What Are the Newest Epilepsy Drugs and How Do They Work?

Several new epilepsy drugs have arrived in the past few years, and more than 20 have been introduced since the 1980s.¹ That means many people whose seizures weren’t controlled now have options that didn’t exist a decade ago. What sets the newest ones apart is that many are designed to hit a specific target in the brain, and some hit more than one at once.² They are usually added to existing treatment rather than replacing it, and for many people they reduce seizures more often than they end them.

How Seizure Drugs Calm the Brain

A seizure is a burst of brain cells firing too much at once, which happens when the brain’s “go” signals overwhelm its “stop” signals. GABA is the brain’s main calming signal, and glutamate is its main exciting signal. Most epilepsy drugs either strengthen GABA’s calming effect, weaken glutamate’s excitement, or slow the electrical channels that let cells fire repeatedly. Combining drugs that work differently can help when one isn’t enough.

Older drugs such as phenytoin, carbamazepine and valproate were mostly found by testing compounds, not designed for a target.³ The third generation, starting in the 1980s, was built around specific targets in the brain.⁴ A drug’s target also partly predicts side effects, such as drowsiness from strong braking, and it helps explain why a new drug may work after old ones failed.

That last situation has a name. Epilepsy is usually called drug-resistant when seizures continue despite adequate trials of two appropriately chosen, well-tolerated seizure drugs, taken alone or together. It doesn’t mean the person did something wrong or that medicine is hopeless, because the next drug may work through a different route. This is where newer drugs with unusual targets are most often brought in. Many of the drugs below are used for focal seizures, which are seizures that start in one area of the brain.

Cenobamate for Hard-to-Control Focal Seizures

Cenobamate (brand name Xcopri) was approved in the US in 2019 for focal seizures.⁵ It blocks a slow, lingering type of sodium current that keeps brain cells firing over and over.⁶ It also strengthens the brain’s main calming signal, at a different spot from where drugs like diazepam act.⁷ That makes it one of few seizure drugs that both eases the gas and presses the brake.⁸ Scientists say its full mechanism is still not completely understood.⁹

It is given as an add-on treatment, meaning it is added to the drugs a person already takes.¹⁰ In one trial, typical seizure counts fell by about 55% on cenobamate versus about 22% on dummy pills.¹¹ The effect grew with dose: about 4 in 10 people halved their seizures at 100 mg a day, about 6 in 10 at 400 mg, versus 1 in 4 on dummy pills.¹² Across trials, people on cenobamate were nearly 4 times as likely as those on dummy pills to become seizure-free during the study.¹³ Seizure freedom is the bigger goal but remains the less common outcome. Results vary widely.

Starting is slow. Doctors raise the dose over weeks rather than beginning at a full dose, and because cenobamate interacts with other seizure drugs, those may need dose changes. A seizure diary helps you judge whether it is working, and benefit is judged over months, not days.

Common side effects include sleepiness, dizziness, tiredness, headache and double vision. A rare but serious allergic-type reaction involving rash, fever and organ involvement has been linked to starting at too fast a dose, which is why the slow schedule matters. Cenobamate isn’t suitable for people with familial short QT syndrome, a heart rhythm abnormality, so doctors check heart history first.

New Drugs for Rare Childhood Epilepsy Syndromes

Dravet and Lennox-Gastaut syndromes involve frequent seizures that often resist standard drugs. Children with these conditions often also have developmental, sleep and behavior difficulties, so seizure control is only one part of care. Some drugs that help other epilepsies, such as certain sodium-channel blockers, can make Dravet syndrome worse, so choosing the correct drug matters. Approval for one syndrome means a drug was tested in that group specifically, and a genetic diagnosis can open access to a drug approved for that condition.

Fenfluramine (Fintepla) was approved for Dravet syndrome, a severe genetic epilepsy starting in infancy, in 2020 and for Lennox-Gastaut syndrome in 2022.¹⁴ It acts on several serotonin receptors, which boosts the brain’s calming signals.¹⁵ It also acts on a protein called sigma-1, which appears to turn down glutamate’s excitement.¹⁶ The idea is that it works on both sides of the balance at once, though this model is still a hypothesis.¹⁷

Families may hear that fenfluramine was once a diet drug, withdrawn over heart valve problems at higher doses. In epilepsy it comes with regular heart scans as a safety step, so ask the care team how often they are scheduled.

Cannabidiol (CBD, prescription form Epidiolex) has been introduced as a seizure medicine since 2018.¹⁸ Rather than acting like cannabis’s high-causing compound, it appears to work through three other targets that affect how excitable cells are.¹⁹ This prescription form is a measured, tested medicine, unlike shop CBD products of uncertain strength.

Ganaxolone is a lab-made version of a natural brain steroid that strengthens GABA receptors.²⁰ It is approved in the US and Europe for CDKL5 deficiency disorder, a rare genetic epilepsy, after trials showed it cut seizures.²¹ Researchers have found it may act on a second target too.²²

All three are usually used as add-on treatment alongside existing medicines. In children, doses are usually set by body weight and raised gradually. Cannabidiol can raise blood levels of some other seizure drugs, notably clobazam, so sleepiness can increase and doses may need adjusting.

Brivaracetam and Perampanel

Brivaracetam works on the same target as the widely used levetiracetam (Keppra), a protein in nerve endings involved in releasing signals.²³ It binds that target much more tightly, about 9 times more in people’s brains.²⁴ It may also grip the protein in a different way, which could explain why the two drugs behave differently.²⁵ Some people who stopped levetiracetam because of mood side effects may be offered brivaracetam instead.

