Topiramate dose effects on cognition

• Authors: David W Loring, Emory University; D.J. Williamson, Johnson & Johnson Pharmaceutical Services; Kim J Meador, Emory University; F. Wiegand, Johnson & Johnson Pharmaceutical Services; J. Hulihan, Ortho-McNeil Janssen Scientific Affairs, LLC
• Journal Title: Neurology
• Volume: Volume 76, Number 2
• Publisher: Lippincott Williams & Wilkins | 2011-01-11, Pages 131-137
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1212/WNL.0b013e318206ca02
• Subjects: Biology, Neuroscience

Abstract

Background: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. Objective: To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). Methods: Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. Results: Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. Conclusions: Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk. Classification of evidence: This study provides Class II evidence that TPM-induced cognitive impairment is dose-dependent with statistically significant effects at 192 mg/day (p < 0.01) and 384 mg/day (p < 0.0001).