Major Depressive Disorder
Conditions
Keywords
Mood Disorder, MDD, Endotoxin, MRI, CRP
Brief summary
LPS Challenge in Individuals with Major Depressive Disorder
Detailed description
The aim of this project is to understand the biological differences between two distinct subtypes of depression, patients with and without inflammation as defined by c-reactive protein (CRP). Using a double-blinded, parallel group, placebo-controlled design, participants will be phenotyped before and after a low-dose lipopolysaccharide (LPS) challenge designed to perturb the immune system and trigger a transient, mild inflammatory response. This experimental design will allow for the delineation of the homeostatic mechanisms underlying sensitivity to inflammation-related depression. Low-dose LPS has been used by multiple groups to safely induce transient inflammatory responses in humans.
Interventions
BIOLOGICALLipopolysaccharide
Lipopolysaccharide (LPS) derived from E. Coli group O 113:H10:K negative
BIOLOGICALPlacebo
Saline solution
Sponsors
Laureate Institute for Brain Research, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Depressed participants will be required to be in good general health (as evaluated during Visit 1, including EKG) and to be 18-55 years of age. Depressed participants will be required to have symptoms of depression (i.e. a PHQ-9 score ≥10) and be unmedicated for at least 3 weeks (8 weeks for fluoxetine) or treated with only one anti-depressant medication. Half the depressed participants (N=50) will be required to have a high-sensitivity C-Reactive Protein (CRP) score of ≥3 mg/L, and half the participants will be required to have a CRP score of ≤1 mg/L. General
Exclusion criteria
* Pregnancy * Previous history of fainting during blood draws. Medical Conditions: * A history of a head injury with loss of consciousness. * Presence of co-morbid medical conditions not limited to but including cardiovascular (e.g., history of acute coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders. * Presence of co-morbid inflammatory disorders such as rheumatoid arthritis or other autoimmune disorders. * Presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or to put the study participant at undue risk. * Presence of chronic infection that may elevate pro-inflammatory cytokines. * Presence of an acute infectious illness or receipt of a vaccination in the two weeks prior to an experimental session. Psychiatric Disorders: * Current severe suicidal ideation or attempt within the past 12 months. * Psychosis * Bipolar disorder * Substance abuse or dependence within the previous 6 months * Age of onset of depression \>40 years Contraindications for MRI: * Severe claustrophobia * Bodily implants of unsafe paramagnetic materials such as pace-makers and aneurysm clips. Medications: * Current and/or past regular use of hormone-containing medications (excluding contraceptives) * Current use of non-steroid anti-inflammatory drugs that is deemed by the investigators to potentially confound the results of the study * Current and/or past regular use of immune modifying drugs that target specific immune responses such as TNF antagonists * Current use of analgesics such as opioids or history of addiction to opioids or other analgesics * Current and/or past regular use of cardiovascular medications, including antihypertensive, antiarrhythmic, anti-anginal, and anticoagulant drugs (does not apply where medications are taken for different purpose e.g. anti-hypertensives for migraine). * Evidence of recreational drug use from urine test. * Lifetime use of methamphetamine Health Factors: * BMI \> 35 because of the effects of obesity on pro-inflammatory cytokine activity * Clinically significant abnormalities on screening laboratory tests * Abnormal EKG * In addition, participants who on arrival to the study, show any of the following symptoms will not be allowed to complete the study: 1. screening supine systolic blood pressure \>140 mmHg or \<100 mmHg 2. screening supine diastolic blood pressure \>90 mmHg or \<60 mmHg 3. 12-lead EKG demonstrating a PR interval \> 0.2 msec, QTc \>450 or QRS \>120 msec If the QTc exceeds 450 msec, or QRS exceeds 120 msec, the EKG will be repeated 2 more times and the median value will be used 4. pulse less than 50 beats/minute or greater than 100 beats/minute 5. temperature greater than 99.5F. Non-English speaking participants: * The majority of the assessments proposed for this study have not been translated from English, thus, non-English speaking volunteers will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Snaith-Hamilton Pleasure Scale (SHAPS) | 2-hours | The SHAPS is a 14-item self-administered questionnaire, with each item scored from 1-4 (strongly agree through strongly disagree; range 14-56), with higher scores indicating greater anticipatory, not consummatory, anhedonia. Disagreement (i.e. score of 3 or 4) on at least three items is defined as indicating clinically significant anhedonia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Interleukin 6 (IL-6) Protein Levels | 2-hours | pro-inflammatory cytokine measured in pg/mL |
