The promise of new antiepileptic drugs

John S. Duncan
NSE-UCL Epilepsy Centre, Chalfont St Peter, Buckinghamshire, SL9 0LR

Epilepsy is the most common serious disorder of the brain and comprises a wide range
of different conditions with varying aetiologies. The long-established antiepileptic
drugs (AEDs) control seizures in 50% of patients developing partial seizures, and
60±70% of those developing generalized seizures. Several AEDs were made available
in the 1990s. These drugs have ef®cacy, but have had only a modest impact on those
with refractory epilepsies. A 50% seizure reduction, which is commonly used as an
endpoint in clinical trials, confers little bene®t to a patient. Of the newer AEDs,
lamotrigine and oxcarbazepine are now licensed for use as monotherapy and vigabatrin
has a monotherapy licence for infantile spasms. Careful and prolonged postmarketing
surveillance is essential to detect adverse effects, which may not be evident in
premarketing clinical trials. At this time, there are 10 AEDs currently in varying stages
of clinical development. Current strategies for selecting an AED for a particular patient
are crude. Magnetic resonance spectroscopic measures of cerebral neuro-transmitters
and genetic analysis may allow better prediction of which drug is most likely to be
ef®cacious and to have low risk of adverse effects. Present AEDs suppress the
occurrence of seizures. Agents that prevent the development of epilepsy and which
protect the brain from the consequences of seizures would be of great value, but it
will be dif®cult to prove their effectiveness. At present AEDs are given continually
and systemically. Local drug delivery is feasible and could avoid the adverse effects of
AEDs. The combination of local drug delivery with prediction of seizure occurrence
could revolutionize the treatment of currently refractory epilepsies.

against Epilepsy (ILAE) has produced classi®cations of

The clinical problem
seizures [2] and epilepsy syndromes [3]. At present, the
Epilepsy is the most common serious neurological dis- syndrome classi®cation largely in¯uences strategies of
order, with an incidence of 50/100 000/year, a cumulative initiation, intensity and withdrawal of treatment, and the
lifetime incidence of 1 in 20 and a prevalence of 1 in classi®cation of seizure types, particularly the dichotomy
200 [1]. In the United Kingdom, these ®gures translate to between partial and generalized seizures, in¯uences which
30 000 new cases per year and 350 000 individuals with AED is chosen for initial and for add-on therapy. These
active epilepsy, or requiring regular AEDs to control the classi®cations are reasonably pragmatic, but were heavily
occurrence of seizures. based on videotaped seizures in tertiary referral centres.
The term epilepsy is a misnomer and conceals the The ILAE has recently proposed a further classi®cation
diversity and heterogeneity of conditions and syndromes of seizure types and syndromes [4]. It is not yet clear,
of which epileptic seizures may be part, that may occur however, whether this revised classi®cation will aid
from the neonatal to the geriatric age ranges. It is more selection of particular AEDs for individual patients.
appropriate to refer to the epilepsies. Failure to appreciate
this may result in oversimpli®ed overviews of responses
to antiepileptic drug treatment. The International League Effectiveness of current AEDs
The long-established AEDs, that are used as ®rst line
Correspondence: Professor J. S. Duncan, NSE-UCL Epilepsy Centre, Chalfont agents, carbamazepine and valproate, and the older agents
St Peter, Buckinghamshire, SL9 0LR. Tel.: 01494 601341; Fax: 01494 876294; phenytoin and phenobarbitone, will result in seizure
E-mail: [email protected] control in 50% of patients developing partial seizures, and
Received 23 March 2001, accepted 26 September 2001. 60±70% of those developing generalized seizures [5±7].

