Lipopolysaccharide (LPS) Challenge in Depression

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.

• Lipopolysaccharide (Biological), also known as Endotoxin, CCRE: Lipopolysaccharide (LPS) derived from E. Coli group O 113:H10:K negative
• Placebo (Biological), also known as Saline solution: Saline solution

Primary outcomes

• 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 outcomes

• 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 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
• 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.
• 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.

Sex: All, ages: 18 Years to 55 Years

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.

Participant flow

Outcome results

• Change in Snaith-Hamilton Pleasure Scale (SHAPS) (Primary), Mean, units on a scale: High CRP LPS Intervention 38.4 +/- 11.3; Low CRP LPS Intervention 33.2 +/- 8.7; High CRP LPS Placebo 27.2 +/- 5.9; Low CRP LPS Placebo 26.2 +/- 7.0
• Change in Montgomery-Asberg Depression Rating Scale (MADRS) (Secondary), Mean, units on a scale: High CRP LPS Intervention 9.7 +/- 4.2; Low CRP LPS Intervention 18.6 +/- 8.6; High CRP LPS Placebo 16.0 +/- 9.9; Low CRP LPS Placebo 18.0 +/- 8.5
• Change in Interleukin 6 (IL-6) Protein Levels (Secondary), Median, pg/mL: High CRP LPS Intervention 116.4 (36.2 to 586.9); Low CRP LPS Intervention 54.0 (20.7 to 152.8); High CRP LPS Placebo 0.6 (0.6 to 1.6); Low CRP LPS Placebo 0.5 (0.3 to 0.6)
• Change in Interleukin 10 (IL-10) Protein Levels (Secondary), Median, pg/mL: High CRP LPS Intervention 24.1 (17.9 to 34.8); Low CRP LPS Intervention 12.8 (8.6 to 20.0); High CRP LPS Placebo 0.2 (0.1 to 0.2); Low CRP LPS Placebo 0.2 (0.1 to 0.3)
• Change in Tumor Necrosis Factor (TNF) Protein Levels (Secondary), Median, pg/mL: High CRP LPS Intervention 146.0 (48.3 to 896.4); Low CRP LPS Intervention 130.8 (66.7 to 377.4); High CRP LPS Placebo 1.5 (1.3 to 2.1); Low CRP LPS Placebo 1.2 (0.9 to 2.0)
• Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Ventral Striatum Reward Versus No Reward Condition (Secondary), Mean, Percent Signal Change: High CRP LPS VS -0.09 +/- 0.35; Low CRP LPS -0.01 +/- 0.22; Low CRP Saline -0.03 +/- 0.21; High CRP Saline 0.01 +/- 0.24
• Change in Temperature (Secondary), Median, Degrees Fahrenheit: High CRP LPS Intervention 98.5 (98.4 to 99.2); Low CRP LPS Intervention 98.0 (97.6 to 99.2); High CRP LPS Placebo 98.1 (97.8 to 98.6); Low CRP LPS Placebo 98.0 (97.8 to 98.6)
• Percent Signal Change in Blood Oxygenation Level Dependent Signal (BOLD) of the Insula (Interoceptive vs Exteroceptive Condition) (Secondary), Mean, Percent Signal Change: High CRP LPS Insula 0.01 +/- 0.10; Low CRP LPS -0.06 +/- 0.15; Low CRP Saline 0.01 +/- 0.14; High CRP Saline -0.10 +/- 0.17

Adverse events

Time frame: One week

Other adverse events by term

• Study Protocol (PDF, 2020-07-08)
• Statistical Analysis Plan (PDF, 2017-10-12)
• Informed Consent Form (PDF, 2017-10-12)