| Change in Interleukin 10 (IL-10) Protein Levels | 2-hours | Measure of systemic inflammation in pg/mL |
| Change in Tumor Necrosis Factor (TNF) Protein Levels | 2-hours | Measure of systemic inflammation in pg/mL |
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) | 24 hours | Clinician-administered depression rating scale with scores ranging from 0-60. Higher scores indicate more depression. |
| Change in Temperature | 4-hours | Body temperature measured in degrees Fahrenheit. |
| Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition) | Baseline line 2-3 hours | Percent change of bold signal in the insula between exteroceptive and interoceptive conditions at t2 - % change of bold signal in insula between exteroceptive and interoceptive conditions at t1. t1= baseline scan; t2= scan performed 2 hours after LPS/saline. Data only collected at 2 timepoints. |
| Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition | Baseline line; 2-3 hours | Percent change of bold signal in the ventral striatum between conditions p5 and p0 at t2 - % change of bold signal in ventral striatum between conditions p5 and p0 at t1. t1= baseline scan; t2= scan performed 2 hours after LPS/saline. P5= $5 reward; p0=no reward. Data only collected at 2 timepoints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High CRP LPS Intervention High CRP Individuals with Major Depressive Disorder receiving LPS intervention
Lipopolysaccharide: Lipopolysaccharide (LPS) derived from E. Coli group O 113:H10:K negative | 13 |
| Low CRP LPS Intervention Low CRP Individuals with Major Depressive Disorder receiving LPS intervention
Lipopolysaccharide: Lipopolysaccharide (LPS) derived from E. Coli group O 113:H10:K negative | 19 |
| High CRP LPS Placebo High CRP Individuals with Major Depressive Disorder receiving placebo
Placebo: Saline solution | 13 |
| Low CRP LPS Placebo Low CRP Individuals with Major Depressive Disorder receiving placebo
Placebo: Saline solution | 19 |
| Total | 64 |
Baseline characteristics
| Characteristic | Low CRP LPS Intervention | Total | Low CRP LPS Placebo | High CRP LPS Intervention | High CRP LPS Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 30.3 Years STANDARD_DEVIATION 10.9 | 31.5 Years STANDARD_DEVIATION 10.8 | 29.6 Years STANDARD_DEVIATION 10 | 38.0 Years STANDARD_DEVIATION 11.1 | 29.7 Years STANDARD_DEVIATION 10 |
| Interleukin 10 | 0.2 pg/mL | 0.2 pg/mL | 0.3 pg/mL | 0.2 pg/mL | 0.2 pg/mL |
| Interleukin 6 | 0.4 pg/mL | 0.6 pg/mL | 0.4 pg/mL | 0.9 pg/mL | 0.5 pg/mL |
| Montgomery Asberg Depression Rating Scale | 25.1 units on a scale STANDARD_DEVIATION 5.6 | 23.9 units on a scale STANDARD_DEVIATION 5.9 | 23.7 units on a scale STANDARD_DEVIATION 5.7 | 23.7 units on a scale STANDARD_DEVIATION 6.5 | 22.6 units on a scale STANDARD_DEVIATION 6.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 8 Participants | 2 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 6 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 43 Participants | 12 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Female | 14 Participants | 47 Participants | 13 Participants | 10 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 17 Participants | 6 Participants | 3 Participants | 3 Participants |
| Snaith-Hamilton Pleasure Scale | 28.7 units on a scale STANDARD_DEVIATION 6.3 | 27.2 units on a scale STANDARD_DEVIATION 6.2 | 26.5 units on a scale STANDARD_DEVIATION 7.6 | 27.8 units on a scale STANDARD_DEVIATION 5.4 | 25.7 units on a scale STANDARD_DEVIATION 4.6 |
| Temperature | 97.6 Degrees Fahrenheit | 97.7 Degrees Fahrenheit | 97.8 Degrees Fahrenheit | 97.7 Degrees Fahrenheit | 97.3 Degrees Fahrenheit |
| Tumor Necrosis Factor | 1.6 pg/mL | 1.6 pg/mL | 1.5 pg/mL | 1.8 pg/mL | 1.6 pg/mL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 19 | 0 / 13 | 0 / 19 |
| other Total, other adverse events | 3 / 13 | 2 / 19 | 0 / 13 | 1 / 19 |
| serious Total, serious adverse events | 0 / 13 | 0 / 19 | 0 / 13 | 0 / 19 |
Outcome results
Primary
Change in Snaith-Hamilton Pleasure Scale (SHAPS)
The SHAPS is a 14-item self-administered questionnaire, with each item scored from 1-4 (strongly agree through strongly disagree; range 14-56), with higher scores indicating greater anticipatory, not consummatory, anhedonia. Disagreement (i.e. score of 3 or 4) on at least three items is defined as indicating clinically significant anhedonia.
