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

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00591006
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arm: 1
• Duration (Months): 18
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Phenytoin (brand name Dilantin); Drug: Hydrocortisone; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Four Treatments Per Participant This study has one arm due to a crossover design. All 17 subjects received 4 treatments: placebo then placebo, phenytoin then placebo, placebo then hydrocortisone, and phenytoin then hydrocortisone. Each treatment was randomly assigned and had a unique sequence out of 24 possible sequences.

Drug: Phenytoin (brand name Dilantin); 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).; Other Names: 5,5-Diphenylhydantoin Fenitoin Antisacer Difenin Dihydan Dilantin Diphenylhydantoin Epamin Hydantol Sodium Diphenylhydantoinate ; Drug: Hydrocortisone; 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.; Other Names: Cortef Corticosteroids ; Drug: Placebo; 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 Names: Sugar pill

Outcome Measures

Primary Outcome Measures

1. Difference in RAVLT Total T-Score Between Treatments [At end of each treatment condition (on average 21 days between treatments)]

   The Rey Auditory Verbal Learning Test (RAVLT) evaluates a wide diversity of functions, including short-term auditory-verbal memory, and retention of information. Test raw scores are converted to T-scores. T-scores have a mean of 30 ± 10 where higher scores are indicative of better verbal memory. Total T-score differences following study treatment interventions are reported.

Secondary Outcome Measures

1. Hippocampal Activation Differences Between Treatment Conditions [At the end of each treatment condition]

2. Para-Hippocampal Activation Differences Between Treatment Conditions [At the end of each treatment condition]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Southwestern Medical Center of Dallas/Parkland Memorial Hospital	Dallas	Texas	United States	75390-8849

Sponsors and Collaborators

• University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Sherwood Brown, M.D.,Ph.D., UT Southwestern Medical Center of Dallas

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Psychoneuroendocrine Research Group Website

Publications

None provided.

• Responsible Party: Sherwood Brown, Professor, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT00591006
• Other Study ID Numbers: 1R21MH078182
• First Posted: Jan 11, 2008
• Last Update Posted: Aug 19, 2015
• Last Verified: Aug 1, 2015

• Keywords provided by Sherwood Brown, Professor, University of Texas Southwestern Medical Center: Phenytoin; Dilantin; Corticosteroid; Neuroprotection; Mania; Cognition; Mood; Memory; Hydrocortisone; Healthy Controls; MRI; hippocampal activation
• Additional relevant MeSH terms: Hydrocortisone; Phenytoin

Study Results

Participant Flow

Recruitment Details	Enrollment began 3/11/2008 and was completed 4/23/2009. Subjects were recruited through flyers posted at UTSW medical clinics.
Pre-assignment Detail	Subjects were enrolled and randomized to one out of 4 treatments. The study design is a 4-phase crossover study, meaning all subjects received all four treatments during the course of the study. Subjects washed out of each medication cycle for 21 days before beginning the next treatment cycle. Total number of subjects enrolled is 17.

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Arm/Group Description	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400 mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by hydrocortisone (160 mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400 mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone 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 imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours (20mg) and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing hydrocortisone also at 0900 hours and 2100 hours (160mg/day) with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by placebo. The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take phenytoin (400mg/day) followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing placebo tablets by mouth at 0900 hours and 2100 hours for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking phenytoin tablets (400mg/day) followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by hydrocortisone. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by placebo. The imaging will be performed at 1300 hours.	Participants take two capsules containing phenytoin tablets by mouth at 0900 hours and 2100 hours (400 mg/day) for three days with the last dose at 0900 hours on the day of the imaging (7 doses total). Two days prior to the imaging (the day after initiating the phenytoin), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will repeat this cycle, instead taking placebo tablets followed by hydrocortisone (160mg/day). The imaging will be performed at 1300 hours and participants washout for 21 days. Participants then take placebo followed by placebo. The imaging will be performed at 1300 hours. Participants washout for 21 days. Participants will then take phenytoin followed by hydrocortisone. The imaging will be performed at 1300 hours.
Period Title: Overall Study
STARTED	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	1	0	1	0	1	0	1	1	1
Treatment #2	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	1	1
Treatment #3	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	1	1
Treatment #4	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	0	0
COMPLETED	1	0	1	1	1	0	1	0	1	1	0	1	1	2	0	0	0	1	0	1	0	1	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1	1