Brivaracetam is used for focal seizures, usually as an add-on and sometimes alone. Tighter binding doesn’t guarantee better seizure control, so it isn’t automatically a stronger version. Don’t stop either drug suddenly without your neurologist’s plan.

Perampanel (Fycompa) was the first drug to block AMPA receptors, a main doorway for glutamate’s exciting signal.²⁶ It blocks them no matter how much glutamate is present.²⁷ That eases the gas pedal directly, a different route from most other seizure drugs.

Side Effects and Effects on Thinking

Newer drugs are generally better tolerated and safer than older ones like phenobarbital, phenytoin, carbamazepine and valproate.²⁸ Even so, dizziness and drowsiness are still among the most commonly reported side effects, and rash is the most reported of all.²⁹ Among the newest drugs, brivaracetam had the lowest rate of side effects in comparisons of drug-resistant epilepsy treatments, while lacosamide had the highest.³⁰

Controlling seizures can itself help thinking, since frequent seizures harm it.³¹ Brivaracetam, lacosamide, cannabidiol, fenfluramine and ganaxolone generally have little effect on thinking at recommended doses.³² Cenobamate and eslicarbazepine may cause mild thinking effects, only near the top of the dose range.³³ Topiramate and zonisamide remain the most linked to thinking problems.³⁴ Older adults and people with intellectual disabilities are most sensitive and benefit most from the gentlest drugs.³⁵

To tell a drug’s effects from seizure effects, watch the timing. Fogginess that starts after a dose increase is one clue that the drug may be responsible, and slowed speed and attention are the most typical thinking effects. Note when symptoms started relative to dose changes, and bring a family member’s observations to appointments.

Mild dizziness often fades as the body adjusts. Mood changes or dark thoughts should be reported right away.

Rash deserves special attention. Most rashes are mild, but a small number are serious, especially those with fever, blistering, mouth sores or swelling of the face. Serious reactions to drugs such as carbamazepine and lamotrigine are most likely in the first weeks, which is why timing matters. Anyone with a new rash should contact their care team the same day rather than wait for the next visit.

Gene Tests That Shape Drug Choice

Certain gene variants, HLA-B*15:02 and HLA-A*31:01, strongly predict severe skin reactions to carbamazepine, oxcarbazepine and phenytoin.³⁶ Testing is especially recommended for people of Asian ancestry before these drugs.³⁷ Variants in a liver enzyme gene, CYP2C9, are linked to phenytoin toxicity.³⁸

The tests use a blood or saliva sample, usually before the drug is started. A positive result raises the risk of a severe skin reaction, so doctors usually choose a different drug. A negative result lowers the risk but doesn’t remove it, so a new rash still needs attention. HLA-B*15:02 and carbamazepine are most notably linked in people of Asian ancestry, while HLA-A*31:01 matters in other groups, such as people of European ancestry. If you have Asian family roots, ask about testing before starting carbamazepine.

In some genetic epilepsies, knowing the gene allows a targeted treatment, as in Dravet syndrome and glucose transporter deficiency.³⁹ Children with early, severe epilepsy are the most likely to have a findable gene, and a result can rule drugs out, not just in. For most proposed gene-matched treatments, though, good proof that they work is still missing.⁴⁰

What’s in the Pipeline

An experimental drug called XEN1101 (azetukalner) opens potassium channels, which help brain cells settle after firing.⁴¹ At its highest dose it cut monthly focal seizures by about half, versus 18% on dummy pills, with side effects similar to common seizure drugs.⁴²

Zorevunersen, an experimental gene-targeted treatment for Dravet syndrome, reduced convulsive seizures in early trials in children and teens.⁴³ It aims to boost the brain’s own production of the sodium-channel protein that people with Dravet lack.⁴⁴

Further out, researchers are exploring treatments that calm inflammation and an overactive growth pathway in brain cells, aiming to stop epilepsy from developing rather than just suppress seizures.⁴⁵ Tiny particle carriers given as nasal sprays may get drugs into the brain faster with fewer body-wide side effects.⁴⁶ These remain mostly in lab and early testing stages.

Drugs generally pass through early safety testing, then trials in a few hundred people, then larger trials, before regulators decide on approval. Even a drug with promising mid-stage results can fail later, so “in trials” doesn’t mean “coming soon.” Pipeline news is best treated as hope, not a plan for treatment.

Trials are often the only way to get pipeline drugs. Ask your neurologist or check registries like ClinicalTrials.gov, and know that some participants receive dummy pills for part of the study. Patient groups for Dravet and other syndromes track open trials.

Getting Access and Paying for New Drugs

High costs and regulatory hurdles slow fair access to new seizure treatments.⁴⁷ In some lower-income Asian countries, a month’s supply of a newer drug cost about 6 to 15 days’ wages, and one country had none available.⁴⁸ Levetiracetam, topiramate and lamotrigine were the most widely available newer options.⁴⁹ In the US, insurers often require trying older, cheaper drugs first.

Prior authorization is the usual gate. The doctor’s office submits forms showing the diagnosis and the drugs already tried, and details like names, doses, dates and the reason each earlier drug failed or caused side effects make the request stronger. Keep a personal list of past drugs in case records are incomplete or you change doctors.

If the first request is denied, ask for an appeal. Check manufacturer patient-assistance programs, and ask whether a cheaper generic with a similar target could work.