS-SR) Score [ Time Frame: Baseline, Day 14 ]
    The IDS-SR is a 30 item measure designed to assess the severity of depressive symptoms. A higher score indicates more depressive symptoms.

  • Change in the Positive Affect/Negative Affect Scale - Now (PANAS-X) Score [ Time Frame: Baseline, Day 14 ]
    The PANAS-X measures four basic negative emotions (fear, hostility, guilt, and sadness), three basic positive emotions (joviality, self-assurance, and attentiveness), and four more complex affective states (shyness, fatigue, serenity, and surprise).The PANAS scale gives a score for positive and negative affect between 10 and 50 points. A higher score expresses more affect.

  • Change in the Snaith-Hamilton Pleasure Scale (SHAPS) Score [ Time Frame: Baseline, Day 14 ]
    The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-administered, paper-pencil questionnaire with 14 items assessing four domains of pleasure response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink. The SHAPS is scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of anhedonia. A cut-off score of 2 provides the best discrimination between "normal" and "abnormal" level of hedonic tone.

  • Change in the Fatigue Severity Scale (FSS) Score [ Time Frame: Baseline, Day 14 ]
    The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms. A total score of less than 36 suggests that a participant may not be suffering from fatigue. A total score of 36 or more suggests that a participant may need further evaluation by a physician.

  • Change in the Mood and Pleasure Scale (MAP-SR) Score [ Time Frame: Baseline, Day 14 ]
    The MAP-SR is an 18-item self-report measure related to social and recreational or work domains, feelings and motivations to be around family, romantic partners, and friends, and effort to engage in activities. All items are rated on a 5-point Likert scale; higher scores reflect greater pathology.

  • Change in the Go No-Go Variant Task Score [ Time Frame: Baseline, Day 14 ]
    During the Go No-Go variant task stimuli are presented in a continuous stream and participants perform a binary decision on each stimulus. One of the outcomes requires participants to make a motor response (go), whereas the other requires participants to withhold a response (no-go). Accuracy and reaction time are measured for each event.

  • Change in Finger Tapping Task (FTT) Score [ Time Frame: Baseline, Day 14 ]
    The FTT uses a specially adapted tapper that the subject taps as fast as possible using the index finger. The subject is given 5 consecutive 10-second trials for the preferred and non-preferred hands. The finger tapping score is the mean of 5 trials and is computed for each hand.

  • Change in Reaction Time Task (RTT) Score [ Time Frame: Baseline, Day 14 ]
    The RTT provides measures of simple and choice movement and reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses and providing distinction between reaction (or decision) time and movement latencies. The test measures assessing correct and incorrect responses, errors of commission and omission (late and early responses), and latency (response speed).

  • Change in Digit Symbol Task (DST) Score. [ Time Frame: Baseline, Day 14 ]
    The DST consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% by memory. The number of correct symbols within the allowed time is measured.

  • Change in Plasma C-reactive Protein (CRP) Level [ Time Frame: Baseline, Day 14 ]
    C-reactive protein (CRP) is a blood test marker for inflammation in the body. CRP is produced in the liver and its level is measured by testing the blood. Change is defined as the difference in CRP level from baseline to Day 14.

  • Change in Plasma Tumor Necrosis Factor (TNF) Alpha Level [ Time Frame: Baseline, Day 14 ]
    Plasma TNF-alpha level will be collected via blood draw. Change is defined as the difference in TNF-alpha level from baseline to Day 14.

  • Change in Plasma Soluble Tumor Necrosis Factor (TNF) Receptor 1 Level [ Time Frame: Baseline, Day 14 ]
    Plasma TNF Receptor 1 level will be collected via blood draw. Change is defined as the difference in TNF Receptor 1 level from baseline to Day 14.

  • Change in Plasma Soluble Tumor Necrosis Factor (TNF) Receptor 2 Level [ Time Frame: Baseline, Day 14 ]
    Plasma TNF Receptor 2 level will be collected via blood draw. Change is defined as the difference in TNF Receptor 2 level from baseline to Day 14.

  • Change in Plasma Interleukin-1 (IL-1) Level [ Time Frame: Baseline, Day 14 ]
    Plasma IL-1 level will be collected via blood draw. Change is defined as the difference in IL-1 level from baseline to Day 14.

