Inflammation's Impact on Reward Response in Aging and Anxiety

(ARIA Trial)

Overseen By Michael R Irwin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Los Angeles

Must not be taking: Steroids, NSAIDs, Antidepressants, others

Disqualifiers: Chronic illness, Cardiovascular, Neurological, others

Compensation: Varies

Number of Visits: 4

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how inflammation might affect joy and drive in older adults with anxiety. Researchers will administer a small dose of endotoxin, a substance that causes inflammation, to observe its impact on moods and motivation, comparing these effects to a placebo, a harmless substance. The trial uses questionnaires, computer tasks, and brain scans to gather data. It seeks participants aged 60 to 80 who have significant anxiety and are in good health, without chronic illnesses or frequent medication use. Participants must not have severe medical conditions or recent changes in time zones.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to contribute to groundbreaking research.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications. The trial excludes participants who currently use prescription medications like steroids, anti-inflammatory drugs, antidepressants, and several others. You must not have used these medications in the last 6 months.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using endotoxin as a treatment is generally safe for people. Studies have found that while endotoxins can cause temporary discomfort or sickness, they do not lead to long-term harm in humans.

Some animal studies, such as those with mice, have suggested that endotoxins might affect behavior and thinking, potentially causing more anxiety-like behavior. However, these effects may not occur in humans.

Since this trial is in its early stages, the main goal is to ensure the treatment's safety and assess how well people tolerate it. So far, evidence suggests that endotoxin is well-tolerated in humans, though participants might experience some short-term side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how inflammation might affect how older adults with anxiety experience rewards. Unlike standard treatments that typically focus on reducing anxiety symptoms through medications like SSRIs or therapy, this trial investigates the biological link between inflammation and brain responses to rewards. By using a controlled dose of endotoxin to induce inflammation, researchers aim to understand its direct impact on the brain's reward system. This could open new pathways for treating anxiety by targeting inflammation rather than just managing symptoms.

What evidence suggests that this trial's treatments could be effective for anxiety in older adults?

This trial will compare the effects of endotoxin with a placebo to study its impact on anxiety and motivation in aging. Research has shown that endotoxin, a component of some bacteria, can influence emotions and behavior. Studies have found that when endotoxin enters the body, it can increase anxiety and decrease motivation, particularly in older adults. This occurs because endotoxin can cause inflammation, altering how the brain responds to rewards and making activities less enjoyable or motivating. Older individuals are more affected by this inflammation. These findings clarify why researchers are studying endotoxin's effects on anxiety and motivation in aging. ^{6 7 8 9 10}

Who Is on the Research Team?

Chloe C Boyle, PHD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

This trial is for adults aged 60-80, with or without anxiety. Participants must be in good health and not have severe chronic diseases, autoimmune disorders, uncontrolled medical conditions, a BMI over 35, or use certain medications like steroids or anti-inflammatories. They can't have a history of serious psychiatric issues or current sleep disorders.

Inclusion Criteria

I am between 60 and 80 years old.

Revised Criterion: Half of the participants (40 out of the total) will be those who have significant anxiety, which is determined by a score of 5 or higher on the GAD-7 questionnaire.

Half of the participants (40 out of the total) will be those who have very low anxiety, as indicated by a GAD-7 score of less than 5.

Exclusion Criteria

You have used recreational drugs, as shown by a urine test.

You have tried to harm yourself or have been hospitalized for mental health reasons in the past.

You drink a lot of caffeine every day (more than 600 mg), which can affect certain substances in the body that cause inflammation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 30 minutes

Phone screening

Visit 1

In-person evaluation including clinical interviews, questionnaires, and computer tasks to assess motivation and sensitivity to reward

4 hours

1 visit (in-person)

Visit 2

Administration of endotoxin vs. placebo, repeated blood sampling, mood and symptom questionnaires, and a brain scan

10.5 hours

1 visit (in-person)

Follow-up

Participants are monitored for physical and mood symptoms post-treatment

2 weeks

2 follow-up calls

What Are the Treatments Tested in This Trial?

Interventions

• N/A

Trial Overview The study tests how older adults with varying levels of anxiety respond to an experimental inflammation challenge (using Endotoxin vs Placebo). It measures changes in pleasure and motivation through questionnaires, computer tasks, and brain scans.

How Is the Trial Designed?

Group I: Endotoxin Experimental Treatment 1 Intervention

Endotoxin 0.8 ng/kg body weight

Group II: Placebo Placebo Group 1 Intervention

same volume of 0.9% saline

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

In a study of 64 adolescents with psychiatric symptoms, C-Reactive Protein (CRP), an inflammation biomarker, did not correlate with the severity of clinical symptoms like anxiety or depression.

However, higher CRP levels were linked to increased brain activation during reward-related tasks, suggesting that inflammation may influence brain function in the context of psychiatric conditions, even if it doesn't directly relate to symptom severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms. Liu, Q., Ely, B., Simkovic, S., et al.[2023]

Chronic low-grade inflammation can lead to reduced levels of dopamine in the brain's reward system, which may make individuals less willing to put in effort to achieve rewards.

