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Author Notes:

Address correspondence and reprint requests to Dr. David W. Loring, Department of Neurology, Emory University, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322dloring@emory.edu

Study funding: Funding for the original TPM obesity trial (Study ID NCT00236613) was provided by Johnson & Johnson Pharmaceutical Research & Development, LLC. Post hoc analyses were conducted under the direction of JJPRD statisticians (Steve Ascher and C.V. Damaraju).

Subject:

Research Funding:

Dr. Loring serves/has served on scientific advisory boards for the Epilepsy Foundation and Sanofi-Aventis; serves as a consulting editor for the Journal of Clinical and Experimental Neuropsychology, as contributing editor for Epilepsy Currents, and on the editorial board of Neuropsychology Review; serves as a consultant for NeuroPace, Inc., Sanofi-Aventis, and UCB; receives royalties from the publication of Neuropsychological Assessment, 4th ed. (Oxford University Press, 2004) and INS Dictionary of Neuropsychology (Oxford University Press, 1999); estimates that 50% of his clinical effort involves neuropsychological testing; and receives research support from NeuroPace, Inc., SAM Technology Inc., Myriad Pharmaceuticals, Inc., Novartis, the NIH/NINDS, and the Epilepsy Foundation. Dr. Williamson is a salaried employee of Ortho-McNeil Janssen Scientific Affairs, LLC; and receives stock and stock options from Johnson & Johnson, parent company of Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Meador serves on the editorial boards of Neurology and Behavior & Neurology, Epilepsy and Behavior, Epilepsy Currents, Epilepsy.com, and the Journal of Clinical Neurophysiology and on the Professional Advisory Board for the Epilepsy Foundation; received travel support from Sanofi-Aventis; and received research support from GlaxoSmithKline, Eisai Inc., Marinus Pharmaceuticals, Inc., Myriad Genetics, Inc., NeuroPace, Inc., Pfizer, SAM Technology Inc., Schwartz Pharma (UCB), the NIH/NINDS, and the Epilepsy Foundation. Dr. Wiegand is a salaried employee of Johnson & Johnson Pharmaceutical Services LLC. Dr. Hulihan is a salaried employee of Ortho-McNeil Janssen Scientific Affairs, LLC; and receives stock and stock options from Johnson & Johnson, parent company of Ortho-McNeil Janssen Scientific Affairs, LLC.

Topiramate dose effects on cognition

Tools:

Journal Title:

Neurology

Volume:

Volume 76, Number 2

Publisher:

, Pages 131-137

Type of Work:

Article | Post-print: After Peer Review

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).

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