Study of Ibuprofen Effects on Brain Function
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Ibuprofen
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Placebo
Intervention MeSH terms: Ibuprofen
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science