title: Topiramate dose effects on cognition: a randomized double-blind study.
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.
authors.affiliation: Department of Neurology, Emory University, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA. dloring@emory.edu
authors.forename: D W
authors.initials: DW
authors.lastname: Loring
authors.forename: D J
authors.initials: DJ
authors.lastname: Williamson
authors.forename: K J
authors.initials: KJ
authors.lastname: Meador
authors.forename: F
authors.initials: F
authors.lastname: Wiegand
authors.forename: J
authors.initials: J
authors.lastname: Hulihan
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects*; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D013997:Time Factors; D000077236:Topiramate; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose