ASM Pharmacology and Clinical Efficacy 2021 PDF

CNS Drugs
https://doi.org/10.1007/s40263-021-00827-8
REVIEW ARTICLE
The Pharmacology and Clinical Efficacy of Antiseizure Medications:

From Bromide Salts to Cenobamate and Beyond
Wolfgang Löscher1,2 · Pavel Klein3
Accepted: 4 May 2021

© The Author(s) 2021
Abstract
Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previ-
ously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a
multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Further-
more, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder,
and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often
prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma
aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade
of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of
action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy
therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo
and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued
drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30
new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover,
therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall,
the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while
new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse
effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high
quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.
1 Introduction
Key Points
Epilepsy is one of the most common and disabling chronic
neurological disorders, affecting approximately 1% of the Epilepsy is a multifaceted complex disease and so is its
general population. Epilepsy affects all age groups and is treatment.
characterized by an enduring predisposition to generate epi- We review the pharmacology of the ~ 30 approved
leptic seizures and the associated cognitive, psychological, antiseizure medications, including their preclinical and
and social consequences [1]. clinical efficacy, pharmacokinetics, and mechanisms of
action.
We summarize the available data on the > 30 novel epi-
* Wolfgang Löscher lepsy therapies that are in the preclinical or clinical drug
[email protected]
development pipeline, including new potentially disease-
1
Department of Pharmacology, Toxicology, and Pharmacy, modifying treatments.
University of Veterinary Medicine, Bünteweg 17,
30559 Hannover, Germany
2
Center for Systems Neuroscience, Hannover, Germany
3
Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD,
USA
Vol.:(0123456789)
W. Löscher, P. Klein
Epilepsy is not a specific disease, or even a single syn- 2 The Development of Antiseizure
drome, but rather a complex group of disorders with widely Medications
varying types of epileptic seizures, ranging from nonconvul-
sive to convulsive and focal to generalized [2]. Early drugs (such as potassium bromide and phenobarbital),
The causes of epilepsy are only partially understood which were discovered by serendipity, had relatively unfa-
and include a variety of insults that perturb brain function, vorable efficacy-to-tolerability profiles. This changed with
including acquired causes (e.g., stroke or traumatic brain the event of drug screening in animal seizure models in the
injury [TBI]), infectious diseases (such as neurocysticerco- 1930s, initiated by H. Houston Merritt and Tracy J. Putnam.
sis and cerebral malaria), autoimmune diseases, and genetic These scientists, working at the Neurological Unit of the
mutations [1]. Boston City Hospital, used an electroshock seizure model
There is currently no cure, so symptomatic pharmaco- in cats for drug screening for ASM efficacy, leading to the
logical treatment remains the mainstay of therapy for people discovery of phenytoin as the first nonsedating ASM [13].
with epilepsy [3]. Phenytoin (5,5-diphenylhydantoin) was first synthesized
By definition, antiseizure medications (ASMs) prevent or in 1908 as a barbiturate derivative in Germany by Heinrich
suppress the generation, propagation, and severity of epilep- Biltz and subsequently resynthesized by an American chem-
tic seizures. The term “antiseizure medication” has replaced ist at Parke-Davis in 1923 in Detroit. Screening of phenytoin
the old term “anticonvulsant drugs” because epilepsy thera- did not reveal sedative side effects such as those seen with
pies suppress not only convulsive but also nonconvulsive sedative/hypnotic barbiturates, so Parke-Davis discarded this
seizures [4, 5]. Furthermore, the term “antiseizure medica- compound as a useful drug. In 1936, phenytoin’s antiseizure
tion” more and more replaces the term “antiepileptic drug” properties were identified by Putnam and Merritt, who also
because such drugs provide symptomatic treatment only and evaluated its clinical value in a number of patients in the
have not been demonstrated to alter the course of epilepsy period 1937–1940 [14].
[1, 6]. The history of phenytoin is considered a keystone event
Achieving complete seizure control is the most important for drug discovery and development and the beginning of
objective in the treatment of epilepsy. For this goal, ASMs modern ASM development because it demonstrated that (1)
are administered chronically to prevent seizure recurrence systematic screening of large numbers of compounds may
in patients with spontaneous recurrent seizures (SRS). In lead to a hit with the desired effect and (2) an antiseizure
addition, ASMs are being used to treat status epilepticus effect determined in an animal model can be translated to
(SE) and interrupt acute symptomatic seizures in response to patients.
a variety of causes, including intoxication. However, despite As illustrated in Fig. 2, the discovery and subsequent suc-
the availability of numerous ASMs with different mecha- cess of phenytoin led to the systematic search for chemically
nisms of action (MOAs), both SRS and SE may be resist- related and unrelated compounds with antiseizure efficacy
ant to treatment in about 30% of all patients with epilepsy and, subsequently, to the marketing of more than ten novel
[7–10]. Interestingly, seizure freedom outcomes have not ASMs, which are commonly referred to as the “first genera-
changed much since 1939, the year that phenytoin came into tion” of ASMs because they were derived mainly by modifi-
use, in spite of the development of numerous novel ASMs in cation of the barbiturate structure. They include mephobar-
recent decades [9–11]. Mechanisms of ASM resistance are bital, primidone, oxazolidinediones such as trimethadione,
incompletely understood [12]. and succinimides such as ethosuximide.
Epilepsy is a multifaceted complex disease and so is its The second-generation ASMs, including carbamazepine,
treatment. About 30 different ASMs are available for the valproate, and benzodiazepines, which were introduced
treatment of epilepsy (Fig. 1). For the treatment of epilepsy, between 1960 and 1975 (Fig. 2), differed chemically from
the initial ASM should be individualized based on the epi- the cyclic ureides (barbiturates, hydantoins, succinimides,
lepsy syndrome and seizure type, the adverse effects profile, oxazolidinediones; see Fig. 1) and exhibited superior toler-
the pharmacokinetic profile, potential interactions with other ability to cyclic ureide-based structures [15].
drugs, comorbidities that the ASM may affect, the age of the The era of the third-generation ASMs started in the 1980s
patient, reproductive considerations, and cost [1]. with the ‘‘rational’’ development of drugs such as progabide
We review the pharmacology of ASMs, including their and vigabatrin, i.e., drugs that were designed to selectively
preclinical efficacy, pharmacokinetics, and MOAs, and their target a mechanism (GABAergic inhibition) thought to be
clinical efficacy. Rather than discussing each of the ~ 30 critical for ictogenesis [16]. Several of the new drugs that
ASMs separately, we highlight commonalities and differ- have been introduced since the 1980s have advantages over
ences as well as general principles in their pharmacology. the older ASMs in terms of pharmacokinetics and drug–drug
Furthermore, we review novel epilepsy therapies that are in interactions, and some drugs have better tolerability and
the preclinical or clinical drug development pipeline.
Antiseizure Medications
Fig. 1 Chemical structures of clinically approved antiseizure drugs discussed in this review
potentially fewer long-term adverse effects and reduced tera- lacosamide, retigabine, and cannabidiol and a contributory
togenicity, although this remains to be proven. However, as role in the development of vigabatrin, lamotrigine, oxcar-
mentioned, new drugs have not increased the percentage of bazepine, and gabapentin [17–19].
seizure-free patients [1, 8, 10, 11]. One of the most recent third-generation ASMs is cenoba-
The development of third-generation ASMs was spurred mate (Fig. 2), which was approved in 2019 for the treatment
largely by the Anticonvulsant Screening Program, currently of patients with focal-onset seizures. In randomized con-
known as the Epilepsy Therapy Screening Program (ETSP), trolled trials, cenobamate produced high seizure-free rates
set up in 1975 by J. Kiffin Penry at the National Institutes (20/111 subjects [18%] treated with the highest [400 mg/
of Neurological Disorders and Stroke of the National Insti- day] dose during a 12-week maintenance period), suggesting
tutes of Health [17]. Throughout its history, the program has that this novel ASM can outperform existing options [20].
tested over 32,000 compounds from more than 600 phar- This has so far been borne out in long-term open-label exten-
maceutical firms and other organizations and has played sion studies [21]. However, further safety studies and clinical
a major role in the development of felbamate, topiramate, experiences are needed to determine its clinical value.
Fig. 2 Introduction of antiseizure drugs (ASMs) to the market from and benzodiazepines, which were introduced between 1960 and
1853 to 2020. Licensing varied from country to country. Figure 1975, differed chemically from the barbiturates. The era of the third-
shows the year of first licensing or first mention of clinical use in generation ASMs started in the 1980s with “rational” (target-based)
Europe, the USA, or Japan. We have not included all derivatives of developments such as progabide, vigabatrin, and tiagabine, i.e., drugs
listed ASMs nor ASMs used solely for the treatment of status epilep- designed to selectively target a mechanism thought to be critical for
ticus. The first generation of ASMs, entering the market from 1857 the occurrence of epileptic seizures. Note that some drugs have been
to 1958, included potassium bromide, phenobarbital, and a variety removed from the market. Modified from Löscher and Schmidt [11].
of drugs mainly derived by modification of the barbiturate structure, For further details, see Löscher et al. [30]. ACTH adrenocorticotropic
including phenytoin, primidone, trimethadione, and ethosuximide. hormone
The second-generation ASMs, including carbamazepine, valproate,
It is important to note that significant methodologi- Novartis, and Pfizer, have withdrawn from the field. This
cal changes in clinical ASM trials were introduced over has increased interest, particularly among small- and
the eight decades since the discovery of phenytoin [22]. medium-sized companies, in developing novel molecules
Today, the randomized, double-blind, placebo-controlled for orphan indications (i.e., rare genetic epilepsies) where
adjunctive therapy trial in patients with drug-resistant unmet needs are particularly large [22]. In fact, five of
focal seizures continues to be the primary tool to obtain the 11 ASMs introduced after 2005 (vs. none of the
regulatory approval of novel ASMs. Because of the exist- ten ASMs licensed between 1989 and 2005) have been
ence of ~30 ASMs on the market, this creates major hur- licensed exclusively for the treatment of orphan disorders
dles to demonstrating the efficacy of any novel compound, such as Dravet syndrome (stiripentol, cannabidiol, fenflu-
discouraging pharmaceutical companies from investing in ramine), Lennox–Gastaut syndrome (rufinamide, canna-
ASM development [22, 23]. The ASM market is crowded, bidiol), and tuberous sclerosis complex (TSC; everolimus,
and the costs of drug development are steadily increasing. cannabidiol).
As a result, many of the large pharmaceutical companies As shown in Fig. 3, ASMs have a wide clinical spectrum
previously active in epilepsy, such as GlaxoSmithKline, of indications in both epileptic and nonepileptic disorders.
Fig. 3 The clinical spectrum of antiseizure drugs. For details see text. i.v. intravenous
Because of this wide spectrum of therapeutic activity, ASMs (Wistar Albino Glaxo from Rijswijk) model. The MES and
are among the most often prescribed centrally active agents 6-Hz tests are models in which acute seizures are induced
[24, 25]. We compare the preclinical and clinical profiles of by transcorneal electrical stimulation in normal mice or
ASMs in the treatment of epileptic seizures. rats, whereas the kindling and genetic absence models use
animals that exhibit chronic epilepsy-like brain alterations
[29]. Previously, seizures induced by the convulsant pentyl-
3 The Preclinical Profile of Antiseizure enetetrazole (PTZ) have been used as a model for identify-
Medications in the Treatment of Epilepsy ing compounds acting against absence seizures, but the PTZ
model produced too many false-positive and false-negative
During preclinical development, novel ASMs are typically results so has been largely abandoned [27].
being tested in a battery of animal models of seizures and The advantage of using batteries of animal models
epilepsy [15, 19, 26–28]. Only compounds that exert antisei- as shown in Table 1 is their translational value, which is
zure activity at doses far below those inducing behavioral superior to various other areas of neurology [30]. Thus,
adverse effects such as sedation or ataxia are developed starting with phenytoin, all ASMs shown in Figs. 1 and 2
further. were discovered using animal models, such as MES or kin-
A typical battery of rodent seizure models is shown in dling. The best predictivity of clinical activity is obtained
Table 1, including the maximal electroshock seizures (MES) by using amygdala-kindled rats, which correctly predicted
test for identifying efficacy against generalized tonic-clonic the efficacy of numerous ASMs against focal-onset seizures
seizures, the 6-Hz seizure test and chronic kindling mod- in patients (Table 1). The term “kindling” is used for the
els for identifying activity against focal-onset seizures, and progressive development of seizures in response to a pre-
genetic rat models for identifying activity against general- viously subconvulsant stimulus administered in a repeated
ized absence seizures, i.e. the GAERS (Genetic Absence and intermittent fashion [31]. Kindling can be achieved by
Epilepsy Rat from Strasbourg) model and the WAG/Rij electrical stimulation of limbic brain regions such as the

Table 1 Spectrum of antiseizure effects of approved antiseizure medications in preclinical seizure models and patients with epilepsy
Drug Efficacy in preclinical rodent models Clinical efficacy
Primary generalized Focal seizures (6-Hz Focal seizures Absence seizures Focal-onset Primary generalized seizures Lennox–Gastaut Infantile spasms Dravet
tonic-clonic seizures test; 32 or 44 mA) (kindling) (GAERS or WAG/Rij seizures syndrome (West syndrome) syndrome
(MES test) rat strains) Tonic-clonic Absence Myoclonic
Acetazolamidea + ? ?+ ? ?+ ?+ ?+ ?+ ? ? ?
Brivaracetam + + + + + ?+ ?+ ?+ ? ? ?
Cannabidiol + + ?+ ? + ? ? ? + ? +
Carbamazepine + ?+ + 0 + + 0 0 0 0 0
Cenobamate + + + + + ? ? ? ? ? ?
Clobazam + + + ? + + ? + + ?+ +
Clonazepama + + + + + + ? + ?+ ?+ ?+
Eslicarbazepine acetate + + + ? + ? ? ? ? ? ?
Ethosuximide 0 0 0 + 0 0 + 0 0 0 ?+
Felbamate + + + ? + + ?+ ? + + ?
Fenfluramine ?+ ?+ 0 ? ? ? ? ? ? ? +
Gabapentin + + + 0 + ?+ 0 0 ? ? 0
Lacosamide + + + ? + + ? ? ? ? ?
Lamotrigine + 0 + + + + + + + ?+ 0
Levetiracetam 0 + + + + + ?+ + ?+ ? +
Oxcarbazepine + ? + 0 + + 0 0 0 0 0
Perampanel + + + 0 + + ?+ ?+ ?+ ? ?+
Phenobarbital + + + + + + + 0 ? ? ?+
Phenytoin + ?+ + 0 + + 0 0 0 0 0
Pregabalin + + + 0 + ? ? ? ? ? 0
Primidone + ? 0 0 + + 0 ? ? ? ?
Retigabine (ezogabine)b + + + 0 + ? ? ? ? ? ?
Rufinamide + + 0 ? + + ?+ ?+ + ? 0
Stiripentol + ? ? ? + + ?+ + ?+ ?+ +
Sulthiamec + ? ? ?+ ? ? ? ? ? ?+ ?
Tiagabine 0 + + 0 + ? 0 ? ? ?+ 0
Topiramate + 0 + + + + ? + + ? +
Valproate + + + + + + + + + + +
Vigabatrin 0 ? + 0 + ?+ 0 0 ? + 0
Zonisamide + + + ? + ?+ ?+ ?+ ?+ ?+ +
Data sourced from various publications [5, 11, 29, 62, 63, 168, 169] and a PubMed search of recent literature
GAERS genetic absence epilepsy rat from Strasbourg, Hz Herz, MES maximal electroshock seizures, WAG/Rij Wistar Albino Glaxo from Rijswijk, + indicates efficacy, 0 indicates inefficacy or
worsening of seizures, ?+ indicates inconsistent or preliminary findings, ? indicates insufficient data
a
Loss of efficacy (tolerance) during chronic administration
b
Withdrawn in 2017
c
Used in Europe in self-limited childhood (rolandic) epilepsy with centrotemporal spikes
amygdala, by transcorneal application of electrical stimuli, 4 The Clinical Profile and Efficacy

