Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes
Condition: Healthy
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this research is to determine if patients who receive phenytoin (also commonly
      known as Dilantin) before taking corticosteroids will show less memory impairment and
      hypomanic symptoms (feelings of agitation, overexcitement or hyperactivity) than those
      receiving placebo (an inactive substance). This research also seeks to determine if patients
      taking phenytoin before corticosteroids show more activity in the area of the brain involved
      with memory than those receiving placebo.

      This research is being done because increased levels of cortisol (the body's natural
      corticosteroid) in the body are frequently associated with forgetfulness, and interventions
      that may prevent or reverse this effect are of great importance.
    

Detailed description: 
      Introduction and aims: Stress and corticosteroid exposure are associated with changes in the
      human and animal hippocampus. In animals, phenytoin prevents dendritic changes in the
      hippocampus secondary to corticosterone. We propose to use functional magnetic resonance
      imaging (fMRI) to explore the effects of 3-days of exposure to placebo, hydrocortisone,
      phenytoin and hydrocortisone plus phenytoin on hippocampal activation. If phenytoin
      attenuates the effects of hydrocortisone, we will use this model system to explore other
      potential neuroprotective agents

      CONCISE SUMMARY OF PROJECT: Sixteen healthy participants will, in a one-hour imaging session,
      receive a structural magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS)
      and fMRI scan four separate times with a 21 day washout between each study drug exposure in a
      crossover design. Prior to each scan each participant will receive placebo + placebo,
      phenytoin + placebo, hydrocortisone + placebo, or hydrocortisone + phenytoin in a random
      fashion. Thus, each participant will receive each of the four possible study drug
      combinations in a random order with an extended drug washout between each exposure.
      Hippocampal activation, volume and biochemistry, as well as mood and memory will be assessed.
      The figure in Appendix I illustrates the study design.

      All participants will complete a University of Texas (UT) Southwestern (UTSW) Institutional
      Review Board (IRB) approved informed consent process and give written consent to participate
      prior to study entry.

      At the first screening visit, demographic information and a complete medical and psychiatric
      history will be obtained. The Structured Clinical Interview for DSM-IV (SCID) (First et al
      1995) will be used to rule out exclusionary psychiatric illnesses. Mood will be assessed with
      the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and
      Activation (ACT) subscale of the ISS. Cognition will be assessed with the Rey Auditory Verbal
      Learning Test (RAVLT) (declarative memory-hippocampus), Digit Span Backwards, and two
      computer tests - the Sternberg Memory Task (SMT, declarative memory-hippocampus) (Sternberg
      1969), and Running Memory Continuous Performance Task (RMCPT, working memory-prefrontal
      cortex) (Baddeley 1986). Alternative versions of the tests will be used throughout the study
      to minimize any learning effects. For subjects who successfully pass the screening, fMRI
      sessions will be scheduled, and they will be asked to return 4 days prior to their first
      scan. If subjects feel uncomfortable answering any questions on the questionnaires during
      their screening visit, they can refuse to do so, and they will be removed from the study. If
      any psychological disorders are diagnosed at this stage (e.g., mood disorders such as
      depression), subjects will be removed from the study and referred either to Parkland hospital
      or to a private psychiatrist based on their insurance coverage for further evaluations and
      treatment. If at a later stage any abnormalities are uncovered through imaging, subjects will
      be notified immediately. Subjects will be provided with a referral to either Parkland
      Hospital or a different facility based on their insurance coverage. With the subject's
      consent, we will also notify their primary physician. Pregnancy tests will be obtained for
      females at baseline and prior to the start of each new medication cycle to ensure that no
      pregnant women are participating in the study (5 times total during the study).

      One day prior to each study drug course, mood will be assessed with HRSD, YMRS, and ACT
      subscale of Internal State Scale, and cognition will be assessed with the Sternberg Memory
      Task.

      Three days prior to imaging, participants will take two capsules containing phenytoin tablets
      (100 mg) or identical placebo by mouth at 0900 hours and 2100 hours (400 mg/day) for a total
      of three days with the last dose at 0900 hours on the day of the imaging (7 doses total).
      Beginning two days prior to the imaging (the day after initiating the phenytoin or placebo),
      participants will begin taking 4 tablets containing hydrocortisone (20 mg) or placebo also at
      0900 hours and 2100 hours (160 mg/day) with the last dose at 0900 hours on the day of the
      imaging (5 doses total). The doses were selected to achieve a low therapeutic blood level of
      phenytoin and stress level of cortisol. Newcomer et al. (1999) used this dose of
      hydrocortisone in healthy controls. The imaging will be performed at approximately 1300
      hours.

      Imaging will be performed after each three day exposure to study medications. Mood
      assessments and the SMT will be conducted at baseline and prior to and after each course of
      study medication (day medication course begins and on the day of the neuroimaging). The SMT
      has a large number of equivalent versions and thus can be administered numerous times. By
      administering prior to each exposure to study drug we can determine whether or not memory
      will, as expected, have returned to baseline after each washout period. Other cognitive
      testing including the RAVLT, Digits Backwards, and RMCPT will be performed after each course
      of study medication. Cognitive testing is not performed prior to receiving the study
      medication to avoid multiple testing over a short period of time which is unnecessary given
      the baseline and placebo data which can be used for comparison.

      Monitoring study drug levels: Blood will be drawn at baseline (approximately 1400 hours) to
      assess cortisol levels. Blood will be drawn after each scan (approximately 1400 hours) to
      assess cortisol and phenytoin levels and to ensure adherence to the medications. We
      anticipate an increase in cortisol levels following administration of cortisol compared to
      baseline in subjects taking cortisol, and that therapeutic levels of phenytoin for seizures
      (10 to 20 mg/l) will be achieved.
    

Intervention name(s): Phenytoin (brand name Dilantin); Hydrocortisone; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Three days prior to imaging, participants will take two capsules containing phenytoin tablets (100 mg) by mouth at 0900 hours and 2100 hours (400 mg/day) for a total of three days with the last dose at 0900 hours on the day of the imaging (7 doses total).; Beginning two days prior to the imaging (the day after initiating the phenytoin or placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) or placebo also at 0900 hours and 2100 hours (160 mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The doses were selected to achieve a low therapeutic blood level of phenytoin and stress level of cortisol. Newcomer et al. (1999) used this dose of hydrocortisone in healthy controls. The imaging will be performed at approximately 1300 hours.; Participants take two capsules of placebo 100 mg at 0900 hours and 2100 hours for a total of 3 days with the last dose at 0900 hours on the day of imaging (7 doses total). Beginning two days prior to the imaging (the day after initiating placebo), participants will being taking 4 tablets containing placebo (20 mg) also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total).
Other intervention name(s): 5,5-Diphenylhydantoin; Fenitoin; Antisacer; Difenin; Dihydan; Dilantin; Diphenylhydantoin; Epamin; Hydantol; Sodium Diphenylhydantoinate; Cortef; Corticosteroids; Sugar pill
Intervention MeSH terms: Hydrocortisone; Phenytoin
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Phenytoin; Dilantin; Corticosteroid; Neuroprotection; Mania; Cognition; Mood; Memory; Hydrocortisone; Healthy Controls; MRI; hippocampal activation