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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Four Treatments Per Participant | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Phenytoin (brand name Dilantin) | Drug | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in RAVLT Total T-Score 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. | At end of each treatment condition (on average 21 days between treatments) |
| Measure | Description | Time Frame |
|---|---|---|
| Hippocampal Activation Differences Between Treatment Conditions | At the end of each treatment condition | |
| Para-Hippocampal Activation Differences Between Treatment Conditions | At the end of each treatment condition |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sherwood Brown, M.D.,Ph.D. | UT Southwestern Medical Center of Dallas | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UT Southwestern Medical Center of Dallas/Parkland Memorial Hospital | Dallas | Texas | 75390-8849 | United States |
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.
Enrollment began 3/11/2008 and was completed 4/23/2009. Subjects were recruited through flyers posted at UTSW medical clinics.
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| ID | Title | Description |
|---|---|---|
| FG000 | PH + PL Then PL + H Then PL + H Then PL + PL | 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. |
| FG001 | PH + H Then PH + PL Then PL + H Then PL + PL | 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. |
| FG002 | PL + PL Then PH + PL Then PH + H Then PL + H | 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. |
| FG003 | PL + H Then PL + PL Then PH + PL Then PH + H | 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. |
| FG004 | PL + H Then PH + PL Then PL + PL Then PH + H | 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. |
| FG005 | PL + H Then PL + PL Then PH + H Then PH + PL | 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. |
| FG006 | PL + H Then PH +H Then PH + PL Then PL + PL | 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. |
| FG007 | PL + H Then PH + H Then PL + PL Then PH + PL | 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. |
| FG008 | PL + H Then PH + PL Then PH + H Then PL + PL | 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. |
| FG009 | PH + H Then PL + H Then PL + PL Then PH + PL | 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. |
| FG010 | PH + H Then PL + H Then PH + PL Then PL + PL | 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. |
| FG011 | PH + H Then PH + PL Then PL + PL Then PL + H | 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. |
| FG012 | PH + H Then PL + PL Then PH + PL Then PL + H | 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. |
| FG013 | PH + H Then PL + PL Then PL + H Then PH + PL | 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. |
| FG014 | PH + PL Then PL + PL Then PH + H Then PL + H | 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. |
| FG015 | PH + PL Then PL + PL Then PL + H Then PH + H | 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. |
| FG016 | PH + PL Then PH + H Then PL + PL Then PL + H | 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. |
| FG017 | PH + PL Then PH + H Then PL + H Then PL + PL | 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. |
| FG018 | PL + PL Then PH + PL Then PL + H Then PH + H | 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. |
| FG019 | PL + PL Then PH + H Then PH + PL Then PL + H | 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. |
| FG020 | PL + PL Then PL + H Then PH + PL Then PH + H | 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. |
| FG021 | PL + PL Then PL + H Then PH + H Then PH + PL | 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. |
| FG022 | PL + PL Then PH + H Then PL + H Then PH + PL | 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. |
| FG023 | PH + PL Then PL + H Then PL + PL Then PH + H | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Total Study Population | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Difference in RAVLT Total T-Score 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. | Posted | Mean | Standard Error | T-score | At end of each treatment condition (on average 21 days between treatments) |
|
Throughout entirety of trial
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Phenytoin, Then Hydrocortisone | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| MRI anxiety | General disorders | Non-systematic Assessment | Physical symptoms manifesting from stress of MRI scan during scan (e.g. difficulty breathing, sweating, tremors, disorientation, etc.) |
Not provided
The sample size in this pilot study was modest; The duration of exposure to hydrocortisone was subacute;
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| E. Sherwood Brown | The University of Texas Southwestern Medical Center | 214 645 6950 | sherwood.brown@utsouthwestern.edu |
Not provided
| ID | Term |
|---|---|
| D000087122 | Mania |
| ID | Term |
|---|---|
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D010672 | Phenytoin |
| D006854 | Hydrocortisone |
| D000305 | Adrenal Cortex Hormones |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D006827 | Hydantoins |
| D048289 | Imidazolidines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
|
| Hydrocortisone | Drug | 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. |
|
|
| Placebo | Drug | 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). |
|
|
| Adverse Event |
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Examining all participants for the condition in which they took placebo for both administrations.
| OG002 | Phenytoin&Placebo | Examining all participants for the condition in which they took phenytoin and placebo. |
| OG003 | Placebo&Hydrocortisone | Examining all participants for the condition in which they took placebo and hydrocortisone. |
|
|
|
| Secondary | Hippocampal Activation Differences Between Treatment Conditions | Posted | Mean | Standard Deviation | percentage of BOLD activation | At the end of each treatment condition |
|
|
|
|
| Secondary | Para-Hippocampal Activation Differences Between Treatment Conditions | Posted | Mean | Standard Deviation | percentage of BOLD activation | At the end of each treatment condition |
|
|
|
|
| 1 |
| 16 |
| 0 |
| 16 |
| EG001 | Phenytoin, Then Placebo | 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. | 0 | 16 | 0 | 16 |
| EG002 | Placebo, Then Hydrocortisone | 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. | 1 | 14 | 0 | 14 |
| EG003 | Placebo, Then Placebo | 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. | 0 | 15 | 0 | 15 |
|
| Pre-existing condition discovered during MRI | Nervous system disorders | Non-systematic Assessment | Mega cisterna magna discovered at initial MRI. Determined to be benign. |
|
Not provided
Not provided
| D013568 | Pathological Conditions, Signs and Symptoms |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
| D002241 | Carbohydrates |
| 2-Sided |
| No |
| Superiority or Other |
| Mixed Models Analysis | <.01 | 2-Sided | No | Superiority or Other |
| Mixed Models Analysis | .02 | 2-Sided | No | Superiority or Other |
| 2-Sided |
| No |
| Superiority or Other |
| Mixed Models Analysis | .11 | 2-Sided | No | Superiority or Other |
| Mixed Models Analysis | .06 | 2-Sided | No | Superiority or Other |