In this study, we have administered topiramate to a cohort of healthy controls and measured how it affects their cognition. We have found that topiramate plasma concentrations vary widely among individuals after an acute oral dose and that these plasma levels explain much of the variation in cognitive response to topiramate. However, no genetic variants were significantly associated with the phenotypes studied.
We used retest data from controls to establish the expected changes in the test scores of those who took topiramate; we then calculated cognitive response outcomes for each measure in our cognitive battery based on this expectation, controlling for practice effects and the influence of demographics on change. We found that all tests in this battery were significantly affected by having taken topiramate except for Stroop Color-Word. Previous studies had shown that Stroop Color-Word was not affected by topiramate (for example, (Salinsky, et al. 2005
)), so this result was expected. For the tests that were affected by topiramate, plasma topiramate levels were always the most important predictor of the magnitude of the effect. This result was interesting as it is known that the majority of topiramate is excreted unmetabolized, and previous studies have not reported large differences in absorption rates or drug distribution (for example, (Perucca 1997
Although previous studies have shown that topiramate affects some of the tests studied here, few have examined the variables that might influence such a response. We have shown that after accounting for the effect of plamsa levels, there are some variables that impact change scores: ethnicity, native language, BDI, weight, certain testing strategies, days between test sessions, whether it was the third testing session, and time between drug administration and testing (). However, the effects of these variables were small and test-specific. Interestingly, we found no variables with a consistent effect on the change scores for all or even most tests, and we found no effect of age, gender or education. There has been some evidence that individuals with learning disabilities are less likely to complain of adverse side effects of topiramate(Lhatoo, et al. 2000
). In our study, we did not include individuals with learning disabilities, but a linear regression that corrected for native language and topiramate plasma levels showed no relationship between initial PC1, our proxy for baseline cognition, and ChangePC1 (p=0.31).
A study design such as the one utilized here allows for the collection of a large cohort of subjects that have been given both topiramate and a battery of cognitive tests in a standardized manner. The current study was under-powered to detect the effects of genetic variants, with only 80% power to detect a common variant explaining 25% of the variation in ChangePC1 (19% of the variation if restricted to candidate genes). However, the quantitative cognitive phenotype assessed here, unclouded by disease conditions, would allow for a powerful study if a larger number of subjects were assessed. Such a study would facilitate the identification of genetic variants that influence one’s cognitive response to topiramate. This would immediately be of practical importance, as doctors could selectively prescribe topiramate to patients who are unlikely to have cognitive side effects. More broadly, understanding what genes mediate the specific cognitive effects of topiramate would also allow a deeper understanding of how those specific cognitive processes are controlled.