f 2002 Blackwell Science Ltd Br J Clin Pharmacol, 53, 123±131 123

J. S. Duncan

After a lull of over a decade, many new AEDs were more likely to stop taking the medication but have the
introduced, starting with vigabatrin in 1989, followed limitations of being uncontrolled, nonrandomized and
by zonisamide, lamotrigine, gabapentin, felbamate, subject to selection bias. Eighty-six percent of those who
topiramate, tiagabine, oxcarbazepine and most recently, commenced lamotrigine and vigabatrin during clinical
in late 2000, levetiracetam. trials had the new drugs withdrawn in 6±8 years [13].
In an open follow-up of patients attending an epilepsy
clinic there was a 57% probability of patients continuing
The impact of recently licensed AEDs
to take lamotrigine and 43% continuing on vigabatrin
in refractory patients
after 40 months [14]. In an open follow-up study of
New AEDs are generally evaluated ®rst in patients with 174 patients treated with topiramate, 55% remained on
frequent partial seizures who have been refractory to the drug at 1 year [15].
previously available AEDs, with randomized clinical trials Other post-marketing studies of long-term continua-
in which the new agent or a placebo is added to the tion have shown less than 30% of patients continuing on
baseline therapy. The numbers of seizures are usually the new agents 3±5 years after commencement [16, 17].
counted over a 8±16 weeks baseline period, followed by Whilst a 50% reduction of seizures is a pragmatic
a titration phase, and then a 12±16 week treatment period. measure of demonstrating more antiepileptic ef®cacy than
These studies are designed and ®nanced by the phar- a placebo in add-on trials of new agents in patients with
maceutical industry, with the speci®c aim of satisfying refractory seizures, it is also an admission of defeat.
the Regulatory authorities that the new compound has Reducing the number of seizures by half does little for the
ef®cacy and is safe. It is very rare for a patient with quality of life of patients. The attacks can still occur at any
refractory partial seizures to become seizure free with the time, in any place, with the consequent restrictions on
addition of a new AED [8]. The usual outcome measures activity, embarrassment as well as the risk of physical
are the proportion of patients who have a 50% or more morbidity and mortality [18, 19]. The measurement of
reduction in seizures, and the median seizure frequency. seizure severity is an important facet of AED ef®cacy that
Meta-analyses of placebo-controlled trials of new AEDs has only been assessed recently [20±22]. This is important,
has shown ef®cacy for gabapentin, tiagabine, topiramate, as the occurrence of simple partial seizures is less disruptive
vigabatrin, lamotrigine, levetiracetam, oxcarbazepine and to patients than more severe episodes. Clinical trials of
zonisamide (licensed in Countries outside Europe), and no AEDs have used a variety of neuropsychological and
de®nite differences in ef®cacy have been found between behavioural measures. This diversity makes it dif®cult to
them [9, 10]. Regression models, examining the effects of draw conclusions on the effects of AEDs. A more uniform
varying doses have suggested that there is no ¯attening off approach to evaluating these effects would be advan-
of the response with higher doses of tiagabine and gaba- tageous [23]. It must also be recognized that the duration
pentin, suggesting that less than optimal doses may have of add-on trials of AEDs, which are usually 12±16 weeks,
been used. In contrast, vigabatrin and topiramate showed are not suf®ciently prolonged for any changes in the
¯attening off of the therapeutic response at higher doses. perceived quality of life of a person with epilepsy to be
There have been much fewer evaluations of AEDs develop and to be measurable.
in generalized epilepsies. Lamotrigine and topiramate
have shown ef®cacy in the refractory generalized
Status epilepticus
Lennox±Gastaut syndrome [11, 12].
Whilst such randomized trials satisfy Drug Regulatory Lorazepam is increasingly favoured over diazepam for
authorities, they do not provide data that are of much the ®rst line treatment of status epilepticus. Lorazepam
clinical relevance. Clinicians and their patients need to has a lesser volume of distribution, is less lipid soluble,
know which drug is most likely to be effective for them a slower onset but longer duration of action, with ef®cacy
and what adverse effects may be encountered. It is only extending for several hours. As distribution is slow, the
adequately powered long-term head to head comparisons rate of intravenous injection is not critical. In adults, a
between AEDs, in homogenous groups of patients with bolus dose of 0.07 mg kgx1 (to a maximum of 4 mg)
well described syndromes, that can provide this guidance. is used, which may be repeated once after 20 min if
Such trials are conspicuous by their absence, principally necessary. In children under 10 years, bolus doses of
because of their expense and the lack of incentive for the 0.1 mg kgx1 are recommended [24].
pharmaceutical industry to undertake such work once Fosphenytoin has been introduced as an alternative to
their compound is marketed. phenytoin for intravenous use. Fosphenytoin is converted
Studies of the long-term continuation of AED therapy in vivo to phenytoin with a half-life of 8±15 min and has
are attractive in that they re¯ect clinical practice, as those the advantages of solubility in water at neutral pH, and so
with adverse effects and a failure to respond will be is not presented in an irritant alkaline solution [25]. It was

