NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 1 NEWS & VIEWS EPILEPSY Perampanel—new promise for refractory epilepsy? Wolfgang Löscher and Dieter Schmidt Three recent phase III trials have shown that adjunctive treatment with perampanel—a irst-in-class, noncompetitive AMPA antagonist —decreases seizure frequency in patients with refractory focal epilepsy. Although the introduction of perampanel offers more treatment choice for epilepsy, whether it brings urgently needed clinical beneit over existing drugs remains to be addressed. Löscher, W. & Schmidt, D. Nat. Rev. Neurol. advance online publication 13 November 2012; doi:10.1038/nrneurol.2012.222 Over the past 30 years, 16 new compounds have been approved in the USA or Europe for the treatment of epilepsy, but seizure outcome has not improved substantially. One in three patients with new-onset epilepsy experiences uncontrolled sei- zures. 1 For patients with uncontrolled focal seizures who are treated with adjunc- tive modern antiepileptic drugs, less than 10% achieve remission above those who are given placebo. 2 More-efficacious and better-tolerated antiepileptic drugs are clearly a major unmet need in the treat- ment of uncontrolled focal seizures. With that in mind, perampanel—a drug that has a highly selective mechanism of anti- glutamatergic action (Figure 1)—raises hope for better treatment of refractory epi- lepsy. Indeed, the results of three phase III trials have recently been published, and all report efficacy, safety and acceptable tolerability of perampanel as an adjunctive antiepileptic treatment in patients with uncontrolled seizures. 3–5 Glutamate, the main excitatory neuro- transmitter in the brain, is thought to have a central role in the generation of seizures. Consequently, glutamate receptors, par- ticularly ionotropic N-methyl-d-aspartate (NMDA) receptors and α-amino-3- hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, have long been investigated as therapeutic targets in epi- lepsy. 6 Disappointing clinical results with NMDA antagonists in the 1990s, however, dampened enthusiasm for this approach. 7 Subsequent development and testing of competitive and noncompetitive AMPA antagonists indicated that such drugs may be more effective and tolerable than NMDA antagonists for the treatment of epilepsy, and led to the development of the AMPA antagonist perampanel. 6,8 The AMPA receptor is the predomi- nant mediator of excitatory neurotrans- mission in the brain, being critical to the generation and spread of epileptic activ- ity. 6 Furthermore, AMPA receptors may have a role in epileptogenesis and seizure- induced brain damage. 6 The development of AMPA antagonists is only the second rational strategy (after the development of γ-aminobutyric acid-mimetic drugs such as vigabatrin or tiagabine in the 1980s and 1990s 7 ) that has led to approval of a new antiepileptic drug. Specifically, and unlike the majority of current antiepileptic drugs, which were found or developed after random drug screening, via structural vari- ations of known drugs, or through seren- dipity, the AMPA antagonist drug design strategy was based on the basic mecha- nisms that underlie the generation and propagation of seizures. 1,7 In July 2012, perampanel was granted market authorization by the European Ca 2+ T-type Ca 2+ channel K + KCNQ K + channel AMPA receptor Na + Glutamate Voltage-gated Na + channel Propagated action potential KCNQ K + channel K + Na + Ca 2+ SV2A Also inhibits glial GAT-1 GAT-1 GABA GABA A receptor Cl – Postsynaptic neuron α 2 δ-subunit of Ca 2+ channel Depolarization Vesicular release Inhibitory synapse Excitatory synapse Retigabine Levetiracetam Phenytoin Carbamazepine Oxcarbazepine Eslicarbazepine acetate Lamotrigine Lacosamide Zonisamide Retigabine Perampanel Gabapentin Pregabalin Ethosuximide Benzodiazepines Barbiturates Tiagabine Not illustrated: ■ Vigabatrin GABA degradation and drugs with multiple mechanisms: ■ Valproate GABA turnover, Na + channels, NMDA receptors ■ Topiramate Na + channels, AMPA/kainate receptors, GABA A receptors ■ Felbamate Na + channels, GABA A receptors, NMDA receptors Figure 1 | Mechanisms of action of antiepileptic drugs. Clinically approved antiepileptic drugs such as perampanel display a spectrum of mechanisms of action, with effects on both inhibitory (left- hand side) and excitatory (right-hand side) nerve terminals. Abbreviations: AMPA, α-amino-3- hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GAT-1, sodium- and chloride- dependent GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A. Modified with permission from Macmillan Publishers Ltd © Bialer, M. & White, H. S. Nat. Rev. Drug Discov. 9, 68–82 (2010). © 2012 Macmillan Publishers Limited. All rights reserved