Advertisement

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

  • Ambica Golyala
    Affiliations
    Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia
    Search for articles by this author
  • Patrick Kwan
    Correspondence
    Corresponding author at: Department of Neurology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia. Fax: +61 3 9342 8628.
    Affiliations
    Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia

    Department of Neurology, Royal Melbourne Hospital, Parkville, Australia
    Search for articles by this author
Open ArchivePublished:December 06, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.022

      Abstract

      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.

      Keywords

      1. Introduction

      The mainstay of treatment for epilepsy is pharmacological therapy for seizure control. Driven by the limited efficacy of the established antiepileptic drugs (which generally include carbamazepine, ethosuximide, phenobarbital, phenytoin and valproic acid), antiepileptic drug (AED) development has exploded in the past 25 years (Fig. 1). But despite the release of a new agent almost annually over this period, epilepsy remains uncontrolled in one third of patients [
      • Kwan P.
      • Brodie M.J.
      Early identification of refractory epilepsy.
      ]. Uncontrolled epilepsy is associated with poorer quality of life, increased physical and psychological comorbidities, and increased risk of sudden unexplained death in epilepsy, placing substantial burden on the individuals, carers, and society [
      • Jacoby A.
      • Baker G.A.
      Quality-of-life trajectories in epilepsy: a review of the literature.
      ,
      • Tomson T.
      • Nashef L.
      • Ryvlin P.
      Sudden unexpected death in epilepsy: current knowledge and future directions.
      ].
      Fig. 1
      Fig. 1Chronological development of antiepileptic drugs.
      Adapted from Kwan [
      • Kwan P.
      Refractory epilepsy: natural history and pathogenesis. PhD thesis.
      ]
      This article reviews the pre-clinical and clinical development paradigms of modern AEDs, and summarises the clinical trials and properties of the newer AEDs approved for the treatment of drug-resistant epilepsy over the past 25 years. We discuss possible reasons for the lack of fundamental improvement in treatment efficacy, and provide an overview of promising research directions in pharmacotherapy for drug-resistant epilepsy.

      2. Preclinical drug development paradigms

      Three main approaches have been employed to identify compounds with potential anti-seizure activity: random screening of synthesized chemicals, structural variations of known AEDs, and rational drug development through selective targeting of seizure-inducing mechanisms [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ]. All approaches rely on the preclinical use of animal models to establish safety and efficacy of the investigational compounds prior to human trials. The maximal electric shock (MES) and the subcutaneous pentylenetetrazol (scPTZ) rodent models have traditionally been the first-line models for the discovery of new AEDs. In the MES model, seizures are induced by bilateral trans-auricular or corneal electrical stimulation. The model tends to identify drugs that block generalized tonic-clonic seizures [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ,
      • Toman J.E.
      • Swinyard E.A.
      • Goodman L.S.
      Properties of maximal seizures, and their alteration by anticonvulant drugs and other agents.
      ]. However, several newer AEDs (such as vigabatrin and levetiracetam) with demonstrated efficacy for focal seizures in human epilepsy are ineffective in the MES model. In the scPTZ model, clonic seizures are evoked through subcutaneous administration of convulsant doses of PTZ, which acts as a GABAA receptor antagonist [
      • Loscher W.
      Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs.
      ]. The scPTZ model tends to identify drugs that block generalized non-convulsive (myoclonic, absence) seizures.
      The MES and scPTZ models have proven useful for detecting anti-seizure effects of drugs in healthy rodents, and have provided insight into the pharmacokinetic and pharmacodynamic interactions of potential AEDs [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ]. However, both models can produce false negative results, the notable example being levetiracetam. Importantly, these acute seizure models are not designed to identify compounds which act to inhibit spontaneous seizures or drug-resistant epilepsy [
      • Perucca E.
      • French J.
      • Bialer M.
      Development of new antiepileptic drugs: challenges, incentives, and recent advances.
      ]. These models may also fail to detect potentially efficacious compounds that act via mechanisms not present in these models [
      • Loscher W.
      Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs.
      ]. Since chemicals not effective in these models are excluded from further development, this is of significant concern. The diversity of human epilepsy syndromes poses a need for animal models that more fully capitulate the clinical scenarios.
      To address this need, other animal models have recently been developed to supplement the MES and scPTZ tests [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ]. These include the 6 Hz psychomotor seizure model, phenytoin-resistant kindled rat, lamotrigine kindled-rat, post-status epilepticus models of temporal lobe epilepsy, and the methylazozymethanol (MAM) model [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ]. In particular, the 6 Hz test has been readily adopted in the National Institutes of Health AED discovery program. This model administers low-frequency and long-duration electrical stimulation via corneal electrodes to induce focal seizures [
      • Barton M.E.
      • Klein B.D.
      • Wolf H.H.
      • White H.S.
      Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy.
      ]. It successfully detects the efficacy of levetiracetam, which is ineffective in the MES and scPTZ models [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ]. The kindling model aims to mimic the development of focal epilepsy through repeated applications of subthreshold electrical stimulations to specific brain regions (usually the amygdala or hippocampus) to induce increasingly severe seizure behaviour. It has been noted, however, that AEDs which exhibit high efficacy in the kindling model do not necessarily have higher clinical efficacy in patients with drug-resistant focal seizures.

      3. Limitations of animal models in AED development

      The MES and scPTZ preclinical models have proven useful for identifying various new AEDs, but they have not resulted in the development of AEDs with higher efficacy than established agents in drug-resistant patients. This is likely due to the intrinsic limitations of these models. First, seizure definitions used in experimental animal models are limited to specific convulsive phenotypes and minimum durations, and fail to account for the short non-convulsive seizures often observed in human focal epilepsies. Second, these pre-clinical models were originally validated by the older AEDs, which may explain the failure to identify novel AEDs with better efficacy and tolerability [
      • Bialer M.
      • White H.S.
      Key factors in the discovery and development of new antiepileptic drugs.
      ]. This contributes to the redundancy of “me-too” drugs. Third, the determination of drug efficacy is dependent upon the ability of an investigational drug to inhibit provoked seizures, whereas the seizures in human epilepsy are characteristically unprovoked and originate from a molecular substrate. However, it has been observed that the pharmacology of the provoked seizures in the kindling model and the spontaneous seizures in the post-status epilepticus model is similar, suggesting that the model’s brain alterations may be more important than the method of seizure induction [
      • Loscher W.
      Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs: a comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy.
      ].

