Motivation, Stress, Psychological
Conditions
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.
Interventions
DRUGMinocycline
Participants will take 2 pills of 100 mg totaling a 200 mg dose of minocycline per day.
DRUGPlacebo
A placebo is a sugar pill that has no therapeutic effect and will be administered orally. Participants will receive 2 placebo tablets matching the Minocycline tablets daily for 5 days.
Sponsors
Robert Wood Johnson Foundation
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to 60 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Response Bias During the Probabilistic Reward Task | within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo | The aim of Probabilistic Reward Task (PRT) is to win as much money as possible by correctly identifying the presence of a short versus long mouth on a cartoon face. The task aims to produce a response bias toward the mouth length that is more often positively reinforced. The response bias score is a ratio of the number of times the participant chooses the high reward versus the low reward stimulus. Scores range from -1 to +1, with a positive score indicating a stronger bias toward the high reward stimulus. The change in response bias is calculated by subtracting response bias during the PRT in the placebo condition from the minocycline condition. This difference measures an individual's change in reward behavior after a 5-day dosage of an anti-neuroinflammatory agent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Snaith Hamilton Pleasure Scale Score | within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo | The Snaith-Hamilton Pleasure Scale (SHAPS) is a tool to assess symptoms of reduced motivation. The SHAPS uses 14 questions, each rated on a Likert scale of 1-4. The total score on the scale ranges from 14-56, with lower scores reflecting lower motivation. Scores will be compared across conditions to determine whether motivation changes in the minocycline condition as compared to the placebo. |
| Change in Motivation and Pleasure Scale (MAPS) Score | within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo | The Motivation and Pleasure Scale (MAP) will be used to capture self-reported aspects of reduced motivation. The scale uses 18 questions, each rated on a Likert scale of 0-4. The total score on the scale ranges from 0-72, with lower scores reflecting lower motivation. Scores will be compared across conditions to determine whether motivation changes in the minocycline condition as compared to the placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Individuals who completed at least one treatment period. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 10 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 8 / 10 | 2 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 |
Outcome results
Primary
Change in Response Bias During the Probabilistic Reward Task
The aim of Probabilistic Reward Task (PRT) is to win as much money as possible by correctly identifying the presence of a short versus long mouth on a cartoon face. The task aims to produce a response bias toward the mouth length that is more often positively reinforced. The response bias score is a ratio of the number of times the participant chooses the high reward versus the low reward stimulus. Scores range from -1 to +1, with a positive score indicating a stronger bias toward the high reward stimulus. The change in response bias is calculated by subtracting response bias during the PRT in the placebo condition from the minocycline condition. This difference measures an individual's change in reward behavior after a 5-day dosage of an anti-neuroinflammatory agent.
Time frame: within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Change in Response Bias During the Probabilistic Reward Task | 0.195 Ratio (Response Bias Score) | Standard Deviation 0.206 |
| Placebo | Change in Response Bias During the Probabilistic Reward Task | 0.203 Ratio (Response Bias Score) | Standard Deviation 0.199 |
p-value: 0.856t-test, 2 sided
p-value: 0.613t-test, 2 sided
Secondary
Change in Motivation and Pleasure Scale (MAPS) Score
The Motivation and Pleasure Scale (MAP) will be used to capture self-reported aspects of reduced motivation. The scale uses 18 questions, each rated on a Likert scale of 0-4. The total score on the scale ranges from 0-72, with lower scores reflecting lower motivation. Scores will be compared across conditions to determine whether motivation changes in the minocycline condition as compared to the placebo.
Time frame: within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Change in Motivation and Pleasure Scale (MAPS) Score | 37.786 score on a scale | Standard Deviation 10.984 |
| Placebo | Change in Motivation and Pleasure Scale (MAPS) Score | 39.267 score on a scale | Standard Deviation 12.87 |
p-value: 0.225t-test, 2 sided
p-value: 0.667t-test, 2 sided
Secondary
Change in Snaith Hamilton Pleasure Scale Score
The Snaith-Hamilton Pleasure Scale (SHAPS) is a tool to assess symptoms of reduced motivation. The SHAPS uses 14 questions, each rated on a Likert scale of 1-4. The total score on the scale ranges from 14-56, with lower scores reflecting lower motivation. Scores will be compared across conditions to determine whether motivation changes in the minocycline condition as compared to the placebo.
Time frame: within approximately 24 hours after the final dose; Day 6 minocycline to Day 6 placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Change in Snaith Hamilton Pleasure Scale Score | 3.286 score on a scale | Standard Deviation 1.59 |
| Placebo | Change in Snaith Hamilton Pleasure Scale Score | 2.933 score on a scale | Standard Deviation 1.58 |
p-value: 1t-test, 2 sided
p-value: 0.691t-test, 2 sided