Study of Ibuprofen Effects on Brain Function

• Sponsor: Laureate Institute for Brain Research, Inc. (Other)
• Overall Status: Completed
• CT.gov ID: NCT02507219
• Collaborator: University of Oklahoma (Other)
• Enrollment: 24
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 7.9

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Jul 1, 2015
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

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 Names: 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 Names: 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 Names: Placebo

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts 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 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Laureate Institute for Brain Research	Tulsa	Oklahoma	United States	74136

Sponsors and Collaborators

• Laureate Institute for Brain Research, Inc.
• University of Oklahoma

Investigators

• Study Director: Martin P Paulus, M.D., Laureate Institute for Brain Research

Study Documents (Full-Text)

None provided.

More Information

Publications

• Andrade C. Antidepressant augmentation with anti-inflammatory agents. J Clin Psychiatry. 2014 Sep;75(9):975-7. doi: 10.4088/JCP.14f09432.
• Delaney JA, Biggs ML, Kronmal RA, Psaty BM. Demographic, medical, and behavioral characteristics associated with over the counter non-steroidal anti-inflammatory drug use in a population-based cohort: results from the Multi-Ethnic Study of Atherosclerosis. Pharmacoepidemiol Drug Saf. 2011 Jan;20(1):83-9. doi: 10.1002/pds.2065. Epub 2010 Nov 11.
• Delli Pizzi S, Mantini D, Ferretti A, Caulo M, Salerio I, Romani GL, Del Gratta C, Tartaro A. Pharmacological functional MRI assessment of the effect of ibuprofen-arginine in painful conditions. Int J Immunopathol Pharmacol. 2010 Jul-Sep;23(3):927-35.
• Fields C, Drye L, Vaidya V, Lyketsos C; ADAPT Research Group. Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: findings from a randomized controlled trial. Am J Geriatr Psychiatry. 2012 Jun;20(6):505-13. doi: 10.1097/JGP.0b013e318227f4da.
• Hersh EV, Pinto A, Moore PA. Adverse drug interactions involving common prescription and over-the-counter analgesic agents. Clin Ther. 2007;29 Suppl:2477-97. doi: 10.1016/j.clinthera.2007.12.003. Review.
• Iyengar RL, Gandhi S, Aneja A, Thorpe K, Razzouk L, Greenberg J, Mosovich S, Farkouh ME. NSAIDs are associated with lower depression scores in patients with osteoarthritis. Am J Med. 2013 Nov;126(11):1017.e11-8. doi: 10.1016/j.amjmed.2013.02.037. Epub 2013 Aug 29.
• Saleh LA, Hamza M, El Gayar NH, Abd El-Samad AA, Nasr EA, Masoud SI. Ibuprofen suppresses depressive like behavior induced by BCG inoculation in mice: role of nitric oxide and prostaglandin. Pharmacol Biochem Behav. 2014 Oct;125:29-39. doi: 10.1016/j.pbb.2014.07.013. Epub 2014 Aug 4.
• Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9262-7. doi: 10.1073/pnas.1104836108. Epub 2011 Apr 25. Erratum in: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11297.

• Responsible Party: Laureate Institute for Brain Research, Inc.
• ClinicalTrials.gov Identifier: NCT02507219
• Other Study ID Numbers: 2015-007-00
• First Posted: Jul 23, 2015
• Last Update Posted: Feb 23, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Ibuprofen

Study Results

Participant Flow

Recruitment Details	24 participants were recruited for the study at the Laureate Institute for Brain Research in Tulsa, Oklahoma.
Pre-assignment Detail	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.

Arm/Group Title	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
Arm/Group Description	Subjects will receive one dose of placebo or ibuprofen at three testing sessions in a randomized, double-blind, counter-balanced order. In this arm, the subject will receive the doses in the following order: Placebo, Ibuprofen 200mg, Ibuprofen 600mg. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.	Subjects will receive one dose of placebo or ibuprofen at three testing sessions in a randomized, double-blind, counter-balanced order. In this arm, the subject will receive the doses in the following order: Placebo, Ibuprofen 600mg, Ibuprofen 200mg. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.	Subjects will receive one dose of placebo or ibuprofen at three testing sessions in a randomized, double-blind, counter-balanced order. In this arm, the subject will receive the doses in the following order: Ibuprofen 200mg, Placebo, Ibuprofen 600mg. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.	Subjects will receive one dose of placebo or ibuprofen at three testing sessions in a randomized, double-blind, counter-balanced order. In this arm, the subject will receive the doses in the following order: Ibuprofen 200mg, Ibuprofen 600mg, Placebo. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.	Subjects will receive one dose of placebo or ibuprofen at three testing sessions in a randomized, double-blind, counter-balanced order. In this arm, the subject will receive the doses in the following order: Ibuprofen 600mg, Placebo, Ibuprofen 200mg. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.	Subjects will receive one dose of placebo or ibuprofen at three testing sessions in a randomized, double-blind, counter-balanced order. In this arm, the subject will receive the doses in the following order: Ibuprofen 600mg, Placebo, Ibuprofen 200mg. Each study session will occur 1-2 weeks following the previous session. Ibuprofen will be capsuled, and identical placebo capsules will be produced.
Period Title: Overall Study
STARTED	5	4	3	3	4	3
COMPLETED	4	4	3	3	3	3
NOT COMPLETED	1	0	0	0	1	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	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.
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 100%
>=65 years	0 0%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	31.75 (6.72)
Sex: Female, Male (Count of Participants)
Female	10 50%
Male	10 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10%
Not Hispanic or Latino	18 90%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Dose-dependent Differences in the BOLD Response to fMRI Tasks in the Amygdala
Description	Change in amygdala activation following administration of placebo, 200mg of ibuprofen or 600mg of ibuprofen
Time Frame	3-6 weeks

Outcome Measure Data

Analysis Population Description

Scans that had average Euclidean norm of motion parameters less than 0.15 were included in the analyses.

Arm/Group Title	Placebo	Ibuprofen, 200mg	Ibuprofen, 600mg
Arm/Group Description	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. 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.	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. 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.	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. 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.
Measure Participants	19	18	19
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ibuprofen, 200mg, Ibuprofen, 600mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.512
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.000055
	Confidence Interval	(2-Sided) 95%; -0.00011 to 0.00022
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope is percent signal change per milligram of ibuprofen.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ibuprofen, 200mg, Ibuprofen, 600mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.221
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.00012
	Confidence Interval	(2-Sided) 95%; -0.00030 to 0.000067
	Parameter Dispersion	Type: Value:
	Estimation Comments	Slope is the percent signal change per mg of ibuprofen.

Adverse Events

Arm/Group Title	Placebo		Ibuprofen, 200mg		Ibuprofen, 600mg
Arm/Group Description	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. 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.		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. 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.		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. 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.
All Cause Mortality
	Placebo		Ibuprofen, 200mg		Ibuprofen, 600mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Ibuprofen, 200mg		Ibuprofen, 600mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Ibuprofen, 200mg		Ibuprofen, 600mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.