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Abstract
This neuroteratology study investigates behavioral outcomes for three commonly used antiepileptic drugs (AEDs) (valproate, carbamazepine, and lamotrigine), with a special emphasis on outcomes indicative of impaired creativity. Background. Rodent studies demonstrate that AEDs induce a proapoptotic effect limited to a developmental period characterized by rapid brain growth and synaptogenesis that, in humans, equates to the third trimester and early postnatal development. Third trimester apoptosis in cortical regions that develop to mediate associative neural activity would be expected to impair associative cognitive processes—associative processes like divergent thinking that comprise the uniquely human capacity for creativity. Hypothesis. Performance on divergent thinking measures will be 0.5–1.0 standard deviation below the normal population for children exposed in utero to AEDs, with the greatest effect seen in children exposed in utero to valproate. Subjects. Prospectively-enrolled mother-child pairs (n=421) from participating neurology departments and epilepsy centers enrolled in the NEAD Study2. Methods. Psychometric assessment of divergent thinking for fluency and originality, and statistical analysis of behavioral measures, dose-effects, and related biological data. Findings. Across monotherapy groups, this population of children had mean fluency of 91.2 (SD=16.0), which is significantly lower than the normal population (p=0.001). This difference is not evident for originality (mean=97.7, SD=15.7). The strongest factor influencing divergent thinking was AED exposure, with reduced scores for valproate subjects in fluency (p=0.003) and originality (p=0.009). Additionally, across monotherapy groups, 39.1% children showed non-right hand preference, which is significantly different from the normal population average of 90% (p=0.0001).
1Total number after excluding phenytoin subjects. 2NINDS RO1: Neurodevelopmental Effects of Antiepileptic Drugs
