TY - JOUR
T1 - A randomized, placebo-controlled proof-of-concept, crossover trial of phenytoin for hydrocortisone-induced declarative memory changes
AU - Brown, E. Sherwood
AU - Lu, Hanzhang
AU - Denniston, Daren
AU - Uh, Jinsoo
AU - Thomas, Binu P.
AU - Carmody, Thomas J.
AU - Auchus, Richard J.
AU - Diaz-Arrastia, Ramon
AU - Tamminga, Carol
N1 - Funding Information:
Dr. Auchus reports research support from NIGMS, the Burroughs-Wellcome Fund, the Thrasher Foundation, the American Cancer Society, and the Partnership for Clean Competition; he participates in contracted research with Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Corcept Therapeutics; he is or was a paid consultant for Janssen Pharmaceuticals/Johnson & Johnson, Viamet Pharmaceuticals, Orphagen Pharmaceuticals, Bristol-Myers Squibb, and BioMarin Pharmaceuticals.
Funding Information:
Financial Support: Funded by NIH grant MH078182 to ESB and MH084021 to HL.
PY - 2013/9/5
Y1 - 2013/9/5
N2 - 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. Limitations: 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.
AB - 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. Limitations: 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.
KW - Anticonvulsant
KW - Cognition
KW - Corticosteroid
KW - Hippocampus
KW - fMRI
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U2 - 10.1016/j.jad.2013.01.038
DO - 10.1016/j.jad.2013.01.038
M3 - Article
C2 - 23453674
AN - SCOPUS:84882897780
SN - 0165-0327
VL - 150
SP - 551
EP - 558
JO - Journal of Affective Disorders
JF - Journal of Affective Disorders
IS - 2
ER -