or by convulsants such as PTZ. The best-characterized and of Antiseizure Medications
predictive model is amygdala kindling [29]. Importantly, in the Treatment of Epilepsy
testing of novel compounds in the kindling model was more
predictive of clinical efficacy than testing in the MES test, as Although ASMs share a common property of suppressing
for instance demonstrated by vigabatrin, levetiracetam, and seizures, they all have different pharmacologic profiles that
tiagabine (Table 1). The finding of Löscher and Hönack [32] are relevant when selecting and prescribing these agents in
that levetiracetam is particularly effective in the amygdala- patients with epilepsy and other conditions. This includes
kindling model was essential in the further development of a spectrum of antiseizure efficacy against different types of
this compound, which is now one of the most widely used seizures and epilepsies (Table 1), MOA, pharmacokinetic
ASMs [33]. properties, propensity for drug–drug interactions, and side
As shown in Table 1, ASMs differ markedly in their effect profiles and toxicities.
efficacy in animal models. ASMs can be grouped into As shown in Fig. 1, ASMs markedly differ in their chemi-
three categories: (1) ASMs with a narrow spectrum of cal structures, ranging from barbiturate-like compounds to
efficacy such as ethosuximide (only active against absence γ-aminobutyric acid (GABA) derivatives and branched fatty
seizures) or vigabatrin (active in the kindling model but acids. Often, the success of a novel ASM initiates the syn-
not the other models shown in Table 1); (2) ASMs that thesis and development of additional compounds from the
mainly act in MES and focal-onset seizure models (the same chemical family (Fig. 1), as exemplified by cyclic urei-
vast majority of compounds shown in Table 1), and (3) des (barbiturate-like ASMs such as phenobarbital and primi-
ASMs with a broad spectrum of efficacy such as the ben- done, hydantoins such as phenytoin and fosphenytoin, oxa-
zodiazepines, brivaracetam, topiramate, valproate, and zolidinediones such as trimethadione and paramethadione,
alkyl-carbamates such as cenobamate. At least in part, the and succinimides such as ethosuximide and methsuximide),
preclinical spectrum of antiseizure efficacies resembles iminostilbenes (carbamazepine, oxcarbazepine, eslicarbaz-
the clinical spectrum (Table 1). For instance, ethosux- epine acetate), benzodiazepines (clonazepam, clobazam,
imide is only effective in the GAERS model and almost diazepam, lorazepam, midazolam), piracetam derivatives
exclusively used for the treatment of absence seizures in (levetiracetam, brivaracetam), and alkyl-carbamates (fel-
humans; phenytoin and carbamazepine act mainly against bamate, retigabine, cenobamate).
focal-onset and primarily generalized tonic-clonic seizures The clinical use of ASMs is tailored first by the patient’s
in animal models and patients, and benzodiazepines and type of epilepsy [2]. Only certain ASMs are effective in
valproate exhibit a broad spectrum of preclinical and clini- generalized epilepsies (GE). These include valproate, lev-
cal efficacy. etiracetam, lamotrigine, topiramate, zonisamide, felbamate,
In addition to the preclinical models illustrated in perampanel, and lacosamide. Seizure types within the broad
Table 1, specific animal models for pediatric genetic grouping of GE include primary generalized tonic and tonic-
epilepsies, such as Lennox–Gastaut syndrome, infantile clonic seizures, absence seizures, myoclonic seizures, and
spasms (West syndrome), Dravet syndrome, and TSC can atonic seizures [37]. Although all the ASMs mentioned are
be used to discover novel ASMs for the difficult-to-treat effective against generalized tonic/tonic-clonic seizures,
seizures in these syndromes [34]. As described, several some, such as lamotrigine may be less effective against
ASMs, including cannabidiol, rufinamide, stiripentol, absence seizures and not effective against myoclonic sei-
everolimus, and fenfluramine, are almost exclusively zures. Levetiracetam is effective in generalized tonic-clonic
used in such pediatric epilepsies (Table 1). Furthermore, seizures but not against absence, tonic, or atonic seizures
infantile spasms, which rarely respond to usual ASMs, are (although it is commonly used off-label with those seizures).
treated with high doses of adrenocorticotropic hormone Our knowledge remains insufficient to marry an ASM’s
(ACTH) or prednisone for the rapid and complete elimina- known antiseizure MOA in animals to the treatment of spe-
tion of these seizures. Efficacy has been demonstrated in cific seizure types in humans, primarily because the mecha-
prospective controlled studies [35], but it is not fully under- nisms of ictogenesis in humans are still largely unknown.
stood how these drugs work for this condition. Current Thus, ASMs effective in GE include ASMs with diverse
preclinical models of pediatric epilepsies include mouse, known MOAs, including sodium channel blocking (lamo-
rat, and zebrafish models carrying the mutations that are trigine, lacosamide), presynaptic neurotransmitter release
responsible for the genetic epilepsies as well as in vitro modulation (levetiracetam), antiglutamatergic activity (per-
models, such as induced pluripotent stem cells, which are ampanel), and multiple MOAs (valproate, topiramate, zon-
increasingly used for screening novel compounds for the isamide, felbamate, cannabinoids) [38]. Yet, certain other
treatment of epileptic encephalopathies [36]. ASMs with similar MOA may be ineffective in GE (e.g., the
sodium channel blockers carbamazepine, oxcarbazepine or than to all other ASMs [50, 51] (see below), a weight loss
phenytoin), which may in fact sometimes exacerbate GE- medication with serotonergic MOA.
related seizures [39]. Why one sodium channel blocker is Often, novel ASMs resulting from the structural variation
effective in GE and others are not remains unknown. In some of older ASMs differ in their pharmacology from the older
instances, the use or non-use of an ASM may be dictated drugs in terms of potency, efficacy, spectrum of activity, and
by the regulatory approval process rather than biology. For tolerability. However, most novel (third-generation) ASMs
instance, brivaracetam, closely related to levetiracetam, are not more effective than older drugs [8, 12]. Thus, analy-
which is approved for the treatment of GE, is effective in sis of a longitudinal cohort study of adolescents and adults
several animal models of GE [40] but is not approved for with newly diagnosed epilepsy attending a specialist clinic in
the treatment of GE because the necessary clinical studies Glasgow, Scotland, indicated that levetiracetam, zonisamide,
have not been done. eslicarbazepine acetate, and lacosamide are as efficacious
The second, largest group of epilepsies are focal epilep- as carbamazepine for focal epilepsy [3]. There has been no
sies with focal seizures, with or without evolution to bilat- gain in efficacy with second-generation or third-generation
eral tonic-clonic seizures (previously known as secondary ASMs over valproate for GEs and unclassified epilepsies [3].
generalization). Nearly all medications on the market are In fact, most second- and third-generation ASMs are less
effective in focal seizures, again, without a clear coupling efficacious than valproate in those epilepsies. Similar results
of known MOA and putative mechanisms of ictogenesis of on the comparative efficacies of ASMs were obtained by net-
focal seizures. work meta-analyses of monotherapy studies [52, 53]. Indeed,
The third group includes special epilepsy syndromes, the widespread use and the unsurpassed clinical efficacy of
which may be treated by a limited number of ASMs. These carbamazepine and valproate made them benchmarks for
syndromes include rare childhood epilepsies, comprising comparison with third-generation ASMs [11].
some genetic epilepsies. For absence seizures associated It has been argued that one of the major reasons for the
with childhood or juvenile absence epilepsy, both examples apparent failure to discover drugs with higher efficacy is
of GE, ethosuximide is the drug of choice, followed by val- that, with few exceptions, all ASMs have been discovered
proate and other ASMs used for GE [41]. Ethosuximide has using the same conventional animal models, particularly the
a unique MOA of T-type calcium channel modulation (see MES test in rodents, which served as a critical gatekeeper
Sect. 10). Infantile spasms, primary generalized seizures [11].
of infancy seen with a number of different and often cata- Evaluation of most new ASMs for treatment of epilepsy
strophic causes of epilepsy respond uniquely to the hormone has followed broadly similar randomized, double-blind,
ACTH or to prednisone and to vigabatrin [42, 43]. Len- placebo-controlled study designs in which the new ASM
nox–Gastaut syndrome, a syndrome with multiple seizure or placebo is added to baseline medications in patients with
types, developmental delay, and characteristic slow spike refractory epilepsy; patients are then treated for ~3 months,
and wave electroencephalogram (EEG) characteristics that and seizure frequency is compared between active treatment
can be caused by multiple etiologies, responds to the benzo- and pretreatment baseline periods between the ASM- and
diazepine clobazam and to cannabidiol, amongst others [44]. placebo-treated groups [10, 54, 55]. Standard primary effi-
TSC, which can also result in multiple seizure types, can be cacy outcomes are median percent seizure frequency reduc-
treated specifically and mechanistically by the mechanistic tion and proportion of patients who achieve ≥50% seizure
target of rapamycin (mTOR) inhibitor everolimus [45] in frequency reduction, the 50% responder rate. Secondary
addition to multiple other medications [46]. Surprisingly, efficacy outcomes sometimes include 75% responder rate
this mechanistically very targeted form of treatment appears and seizure freedom. Results of pivotal studies of different
to be no more effective than treatment with other ASMs new ASMs cannot be directly compared, but it is striking
whose MOA is unrelated to the cause of TSC. A rare genetic that, until recently, the outcome figures were very similar for
form of severe epilepsy, Dravet syndrome, can similarly be most of the new ASMs. Most ASMs achieve 20–30% median
treated by clobazam and cannabidiol but with only modest seizure frequency reduction over and above placebo effect
results [47, 48]. In 80% of cases, this condition is caused and a 30–50% responder rate [10, 55–58]. In the more recent
by de novo mutations in the gene responsible for voltage- studies, 75% responder rate has been achieved in about 20%
gated sodium channel protein SCNA1 or 2, which results of patients. Typically, seizure freedom rate is low, ranging
in loss of function of small inhibitory neurons, increase in from 2 to 5% [59, 60].
hyperexcitability, and seizures that are very difficult to treat Recently, a possible breakthrough may have been
[49]. Treatment with sodium channel blockers exacerbates achieved for two new medications. In adults with refrac-
seizures in Dravet syndrome. Seizures in Dravet syndrome tory focal epilepsy, treatment with a new ASM, cenobamate,
appear to be significantly more responsive to fenfluramine resulted in seizure freedom of 21% of patients treated with
the highest approved dose, 400 mg/day, during the 12-week cause central nervous system (CNS) side effects, such as
maintenance period (20/111; 18% of all patients when those somnolence, fatigue, and dizziness, many have ASM-spe-
who discontinued the study during the titration period were cific side effect potential, which should be avoided in poten-
included) [61]. The seizure freedom was sustained in an tially vulnerable patients. For instance, valproate may cause
open-label extension study with treatment lasting up to 4 weight gain, hyperandrogenemia, metabolic syndrome, exac-
years [21]. Cenobamate has two known MOAs: a block of erbation of diabetes, polycystic ovarian syndrome, hepatitis,
the “persistent current” of the voltage-gated sodium chan- and pancreatitis and should therefore be avoided in patients
nels and a weak positive allosteric modulation of GABA-A with these conditions or predisposition for them [70]. Other
receptors [62]. In children with Dravet syndrome, treatment medications that may cause weight gain include gabapentin,
with the serendipitously discovered weight-loss medication pregabalin, vigabatrin, and benzodiazepines. One common
fenfluramine similarly resulted in an 8% seizure freedom mechanism of these drugs that could explain weight gain is
during the entire 14-week treatment period, which was also the potentiation of GABAergic inhibition by presynaptic or
sustained long term [50]. Fenfluramine acts primarily as postsynaptic effects (see Sect. 10).
a serotonin releasing agent but also positively modulates Phenytoin, phenobarbital, carbamazepine, oxcarbaze-
different subtypes of serotonin receptors and the sigma 1 pine, and lamotrigine have the potential for serious allergic
receptor [38]. In both cenobamate and fenfluramine, it is reaction and should be eschewed in patients who have had
unknown whether the known MOAs are responsible for the previous serious or multiple allergic drug reactions [71].
notably higher efficacy rates of these medications compared Phenytoin, phenobarbital, carbamazepine, valproate, and
with all other new ASMs. zonisamide can cause liver disease. Valproate should be
avoided in liver-compromised patients, and caution should
be exercised when using the other medications in these
5 The Selection of Antiseizure Medications patients [72]. Topiramate and zonisamide can both cause
for the Treatment of Epilepsy in Children renal stones and are therefore not a good choice in patients
and Adults with a history of renal stones. Levetiracetam can cause or
exacerbate depression and anxiety, and both it and peram-
The number of available ASMs has increased rapidly in the panel can cause irritability, hostility, and anger and should
past 30 years, giving more choice when initiating therapy probably be avoided or used with caution in patients with
but also making drug selection a much more complex pro- significant psychiatric disease [8]. Carbamazepine and its
cess. Major evidence-based guidelines have been devel- derivatives, oxcarbazepine and eslicarbazepine, can cause
oped during this time, assisting clinicians and patients in hyponatremia, which is most common in the elderly treated
making appropriate treatment choices in newly diagnosed with antihypertensives such as diuretics or angiotensin-con-
epilepsy [63, 64]. These include guidelines issued by the verting enzyme inhibitors [73]. The old hepatic enzyme-
International League Against Epilepsy [65, 66], the Ameri- inducing medications—phenytoin, phenobarbital, and car-
can Academy of Neurology/American Epilepsy Society bamazepine—and also long-term treatment with valproate
[67, 68], and others. These guidelines are based on the best can contribute to osteoporosis, particularly in postmenopau-
available evidence. However, they are limited by the lack sal women or immobile patients with epilepsy and severe
of controlled head-to-head comparative efficacy studies for encephalopathy, and should be avoided in these patients
most ASMs. They may not be a substitute for knowledge, [74]. Phenytoin, phenobarbital, and carbamazepine also have
skill, and experience in managing individual patients [63]. the potential to cause hypoandrogenism and hyposexuality
Figure 4 shows an extract of these guidelines and common (in both males and females) [75]. Valproate and lamotrigine
treatment options, including more recent ASMs. can cause or exacerbate tremor and are therefore not the
The availability of so many ASMs allows for some tailor- drugs of choice for patients with essential tremor.
ing of treatment to each patient’s specific situation, even if The potential for secondary effects can also be used to
the relevance of the ASM’s MOA to the patient’s seizures advantage where these secondary effects may be beneficial.
is unknown and the efficacy may be similar to that of many Valproate and topiramate are effective antimigraine treat-
other ASMs. The patient specificity of ASM choices may ments and are used for dual purpose in patients with epilepsy
relate to the ASM’s side effect profile; its potential beneficial and migraine [76]. Valproate and lamotrigine are both effec-
or adverse effect on the patient’s comorbid conditions; the tive in mood stabilization and treatment of bipolar affective
potential for drug–drug interactions or lack thereof; ease of disorder and depression, both common morbidities in epi-
use, such as initiation titration and once-daily administra- lepsy; carbamazepine and oxcarbazepine are also sometimes
tion; and specific patient populations such as the elderly, used off-label for mood stabilization [77, 78]. Pregabalin
those planning pregnancy, and patients with renal or liver and clonazepam have anxiolytic effects and may be used
disease [1, 69]. While most ASMs have the potential to for comorbid anxiety [77]. Topiramate, zonisamide, and
Fig. 4 Choice of antiseizure
medications (ASMs) in adults
and children. Common first
monotherapy refers to the first
treatment choice in a patient
without any specific factors
precluding the use of this.
Monotherapy alternatives refer
to ASMs chosen when certain
patient- or ASM-related fac-
tors preclude the use of the
first-choice ASM. Data from
various sources [63, 64, 67,
68] and guidelines discussed in
these papers. Note that several
additional childhood epilepsy
syndromes are not illustrated in
this figure. ACTH adrenocorti-
cotropic hormone
felbamate may cause weight loss; topiramate and zonisamide the treatment of fibromyalgia, and carbamazepine, gabapen-
can be used beneficially in patients with epilepsy and obe- tin, and pregabalin are used for the treatment of restless leg
sity. Notably, topiramate, one of a number of serendipitously syndrome [83–85]. Primidone and topiramate are treatments
discovered ASMs, was initially developed for the treatment for essential tremor [86].
of type 2 diabetes mellitus [79]. Phenobarbital, gabapentin, Valproate, phenobarbital, and topiramate increase the risk
pregabalin, and perampanel all have sedating effects, which of major congenital malformations in babies born to peo-
can help with insomnia, another common comorbidity of ple with epilepsy and should therefore be avoided in those
epilepsy [80]. Gabapentin, pregabalin, carbamazepine, and planning to conceive or who are pregnant [87]. Valproate in
oxcarbazepine may be effective in painful neuropathy [81, addition negatively impacts fetal neurocognitive develop-
82]. Carbamazepine and oxcarbazepine are used for the ment, reducing the child’s intelligence quotient and increas-
treatment of trigeminal neuralgia, pregabalin is indicated for ing the risk for autism [87, 88]. Conversely, lamotrigine
and levetiracetam have been shown to have no increase in Patients with drug-resistant epilepsy are often treated
the risk of major congenital malformation and are ASMs with more than one ASM. Robust evidence to guide clini-
of choice for people planning pregnancy. The elderly are cians on when and how to combine ASMs is lacking, and
often more sensitive to the adverse events of ASMs and current practice recommendations are largely empirical
are also often on multiple other medications [89]. ASMs [93–95]. A popular strategy for combination therapy is a
with a good side effect profile and little or no interaction pharmacomechanistic approach based on the (perceived)
with other drugs are of advantage in this population. These modes of action of ASMs (see Sect. 10). For instance,
include levetiracetam, gabapentin, pregabalin, lamotrigine, Deckers et al. [96] reviewed the available animal and human
and lacosamide. data and concluded that combinations involving a sodium
For patients with renal disease, drugs that are renally channel modulator and a drug with GABAergic properties
excreted should be used with caution or avoided. These appeared to be particularly beneficial. Indeed, one of the few
include, amongst others, levetiracetam, lacosamide, gabap- clinically proven synergistic ASM combinations is a com-
entin, and pregabalin. In patients with liver disease, liver- bination of lamotrigine and valproate [97, 98]. In general,
metabolized medications such as phenytoin, phenobarbital, mainly based on data in animal models, combining ASMs
carbamazepine, valproate clobazam, and cannabidiol are with different MOAs seems to provide greater effectiveness
best avoided [88]. and a lower risk of adverse events than combining ASMs
Drug–drug interactions and pharmacokinetics are also with similar mechanisms [95, 99]. However, one drug spe-
important in the choice of ASM. This can be complicated, cifically developed on this principle, padsevonil, which has
but a number of the new ASMs have little or no drug–drug a dual action of synaptic vesicle protein (SV)-2A, B, and
interactions and straightforward pharmacokinetics [90]. C modulation and GABA-A receptor potentiation, failed a
These include levetiracetam, brivaracetam, lacosamide, recently completed phase IIb study, leading to discontinua-
gabapentin, and pregabalin. Medications that are easy to tion of its development.
use, with quick straightforward titration or no titration (e.g.,
levetiracetam, brivaracetam, oxcarbamazepine, eslicarbaze-
pine, lacosamide, and zonisamide as well as the older ASMs 7 Aggravation of Seizures by Antiseizure
phenytoin, phenobarbital, and carbamazepine) may be easier Medications
for a patient to use and adhere to than medications with more
complicated slower initiation, which may be necessary to ASMs may also aggravate seizures, including an increase in
mitigate the side effect potential, for instance with lamo- the frequency or severity of existing seizures, the emergence
trigine, topiramate, perampanel, or cenobamate. of new types of seizures, or the occurrence of SE [100–102].
Seizure aggravation by ASMs is an infrequent phenomenon,
occurring mostly in primary GE treated with drugs that are
6 Resistance to Antiseizure Medications more efficacious against partial seizures [103]. Thus, a major
in Patients with Epilepsy reason for seizure aggravation is an inappropriate choice of
ASMs, which is best documented for the use of carbamaz-
An unresolved problem is the drug resistance of many types epine in idiopathic generalized and myoclonic epilepsies
of epilepsy, including temporal lobe epilepsy (TLE), the [101]. Most other ASMs have been reported only occasion-
most common type of epilepsy in adults [9]. More than 50% ally to cause seizure aggravation. In addition to inappropri-
of patients with TLE do not become seizure free with the ate choice of ASMs, risk factors for worsening of seizures
current ASMs, despite the diverse MOAs by which these are polytherapy, excessive ASM doses with some ASMs,
compounds work (see below). Thus, preclinical models high frequency of seizures, epileptic encephalopathy, and
reflecting such ASM resistance were developed and now cognitive impairment [100–102].
are used after the drug identification phase shown in Table 1
for further differentiation of novel compounds [19]. Exam-
ples are the lamotrigine-resistant amygdala-kindled rat 8 Use of Antiseizure Medications for Acute
model [91] and amygdala-kindled rats selected for resist- Interruption of Seizures, Seizure Clusters,
ance to phenytoin and other ASMs [92]. Such models are, or Status Epilepticus
for instance, used in the differentiation phase of the ETSP
[19]. It remains to be established whether the implementa- In addition to using ASMs for long-term oral treatment of
tion of models of ASM resistance will lead to more effective patients with SRS, several ASMs are used for acute inter-
drugs. In this respect, drugs that combine several MOAs ruption or prevention of acute symptomatic seizures, sei-
may be particularly interesting, as exemplified by the novel zure clusters, and SE (Fig. 3). Acute symptomatic seizures
ASM cenobamate. by definition occur in close proximity to an event and are
considered to be situational [104, 105]. Acute sympto- are the most commonly used agents, partly because of their
matic (or provoked) seizures must be distinguished from short half-life. Barbiturates (pentobarbital or phenobarbi-
unprovoked seizures and may occur as a result of tempo- tal) were common agents in the past but have largely been
rary metabolic, toxic, and other systemic illness, e.g., due replaced because of their long half-life, which makes neuro-
to illicit drugs, drug withdrawal, toxins, or drug adverse logical evaluation difficult when the agent is stopped. About
effects or overdose. Furthermore, acute symptomatic sei- 20–40% of patients with SE exhibit treatment resistance
zures (or early seizures) may occur in the first week after a despite aggressive treatment [113]. The short-term fatality
brain lesion or an injury such as stroke, TBI, or infectious rates for resistant SE (RSE) have been estimated as between
encephalitis. While intravenous benzodiazepines are used 16 and 39%; mortality after RSE is about three times higher
as rescue treatment for acute symptomatic seizures associ- than for nonrefractory SE [113].
ated with metabolic, toxic, and other systemic illness, acute Additional indications of ASMs in the pediatric popula-
symptomatic seizures associated with brain insults such tion include the treatment of neonatal seizures and febrile
as may occur during the first week after TBI are typically seizures (Fig. 3). Neonatal seizures are the most frequent
prevented by treatment with ASMs such as levetiracetam, neurological event in newborn babies, most commonly due
phenytoin, valproate, carbamazepine, or lacosamide after to hypoxic–ischemic encephalopathy as a result of birth
the insult [105]. asphyxia [114]. Despite suboptimal efficacy, intravenous
Seizure clusters, i.e., acute repetitive seizures, are broadly phenobarbital remains the first-line ASM of choice for
defined as intermittent stereotypic episodes of frequent sei- interruption of neonatal seizures [115]. In a recent mul-
zure activity with periods of recovery, thus distinguishing ticenter, randomized, blinded, controlled, phase IIb trial,
seizure clusters from SE [106–108]. While there are differ- intravenous phenobarbital was more effective than intra-
ent definitions of cluster seizures, the most inclusive one venous levetiracetam for the treatment of neonatal sei-
is two or more seizures within 24 h. Cluster seizures are zures, but higher rates of adverse effects were seen with
not uncommon, with their frequency estimated in differ- phenobarbital treatment [116]. There is an urgent need
ent studies as between ~15 and 70% of patients with epi- for more effective treatments for neonatal seizures to be
lepsy. Seizure clusters occur despite optimal/maximal oral developed, and a variety of animal models is used in this
therapy with ASMs and are distinguishable from a patient’s respect [117].
“normal” seizure pattern. Cluster seizures are a medical Febrile seizures are the most common neurologic dis-
emergency unique to patients with epilepsy, whereas SE order of infants and young children, occurring in 2–4% of
can occur in any individual, thereby further differentiating children aged < 5 years [118]. Febrile seizures are caused
these two clinical conditions. Until recently, rectal diazepam by a spike in body temperature, often from an infection.
gel was the only US FDA-approved rescue medication for Most febrile seizures are self-limited (“simple febrile sei-
seizure clusters. In 2019 and 2020, the FDA approved two zures”); however, when seizures last longer than 5 min-
nasal sprays, one with diazepam and the other with mida- utes (“complex febrile seizures” or “febrile SE”), a ben-
zolam, as rescue treatments for seizure clusters in people zodiazepine should be administered to break the seizure
with epilepsy. In addition, buccal midazolam is approved in [118]. A 2018 Cochrane review concluded that intravenous
European countries for the treatment of prolonged seizures lorazepam and diazepam have similar rates of seizure ces-
and is under review by the FDA for use in the USA. How- sation and respiratory depression [119]. When intravenous
ever, various non-rectal non-intravenous benzodiazepines access is unavailable, buccal midazolam or rectal diazepam
are safe and effective in treating acute seizures and clusters is acceptable.
[107, 108].
SE, the condition of ongoing seizures or repetitive seizure
activity without recovery of consciousness between seizures, 9 Use of Antiseizure Medications
is a life-threatening emergency that necessitates immedi- for Nonepileptic Conditions
ate treatment [109]. The most common treatment protocols
for SE specify an intravenous benzodiazepine (either mida- ASMs are used not only for the treatment of seizures and
zolam, lorazepam, or diazepam) as initial ASM therapy, SE but also for nonepileptic conditions (Fig. 3), includ-
followed—if seizures continue—by fosphenytoin (or phe- ing migraine headache, chronic neuropathic pain, mood
nytoin), valproate, levetiracetam, or, if none of the afore- disorders (such as bipolar disorder), generalized anxiety
mentioned options are available, phenobarbital [110–112]. disorder, schizophrenia, and various neuromuscular syn-
If seizures continue, either second-line therapy is repeated, dromes [24, 25, 120, 121]. In many of these conditions,
other medications such as lacosamide or topiramate may be as in epilepsy, the drugs act by modifying the excitabil-
used, or third-line therapy is instituted using intravenous ity of nerve (or muscle) through effects on voltage-gated
sedation (“therapeutic coma”). Propofol and midazolam sodium and calcium channels or by promoting inhibition
mediated by GABAA receptors (see below). Examples of 10 Mechanisms of Action of Antiseizure

