Preclinical development of antiepileptic drugs: past, present, and future directions

Since 1993, nine new antiepileptic drugs (AEDs) have been introduced into the U.S. market for the symptomatic treatment of partial epilepsy. Their antiepileptic activity was, for the most part, defined by acute seizure models such as the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) seizure tests and the kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage the patient with refractory seizures. In recent years, a number of in vivo and in vitro models have been developed that display varying degrees of pharmacoresistance. As such, they may provide a unique opportunity for identifying the truly novel AED. Through a greater understanding of the pathophysiology of acquired epilepsy at the molecular and genetic level, it may be possible to identify a new therapeutic approach that reaches beyond the symptomatic treatment of epilepsy to modify the progression, or, dare we suggest, prevent the development of epilepsy in the susceptible patient. The realization of such a possibility will necessitate a change in our current AED discovery approach. The present review describes the current approach used in the search for new AEDs and offers some insight into future directions incorporating new and emerging models of therapy resistance and epileptogenesis.