Drug development for refractory epilepsy: The past 25 years and beyond.

Despite the exponential growth of approved antiepileptic drugs (AEDs) over the past 25 years, epilepsy remains uncontrolled in approximately a third of patients. This article summarises the clinical trials and properties of the AEDs developed over this period, and reviews the pre-clinical and clinical development paradigms of modern AEDs. We discuss possible reasons for the apparent failure to develop more efficacious compounds. We also review the current regulatory frameworks for drug approval in the United States and Europe, and the changes on the horizon. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning pharmacoresistance and the epilepsies by recent research has enabled a revised approach to the development of more promising therapies. A new era of pharmacological treatment for epilepsy appears imminent. Future research in pharmacotherapy for drug-resistant epilepsy will be advanced through concerted effort between scientists, clinicians, and the industry.