ASMs approved for the treatment of nonepileptic condi- Medications
tions are gabapentin and pregabalin for neuropathic pain,
carbamazepine for trigeminal neuralgia, valproate and In recent years, there have been dramatic advances in our
lamotrigine for bipolar disorder, benzodiazepines for gen- understanding of how ASMs prevent seizures. As shown
eralized anxiety disorder, and valproate and topiramate for in Fig. 5 and Table 2, current ASMs act by diverse molecu-
migraine (see also Sect. 5). In addition, combined findings lar mechanisms. Based on their molecular targets, ASMs
of randomized controlled trials and meta-analyses indicate can be categorized into drugs that act quite selectively via
that pregabalin is efficacious in both acute treatment and a single target (e.g., several of the sodium channel modula-
relapse prevention in generalized anxiety disorder [121, tors) or act more broadly via several targets (e.g., valproate,
122]. Pregabalin was approved for generalized anxiety topiramate, felbamate, and cenobamate). ASMs that act via
disorder in the European Union in 2006 [121]. Further- several targets are typically also wide-spectrum ASMs in
more, based on randomized controlled trials, zonisamide the clinic (Table 1).
is considered a safe and efficacious add-on treatment in The actions of most ASMs on molecular targets can be
Parkinson‘s disease [123], whereas no robust efficacy was categorized into four broad groups [38, 126]: (1) modula-
reported for topiramate or levetiracetam [124]. Preliminary tion of voltage-gated ion channels, including sodium, cal-
clinical data indicated that cannabidiol improved quality of cium, and potassium channels; (2) enhancement of GABA-
life but not motor symptoms in patients with Parkinson’s mediated inhibition through effects on G ABAA receptors,
disease [125], and larger randomized controlled trials are the GABA transporter (GAT)-1, GABA transaminase, or the
ongoing [124]. GABA synthesizing enzyme glutamate decarboxylase; (3)
Fig. 5 Mechanism of action of clinically approved antiseizure medi- mechanism(s) of action are described in Table 2. AMPA α-amino-3-
cations (ASMs) [162]. Updated and modified from Löscher and hydroxy-5-methyl-4-isoxazolepropionic acid, GABA γ-aminobutyric
Schmidt [167] and Löscher et al. [33]. Asterisks indicate that these acid, GABA-T GABA aminotransferase, GAT-1 GABA transporter 1,
compounds act by multiple mechanisms (not all mechanisms shown KCNQ Kv7 potassium channel family, NMDA N-methyl-D-aspartate,
here). Some ASMs, e.g., fenfluramine, are not shown here, but their SV2A synaptic vesicle protein 2A
Table 2 Molecular targets of clinically used antiseizure medications [38, 126, 170, 171]
Mechanistic classes of antiseizure medications Antiseizure medications that belong to this mechanistic class
Modulators of voltage-gated sodium channels

