Mechanisms of neurodevelopmental toxicity of topiramate

Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate on the neuromolecular mechanisms by which prenatal exposure may perturb neurocognitive development. Specifically, we explore the potential role of topiramate's pharmacological interactions with ligand- and voltage-gated ion channels, especially GABAergic signaling, its effects on DNA methylation and histone acetylation, whether topiramate induces oxidative stress, and its association with fetal growth restriction as possible mechanisms contributing to neurodevelopmental toxicity. Resolving this biology will be necessary to reduce the risk of adverse pregnancy outcomes caused by topiramate or other ASMs.