      4. Clinical drug development paradigms

      4.1 Adjunctive therapy

      Due to ethical reasons, investigational compounds are initially tested as adjunctive treatment in patients with uncontrolled epilepsy. Similar paradigms have been adopted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical AED development. Generally speaking, a new molecular agent is required to undergo at least two independent studies before regulatory submission can be accepted for approval. Regulatory trials are randomized, double-blind and placebo-controlled, and usually evaluate a number of fixed doses [
      • Ben-Menachem E.
      • Biton V.
      • Jatuzis D.
      • Abou-Khalil B.
      • Doty P.
      • Rudd G.D.
      Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures.
      ]. A Phase III trial typically includes a baseline period, a titration period and a maintenance period. The titration period involves increasing the dose of the drug up to the maximal tolerated dose, or a pre-defined fixed dose, which is maintained for usually 12–16 weeks. Although there is no regulatory guidance regarding forced or flexible dose titration, both the FDA and EMA prefer pre-defined target doses, covering the purportedly minimal effective dose to the maximal tolerated dose [
      • Porter R.J.
      • Baulac M.
      • Nohria V.
      Clinical development of drugs for epilepsy: a review of approaches in the United States and Europe.
      ]. Phase III programs often include an open label extension phase to assess long-term safety and seizure outcomes.
      There are minor differences in the primary efficacy outcome measure accepted by the agencies: the EMA prefers responder rate (percentage of patients with at least 50% reduction in seizure frequency during the treatment phase compared with the baseline), while the FDA requires outcomes to be measured as median percent seizure reduction.
      Table 1 summarizes the phase III clinical trials that evaluated investigational AEDs in the past 25 years. The pharmacological properties of the AEDs approved in this period are provided in Table 2 [
      • Brodie M.J.
      • Kwan P.
      Newer drugs for focal epilepsy in adults.
      ,
      • Brodie M.J.
      • Schachter S.C.
      • Kwan P.
      Fast facts: epilepsy.
      ].
      Table 1Summary of double-blind, randomized phase III trials of antiepileptic drugs for treatment of refractory partial (focal) onset seizures (+/− other seizure types).
      DrugSeizure typeStudy design (number of trials performed)Total population (number of patients in active arm(s))ComparatorPrimary outcome measureReference(s)
      VigabatrinPartial onsetAdjunctive, cross-over (n = 3)n = 23 (n = 23); n = 31 (n = 31); n = 97 (n = 97)PlaceboDecrease in total number of seizures; percent change in mean weekly seizure frequency; monthly seizure rate, calculated for each of the four-week study periods
      • Beran R.G.
      • Berkovic S.F.
      • Buchanan N.
      • Danta G.
      • Mackenzie R.
      • Schapel G.
      • et al.
      A double-blind, placebo-controlled crossover study of vigabatrin 2 g/day and 3 g/day in uncontrolled partial seizures.
      ,
      • Tartara A.
      • Manni R.
      • Galimberti C.A.
      • Hardenberg J.
      • Orwin J.
      • Perucca E.
      Vigabatrin in the treatment of epilepsy: a double-blind, placebo-controlled study.
      ,
      • Tassinari C.A.
      • Michelucci R.
      • Ambrosetto G.
      • Salvi F.
      Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy.
      Adjunctive (n = 1)n = 111 (n = 58)PlaceboDecrease in median monthly seizure frequency
      • Bruni J.
      • Guberman A.
      • Vachon L.
      • Desforges C.
      Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.
      LamotriginePartial onsetImmediate release (n = 1)n = 156 (n = 76)Low-dose VPAProportion of patients meeting exit criteria
      • Gilliam F.
      • Vazquez B.
      • Sackellares J.C.
      • Chang G.Y.
      • Messenheimer J.
      • Nyberg J.
      • et al.
      An active-control trial of lamotrigine monotherapy for partial seizures.
      Idiopathic generalized, mixed seizure typesAdjunctive, cross over (n = 1)n = 26 (n = 26)PlaceboPercent reduction in seizure rate for individual seizure types
      • Beran R.G.
      • Berkovic S.F.
      • Dunagan F.M.
      • Vajda F.J.
      • Danta G.
      • Black A.B.
      • et al.
      Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.
      Primary generalized tonic-clonic seizuresAdjunctive (n = 1)n = 121 (n = 58)PlaceboMedian percent change from the baseline phase in the average monthly primary generalized tonic-clonic seizures seizure frequency
      • Biton V.
      • Sackellares J.C.
      • Vuong A.
      • Hammer A.E.
      • Barrett P.S.
      • Messenheimer J.A.
      Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.
      Partial onsetHistorical pseudo-placebo Extended release (n = 1)n = NA (n = 174)Historical pseudo placeboProportion of patients meeting exit criteria
      • French J.A.
      • Temkin N.R.
      • Shneker B.F.
      • Hammer A.E.
      • Caldwell P.T.
      • Messenheimer J.A.
      Lamotrigine XR conversion to monotherapy: first study using a historical control group.
      OxcarbazepinePartial onsetPre-surgical (n = 1)n = 102 (n = 51)PlaceboTime to meet one of exit criteria
      • Schachter S.C.
      • Vazquez B.
      • Fisher R.S.
      • Laxer K.D.
      • Montouris G.D.
      • Combs-Cantrell D.T.
      • et al.
      Oxcarbazepine double-blind, randomized, placebo-control, monotherapy trial for partial seizures.
      Conversion-to monotherapy (n = 2)n = 87 (n = 41); n = 143 (n = 96)2400 vs. 300 mg/dayPercent of patients meeting one of four exit criteria; time to meet one of four exit criteria
      • Beydoun A.
      • Sachdeo R.C.
      • Rosenfeld W.E.
      • Krauss G.L.
      • Sessler N.
      • Mesenbrink P.
      • et al.
      Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial.
      ,
      • Sachdeo R.
      • Beydoun A.
      • Schachter S.
      • Vazquez B.
      • Schaul N.
      • Mesenbrink P.
      • et al.
      Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures.
      FelbamatePartial onsetAdjunctive, cross-over (n = 1)n = 30 (n = 30)PlaceboNumber of seizures experienced by the patient during each of the analysis periods
      • Theodore W.H.
      • Raubertas R.F.
      • Porter R.J.
      • Nice F.
      • Devinsky O.
      • Reeves P.
      • et al.
      Felbamate: a clinical trial for complex partial seizures.
      Adjunctive, pre-surgical (n = 1)n = 64 (n = 30)PlaceboTime to fourth seizure
      • Bourgeois B.
      • Leppik I.E.
      • Sackellares J.C.
      • Laxer K.
      • Lesser R.
      • Messenheimer J.A.
      • et al.
      Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures.
      Conversion-to-monotherapy (n = 2)n = 44 (n = 22); n = 111 (n = 56)Low dose VPANumber of patients in each treatment group who met escape criteria; number of patients in each group who met escape criteria
      • Faught E.
      • Sachdeo R.C.
      • Remler M.P.
      • Chayasirisobhon S.
      • Iragui-Madoz V.J.
      • Ramsay R.E.
      • et al.
      Felbamate monotherapy for partial-onset seizures: an active-control trial.
      ,
      • Sachdeo R.
      • Kramer L.D.
      • Rosenberg A.
      • Sachdeo S.
      Felbamate monotherapy: controlled trial in patients with partial onset seizures.
      Pre-surgical (n = 2)n = 52 (n = 25); n = 40 (n = 21)PlaceboAverage daily seizure frequency during treatment; average frequency of all seizure types among study completers
      • Devinsky O.
      • Faught R.E.
      • Wilder B.J.
      • Kanner A.M.
      • Kamin M.
      • Kramer L.D.
      • et al.
      Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures.
      ,
      • Theodore W.H.
      • Albert P.
      • Stertz B.
      • Malow B.
      • Ko D.
      • White S.
      • et al.
      Felbamate monotherapy: implications for antiepileptic drug development.
      GabapentinPartial onsetConversion-to-monotherapy, dose-controlled (n = 1)n = 274 (n = 91)2400 vs 1200 vs 600 mg/dayTime to exit from double-blind phase
      • Beydoun A.
      • Fischer J.
      • Labar D.R.
      • Harden C.
      • Cantrell D.
      • Uthman B.M.
      • et al.
      Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.
      Pre-surgical, dose-controlled (n = 1)n = 82 (n = 40)3600 vs 300 mg/dayTime to exit from study
      • Bergey G.K.
      • Morris H.H.
      • Rosenfeld W.
      • Blume W.T.
      • Penovich P.E.
      • Morrell M.J.
      • et al.
      Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 88/89.
      Adjunctive (n = 1)n = 209 (n = 127)PlaceboResponse ratio, calculated according to the RRatio formula
      • Yamauchi T.
      • Kaneko S.
      • Yagi K.
      • Sase S.
      Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study.
      TopiramatePartial onsetAdjunctive (n = 3)n = 181 (n = 136); n = 47 (n = 23); n = 41 (n = 20)PlaceboPercent reduction in average monthly seizure rate; (1) median percent seizure reduction (2) ≥50% reduction; proportion of patients with ≥50% seizure reduction
      • Faught E.
      • Wilder B.J.
      • Ramsay R.E.
      • Reife R.A.
      • Kramer L.D.
      • Pledger G.W.
      • et al.
      Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group.
      ,
      • Sharief M.
      • Viteri C.
      • Ben-Menachem E.
      • Weber M.
      • Reife R.
      • Pledger G.
      • et al.
      Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy.
      ,
      • Yen D.J.
      • Yu H.Y.
      • Guo Y.C.
      • Chen C.
      • Yiu C.H.
      • Su M.S.
      A double-blind, placebo-controlled study of topiramate in adult patients with refractory partial epilepsy.
      Partial onsetConversion-to-monotherapy (n = 1)n = 46 (n = 23)1000 vs 100 mg/dayFulfilment of exit criteria
      • Sachdeo R.C.
      • Reife R.A.
      • Lim P.
      • Pledger G.
      Topiramate monotherapy for partial onset seizures.
      Generalized tonic-clonic seizuresAdjunctive (n = 1)n = 88 (n = 39)PlaceboPercentage reduction in PGTC seizure rate during double-blind phase
      • Biton V.
      • Montouris G.D.
      • Ritter F.
      • Riviello J.J.
      • Reife R.
      • Lim P.
      • et al.
      A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group.
      Partial onsetAdjunctive (n = 1)n = 249 (124)PlaceboMedian percent reduction in weekly partial onset seizure frequency.
      • Chung S.S.
      • Fakhoury T.A.
      • Hogan R.E.
      • Nagaraddi V.N.
      • Blatt I.
      • Lawson B.
      • et al.
      Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study.
      TiagabinePartial onsetPre-surgical (n = 1)n = 11(n = 7)PlaceboMedian reduction in 4-week complex partial seizure rates from baseline to the combined titration and fixed-dose periods for each treatment group
      • Schachter S.C.
      Tiagabine monotherapy in the treatment of partial epilepsy.
      Low vs high dose (n = 1)n = 198 (n = 96)36 vs 6 mg/dayMedian reduction in 4-week complex partial seizure rates from baseline to the combined titration and fixed-dose periods for each treatment group
      • Schachter S.C.
      Tiagabine monotherapy in the treatment of partial epilepsy.
      Adjunctive, crossover (n = 1)n = 94,open screening phase (n = 46, double-blind cross-over phase)PlaceboFour-week seizure frequency in the double-blind crossover phase of the study
      • Richens A.
      • Chadwick D.W.
      • Duncan J.S.
      • Dam M.
      • Gram L.
      • Mikkelsen M.
      • et al.
      Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial.
      Adjunctive (n = 2)n = 154 (n = 77); n = 297 (n = 206)PlaceboProportion of responders (patients achieving a reduction of 50% or more in the 4-weekly seizure rate) calculated for all partial seizures and for each seizure subtype; median change in 4-week seizure frequency
      • Kalviainen R.
      • Brodie M.J.
      • Duncan J.
      • Chadwick D.
      • Edwards D.
      • Lyby K.
      A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.
      ,
      • Uthman B.M.
      • Rowan A.J.
      • Ahmann P.A.
      • Leppik I.E.
      • Schachter S.C.
      • Sommerville K.W.
      • et al.
      Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial.
      LevetiracetamPartial onsetAdjunctive (n = 3)n = 294 (n = 199); n = 324 (n = 212); n = 56 (n = 28)PlaceboMean number of partial seizures per week; weekly partial seizure frequency; logarithmically transformed weekly frequency of partial seizures over the 16-week, double-blind treatment phase
      • Cereghino J.J.
      • Biton V.
      • Abou-Khalil B.
      • Dreifuss F.
      • Gauer L.J.
      • Leppik I.
      Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial.
      ,
      • Shorvon S.D.
      • Lowenthal A.
      • Janz D.
      • Bielen E.
      • Loiseau P.
      Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group.
      ,
      • Xiao Z.
      • Li J.M.
      • Wang X.F.
      • Xiao F.
      • Xi Z.Q.
      • Lv Y.
      • et al.
      Efficacy and safety of levetiracetam (3,000 mg/Day) as an adjunctive therapy in Chinese patients with refractory partial seizures.
      Partial onsetConversion-to-monotherapy (n = 1)n = 286 (n = 181)PlaceboPercentage of patients who completed monotherapy phase relative to number of patients randomized to receive medication
      • Ben-Menachem E.
      • Falter U.
      Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group.
      Generalized tonic-clonic seizuresAdjunctive (n = 1)n = 164 (n = 80)PlaceboPercentage reduction from the combined baseline period in GTC seizure frequency per week
