Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor.
Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC.
Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations.
We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.
From the *Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN;
†Department of Biomedical Engineering, University of Florida, Gainesville, FL; and
‡Division of Biostatistics, University of Minnesota, Minneapolis, MN.
Received March 16, 2018; accepted after revision July 10, 2018.
This work was funded by NIH NINDS R01 NS076665 (principal investigator S.E.M.).
Reprints: Christopher M. Barkley, PhD, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St, Minneapolis, MN 55455 (e-mail: firstname.lastname@example.org).