Major Depressive Disorder
Conditions
Brief summary
The aim of this project is to determine whether the acute oral administration of Ibuprofen changes the activation pattern in the amygdala and other brain structures during functional magnetic resonance imaging. The investigators use a double-blind, randomized, repeated-measures design. Each of the 20 healthy control subjects will be tested three times and receive placebo, 200 mg or 600 mg dose of ibuprofen p.o. The study will consist of 4 sessions: a baseline screening session and 3 testing sessions scheduled 1-2 weeks apart. Each of these individuals will undergo a multi-level assessment based on the RDoC approach that consists of (a) a standardized diagnostic assessment, (b) self-report questionnaires assessing the positive and negative valence domains as well as interoception, (c) behavioral tasks assessing reward-related processing, avoidance, and aversive processing, cognition, and interoception; (d) physiological measurements consisting of facial emotion expression monitoring, heart rate and respiration, (e) functional magnetic resonance imaging focusing on reward-related processing, fear conditioning and extinction, cognitive inhibition, and interoceptive processing, and (f) biomarker assessments.
Detailed description
Occasional OTC nonsteroidal anti-inflammatory drugs (NSAID) use is prevalent in the United States (25% aspirin, 9% ibuprofen, and 2% naproxen). An estimated 36 million Americans use over-the-counter (OTC) analgesics daily, however, considering the widespread use of analgesic agents, the overall incidence of serious drug-drug interactions involving these agents has been relatively low. Neuroinflammatory mechanisms have been implicated in depression, and NSAIDs have been found effective in animal models of depression both in monotherapy and when used to augment antidepressant drugs. However, results with NSAIDs have been mixed in human observational studies, with both better and worse depression outcomes reported. In animal studies, mice injected with BCG showed an increase in the total immobility time during the forced swim test (FST) and the tail suspension test (TST) and an increase in cerebral PGE2 and NO levels. Ibuprofen decreased the total immobility time during FST and TST and decreased cerebral PGE2 and NO levels, which was comparable to fluoxetine's effect. This would suggest that ibuprofen might have an antidepressant effect through inhibition of PGE2 and NO production. Some studies have demonstrated the success of augmentation of antidepressant therapy with nonsteroidal anti-inflammatory drugs (NSAID) in decreasing depressive symptoms. However, little is known about the benefit of NSAID therapy on depressive symptoms. In a recent meta-analysis, using multivariable regression analysis a detectable effect in lowering PHQ-9 score in the ibuprofen or naproxen group (-0.31) and Celebrex group (-0.61) (p= .0390) was observed. However, in a study with cognitively normal volunteers age 70 and older with a family history of Alzheimer-like dementia who were randomly assigned to receive celecoxib 200 mg twice daily, naproxen sodium 220 mg twice daily, or placebo the investigators found no treatment effect on geriatric depression scores over time in the subgroup of participants with significant depressive symptoms at baseline. Moreover, there is some concern that anti-inflammatory drugs inhibit the antidepressant effects of SSRIs. In the only published fMRI study, ten healthy subjects underwent a double-blind, placebo-controlled, randomized, cross-over phFMRI study with somatosensory painful stimulation of the right median nerve. These authors reported a task-related increase of BOLD signal between drug and placebo in the primary somatosensory area and the middle frontal gyrus that was not related to changes in subjective pain scores. Thus there is some evidence that ibuprofen influences the BOLD response in specific pain-related brain areas. Taken together, there is mixed evidence for the effect of ibuprofen on mood and no data on its effect on the emotion circuitry. Hypotheses: 1. The activation pattern in the amygdala during risk-taking decision-making will be attenuated by ibuprofen in a dose dependent manner. 2. The activation pattern in the amygdala during anticipatory emotional arousal will be attenuated by ibuprofen in a dose dependent manner. 3. The activation pattern in the amygdala during emotional face processing will be attenuated by ibuprofen in a dose dependent manner. 4. The behavioral response during tasks assessing emotional and cognitive processes including positive and negative valence and reward based learning will be modulated by ibuprofen in a dose dependent manner.
Interventions
DRUGIbuprofen
On the day of sessions 2-4, subjects will receive either placebo, 200 mg of ibuprofen or 600 mg of ibuprofen after signing the consent form for this study in a randomized, double-blind, counter balanced order. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.