      • Berkovic S.F.
      • Knowlton R.C.
      • Leroy R.F.
      • Schiemann J.
      • Falter U.
      • Levetiracetam N.S.G.
      Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy.
      Partial onsetConversion-to-monotherapy, Historical pseudo-placebo, extended release (n = 1)n = NA (n = 171)Historical pseudo-placeboCumulative exit rate at day 112 due to exit criteria compared with historical control
      • Chung S.
      • Ceja H.
      • Gawlowicz J.
      • Avakyan G.
      • McShea C.
      • Schiemann J.
      • et al.
      Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.
      Zonisamide
      Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
      Partial onsetAdjunctive (n = 2)n = 139 (n = 71); n = 152 (n = 78)PlaceboMedian percentage reduction from baseline in seizure frequency
      • Sackellares J.C.
      • Ramsay R.E.
      • Wilder B.J.
      • Browne 3rd, T.R.
      • Shellenberger M.K.
      Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures.
      ,
      • Schmidt D.
      • Jacob R.
      • Loiseau P.
      • Deisenhammer E.
      • Klinger D.
      • Despland A.
      • et al.
      Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial.
      Stiripentol
      Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
      Partial onsetAdjunctive, enrichment and withdrawal (n = 1)n = 67 (n = 17)PlaceboNumber of patients meeting the escape criteria during the double-blind period
      • Chiron C.
      • Tonnelier S.
      • Rey E.
      • Brunet M.L.
      • Tran A.
      • d’Athis P.
      • et al.
      Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design.
      PregabalinPartial onsetAdjunctive (n = 5)n = 453 (n = 353); n = 287 (n = 191); n = 313 (n = 225); n = 341 (n = 268); n = 178 (n = 119)PlaceboReduction in seizure frequency as measured by RRatio; reduction in seizure frequency during treatment as compared to baseline; change in seizure frequency from baseline; reduction in seizure frequency as measured by RRatio; reduction in seizure frequency as measured by RRatio
      • Arroyo S.
      • Anhut H.
      • Kugler A.R.
      • Lee C.M.
      • Knapp L.E.
      • Garofalo E.A.
      • et al.
      Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures.
      ,
      • Beydoun A.
      • Uthman B.M.
      • Kugler A.R.
      • Greiner M.J.
      • Knapp L.E.
      • Garofalo E.A.
      • et al.
      Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy.
      ,
      • Elger C.E.
      • Brodie M.J.
      • Anhut H.
      • Lee C.M.
      • Barrett J.A.
      Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study.
      ,
      • French J.A.
      • Kugler A.R.
      • Robbins J.L.
      • Knapp L.E.
      • Garofalo E.A.
      Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures.
      ,
      • Lee B.I.
      • Yi S.
      • Hong S.B.
      • Kim M.K.
      • Lee S.A.
      • Lee S.K.
      • et al.
      Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial.
      Historical pseudo-placebo (n = 1)n = NA (n = 161)Historical pseudo-placeboProportion of the pregabalin 600 mg/d group meeting ≥ 1 of the predefined seizure-related exit criteria
      • French J.
      • Kwan P.
      • Fakhoury T.
      • Pitman V.
      • DuBrava S.
      • Knapp L.
      • et al.
      Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial.
      Rufinamide
      Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
      Partial onsetAdjunctive (n = 2)n = 313 (n = 156); n = 357 (n = 176)PlaceboPercent change in partial seizure frequency
      • Biton V.
      • Krauss G.
      • Vasquez-Santana B.
      • Bibbiani F.
      • Mann A.
      • Perdomo C.
      • et al.
      A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures.
      ,
      • Brodie M.J.
      • Rosenfeld W.E.
      • Vazquez B.
      • Sachdeo R.
      • Perdomo C.
      • Mann A.
      • et al.
      Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial.
      LacosamidePartial-onsetAdjunctive (n = 3)n = 497 (n = 421); n = 485 (n = 318); n = 405 (n = 301)Placebo(1) change in seizure frequency per 28 days from baseline to maintenance (2) reduction of at least 50% in seizure frequency from baseline to maintenance
      • Ben-Menachem E.
      • Biton V.
      • Jatuzis D.
      • Abou-Khalil B.
      • Doty P.
      • Rudd G.D.
      Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures.
      ,
      • Chung S.
      • Sperling M.R.
      • Biton V.
      • Krauss G.
      • Hebert D.
      • Rudd G.D.
      • et al.
      Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial.
      ,
      • Halasz P.
      • Kalviainen R.
      • Mazurkiewicz-Beldzinska M.
      • Rosenow F.
      • Doty P.
      • Hebert D.
      • et al.
      Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial.
      Conversion-to-monotherapy, historical control (n = 1)n = NA (n = 425)Historical pseudo-placeboKaplan–Meier-predicted percentage of patients on 400 mg/day in the full analysis set meeting ≥ 1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold
      • Wechsler R.T.
      • Li G.
      • French J.
      • O’Brien T.J.
      • D’Cruz O.
      • Williams P.
      • et al.
      Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.
      Adjunctive (n = 1)n = 548 (n = 364)PlaceboChange in partial onset frequency per 28 days from Baseline to the Maintenance period
      • Hong Z.
      • Inoue Y.
      • Liao W.
      • Meng H.
      • Wang X.
      • Wang W.
      • et al.
      Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: a randomized, double-blind, placebo-controlled study.
      Eslicarbazepine acetatePartial onsetAdjunctive (n = 3)n = 402 (n = 300); n = 253 (n = 165); n = 395 (n = 295)PlaceboSeizure frequency per 4 weeks; seizure frequency as recorded by patient diaries; seizure frequency as recorded by patient diaries
      • Ben-Menachem E.
      • Gabbai A.A.
      • Hufnagel A.
      • Maia J.
      • Almeida L.
      • Soares-da-Silva P.
      Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy.
      ,
      • Elger C.
      • Halasz P.
      • Maia J.
      • Almeida L.
      • Soares-da-Silva P.
      • BIA Investigators Study Group
      Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.
      ,
      • Gil-Nagel A.
      • Lopes-Lima J.
      • Almeida L.
      • Maia J.
      • Soares-da-Silva P.
      • BIA Investigators Study Group
      Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures.
      Conversion-to-monotherapy, historical pseudo-placebo (n = 2)n = NA (n = 172); n = NA (n = 193)Historical pseudo-placeboKaplan–Meier-estimated 112-day exit rate with a threshold value calculated from the historical controls; proportion of patients meeting predefined exit criteria
      • Sperling M.R.
      • Harvey J.
      • Grinnell T.
      • Cheng H.
      • Blum D.
      • Study T.
      Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America.
      ,
      • Jacobson M.P.
      • Pazdera L.
      • Bhatia P.
      • Grinnell T.
      • Cheng H.
      • Blum D.
      • et al.
      Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.
      Retigabine/ezogabine
      Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
      Partial onsetAdjunctive (n = 4)n = 399 (n = 303); n = 538 (n = 359); n = 305 (n = 153); n = 75 (n = 50)PlaceboPercentage change from baseline in monthly seizure frequency and compared across treatment arms; change in 28-day seizure frequency; (1) percent change in 28-day total partial-seizure frequency from baseline to 18-week double-blind period (2) responder rate, defined as the proportion of patients experiencing a ≥50% reduction in 28-day total partial-seizure frequency from baseline to maintenance phase; proportion of responders, defined as patients with ≥50% reduction in 28-day total partial-onset seizure frequency, from the baseline phase to the maintenance phase
      • Brodie M.J.
      • Lerche H.
      • Gil-Nagel A.
      • Elger C.
      • Hall S.
      • Shin P.
      • et al.
      Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy.
      ,
      • French J.A.
      • Abou-Khalil B.W.
      • Leroy R.F.
      • Yacubian E.M.
      • Shin P.
      • Hall S.
      • et al.
      Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.
      ,
      • Lim K.S.
      • Lotay N.
      • White R.
      • Kwan P.
      Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: a randomized, placebo-controlled phase III study.
      ,
      • Porter R.J.
      • Partiot A.
      • Sachdeo R.
      • Nohria V.
      • Alves W.M.
      • Study G.
      Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures.
      Perampanel
      Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
      Partial onsetAdjunctive (n = 4)n = 387 (n = 266); n = 706 (n = 521); n = 386 (n = 250); n = 162 (n = 81)PlaceboThe responder rate (percentage of patients who experienced a 50% reduction in seizure frequency in the maintenance period relative to baseline); median percent change in seizure frequency; (1) percent change in 28-day total partial-seizure frequency from baseline to 18-week double-blind period (2) responder rate, defined as the proportion of patients experiencing a ≥50% reduction in 28-day total partial-seizure frequency from baseline to maintenance phase; Percent change in PGTC seizure frequency
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305.
      ,
      • French J.A.
      • Krauss G.L.
      • Wechsler R.T.
      • Wang X.F.
      • DiVentura B.
      • Brandt C.
      • et al.
      Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy. A randomized trial.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures.
      Brivaracetem
      Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
      Partial onsetAdjunctive (n = 4)n = 396 (n = 298); n = 480 (n = 359); n = 398 (n = 298); n = 768 (n = 501)PlaceboFocal seizure frequency per week; median percent reduction in baseline-adjusted seizure frequency; focal seizure frequency per week; (1) percent reduction in 28-day adjusted partial onset seizure frequency (2) ≥50% responder rate based on percent reduction in seizure frequency from baseline to the treatment period
      • Biton V.
      • Berkovic S.F.
      • Abou-Khalil B.
      • Sperling M.R.
      • Johnson M.E.
      • Lu S.
      Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial.
      ,
      • Klein P.
      • Schiemann J.
      • Sperling M.R.
      • Whitesides J.
      • Liang W.
      • Stalvey T.
      • et al.
      A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures.
      ,
      • Kwan P.
      • Trinka E.
      • Van Paesschen W.
      • Rektor I.
      • Johnson M.E.
      • Lu S.
      Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial.
      ,
      • Ryvlin P.
      • Werhahn K.J.
      • Blaszczyk B.
      • Johnson M.E.
      • Lu S.
      Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial.
      a Approved for adjunctive use only; RRatio = (T − B)/(T + B), where T and B are the seizure frequencies during treatment and during baseline.
      Table 2Properties of modern antiepileptic drugs (adapted from Kwan et al.
      • Kwan P.
      • Schachter S.C.
      • Brodie M.J.
      Drug-resistant epilepsy.
      and Brodie and Kwan
      • Brodie M.J.
      • Kwan P.
      Newer drugs for focal epilepsy in adults.
      ).
      DrugYear of approvalPrimary mechanism(s) of actionIndications (types of seizures/syndromes)Absorption (bioavailability %)Protein binding (% bound)Elimination half-life (h)Metabolism and routes of elimination
      Vigabatrin1989GABAergicPartial onset, West syndromeSlow (60–80)05–7Not metabolized, renal excretion
      Lamotrigine1990Sodium-channel blockadePartial, generalised, Lennox-GastautRapid (95–100)5522–36Glucuronidation
      Oxcarbazepine1990Sodium-channel blockadePartial, GTCSRapid (95–100)408–10Hepatic conversion to active moiety
      Felbamate1993MultiplePartial onset, Lennox-GastautSlow (95–100)22–3613–23Hepatic metabolism, renal excretion
      Gabapentin1993Neuronal calcium-channel bindingPartial onsetSlow (60)06–9Not metabolised, renal excretion
      Topiramate1995MultiplePartial onset, GTCS, myoclonic, Lennox-GastautSlow (80)9–1720–24Hepatic metabolism, renal excretion
      Tiagabine1996GABAergicPartial onsetRapid (95–100)965–9Hepatic metabolism
      Levetiracetam2000Binds to SV2A receptorsPartial onset, GTCS, myoclonicRapid (95–100)<107–8Non-hepatic hydrolysis, Renal excretion
      Zonisamide2000MultiplePartial onset, GTCS, myoclonicRapid (95–100)40–6050–68Hepatic metabolism, renal excretion
      Stiripentol2002GABAergicDravet SyndromeRapid (>70)998.5–23.5Demethylation, glucuronidation, renal excretion.
      Pregabalin2004Neuronal calcium-channel bindingPartial onsetRapid (90–100)06Renal excretion
      Rufinamide2004Sodium-channel blockadeLennox-Gastaut, Partial onsetSlow (>85)346–10Hepatic metabolism
      Lacosamide2008Slow inactivation of sodium channel/interacts with CRMP-2Partial onsetRapid (95–100)<1513Hepatic metabolism
      Eslicarbazepine acetate2009Sodium-channel blockadePartial onset, GTCSRapid (90)4013–20Glucuronidation, renal excretion
      Retigabine/ezogabine2011Activation of low-threshold potassium channelsPartial onsetRapid (60)808Glucuronidation
      Perampanel2012Non-competitive AMPA-receptor antagonistPartial onsetRapid (100)95105Glucoronidation, feces, urine
      Brivaracetam2016Binds to SV2A receptorsPartial onsetRapid (100)<207–8Renal excretion
      AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CRMP-2, collapsin response mediator protein-2; GABA, gamma-aminobutyric acid; GTCS, generalized tonic-clonic seizures; SV2A, synaptic vesicle 2A.

