Clinical trial NCT06044090: Brain and Stress Study
Official title: Neuroinflammatory Mechanisms Linking Chronic Stress to Motivational Deficits
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Stress, Psychological
Motivation
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Robert Wood Johnson Foundation
First posted: 2023-09-21
Enrollment: 10
Sex: ALL
Minimum age (years): 25
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Motivational deficits such as anhedonia are core to several psychiatric disorders and underlie significant functional impairment. This double-blind, placebo-controlled crossover trial of minocycline, an anti-\[neuro\]inflammatory agent, examines links between chronic stress and responses to a reward-related motivation task. It will evaluate the effects of pharmacologically attenuating neuroinflammation on behavioral responses to a reward-related motivation task in individuals experiencing unemployment. Understanding the effects of neuroinflammation on reward function among individuals experiencing chronic stress represents a critical first step in identifying novel neuroimmune targets for future clinical trials.

Detailed description: This study seeks to conduct translational work that extends rich preclinical findings to the clinical domain to validate whether neuroinflammatory dysregulation is strongly tied to anhedonia. This project addresses critical gaps in the scientific literature by recruiting a chronically stressed sample of individuals-employment seeking individuals who report significant stress-- and will use an experimental therapeutics approach to attenuate neuroinflammation and assess behavioral changes in motivation.

One major obstacle in understanding how neuroinflammation influences motivation involves technological challenges such that conventional approaches are invasive, expensive, and/or lacking specificity. Although static levels of neuroinflammation in humans have been measured via cross sectional studies, capturing behavioral shifts following experimental manipulation has not been done. This gap limits the ability to develop a more precise understanding of how neuroinflammation causes motivational deficits in humans. The proposed project will employ a mechanistic clinical trial of the anti-\[neuro\]inflammatory agent, minocycline, to address these limitations. In animal models, minocycline has attenuated the deleterious effects of neuroinflammation on neurogenesis, long-term potentiation, and neuronal survival. This study will extend research to humans to examine whether links between neuroinflammation and behavioral responses to a reward-related motivation task differ among chronically stressed individuals taking minocycline and the placebo control. The proposed project will provide preliminary evidence for potential neural targets that have relevance for motivational deficits due to neuroinflammation.

Once screening is complete, participants will come to UNC to complete quality-of-life surveys, learn about the full study schedule, and receive the first dose of medication. This visit will last about 90 minutes. Participants will be asked to participate in two medication periods, meaning they will take both minocycline (antibiotic medication) for 5-days, and an inactive substance (placebo sugar pill) for 5-days. This will investigate whether there are changes in their responses to negative and positive information. After taking the first medication for five days, participants will come in to complete a computer task (Probabilistic Reward Task) and some follow-up surveys (Snaith-Hamilton Pleasure Scale and Motivation and Pleasure Scale). This visit will last about 90 minutes. Participants will then get at least a 2-week break before taking the second medication for five days. Then, they will come back for another 90-minute visit to complete the same computer task and follow-up surveys. The total study duration including the break is about one month. The total time in study sessions on campus over the month will be 4.5 hours.

Eligibility criteria: Inclusion Criteria:

* 25-60 years old
* Unemployed (working less than 20 hours per week)
* Have been unemployed for at least 6 months
* Seeking employment
* Having trouble finding a job (i.e., actively seeking and applying for jobs but not successful in landing a job)
* Reports greater than 5 points on Job Stress Items
* Regular access to a mobile phone

Exclusion Criteria:

* Self-reported physical illnesses: diabetes, cardiovascular diseases, high blood pressure, inflammatory bowel diseases, rheumatoid arthritis, asthma, autoimmune disease, Crohn's disease, ulcerative colitis, lupus
* neurological conditions (e.g., Traumatic Brain Injury, stroke)
* pregnant (as measured by urine pregnancy screen) or breastfeeding
* current use of psychotropic medications
* Current regular recreational drug or alcohol use (i.e., 4 or more times per week)
* chronic diseases that significantly impact inflammatory markers (e.g., cancer)
* known allergies or hypersensitivities to tetracycline antibiotics, aspirin or other NSAIDs
* current antibiotic use
* regular use of steroidal or non-steroidal anti-inflammatory medications (i.e., 2 or more times a week)

Primary outcomes:
measure: Change in Response Bias During the Probabilistic Reward Task
timeFrame: within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo
Secondary outcomes:
measure: Change in Snaith Hamilton Pleasure Scale Score
timeFrame: within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo
measure: Change in Motivation and Pleasure Scale (MAPS) Score
timeFrame: within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Howell Hall
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Gabriella Alvarez, PhD
role: STUDY_DIRECTOR
affiliation: University of North Carolina, Chapel Hill
name: Keely Muscatell, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kangas BD, Der-Avakian A, Pizzagalli DA. Probabilistic Reinforcement Learning and Anhedonia. Curr Top Behav Neurosci. 2022;58:355-377. doi: 10.1007/7854_2022_349.
citation: Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99.
citation: Llerena K, Park SG, McCarthy JM, Couture SM, Bennett ME, Blanchard JJ. The Motivation and Pleasure Scale-Self-Report (MAP-SR): reliability and validity of a self-report measure of negative symptoms. Compr Psychiatry. 2013 Jul;54(5):568-74. doi: 10.1016/j.comppsych.2012.12.001. Epub 2013 Jan 22.