Sponsors
University of Oklahoma
Laureate Institute for Brain Research, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male, or female 2. Between the ages of 18-50. 3. In good general health
Exclusion criteria
1. Subjects who report a history of any mental health disorder such as dysthymia, simple phobia, major depression, obsessive compulsive disorder or panic disorder as a primary diagnosis currently or within 6 months prior to the screening visit. 2. Subjects with a history of schizophrenia, schizoaffective disorder, or a bipolar disorder. 3. Subjects who report DSM-V criteria for substance use disorder (alcohol or drugs) currently or within 6 months prior to screening 4. Subjects who have a positive urine illicit drug screen. 5. Subjects that regularly (more than 15 days for past 30 days) use NSAIDS and have not used NSAIDS in the previous 5 days. 6. Subjects with a history of clinically significant hepatic cardiac, renal, neurologic, cerebrovascular, metabolic or pulmonary disease, gastric disease. 7. Subjects who have taken psychotropic drugs or antidepressants (including monoamine oxidase inhibitors, MAOI's) within the last year 8. Subjects with a history of seizure disorders (except for febrile seizures in childhood). 9. Subjects who, in the investigator's judgment pose a current, serious suicidal or homicidal risk or have made a suicide attempt within the past 6 months. 10. Women who have a positive serum HCG pregnancy test at screen visit or who are lactating or planning to become pregnant within the next 18 weeks following the screen visit. 11. Women who are currently menstruating. 12. The subject suffers from claustrophobia, or phobia for injections or blood. 13. Magnetic Resonance Imaging related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | 3-6 weeks | Change in amygdala activation following administration of placebo, 200mg of ibuprofen or 600mg of ibuprofen |
Countries
United States
Participant flow
Recruitment details
24 participants were recruited for the study at the Laureate Institute for Brain Research in Tulsa, Oklahoma.
Pre-assignment details
22 of 24 participants who signed informed consent were randomized. 2 participants withdrew from the study prior to randomization due to work schedule and no response to scheduling attempts.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Subjects received either placebo, 200 mg of ibuprofen or 600 mg of ibuprofen after signing the consent form for this study in a randomized, double-blind, counter-balanced study. Each participant received all interventions. Each study session occurred 1-2 weeks following the previous session. Ibuprofen was capsuled, and identical placebo capsules were produced. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 31.75 Years STANDARD_DEVIATION 6.72 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 20 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 21 | 0 / 20 | 0 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 20 | 0 / 21 |
Outcome results
Primary
Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala
Change in amygdala activation following administration of placebo, 200mg of ibuprofen or 600mg of ibuprofen
Time frame: 3-6 weeks
Population: Scans that had average Euclidean norm of motion parameters less than 0.15 were included in the analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | Left amygdala | 0.20 percent signal change | Standard Error 0.045 |
| Placebo | Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | Right amygdala | 0.23 percent signal change | Standard Error 0.037 |
| Ibuprofen, 200mg | Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | Left amygdala | 0.21 percent signal change | Standard Error 0.032 |
| Ibuprofen, 200mg | Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | Right amygdala | 0.23 percent signal change | Standard Error 0.037 |
| Ibuprofen, 600mg | Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | Left amygdala | 0.23 percent signal change | Standard Error 0.047 |
| Ibuprofen, 600mg | Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala | Right amygdala | 0.17 percent signal change | Standard Error 0.063 |
Comparison: A linear mixed effects model was run for the left amygdala with contrast and percent signal change between faces and shapes as the dependent variable and ibuprofen dose as a continuous predictor. Each subject had up to 3 visits and each visit contained 3 contrasts (happy - shape, angry - shape, fearful - shape) so subject and drug were used as random effects. Drug was nested inside of subject.p-value: 0.51295% CI: [-0.00011, 0.00022]Mixed Models Analysis
Comparison: A linear mixed effects model was run for the right amygdala with contrast and percent signal change between faces and shapes as the dependent variable and ibuprofen dose as a continuous predictor. Each subject had up to 3 visits and each visit contained 3 contrasts (happy - shape, angry - shape, fearful - shape) so subject and drug were used as random effects. Drug was nested inside of subject.p-value: 0.22195% CI: [-0.0003, 0.000067]Mixed Models Analysis