Abstracts

Rationale: Differential side-effect profiles of AEDs play an important role in therapeutic decisions for the treatment of epilepsy. Older AEDs, such as carbamazepine (CBZ) are known to produce untoward cognitive effects. The purpose of this study was to formally evaluate the neuropsychological effects of lacosamide (LCM) using validated neuropsychological assessment tools and to compare to CBZ Immediate Release (CBZ-IR). Methods: The neuropsychological effects of LCM (300mg/day) and CBZ-IR (600mg/day) were compared in healthy adults using a randomized, double-blind, double-dummy, two-period crossover design. Cognitive and behavioral assessments were conducted at screening, baseline pre-drug treatment, end of each treatment period (3-week Titration; 3-week Maintenance Period), and end of each washout period (4 weeks) after drug treatment. The primary outcome variable was an overall neuropsychological composite Z-score derived from selected computerized cognitive tests and performance on traditional neuropsychological paper/pencil measures, which assessed attention, processing speed, executive functions, and memory at the end of each 6-week treatment period as well off-drug visits. Other variables included the individual subcomponents of the composite scores. Additional EEG, safety variables, and pharmacokinetic data on LCM, CBZ-IR and their metabolites were collected. Results: 60 adult subjects (56.7% female, mean age 34.4y [SD 10.5]) were randomized and 44 completed both treatment periods. 41 per protocol subjects were included in the primary analysis. Using a Wilcoxon rank sum test, the overall composite Z-score revealed worse effects for CBZ-IR compared to LCM (0.33 [SD 1.36], p = 0.01) in the primary analysis. Absolute Z-score differences compared to the average of non-drug conditions were -0.27 for CBZ-IR and +0.07 for LCM. In secondary analyses across the 16 individual variables, CBZ-IR was statistically worse than LCM in 25% (4/16); none favored CBZ-IR. Raw mean scores for CBZ-IR were worse than LCM on 75% (12/16) of the variables. Adverse events (AEs) were reported in 60.0% of subjects during LCM and 75.4% during CBZ-IR treatment. AEs reported by more than 10% of subjects were headache (10.0%) for LCM versus headache (24.6%) and fatigue (12.3%) for CBZ-IR. Drug related AEs were reported in 22.0% of subjects on LCM and 49.1% on CBZ-IR. Discontinuations due to AEs occurred in 2 subjects during LCM and 8 during CBZ-IR treatment. Conclusions: Using validated neuropsychological assessment tools, LCM 300mg/day monotherapy showed statistically significantly fewer untoward neuropsychological effects than CBZ-IR 600mg/day monotherapy in healthy subjects. Significant differences were observed for verbal memory, processing speed and complex attention. Overall, fewer AEs and AEs leading to discontinuation were observed during LCM than during CBZ-IR treatment.