LPS for Major Depressive Disorder

Overseen By Jonathan Savitz, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Laureate Institute for Brain Research, Inc.

Must not be taking: Hormones, Corticosteroids, NSAIDs, others

Disqualifiers: Pregnancy, Cardiovascular, Neurological, others

Trial Summary

What is the purpose of this trial?

This is a parallel group, double-blinded, placebo-controlled study. Participants with MDD (n=90) and HC (n=90) will be randomly assigned (2:1) to receive either lipopolysaccharide (LPS) (0.8ng/kg of body weight) or placebo (same volume of 0.9% saline) administered as an intravenous bolus. This will yield the following groups: MDD-LPS (n=60), MDD-Placebo (n=30), HC-LPS (n=60), HC-placebo (n=30). There are three main aims: to identify immune pathways and neural circuits that respond differently to LPS in MDD vs. HC subjects; (2) to test whether the strength of inflammatory changes induced by LPS is associated with degree of change in anhedonic symptoms and neural circuits in the MDD group, and (3) to identify a biotype of MDD that shows a differential immunological and neurophysiological response to LPS. The main outcome variables are symptoms of anhedonia measured with the Snaith-Hamilton Pleasure Scale (SHAPS), cytokines (Il-6, IL-8, IL-10, and TNF), and BOLD signal change in the neural circuitry mediating interoceptive processing, i.e. the insula and cingulate cortex. The exploratory aim is to determine whether the acute inflammatory response to LPS can predict the clinical course of depression over a period of six months. The main outcome of this component of the study is self-reported depressive symptoms assessed with the QIDS-SR.

Do I need to stop taking my current medications to join the trial?

The trial requires that you stop taking certain medications, such as hormone-containing medications (excluding contraceptives), oral corticosteroids, non-steroid anti-inflammatory drugs used frequently, immune-modifying drugs, certain cardiovascular medications, chronic antibiotics, and opioids. If you are taking other medications or supplements, the decision will be made by the principal investigator based on their potential effects on immune function, the microbiome, brain function, or blood flow.

Is there any evidence that the drug LPS is effective for treating major depressive disorder?

Research shows that LPS can have antidepressant effects in mice under chronic stress by activating certain brain cells called microglia, which are involved in the immune response. This suggests that LPS might help with depression linked to inflammation, but more studies are needed to confirm its effectiveness in humans. ^{1 2 3 4 5}

Is lipopolysaccharide (LPS) safe for use in humans?

Experimental administration of endotoxin (LPS) in healthy volunteers is considered safe, well-tolerated, and without known long-term health risks, making it a useful tool for studying inflammation-related depression. ^{1 2 3 4 5}

How does the drug LPS differ from other treatments for major depressive disorder?

LPS is unique because it works by stimulating microglia (immune cells in the brain) to produce rapid and long-lasting antidepressant effects, unlike traditional antidepressants that typically target neurotransmitters. It is administered intranasally, which is different from the oral or intravenous routes used by most other depression treatments. ^{1 2 3 4 6}

Eligibility Criteria

This trial is for adults aged 18-65 with Major Depressive Disorder (MDD) and healthy controls, both in good general health. MDD participants must have a PHQ-9 score ≥10 or MADRS score of ≥7. Exclusions include severe brain injury, certain medical conditions like heart disease, autoimmune disorders, uncontrolled illnesses that could affect the study or pose risks, recent infections or vaccinations, severe suicidal ideation within the past year, psychosis, substance abuse within six months, metal implants incompatible with MRI scans, pregnancy and others.

Inclusion Criteria

I am between 18 and 65 years old and in good health.

A DSM-V diagnosis of MDD will be made with the MINI International Neuropsychiatric Interview

My current depression symptoms have been evaluated by a doctor.

Exclusion Criteria

Pregnancy

I do not speak English.

