Despite advances and optimal current therapy, there remains a continuing need for the development of new agents for patients with epilepsy (1, 2, 3, 4). Among those with epilepsy, 30% to 40% continue to have seizures or experience unacceptable side effects that affect their quality of life (5,6). In a prospective study of 525 patients in a single epilepsy center between 1984 and 1997, only 63% remained seizure free for more than 1 year, with seizure-free rates being similar, regardless of whether a new or an established antiepileptic drug (AED) was used (7). Moreover, the available anticonvulsant agents suppress the symptoms of epilepsy and are not truly antiepileptic or antiepileptogenic in nature. None of these agents have been shown to influence the process of epileptogenesis in humans or to alter the underlying brain dysfunction that expresses itself as epilepsy. An ideal agent would provide complete seizure control without significant side effects or idiosyncratic life-threatening reactions; have simple, predictable pharmacokinetics; be unaffected by other drugs or medical conditions; and be nonteratogenic, affordable, and available in a parenteral formulation. An agent that prevents epilepsy (e.g., after a head injury or stroke) or that alters the underlying mechanisms of a particular epilepsy, or prevents or ameliorates its progression (8), could also be considered to be antiepileptogenic or antiepileptic.

Although nine new agents have been introduced in recent years, with attendant marketing considerations, many novel compounds with promise as useful AEDs are currently in various stages of development (Table 68.1 and Table 68.2). Some of these resulted from the Antiepileptic Drug Development (ADD) Program sponsored by the U. S. National Institutes of Health (9), which has screened more than 24,000 compounds (provided by industry and academia) for potential anticonvulsant efficacy in traditional animal models (9,10). These models have traditionally focused mainly on the maximum electroshock (MES) test and the pentylenetetrazol (PTZ) test, which are believed to predict efficacy against tonic-clonic and absence seizures, respectively (see Chapter 44). Although this approach has identified such agents as topiramate, it does not always recognize potentially useful compounds, predict activity in humans, or test antiepileptogenic potential (11). Newer models, such as pilocarpine, kainate, or electrically induced post-status epilepsy models, are aimed at mimicking human disease and may be better suited to identify useful compounds, but are not effective for high-throughput screening of new chemical entities. Research elucidating the molecular mechanisms underlying some specific epilepsy syndromes, such as benign neonatal convulsions (12) and Unverricht-Lundborg progressive myoclonic epilepsy (13), suggests that targeted therapeutic approaches may prove more successful than mass screening techniques for some of the epilepsies. This may also be true for some of the more common forms of epilepsy, such as juvenile myoclonic epilepsy (14). Despite the limitations of screening methods, promising compounds are in development (15, 16, 17, 18). Some are at a late stage of development (e.g., pregabalin), whereas others are at earlier stages of clinical testing (e.g., safinamide, talampanel). However, not all of these compounds will be approved for use, which is exemplified by the fact that three of the compounds discussed in the prior version of this chapter are no longer in development.

In the previous edition of this textbook, this Chapter discussed 10 anticonvulsant drugs (19). Information on harkoseride, retigabine, rufinamide, and the valproate derivatives has been updated. Zonisamide and levetiracetam, now available, are discussed in Chapters 62 and 63. Pregabalin is discussed along with gabapentin in Chapter 59. Losigamone, remacemide, and soretolide are no longer being developed and are not discussed in this chapter.