  • Change in Plasma Interleukin-1 (IL-1) Receptor Agonist Level [ Time Frame: Baseline, Day 14 ]
    Plasma IL-1 Receptor agonist level will be collected via blood draw. Change is defined as the difference in IL-1 receptor agonist level from baseline to Day 14.

  • Change in Plasma Interleukin-6 (IL-6) Level [ Time Frame: Baseline, Day 14 ]
    Plasma IL-6 level will be collected via blood draw. Change is defined as the difference in IL-6 level from baseline to Day 14.

  • Change in Plasma Soluble Interleukin-6 Receptor (sIL-6R) Level [ Time Frame: Baseline, Day 14 ]
    Plasma sIL-6R level will be collected via blood draw. Change is defined as the difference in sIL-6R level from baseline to Day 14.


Estimated Enrollment: 80
Study Start Date: August 2016
Estimated Study Completion Date: March 2021
Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Infliximab
Participants randomized to the infliximab group will receive one infusion of infliximab at 5mg/kg body weight.
Drug: Infliximab
One infusion of Infliximab (Remicade) will be administered intravenously (IV) at 5 mg/kg body weight over a two hour period.
Other Name: Remicade
Placebo Comparator: Placebo
Participants randomized to the placebo group will receive one placebo infusion.
Other: Placebo
One infusion of placebo treatment will be administered intravenously (IV) over a two hour period.
Other Name: Saline Solution

Detailed Description:

The main purpose of this study is to examine the effects of infliximab on measures related to depression symptoms. Infliximab is also known by its brand name Remicade. Infliximab, or Remicade, is given by an intravenous (IV) needle and is currently used to treat rheumatoid arthritis and Crohn's disease. Infliximab is thought to help these conditions because it reduces inflammation in the body. Infliximab (Remicade) reduces inflammation by blocking a chemical in the body called tumor necrosis factor (TNF)-alpha. This chemical produces inflammation. Inflammatory chemicals in the body like TNF-alpha appear to be increased in some people with major depression. Researchers believe that a drug like infliximab, which blocks TNF-alpha, may be helpful in treating depression.

This is a double-blind, placebo-controlled study in which participants will be randomized to receive one infusion of infliximab or placebo. This study will assess neuroimaging measures of corticostriatal circuitry before and after a placebo-controlled pharmacologic blockade of inflammation in 80 depressed patients (n = 40 per group) recruited to ensure high levels of peripheral inflammation (CRP > 3mg/L).

Primary aims are to evaluate whether 1) corticostriatal function during reward motivation and anticipation are associated with change in peripheral inflammation following pharmacologic blockade relative to placebo 2) the temporal dynamics of change in inflammation, gene- expression, reward motivation and reinforcement learning behavior and motivational symptoms assessed at baseline, and 24 hours, 3 days, 1 week and two weeks post infliximab infusion, and 3) test an integrative multi- level path model to determine whether change in corticostriatal circuitry following inflammation blockade mediates the relationship between change in inflammation and change in motivational anhedonia symptoms.

These data will provide further validation of inflammatory cytokines as therapeutic targets for motivational symptoms in depression and will define symptom targets and biomarkers of response for future studies.

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

Inclusion Criteria:

  • All subjects will be fully ambulatory and in good medical health. Note: By DSM-IV definition of depression, subjects will report impairment in ability to carry out daily activities as a result of their major depression.
  • Subjects will be able to read and understand English.
  • Women must be postmenopausal (no menstrual period for a minimum of 1 year) or surgically sterilized and/or have a negative serum pregnancy test within thirty days of infusion (may be repeated closer to infusion date if deemed necessary by the PI or PI's designee) and negative urine pregnancy tests throughout the study (performed at each visit after the serum pregnancy test is completed).
  • Men and women of childbearing potential must use adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, implantable or injectable contraceptives or surgical sterilization) for the duration of the study and should continue such precautions for 6 months after receiving the last infusion.