Increase of fast inactivation (transient sodium current; INaT) Phenytoin, fosphenytoina, carbamazepine, oxcarbazepineb, eslicarbaze-
pine acetatec, lamotrigine; possibly topiramate, zonisamide, rufina-
mide, brivaracetam
Increase of slow inactivation Lacosamide
Block of persistent sodium currents (INaP) Cenobamate, lacosamide, carbamazepine, oxcarbazepine, eslicarbaz-
epine, lamotrigine, phenytoin, topiramate, valproate, gabapentin,
cannabidiol
Blockers of voltage-gated calcium channels (T-type)
High-voltage activated Phenobarbital, phenytoin, levetiracetam
Low-voltage activated T-type ( Cav3) Ethosuximide (Cav3.2 > Cav3.1), methsuximide, eslicarbazepine
(Cav3.2); possibly valproate
Activators of voltage-gated potassium channels (Kv7) Retigabine (ezogabine)
Modulators of GABA-mediated inhibition
Allosteric modulators of GABAA receptors Phenobarbital, primidone, stiripentol, benzodiazepines, (including clon-
azepam, clobazam, diazepam, lorazepam, and midazolam), topira-
mate, felbamate, retigabine (ezogabine), cenobamate
Inhibitors of GAT1 GABA transporter Tiagabine
Inhibitors of GABA transaminase Vigabatrin
Activators of glutamic acid decarboxylase Possibly valproate, gabapentin, pregabalin
Inhibitors of ionotropic glutamate receptors
Antagonists of NMDA receptors Felbamate, topiramate, possibly valproate
Antagonists of AMPA receptors Perampanel, phenobarbital, levetiracetam
Modulators of the presynaptic release machinery
SV2A Levetiracetam, brivaracetam
α2δ subunit of calcium channels Gabapentin, pregabalin
Inhibitors of carbonic anhydrase Acetazolamide, sulthiame, topiramate, zonisamide; possibly lacosamide
Serotonin-releasing agents Fenfluramine
Disease-specific modulators
Inhibitors of mTORC1 s ignalingd Everolimus
Lysosomal enzyme r eplacemente Cerliponase alfa (recombinant tripeptidyl peptidase 1)
Mixed/unknown Valproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorti-
cotrophin, cannabidiol, cenobamate, potassium bromide
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA γ-aminobutyric acid, GAT GABA transporter, mTORC1 mechanistic tar-
get of rapamycin complex 1, NMDA N-methyl-D-aspartate, SV2A synaptic vesicle protein 2A
a
Fosphenytoin is a prodrug for phenytoin
b
Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine (eslicarbazepine)
c
Eslicarbazepine acetate is a prodrug for S-licarbazepine (eslicarbazepine)
d
In patients with epilepsy due to tuberous sclerosis complex
e
In patients with epilepsy due to neuronal ceroid lipofuscinosis type 2
inhibition of synaptic excitation mediated by ionotropic glu- or excitatory neurotransmission. By these actions, ASMs
tamate receptors, including N-methyl-D-aspartate (NMDA) reduce the probability of seizure occurrence by modifying
and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate the bursting properties of neurons (reducing the capacity of
(AMPA) receptors; and (4) direct modulation of synaptic neurons to fire action potentials at a high rate) and reducing
release through effects on components of the release machin- synchronization in localized neuronal ensembles. In addi-
ery, including SV2A and the α2δ subunit of voltage-gated tion, ASMs inhibit the spread of abnormal firing to adjacent
calcium channels (Table 2). The result of the interactions at and distant brain sites [126].
these diverse targets is the modification of the intrinsic excit- Also, inhibition of carbonic anhydrases is involved in the
ability properties of neurons or alteration of fast inhibitory MOA of several ASMs (Table 2). Drugs whose antiseizure
action includes carbonic anhydrase inhibition include TSC is a rare genetic neurocutaneous disorder with epilep-
acetazolamide, topiramate, and zonisamide. Inhibition of tic seizures as a common and early presenting symptom.
carbonic anhydrases reduces the buffering properties of the TSC is caused by loss-of-function mutations in the TSC1 or
HCO3−/CO2 buffer system, leading to acidosis at the whole- TSC2 genes, which lead to constitutive mTOR activation,
organism level, including in the brain. The fall in brain pH resulting in abnormal cerebral cortical development with
suppresses neuronal excitability [126]. The protective action multiple focal structural malformations [132]. Treatment
of carbonic anhydrase inhibitors in generalized seizures has with the mTOR inhibitor everolimus is thus directly aimed
been attributed to the high pH sensitivity of hyperpolariza- at the underlying dysfunction of the affected cells, which
tion-activated and cyclic nucleotide-gated (HCN) channels led to the suggestion that it may modify the disease [132].
in thalamocortical neurons. Dysregulation of HCN channels However, everolimus has not yet fully lived up to its promise
has been strongly implicated in various experimental models as a disease-modifying drug. At least half of patients with
of epilepsy, as well as in human epilepsy, including TLE. In TSC with intractable epilepsy have not shown a clinically
addition to carboanhydrase inhibitors, several other ASMs, relevant seizure frequency reduction. Furthermore, there is
including lamotrigine and gabapentin, have been reported to no evidence yet of a positive effect on the cognitive and
modulate the hyperpolarization-activated ( Ih) current con- neuropsychiatric deficits in patients with TSC [134]. On the
ducted by HCN channels [127]. other hand, everolimus has demonstrated significant reduc-
It should be considered that the mechanisms of ASMs tions in tumor volume in subependymal giant cell astrocy-
illustrated in Table 2 and Fig. 5 focus on the primary MOAs tomas associated with TSC, which led to the approval of the
of ASMs, where these are known. Many drugs used cur- drug for this indication [135].
rently in the treatment of epilepsy have additional, less Concerning disease modification in TSC, recent clini-
well-characterized pharmacological effects that manifest cal data with the GABA-T inhibitor vigabatrin are of inter-
at therapeutic concentrations and might contribute to the est, as they suggest that vigabatrin may have antiepilepto-
drug’s overall clinical profile [38]. genic effects in TSC [131]. Vigabatrin also partly inhibits
More recently, novel epilepsy therapies have been devel- mTOR. It is the treatment of choice for infantile spasms, a
oped that act by disease-specific mechanisms, including common early, severe seizure manifestation in TSC. Serial
everolimus (inhibition of mTOR signaling in TSC) and cer- EEGs started shortly after birth have shown that epileptiform
liponase alfa (for lysosomal enzyme replacement in neuronal activity predictably precedes the onset of seizures. Treat-
ceroid lipofuscinosis type 2) [38]. The latter treatments are ment with vigabatrin starting at the time of appearance of
examples of “precision medicine,” a relatively new area of epileptiform activity instead of at the time of onset of sei-
disease-specific therapies that may revolutionize the therapy zures reduces the risk of seizures and drug-resistant epilepsy
of genetic epilepsies [128]. Indeed, there is now cause for [136].
optimism that we are entering a new paradigm where it will Given the precedent of preventive clinical trials with
be possible to engineer specific treatments for some geneti- vigabatrin for epilepsy in TSC, similar preventive trials with
cally defined epilepsies using disease-mechanism-targeted mTOR inhibitors are in the planning stages but have not yet
small molecules, antisense, gene therapy with viral vectors, been conducted [131]. One barrier to progress has been the
and other biological approaches [38]. Such novel thera- concern for potential adverse effects of mTOR inhibitors
pies may lead to a cure for certain epilepsies [129]. In this in young infants, given the role of the mTOR pathway in
respect, it is also important to note that numerous scientists normal growth and development.
are working on developing novel antiepileptogenic therapies
to prevent epilepsy after head injury in patients at risk [130],
and antiepileptogenic or disease-modifying therapies are an 12 Pharmacokinetics of Antiseizure
area of intensive research in childhood epilepsies [131]. Medications
However, the role of the pharmaceutical industry in devel-
oping antiepileptogenic or disease-modifying therapies for Therapy of epilepsy by ASMs necessitates continuous
patients at risk is currently low. (24/7) maintenance of effective drug levels in the brain
over many years. Thus, current ASMs need to meet several
pharmacokinetic criteria, including (1) bioavailability after
11 Are Some Antiseizure Medications oral administration, (2) sufficiently long half-lives to mini-
also Antiepileptogenic? mize the frequency of daily drug administrations, and (3)
brain target engagement, i.e., sufficient penetration into the
It has been suggested that everolimus not only suppresses brain. To fulfill the third criterion, ASMs are typically small,
seizures in patients with TSC but also may have the potential lipophilic, and uncharged to enable penetration through the
to be a disease-modifying therapy in this disease [132, 133]. blood–brain barrier by passive diffusion [137]. There are
Table 3 Elimination half-life of clinically approved antiseizure medications in adult humans: for comparison, half-lives are shown for adult rats
and mice to demonstrate the marked interspecies differences in drug elimination
Medication Elimination half-life (h) Comments
Humans Rats Mice
Acetazolamide 10–15 0.33 ?

Brivaracetam 7–8 2.8 ?
Cannabidiol 18–32 7.8 4.7
Carbamazepine 25–50 1.2–3.5 3.4 Reduction of half-life during chronic treatment (autoinduction)
Cenobamate 50–60 2.9 ?
Clobazam 10–30 1 0.25 Active metabolite = norclobazam
Clonazepam 17–56 ? 2.1
Eslicarbazepine acetate 10–20 ? 5.2 Half-lives refer to active metabolite = (S)-licarbazepine (eslicarbazepine)
Ethosuximide 40–60 10–16 ?
Everolimus ~ 30 20 4.3 Long persistence in the brain
Felbamate 16–22 2–17 ? In rodents, nonlinear kinetics (half-life increases with increasing doses)
Fenfluramine 13–30 2.6 4.3 Active metabolite = norfenfluramine
Gabapentin 5–9 2–3 ?
Lacosamide 13 3 ?
Lamotrigine 15–35 12–> 30 ?
Levetiracetam 6–8 2–3 1.5
Oxcarbazepine 8–15 0.7–4 6.8 Half-lives refer to active metabolite = (S)-licarbazepine (eslicarbazepine)
Perampanel 70 2 ?
Phenobarbital 70–140 9–20 4–7.5 Reduction of half-life during chronic treatment (autoinduction)
Phenytoin 15–20 ~ 2 5–16 Nonlinear kinetics (half-life increases with increasing doses); autoinduction
Pregabalin 5–7 ? ?
Primidone 6–12 5 2.2 Active metabolite = phenobarbital; autoinduction
Retigabine (ezogabine) 6–8 ? ?
Rufinamide 6–10 ~ 8 ?
Stiripentol 4.5–13 13 ?
Sulthiame 2–16 ? ?
Tiagabine 5–9 1 ?
Topiramate 20–30 2.5 ?
Valproate 8–15 ~1.5 0.8 In rodents, nonlinear kinetics (half-life increases with increasing doses)
Vigabatrin 5–8 ~ 1 ? Duration of action independent of half-life because of irreversible inhibi-
tion of GABA degradation
Zonisamide 50–70 8 ?
Data are from various sources [138, 145, 146, 172] and were updated for this article
? indicates that no data were found in the PubMed database
some exceptions to this criterion, namely everolimus, which acetate, which acts as a prodrug of (S)-licarbazepine (i.e.,
(similar to the prototype mTOR inhibitor rapamycin) only eslicarbazepine), which is also the main active metabolite of
poorly penetrates into the brain, necessitating high plasma oxcarbazepine (Table 3). Other medications act as both par-
levels that may be associated with severe adverse effects. ent compounds and active metabolites (e.g., carbamazepine,
Other examples for relatively poor brain penetration are clobazam, diazepam, cannabidiol).
vigabatrin and valproate, whereas the majority of ASMs are Table 3 also illustrates the striking interspecies dif-
brain permeant [137]. Concerning elimination, all ASMs ferences in ASM elimination, which must be considered
have sufficiently long half-lives to enable maintenance of when using such drugs for preclinical rodent studies, in
active drug levels with one to two administrations per day terms of both dosing intervals and interspecies allomet-
(Table 3). Several ASMs mainly act by active metabolites ric scaling of doses [138]. Such interspecies differences
Examples are primidone (a prodrug of phenobarbital), fos- are often ignored or not known when conducting pre-
phenytoin (a prodrug of phenytoin), and eslicarbazepine clinical studies, which may lead to false-negative data.
Extrapolation of doses between species is also of crucial 14 Therapeutic Drug Monitoring

