A short article published in Lancet Neurology this month presented an overview of some of the new anti-epileptic drugs currently being developed.

Some are "cousins" of drugs already in use, with largely the same chemical structures but with small, significant changes to create either greater efficacy or fewer side effects than the older drug. Others have completely new mechanisms of action. Sometimes these are discovered by chance, sometimes by systematic screening programmes, and sometimes by deliberate chemical design, for example, making a compound to target a specific receptor.

Most of these drugs are currently in Phase 2 trials. These investigate the safety of a new drug in patients with epilepsy and its effectiveness in treating seizures. Four of the drugs are in Phase 3 trials (these are marked). Phase 3 trials compare the new drug to the current standard treatment method. A drug can be licensed only after Phase 3 trials are successfully completed.

Drugs of the "cousin" type currently in development include:

• Brivaracetam and seletracetam, which interact with the same protein in brain cells as levetiracetam, but more strongly.
• Eslicarbazepine, related to oxcarbazepine (in Phase 3).
• Fluorofelbamate and RWJ-333369, related to felbamate, are designed to avoid the serious adverse effects associated with the original: their breakdown process avoids a pathway which leads to a toxic by-product.
• Isovaleramide, valrocemide, and DP-VPA are related to valproic acid. They are designed to avoid the side effects seen with the original, including its potential to damage the babies of mothers with epilepsy who take valproic acid during their pregnancy.

The following drugs work in ways unlike any current drugs available:

• Lacosamide (in Phase 3) has an unknown mechanism of action. Unusually, it appears to be able to protect neurones from the effects of seizures, and may therefore be useful for treating status epilepticus.
• Retigabine (in Phase 3) acts on two potassium channels, creating a current which stabilises cells which can become over-excited, leading to seizures. This drug is structurally quite unlike any other drug in use today.
• Rufinamide (in Phase 3) has an unknown mechanism of action, but may be especially good for treating people with Lennox-Gastaut syndrome.

Other interesting compounds are:

• Talampanel, which was discovered by a targeted programme of research deliberately looking for a compound to interact with specific receptors called AMPA receptors, which are sensitive to glutamate, the principal excitatory neurotransmitter in the brain.
• Ganaxolone, which activates receptors for GABA (the major inhibitory neurotransmitter) and looks promising for use in catamenial epilepsy and infantile spasms.
• Stiripentol's use is limited at present by apparently significant interactions between it and other drugs, but it has shown remarkable efficacy treating patients with severe myoclonic epilepsy of infancy, which is otherwise difficult to treat.
• Safinamide may have several mechanisms of action, and is also under investigation for use in Parkinson's disease.

Not all these compounds may ever be widely used in people with epilepsy, but they do represent hope for the 30% of people with epilepsy whose seizures are not controlled with currently available drugs.

It seems paradoxical that despite highly rational scientific programmes for discovering these drugs, many of their mechanisms of action are still mysterious. This is however also the case for AEDs already licensed.

Other current avenues of AED research include the influence of a person's own genes on the efficacy of drugs they take, and the development of substances designed to prevent the development of epilepsy in high-risk patients.