Abstracts

Several antiepileptic drugs (AEDs) are known to induce mild to moderate negative cognitive effects in well controlled epilepsy patient and healthy volunteer studies. Using the Awake Maintenance Task (AMT), a novel measure of ability to maintain wakefulness, we showed that as a group, patients using AEDs have increased drowsiness as compared to healthy controls. In the present study we investigated whether drowsiness is an intermediate in the process of AED related cognitive test performance decline., 93 healthy volunteers participated in three randomized, controlled, parallel-group studies examining the effects of AEDs on cognitive abilities and the EEG. AEDs studied included carbamazepine, oxcarbazepine, phenytoin, gabapentin and topiramate (TPM). In all studies there was a gradual 8-10 week titration of the AED, followed by a 2-4 week plateau. At baseline, and at 12-weeks of treatment, all subjects underwent a cognitive test battery and the AMT (a 6-minute EEG based measure of total drowsy time in the eyes closed unstimulated condition, with instruction to remain fully awake). Test-retest cognitive change Z-scores were calculated based on regressions derived from 73 untreated controls. Test-retest changes on the AMT were also compared with 73 controls. Group comparisons were made using the Wilcoxon test., Overall, subjects randomized to AEDs showed a greater increase in AMT drowsiness than did untreated controls (p[lt]0.01). Each AED induced a significant increase in drowsiness (p[lt]0.05) as compared to controls, except for TPM (excluded from further analysis). Using a split-halves approach we compared subjects with greater (Z[lt]-2) vs. lesser (Z[gt]-2) AED induced cognitive decline (N=39 per group). Subjects with greater cognitive decline evidenced a significantly greater increase in AMT drowsiness than did subjects with lesser cognitive effects (p[lt]0.05). This difference was particularly pronounced for subjects with the largest negative cognitive effects (Z[lt]-5; N=14)., These results in healthy volunteers confirm our previous patient observation that several AEDs induce drowsiness on the AMT, and additionally demonstrate an association between AED induced drowsiness and AED induced negative effects on standardized cognitive tests. While this association does not prove causality, it appears likely that drowsiness plays a role in the negative cognitive effects of some AEDs, particularly given the well established effects of drowsiness on cognition in sleep deprivation and sedative-hypnotic studies. TPM, a drug with pronounced cognitive effects is a notable exception to this pattern as it did not induce drowsiness., (Supported by: Funded in part by grants from Pfizer Inc., and Novartis Inc.)