importance when estimating the starting dose of novel
compounds for clinical trials, necessitating allometric Measuring ASM plasma concentrations (therapeutic drug
scaling [139]. As indicated in Table 3, vigabatrin differs monitoring [TDM]) can have a valuable role in guiding
from other ASMs in that, although its half-life is shorter in patient management [142, 146]. TDM is useful (1) to estab-
rodents than in humans, its pharmacodynamic effects last lish an individual therapeutic concentration that can sub-
for days in both rodents and humans through irreversible sequently be used to assess potential causes for a change
inhibition of GABA-T [126]. in drug response; (2) as an aid in the diagnosis of clinical
toxicity; (3) to assess compliance, particularly in patients
with uncontrolled seizures or breakthrough seizures; (4)
13 Pharmacokinetic Drug–Drug Interactions to guide dosage adjustment in situations associated with
increased pharmacokinetic variability (e.g., children, the
Several first-generation ASMs, including carbamazepine, elderly, patients with associated diseases, drug formulation
phenytoin, phenobarbital, and primidone, are inducers of changes); (5) when a potentially important pharmacokinetic
isoforms of cytochrome P450 (CYP) enzymes involved in change is anticipated (e.g., in pregnancy, or when an inter-
drug metabolism. Primarily, this is clinically relevant with acting drug is added or removed); and (6) to guide dose
carbamazepine, leading to autoinduction of ASM metabo- adjustments for ASMs with dose-dependent pharmacokinet-
lism during continued treatment and, thus, the development ics, particularly phenytoin [144]. In addition, some ASMs
of pharmacokinetic tolerance [140]. Furthermore, the induc- are heavily protein bound in blood, commonly to albumin.
tion of these enzymes can lower the plasma concentration These include phenytoin, diazepam, and valproate. For these
and hence the efficacy of many psychotropic, immunosup- ASMs, the clinically important blood level is the free (i.e.,
pressant, antineoplastic, antimicrobial, and cardiovascular protein non-bound) level. This may fluctuate according to
drugs [141]. Importantly, carbamazepine, phenytoin, pheno- albumin levels. Thus, in conditions where albumin levels
barbital, oxcarbazepine, eslicarbazepine acetate, felbamate, may change, such as during pregnancy, in liver disease, and
perampanel (at 12 mg/day), and topiramate (at > 200 mg/ in the elderly, both total and free levels of these medications
day) all increase the metabolic clearance of contraceptive should be checked if possible.
steroids, potentially reducing their efficacy and increasing Analysis of ASM plasma levels is also useful when
the risk of unwanted pregnancies [141]; cenobamate may translating preclinical to clinical ASM efficacies [138]. In
have the same potential. Several of the newer ASMs do not fact, effective plasma ASM levels are remarkably similar
affect hepatic drug-metabolizing enzymes and are renally in humans and laboratory rodents (rats, mice). However,
excreted, resulting in a lower potential for drug interactions because of the marked differences in the elimination kinet-
[11, 142]. ics of ASMs between humans and rats (Table 3), rodents
However, pharmacokinetic drug–drug interactions may require much higher doses than humans to achieve and main-
also occur with third-generation ASMs. A recent exam- tain similarly effective ASM levels [138]. Thus, as discussed
ple is the interaction between cannabidiol and clobazam; earlier, interspecies allometric scaling of doses is necessary
cannabidiol causes a three- to fivefold increase in plasma when extrapolating ASM doses from rodents to humans or
concentration of clobazam’s active metabolite norclobazam vice versa [139].
by inhibiting the metabolism of norclobazam during com-
bined treatment [143, 144]. Thus, in four pivotal randomized
placebo-controlled trials of adjunctive therapy with canna- 15 Tolerability and Safety of Antiseizure
bidiol in patients with Dravet syndrome and Lennox–Gastaut Medications
syndrome, at least part of cannabidiol’s antiseizure effects
was due to the inhibited metabolism of norclobazam [143]. Patient tolerability of adverse drug effects is integral to suc-
In turn, clobazam inhibits the metabolism of cannabidiol, cessful treatment [147]. Most modern ASMs are well-toler-
thereby increasing its plasma levels. Similar to cannabid- ated by many patients, which has led to the abandonment of
iol, stiripentol, by inhibition of CYP enzymes, can elevate old treatments such as potassium bromide or phenobarbital,
the plasma concentration of norclobazam and other ASMs which are less tolerable than more modern epilepsy thera-
[145]. Another recent example of complex drug–drug inter- pies [148]. However, phenobarbital still has an important
actions is cenobamate, which decreases plasma concentra- role in the global management of epilepsy, particularly in
tions of lamotrigine and carbamazepine and increases levels resource-poor countries [149]. The most frequently observed
of phenytoin and phenobarbital and of clobazam’s active adverse effects of ASMs are dose dependent and revers-
metabolite norclobazam [145]. ible and include sedation, fatigue, dizziness, coordination
disturbances (ataxia, dysarthria, diplopia), tremor, cogni- combination therapy [3, 8, 94]. As a general rule, treatment
tive deficits, mood alterations, and behavioral changes [141, of epilepsy should be started with a single, appropriately
148]. However, the adverse effect profiles of individual chosen ASM, and combination therapy should be reserved
ASMs may differ greatly and are often a determining factor for patients refractory to two or more sequential (or alter-
in drug selection because of the similar efficacy rates shown native) monotherapies [156]. However, most patients with
by most ASMs. Arguably the most concerning adverse refractory epilepsy take two, three, or even four ASMs [94].
effects associated with ASM usage are idiosyncratic reac- As discussed in Sect. 6, although polytherapy for those who
tions, such as skin rashes, which can be of sudden onset and do not benefit from single-drug treatment is the recom-
sometimes life threatening [148]. Adverse events of ASMs mended standard, little information is available as to which
are described in detail in Sect. 5. drugs might work best in combination, so current practice
Furthermore, possible teratogenic effects of ASMs are recommendations are largely empirical [93–95]. In compari-
of great concern and the risks imposed by the drugs must son with monotherapy, polytherapy gives rise to increased
be weighed against the risks associated with the disorder adverse effects, drug–drug interactions, poorer compliance,
being treated [150]. For instance, the use of valproate mono- higher cost, and, sometimes, decreased seizure control com-
therapy in pregnancy is associated with increased risks for pared with adequately chosen and dosed monotherapy [156,
spina bifida and other major malformations, and valproate 157]. In many instances, polytherapy could be avoided by
exposure in utero can also result in subsequent impaired more careful monitoring and supervision of therapy. Poly-
cognitive development in the infant and increased risk of therapy is clinically useful in a minority of subjects [8] but
autism. These risks are dose (and blood-level) dependent. has been poorly studied despite being a standard treatment
There is also evidence of dose-dependent teratogenicity with strategy for over 100 years [158]. In fact, no evidence-
several other ASMs, including phenobarbital and topiramate based data show a significant difference in seizure outcome
[148, 150]. Detailed knowledge of the adverse effect profiles between monotherapy and polytherapy [158]. Because of
of all ASMs is an essential component of treating epilepsy this, the need for maintaining polypharmacy should be reas-
successfully and maintaining a high quality of life for every sessed at regular intervals, and monotherapy should be re-
patient, particularly those receiving polypharmacy for drug- instituted whenever appropriate [156].
resistant seizures [148].
An important aspect that is often ignored during the pre-
clinical development of novel ASMs is that the chronic brain 17 New Antiseizure Medications
alterations associated with epilepsy may change the adverse in the Preclinical or Clinical Pipeline
effect profile of drugs [16]. An early example illustrating
this problem was that of the competitive antagonists of the As shown in Table 4, > 30 novel ASMs are in the preclinical
NMDA subtype of glutamate receptors, which were well- or clinical drug development pipeline. These compounds
tolerated in healthy volunteers but induced serious CNS act by various mechanisms, including some MOAs that
adverse effects in patients with focal epilepsy [16]. This are not shared by approved ASMs. Also, the renaissance
enhanced potential for NMDA receptor antagonists to induce of “GABAergic” compounds is interesting to note, includ-
severe adverse effects in epilepsy was correctly predicted in ing compounds that act as positive allosteric modulators
amygdala-kindled rats, i.e., a chronic model of focal epilep- (PAMs), inhibitors of GABA degradation with higher selec-
togenesis, but not in nonepileptic rodents [16, 151]. Thus, tivity and tolerability than vigabatrin, and inhibitors of the
kindled or epileptic animals should be included in preclini- GABA transporter GAT-1. PAMs that only act as partial or
cal adverse effect testing of novel ASMs [29, 30, 152, 153]. subtype-selective agonists at GABAA receptors are thought
to resolve the main disadvantages of previous G ABAA
receptor agonists, i.e., tolerance and dependence liability.
16 Polytherapy vs. Monotherapy This approach is not new but has been used by several phar-
maceutical companies in the 1980/90s in the search for non-
Throughout most of history, treatment of epilepsy has usu- sedative anxioselective compounds [159]. Furthermore, one
ally involved the use of many agents in combination, that such compound, abecarnil, has been evaluated in patients
is, polytherapy [154]. Indeed, ASMs were frequently used with photosensitive epilepsy [160]. Whether this approach
as polytherapy until evidence from a series of studies in the leads to more effective antiseizure drugs is currently not
late 1970s and early 1980s suggested that patients derived as known. However, one low-affinity partial G ABAA receptor
much benefit from monotherapy as from polytherapy [155]. agonist, imepitoin, was approved in 2013 for epilepsy treat-
However, the global introduction of numerous new ASMs ment in dogs (Fig. 2) and was shown to be as effective as
over the past 30 years as adjunctive treatment in refrac- phenobarbital [161]. Novel GABAergic compounds may be
tory epilepsy has triggered increased interest in optimizing particularly interesting for genetic epilepsies with GABA
Table 4 New antiseizure medications in different phases of preclinical and clinical development [23, 165, 171, 173–177]
Mechanistic class/drug Company/university Mechanism of action Indication (targeted) Development phase Comments
PAMs at inhibitory or excitatory receptors

JNJ-40411813 Janssen PAM of mGlu2 Not yet known; highly effec- Phase IIa Potentiated levetiracetam in
tive in 6-Hz mouse model, 6-Hz model
but not MES and PTZ tests;

focal epilepsy
CVL-865 (formerly Cerevel Therapeutics α1-sparing GABAA receptor Focal seizures Phase II Also evaluated in chronic low
PF-06372865) (α2/3) PAM back pain and generalized
anxiety disorder. Should be
more tolerable than PAMs
that also modulate the
α1-subunit
Ganaxolone (analog of the Marinus Pharmaceuticals Neurosteroid that acts as PAM Refractory SE; CDKL5 defi- Phase III (SE) Open-label study of ganaxolone
endogenous neurosteroid on synaptic and extrasynap- ciency disorder or PCDH19- in seizures due to TSC has
allopregnanolone) tic GABAA receptors related epilepsy; TSC been initiated
Zuranolone (SAGE 217) SAGE Therapeutics Synthetic neurosteroid that Seizures (based on preclinical Phase I–3 (but not for epi- In clinical development for
acts as PAM on synaptic data) lepsy) major depressive disorder,
and extrasynaptic GABAA postpartum depression,
receptors treatment-resistant depres-
sion, generalized anxiety
disorder, bipolar disorder
SAGE 324 SAGE Therapeutics Synthetic neurosteroid that Epileptiform disorders Phase I Also developed for essential
acts as PAM on synaptic tremor and Parkinson’s
and extrasynaptic GABAA disease
receptors
Gaboxadol (OV101; THIP) Ovid Therapeutics Orthosteric agonist of G
ABAA Angelman syndrome and Phase III First published in 1977; pat-
receptors with high affinity Fragile X syndrome ent 1979 (Lundbeck). In
at extrasynaptic δ-subunit- Angelman syndrome, loss
containing receptors that of synaptic G
ABAA receptor
mediate tonic inhibition subunits but preservation of
extrasynaptic receptors →
drugs that act as agonists
at extrasynaptic receptors
increase tonic inhibition
Selurampanel Novartis AMPA receptor antagonist Focal epilepsy Phase II No current information;
has also been evaluated in
migraine

Table 4 (continued)
JNJ‐55511118 Janssen Negative modulator of AMPA Epilepsy Phase I Modulation of AMPA receptor
receptors containing TARP‐ signaling using a selective
γ8 TARP-γ8 mechanism has
two distinct advantages:
the expression of TARP-γ8
within the brain indicates that
the drug will have its largest
effect within the hippocam-
pus while avoiding direct
inhibitory effects on brain
regions involved in motor
coordination and wakeful-
ness. Second, the compound
negatively modulates but does
not completely inhibit AMPA
receptor signaling
Presynaptic effects on GABAergic transmission
OV329 Ovid Therapeutics Inhibitor of the GABA- Infantile spasms Preclinical More selective than vigabatrin
degrading enzyme GABA-T
E2730 Esai GAT1 inhibitor Epilepsy Phase I Expected to be a new treatment
for neurological diseases such
as epilepsy, including orphan
epilepsy and epileptogenesis
Serotonergic mechanisms
EPX-100 Epygenix Acts via modulation of Dravet syndrome Phase II Derivative of the antihistamine
serotonin clemizole
Lorcaserin (E2023) Eisai Inc. 5-HT2c receptor agonist Dravet syndrome Phase II Phase III study was initiated
for this indication. US FDA
designated it as an orphan
drug for Dravet syndrome
Potassium channel (KCNQ; Kv7) openers
XEN1101 Xenon Pharmaceuticals PAM of neuronal Kv7.2–7.5 Adult focal epilepsy Phase II Second-generation Kv7 chan-
(KCNQ2–5) potassium nel opener
channels
XEN496 (retigabine or Xenon Pharmaceuticals KCNQ (Kv7) channel opener Precision medicine for the Phase III planned New oral formulation
ezogabine) treatment of seizures (multiparticulate granule
associated with KCNQ2 formulation) of retigabine
developmental and epileptic [ezogabine]) i.e., a drug that
encephalopathy was previously approved for
focal epilepsy in adults
KB-3061 Knopp Biosciences Novel Kv7.2/7.3 modulator Precision medicine for the Preclinical
treatment of seizures
associated with KCNQ2
developmental and epileptic
encephalopathy
Sodium channel modulators
NBI-921352 (XEN901) Xenon Pharmaceuticals Selective inhibitor of Nav1.6 SCN8A developmental and Phase I
sodium channels epileptic encephalopathy
and adult focal epilepsy
TD561 and TD562 (oxyny- OB Pharmaceuticals Potent modulatory activity Active in kindling and 6-Hz Preclinical
tones) at voltage‐gated sodium models
channels
Calcium-channel modulators
ACT-709478 Parexel International Blocks three T-type calcium Absence epilepsy Phase I
channel subtypes
CX-8998 Jazz Pharmaceuticals Blocks Cav3 isoform of Absence epilepsy Phase II Also evaluated for essential
T-type calcium channels tremor
FV-137 Trillium Therapeutics Inhibits P/Q-type Ca2+ Broad spectrum potential for Preclinical Emerged from combining Tril-
channels Cav2.1/β4/α2δ1 both focal and generalized lium’s proprietary chemistry
and Cav2.2/β3/α2δ1 and seizures platform with the NIH’s
voltage-gated Na+ channels ETSP in vivo phenotypic
Nav1.6 and Nav1.7 screening strategy
Anti-inflammatory mechanisms
GAO-3-02 (synaptamide GAOMA Therapeutics Anti-inflammatory Not yet known; exerts antisei- Preclinical Cognition-enhancing effect?
derivative) zure effects in amygdala-
kindled rats, but not in PTZ
model
VX-765 (belnacasan) Vertex Pharmaceuticals Inhibits caspase-1 and thus Focal epilepsy Phase II Unimpressive efficacy; has
IL-1β production also been evaluated in other
indications; current status
unknown
Natalizumab Biogen Inhibits leukocyte migra- Focal epilepsy Phase IIa (failed) Approved (Tysabri®) for
tion across the blood–brain therapy of multiple sclerosis
barrier
Anakinra Different academic sites Antagonist at recombinant FIRES (anecdotal clinical ? Mixed results in FIRES. Tocili-
human IL-1 receptors data) zumab used as an alternative.
Anakinra is approved for
the treatment of rheumatoid
arthritis and other inflamma-
tory conditions (Kineret®)

Drugs with multiple mechanisms

Padsevonil UCB Pharma Combines a modulatory effect Drug-resistant focal epilepsy Phase IIb The drug exhibited promising
at SV2A, SV2B, and SV2C effects in phase IIa but failed
with partial effect at the in phase IIb
benzodiazepine site of the
GABAA receptor
Naluzotan Proximagen Dual serotonin (5-HT)1A Focal epilepsy Phase II Was under investigation for
receptor agonist and sigma-1 the treatment of generalized
receptor antagonist anxiety disorder and major
depressive disorder. Current
status unknown
Carisbamate SK- Biopharmaceuticals Blocks voltage-gated N
a+ Lennox–Gastaut syndrome Phase Ib//2 Previously developed for
channels, T-type calcium therapy of drug-resistant focal
channels, and AMPA- and epilepsy, but development
NMDA-receptor mediated halted because of inconsist-
excitatory neurotransmission ent efficacy across different
clinical trials
FV-082 Trillium Therapeutics Multifactorial (interacts with Broad spectrum potential for Preclinical Emerged from combining Tril-
androgen receptors and both focal and generalized lium’s proprietary chemistry
human recombinant enzyme seizures platform with the NIH’s
monoamine oxidase type ETSP in vivo phenotypic
B and inhibits the voltage- screening strategy
gated Na+ channel Nav1.8)
Other mechanisms
2-deoxy-d-glucose (2-DG) NeuroGenomeX and Univer- Inhibits glycolysis in response Limited repetitive dosing for Preclinical; phase II planned Cardiac toxicity. Acute repeti-
sity of Wisconsin to neural activity SE, acute repetitive seizures, tive administration of 2-DG
and focal brain delivery in after both major and mild
combination with brain- traumatic brain injury may
stimulation device therapies prevent delayed consequences
such as posttraumatic epi-
lepsy and posttraumatic stress
disorder
ANAVEX2-73 (blarcamesine) Anavex Life Sciences SIGMAR1 agonist Rett syndrome, infantile Phase I–III for different Also developed for Alzheimer’s
spasms, Fragile X indications disease and Parkinson’s
disease dementia
Soticlestat (OV935/TAK-935) Ovid Pharmaceuticals & Inhibitor of CH24H Dravet and Lennox–Gastaut Phase II Encouraging first data
Takeda Pharmaceuticals syndromes
Huperzine A Supernus Pharma/Biscayne Increasing cholinergic and Dravet syndrome Phase I Huperzine A is a natural
Neurotherapeutics GABAergic signaling compound extracted from the
through suppression of ace- Chinese club moss Huperzia
tylcholine esterase activity serrata. Novel extended-
in the cortex release oral dosage form is
being developed
receptor mutations and other alterations in the GABAergic
Please note that, for most of the investigational compounds shown here, generic names are not yet available, so code designations of the companies involved are given. Note that the list may not
ETSP Epilepsy Therapy Screening Program, FDA US Food and Drug Administration, FIRES febrile-infection–related epilepsy syndrome, GABA gamma aminobutyric acid, GABA-T GABA
aminotransferase, GAT-1 GABA transporter 1, IL interleukin, KCNQ Kv7 potassium channel family, MES maximal electroshock seizure, mGlu2 metabotropic glutamate receptor type 2, mTOR
2-DG 2-deoxyglucose, 5-HT 5-hydroxytryptamine, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, CDKL5 cyclin-dependent kinase-like 5, CH24H cholesterol 24-hydroxylase,
mechanistic target of rapamycin, NIH National Institutes of Health, NMDA N-methyl-D-aspartate, PAM positive allosteric modulator, PCDH19 protocadherin 19, PI3K phosphoinositide 3
chemical group are developed
PQR compounds of the same
as rapamycin or everolimus.
tolerable than rapalogs such
system.
Compounds are much more
brain permeant and more
Indeed, in addition to compounds that are developed for
the treatment of adult drug-resistant focal epilepsies, an
for cancer treatment

increasing number of new medications are developed for
childhood epilepsies, including Dravet and Lennox–Gastaut
kinase, PTZ pentylenetetrazole, SE status epilepticus, SIGMAR1 sigma 1 receptor, TARP transmembrane AMPA receptor regulatory protein, TSC tuberous sclerosis complex
syndromes. It remains to be proven whether any of these new
Comments
ASMs is more efficacious than existing ASMs.

