A Phase 2/3 interventional study of Ibuprofen in Major Depressive Disorder, sponsored by Laureate Institute for Brain Research, Inc.. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-02-23.
Sponsored by Laureate Institute for Brain Research, Inc. · Phase 2/3, Interventional, and Basic science
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.
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:
4,845 studies on the registry are indexed under Depressive Disorder; 514 are open to participants now.
This study's enrollment of 24 is below the median of 80 across 3,999 interventional studies indexed under Depressive Disorder.
Browse Depressive Disorder studies →Laureate Institute for Brain Research, Inc. is the lead sponsor of 53 studies on the registry; 12 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Subjects will receive one dose of placebo (sugar pill) at one of the three testing sessions . Placebo capsules will be produced in the same manner as the ibuprofen by a local compounding pharmacy in Tulsa, OK.
Drug: Ibuprofen
Subjects will receive one oral dose of 200mg at one of the three testing sessions. Ibuprofen capsules will be produced by a local compounding pharmacy in Tulsa, OK.
Drug: Ibuprofen
Subjects will receive one oral dose of 600mg at one of the three testing sessions. Ibuprofen capsules will be produced by a local compounding pharmacy in Tulsa, OK.
Drug: Ibuprofen
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.
Also known as: Placebo
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
24 participants were recruited for the study at the Laureate Institute for Brain Research in Tulsa, Oklahoma.
| Milestone | Placebo, Ibuprofen 200mg, Ibuprofen 600mg | Placebo, Ibuprofen, 600mg, Ibuprofen 200mg | Ibuprofen, 200mg, Placebo, Ibuprofen 600mg | Ibuprofen 200mg, Ibuprofen 600mg, Placebo | Ibuprofen 600mg, Placebo, Ibuprofen 200mg | Ibuprofen 600mg, Ibuprofen 200mg, Placebo |
|---|---|---|---|---|---|---|
| Started | 5 | 4 | 3 | 3 | 4 | 3 |
| Completed | 4 | 4 | 3 | 3 | 3 | 3 |
| Not completed | 1 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Physician decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 1 | 0 |
Change in amygdala activation following administration of placebo, 200mg of ibuprofen or 600mg of ibuprofen
| percent signal change | Placebo | Ibuprofen, 200mg | Ibuprofen, 600mg |
|---|---|---|---|
| Left amygdala | 0.20 ± 0.045 | 0.21 ± 0.032 | 0.23 ± 0.047 |
| Right amygdala | 0.23 ± 0.037 | 0.23 ± 0.037 | 0.17 ± 0.063 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | — | 0/21 (0%) | 0/21 (0%) |
| Ibuprofen, 200mg | — | 0/20 (0%) | 0/20 (0%) |
| Ibuprofen, 600mg | — | 0/21 (0%) | 0/21 (0%) |
The analysis population is based on the 20 participants who completed all 3 arms of the study: placebo, ibuprofen 200mg and 600mg. The 2 participants who entered drug randomization but did not complete the study are not included. The 2 participants who signed informed consent but were not randomized are also not included.
| Age, Categorical(Participants) | All Study Participants |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 20 |
| >=65 years | 0 |
| Age, Continuous(Years) | All Study Participants |
|---|---|
| Mean | 31.75 ± 6.72 |
| Sex: Female, Male(Participants) | All Study Participants |
|---|---|
| Female | 10 |
| Male | 10 |
| Ethnicity (NIH/OMB)(Participants) | All Study Participants |
|---|---|
| Hispanic or Latino | 2 |
| Not Hispanic or Latino | 18 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | All Study Participants |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 20 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(Participants) | All Study Participants |
|---|---|
| United States | 20 |
Plan to share: Undecided
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Laureate Institute for Brain Research, Inc.