Sleep and Healthy Aging Research on Depression for Younger Women

NCT03848715 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 16-000583-AM-00016
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Compelling evidence indicates inflammation plays a role in depression, but potential mechanisms linking inflammation to depression, such as dysregulated reward processing, are poorly understood. This study comprehensively evaluates effects of inflammation on reward across dimensions (e.g., anticipating versus receiving a reward) and types (e.g., money vs. smiling faces) in younger and older women. Characterizing how inflammation shapes the dynamic and multidimensional reward system, and how this may differ by age, may give insight into risk factors for depression and help identify critical points for intervention.

Conditions

Anhedonia; Depression

Outcome Measures

Primary Outcomes (6)

• Non-social (Monetary) Reward Response (Reward Learning and Sensitivity)

  Implicit reward learning and sensitivity to monetary reward is assessed with the probabilistic reward task (PRT) a behavioral computer task; change in the magnitude of response bias from baseline to post-injection is the outcome measure. More positive response bias indicates a bias towards the more frequently reward stimuli (a better outcome); more negative response bias indicates a bias towards the less frequently reward stimuli (a worse outcome). This is not a standardized scale with minimum and maximum values. Response bias is calculated using a formula from signal detection theory and is a logarithmic ratio derived from choice frequencies. The formula is log b=1/2log((Rich-correct+.5) \*(Lean-incorrect+.5)/(rich-incorrect+.5) \* (lean-incorrect+.5)), where rich refers to the more frequently rewarded option and lean refers to the less frequently rewarded option.

  Baseline and post-injection (2.25 hrs)

• Non-social (Monetary) Reward Response (Reward Motivation)

  Motivation for monetary reward is assessed with a 10-minute version of the Effort Expenditure for Rewards Task (EEfRT), a behavioral computer task; change in the amount of hard trials chosen (relative to total trials) from baseline to post-injection is the outcome measure. The task is analyzed using generalized estimating equations (GEE) with a binary outcome; outcome values at each timepoint therefore range from 0 to 1, with higher numbers indicating higher motivation (a better outcome). The predictor for the GEE model is a time (coded as 0 and 1) by condition (coded as 0 and 1) interaction term. A negative result in the boxes below for each condition separately indicates a pre-to post-injection decrease in the proportion of hard trials chosen.

  Baseline and post-injection (2.1 hrs)

• Non-social (Monetary) Reward Response (Reward Sensitivity)

  Sensitivity for monetary reward is assessed with a 10-minute version of the Effort Expenditure for Rewards Task (EEfRT) a behavioral computer task, tested as the strength of the association between increases in potential monetary reward for hard trials and selection of hard (vs) easy trials during the task. This is tested using generalized estimating equations, with condition (LPS vs. placebo) by time (pre vs post-injection) by reward magnitude (ranges from $1-$4.12) predicting hard (vs easy) trial choice. More positive values indicate higher reward sensitivity ( a better outcome), and lower values indicate lower reward sensitivity. The unit of measurement for the task is the proportion of hard trials chosen; the unit of measurement for the reward sensitivity outcome is a beta coefficient. For example, a positive coefficient for reward magnitude in the GEE output means that as the reward amount increases by one unit (e.g., $1), the odds of choosing the high-effort option increase.

  Baseline and post-injection (2.1 hrs)

• General Social Reward Response (Reward Sensitivity Via Emotional Dot Probe)

  Sensitivity to general social reward cues (i.e., response to positive emotional faces) assessed as positive attentional bias with an emotional dot probe task. Attentional bias is assessed by measuring reaction times to targets that appear in the same location as emotional (e.g., happy faces) versus neutral cues (e.g., neutral faces). Outcomes are change from baseline to post-injection in attentional bias towards positive vs neutral faces. Higher positive attentional bias scores indicate higher sensitivity to reward; negative attentional bias score indicate less sensitivity to reward. A score of 0 indicates no bias. The attentional bias score is derived by subtracting the reaction time in ms on congruent trials (dot replaces an emotional face) from the reaction time on incongruent trials (dot replaces the neutral face).

  Baseline and post-injection (2.7 hrs)

• General Social Reward Response (Reward Sensitivity Via Face Morphing Task)

  Sensitivity to general social reward cues (i.e., response to positive emotional faces) assessed as positive emotion detection with a face morphing task. The outcome is the absolute change from baseline to post-injection in the percent of accurate responses. Higher accuracy is an indicator of higher sensitivity to reward and lower accuracy is an indicator of lower sensitivity to reward.

