title: A randomized, placebo-controlled proof-of-concept, crossover trial of phenytoin for hydrocortisone-induced declarative memory changes.
abstract: BACKGROUND
  Corticosteroid excess is associated with declarative memory impairment and hippocampal atrophy. These findings are clinically important because approximately 1% of the population receives prescription corticosteroids at any time, and major depressive disorder is associated with elevated cortisol levels and hippocampal atrophy. In animals, hippocampal changes with corticosteroids are blocked by phenytoin. The objective of the current study was to extend these preclinical findings to humans. We examined whether phenytoin attenuated the effects of hydrocortisone on declarative memory. Functional magnetic resonance imaging (fMRI) assessed task-related hippocampal activation.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in 17 healthy adult volunteers. Participants received hydrocortisone (2.5 days), phenytoin (3.5 days), both medications together, or placebo, with 21-day washouts between conditions. Differences between treatments were estimated using a mixed-effects repeated measures analysis.
  
  
  RESULTS
  Fifteen participants had data from at least two treatment conditions and were used in the analysis. Basal cortisol levels negatively correlated with fMRI BOLD activation in the para-hippocampus with a similar trend observed in the hippocampus. Decrease in declarative memory with hydrocortisone was blocked with concomitant phenytoin administration. Relative to the placebo condition, a significant decrease in hippocampal BOLD activation was observed with hydrocortisone and phenytoin alone, and the two medications in combination. Declarative memory did not show significant correlations with hippocampal activation.
  
  
  CONCLUSIONS
  The modest sample size, which limited our statistical power, was a limitation.
  
  
  CONCLUSIONS
  Findings from this pilot study suggest phenytoin attenuated effects of corticosteroids memory in humans, but potentiated the reduction in hippocampal activation.
authors: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8849, USA. sherwood.brown@UTSouthwestern.edu
authors: E Sherwood
authors: ES
authors: Brown
authors: Hanzhang
authors: H
authors: Lu
authors: Daren
authors: D
authors: Denniston
authors: Jinsoo
authors: J
authors: Uh
authors: Binu P
authors: BP
authors: Thomas
authors: Thomas J
authors: TJ
authors: Carmody
authors: Richard J
authors: RJ
authors: Auchus
authors: Ramon
authors: R
authors: Diaz-Arrastia
authors: Carol
authors: C
authors: Tamminga
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001284:Atrophy; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D006854:Hydrocortisone / Q000009:adverse effects* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin; D006854:Hydrocortisone
keywords: Anticonvulsant; Cognition; Corticosteroid; Hippocampus; fMRI