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 New antiepileptic drugs

initially thought that the risk of cardiac side-effects and only be detected by post-marketing surveillance. A good
the need to give by slow intravenous infusion was example of this is the AED felbamate, which was licensed
averted, but clinical experience has shown that a maxi- in 1993 and was found in the subsequent months to
mal advised infusion rate is 50±100 mg of phenytoin result in liver failure or aplastic anaemia in about 1 in
equivalents minx1. 4000 patients exposed to the drug.
Chronic effects may also be identi®ed by post-
marketing surveillance, often after a long interval. The
The impact of the new AEDs in
®rst report of visual ®eld constriction in patients taking
newly diagnosed patients
vigabatrin was in 1997 [40], 8 years after the drug was
New AEDs are usually evaluated for monotherapy use licensed, and this is now estimated to occur in 40%
after ef®cacy and safety data have been acquired with of patients who take the drug chronically [41]. In con-
add-on use in refractory patients. The use of adequately sequence, the use of vigabatrin is now restricted to
powered comparative monotherapy to detect equivalence children with infantile spasms and as a remedy of last
between AEDs has been recommended [26]. A new drug resort for refractory partial seizures.
would be recommended for ®rst-line use if it was as Lamotrigine has been associated with a risk of skin rash
ef®cacious as a standard agent and better tolerated. A new of up to 9.5%. In 0.4% the rash, due to a hypersensitivity
drug would be regarded as a second line drug if its ef®cacy reaction, has required admission to hospital [42]. The
and tolerability was not different from the standard. To be risk of a severe skin rash has been higher, approximately
adequately powered, such studies would require patients 1%, in children [43]. The risk of a skin rash is reduced
to be regarded in fairly broad categories, with the risk that by using a low starting dose and building up slowly [44].
subgroups with particular responses may not be detected. There are suggestions that the new AEDs may have
This study design causes regulatory dif®culties as whilst the less adverse cognitive effects than the older agents.
European Medicine Evaluation Agency is willing to accept Lamotrigine appears favourable in this regard [45, 46].
equivalence to a standard AED as evidence of ef®cacy, the Vigabatrin has generally not been associated with impair-
US Food & Drug Administration is not and currently ment of cognitive performance, but an increase of depres-
requires the use of a placebo arm in monotherapy com- sion, irritability, behavioural disturbance and psychosis has
parisons. Such a design raises serious ethical and medico- been noted [47, 48]. Gabapentin has been found to be well
legal issues, which are likely to come to the fore should tolerated, in the main [49]. In some patients, topiramate
a patient die as a result of a seizure whilst receiving only a may be associated with marked impairment of verbal
placebo. ¯uency, memory and thinking [50, 51]. This has not been
Lamotrigine is licensed for use as monotherapy in the a universal ®nding, however, [52], and it will be important
UK, having shown similar ef®cacy and better tolerability to identify the individual patient factors that underlie
than carbamazepine [27, 28]. No signi®cant difference susceptibility to the negative effects of this drug. Tiagabine
was found between gabapentin and carbamazepine [29]. has not been reported to have adverse cognitive effects
Vigabatrin has been compared with carbamazepine and [53, 54]. Oxcarbazepine has been studied little, but does
withdrawal because of recurrent seizures was more likely not appear to have marked effects. Small studies have
in those receiving vigabatrin [30±32]. No signi®cant not reported marked effects with levetiracetam [55].
difference has been found between oxcarbazepine and The potential teratogenic effects of the new AEDs are
carbamazepine [33], phenytoin [34, 35] or valproate [36], not established at present. The prospective follow-up of
with the exception that oxcarbazepine appeared better women taking AEDs through pregnancy with careful
tolerated than phenytoin. These studies, however, were not documentation of foetal outcome is crucial and this is
large enough to rule out potentially relevant differences. underway in many countries. The establishment of multi-
Oxcarbazepine is licensed for the treatment of partial national Registries such as the European Antiepileptic
seizures as monotherapy or in combination with other Drugs and Pregnancy Registry (EURAP), which has
AEDs in adults and children over 6 years [37]. Vigabatrin is already enrolled over 600 patients prospectively, is a major
licensed for the initial therapy of children with infantile step forward. This endeavour will produce very important
spasms and has considerable ef®cacy in this syndrome data that will assist treatment decisions and the counsel-
[38, 39]. ing of women who are contemplating pregnancies, to
minimize the risk of teratogenesis.
Adverse effects of the new antiepileptic drugs
The clinical evaluation of antiepileptic drugs
The numbers of patients exposed in a clinical develop-
ment program (usually 1500±2000) is not suf®cient to There is an acknowledged need for a practical clinical
identify occasional adverse effects. These effects will comparison of the long-established and newer AEDs and