      4.2 Monotherapy

      Following the approval of an AED as adjunctive therapy, its further development for monotherapy use is under different regulatory frameworks in the US and Europe. The FDA requires that trials show superiority of the investigational drug over a comparator agent. However, randomizing patients to placebo has ethical concerns. Several new study designs were developed to comply with this regulation, but were eventually abandoned for ethical reasons. These included the once widely implemented “pseudo-placebo” design, in which a small dose of a single agent is given to patients in one arm [
      • Chadwick D.W.
      • Anhut H.
      • Greiner M.J.
      • Alexander J.
      • Murray G.H.
      • Garofalo E.A.
      • et al.
      A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77.
      ].
      In contrast to the FDA, the EMA accepts direct comparison of a new drug with an existing drug. In this paradigm, demonstration of equivalence or non-inferiority is adequate for approval. Several drugs have gained monotherapy approval using the non-inferiority design, including levetiracetam [
      • Brodie M.J.
      • Perucca E.
      • Ryvlin P.
      • Ben-Menachem E.
      • Meencke H.J.
      • Levetiracetam Monotherapy Study Group
      Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy.
      ] and zonisamide [
      • Baulac M.
      • Brodie M.J.
      • Patten A.
      • Segieth J.
      • Giorgi L.
      Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
      ], which both used a flexible-dosing design and controlled-release carbamazepine as the comparator. The main concern with non-inferiority designs, and the reason why the FDA requires a superiority outcome, is their unproved assay sensitivity. This is based on the argument that equivalent efficacy in the two trial arms could have been similarly achieved by a placebo.

      4.3 The historical-control design

      In the US, monotherapy efficacy assessment in drug-resistant patients had traditionally employed either “withdrawal-to-monotherapy” or “withdrawal-to-placebo.” These approaches have raised ethical concerns and may not adequately reflect intended use, and have thus attracted widespread criticism [
      • Karlawish J.H.
      • French J.
      The ethical and scientific shortcomings of current monotherapy epilepsy trials in newly diagnosed patients.
      ]. Recently, the historical-control approach has attempted to overcome the ethical difficulties of monotherapy vs. placebo trials [
      • French J.A.
      • Wang S.
      • Warnock B.
      • Temkin N.
      Historical control monotherapy design in the treatment of epilepsy.
      ]. In this approach, drug-resistant patients are withdrawn to the study drug in monotherapy, and compared to a historic control group modelled from previous conversion-to-monotherapy study data. This design has been adopted for evaluating monotherapy indication of eslicarbazepine acetate, lacosamide, lamotrigine extended release, levetiracetam extended release and pregabalin [
      • Chung S.
      • Ceja H.
      • Gawlowicz J.
      • Avakyan G.
      • McShea C.
      • Schiemann J.
      • et al.
      Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.
      ,
      • French J.
      • Kwan P.
      • Fakhoury T.
      • Pitman V.
      • DuBrava S.
      • Knapp L.
      • et al.
      Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial.
      ,
      • French J.A.
      • Temkin N.R.
      • Shneker B.F.
      • Hammer A.E.
      • Caldwell P.T.
      • Messenheimer J.A.
      Lamotrigine XR conversion to monotherapy: first study using a historical control group.
      ,
      • Sperling M.R.
      • Harvey J.
      • Grinnell T.
      • Cheng H.
      • Blum D.
      • Study T.
      Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America.
      ,
      • Wechsler R.T.
      • Li G.
      • French J.
      • O’Brien T.J.
      • D’Cruz O.
      • Williams P.
      • et al.
      Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.
      ]. However, this design has inherent concerns relating to the inconsistency between study cohorts and time-dependent population changes. Additionally, the lack of a parallel control group prevents effective blinding of treatment (some trials used blinded doses). For these reasons, the EMA regards historical-control studies as complementary rather than conclusive for the assessment of monotherapy indication [

      European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment of epileptic disorders. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070043.pdf.

      ].

      4.4 Should separate monotherapy indication be re-examined?

      To expedite monotherapy approval, Mintzer et al. recently proposed re-examination of the policy of separate approvals for AEDs as monotherapy and adjunctive therapy [
      • Mintzer S.
      • French J.A.
      • Perucca E.
      • Cramer J.A.
      • Messenheimer J.A.
      • Blum D.E.
      • et al.
      Is a separate monotherapy indication warranted for antiepileptic drugs?.
      ]. It is noted that AEDs are the only neurotherapeutics with separate indications for monotherapy and adjunctive use, which creates complications to the approval process. They suggest that regulatory restrictions that prevent or delay monotherapy approval for valuable new drugs is harmful to patients (for example, levetiracetam is not granted monotherapy indication in the US). They propose that AEDs should be approved for the treatment of specific seizure types, with approval for monotherapy and adjunctive use granted simultaneously. Whether the FDA can be persuaded remains to be seen. However, sequential licensing has recently been accepted by the EMA [

      European Medicines Agency. Post-authorisation safety studies (PASS) and post-authorisation efficacy studies. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000377.jsp&mid=WC0b01ac058066e979.

      ]. The AED under examination would be approved for adjunctive and second-intention monotherapy use, and then granted unrestricted monotherapy license after successfully adhering to a series of safety checkpoints. No monotherapy AED approval has been granted under these new pathways yet.