As described in Sect. 11, in addition to new ASMs, the
development of novel therapeutic strategies to prevent
or modify epilepsy is an intensive area of research. This
includes evaluation of ASMs such as vigabatrin, peram-
panel, or eslicarbazepine acetate for antiepileptogenic or
Development phase
disease-modifying potential in patients at risk of developing

genetic or acquired epilepsies. Also, as described in Sect. 10,
Preclinical
mTOR inhibitors such as everolimus may exert disease-

modifying effects in patients with TSC. A novel strategy for
epilepsy prevention is to form rationally chosen combina-
tions of repurposed drugs that target several of the processes
involved in epileptogenesis [30, 162, 163]. Another interest-
ing approach of disease modification is increasing the brain
Indication (targeted)
concentration of the endogenous neuromodulator adeno-

sine by inhibiting its degradation, which can be achieved by
inhibitors of the astroglial enzyme adenosine kinase [164].
A new category of novel potentially disease-modifying
medications is antisense oligonucleotide therapy, which
TSC
modulates splicing of pre-messenger RNA transcript to

bypass exon nonsense mutations [165]. For instance, non-
Inhibition of mTORC1/C2 or
sense mutations in sodium channel (SCN1A) and GABRG2

account for a proportion of Dravet syndrome. Antisense oli-
Mechanism of action
gonucleotide therapies under preclinical or clinical devel-

PI3K/mTORC1/2
opment in epilepsy include ataluren, STK-001, and CUR-

196 [165]. Furthermore, preclinical findings support gene
therapy studies in Dravet syndrome [165].
18 Conclusions and Outlook
The ideal ASM protects against different types of epilep-

Company/university
Piqur Therapeutics
tic seizures without adversely affecting the function of the

CNS and inducing adverse effects that impair the patient’s
quality of life. Because seizure activity represents a subtle
functional perturbation of the normal physiologic activity
of the nervous system, this goal is difficult to attain. Conse-
quently, CNS adverse effects of ASMs are common. They
can have a considerable impact on the quality of life and they
PQR530, PQR620, PQR626
contribute to treatment failure. This is probably because all

Mechanistic class/drug
current ASMs have been developed to counteract the hyper-

excitability of neurons by targeting mechanisms that also

interfere with normal neurotransmission; this is why they
be complete
all—to a large extent—have similar issues associated with

CNS tolerability [30]. Nevertheless, the long-held goal of
epilepsy treatment, of “no seizures and no side effects,” can
be achieved in a substantial proportion (~50%) of patients Declarations

