Depression
Conditions
Keywords
Neuroscience, Behavioral, Social
Brief summary
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.
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.
Interventions
DRUGInfliximab
One infusion of Infliximab (Remicade) will be administered intravenously (IV) at 5 mg/kg body weight over a two hour period.
OTHERPlacebo
One infusion of placebo treatment will be administered intravenously (IV) over a two hour period.
Sponsors
National Institute of Mental Health (NIMH)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* All subjects will be fully ambulatory and in good medical health. Note: By Diagnostic and Statistical Manual of Mental Disorders (DSM-4) 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 purified protein derivative (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 cyclooxygenase-2 (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 (excluding binge-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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effort-based Decision-making (EBDM) Task Score | Baseline, Day 14 | Reward motivation was assessed by a laboratory effort-based decision-making (EBDM) task. On each trial, participants make a choice about expending more or less physical effort (rapid button pressing) in exchange for varying amounts of monetary rewards. Models of subjective value were fit to each participants' data using maximum likelihood estimation and were compared using Bayesian Information Criterion to identify the model that provides the best fit for participants' responses. Discounting functions were based on previous work and include linear, quadratic, hyperbolic, flexible power models. Models considering the potential effects of fatigue and examination of post-scan switching behavior were also evaluated. The best-fitting model from baseline data was applied to look at changes related to infliximab. Reported values reflect a model-derived summary statistic for effort discounting behavior, without a fixed range, where lower values associated with greater motivation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma C-reactive Protein (CRP) Level | 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. CRP level was measured at baseline and Day 14. Lower result correlates with better outcome. |
| Plasma Interleukin-6 (IL-6) Level | Baseline, Day 14 | Plasma IL-6 level will be collected via blood draw. IL-6 level was collected at baseline and Day 14. Lower result correlates with better outcome. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Emory University in Atlanta, Georgia, USA. Enrollment began in August 2016 and all follow up was complete by September 26, 2020.
Participants by arm
| Arm | Count |
|---|---|
| Infliximab Participants randomized to the infliximab group received one infusion of Infliximab (Remicade) administered intravenously (IV) at 5 mg/kg body weight over a two hour period. | 21 |
| Placebo Participants randomized to the placebo group received one infusion of placebo treatment administered intravenously (IV) over a two hour period. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Infliximab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 9.2 | 39.03 years STANDARD_DEVIATION 8.53 | 38.0 years STANDARD_DEVIATION 7.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 36 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 20 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 18 Participants | 5 Participants |
| Region of Enrollment United States | 21 participants | 42 participants | 21 participants |
| Sex: Female, Male Female | 18 Participants | 37 Participants | 19 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 19 / 21 | 13 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 |
Outcome results
Primary
Effort-based Decision-making (EBDM) Task Score
Reward motivation was assessed by a laboratory effort-based decision-making (EBDM) task. On each trial, participants make a choice about expending more or less physical effort (rapid button pressing) in exchange for varying amounts of monetary rewards. Models of subjective value were fit to each participants' data using maximum likelihood estimation and were compared using Bayesian Information Criterion to identify the model that provides the best fit for participants' responses. Discounting functions were based on previous work and include linear, quadratic, hyperbolic, flexible power models. Models considering the potential effects of fatigue and examination of post-scan switching behavior were also evaluated. The best-fitting model from baseline data was applied to look at changes related to infliximab. Reported values reflect a model-derived summary statistic for effort discounting behavior, without a fixed range, where lower values associated with greater motivation.
Time frame: Baseline, Day 14
Population: This analysis includes participants who completed the indicated study visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Effort-based Decision-making (EBDM) Task Score | Baseline | 2.13 score on a scale | Standard Deviation 1.76 |
| Infliximab | Effort-based Decision-making (EBDM) Task Score | Day 14 | 1.85 score on a scale | Standard Deviation 1.28 |
| Placebo | Effort-based Decision-making (EBDM) Task Score | Baseline | 2.09 score on a scale | Standard Deviation 1.52 |
| Placebo | Effort-based Decision-making (EBDM) Task Score | Day 14 | 2.78 score on a scale | Standard Deviation 1.7 |
Secondary
Plasma C-reactive Protein (CRP) Level
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. CRP level was measured at baseline and Day 14. Lower result correlates with better outcome.
Time frame: Baseline, Day 14
Population: This analysis includes participants who completed the indicated study visit and had usable blood samples. Some participants did not complete the trial and another participant had a blood sample of poor quality.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Plasma C-reactive Protein (CRP) Level | Baseline | 4.18 mg/L | Standard Deviation 3.28 |
| Infliximab | Plasma C-reactive Protein (CRP) Level | Day 14 | 2.78 mg/L | Standard Deviation 4.63 |
| Placebo | Plasma C-reactive Protein (CRP) Level | Baseline | 7.81 mg/L | Standard Deviation 7.85 |
| Placebo | Plasma C-reactive Protein (CRP) Level | Day 14 | 6.35 mg/L | Standard Deviation 6.96 |
Secondary
Plasma Interleukin-6 (IL-6) Level
Plasma IL-6 level will be collected via blood draw. IL-6 level was collected at baseline and Day 14. Lower result correlates with better outcome.
Time frame: Baseline, Day 14
Population: This analysis includes participants who completed the indicated study visit and had usable blood samples. Some participants did not complete the trial and another participant had a blood sample of poor quality.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Plasma Interleukin-6 (IL-6) Level | Baseline | 1.13 pg/ml | Standard Deviation 0.96 |
| Infliximab | Plasma Interleukin-6 (IL-6) Level | Day 14 | 0.97 pg/ml | Standard Deviation 1 |
| Placebo | Plasma Interleukin-6 (IL-6) Level | Baseline | 1.07 pg/ml | Standard Deviation 0.97 |
| Placebo | Plasma Interleukin-6 (IL-6) Level | Day 14 | 1.19 pg/ml | Standard Deviation 1.25 |