Study of Ibuprofen Effects on Brain Function
| Status: | Completed |
|---|---|
| Conditions: | Depression, Depression, Major Depression Disorder (MDD) |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 2/24/2018 |
| Start Date: | July 2015 |
| End Date: | October 2015 |
Placebo-controlled, Dose-response Study of Ibuprofen Effects on Brain Function
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.
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:
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.
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.
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).
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