This reduction in dopamine is linked to a steeper effort-discounting curve, suggesting that inflammation affects not just motivation but also how people perceive their ability to achieve rewards, which could have implications for various psychiatric and medical disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive. Treadway, MT., Cooper, JA., Miller, AH.[2021]

In a study involving 15 healthy volunteers, the inflammatory agent lipopolysaccharide (LPS) was shown to significantly impair sensitivity to rewards compared to punishments, indicating that inflammation can negatively affect motivation and mood.

Minocycline, an antibiotic with anti-inflammatory properties, was effective in attenuating the negative effects of LPS on reward versus punishment sensitivity, suggesting a potential role for microglia in the motivational changes associated with inflammation and implications for treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by minocycline. De Marco, R., Barritt, AW., Cercignani, M., et al.[2023]

In a study with 27 male mice, inflammation induced by lipopolysaccharide (LPS) reduced their motivation to perform tasks for food rewards, indicating that inflammation can affect incentive motivation rather than just appetite.

The mice showed a significant decrease in low-effort food-seeking behavior while still earning more high-effort rewards, suggesting that inflammation alters their willingness to exert effort for rewards rather than their sensitivity to the rewards themselves.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. Vichaya, EG., Hunt, SC., Dantzer, R.[2021]

Inflammation can lead to motivational deficits and anhedonia, a key symptom of depression, by affecting neurotransmitter systems like dopamine and glutamate in brain regions involved in reward processing, such as the ventral striatum.

There is a significant opportunity to develop new or repurposed medications targeting inflammation and its effects on the brain, but current clinical trials have not effectively utilized this knowledge, highlighting the need for innovative trial designs that focus on motivation-related outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications. Lucido, MJ., Bekhbat, M., Goldsmith, DR., et al.[2022]

In a study of 46 youth with psychiatric symptoms, specific inflammatory markers were found to negatively impact brain activity during reward anticipation and attainment, suggesting inflammation may disrupt reward processing in young people.

Certain cytokines were linked to reduced activation in key brain areas involved in reward processing, such as the basal ganglia and anterior cingulate cortex, highlighting the potential role of inflammation in psychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms. Bradley, KA., Stern, ER., Alonso, CM., et al.[2023]

In a study involving 12 participants (5 with remitted major depressive disorder and 7 healthy controls), an inflammatory stimulus from a typhoid vaccine reduced motivation for effort-based tasks in those with a history of depression, indicating ongoing challenges in reward processing even after clinical remission.

The results showed that while healthy controls were more likely to choose harder tasks for rewards after a placebo, this difference disappeared after the inflammatory stimulus, suggesting that inflammation can diminish motivation in individuals with remitted depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of an experimentally induced inflammatory stimulus on motivational behavior in remitted depressed patients. Suchting, R., Razouq, D., Jose, L., et al.[2023]

Citations

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Effects of gut-derived endotoxin on anxiety-like and repetitive ... Our results suggest that an increased intestinal load of LPS similarly increases anxiety-like behavior and suppresses repetitive behavior in ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/17499821/

Age increases vulnerability to bacterial endotoxin-induced ... LPS-treated subjects show impaired acquisition of the task regardless of the age of the subject, as these animals performed significantly fewer ...

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Age increases vulnerability to bacterial endotoxin-induced ... Previous research from our laboratory and others indicate that LPS-induced behavioral deficits are greater in older subjects.

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Dose-Dependent Effects of Endotoxin on Neurobehavioral ... Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate.

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Differential sensitivity to endotoxin exposure in young and ... The data suggest that in some respects middle-aged mice are more sensitive to endotoxin exposure, as they show enhanced weight loss, splenic cytokine levels, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29328416/

Endotoxin tolerance induced by lipopolysaccharide ... Therefore, it was hypothesized that endotoxin tolerance induced by LPS preconditioning may protect against surgery‑induced cognitive impairment in aging mice.

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Endotoxin-Induced Physiological and Psychological Sickness ... These findings confirm that experimental endotoxemia in humans is a robust and safe model of systemic inflammation that does not cause long-term changes in ...

8. bsd.biomedcentral.com bsd.biomedcentral.com/articles/10.1186/s13293-018-0166-x

Effects of gut-derived endotoxin on anxiety-like and repetitive ... Our results suggest that an increased intestinal load of LPS similarly increases anxiety-like behavior and suppresses repetitive behavior in ...

9. stacks.cdc.gov stacks.cdc.gov/view/cdc/230761

Intermittent Systemic Exposure to Lipopolysaccharide ... Intermittent Systemic Exposure to Lipopolysaccharide-Induced Inflammation Disrupts Hippocampal Long-Term Potentiation and Impairs Cognition in Aging Male Mice.

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Endotoxin exposure in early life alters the development of ... Specifically, adult and senescent endotoxin treated animals displayed significantly more anxiety-like behaviour than vehicle treated controls. Interestingly no ...