Abstracts

Rationale: Higher doses of topiramate (TPM) have been associated with neuropsychological impairment in epilepsy patients and in healthy volunteers. Whether neuropsychological impairment emerges in a dose-dependent fashion, and at what dosing levels neuropsychological impairments begin to emerge, have not yet been established, and the full spectrum of dose effects is not known. Dose effects are important since lower TPM doses than originally recommended are increasingly being used to treat epilepsy, particularly in monotherapy, and in migraine prophylaxis.Methods: 183 cognitively normal adults ranging in age from 18-75 years participated in a double-blind, placebo-controlled, parallel group, dose-ranging study that was 24 weeks in duration. The main goal of the study was to examine TPM dose effects on weight in obese patients, but here we report neuropsychological test results that were obtained in a subset of subjects (74% of 248 study completers). Dosing was initiated at 16 mg bid, and increased to target doses of 64, 96, 192, or 384 mg per day in weekly increments of 32 mg/day. Neuropsychological function was assessed using the Computerized Neuropsychological Test Battery (CNTB). Subjects were tested neuropsychologically at baseline and 6, 12, and 24 weeks after entering the trial.Results: There were no significant TPM effects at 64 mg for any of the CNTB subtests relative to placebo. Likewise, the summary score for the patients receiving 96 mg at 24 weeks did not differ significantly from placebo, although this group did perform more poorly on a visual memory task. Additional significant TPM effects were noted for the 192 mg and 384 mg dosages. At 192 mg, additional differences from placebo included paired association with delayed recall and simple reaction time. At 384 mg, additional effects were observed on word list learning with delayed recall and choice reaction time. No statistically significant effects on the CNTB were evident in the 64 mg condition at six weeks, and those effects noted in the 96 mg group at six weeks improved significantly by twelve weeks suggesting habituation. In contrast, response habituation was not evident in the 192 mg or 384 mg groups. Significant performance improvements were present for all groups with the exception of 384 mg at the 12 to 24 week assessments. Proportions of subjects demonstrating cognitive impairment varied by dose.Conclusions: This study in cognitively normal individuals indicates that the neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Low dosages did not lead to a significant change in overall cognitive function in subjects who completed the study. With the exception of subjects in the highest dose group (384 mg/day), the majority of cognitive side effects improved during and after the titration. Further studies will help to better understand if there are individual patient characteristics that would be predictors of TPM-induced neuropsychological side effects, and which of the multiple modes of action of the drug is mainly responsible for the unique cognitive profile.