Newswise — Selecting a medication for new onset epilepsy is an issue without much guidance.  The second Standard And New Anti-epileptic Drugs study (SANAD II) was a phase IV, open-label study that compared anti-seizure medications (ASMs) for efficacy and adverse effects, in focal and generalized or unclassified epilepsies.

Results, published in April 2021, found that people with focal epilepsy taking lamotrigine had a shorter time to 12-month remission than those taking levetiracetam or zonisamide. In people with generalized or unclassified epilepsy, valproate was more effective than levetiracetam.

SANAD II was a randomized trial, but not blinded.

“The SANAD trials are pragmatic trials, trying to inform everyday clinical decision making,” said Tony Marson, professor of neurology at the University of Liverpool and first author of the most recent papers, which were published in The Lancet in April 2021.

Generalized epilepsies

SANAD II is the first randomized trial to compare levetiracetam and valproate for newly diagnosed generalized (or unclassified) epilepsies. The publication is available open access.

At the time the trial was designed, valproate was recommended as first-line treatment for generalized epilepsies, but the evidence base for the recommendation was sparse. SANAD I results had shown that valproate was more effective than topiramate, but other studies have shown mixed results.

SANAD II compared valproate with levetiracetam and found that levetiracetam was inferior to valproate in:

  • Time to 12-month remission (primary outcome)
  • Time to treatment failure
  • Two-year remission
  • First subsequent seizure
  • Cost effectiveness

“I think we all knew that levetiracetam was less effective than valproate,” said Marson. “But there wasn’t any good evidence to that effect, so it was very important to be able to document that.”

At two years of follow-up, there was an overall 15% (95% CI: 6%–23%) difference in the treatment failure rate for levetiracetam compared with valproate due to either adverse effects or a lack of seizure control. Valproate had lower rates of failure due to inadequate seizure control.  Both drugs had similar rates of failure due to adverse reactions.

Quality-of-life (QoL) analyses did not show differences between the two medications, though the paper said that the return rate of QoL questionnaires was “disappointingly low.”

Subgroup analysis: Generalized epilepsies

Subgroup analysis showed that time to 12-month remission was similar for both ASMs in people with absence epilepsy and unclassified epilepsy.

Because absence seizures tend to occur frequently, people with absence seizures were not necessarily disadvantaged by starting with levetiracetam, Marson noted.

“Whether you start with valproate or levetiracetam, you can see very quickly if the drug is working or not, and then get the person on other treatment if needed.”

For other generalized epilepsies, valproate had an advantage over levetiracetam.

“People in this group, having tonic-clonic seizures, have relatively infrequent seizures to start with, so it’s going to take longer to work out that their treatment is failing,” said Marson. “And then it’s going to take longer to find a treatment that benefits them.”


The study authors recommend valproate for men with generalized epilepsies and note that ethosuximide is an alternative for absence epilepsies, but not for other seizure types.

Because valproate may harm a fetus, the authors encourage “further debate to inform practice and policy about avoiding the most effective treatment to minimize the potential risk of harm in future pregnancies.”

Valproate concerns

In March 2018, a regulatory body representing the European Union (EU) Member States as well as Iceland, Liechtenstein, and Norway endorsed new measures to avoid fetal exposure to valproate. Valproate-containing medicines were banned for treating migraine and bipolar disorder. They also were banned for treating epilepsy “unless there is no other effective treatment available.”

Before taking valproate, a woman of childbearing age must complete a new pregnancy prevention program that ensures she is fully aware of the risks. The measures were proposed by the European Medicines Agency in February 2018.

For women, the SANAD II results complicate decision making. “The results show that women of childbearing age are disadvantaged by not being prescribed valproate to control their seizures,” said Marson, “but obviously levetiracetam is a safer treatment if they are thinking about pregnancy.”

Treatment conundrum

“You don’t treat young women with valproate,” said Martin Brodie, director of the Epilepsy Unit at Glasgow’s Western Infirmary, who was not involved in SANAD II. “Yes, the study showed valproate was better than levetiracetam, but not by a lot, and there’s no way you treat women with a drug that could damage their baby.”

“My experience in clinical practice is that most women choose an alternative to valproate,” said Marson. “The challenge is, what if that fails? And that remains a difficult question.”

In 2018, Marson and others published a study using discrete choice experiments, an economic model designed to clarify people’s preferences given certain benefits and risks. The study found that women would accept a 5% reduction in the chances of their own seizure freedom if it meant a 1% reduction in the chances of fetal malformation.

The results highlight the need for more therapeutic options for generalized and unclassified epilepsy, to minimize difficult decisions and avoid scenarios that could cause harm—such as a young woman who had been seizure free on a modest dose of valproate but stopped taking it when she learned about the fetal risks.  Other medications didn’t work. 

“No one could get her to take valproate again,” Brodie said. “She was 22 when she died of SUDEP.”

Focal epilepsies

SANAD II participants with focal epilepsies were randomized to start with zonisamide, lamotrigine, or levetiracetam. The primary endpoint was time to 12-month remission: how long did someone take the medication before they were seizure free for 12 consecutive months?

