Severity of Topiramate-Related Working Memory Impairment Is Modulated by Plasma Concentration and Working Memory Capacity

Samuel P. Callisto, Sílvia M. Illamola, Angela K. Birnbaum, Christopher M. Barkley, Sai Praneeth R. Bathena, Ilo E. Leppik, Susan E. Marino

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 μg/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.

Original languageEnglish (US)
Pages (from-to)1166-1176
Number of pages11
JournalJournal of Clinical Pharmacology
Volume60
Issue number9
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
Study sponsored by NINDS R01NS076665 (PI: Marino), NINDS P50NS16308 (PI: Leppik), and the Macmillan Innovation in Epilepsy Research and Education Fund.

Funding Information:
Study sponsored by NINDS R01NS076665 (PI: Marino), NINDS P50NS16308 (PI: Leppik), and the Macmillan Innovation in Epilepsy Research and Education Fund. The authors thank the subjects who participated in this trial, Characterizing and Predicting Drug Effects on Cognition (NCT01889602). Funding for this project was provided by NINDS R01NS076665 awarded to S. E. Marino, NINDS P50NS16308 awarded to I. E. Leppik, and the Macmillan Innovation in Epilepsy Research and Education Fund.

Funding Information:
The authors thank the subjects who participated in this trial, Characterizing and Predicting Drug Effects on Cognition (NCT01889602). Funding for this project was provided by NINDS R01NS076665 awarded to S. E. Marino, NINDS P50NS16308 awarded to I. E. Leppik, and the Macmillan Innovation in Epilepsy Research and Education Fund.

Publisher Copyright:
© 2020, The American College of Clinical Pharmacology

Keywords

  • cognitive impairment
  • modeling
  • pharmacokinetic/pharmacodynamic
  • topiramate
  • working memory

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