I am not taking hormone meds, steroids, NSAIDs, immune drugs, painkillers, heart drugs, antibiotics, or using recreational drugs.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline and Experimental Session

Participants undergo baseline assessments and receive LPS or placebo infusion with monitoring and MRI scans

1 week

2 visits (in-person)

Follow-up

Participants are monitored for mood ratings, blood draws, and MRI sessions post-infusion

1 week

2 visits (in-person)

Longitudinal Follow-up

MDD participants are followed for 6 months with psychological assessments

6 months

Monthly assessments (remote or in-person)

Treatment Details

Interventions

• LPS (Other)
• Placebo (Other)
• Saline (Other)

Trial Overview The study tests how an inflammatory challenge (LPS injection) affects individuals with MDD compared to healthy controls. It's double-blinded and placebo-controlled; some get LPS while others receive saline as a placebo. The focus is on immune response differences between groups and whether inflammation correlates with changes in pleasurelessness symptoms and specific neural circuits.

Participant Groups

Group I: LPS Experimental Treatment 1 Intervention

Lipopolysaccharide (LPS) (0.8ng/kg of body weight; E. coli group O:113) administered as an intravenous bolus.

Group II: Placebo Placebo Group 1 Intervention

Placebo (same volume of 0.9% saline) administered as an intravenous bolus

Who Is Running the Clinical Trial?

Laureate Institute for Brain Research, Inc.

Lead Sponsor

Trials

53

Recruited

5,400+

Findings from Research

In a study using a rat model of depression induced by lipopolysaccharide (LPS), all tested antidepressants (ADs) effectively prevented despair-like behavior caused by LPS, indicating their efficacy in counteracting neuroinflammatory effects associated with depression.

Vortioxetine (VORT) not only prevented despair-like behavior but also specifically rescued impaired self-care behavior and showed a superior anti-inflammatory profile by increasing levels of the anti-inflammatory cytokine IL-4, suggesting it may have unique benefits in treating depression linked to immune activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression. Tomaz, VS., Chaves Filho, AJM., Cordeiro, RC., et al.[2022]

Chronic exposure to escalating doses of lipopolysaccharide (LPS) in mice resulted in sustained sickness behaviors, such as weight loss and reduced food intake, which were not observed with single or repeated lower doses.

The escalating LPS doses led to significantly elevated levels of inflammatory cytokines and reduced neuroblast maturation in the dentate gyrus, suggesting this method may better mimic the chronic inflammatory state associated with mood disorders in depression research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated lipopolysaccharide exposure modifies immune and sickness behaviour response in an animal model of chronic inflammation. Musaelyan, K., Aldridge, S., Du Preez, A., et al.[2022]

A single intranasal administration of lipopolysaccharide (LPS) at doses of 5 or 10 μg/mouse effectively reversed depression-like behavior in mice subjected to chronic unpredictable stress, with effects lasting at least 10 days.

The antidepressant effect of LPS is linked to the activation of microglia in the brain, as blocking microglial activity prevented the positive effects of LPS, highlighting the importance of the immune response in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal administration of lipopolysaccharide reverses chronic stress-induced depression-like behavior in mice by microglial stimulation. Huang, C., Ye, T., Chen, B., et al.[2023]

A single injection of lipopolysaccharide (LPS) at doses of 75 and 100 μg/kg produced significant antidepressant effects in mice experiencing chronic unpredictable stress, with effects lasting up to 10 days after administration.

The antidepressant action of LPS is linked to the reversal of microglial decrease in the hippocampus, as inhibiting microglia blocked the antidepressant effects, suggesting that targeting microglial activity could be a novel approach for treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress. Cai, Z., Ye, T., Xu, X., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Repeated lipopolysaccharide exposure modifies immune and sickness behaviour response in an animal model of chronic inflammation. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Intranasal administration of lipopolysaccharide reverses chronic stress-induced depression-like behavior in mice by microglial stimulation. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Behavioral and systemic consequences of long-term inflammatory challenge. [2015]