      5. Future research directions

      Despite the introduction of over 15 new compounds in the past 25 years, the overall proportion of patients with refractory epilepsy has remained largely unchanged. A shift from symptomatic seizure control to targeting underlying biological mechanisms is needed. The transition towards the development of disease-modifying treatments would be accelerated by a better understanding of the heterogeneous nature of epilepsy and the multiple complex factors that contribute to the abnormal neural discharges. Table 3 lists selected new compounds currently under early clinical investigation.
      Table 3Selected compounds currently under clinical investigation.
      Developmental approachName of compoundMechanism of actionReferences
      Mechanisms of action similar to those of marketed AEDsGanaxoloneGABA receptor modulator
      • Kerrigan J.F.
      • Shields W.D.
      • Nelson T.Y.
      • Bluestone D.L.
      • Dodson W.E.
      • Bourgeois B.F.
      • et al.
      Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.
      ,
      • Laxer K.
      • Blum D.
      • Abou-Khalil B.W.
      • Morrell M.J.
      • Lee D.A.
      • Data J.L.
      • et al.
      Assessment of ganaxolone’s anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group.
      ,
      • Pieribone V.A.
      • Tsai J.
      • Soufflet C.
      • Rey E.
      • Shaw K.
      • Giller E.
      • et al.
      Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy.
      Allopregnanolone (SAGE-547)GABAA receptor modulator
      • Belelli D.
      • Peden D.R.
      • Rosahl T.W.
      • Wafford K.A.
      • Lambert J.J.
      Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics.
      Selurampanel (BGG492)Competitive antagonist for AMPA and kainate receptors
      • Faught E.
      BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy.
      ICA-105665Selective opener of neuronal Kv7 potassium channels
      • Kasteleijn-Nolst Trenite D.G.
      • Biton V.
      • French J.A.
      • Abou-Khalil B.
      • Rosenfeld W.E.
      • Diventura B.
      • et al.
      Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy.
      YKP3089 (cenobamate)Selective blocker for the inactivated state of the sodium channel, facilitates presynaptic GABA release
      • Bialer M.
      • Johannessen S.I.
      • Levy R.H.
      • Perucca E.
      • Tomson T.
      • White H.S.
      Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII).
      Novel mechanisms of actionBeprodoneAgonist of the melatonin type 3 receptor
      • Bialer M.
      • Johannessen S.I.
      • Levy R.H.
      • Perucca E.
      • Tomson T.
      • White H.S.
      Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII).
      Huperzine AInhibitor of AChE receptor
      • Bialer M.
      • Johannessen S.I.
      • Levy R.H.
      • Perucca E.
      • Tomson T.
      • White H.S.
      Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII).
      Repurposed compounds which were initially developed for treatment of other diseasesEverolimusSelective inhibitor of mTOR pathway
      • French J.A.
      • Lawson J.A.
      • Yapici Z.
      • Ikeda H.
      • Polster T.
      • Nabbout R.
      • et al.
      Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study.
      FenfluramineSerotonin reuptake inhibitor
      • Ceulemans B.
      • Boel M.
      • Leyssens K.
      • Van Rossem C.
      • Neels P.
      • Jorens P.G.
      • et al.
      Successful use of fenfluramine as an add-on treatment for Dravet syndrome.
      ,
      • Ceulemans B.
      • Schoonjans A.S.
      • Marchau F.
      • Paelinck B.P.
      • Lagae L.
      Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine.
      ,
      • Schoonjans A.S.
      • Lagae L.
      • Ceulemans B.
      Low-dose fenfluramine in the treatment of neurologic disorders: experience in Dravet syndrome.
      NalutozanNonazapirone 5-HT1A partial agonist
      • Merlet I.
      • Ostrowsky K.
      • Costes N.
      • Ryvlin P.
      • Isnard J.
      • Faillenot I.
      • et al.
      5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study.
      PitolisantHistamine 3 receptor antagonist
      • Kasteleijn-Nolst Trenite D.
      • Parain D.
      • Genton P.
      • Masnou P.
      • Schwartz J.C.
      • Hirsch E.
      Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model.
      QuinidinePartial antagonist of KCNT1
      • Bearden D.
      • Strong A.
      • Ehnot J.
      • DiGiovine M.
      • Dlugos D.
      • Goldberg E.M.
      Targeted treatment of migrating partial seizures of infancy with quinidine.
      ValnoctamideGABAA receptor agonist
      • Barel S.
      • Yagen B.
      • Schurig V.
      • Soback S.
      • Pisani F.
      • Perucca E.
      • et al.
      Stereoselective pharmacokinetic analysis of valnoctamide in healthy subjects and in patients with epilepsy.
      VerapamilInhibitor of P-glycoprotein
      • Asadi-Pooya A.A.
      • Razavizadegan S.M.
      • Abdi-Ardekani A.
      • Sperling M.R.
      Adjunctive use of verapamil in patients with refractory temporal lobe epilepsy: a pilot study.
      ,
      • Borlot F.
      • Wither R.G.
      • Ali A.
      • Wu N.
      • Verocai F.
      • Andrade D.M.
      A pilot double-blind trial using verapamil as adjuvant therapy for refractory seizures.
      Unknown mechanisms of actionJNJ-26489112Multiple, unknown
      • Di Prospero N.A.
      • Gambale J.J.
      • Pandina G.
      • Ford L.
      • Girgis S.
      • Moyer J.A.
      • et al.
      Evaluation of JNJ-26489112 in patients with photosensitive epilepsy: a placebo-controlled, exploratory study.
      CannabidiolMultiple, unknown (Agonist of Melatonin 3 receptor is one known mechanism)
      • Paolino M.C.
      • Ferretti A.
      • Papetti L.
      • Villa M.P.
      • Parisi P.
      Cannabidiol as potential treatment in refractory pediatric epilepsy.

      5.1 Promising approaches for pharmacological therapy

      There is a need to elucidate the pathology underpinning pharmacoresistance to develop novel therapies. Several hypotheses have been formulated. These include the target hypothesis, the multidrug transporter hypothesis and the network hypothesis [
      • Loscher W.
      Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs.
      ,
      • Loscher W.
      • Potschka H.
      Drug resistance in brain diseases and the role of drug efflux transporters.
      ,
      • Remy S.
      • Beck H.
      Molecular and cellular mechanisms of pharmacoresistance in epilepsy.
      ]. The target hypothesis suggests that alteration of molecular drug targets results in reduced response to treatment. This hypothesis is based on studies of AED effects on hippocampal voltage-gated sodium channels [
      • Vreugdenhil M.
      • van Veelen C.W.
      • van Rijen P.C.
      • Lopes da Silva F.H.
      • Wadman W.J.
      Effect of valproic acid on sodium currents in cortical neurons from patients with pharmaco-resistant temporal lobe epilepsy.
      ,
      • Vreugdenhil M.
      • Wadman W.J.
      Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis.
      ]. The multidrug transporter hypothesis postulates that an overexpression of efflux transporters at the blood–brain barrier restricts penetration of AEDs and reduces drug concentrations to subtherapeutic levels. Bankstahl et al. addressed this hypothesis by determining the efficacy of six AEDs in wildtype mice and mice deficient in P-glycoprotein (Pgp), one of the best studied efflux transporters, in a kainate-induced status epilepticus model of mesial temporal lobe epilepsy [
      • Bankstahl M.
      • Klein S.
      • Romermann K.
      • Loscher W.
      Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice.
      ]. No significant differences in anti-seizure drug efficacies were observed between wildtype and Pgp-deficient mice. While this finding does not invalidate the multi-drug transporter hypothesis, it suggests that Pgp may not be functionally relevant in the mechanisms underlying drug resistant seizures. The co-administration of transporter inhibitors with AEDs is a promising therapeutic avenue to overcome drug resistance, but further research into other efflux transporters is needed. The network hypothesis suggests that neurodegeneration occurs in drug-resistant brains, and postulates that drugs with neuroprotective actions may be beneficial. Stemming from this hypothesis, immunosuppressive treatments and inhibitors of inflammation have been considered as potential therapeutic options. They include inhibitors of cytokine synthesis, neuro-immunophilins, corticosteroids and interleukin-1 receptor antagonists [
      • Vezzani A.
      • Auvin S.
      • Ravizza T.
      • Aronica E.
      Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators.
      ].
      Agents with disease-modifying effects are of emergent interest in epilepsy treatment research. Although evidence for anti-epileptogenic effect of approved AEDs (including levetiracetam, phenobarbital, valproate and topiramate) is present in the post-status epilepticus animal models, this property has not been demonstrated in humans. These models have also been employed to screen for disease-modifying effects of non-AED compounds. Lorsartan is an example of such a compound, and has been shown to inhibit epileptogenic mechanisms in vivo [
      • Lukawski K.
      • Gryta P.
      • Luszczki J.
      • Czuczwar S.J.
      Exploring the latest avenues for antiepileptic drug discovery and development.
      ]. Rapamycin and derivative molecules (everolimus, temsirolimus, deforolimus, ridaforolimusm) inhibit the mTOR signalling system and represent another potential class of epileptogenic compounds. They have been explored in animal models of tuberous sclerosis complex and some models of acquired epilepsy, and display promising results in human trials of tuberous sclerosis complex [
      • Loscher W.
      • Klitgaard H.
      • Twyman R.E.
      • Schmidt D.
      New avenues for anti-epileptic drug discovery and development.
      ].
      The blood–brain barrier is also under investigation as a possible target. Agents such as doxycline and minocycline that affect blood–brain barrier permeability are potential anti-epileptogenic candidates. Other compounds that have been of emerging interest are anti-apoptotic agents (such as corticotropin releasing hormone, and some AEDs), antioxidants (lipoic acid, adenosine, melatonin, vitamins C and E) and activators of neurotrophic receptors (fibroblast growth factor 2, brain derived neurotrophic factor, neuropeptide Y, inhibitors of TrkB kinase, erythropoietin) [
      • Moshe S.L.
      • Perucca E.
      • Ryvlin P.
      • Tomson T.
      Epilepsy: new advances.
      ].
      Lastly, there has been a resurgence of interest in the proposed anti-seizure properties of cannabidiol, derived from the cannabis plant [
      • Devinsky O.
      • Cilio M.R.
      • Cross H.
      • Fernandez-Ruiz J.
      • French J.
      • Hill C.
      • et al.
      Cannabidiol pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.
      ,
      • Devinsky O.
      • Marsh E.
      • Friedman D.
      • Thiele E.
      • Laux L.
      • Sullivan J.
      • et al.
      Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
      ]. Interestingly, cannabidiol’s anti-seizure properties are not mediated by an interaction with cannabinoid receptors, despite its structural similarity to tetrahydrocannabinol [
      • Mula M.
      Investigational new drugs for focal epilepsy.
      ]. Pre-clinical evaluations have confirmed these properties, and cannabidiol is now being subject to various clinical trials. In addition to its potential as an anti-seizure agent, cannabidiol has been shown to possess neuroprotective and anti-inflammatory effects. Promising results were found in a recently completed open-label study investigating the use of cannabidiol oral solution as an adjunctive therapy for paediatric and adult patients with drug-resistant epilepsy [
      • Devinsky O.
      • Marsh E.
      • Friedman D.
      • Thiele E.
      • Laux L.
      • Sullivan J.
      • et al.
      Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
      ]. A number of randomized controlled trials are underway to elucidate the efficacy and safety profile of cannabidiol.

      5.2 Precision medicine

      Individual response to pharmacological treatment is influenced by the genetic profile. Pharmacogenomics is a new addition to epilepsy research, offering the potential to personalise treatment for individuals with epilepsy. The EMA defines pharmacogenomics as the “study of the variability of individual genes relevant to disease susceptibility as well as drug response at cellular, tissue, individual or population level” [

      Committee for Proprietary Medicinal Products. Position paper on terminology in pharmacogenetics. http://www.ema.europa.eu/.