with epilepsy.
Epilepsy is a diverse disease, with multiple seizure Funding Open Access Publishing enabled and organized by Projekt
types and epilepsy syndromes, and is associated with sub- DEAL. The open access publication was supported by the Deutsche
Forschungsgemeinschaft and University of Veterinary Medicine Han-
stantial comorbidity, including depression, anxiety, and nover, Foundation, within the funding program. No sources of funding
increased mortality [1]. ASMs are often unable to treat were used to conduct this study or prepare this manuscript.
these comorbidities or to reduce the burden of disease in a
holistic sense [30]. Furthermore, current ASMs are unable Conflict of interest WL and PK are co-founders as well as CFO and
to prevent or reverse the development of drug-resistant CSO, respectively, of PrevEp, Inc. (Bethesda, MD, USA). PrevEp did
not fund this review and played no role in the writing of the review.
epilepsy. A particularly disquieting aspect of current
WL was involved in the development of levetiracetam (UCB Pharma)
epilepsy treatments is that we have not made substantial and imepitoin (Elbion/Boehringer Ingelheim); has received consultan-
progress in seizure freedom despite the development of cy fees from Lundbeck, AC Immune, Clexio Biosciences, UCB Phar-
numerous “modern” (third-generation) ASMs. However, ma, Pragma Therapeutics, Boehringer Ingelheim, Pfizer, and Johnson
& Johnson; and has served on the advisory boards of Grünenthal, UCB
there is some evidence that third-generation ASMs may in
Pharma, and Angelini Pharma. PK receives grant support from CURE/
some cases be associated with better tolerability, includ- US Department of Defense; has received consulting or speaker fees
ing fewer or no dermatological hypersensitivity reactions from or been on the advisory boards of Abbot, Aquestive, Arvelle, Ei-
[148] and lack of drug–drug interactions, and may pos- sai, Greenwich Pharmaceuticals, Neurelis, SK Life Science, Sunovion,
and UCB Pharma; and is on the medical advisory board of Alliance-
sibly be associated with lessening of seizure severity and
Stratus and the scientific advisory board of OB Pharma.
frequency. Furthermore, very recently, two ASMs were
introduced that may achieve seizure freedom in a signifi- Ethics approval Not applicable.
cant proportion of patients with drug-resistant epilepsy:
Consent to participate Not applicable.
cenobamate in focal epilepsy and fenfluramine in Dravet
syndrome [166]. Consent for publication Not applicable.
Our understanding of the mechanisms mediating the
development of epilepsy and the causes of drug resistance Availability of data and material Not applicable.
has grown substantially over the past two decades, providing
Code availability Not applicable.
opportunities for the discovery and development of more
efficacious ASMs. For this goal, it is mandatory to revisit Author contributions WL and PK performed the literature search and
ASM discovery and development. The focus should be on wrote the manuscript. Both authors read and approved the final manu-
script.
new treatments that address key unmet medical needs: that
is, drug-resistant epilepsy, comorbidities, refractory SE, and
epilepsy prevention. Furthermore, treatments that modify Open Access This article is licensed under a Creative Commons Attri-
bution-NonCommercial 4.0 International License, which permits any
the natural history of epilepsy, rendering the disease less
non-commercial use, sharing, adaptation, distribution and reproduction
progressive and easier to treat, would be highly welcome in any medium or format, as long as you give appropriate credit to the
given that new-onset epilepsy is progressive in as many as original author(s) and the source, provide a link to the Creative Com-
one in three patients [30]. Identifying interventions that will mons licence, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative
prevent the development of epilepsy in patients at risk, as
Commons licence, unless indicated otherwise in a credit line to the
well as cure the disorder once established, will require a material. If material is not included in the article’s Creative Commons
multifaceted approach from basic scientists and clinicians licence and your intended use is not permitted by statutory regula-
as well as industry [129]. A major incentive for the industry tion or exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this licence, visit
to adopt this approach and to execute it successfully will be
http://creativecommons.org/licenses/by-nc/4.0/.
the availability of valid and druggable targets, interpretable
and target-population-relevant preclinical proof-of-concept
studies, disease and target-related biomarkers, diagnostic
methodology for the identification of the specific patient References
populations, and innovative clinical trial designs [30].
1. Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, De
Acknowledgements This review is dedicated to the late Professor Curtis M, Perucca P. Epilepsy. Nat Rev Dis Prim. 2018;4:18024.
Hans-Hasso Frey, who acted as a mentor for W. Löscher throughout 2. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J,
his scientific career. Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli
DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM.
ILAE classification of the epilepsies: position paper of the ILAE
Commission for Classification and Terminology. Epilepsia. 24. Rogawski MA, Löscher W. The neurobiology of antiepileptic
2017;58:512–21. drugs for the treatment of nonepileptic conditions. Nat Med.
3. Chen Z, Brodie MJ, Kwan P. What has been the impact of new 2004;10:685–92.
drug treatments on epilepsy? Curr Opin Neurol. 2020;33:185–90. 25. Bialer M. Why are antiepileptic drugs used for nonepileptic con-
4. Browne TR. Drug therapy reviews: clinical pharmacology of ditions? Epilepsia. 2012;53(Suppl 7):26–33.
antiepileptic drugs. Am J Hosp Pharm. 1978;35:1048–56. 26. Swinyard EA, Kupferberg HJ. Antiepileptic drugs: detection,
5. Shorvon S, Perucca E, Engel JJ (2020) The treatment of epilepsy. quantification, and evaluation. Fed Proc. 1985;44:2629–33.
Third edition. In: Shorvon S, Perucca E, Engel JJ (eds) (Oxford: 27. Löscher W, Schmidt D. Which animal models should be used
Wiley-Blackwell). in the search for new antiepileptic drugs? A proposal based
6. Porter RJ, Dhir A, Macdonald RL, Rogawski MA (2012). Mecha- on experimental and clinical considerations. Epilepsy Res.
nisms of action of antiseizure drugs. In: Stefan H, Theodore WH, 1988;2:145–81.
editors. Handbook of clinical neurology, vol. 108. Amsterdam: 28. Bialer M, White HS. Key factors in the discovery and devel-
Elsevier. pp. 663–681. opment of new antiepileptic drugs. Nat Rev Drug Discov.
7. Kwan P, Brodie MJ. Early identification of refractory epilepsy. 2010;9:68–82.
N Engl J Med. 2000;342:314–9. 29. Löscher W. Fit for purpose application of currently existing ani-
8. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in mal models in the discovery of novel epilepsy therapies. Epilepsy
patients with newly diagnosed epilepsy treated with established Res. 2016;126:157–84.
and new antiepileptic drugs: a 30-year longitudinal cohort study. 30. Löscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues
JAMA Neurol. 2018;75:279–86. for antiepileptic drug discovery and development. Nat Rev Drug
9. Janmohamed M, Brodie MJ, Kwan P. Pharmacoresistance— Discov. 2013;12:757–76.
epidemiology, mechanisms, and impact on epilepsy treatment. 31. Sato M, Racine RJ, McIntyre DC. Kindling: basic mecha-
Neuropharmacology. 2020;168:107790. nisms and clinical validity. Electroenceph Clin Neurophysiol.
10. Perucca E, Brodie MJ, Kwan P, Tomson T. 30 years of second- 1990;76:459–72.
generation antiseizure medications: impact and future perspec- 32. Löscher W, Hönack D. Profile of ucb L059, a novel anticonvul-
tives. Lancet Neurol. 2020;19:544–56. sant drug, in models of partial and generalized epilepsy in mice
11. Löscher W, Schmidt D. Modern antiepileptic drug development and rats. Eur J Pharmacol. 1993;232:147–58.
has failed to deliver: ways out of the current dilemma. Epilepsia. 33. Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H.
2011;52:657–78. synaptic vesicle glycoprotein 2A ligands in the treatment of epi-
12. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resist- lepsy and beyond. CNS Drugs. 2016;30:1055–77.
ance in epilepsy: clinical impact, potential mechanisms, and new 34. Demarest ST, Brooks-Kayal A. From molecules to medicines:
innovative treatment options. Pharmacol Rev. 2020;72:606–38. the dawn of targeted therapies for genetic epilepsies. Nat Rev
13. Putnam TJ, Merritt HH. Experimental determination of the Neurol. 2018;14:735–45.
anticonvulsant properties of some phenyl derivatives. Science. 35. Brunson KL, Avishai-Eliner S, Baram TZ. ACTH treatment of
1937;85:525–6. infantile spasms: mechanisms of its effects in modulation of neu-
14. Keppel Hesselink JM, Kopsky DJ. Phenytoin: 80 years young, ronal excitability. Int Rev Neurobiol. 2002;49:185–97.
from epilepsy to breast cancer, a remarkable molecule with mul- 36. Niu W, Parent JM. Modeling genetic epilepsies in a dish. Dev
tiple modes of action. J Neurol. 2017;264:1617–21. Dyn. 2020;249:56–75.
15. Löscher W. Animal models of seizures and epilepsy: past, pre- 37. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen
sent, and future role for the discovery of antiseizure drugs. Neu- FE, Lagae L, Moshé SL, Peltola J, Roulet PE, Scheffer IE, Zuberi
rochem Res. 2017;42:1873–88. SM. Operational classification of seizure types by the Interna-
16. Löscher W, Schmidt D. Strategies in antiepileptic drug develop- tional League Against Epilepsy: Position Paper of the ILAE
ment: is rational drug design superior to random screening and Commission for Classification and Terminology. Epilepsia.
structural variation? Epilepsy Res. 1994;17:95–134. 2017;58:522–30.
17. Porter RJ, Kupferberg HJ. The anticonvulsant screen- 38. Sills GJ, Rogawski MA. Mechanisms of action of currently used
ing program of the national institute of neurological disor- antiseizure drugs. Neuropharmacology. 2020;168:107966.
ders and stroke, NIH: history and contributions to clinical 39. Berkovic SF. Aggravation of generalized epilepsies. Epilepsia.
care in the twentieth century and beyond. Neurochem Res. 1998;39(Suppl 3):S11–4.
2017;42:1889–93. 40. Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y,
18. Kehne JH. National Institute of Neurological Disorders and De Ryck M, Kaminski RM, Leclercq K, Niespodziany I, Wolff
Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). C, Wood M, Hannestad J, Kervyn S, Kenda B. Brivaracetam:
Neurochem Res. 2017;42:1894–903. rationale for discovery and preclinical profile of a selective SV2A
19. Wilcox KS, West PJ, Metcalf CS. The current approach of the ligand for epilepsy treatment. Epilepsia. 2016.
epilepsy therapy screening program contract site for identify- 41. Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D,
ing improved therapies for the treatment of pharmacoresistant Clark PO, Capparelli EV, Adamson PC. Ethosuximide, valproic
seizures in epilepsy. Neuropharmacology. 2020;166:107811. acid, and lamotrigine in childhood absence epilepsy. N Engl J
20. French JA. Cenobamate for focal seizures - a game changer? Nat Med. 2010;362:790–9.
Rev Neurol. 2020;16:133–4. 42. Song JM, Hahn J, Kim SH, Chang MJ. Efficacy of treatments
21. Klein P, Krauss GL, Aboumatar S, Kamin M. Long-term effi- for infantile spasms: a systematic review. Clin Neuropharmacol.
cacy and safety of adjunctive cenobamate in patients with uncon- 2017;40:63–84.
trolled focal seizures: open-label extension of a randomized clini- 43. Riikonen R. Infantile spasms: outcome in clinical studies. Pediatr
cal study. Neurology. 2020;94(Suppl. 15):1008. Neurol. 2020;108:54–64.
22. Perucca E. Antiepileptic drugs: evolution of our knowledge and 44. Verrotti A, Striano P, Iapadre G, Zagaroli L, Bonanni P, Coppola
changes in drug trials. Epileptic Disord. 2019;21:319–29. G, Elia M, Mecarelli O, Franzoni E, Liso P, Vigevano F, Curatolo
23. Boada CM, French JA, Dumanis SB. Proceedings of the 15th
antiepileptic drug and device trials meeting: state of the science.
Epilepsy Behav. 2020;111:107189.
P. The pharmacological management of Lennox–Gastaut syn- seizures: a multicentre, double-blind, randomised, placebo-con-
drome and critical literature review. Seizure. 2018;63:17–25. trolled, dose-response trial. Lancet Neurol. 2020;19:38–48.
45. French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout 62. Guignet M, Campbell A, White HS. Cenobamate (XCOPRI®):
R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, can preclinical and clinical evidence provide insight into its
Peyrard S, Pelov D, Franz DN. Adjunctive everolimus therapy mechanism of action? Epilepsia. 2020;61:2329–39.
for treatment-resistant focal-onset seizures associated with tuber- 63. Stephen LJ, Brodie MJ. Selection of antiepileptic drugs in adults.
ous sclerosis (EXIST-3): a phase 3, randomised, double-blind, Neurol Clin. 2009;27:967–92.
placebo-controlled study. Lancet. 2016;388:2153–63. 64. Boon P, Ferrao SS, Jansen AC, Lagae L, Legros B, Weckhuysen
46. Canevini MP, Kotulska-Jozwiak K, Curatolo P, La Briola F, S. Recommendations for the treatment of epilepsy in adult and
Peron A, Slowinska M, Strzelecka J, Vignoli A, Jozwiak S. Cur- pediatric patients in Belgium: 2020 update. Acta Neurol Belg.
rent concepts on epilepsy management in tuberous sclerosis com- 2021;121:241–257.
plex. Am J Med Genet C Semin Med Genet. 2018;178:299–308. 65. Glauser T, Ben Menachem E, Bourgeois B, Cnaan A, Chadwick
47. Wheless JW, Fulton SP, Mudigoudar BD. Dravet syndrome: a D, Guerreiro C, Kalviainen R, Mattson R, Perucca E, Tomson T.
review of current management. Pediatr Neurol. 2020;107:28–40. ILAE treatment guidelines: evidence-based analysis of antiepi-
48. Cross JH, Caraballo RH, Nabbout R, Vigevano F, Guerrini R, leptic drug efficacy and effectiveness as initial monotherapy for
Lagae L. Dravet syndrome: treatment options and management epileptic seizures and syndromes. Epilepsia. 2006;47:1094–120.
of prolonged seizures. Epilepsia. 2019;60(Suppl 3):S39–48. 66. Glauser T, Ben Menachem E, Bourgeois B, Cnaan A, Guerreiro
49. Mei D, Cetica V, Marini C, Guerrini R. Dravet syndrome as part C, KÃlviÃinen R, Mattson R, French JA, Perucca E, Tomson T.
of the clinical and genetic spectrum of sodium channel epilepsies Updated ILAE evidence review of antiepileptic drug efficacy and
and encephalopathies. Epilepsia. 2019;60(Suppl 3):S2–7. effectiveness as initial monotherapy for epileptic seizures and
50. Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, syndromes. Epilepsia. 2013;54:551–63.
Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, 67. Kanner AM, Ashman E, Gloss D, Harden C, Bourgeois B, Bau-
Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agar- tista JF, Abou-Khalil B, Burakgazi-Dalkilic E, Llanas PE, Stern
wal A, Lai WW, Ceulemans B. Fenfluramine hydrochloride for J, Hirtz D, Nespeca M, Gidal B, Faught E, French J. Practice
the treatment of seizures in Dravet syndrome: a randomised, dou- guideline update summary: Efficacy and tolerability of the new
ble-blind, placebo-controlled trial. Lancet. 2019;394:2243–54. antiepileptic drugs I: treatment of new-onset epilepsy: report of
51. Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, the Guideline Development, Dissemination, and Implementation
Sanchez-Carpintero R, Stephani U, Laux L, Wirrell E, Knupp K, Subcommittee of the American Academy of Neurology and the
Chiron C, Farfel G, Galer BS, Morrison G, Lock M, Agarwal A, American Epilepsy Society. Neurology. 2018;91:74–81.
Auvin S. Fenfluramine for treatment-resistant seizures in patients 68. Kanner AM, Ashman E, Gloss D, Harden C, Bourgeois B, Bau-
with dravet syndrome receiving stiripentol-inclusive regimens: a tista JF, Abou-Khalil B, Burakgazi-Dalkilic E, Llanas PE, Stern
randomized clinical trial. JAMA Neurol. 2020;77:300–8. J, Hirtz D, Nespeca M, Gidal B, Faught E, French J. Practice
52. Campos MSA, Ayres LR, Morelo MRS, Carizio FAM, Pereira guideline update summary: Efficacy and tolerability of the new
LRL. Comparative efficacy of antiepileptic drugs for patients antiepileptic drugs II: treatment-resistant epilepsy: report of the
with generalized epileptic seizures: systematic review and net- Guideline Development, Dissemination, and Implementation
work meta-analyses. Int J Clin Pharm. 2018;40:589–98. Subcommittee of the American Academy of Neurology and the
53. Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Sil- American Epilepsy Society. Neurology. 2018;91:82–90.
vestrini M, Trinka E, Brigo F. Antiepileptic monotherapy in 69. Burakgazi E, French JA. Treatment of epilepsy in adults. Epilep-
newly diagnosed focal epilepsy. A network meta-analysis. Acta tic Disord. 2016;18:228–39.
Neurol Scand. 2019;139:33–41. 70. Tomson T, Battino D, Perucca E. Valproic acid after five decades
54. Perucca E. From clinical trials of antiepileptic drugs to treatment. of use in epilepsy: time to reconsider the indications of a time-
Epilepsia Open. 2018;3:220–30. honoured drug. Lancet Neurol. 2016;15:210–8.
55. Golyala A, Kwan P. Drug development for refractory epilepsy: 71. Wyllie E. Wyllie’s treatment of epilepsy. In: Wyllie E, editor.
the past 25 years and beyond. Seizure. 2017;44:147–56. Philadelphia: Wolters Kluwer; 2021.
56. Costa J, Fareleira F, Ascencao R, Borges M, Sampaio C, Vaz- 72. Vidaurre J, Gedela S, Yarosz S. Antiepileptic drugs and liver
Carneiro A. Clinical comparability of the new antiepileptic drugs disease. Pediatr Neurol. 2017;77:23–36.
in refractory partial epilepsy: a systematic review and meta-anal- 73. Lu X, Wang X. Hyponatremia induced by antiepileptic drugs in
ysis. Epilepsia. 2011;52:1280–91. patients with epilepsy. Expert Opin Drug Saf. 2017;16:77–87.
57. Hu Q, Zhang F, Teng W, Hao F, Zhang J, Yin M, Wang N. 74. Diemar SS, Sejling AS, Eiken P, Andersen NB, Jörgensen NR.
Efficacy and safety of antiepileptic drugs for refractory An explorative literature review of the multifactorial causes of
partial-onset epilepsy: a network meta-analysis. J Neurol. osteoporosis in epilepsy. Epilepsy Behav. 2019;100:106511.
2018;265:1–11. 75. Klein P, Herzog AG. Endocrine aspects of partial epilepsy.
58. Gao L, Xia L, Zhao FL, Li SC. Clinical efficacy and safety in the comprehensive management and treatment of epilepsy.
of the newer antiepileptic drugs as adjunctive treatment in In: Schachter SC, Schomer DL, editors. San Diego: Academic
adults with refractory partial-onset epilepsy: a meta-analy- Press; 1997. pp. 207–232.
sis of randomized placebo-controlled trials. Epilepsy Res. 76. Parikh SK, Silberstein SD. Current status of antiepileptic
2013;103:31–44. drugs as preventive migraine therapy. Curr Treat Opt Neurol.
59. Gazzola DM, Balcer LJ, French JA. Seizure-free outcome in ran- 2019;21:16.
domized add-on trials of the new antiepileptic drugs. Epilepsia. 77. Goh KK, Chang SC, Chen CH, Lu ML. Therapeutic strategies
2007;48:1303–7. for treatment-resistant depression: state of the art and future
60. Halford JJ, Edwards JC. Seizure freedom as an outcome perspectives. Curr Pharm Des. 2020;26:244–52.
in epilepsy treatment clinical trials. Acta Neurol Scand. 78. Kanner AM. Management of psychiatric and neurological
2020;142:91–107. comorbidities in epilepsy. Nat Rev Neurol. 2016;12:106–16.
61. Krauss GL, Klein P, Brandt C, Lee SK, Milanov I, Milovanovic 79. Faught E. Topiramate in the treatment of partial and general-
M, Steinhoff BJ, Kamin M. Safety and efficacy of adjunctive ized epilepsy. Neuropsychiatr Dis Treat. 2007;3:811–21.
cenobamate (YKP3089) in patients with uncontrolled focal
80. Shvarts V, Chung S. Epilepsy, antiseizure therapy, and sleep 104. Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren
cycle parameters. Epilepsy Res Treat. 2013;2013:670682. K, Sander JW, Tomson T, Hauser WA. Recommendation
81. Vinik A. Clinical review: use of antiepileptic drugs in the treat- for a definition of acute symptomatic seizure. Epilepsia.
ment of chronic painful diabetic neuropathy. J Clin Endocrinol 2010;51:671–5.
Metab. 2005;90:4936–45. 105. Gunawardane N, Fields M. Acute symptomatic seizures and
82. Goodman CW, Brett AS. A clinical overview of off-label use of provoked seizures: to treat or not to treat? Curr Treat Opt Neu-
gabapentinoid drugs. JAMA Intern Med. 2019;179:695–701. rol. 2018;20:41.
83. Cruccu G, Di Stefano G, Truini A. Trigeminal neuralgia. N 106. Haut SR. Seizure clusters: characteristics and treatment. Curr
Engl J Med. 2020;383:754–62. Opin Neurol. 2015;28:143–50.
84. Tzadok R, Ablin JN. Current and emerging pharmacotherapy 107. Jafarpour S, Hirsch LJ, GaÃn za-Lein M, Kellinghaus C,
for fibromyalgia. Pain Res Manag. 2020;2020:6541798. Detyniecki K. Seizure cluster: definition, prevalence, conse-
85. Anguelova GV, Vlak MHM, Kurvers AGY, Rijsman RM. Phar- quences, and management. Seizure. 2019;68:9–15.
macologic and nonpharmacologic treatment of restless legs 108. Gidal B, Klein P, Hirsch LJ. Seizure clusters, rescue treat-
syndrome. Sleep Med Clin. 2020;15:277–88. ments, seizure action plans: Unmet needs and emerging for-
86. Ondo WG. Current and emerging treatments of essential mulations. Epilepsy Behav. 2020;112:107391.
tremor. Neurol Clin. 2020;38:309–23. 109. Lowenstein DH. The management of refractory status epilep-
87. Tomson T, Battino D, Bromley R, Kochen S, Meador K, ticus: an update. Epilepsia. 2006;47(Suppl 1):35–40.
Pennell P, Thomas SV. Executive summary: management of 110. Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bain-
epilepsy in pregnancy: a report from the international league bridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda
against epilepsy task force on women and pregnancy. Epilep- A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman
sia. 2019;60:2343–5. DM. Evidence-based guideline: treatment of convulsive sta-
88. Kellogg M, Meador KJ. Neurodevelopmental effects of antiepi- tus epilepticus in children and adults: report of the Guideline
leptic drugs. Neurochem Res. 2017;42:2065–70. Committee of the American Epilepsy Society. Epilepsy Curr.
89. Sen A, Jette N, Husain M, Sander JW. Epilepsy in older people. 2016;16:48–61.
Lancet. 2020;395:735–48. 111. Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein
90. Anderson G. Pharmacokinetics and drug interactions. In: Wyl- D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor
lie’s treatment of epilepsy. In: Wyllie E, editor. Philadelphia: JT, Silbergleit R. Randomized trial of three anticonvulsant medi-
Wolters and Kluwer; 2021. pp. 520–531. cations for status epilepticus. N Engl J Med. 2019;381:2103–13.
91. Srivastava AK, Alex AB, Wilcox KS, White HS. Rapid loss of 112. Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Bab-
efficacy to the antiseizure drugs lamotrigine and carbamazepine: cock L, Rogers A, Barsan W, Cloyd J, Lowenstein D, Bleck TP,
a novel experimental model of pharmacoresistant epilepsy. Epi- Conwit R, Meinzer C, Cock H, Fountain NB, Underwood E,
lepsia. 2013;54:1186–94. Connor JT, Silbergleit R. Efficacy of levetiracetam, fospheny-
92. Löscher W, Rundfeldt C, Hönack D. Pharmacological characteri- toin, and valproate for established status epilepticus by age group
zation of phenytoin-resistant amygdala-kindled rats, a new model (ESETT): a double-blind, responsive-adaptive, randomised con-
of drug-resistant partial epilepsy. Epilepsy Res. 1993;15:207–19. trolled trial. Lancet. 2020;395:1217–24.
93. Kwan P, Brodie MJ. Combination therapy in epilepsy: when and 113. Rossetti AO, Lowenstein DH. Management of refractory status
what to use. Drugs. 2006;66:1817–29. epilepticus in adults: still more questions than answers. Lancet
94. Brodie MJ, Sills GJ. Combining antiepileptic drugs—rational Neurol. 2011;10:922–30.
polytherapy? Seizure. 2011;20:369–75. 114. Silverstein FS, Jensen FE. Neonatal seizures. Ann Neurol.
95. Verrotti A, Lattanzi S, Brigo F, Zaccara G. Pharmacodynamic 2007;62:112–20.
interactions of antiepileptic drugs: from bench to clinical prac- 115. Donovan MD, Griffin BT, Kharoshankaya L, Cryan JF, Boylan
tice. Epilepsy Behav. 2020;104:106939. GB. Pharmacotherapy for neonatal seizures: current knowledge
96. Deckers CL, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, and future perspectives. Drugs. 2016;76:647–61.
Meinardi H, Patsalos PN, Renier WO, van Rijn CM. Selection of 116. Sharpe C, Reiner GE, Davis SL, Nespeca M, Gold JJ, Rasmussen
antiepileptic drug polytherapy based on mechanisms of action: M, Kuperman R, Harbert MJ, Michelson D, Joe P, Wang S, Ris-
the evidence reviewed. Epilepsia. 2000;2000(41):1364–74. manchi N, Le NM, Mower A, Kim J, Battin MR, Lane B, Honold
97. Brodie MJ, Yuen AWC. Lamotrigine substitution study: evi- J, Knodel E, Arnell K, Bridge R, Lee L, Ernstrom K, Raman
dence for synergism with sodium valproate? Epilepsy Res. R, Haas RH. Levetiracetam versus phenobarbital for neonatal
1997;26:423–32. seizures: a randomized controlled trial. Pediatrics. 2020;145.
98. Pisani F, Oteri G, Russo MF, Di Perri R, Perucca E, Richens A. 117. Millar LJ, Shi L, Hoerder-Suabedissen A, MolnÃ¡r Z. Neonatal
The efficacy of valproate-lamotrigine comedication in refrac- hypoxia ischaemia: mechanisms, models, and therapeutic chal-
tory complex partial seizures: evidence for a pharmacodynamic lenges. Front Cell Neurosci. 2017;11:78.
interaction. Epilepsia. 1999;40:1141–6. 118. Smith DK, Sadler KP, Benedum M. Febrile seizures: risks, evalu-
99. Blaszczyk B, Miziak B, Czuczwar P, Wierzchowska-Cioch ation, and prognosis. Am Fam Physician. 2019;99:445–50.
E, Pluta R, Czuczwar SJ. A viewpoint on rational and irra- 119. McTague A, Martland T, Appleton R. Drug management
tional fixed-drug combinations. Expert Rev Clin Pharmacol. for acute tonic-clonic convulsions including convulsive sta-
2018;11:761–71. tus epilepticus in children. Cochrane Database Syst Rev.
100. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs 2018;1:CD001905.
as a cause of worsening seizures. Epilepsia. 1998;39:5–17. 120. Alles SRA, Smith PA. Etiology and pharmacology of neuropathic
101. Gayatri NA, Livingston JH. Aggravation of epilepsy by anti- pain. Pharmacol Rev. 2018;70:315–47.
epileptic drugs. Dev Med Child Neurol. 2006;48:394–8. 121. Garakani A, Murrough JW, Freire RC, Thom RP, Larkin K,
102. Somerville ER. Some treatments cause seizure aggravation in Buono FD, Iosifescu DV. Pharmacotherapy of anxiety disor-
idiopathic epilepsies (especially absence epilepsy). Epilepsia. ders: current and emerging treatment options. Front Psychiatry.
2009;50(Suppl 8):31–6. 2020;11:595584.
103. Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepi-
leptic drugs. Pediatr Neurol. 2005;33:227–34.
122. Baldwin DS, Ajel K, Masdrakis VG, Nowak M, Rafiq R. Prega- 141. Perucca E, Meador KJ. Adverse effects of antiepileptic drugs.
balin for the treatment of generalized anxiety disorder: an update. Acta Neurol Scand Suppl. 2005;181:30–5.
Neuropsychiatr Dis Treat. 2013;9:883–92. 142. Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitor-
123. Li C, Xue L, Liu Y, Yang Z, Chi S, Xie A. Zonisamide for the ing of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug
treatment of Parkinson disease: a current update. Front Neurosci. Monit. 2018;40:526–48.
2020;14:574652. 143. Bialer M, Perucca E. Does cannabidiol have antiseizure activ-
124. Gonzalez-Latapi P, Bhowmick SS, Saranza G, Fox SH. Non- ity independent of its interactions with clobazam? An appraisal
dopaminergic treatments for motor control in Parkinson’s dis- of the evidence from randomized controlled trials. Epilepsia.
ease: an update. CNS Drugs. 2020;34:1025–44. 2020;61:1082–9.
125. Chagas MH, Eckeli AL, Zuardi AW, Pena-Pereira MA, Sobreira- 144. Klein P, Tolbert D, Gidal BE. Drug–drug interactions and
Neto MA, Sobreira ET, et al. Cannabidiol can improve complex pharmacodynamics of concomitant clobazam and canna-
sleep-related behaviours associated with rapid eye movement bidiol or stiripentol in refractory seizures. Epilepsy Behav.
sleep behaviour disorder in Parkinson’s disease patients: a case 2019;99:106459.
series. J Clin Pharm Ther. 2014;39:564–6. 145. Sommerfeld-Klatta K, Zielinska-Psuja B, Karazniewcz-Lada,
126. Rogawski MA, Löscher W, Rho JM. Mechanisms of action of Glowka FK. New methods used in pharmacokinetics and thera-
antiseizure drugs and the ketogenic diet. Cold Spring Harb Per- peutic monitoring of the first and newer generations of antiepi-
spect Med. 2016. leptic drugs (AEDs). Molecules. 25;2020.
127. Brennan GP, Baram TZ, Poolos NP. Hyperpolarization-activated 146. Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA,
cyclic nucleotide-gated (HCN) channels in epilepsy. Cold Spring Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepileptic
Harb Perspect Med. 2016;6:a022384. drugs–best practice guidelines for therapeutic drug monitoring: a
128. Sisodiya SM. Precision medicine and therapies of the future. position paper by the subcommission on therapeutic drug moni-
Epilepsia. 2021;62(Suppl.2):S90–S105. toring, ILAE Commission on Therapeutic Strategies. Epilepsia.
129. Carvill GL, Dulla CG, Lowenstein DH, Brooks-Kayal AR. The 2008;49:1239–76.
path from scientific discovery to cures for epilepsy. Neurophar- 147. Cramer JA. Tolerability of antiepileptic drugs: can we determine
macology. 2020;167:107702. differences? Epilepsy Behav. 2012;23:187–92.
130. Löscher W. The holy grail of epilepsy prevention: preclinical 148. Brodie MJ. Tolerability and safety of commonly used antiepilep-
approaches to antiepileptogenic treatments. Neuropharmacology. tic drugs in adolescents and adults: a clinician’s overview. CNS
2020;167:107605. Drugs. 2017;31:135–47.
131. Jozwiak S, Kotulska-Jozwiak K, Bebin M, Wong M. Modify- 149. Brodie MJ, Kwan P. Current position of phenobarbital in epilepsy
ing genetic epilepsies—results from studies on tuberous scle- and its future. Epilepsia. 2012;53(Suppl 8):40–6.
rosis complex and their potential mpact. Neuropharmacology. 150. Tomson T, Battino D. Teratogenic effects of antiepileptic drugs.
2020;166:107908. Lancet Neurol. 2012;11:803–13.
132. Jeong A, Wong M. mTOR inhibitors in children: current indica- 151. Löscher W, Hönack D. The novel competitive N-methyl-D-
tions and future directions in neurology. Curr Neurol Neurosci aspartate (NMDA) antagonist CGP 37849 preferentially induces
Rep. 2016;16:102. phencyclidine-like behavioral effects in kindled rats: attenuation
133. van der Poest CE, Jansen FE, Braun KPJ, Peters JM. Update on by manipulation of dopamine, alpha-1 and serotonin1A receptors.
Drug Management of Refractory Epilepsy in Tuberous Sclerosis J Pharmacol Exp Ther. 1991;257:1146–53.
Complex. Paediatr Drugs. 2020;22:73–84. 152. Klitgaard H, Matagne A, Lamberty Y. Use of epileptic animals
134. Overwater IE, Rietman AB, van Eeghen AM, de Wit MCY. for adverse effect testing. Epilepsy Res. 2002;50:55–65.
Everolimus for the treatment of refractory seizures associated 153. Meldrum B. Do preclinical seizure models preselect cer-
with tuberous sclerosis complex (TSC): current perspectives. tain adverse effects of antiepileptic drugs. Epilepsy Res.
Ther Clin Risk Manag. 2019;15:951–5. 2002;50:33–40.
135. Franz DN, Weiss BD. Molecular therapies for tuberous scle- 154. Leppik IE. Rational polypharmacy. Amsterdam: Elsevier; 1996.
rosis and neurofibromatosis. Curr Neurol Neurosci Rep. 155. Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epi-
2012;12:294–301. lepsy? Epilepsia. 1981;22:1–10.
136. Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, 156. Perucca E. General principles of medical management. In:
Jansen F, Feucht M, Krsek P, Nabbout R, Jansen AC, Wojdan K, Shorvon S, Perucca E, Engel JJ, editors. The treatment of epi-
Sijko K, Glowacka-Walas J, Borkowska J, Sadowski K, Doman- lepsy. 3rd ed. Oxford: Wiley-Blackwell; 2009. p. 121–39.
ska-Pakiela D, Moavero R, Hertzberg C, Hulshof H, Scholl T, 157. Guberman A. Monotherapy or polytherapy for epilepsy? Can J
Benova B, Aronica E, de Ridder J, Lagae L, Joszwiak S. Preven- Neurol Sci. 1998;25:S3–8.
tion of epilepsy in infants with tuberous sclerosis complex in the 158. Schmidt D. Drug treatment strategies for epilepsy revisited: start-
EPISTOP trial. Ann Neurol. 2021;89:304–14. ing early or late? One drug or several drugs? Epileptic Disord.
137. Löscher W, Friedman A. Structural, molecular and functional 2016;18:356–66.
alterations of the blood-brain barrier during epileptogenesis 159. Skolnick P. Anxioselective anxiolytics: on a quest for the Holy
and epilepsy: a cause, consequence or both? Int J Mol Sci. Grail. Trends Pharmacol Sci. 2012;33:611–20.
2020;21:591. 160. Kasteleijn-Nolst Trenité DG, Groenwold RH, Schmidt B, Löscher
138. Löscher W. The pharmacokinetics of antiepileptic drugs in rats: W. Single dose efficacy evaluation of two partial benzodiazepine
consequences for maintaining effective drug levels during pro- receptor agonists in photosensitive epilepsy patients: a placebo-
longed drug administration in rat models of epilepsy. Epilepsia. controlled pilot study. Epilepsy Res. 2016;122:30–6.
2007;48:1245–58. 161. Rundfeldt C, Löscher W. The pharmacology of imepitoin: the
139. Nair AB, Jacob S. A simple practice guide for dose conversion first partial benzodiazepine receptor agonist developed for the
between animals and human. J Basic Clin Pharm. 2016;7:27–31. treatment of epilepsy. CNS Drugs. 2014;28:29–43.
140. Löscher W, Schmidt D. Experimental and clinical evidence for 162. Schidlitzki A, Bascunana P, Srivastava PK, Welzel L, Twele F,
loss of effect (tolerance) during prolonged treatment with antie- Töllner K, Käufer C, Gericke B, Feleke R, Meier M, Polyak A,
pileptic drugs. Epilepsia. 2006;47:1253–84. Ross TL, Gerhauser I, Bankstahl JP, Johnson MR, Bankstahl
M, Löscher W. Proof-of-concept that network pharmacology is 171. Löscher W, Sills GJ, White HS. The ups and downs of alkyl-
effective to modify development of acquired temporal lobe epi- carbamates in epilepsy therapy: How does cenobamate differ?
lepsy. Neurobiol Dis. 2020;134:104664. Epilepsia. 2021 (in press).
163. Welzel L, Bergin D, Schidlitzki A, Twele F, Johne A, Klein P, 172. Baraban SC, Löscher W. What new modeling approaches will
Löscher W. Systematic evaluation of rationally chosen multi- help us identify promising drug treatments? Adv Exp Med Biol.
targeted drug combinations: a combination of low doses of lev- 2014;813:283–94.
etiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic 173. Kaur H, Kumar B, Medhi B. Antiepileptic drugs in development
effects in a mouse model of acquired epilepsy. Neurobiol Dis. pipeline: a recent update. eNeurologicalSci. 2016;4:42–51.
2021;149:105227. 174. Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Tom-
164. Boison D, Jarvis MF. Adenosine kinase: a key regulator of son T, White HS. Progress report on new antiepileptic drugs: a
purinergic physiology. Biochem Pharmacol. 2020;114321. summary of the fourteenth eilat conference on new antiepileptic
165. Steriade C, French J, Devinsky O. Epilepsy: key experimental drugs and devices (EILAT XIV). I. Drugs in preclinical and early
therapeutics in early clinical development. Expert Opin Investig clinical development. Epilepsia. 59;2018:1811–41.
Drugs. 2020;29:373–83. 175. Auvin S. Lennox–Gastaut syndrome: new treatments and treat-
166. Klein P, Tyrlikova I. No prevention or cure of epilepsy as yet. ments under investigation. Rev Neurol (Paris). 2020;176:444–7.
Neuropharmacology. 2020;168:107762. 176. Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E,
167. Löscher W, Schmidt D. Epilepsy: perampanel-new promise for Perucca P, Tomson T, White HS. Progress report on new antiepi-
refractory epilepsy? Nat Rev Neurol. 2012;8:661–2. leptic drugs: a summary of the fifteenth eilat conference on new
168. Pitkänen A, Buckmaster PS, Galanopoulou AS, Moshé SL. Mod- antiepileptic drugs and devices (EILAT XV). I. Drugs in preclini-
els of seizures and epilepsy. 2nd ed. London: Academic Press; cal and early clinical development. Epilepsia. 2020;61:2340–64.
2017. 177. Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E,
169. Wirrell EC, Nabbout R. Recent advances in the drug treatment Perucca P, Tomson T, White HS. Progress report on new antiepi-
of Dravet syndrome. CNS Drugs. 2019;33:867–81. leptic drugs: a summary of the fifteenth eilat conference on new
170. Rogawski MA, Löscher W. The neurobiology of antiepileptic antiepileptic drugs and devices (EILAT XV). II. Drugs in more
drugs. Nat Rev Neurosci. 2004;5:553–64. advanced clinical development. Epilepsia. 2020;61:2365–85.