Lamotrigine was most effective with the shortest time to 12-month remission and significantly fewer adverse reactions (33%, versus 44% for levetiracetam and 45% for zonisamide). Lamotrigine also was found to be most cost-effective. The publication is available open access

Spotlight on lamotrigine

“The results of the SANAD II studies were slightly surprising to me, particularly the fact that levetiracetam did not prove to be the ‘winner’,” said Marian Galovic, head of the epilepsy unit at University Hospital Zurich, who was not involved in the studies. “Many of my neurology colleagues who are not experts in epilepsy use it as the go-to medication because it’s easy to use, and it doesn’t have complicated interactions, and the dosing is straightforward.”

“In my perception, the impact of the study was to reinforce the value of lamotrigine, which is perhaps not so widely appreciated,” said Emilio Perucca, adjunct professor in the Department of Neuroscience at Monash University, Melbourne, Australia. “Lamotrigine is a valuable drug, mainly because of its tolerability profile.”

The gradual titration required in starting lamotrigine has been an issue for many prescribers. 

“People are still mostly prescribed levetiracetam by general neurologists at our hospital,” said Galovic. “Probably because they are used to it, and they want to do something quickly. In the emergency department, my experience is that they use levetiracetam because they feel they need to do something immediately.”  There was no evidence from SANAD II that the titration period for lamotrigine resulted in any untoward outcomes.

Levetiracetam’s ease of use likely enhances its effectiveness, said Brodie. “A drug that’s easy to use, like levetiracetam, looks better [in data] than a drug like phenytoin, which you have to know how to use,” he said. “And if you don’t know how to use the drug, you don’t get good results.”

Side effects matter

Though a frequent choice for first-line treatment of focal epilepsy, levetiracetam can have adverse behavioral and psychiatric effects. These were not identified in early studies; the SANAD II study shows a markedly lower quality of life measure for people taking levetiracetam for focal epilepsy, however.

“When you’re looking for benefit, you know what you’re looking for, but when you’re looking for harm, if you’re just looking for traditional adverse effects you could miss things,” said Marson. “As a field, we initially hadn’t been looking for psychiatric side effects [in levetiracetam] and weren’t really picking up the impact of those on people’s quality of life.”

The quality-of-life evaluation was important, said Galovic. “I tell our patients that we want them to be seizure free, but we also want to give them a medication they can tolerate excellently,” he said. “I don’t want to give them a medication that makes them seizure free but worsens their quality of life.”

Choosing an anti-seizure medication takes more than data, said Brodie. “We are treating the patient, not the epilepsy,” he said. “Just because one drug does better than the other doesn’t mean you never use the other drug.”

Lower-resource countries

With both lamotrigine and levetiracetam available in generic form, do the SANAD II results have major implications for lower-income regions of the world?

In Zambia, publicly available medications are limited—usually to carbamazepine and phenobarbital, said Melody Asukile, a neurologist with the Zambian Ministry of Health. “For patients who can afford it, we can recommend levetiracetam, which is relatively more affordable than other drugs,” she said.

“We face major challenges with access to anti-seizure medications,” said Naluca Mwendaweli, a physician at University Teaching Hospital, Lusaka. “Lamotrigine may be available, but patients have to purchase it, and the cost is beyond reach of most people’s financial situations."

Pakistan has both brand-name and generic valproate and levetiracetam, as well as generic lacosamide and zonisamide, said Zarine Mogal, consultant neurologist at the National Epilepsy Centre, Karachi. In general, carbamazepine is preferred as first-line treatment for focal epilepsies, followed by levetiracetam and valproate, she said.

In Viet Nam, both lamotrigine and levetiracetam are available and part of the national insurance system for epilepsy, said Minh-An Thuy Le, neurologist and faculty member at the University of Medicine and Pharmacy of Ho Chi Minh City. However, she said that levetiracetam is more widely distributed than is lamotrigine.


The first set of SANAD studies, published in 2007, found that valproate was more effective than either lamotrigine or topiramate for generalized seizures, and that lamotrigine was a cost-effective alternative to carbamazepine.

The SANAD studies test already-approved medications as monotherapy. The patients are randomized to which drug they are receiving, but both patient and physician are aware of the drug being given.

“When a clinician is not blinded, clinical decisions are influenced by the knowledge of the drug you are giving and that can distort results,” said Perucca. “For example, if I see a minor skin rash in a patient that I know is on lamotrigine, I may stop the drug. But if I know they are on levetiracetam, I may wait and see if it goes away, or attribute it to something else.”

Marson acknowledges that regulatory trials should never be unblinded. “But if you want to answer the question, ‘Does this treatment work in the real world, and how does it compare with other treatments?’ you have to make some compromises in design,” he said. “You lose some internal validity to improve the external validity.”

Marson noted that in SANAD II, about half of participants came off their initial medication and were given a different one. “If you’re going to make a decision about what to do next in those cases, you have to know what they were given initially,” he said. “And if you blind a trial that involves valproate, you can’t recruit most women of childbearing age because they need to know what they’re taking so they can make decisions about contraception. As soon as you blind a trial like this, you start designing a study that doesn’t inform or reflect clinical practice.” 


Founded in 1909, the International League Against Epilepsy (ILAE) is a global organization with more than 125 national chapters.

Through promoting research, education and training to improve the diagnosis, treatment and prevention of the disease, ILAE is working toward a world where no person’s life is limited by epilepsy.

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