Time frame: 2-hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High CRP LPS Intervention | Change in Snaith-Hamilton Pleasure Scale (SHAPS) | 38.4 units on a scale | Standard Deviation 11.3 |
| Low CRP LPS Intervention | Change in Snaith-Hamilton Pleasure Scale (SHAPS) | 33.2 units on a scale | Standard Deviation 8.7 |
| High CRP LPS Placebo | Change in Snaith-Hamilton Pleasure Scale (SHAPS) | 27.2 units on a scale | Standard Deviation 5.9 |
| Low CRP LPS Placebo | Change in Snaith-Hamilton Pleasure Scale (SHAPS) | 26.2 units on a scale | Standard Deviation 7 |
Secondary
Change in Interleukin 10 (IL-10) Protein Levels
Measure of systemic inflammation in pg/mL
Time frame: 2-hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High CRP LPS Intervention | Change in Interleukin 10 (IL-10) Protein Levels | 24.1 pg/mL |
| Low CRP LPS Intervention | Change in Interleukin 10 (IL-10) Protein Levels | 12.8 pg/mL |
| High CRP LPS Placebo | Change in Interleukin 10 (IL-10) Protein Levels | 0.2 pg/mL |
| Low CRP LPS Placebo | Change in Interleukin 10 (IL-10) Protein Levels | 0.2 pg/mL |
Secondary
Change in Interleukin 6 (IL-6) Protein Levels
pro-inflammatory cytokine measured in pg/mL
Time frame: 2-hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High CRP LPS Intervention | Change in Interleukin 6 (IL-6) Protein Levels | 116.4 pg/mL |
| Low CRP LPS Intervention | Change in Interleukin 6 (IL-6) Protein Levels | 54.0 pg/mL |
| High CRP LPS Placebo | Change in Interleukin 6 (IL-6) Protein Levels | 0.6 pg/mL |
| Low CRP LPS Placebo | Change in Interleukin 6 (IL-6) Protein Levels | 0.5 pg/mL |
Secondary
Change in Montgomery-Asberg Depression Rating Scale (MADRS)
Clinician-administered depression rating scale with scores ranging from 0-60. Higher scores indicate more depression.
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High CRP LPS Intervention | Change in Montgomery-Asberg Depression Rating Scale (MADRS) | 9.7 units on a scale | Standard Deviation 4.2 |
| Low CRP LPS Intervention | Change in Montgomery-Asberg Depression Rating Scale (MADRS) | 18.6 units on a scale | Standard Deviation 8.6 |
| High CRP LPS Placebo | Change in Montgomery-Asberg Depression Rating Scale (MADRS) | 16.0 units on a scale | Standard Deviation 9.9 |
| Low CRP LPS Placebo | Change in Montgomery-Asberg Depression Rating Scale (MADRS) | 18.0 units on a scale | Standard Deviation 8.5 |
Secondary
Change in Temperature
Body temperature measured in degrees Fahrenheit.
Time frame: 4-hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High CRP LPS Intervention | Change in Temperature | 98.5 Degrees Fahrenheit |
| Low CRP LPS Intervention | Change in Temperature | 98.0 Degrees Fahrenheit |
| High CRP LPS Placebo | Change in Temperature | 98.1 Degrees Fahrenheit |
| Low CRP LPS Placebo | Change in Temperature | 98.0 Degrees Fahrenheit |
Secondary
Change in Tumor Necrosis Factor (TNF) Protein Levels
Measure of systemic inflammation in pg/mL
Time frame: 2-hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High CRP LPS Intervention | Change in Tumor Necrosis Factor (TNF) Protein Levels | 146.0 pg/mL |
| Low CRP LPS Intervention | Change in Tumor Necrosis Factor (TNF) Protein Levels | 130.8 pg/mL |
| High CRP LPS Placebo | Change in Tumor Necrosis Factor (TNF) Protein Levels | 1.5 pg/mL |
| Low CRP LPS Placebo | Change in Tumor Necrosis Factor (TNF) Protein Levels | 1.2 pg/mL |
Secondary
Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition)
Percent change of bold signal in the insula between exteroceptive and interoceptive conditions at t2 - % change of bold signal in insula between exteroceptive and interoceptive conditions at t1. t1= baseline scan; t2= scan performed 2 hours after LPS/saline. Data only collected at 2 timepoints.
Time frame: Baseline line 2-3 hours
Population: Note that there was missing data for 9 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High CRP LPS Intervention | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition) | 0.01 Percent Signal Change | Standard Deviation 0.1 |
| Low CRP LPS Intervention | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition) | -0.06 Percent Signal Change | Standard Deviation 0.15 |
| High CRP LPS Placebo | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition) | 0.01 Percent Signal Change | Standard Deviation 0.14 |
| Low CRP LPS Placebo | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition) | -0.10 Percent Signal Change | Standard Deviation 0.17 |
Secondary
Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition
Percent change of bold signal in the ventral striatum between conditions p5 and p0 at t2 - % change of bold signal in ventral striatum between conditions p5 and p0 at t1. t1= baseline scan; t2= scan performed 2 hours after LPS/saline. P5= $5 reward; p0=no reward. Data only collected at 2 timepoints.
Time frame: Baseline line; 2-3 hours
Population: Note that there was missing data for 9 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High CRP LPS Intervention | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition | -0.09 Percent Signal Change | Standard Deviation 0.35 |
| Low CRP LPS Intervention | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition | -0.01 Percent Signal Change | Standard Deviation 0.22 |
| High CRP LPS Placebo | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition | -0.03 Percent Signal Change | Standard Deviation 0.21 |
| Low CRP LPS Placebo | Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition | 0.01 Percent Signal Change | Standard Deviation 0.24 |