f 2002 Blackwell Science Ltd Br J Clin Pharmacol, 53, 123±131 125

J. S. Duncan

this is being addressed in the UK by the NHS funded Table 1 Potential AEDs in development.
Standard and New Antiepileptic Drugs (SANAD) trial
Drug Class Phase
which will compare carbamazepine, valproate, lamotri-
gine, gabapentin, topiramate and oxcarbazepine. By their AWD131±138 Imidazolin Phase I
very nature, however, such studies are of populations of Harkoseride Aceto-propionamide amino acid Phase I
patients that include a range of syndromes and aetiologies. NPS 1776 Aliphatic amide Phase I
Ideally trials would be strati®ed by syndrome. Even if NW1015 Methansulphonate Phase I
that were done, however, it is not uncommonly the SP0294 (DP-VPA) Valproate in a phospholipid carrier Phase I
case that two individual patients with the same clinical Talamparel AMPA antagonist Phase II
Valrocemide Valproryl derivative of GABA Phase II
features and epilepsy syndrome may respond to different
Carabersat Benzopyran Phase II
AEDs, and have differing adverse effects.

Future prospects ± the need

serendipitous discovery and as a result of scienti®c inquiry
From the above, it is evident that whilst several new into the mechanisms underlying the epilepsies and
AEDs have become available in the last decade, these epileptic seizures. Increasingly, new AEDs are being
have been of limited bene®t for those with refractory developed in tandem for other applications, such as pain
seizures. To date, AEDs that have been licensed in the and migraine.
last decade have not had a great impact on the treatment
of newly diagnosed patients, although lamotrigine and
How to predict which drug is best for
oxcarbazepine are being taken up as drugs of ®rst choice,
which patient?
primarily because of their more favourable adverse effect
pro®le. There is still a clear need for further research to At present, the strategy for choosing a particular AED
develop new AEDs, and to consider new avenues and for a patient is about as sophisticated as choosing an
strategies to treat the processes of epilepsy and its con- antimicrobial on the basis of the Gram staining of
sequences, rather than just having the rather blinkered bacteria, and consideration of the likely adverse effects
objective of suppressing seizures. of the drug. Strategies that allow for a better prediction of
which AED, or class of AEDs, are most likely to help
and with least risk of adverse effects would be useful, and
Antiepileptic drugs currently in development
would help to ensure that individual patients were
At present there are several potential antiepileptic com- prescribed the optimal therapy sooner rather than later.
pounds currently undergoing clinical evaluation. The There are possibilities. Magnetic resonance spectros-
three most advanced agents: pregabalin, retigabine and copy (MRS) may be used to measure the concentrations of
ru®namide, are currently in phase III development. GABA, glutamate and glutamine in the brain, non-
Pregabalin, a gabapentin derivative is also a structural invasively in vivo. At present, the neurotransmitter and
GABA analogue, which does not seem to affect transmitter metabolic pools of these compounds cannot be differ-
response. It does, however, increase GABA content in entiated and the promise of MRS is predicated on the
neuronal tissues and binds to a subunit of Ca++ channels hypothesis that the overall concentrations of these com-
and this is likely to be the basis of its antiepileptic action pounds in a volume of brain is relevant in the pathogenesis
[56]. Retigabine, is structurally unrelated to other of epilepsy and of epileptic seizures, and their prevention
marketed AEDs and its potent anticonvulsant activity by medications. It has been found that low GABA
in animal models is likely to be mediated by increasing concentrations are associated with an ongoing tendency
K+ conductance in neuronal cells [57]. The mode of to seizures, and a range of AEDs result in elevation of
action of ru®namide, a triazole derivative, is likely to be cerebral GABA concentrations [59]. It is possible that
mediated by interaction with the inactivated state of particular metabolic patterns will predict responsiveness to
the Na+, limiting high-frequency ®ring of action poten- a particular AED, and that serial studies may assist optimal
tials in neurones [58]. Three further agents, losigamone, dosing.
ganoxolone and remacemide recently had their develop- The response to AEDs may be genetically determined.
ment terminated. Potential AEDs that are less advanced in Mice with point mutations in the alpha 1 subunit of the
their development programme are shown in Table 1. GABA/A receptor have been found to be less sensitive to
At present there are several routes of new AED the sedating effects of diazepam but to show no difference
development: high throughput screening of potential in anticonvulsant sensitivity compared with the wild-type
agents, modi®cation of existing compounds, enhanc- strain [60, 61]. Drug resistance may also be genetically
ing delivery to the brain of current existing drugs, determined [62, 63]. Automated high throughput analysis

