Lipopolysaccharide (LPS) Challenge in Depression

Response to Inflammatory Challenge in Major Depressive Disorder

LPS Challenge in Individuals with Major Depressive Disorder

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Biological: Placebo; Biological: Lipopolysaccharide

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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Laureate Institute for Brain Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High CRP LPS Intervention; High CRP Individuals with Major Depressive Disorder receiving LPS intervention	Biological: Lipopolysaccharide; Lipopolysaccharide (LPS) derived from E. Coli group O 113:H10:K negative; Other Names: Endotoxin, CCRE
Active Comparator: Low CRP LPS Intervention; Low CRP Individuals with Major Depressive Disorder receiving LPS intervention	Biological: Lipopolysaccharide; Lipopolysaccharide (LPS) derived from E. Coli group O 113:H10:K negative; Other Names: Endotoxin, CCRE
Placebo Comparator: High CRP LPS Placebo; High CRP Individuals with Major Depressive Disorder receiving placebo	Biological: Placebo; Saline solution; Other Names: Saline solution
Placebo Comparator: Low CRP LPS Placebo; Low CRP Individuals with Major Depressive Disorder receiving placebo	Biological: Placebo; Saline solution; Other Names: Saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 1 hour, 2-hours, 3-hours, 4-hours, 6 hours, 24 hours, one week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Montgomery-Asberg Depression Rating Scale (MADRS)	Clinician-administered depression rating scale with scores ranging from 0-60. Higher scores indicate more depression.	Baseline, 6 hours, 24 hours, one week
Change in Interleukin 6 (IL-6) protein levels	pro-inflammatory cytokine measured in pg/mL	Baseline, 1 hour, 2-hours, 3-hours, 6 hours, 24 hours, one week
Change in Interleukin 10 (IL-10) protein levels	Measure of systemic inflammation in pg/mL	Baseline, 1 hour, 2-hours, 3-hours, 6 hours, 24 hours, one week
Change in Tumor Necrosis Factor (TNF) protein levels	Measure of systemic inflammation in pg/mL	Baseline, 1 hour, 2-hours, 3-hours, 6 hours, 24 hours, one week
Change in Blood Oxygenation Level Dependent signal (BOLD) Ventral Striatum	Beta-weights for the average activity across the ventral striatum	Baseline line; 2-3 hours
Change in Blood Oxygenation Level Dependent signal (BOLD) Insula	Beta-weights for the average activity across the insula	Baseline line; 2-3 hours
Change in Temperature	Body temperature measured in degrees Fahrenheit.	Baseline, 1 hour, 2-hours, 3-hours, 4-hours, 6 hours, 24 hours, one week

Collaborators and Investigators

• Sponsor: Laureate Institute for Brain Research, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2017
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: April 28, 2017
• First Submitted That Met QC Criteria: May 3, 2017
• First Posted (Actual): May 8, 2017

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MRI; Mood Disorder; Endotoxin; MDD; CRP
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 2016-002-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No