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CNS Drugs

The Pharmacology and Clinical Efficacy of Antiseizure Medications:

Accepted: 4 May 2021

Fig. 1 Chemical structures of clinically approved antiseizure drugs discussed in this review

amygdala, by transcorneal application of electrical stimuli, 4 The Clinical Profile and Efficacy

mediated by ­GABAA receptors (see below). Examples of 10 Mechanisms of Action of Antiseizure

Modulators of voltage-gated sodium channels

Acetazolamide 10–15 0.33 ?

Extrapolation of doses between species is also of crucial 14 Therapeutic Drug Monitoring

PAMs at inhibitory or excitatory receptors

but not MES and PTZ tests;

Drugs with multiple mechanisms

receptor mutations and other alterations in the GABAergic

for cancer treatment

ASMs is more efficacious than existing ASMs.

disease-modifying potential in patients at risk of developing

mTOR inhibitors such as everolimus may exert disease-

concentration of the endogenous neuromodulator adeno-

modulates splicing of pre-messenger RNA transcript to

sense mutations in sodium channel (SCN1A) and GABRG2

gonucleotide therapies under preclinical or clinical devel-

opment in epilepsy include ataluren, STK-001, and CUR-

The ideal ASM protects against different types of epilep-

tic seizures without adversely affecting the function of the

contribute to treatment failure. This is probably because all

current ASMs have been developed to counteract the hyper-

excitability of neurons by targeting mechanisms that also

all—to a large extent—have similar issues associated with

be achieved in a substantial proportion (~50%) of patients Declarations

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Fig. 1 Chemical structures of clinically approved antiseizure drugs discussed in this review

amygdala, by transcorneal application of electrical stimuli, 4 The Clinical Profile and Efficacy

mediated by GABAA receptors (see below). Examples of 10 Mechanisms of Action of Antiseizure

Extrapolation of doses between species is also of crucial 14 Therapeutic Drug Monitoring