Antiepileptic drug discovery: does mechanism of action matter?

This commentary discusses briefly the role of the mechanism of antiepileptic action in discovery of drugs for the treatment of epilepsy. More specifically, two questions are addressed. (1) Has mechanism-driven antiepileptic drug discovery brought us better epilepsy treatment? Although this question is difficult to answer, the short answer is "not yet." Modern antiepileptic drugs with new or modified mechanisms of action do not seem to have substantially improved the efficacy or the safety of epilepsy treatment. In fact, some modern antiepileptic drugs such as progabide, tiagabine, and vigabatrin have been associated with a number of safety issues. (2) Why do drugs with new mechanisms seem to have failed to deliver better treatment? Although it is always difficult to know why something did not occur, one putative explanation may be worthwhile to consider. The past development of new antiepileptic drugs targeted putative mechanisms of seizure generation. As seizures are only symptoms of the underlying epilepsy, blocking seizure generation can provide at best only symptomatic treatment. It may be that the failure in treating drug-resistant seizures is related, at least in part, to the failure of current drugs in targeting the mechanisms underlying epilepsy. In conclusion, continuing to develop new antiepileptic drugs for drug-resistant epilepsy by targeting seizure generation may be futile and one possible explanation of why we do not seem to make substantial progress in the treatment of drug-resistant epilepsy. Developing antiepileptic drugs with antiepileptogenic activity may be a clue to better treatment of presently drug-resistant epilepsy.