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Study of Ibuprofen Effects on Brain Function

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ClinicalTrials.gov Identifier: NCT02507219
Recruitment Status : Completed
First Posted : July 23, 2015
Results First Posted : February 23, 2018
Last Update Posted : February 23, 2018
Sponsor:
Collaborator:
University of Oklahoma
Information provided by (Responsible Party):
Laureate Institute for Brain Research, Inc.

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.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Ibuprofen Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Placebo-controlled, Dose-response Study of Ibuprofen Effects on Brain Function
Study Start Date : July 2015
Actual Primary Completion Date : October 2015
Actual Study Completion Date : October 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
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
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.
Other Name: Placebo

Active Comparator: Ibuprofen, 200mg
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
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.
Other Name: Placebo

Active Comparator: Ibuprofen, 600mg
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.
Other Name: Placebo




Primary Outcome Measures :
  1. Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala [ Time Frame: 3-6 weeks ]
    Change in amygdala activation following administration of placebo, 200mg of ibuprofen or 600mg of ibuprofen



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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 exclusion criteria: cardiac pacemaker, metal fragments in eyes/skin/body (shrapnel), subjects who have ever been a metal worker/welder; history of eye surgery/eyes washed out because of metal, aortic/aneurysm clips, prosthesis, by-pass surgery/coronary artery clips, hearing aid, heart valve replacement, subjects who are in the first trimester of pregnancy, subjects with an I.U.D. (birth control device), a shunt (ventricular or spinal), electrodes, metal plates/pins/screws/wires, or neuro/bio-stimulators (TENS unit).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02507219


Locations
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United States, Oklahoma
Laureate Institute for Brain Research
Tulsa, Oklahoma, United States, 74136
Sponsors and Collaborators
Laureate Institute for Brain Research, Inc.
University of Oklahoma
Investigators
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Study Director: Martin P Paulus, M.D. Laureate Institute for Brain Research

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Laureate Institute for Brain Research, Inc.
ClinicalTrials.gov Identifier: NCT02507219     History of Changes
Other Study ID Numbers: 2015-007-00
First Posted: July 23, 2015    Key Record Dates
Results First Posted: February 23, 2018
Last Update Posted: February 23, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Ibuprofen
Depressive Disorder
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action