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 New antiepileptic drugs

of genotypes of populations is now feasible, using a In contrast, NMDA receptor antagonists are effective
variety of tools such as characterization of single nucleo- against kindling, but not against kindled seizures [76].
tide polymorphisms (SNP). This development leads to Free-radical scavengers and antiperoxidants may have
pharmacogenetic studies of populations of patients with useful antiepileptogenic properties [77].
seizures that do, and do not, respond to particular AEDs, Clearly an AED that was also antiepileptogenic would
or classes of drugs. Large populations need to be ascer- be a therapeutic advance. Antiepileptogenic activity
tained and it is anticipated that these investigations will would be very dif®cult to evaluate in the clinical setting.
lead to the identi®cation of SNP patterns in individ- Prospective randomized clinical studies would need to be
ual subjects that will predict responsiveness to individual carried out in cohorts of patients who were at risk of
AEDs prior to the ®rst prescription being written. Further, developing epilepsy, for example after a stroke or serious
these studies are likely to identify targets for potential new head injury. As epilepsy may develop after a considerable
antiepileptic therapies. These techniques may also be used latent period the trial would need to be of long dura-
to identify patients who are at high risk of adverse effects tion, such as 5 years. In order to show a worthwhile
from a particular AED, for example aplastic anaemia from reduction of risk of developing epilepsy, such as 20%,
felbamate, an allergic reaction to carbamazepine [64] or large groups would be needed. In addition to the cost
lamotrigine, or a teratogenic consequence from usage and logistic issues, such a trial of preventive therapy over
during pregnancy [65]. Dosing may also be facilitated 5 years would strain compliance in all but the most
by examination of polymorphisms of genes coding for motivated patients, particularly if the medication had any
enzymes responsible for the metabolism of AEDs. adverse effects.

Is there a prospect for antiepileptic drugs to Neuroprotection

do more than suppress seizures?
It has been known for many years that status epilepticus
There has been a long debate about whether seizures beget may result in signi®cant hippocampal and cerebral damage,
seizures, and whether the course of epilepsy is progressive and this may be demonstrated with serial MRI scans
by virtue of the occurrence of further seizures, that is in vivo [78]. Seizure induced damage is likely to be due to
beyond the scope of this review [6, 66]. There are two excitotoxicity and is of two types: necrotic and apoptotic,
related issues: antiepileptogenesis and neuroprotection. although the distinction is not always clear [79]. It is less
clear whether individual tonic-clonic and complex partial
seizures cause secondary brain damage. It is generally held
Antiepileptogenesis
that brief febrile convulsions, simple partial seizures,
Epileptogenesis refers to the process of changes in the brain absences and myoclonic seizures and interictal epileptic
that leads to the development of a recurring tendency to activity do not cause cerebral damage, although this has
have spontaneous seizures. Animal models of this are not been proven.
kindling and perforant path stimulation, whereby repeated It has been suggested that felbamate [80], lamotrigine
electrical stimulation results in the generation of spon- [81±83] and topiramate [84] may have neuroprotectant
taneous seizures. These processes are the subject of intense properties. The neuroprotection offered by most anti-
scrutiny at the receptor, cellular and network levels. epileptic drugs in models of ischaemia, however, has yet
Identi®ed changes include loss of speci®c cell types, gliosis, to ®nd a clinical correlate, and indeed its relevance in
axonal sprouting, neuronal neogenesis, synaptic reorga- ischaemia in humans, let alone epilepsy, is uncertain.
nization and alterations in neurotransmitter receptors Cross-sectional brain imaging studies cannot determine
[67±71]. It is unclear which of these processes are detri- whether secondary brain damage occurs as a consequence
mental or bene®cial, or are merely epiphenomena. of epilepsy. Longitudinal follow-up studies of patients
Medication that is antiepileptogenic is not necessarily and control groups are necessary to ascertain whether
neuroprotectant, and vice-versa. this does occur, and to identify the risk factors, which are
Valproate and phenobarbitone have been found to be very likely to include individual genetic factors. The most
antiepileptogenic, but carbamazepine is not [72] and promising methods are quantitative magnetic resonance
lamotrigine did not retard the development of seizures in imaging (MRI) for which patient acceptability and test-
the kindling model [73]. Levetiracetam has antiepilep- retest reliability is excellent [85]. Such studies have been
togenic effects [74]. Although AMPA receptors are set up and are underway [86, 87]. Other possible methods
fundamental to the occurrence of kindled seizures, they include MRS measures of the concentration of cerebral
appear to be less important to the kindling process, and metabolites. These may be more sensitive than quantita-
GluR5 kainate receptors did not contribute to epilep- tive MRI but at present the data are also noisier and less
togenesis in the mouse amygdala kindling model [75]. reproducible. If the occurrence of secondary cerebral

f 2002 Blackwell Science Ltd Br J Clin Pharmacol, 53, 123±131 127

J. S. Duncan

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