      ]. Taking this approach further, precision medicine aims to stratify individuals into subpopulations based on differences in disease susceptibility, prognosis and treatment response. Precision medicine thus promises to maximise outcomes and minimise unnecessary adverse drug reactions and expenditure, providing clinical and socioeconomic benefits for both the individual patients and the community. A battery of genetic tests is currently used for screening epilepsy susceptibility genes and to characterize gene variant profiles at the family and population level. It is proposed that by identifying the causative mutation for an individual epilepsy case, targeted therapeutic choices can be made. Under this paradigm, clinical practice will no longer be directed by the suboptimal “trial and error” methods.
      The repurposing of existing drugs not currently indicated for epilepsy has the potential to overcome drug resistance. Personalized genomic medicine was successfully implemented in the diagnosis and treatment in a recent case of drug-resistant infantile-onset epilepsy [
      • Pierson T.M.
      • Yuan H.
      • Marsh E.D.
      • Fuentes-Fajardo K.
      • Adams D.R.
      • Markello T.
      • et al.
      GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.
      ]. A novel mutation was found in the GRIN2A gene, coding for the NMDA receptor (which has a pivotal role in neuronal communication). Following administration of the Alzheimer disease drug memantine, which reduces chronic overstimulation of NMDAR, a reduction in seizure frequency was observed. Another important example of drug repositioning in precision medicine is the use of quinidine. Case reports show that this cardiac anti-arrhythmia drug is effective in epilepsy syndromes with an underlying gain-of-function mutation in the KCNT1 gene [
      • Milligan C.J.
      • Li M.
      • Gazina E.V.
      • Heron S.E.
      • Nair U.
      • Trager C.
      • et al.
      KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine.
      ]. Quinidine inhibits the KCNT1 sodium-activated potassium channel, encoded by the KCNT1 gene. It is hypothesized that quinidine may counteract the effect of the mutation of the channel.

      6. Conclusion

      While the lack of substantial progress of treatment for drug-resistant epilepsy over the past two decades has been attributed to deficiencies in the preclinical and clinical stages of development, there is a sense that a new era of treatment for drug-resistant therapy is imminent. A better understanding of the underlying physiological mechanisms leading to epilepsy has permitted the move towards developing novel target-driven therapeutic strategies [
      • Pitkanen A.
      • Lukasiuk K.
      Mechanisms of epileptogenesis and potential treatment targets.
      ]. This may allow optimization of the translation of preclinical findings to clinical research through thorough validation of novel drug-targets prior to extensive drug discovery work. The multifactorial mechanisms underpinning drug resistance will continue to demand collective effort from basic science and clinical research.

      Conflict of interest statement

      PK has received research grants from the National Health and Medical Research Council of Australia, the Australian Research Council, RMH Neuroscience Foundation, the US National Institutes of Health, Bill & Melinda Gates Foundation, Hong Kong Research Grants Council, Innovation and Technology Fund, Health and Health Services Research Fund, and Health and Medical Research Fund. He/his institution also received speaker or consultancy fees and/or research grants from Eisai, GlaxoSmithKline, Johnson & Johnson, Pfizer, and UCB Pharma.

      Acknowledgement

      AG is supported by the University of Melbourne Chancellor’s Scholars Program .

      References

        • Kwan P.
        • Brodie M.J.
        Early identification of refractory epilepsy.
        N Engl J Med. 2000; 342: 314-319
        • Jacoby A.
        • Baker G.A.
        Quality-of-life trajectories in epilepsy: a review of the literature.
        Epilepsy Behav. 2008; 12: 557-571
        • Tomson T.
        • Nashef L.
        • Ryvlin P.
        Sudden unexpected death in epilepsy: current knowledge and future directions.
        Lancet Neurol. 2008; 7: 1021-1031
        • Bialer M.
        • White H.S.
        Key factors in the discovery and development of new antiepileptic drugs.
        Nat Rev Drug Discov. 2010; 9: 68-82
        • Toman J.E.
        • Swinyard E.A.
        • Goodman L.S.
        Properties of maximal seizures, and their alteration by anticonvulant drugs and other agents.
        J Neurophysiol. 1946; 9: 231-239
        • Loscher W.
        Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs.
        Seizure. 2011; 20: 359-368
        • Perucca E.
        • French J.
        • Bialer M.
        Development of new antiepileptic drugs: challenges, incentives, and recent advances.
        Lancet Neurol. 2007; 6: 793-804
        • Barton M.E.
        • Klein B.D.
        • Wolf H.H.
        • White H.S.
        Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy.
        Epilepsy Res. 2001; 47: 217-227
        • Loscher W.
        Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs: a comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy.
        Epilepsy Res. 2002; 50: 105-123
        • Ben-Menachem E.
        • Biton V.
        • Jatuzis D.
        • Abou-Khalil B.
        • Doty P.
        • Rudd G.D.
        Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures.
        Epilepsia. 2007; 48: 1308-1317
        • Porter R.J.
        • Baulac M.
        • Nohria V.
        Clinical development of drugs for epilepsy: a review of approaches in the United States and Europe.
        Epilepsy Res. 2010; 89: 163-175
        • Brodie M.J.
        • Kwan P.
        Newer drugs for focal epilepsy in adults.
        BMJ. 2012; 344: e345
        • Brodie M.J.
        • Schachter S.C.
        • Kwan P.
        Fast facts: epilepsy.
        Health Press, Oxford2011: 74-75
        • Chadwick D.W.
        • Anhut H.
        • Greiner M.J.
        • Alexander J.
        • Murray G.H.
        • Garofalo E.A.
        • et al.
        A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77.
        Neurology. 1998; 51: 1282-1288
        • Brodie M.J.
        • Perucca E.
        • Ryvlin P.
        • Ben-Menachem E.
        • Meencke H.J.
        • Levetiracetam Monotherapy Study Group
        Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy.
        Neurology. 2007; 68: 402-408
        • Baulac M.
        • Brodie M.J.
        • Patten A.
        • Segieth J.
        • Giorgi L.
        Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
        Lancet Neurol. 2012; 11: 579-588
        • Karlawish J.H.
        • French J.
        The ethical and scientific shortcomings of current monotherapy epilepsy trials in newly diagnosed patients.
        Epilepsy Behav. 2001; 2: 193-200
        • French J.A.
        • Wang S.
        • Warnock B.
        • Temkin N.
        Historical control monotherapy design in the treatment of epilepsy.
        Epilepsia. 2010; 51: 1936-1943
        • Chung S.
        • Ceja H.
        • Gawlowicz J.
        • Avakyan G.
        • McShea C.
        • Schiemann J.
        • et al.
        Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.
        Epilepsy Res. 2012; 101: 92-102
        • French J.
        • Kwan P.
        • Fakhoury T.
        • Pitman V.
        • DuBrava S.
        • Knapp L.
        • et al.
        Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial.
        Neurology. 2014; 82: 590-597
        • French J.A.
        • Temkin N.R.
        • Shneker B.F.
        • Hammer A.E.
        • Caldwell P.T.
        • Messenheimer J.A.
        Lamotrigine XR conversion to monotherapy: first study using a historical control group.
        Neurotherapeutics. 2012; 9: 176-184
        • Sperling M.R.
        • Harvey J.
        • Grinnell T.
        • Cheng H.
        • Blum D.
        • Study T.
        Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America.
        Epilepsia. 2015; 56: 546-555
        • Wechsler R.T.
        • Li G.
        • French J.
        • O’Brien T.J.
        • D’Cruz O.
        • Williams P.
        • et al.
        Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.
        Epilepsia. 2014; 55: 1088-1098
      1. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment of epileptic disorders. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070043.pdf.

        • Mintzer S.
        • French J.A.
        • Perucca E.
        • Cramer J.A.
        • Messenheimer J.A.
        • Blum D.E.
        • et al.
        Is a separate monotherapy indication warranted for antiepileptic drugs?.
        Lancet Neurol. 2015; 14: 1229-1240
      2. European Medicines Agency. Post-authorisation safety studies (PASS) and post-authorisation efficacy studies. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000377.jsp&mid=WC0b01ac058066e979.

        • Loscher W.
        • Potschka H.
        Drug resistance in brain diseases and the role of drug efflux transporters.
        Nat Rev Neurosci. 2005; 6: 591-602
        • Remy S.
        • Beck H.
        Molecular and cellular mechanisms of pharmacoresistance in epilepsy.
        Brain. 2006; 129: 18-35
        • Vreugdenhil M.
        • van Veelen C.W.
        • van Rijen P.C.
        • Lopes da Silva F.H.
        • Wadman W.J.
        Effect of valproic acid on sodium currents in cortical neurons from patients with pharmaco-resistant temporal lobe epilepsy.
        Epilepsy Res. 1998; 32: 309-320
        • Vreugdenhil M.
        • Wadman W.J.
        Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis.
        Epilepsia. 1999; 40: 1512-1522
        • Bankstahl M.
        • Klein S.
        • Romermann K.
        • Loscher W.
        Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice.
        Neuropharmacology. 2016; 109: 183-195
        • Vezzani A.
        • Auvin S.
        • Ravizza T.
        • Aronica E.
        Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators.
        in: Noebels J.L. Avoli M. Rogawski M.A. Olsen R.W. Delgado-Escueta A.V. Jasper’s Basic Mechanisms of the Epilepsies. National Center for Biotechnology Information (US), Bethesda, MD2012
        • Lukawski K.
        • Gryta P.
        • Luszczki J.
        • Czuczwar S.J.
        Exploring the latest avenues for antiepileptic drug discovery and development.
        Expert Opin Drug Discov. 2016; 11: 369-382
        • Loscher W.
        • Klitgaard H.
        • Twyman R.E.
        • Schmidt D.
        New avenues for anti-epileptic drug discovery and development.
        Nat Rev Drug Discov. 2013; 12: 757-776
        • Moshe S.L.
        • Perucca E.
        • Ryvlin P.
        • Tomson T.
        Epilepsy: new advances.
        Lancet. 2015; 385: 884-898
        • Devinsky O.
        • Cilio M.R.
        • Cross H.
        • Fernandez-Ruiz J.
        • French J.
        • Hill C.
        • et al.
        Cannabidiol pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.
        Epilepsia. 2014; 55: 791-802
        • Devinsky O.
        • Marsh E.
        • Friedman D.
        • Thiele E.
        • Laux L.
        • Sullivan J.
        • et al.
        Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
        Lancet Neurol. 2016; 15: 270-278
        • Mula M.
        Investigational new drugs for focal epilepsy.
        Expert Opin Investig Drugs. 2016; 25: 1-5
      3. Committee for Proprietary Medicinal Products. Position paper on terminology in pharmacogenetics. http://www.ema.europa.eu/.