Baseline Characteristics

Arm/Group Title	Total Study Population
Arm/Group Description	Seventeen healthy controls, in a one-hour imaging session, received a structural MRI, 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 received placebo + placebo, phenytoin + placebo, hydrocortisone + placebo, or hydrocortisone + phenytoin in a random fashion. Thus, each participant received 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 was assessed.
Overall Participants	17
Age (Count of Participants)
<=18 years	2 11.8%
Between 18 and 65 years	15 88.2%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.1 (9.6)
Sex: Female, Male (Count of Participants)
Female	9 52.9%
Male	8 47.1%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Difference in RAVLT Total T-Score Between Treatments
Description	The Rey Auditory Verbal Learning Test (RAVLT) evaluates a wide diversity of functions, including short-term auditory-verbal memory, and retention of information. Test raw scores are converted to T-scores. T-scores have a mean of 30 ± 10 where higher scores are indicative of better verbal memory. Total T-score differences following study treatment interventions are reported.
Time Frame	At end of each treatment condition (on average 21 days between treatments)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin&Hydrocortisone	Placebo&Placebo	Phenytoin&Placebo	Placebo&Hydrocortisone
Arm/Group Description	Examining all participants for the condition in which they took both phenytoin and hydrocortisone.	Examining all participants for the condition in which they took placebo for both administrations.	Examining all participants for the condition in which they took phenytoin and placebo.	Examining all participants for the condition in which they took placebo and hydrocortisone.
Measure Participants	15	16	16	15
Mean (Standard Error) [T-score]	57.76 (0.51)	56.11 (0.67)	53.08 (0.45)	42.76 (2.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Hydrocortisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.12
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo&Placebo, Phenytoin&Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.15
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Placebo, Placebo&Hydrocortisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.10
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Hippocampal Activation Differences Between Treatment Conditions
Time Frame	At the end of each treatment condition

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin&Hydrocortisone	PBO&PBO	Phenytoin&PBO	PBO&Hydrocortisone
Arm/Group Description	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), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.	Participants will take two capsules containing 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 placebo), participants will begin taking 4 tablets of 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 imaging will be performed at 1300 hours.	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), participants will begin taking 4 tablets containing 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 imaging will be performed at 1300 hours.	Participants will take two capsules containing 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 placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.
Measure Participants	13	15	15	14
Mean (Standard Deviation) [percentage of BOLD activation]	1.035 (0.180)	1.288 (.06)	1.135 (0.161)	1.121 (0.144)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Hydrocortisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.08
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.01
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo&Placebo, Phenytoin&Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.01
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo&Placebo, Placebo&Hydrocortisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Para-Hippocampal Activation Differences Between Treatment Conditions
Time Frame	At the end of each treatment condition

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenytoin&Hydrocortisone	PBO&PBO	Phenytoin&PBO	PBO&Hydrocortisone
Arm/Group Description	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), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.	Participants will take two capsules containing placebo by mouth at 0900 hours and 2100 hours 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 placebo), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours.	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), participants will begin taking 4 tablets containing placebo also at 0900 hours and 2100 hours with the last dose at 0900 hours on the day of the imaging (5 doses total). The imaging will be performed at 1300 hours.	Participants will take two capsules containing placebo by mouth at 0900 hours and 2100 hours 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 placebo), participants will begin taking 4 tablets containing hydrocortisone (20 mg) 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 imaging will be performed at 1300 hours.
Measure Participants	13	15	15	14
Mean (Standard Deviation) [percentage of BOLD activation]	1.293 (0.264)	1.604 (0.315)	1.464 (0.246)	1.401 (0.202)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Hydrocortisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.08
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phenytoin&Hydrocortisone, Placebo&Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.01
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo&Placebo, Phenytoin&Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.11
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo&Placebo, Placebo&Hydrocortisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.06
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	Throughout entirety of trial
Arm/Group Title	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
Arm/Group Description	Placebo, Placebo Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.		Phenytoin, Placebo Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.		Hydrocortisone, Placebo Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.		Hydrocortisone, Phenytoin Phenytoin, Dilantin : 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 imaging will be performed at 1300 hours.
All Cause Mortality
	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
General disorders
MRI anxiety	0/16 (0%)	0	0/16 (0%)	0	1/14 (7.1%)	1	0/15 (0%)	0
Nervous system disorders
Pre-existing condition discovered during MRI	1/16 (6.3%)	1	0/16 (0%)	0	0/14 (0%)	0	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Phenytoin, Then Hydrocortisone		Phenytoin, Then Placebo		Placebo, Then Hydrocortisone		Placebo, Then Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/14 (0%)		0/15 (0%)

Limitations/Caveats

The sample size in this pilot study was modest; The duration of exposure to hydrocortisone was subacute;

More Information

Certain Agreements

Principal Investigators are NOT 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.