Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes

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.

Inclusion Criteria:

- Age 18-50 years

- Men or women

- Vision corrected to at least 20-40

- No tobacco use

- Education of ≥12 years (No GED)

Exclusion Criteria:

- History of major psychiatric illness defined as major depressive disorder, bipolar
disorder, post traumatic stress disorder, panic disorder, schizoaffective disorder,
schizophrenia or eating disorders

- History of drug or alcohol abuse or dependence

- History of neurological disorders including seizures, brain surgery, multiple
sclerosis, Parkinson's disease

- Taking central nervous system (CNS) acting medications (e.g. antidepressants,
hypnotics)

- History of allergic reaction or medical contraindication to phenytoin or
hydrocortisone therapy

- Metal implants, claustrophobia or other contraindications to MRI

- Significant medical conditions (e.g. myocardial infarction, diabetes)

- Pregnant or nursing women

- Prisoners

- History of mental retardation, special education classes, dementia or other severe
cognitive disorders

- Baseline Hamilton Rating Scale for Depression Score > 7

- History of a suicide attempt

- History of systemic corticosteroid use or current inhaled corticosteroid use