        • Pierson T.M.
        • Yuan H.
        • Marsh E.D.
        • Fuentes-Fajardo K.
        • Adams D.R.
        • Markello T.
        • et al.
        GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.
        Ann Clin Transl Neurol. 2014; 1: 190-198
        • Milligan C.J.
        • Li M.
        • Gazina E.V.
        • Heron S.E.
        • Nair U.
        • Trager C.
        • et al.
        KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine.
        Ann Neurol. 2014; 75: 581-590
        • Pitkanen A.
        • Lukasiuk K.
        Mechanisms of epileptogenesis and potential treatment targets.
        Lancet Neurol. 2011; 10: 173-186
        • Kwan P.
        Refractory epilepsy: natural history and pathogenesis. PhD thesis.
        Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK2000
        • Beran R.G.
        • Berkovic S.F.
        • Buchanan N.
        • Danta G.
        • Mackenzie R.
        • Schapel G.
        • et al.
        A double-blind, placebo-controlled crossover study of vigabatrin 2 g/day and 3 g/day in uncontrolled partial seizures.
        Seizure. 1996; 5: 259-265
        • Tartara A.
        • Manni R.
        • Galimberti C.A.
        • Hardenberg J.
        • Orwin J.
        • Perucca E.
        Vigabatrin in the treatment of epilepsy: a double-blind, placebo-controlled study.
        Epilepsia. 1986; 27: 717-723
        • Tassinari C.A.
        • Michelucci R.
        • Ambrosetto G.
        • Salvi F.
        Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy.
        Arch Neurol. 1987; 44: 907-910
        • Bruni J.
        • Guberman A.
        • Vachon L.
        • Desforges C.
        Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.
        Seizure. 2000; 9: 224-232
        • Gilliam F.
        • Vazquez B.
        • Sackellares J.C.
        • Chang G.Y.
        • Messenheimer J.
        • Nyberg J.
        • et al.
        An active-control trial of lamotrigine monotherapy for partial seizures.
        Neurology. 1998; 51: 1018-1025
        • Beran R.G.
        • Berkovic S.F.
        • Dunagan F.M.
        • Vajda F.J.
        • Danta G.
        • Black A.B.
        • et al.
        Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.
        Epilepsia. 1998; 39: 1329-1333
        • Biton V.
        • Sackellares J.C.
        • Vuong A.
        • Hammer A.E.
        • Barrett P.S.
        • Messenheimer J.A.
        Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.
        Neurology. 2005; 65: 1737-1743
        • Schachter S.C.
        • Vazquez B.
        • Fisher R.S.
        • Laxer K.D.
        • Montouris G.D.
        • Combs-Cantrell D.T.
        • et al.
        Oxcarbazepine double-blind, randomized, placebo-control, monotherapy trial for partial seizures.
        Neurology. 1999; 52: 732-737
        • Beydoun A.
        • Sachdeo R.C.
        • Rosenfeld W.E.
        • Krauss G.L.
        • Sessler N.
        • Mesenbrink P.
        • et al.
        Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial.
        Neurology. 2000; 54: 2245-2251
        • Sachdeo R.
        • Beydoun A.
        • Schachter S.
        • Vazquez B.
        • Schaul N.
        • Mesenbrink P.
        • et al.
        Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures.
        Neurology. 2001; 57: 864-871
        • Theodore W.H.
        • Raubertas R.F.
        • Porter R.J.
        • Nice F.
        • Devinsky O.
        • Reeves P.
        • et al.
        Felbamate: a clinical trial for complex partial seizures.
        Epilepsia. 1991; 32: 392-397
        • Bourgeois B.
        • Leppik I.E.
        • Sackellares J.C.
        • Laxer K.
        • Lesser R.
        • Messenheimer J.A.
        • et al.
        Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures.
        Neurology. 1993; 43: 693-696
        • Faught E.
        • Sachdeo R.C.
        • Remler M.P.
        • Chayasirisobhon S.
        • Iragui-Madoz V.J.
        • Ramsay R.E.
        • et al.
        Felbamate monotherapy for partial-onset seizures: an active-control trial.
        Neurology. 1993; 43: 688-692
        • Sachdeo R.
        • Kramer L.D.
        • Rosenberg A.
        • Sachdeo S.
        Felbamate monotherapy: controlled trial in patients with partial onset seizures.
        Ann Neurol. 1992; 32: 386-392
        • Devinsky O.
        • Faught R.E.
        • Wilder B.J.
        • Kanner A.M.
        • Kamin M.
        • Kramer L.D.
        • et al.
        Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures.
        Epilepsy Res. 1995; 20: 241-246
        • Theodore W.H.
        • Albert P.
        • Stertz B.
        • Malow B.
        • Ko D.
        • White S.
        • et al.
        Felbamate monotherapy: implications for antiepileptic drug development.
        Epilepsia. 1995; 36: 1105-1110
        • Beydoun A.
        • Fischer J.
        • Labar D.R.
        • Harden C.
        • Cantrell D.
        • Uthman B.M.
        • et al.
        Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.
        Neurology. 1997; 49: 746-752
        • Bergey G.K.
        • Morris H.H.
        • Rosenfeld W.
        • Blume W.T.
        • Penovich P.E.
        • Morrell M.J.
        • et al.
        Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 88/89.
        Neurology. 1997; 49: 739-745
        • Yamauchi T.
        • Kaneko S.
        • Yagi K.
        • Sase S.
        Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study.
        Psychiatry Clin Neurosci. 2006; 60: 507-515
        • Faught E.
        • Wilder B.J.
        • Ramsay R.E.
        • Reife R.A.
        • Kramer L.D.
        • Pledger G.W.
        • et al.
        Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group.
        Neurology. 1996; 46: 1684-1690
        • Sharief M.
        • Viteri C.
        • Ben-Menachem E.
        • Weber M.
        • Reife R.
        • Pledger G.
        • et al.
        Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy.
        Epilepsy Res. 1996; 25: 217-224
        • Yen D.J.
        • Yu H.Y.
        • Guo Y.C.
        • Chen C.
        • Yiu C.H.
        • Su M.S.
        A double-blind, placebo-controlled study of topiramate in adult patients with refractory partial epilepsy.
        Epilepsia. 2000; 41: 1162-1166
        • Sachdeo R.C.
        • Reife R.A.
        • Lim P.
        • Pledger G.
        Topiramate monotherapy for partial onset seizures.
        Epilepsia. 1997; 38: 294-300
        • Biton V.
        • Montouris G.D.
        • Ritter F.
        • Riviello J.J.
        • Reife R.
        • Lim P.
        • et al.
        A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group.
        Neurology. 1999; 52: 1330-1337
        • Chung S.S.
        • Fakhoury T.A.
        • Hogan R.E.
        • Nagaraddi V.N.
        • Blatt I.
        • Lawson B.
        • et al.
        Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study.
        Epilepsia. 2014; 55: 1077-1087
        • Schachter S.C.
        Tiagabine monotherapy in the treatment of partial epilepsy.
        Epilepsia. 1995; 36: S2-S6
        • Richens A.
        • Chadwick D.W.
        • Duncan J.S.
        • Dam M.
        • Gram L.
        • Mikkelsen M.
        • et al.
        Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial.
        Epilepsy Res. 1995; 21: 37-42
        • Kalviainen R.
        • Brodie M.J.
        • Duncan J.
        • Chadwick D.
        • Edwards D.
        • Lyby K.
        A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.
        Epilepsy Res. 1998; 30: 31-40
        • Uthman B.M.
        • Rowan A.J.
        • Ahmann P.A.
        • Leppik I.E.
        • Schachter S.C.
        • Sommerville K.W.
        • et al.
        Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial.
        Arch Neurol. 1998; 55: 56-62
        • Cereghino J.J.
        • Biton V.
        • Abou-Khalil B.
        • Dreifuss F.
        • Gauer L.J.
        • Leppik I.
        Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial.
        Neurology. 2000; 55: 236-242
        • Shorvon S.D.
        • Lowenthal A.
        • Janz D.
        • Bielen E.
        • Loiseau P.
        Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group.
        Epilepsia. 2000; 41: 1179-1186
        • Xiao Z.
        • Li J.M.
        • Wang X.F.
        • Xiao F.
        • Xi Z.Q.
        • Lv Y.
        • et al.
        Efficacy and safety of levetiracetam (3,000 mg/Day) as an adjunctive therapy in Chinese patients with refractory partial seizures.
        Eur Neurol. 2009; 61: 233-239
        • Ben-Menachem E.
        • Falter U.
        Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group.
        Epilepsia. 2000; 41: 1276-1283
        • Berkovic S.F.
        • Knowlton R.C.
        • Leroy R.F.
        • Schiemann J.
        • Falter U.
        • Levetiracetam N.S.G.
        Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy.
        Neurology. 2007; 69: 1751-1760
        • Sackellares J.C.
        • Ramsay R.E.
        • Wilder B.J.
        • Browne 3rd, T.R.
        • Shellenberger M.K.
        Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures.
        Epilepsia. 2004; 45: 610-617
        • Schmidt D.
        • Jacob R.
        • Loiseau P.
        • Deisenhammer E.
        • Klinger D.
        • Despland A.
        • et al.
        Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial.
        Epilepsy Res. 1993; 15: 67-73
        • Chiron C.
        • Tonnelier S.
        • Rey E.
        • Brunet M.L.
        • Tran A.
        • d’Athis P.
        • et al.
        Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design.
        J Child Neurol. 2006; 21: 496-502
        • Arroyo S.
        • Anhut H.
        • Kugler A.R.
        • Lee C.M.
        • Knapp L.E.
        • Garofalo E.A.
        • et al.
        Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures.
        Epilepsia. 2004; 45: 20-27
        • Beydoun A.
        • Uthman B.M.
        • Kugler A.R.
        • Greiner M.J.
        • Knapp L.E.
        • Garofalo E.A.
        • et al.
        Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy.
        Neurology. 2005; 64: 475-480
        • Elger C.E.
        • Brodie M.J.
        • Anhut H.
        • Lee C.M.
        • Barrett J.A.
        Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study.
        Epilepsia. 2005; 46: 1926-1936
