2.1. “Me-too” drugs are drugs that largely duplicate the actions of existing drugs and offer little or no therapeutic gain. Since the approval of felbamate in August 1993, nine new AEDs have become available: felbamate, lamotrigine, gabapentin, topiramate, oxcarbazepine, vigabatrin, zonisamide, levetiracetam, and pregabalin. There is now over a decade of experience with these second-generation drugs, yet the number of patients who continue to have uncontrolled epilepsy has not been measurably reduced. A reasonable inference is that the screening models used for AED discovery only identify me-too drugs that act by the same old physiological mechanisms and that new models of treatment-resistant epilepsy are needed to identify drugs with different mechanisms of action (Brodie, 2001
). Does the evidence support this conclusion?
2.2. To address this question, it is useful to consider the broad range of uses of the major AEDs. As shown in , the so-called sodium channel blocking AEDs (many of which also block various types of voltage-activated calcium channels) do not all have identical clinical utilities. In fact, while the older sodium channel blockers phenytoin and cabamazepine are inactive—and may in some cases worsen—absence seizures, lamotrigine is effective for absence seizures. The discovery that lamotrigine is effective in the treatment of absence epilepsy was a surprise and clearly distinguished the drug from other sodium channel blocking AEDs. Lamotrigine is also effective in juvenile myoclonic epilepsy (JME; Buchanan, 1996
) whereas other sodium channel blocking anticonvulsants are inactive against myoclonic seizures or may worsen them. It was a further surprise that lamotrigine is effective in bipolar disorder, with particular activity in acute bipolar depression and also rapid-cycling bipolar disorder (Goodwin et al., 2004
). In contrast, most other AEDs that have been studied in bipolar disorder seem mainly to be useful in the acute treatment of mania. Other new AEDs have also been found to have an enhanced spectrum of activity. For example, valproate and topiramate are probably broadly active in primary generalized epilepsies, including absence and JME. These two drugs are now registered for migraine prophylaxis. Similarly, gabapentin has been found to be very useful for neuropathic pain and migraine prophylaxis; pregabalin is also effective for neuropathic pain. All of these new drugs—lamotrigine, topiramate, gabapentin and pregabalin—are effective in traditional AED screening models. Based upon the results of the preclinical testing, it was assumed that lamotrigine and topiramate would be me-too drugs that would largely duplicate the clinical activities of phenytoin and carbamazepine. As experience with these drugs has accrued, this assumption was found to be incorrect. A lesson learned is that it is not possible to predict the potential clinical uses of AEDs based upon their activities in present-day animal screening models; indeed, the models routinely seem to uncover drugs with unique and unexpected clinical utilities.
Selected Therapeutic Activities of Marketed Antiepileptic Drugs
2.3. A corollary to the clinical lesson is that it is not unusual for animal screening models to identify antiepileptic drugs with novel molecular mechanisms of action. Thus, novel chemical structures identified in screening models may act on well-recognized targets in novel ways or by novel combinations of actions on well-recognized targets. In some cases, the screening models have revealed entirely new AED targets. For example, lamotrigine and topiramate were identified largely by activity in the MES test, yet their pharmacodynamic actions must be different from the prototypical sodium channel blocking AEDs phenytoin and carbamazepine since they have distinct clinical activities. In fact, while all four drugs do interact with fast transient and persistent sodium channels, lamotrigine at clinically relevant concentrations also has substantial effects on high voltage-activated calcium channels (Stefani et al., 1996
). Topiramate has these activities on sodium and calcium channels, and in addition potentiates a subset of GABA receptors and also blocks GluR5 kainate receptors, a new target (White et al., 1997
; Gryder and Rogawski, 2003
; Rogawski and Löscher, 2004a
2.4. Gabapentin and levetiracetam provide examples where the screening models have identified AEDs that act on entirely new molecular targets for AEDs. Evidence from a variety of experimental approaches has revealed that the primary target for gabapentin and pregabalin is the α2δ subunit of voltage-activated calcium channels (Gee et al., 1996
). Binding at this site leads to a reduction in the release of neurotransmitters, including glutamate (Dooley et al., 2000
). Recently, SV2A, a synaptic vesicle protein, has been identified as the likely target for levetiracetam (Lynch et al., 2004
) and two more potent follow-on structural analogs seletracetam (ucb 44212) and brivaracetam (ucb 34714). The mechanism whereby binding to SV2A results in anticonvulsant activity is unknown. SV2A is an abundant protein component of synaptic vesicles that is structurally similar to 12-transmembrane domain transporters, although a transporter activity has not yet been identified. SV2A is not essential for synaptic transmission, but knockout of the protein (along with the closely related protein SV2B which appears to be able to substitute for SV2A) in mice leads to seizures (Janz et al., 1999
). The effect of levetiracetam may be similar to that of AEDs that target voltage-activated sodium and calcium channels, including α2δ, which largely act by inhibition of glutamate release at excitatory synapses (Rogawski and Löscher, 2004a
2.5. Levetiracetam is not active in the traditional MES or s.c. MET AED screening models when conducted according to standard protocols (Klitgaard et al., 1998
; Klitgaard, 2001
). Nevertheless, the drug was discovered in another common screening model: audiogenic seizures in susceptible mice, and subsequently found to have activity in a range of chemoconvulsant models, including seizures induced by sub-maximal pentylenetetrazol doses (Gower et al., 1992
), the 6-Hz model, and also various kindling models, including amygdala kindled rats, where it potently inhibits fully kindled seizures (Löscher and Hönack, 1993
). Levetiracetam is active in a rat genetic model of absence epilepsy (Gower et al., 1995
), which predicts its likely clinical activity in human absence epilepsy (). Levetiracetam also seems to have “antiepileptogenic” activity, in that it retards the development of pentylenetetrazol—kindled seizures (Gower et al., 1992
) as well as conventional amygdala-kindled seizures (Löscher et al., 1998
). Gabapentin and levetiracetam are novel AEDs with distinct clinical profiles that were identified by presently available epilepsy screening models. Remarkably, these compounds have, in turn, led to the discovery of two entirely new drug targets for AEDs—α2δ and SV2A. These targets can now be used to screen for congeners with improved properties. Indeed, this is how seletracetam and brivaracetam were identified.