LPS Challenge in Individuals with Major Depressive Disorder

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.

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.

One week