LPS for Major Depressive Disorder

Overseen By Jonathan Savitz, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Laureate Institute for Brain Research, Inc.

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

Disqualifiers: Pregnancy, Cardiovascular, Neurological, others

Compensation: Varies

Number of Visits: 5

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how lipopolysaccharide (LPS) affects individuals with Major Depressive Disorder (MDD) compared to healthy individuals. Researchers seek to determine how inflammation, the body's response to injury or infection, might alter certain brain functions and symptoms of depression, such as losing interest in previously enjoyable activities. Participants will receive either LPS, an experimental treatment, or a placebo, a harmless substance resembling the treatment, to help identify different responses. Ideal participants are those with ongoing depression symptoms who are otherwise healthy. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this experimental treatment.

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 suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatment under study, lipopolysaccharide (LPS), has been tested in people before. In these studies, LPS was generally safe but often caused temporary symptoms. These symptoms can resemble the flu, such as tiredness and mood changes, typically starting a few hours after receiving LPS and lasting about four hours.

These effects are temporary and result from the body's natural response to inflammation, which includes swelling and redness when the body perceives a threat. The trial carefully controls the treatment dose to minimize discomfort. While LPS can cause these temporary symptoms, similar studies have not consistently reported any serious side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Most treatments for major depressive disorder, like SSRIs and SNRIs, work by altering neurotransmitter levels in the brain. But LPS stands out because it uses lipopolysaccharide, derived from E. coli, to potentially trigger an immune response that might impact depression symptoms. This new approach taps into the body's immune system, offering a fresh angle compared to the usual chemical-based treatments. Researchers are excited about LPS because it could provide quicker relief or work for those who haven't responded to traditional therapies.

What evidence suggests that LPS might be an effective treatment for major depressive disorder?

Research has shown that lipopolysaccharide (LPS) can cause symptoms similar to depression. In animal studies, LPS led to behaviors resembling depression, such as a lack of motivation. Other research indicates that LPS can interfere with cellular function, potentially linking it to depression. Studies have also discovered that individuals with major depressive disorder (MDD) often exhibit higher levels of LPS. This trial will compare the effects of LPS, administered as an intravenous bolus, with a placebo treatment to further investigate its potential role in depression by affecting the body's immune system. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

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

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.

I have been diagnosed with depression based on my PHQ-9 or MADRS scores.

Exclusion Criteria

Pregnancy

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

I arrived with high or low blood pressure, irregular heartbeat, and fever.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• LPS
• Placebo
• Saline

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

Experimental endotoxemia, a model of systemic inflammation, is proposed as a safe and effective method to develop new treatments for depression, particularly for patients with inflammation-related symptoms.

This approach allows researchers to identify potential therapeutic targets and personalize treatment strategies, potentially increasing the number of patients who respond positively to depression therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression. Lasselin, J., Lekander, M., Benson, S., et al.[2022]

Chronic inflammation, modeled by long-term administration of lipopolysaccharide (LPS) in rats, leads to specific changes in brain cytokine levels, particularly increases in interleukin (IL)-1β and interferon (IFN)-γ, which are linked to depression-like behaviors.

Despite similar behavioral outcomes between acute and chronic LPS treatments, chronic administration resulted in metabolic changes such as increased fasting blood glucose, indicating insulin resistance, which may provide insights into the relationship between inflammation and major depressive disorder in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioral and systemic consequences of long-term inflammatory challenge. Fischer, CW., Elfving, B., Lund, S., et al.[2015]

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 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]

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]

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]

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