  Baseline and post-injection (2.8 hrs)

• General Social Reward Response (Social Reward Motivation)

  Motivation for general social reward is assessed via self-report; participants rate their desire to engage in 3 different activities, one of which is social, on a 1 (not at all) to 10 (extremely) Likert scale.; change in desire for the social activity from baseline to post-injection is the outcome variable. Higher values indicate higher motivation.

  Baseline and post-injection (2 hrs)

Secondary Outcomes (5)

• Depressed Mood Subscale of the Profile of Mood States (POMS)

  Hourly, from pre-injection (T0) to 9 hours later (T9)

• Close Social Reward Response

  Post-injection (2.9 hrs)

• Consummatory Daily Reward Response

  14 days (7 days pre-injection; 7 days post-injection).

• Dopaminergic Activity

  Baseline and post-injection (1.9 hrs)

• Anticipatory Daily Reward Response

  14 days (7 days pre-injection; 7 days post-injection).

Other Outcomes (1)

• Negative Emotion Regulation Capacity

  post-injection (approximately 3 hrs)

Study Arms (2)

Endotoxin

EXPERIMENTAL

Endotoxin 0.8 ng/kg body weight; 1 infusion

Biological: Endotoxin

Placebo

PLACEBO COMPARATOR

same volume of 0.9% saline

Biological: Placebo

Interventions

Placebo BIOLOGICAL

Placebo

Placebo

Endotoxin BIOLOGICAL

Endotoxin

Endotoxin

Eligibility Criteria

• Age: 25 Years - 44 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants will be required to be in good general health (as evaluated during the phone and in-person baseline session)
• Participants will be biologically female and premenopausal (as evaluated by self report).
• Participants will 25-44 years of age.

You may not qualify if:

• Presence of chronic mental or physical illness
• History of allergies, autoimmune, liver, or other severe chronic diseases,
• Current and regular use of prescription medications such as steroids, non-steroid anti-inflammatory drugs, aspirin, immune modifying drugs, opioid analgesics, statins, antihypertensive drugs, anti-arrhythmic drugs, and antidepressant medications (none in the last 6 months).
• Nightshift work or time zone shifts (\> 3hrs) within the previous 6 weeks
• Previous history of fainting during blood draws.
• 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 comorbid 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, which may elevate proinflammatory cytokines;
• Presence of an acute infectious illness in the two weeks prior to an experimental session.
• Current Axis I psychiatric disorders as determined by the Research Version of the Structured Clinical Interview including a current major depressive disorder and substance dependence
• Lifetime history of suicide attempt or inpatient psychiatric admission.
• Current history of sleep apnea or nocturnal myoclonus; Phase-shift disorder, which will be identified by the Structured Clinical Interview and the Duke Structured Interview for Sleep Disorders
• Current smoking or excessive caffeine use (\>600 mg/day) because of the known effects on proinflammatory cytokine levels;
• Evidence of recreational drug use from urine test.

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

Norman Cousins Center for Psychoneuroimmunology, University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Related Publications (1)

• Boyle CC, Cho JH, Eisenberger NI, Olmstead R, Sadeghi N, Castillo D, Irwin MR. Inflammation-induced depressed mood and reward responsivity as a function of age in female adults: a randomized controlled trial of endotoxin. Transl Psychiatry. 2025 Nov 26;16(1):6. doi: 10.1038/s41398-025-03752-2.

  PMID: 41298372 DERIVED

MeSH Terms

Conditions

Anhedonia; Depression

Interventions

Endotoxins

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors

Results Point of Contact

• Title: Dr. Chloe Boyle
• Organization: UCLA

ccboyle@mednet.ucla.edu

310 794 9383

Study Officials

• Chloe C Boyle, PhD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

• Michael R Irwin, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Blinded infusion
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Postdoctoral Fellow

Model Details: Endotoxin vs Placebo

Study Record Dates

• First Submitted: February 19, 2019
• First Posted: February 21, 2019
• Study Start: October 2, 2019
• Primary Completion: July 22, 2022
• Study Completion: July 22, 2024
• Last Updated: January 27, 2026
• Results First Posted: January 3, 2025

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)