Abstract
Commentary
The study by Gomer et al. did not find that cognitive tasks were influenced by dosage for either TPM or LEV. The authors support their finding by stating that neither Huppertz et al. (7) nor Kockelmann et al. (8) demonstrated a “clear relationship between daily dosage and cognitive side effects.” However, neither of these studies was conclusive in this regard, as they had limitations and reported some dose-dependent adverse events. The investigation by Huppertz et al. was a nonrandomized, open-label study with only 37 patients, and the authors specifically noted that adverse cognitive effects were decreased in a subset of patients whose doses were reduced 25–150 mg/day. The investigation by Kockelmann et al. was a nonrandomized, retrospective, cross-sectional study with just 42 patients, who received neuropsychological testing only once; however, the study did report significant correlations between TPM serum levels and verbal fluency, verbal memory span, as well as verbal memory (delayed recall and recognition). A recent study by Loring et al. examined dose-dependent cognitive effects of TPM in 183 cognitively normal adults, using a double-blind, placebo-controlled, parallel group, dose-ranging study of 24 weeks duration (9). Dosing was initiated at 32 mg (16 mg/bid) and increased to target doses of 64, 96, 192, or 384 mg/day. The investigators found that the neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Thus, the lack of a dosage effect in the Gomer et al. report likely is due to the sample size and other limitations of the study.
Gomer et al. state that Aldenkamp and coworkers: “proposed that gradual introduction of TPM could prevent cognitive side effects.” Aldenkamp et al. actually stated that: “gradual introduction of TPM can reduce the extent of cognitive impairment” (1). Gomer et al. argue against a critical effect of the initial TPM titration, since their study started with a low dose, gradual titration, and testing was carried out under steady-state conditions. The titration rate used in this study was actually twice the recommended rate, and remarkably, there were no dropouts among the 51 consecutive patients, over approximately 4 months and two neuropsychological evaluations. While rapid titration increases the risk of cognitive side effects for virtually all AEDs, these effects are particularly prominent with TPM. For example, an investigation in healthy adults found that an acute dose of TPM at 2.8 mg/kg produces greater cognitive side effects than a slower titration over 4 weeks to a higher dose of 5.7 mg/kg (10).
Gomer et al. also state that: “Loring and Meador ascribed cognitive side effects of TPM to polypharmacy, higher dosages, and blood levels” (11). This sentence does not appear in the referenced article or in any articles by these authors. Indeed, a variety of factors affect the risk of adverse cognitive function by TPM as well as other AEDs, including polypharmacy, higher dosages, higher blood levels, rapid initiation, individual patient susceptibility, and the risk for the specific AEDs (4). Treatment-emergent adverse events, which are centrally mediated, typically are more frequent in adjunctive than monotherapy clinical trials. Dosage and blood level effects on cognition can be difficult to demonstrate within standard therapeutic ranges and may also be obscured if appropriate study design is not employed. Susceptibility to adverse cognitive effects in a patient is due to their individual pharmacokinetic and pharmacodynamic responses. Finally, there are differences across individual AEDs as demonstrated in the present study and prior investigations (4). Clinician awareness of these factors may help to reduce risks of adverse cognitive effects. Drug treatment often requires a balance between the risk of seizures and the risks posed by AEDs—including systemic side effects as well as cognitive function.