Lipopolysaccharide (LPS) Challenge in Depression

Sponsor

Laureate Institute for Brain Research, Inc. (Other)

Overall Status

Recruiting

CT.gov ID

NCT03142919

Collaborator

(none)

100

Enrollment

Location

Arms

68.7

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

LPS Challenge in Individuals with Major Depressive Disorder

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Biological: Lipopolysaccharide Biological: Placebo	Phase 2

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. The pilot study is expected to take approximately one year to complete.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Basic Science

Official Title:

Response to Inflammatory Challenge in Major Depressive Disorder

Actual Study Start Date :

Sep 7, 2017

Anticipated Primary Completion Date :

May 31, 2022

Anticipated Study Completion Date :

May 31, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Snaith-Hamilton Pleasure Scale (SHAPS) [One week]
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 Outcome Measures

Interleukin 6 (IL-6) protein levels [One week]
pro-inflammatory cytokine measured in pg/mL
Blood Oxygenation Level Dependent signal (BOLD) Ventral Striatum [One week]
Beta-weights for the average activity across the ventral striatum
Blood Oxygenation Level Dependent signal (BOLD) Insula [One week]
Beta-weights for the average activity across the insula
Tumor Necrosis Factor (TNF) protein levels [One week]
Measure of systemic inflammation in pg/mL

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

screening supine systolic blood pressure >140 mmHg or <100 mmHg
screening supine diastolic blood pressure >90 mmHg or <60 mmHg
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
pulse less than 50 beats/minute or greater than 100 beats/minute
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.