        • French J.A.
        • Kugler A.R.
        • Robbins J.L.
        • Knapp L.E.
        • Garofalo E.A.
        Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures.
        Neurology. 2003; 60: 1631-1637
        • Lee B.I.
        • Yi S.
        • Hong S.B.
        • Kim M.K.
        • Lee S.A.
        • Lee S.K.
        • et al.
        Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial.
        Epilepsia. 2009; 50: 464-474
        • Biton V.
        • Krauss G.
        • Vasquez-Santana B.
        • Bibbiani F.
        • Mann A.
        • Perdomo C.
        • et al.
        A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures.
        Epilepsia. 2011; 52: 234-242
        • Brodie M.J.
        • Rosenfeld W.E.
        • Vazquez B.
        • Sachdeo R.
        • Perdomo C.
        • Mann A.
        • et al.
        Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial.
        Epilepsia. 2009; 50: 1899-1909
        • Chung S.
        • Sperling M.R.
        • Biton V.
        • Krauss G.
        • Hebert D.
        • Rudd G.D.
        • et al.
        Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial.
        Epilepsia. 2010; 51: 958-967
        • Halasz P.
        • Kalviainen R.
        • Mazurkiewicz-Beldzinska M.
        • Rosenow F.
        • Doty P.
        • Hebert D.
        • et al.
        Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial.
        Epilepsia. 2009; 50: 443-453
        • Hong Z.
        • Inoue Y.
        • Liao W.
        • Meng H.
        • Wang X.
        • Wang W.
        • et al.
        Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: a randomized, double-blind, placebo-controlled study.
        Epilepsy Res. 2016; 127: 267-275
        • Ben-Menachem E.
        • Gabbai A.A.
        • Hufnagel A.
        • Maia J.
        • Almeida L.
        • Soares-da-Silva P.
        Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy.
        Epilepsy Res. 2010; 89: 278-285
        • Elger C.
        • Halasz P.
        • Maia J.
        • Almeida L.
        • Soares-da-Silva P.
        • BIA Investigators Study Group
        Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.
        Epilepsia. 2009; 50: 454-463
        • Gil-Nagel A.
        • Lopes-Lima J.
        • Almeida L.
        • Maia J.
        • Soares-da-Silva P.
        • BIA Investigators Study Group
        Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures.
        Acta Neurol Scand. 2009; 120: 281-287
        • Jacobson M.P.
        • Pazdera L.
        • Bhatia P.
        • Grinnell T.
        • Cheng H.
        • Blum D.
        • et al.
        Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.
        BMC Neurol. 2015; 15: 46
        • Brodie M.J.
        • Lerche H.
        • Gil-Nagel A.
        • Elger C.
        • Hall S.
        • Shin P.
        • et al.
        Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy.
        Neurology. 2010; 75: 1817-1824
        • French J.A.
        • Abou-Khalil B.W.
        • Leroy R.F.
        • Yacubian E.M.
        • Shin P.
        • Hall S.
        • et al.
        Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.
        Neurology. 2011; 76: 1555-1563
        • Lim K.S.
        • Lotay N.
        • White R.
        • Kwan P.
        Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: a randomized, placebo-controlled phase III study.
        Epilepsy Behav. 2016; 61: 224-230
        • Porter R.J.
        • Partiot A.
        • Sachdeo R.
        • Nohria V.
        • Alves W.M.
        • Study G.
        Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures.
        Neurology. 2007; 68: 1197-1204
        • French J.A.
        • Krauss G.L.
        • Biton V.
        • Squillacote D.
        • Yang H.
        • Laurenza A.
        • et al.
        Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.
        Neurology. 2012; 79: 589-596
        • French J.A.
        • Krauss G.L.
        • Steinhoff B.J.
        • Squillacote D.
        • Yang H.
        • Kumar D.
        • et al.
        Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305.
        Epilepsia. 2013; 54: 117-125
        • French J.A.
        • Krauss G.L.
        • Wechsler R.T.
        • Wang X.F.
        • DiVentura B.
        • Brandt C.
        • et al.
        Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy. A randomized trial.
        Neurology. 2015; 85: 950-957
        • Krauss G.L.
        • Serratosa J.M.
        • Villanueva V.
        • Endziniene M.
        • Hong Z.
        • French J.
        • et al.
        Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures.
        Neurology. 2012; 78: 1408-1415
        • Biton V.
        • Berkovic S.F.
        • Abou-Khalil B.
        • Sperling M.R.
        • Johnson M.E.
        • Lu S.
        Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial.
        Epilepsia. 2014; 55: 57-66
        • Klein P.
        • Schiemann J.
        • Sperling M.R.
        • Whitesides J.
        • Liang W.
        • Stalvey T.
        • et al.
        A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures.
        Epilepsia. 2015; 56: 1890-1898
        • Kwan P.
        • Trinka E.
        • Van Paesschen W.
        • Rektor I.
        • Johnson M.E.
        • Lu S.
        Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial.
        Epilepsia. 2014; 55: 38-46
        • Ryvlin P.
        • Werhahn K.J.
        • Blaszczyk B.
        • Johnson M.E.
        • Lu S.
        Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial.
        Epilepsia. 2014; 55: 47-56
        • Kerrigan J.F.
        • Shields W.D.
        • Nelson T.Y.
        • Bluestone D.L.
        • Dodson W.E.
        • Bourgeois B.F.
        • et al.
        Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.
        Epilepsy Res. 2000; 42: 133-139
        • Laxer K.
        • Blum D.
        • Abou-Khalil B.W.
        • Morrell M.J.
        • Lee D.A.
        • Data J.L.
        • et al.
        Assessment of ganaxolone’s anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group.
        Epilepsia. 2000; 41: 1187-1194
        • Pieribone V.A.
        • Tsai J.
        • Soufflet C.
        • Rey E.
        • Shaw K.
        • Giller E.
        • et al.
        Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy.
        Epilepsia. 2007; 48: 1870-1874
        • Belelli D.
        • Peden D.R.
        • Rosahl T.W.
        • Wafford K.A.
        • Lambert J.J.
        Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics.
        J Neurosci. 2005; 25: 11513-11520
        • Faught E.
        BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy.
        Expert Opin Investig Drugs. 2014; 23: 107-113
        • Kasteleijn-Nolst Trenite D.G.
        • Biton V.
        • French J.A.
        • Abou-Khalil B.
        • Rosenfeld W.E.
        • Diventura B.
        • et al.
        Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy.
        Epilepsia. 2013; 54: 1437-1443
        • Bialer M.
        • Johannessen S.I.
        • Levy R.H.
        • Perucca E.
        • Tomson T.
        • White H.S.
        Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII).
        Epilepsy Res. 2015; 111: 85-141
        • French J.A.
        • Lawson J.A.
        • Yapici Z.
        • Ikeda H.
        • Polster T.
        • Nabbout R.
        • et al.
        Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study.
        Lancet. 2016; 388: 2153-2163
        • Ceulemans B.
        • Boel M.
        • Leyssens K.
        • Van Rossem C.
        • Neels P.
        • Jorens P.G.
        • et al.
        Successful use of fenfluramine as an add-on treatment for Dravet syndrome.
        Epilepsia. 2012; 53: 1131-1139
        • Ceulemans B.
        • Schoonjans A.S.
        • Marchau F.
        • Paelinck B.P.
        • Lagae L.
        Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine.
        Epilepsia. 2016; 57: e129-134
        • Schoonjans A.S.
        • Lagae L.
        • Ceulemans B.
        Low-dose fenfluramine in the treatment of neurologic disorders: experience in Dravet syndrome.
        Ther Adv Neurol Disord. 2015; 8: 328-338
        • Merlet I.
        • Ostrowsky K.
        • Costes N.
        • Ryvlin P.
        • Isnard J.
        • Faillenot I.
        • et al.
        5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study.
        Brain. 2004; 127: 900-913
        • Kasteleijn-Nolst Trenite D.
        • Parain D.
        • Genton P.
        • Masnou P.
        • Schwartz J.C.
        • Hirsch E.
        Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model.
        Epilepsy Behav. 2013; 28: 66-70
        • Bearden D.
        • Strong A.
        • Ehnot J.
        • DiGiovine M.
        • Dlugos D.
        • Goldberg E.M.
        Targeted treatment of migrating partial seizures of infancy with quinidine.
        Ann Neurol. 2014; 76: 457-461
        • Barel S.
        • Yagen B.
        • Schurig V.
        • Soback S.
        • Pisani F.
        • Perucca E.
        • et al.
        Stereoselective pharmacokinetic analysis of valnoctamide in healthy subjects and in patients with epilepsy.
        Clin Pharmacol Ther. 1997; 61: 442-449
        • Asadi-Pooya A.A.
        • Razavizadegan S.M.
        • Abdi-Ardekani A.
        • Sperling M.R.
        Adjunctive use of verapamil in patients with refractory temporal lobe epilepsy: a pilot study.
        Epilepsy Behav. 2013; 29: 150-154
        • Borlot F.
        • Wither R.G.
        • Ali A.
        • Wu N.
        • Verocai F.
        • Andrade D.M.
        A pilot double-blind trial using verapamil as adjuvant therapy for refractory seizures.
        Epilepsy Res. 2014; 108: 1642-1651
        • Di Prospero N.A.
        • Gambale J.J.
        • Pandina G.
        • Ford L.
        • Girgis S.
        • Moyer J.A.
        • et al.
        Evaluation of JNJ-26489112 in patients with photosensitive epilepsy: a placebo-controlled, exploratory study.
        Epilepsy Res. 2014; 108: 709-716
        • Paolino M.C.
        • Ferretti A.
        • Papetti L.
        • Villa M.P.
        • Parisi P.
        Cannabidiol as potential treatment in refractory pediatric epilepsy.
        Expert Rev Neurother. 2016; 16: 17-21
        • Kwan P.
        • Schachter S.C.
        • Brodie M.J.
        Drug-resistant epilepsy.
        N Engl J Med. 2011; 365: 919-926