The following are considered eligible according to the following tuberculosis (TB) screening criteria:

  • Have no history of latent or active TB prior to screening.
  • Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
  • Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation to rule out infection. The candidate will be excluded from study participation if the specialist diagnoses active TB and or determines TB treatment is warranted.
  • Have a chest radiograph (both posterior-anterior and lateral views), taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current active TB or old inactive TB.
  • History of negative PPD test; or documentation of a negative blood test (Quantiferon-TB-Gold). Any candidate testing positive for tuberculosis in the medical screening evaluation, will be excluded from study participation

Exclusion Criteria:

  • Subjects will be excluded for any prior use of a TNF-alpha antagonist (i.e. etanercept, infliximab, adalimumab) and/or use of any other immunosuppressant agent (i.e. systemic corticosteroids or anti-proliferative agents such as methotrexate) within one year of study entry.
  • Subjects chronically (i.e. more than one month) taking more than the equivalent of 2 mg of lorazepam a day of a benzodiazepine will be excluded.
  • Subjects will be required not to use anti-inflammatory agents, non-steroidal anti-inflammatory agents (NSAIDs) (excluding 81mg of aspirin), glucocorticoid containing medicines or statins, or COX-2 inhibitors during the study as these agents may interfere with assessment of the relationship between inflammatory markers and treatment response.

Note: Acetaminophen will be allowed.

Potential subjects will be excluded for a history of any of the following conditions:

  • Abnormal electrocardiogram
  • Auto-immune condition as confirmed by laboratory testing (i.e. rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus)
  • History of significant infectious sequelae, including but not limited to, abscess or sepsis
  • Infection within one month prior to screening that required antibiotic or antiviral therapy
  • History of a more than mild cognitive disorder or ≤ 24 on the Mini-Mental State Exam (MMSE), unless otherwise approved by PI or his designee
  • Unstable cardiovascular or endocrinologic disease (as determined by physical examination and/or laboratory testing)
  • Any other current or past medical condition that might increase the risk of infliximab-related adverse events
  • Potential subjects will be excluded for any of the following conditions:
  • Active suicidal ideation defined as a score of ≥3 on Columbia Suicide Severity Rating Scale (C-SSR).
  • Suicide attempt within six months of study entry
  • Schizophrenia or Schizoaffective Disorder
  • Active eating disorder
  • History of any (non-mood related) psychotic disorder or active psychotic symptoms of any type

Subjects will have had no infectious illnesses for one month prior to infusion. Should a subject develop an infection (i.e. flu, upper respiratory viral infection) between screening and infusion, the infusion will be delayed until 4 weeks after resolution of symptoms. As noted above, patients with a chronic infectious condition or with a past history of serious infectious complications will be excluded.

Subjects will be excluded for any evidence on laboratory testing (or by history) of hematologic, renal or hepatic abnormality. Subjects will be excluded for a positive anti-nuclear antibody (ANA) test.

Infliximab Related Exclusion Criteria:

  • Have had any previous treatment with monoclonal antibodies or antibody fragments.
  • History of receiving human/murine recombinant products or a known allergy to murine products. A known allergy to murine product is definitely an exclusion criterion.
  • Documentation of seropositive for human immunodeficiency virus (HIV). Any candidate testing positive for HIV, in the medical screening evaluation, will be excluded from study participation.
  • Documentation of a positive test for hepatitis B surface antigen or hepatitis C. Any candidate testing positive for hepatitis B or hepatitis C, in the medical screening evaluation, will be excluded from study participation.
  • Are unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access.
  • Use of any investigational drug within 30 days prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
  • Presence of a transplanted solid organ (with the exception of a corneal transplant > 3 months prior to screening).
  • Have a concomitant diagnosis or history of congestive heart failure.
  • Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results. (As determined by SCID-V)
  • Have a known history of serious infections (e.g., hepatitis, pneumonia, or pyelonephritis) in the previous 3 months.
  • Have or have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening.
  • Have a history of lymphoproliferative disease, including lymphoma or signs suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location (e.g., nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or periaortic area), or splenomegaly.
  • Currently have any known malignancy other than the condition being treated or have a history of malignancy within the previous 5 years, with the exception of basal cell or squamous cell carcinoma of the skin that has been fully excised with no evidence of recurrence.
  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): NCT03006393


Contacts
Contact: Chelsea Leonard (404) 727-7541 tread.lab@emory.edu

Locations
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Michael Treadway, PhD    404-727-3166    mtreadway@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Michael Treadway, PhD Emory University
  More Information

Responsible Party: Michael Treadway, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT03006393     History of Changes
Other Study ID Numbers: IRB00087941
First Submitted: December 28, 2016
First Posted: December 30, 2016
Last Update Posted: September 25, 2017
Last Verified: September 2017

Keywords provided by Michael Treadway, Emory University:
Neuroscience
Behavioral
Social

Additional relevant MeSH terms:
Depression
Depressive Disorder
Inflammation
Behavioral Symptoms
Mood Disorders
Mental Disorders
Pathologic Processes
Infliximab
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents