Lamotrigine Is Best Option for Patients With Newly Diagnosed Focal Epilepsy

Brain activity, computer artwork.
The objective of this study was to determine the long-term efficacy and cost-effectiveness of lamotrigine as compared with levetiracetam and zonisamide.

Lamotrigine is the best first-line treatment option for patients newly diagnosed with focal epilepsy, according to study results published in Lancet.

Although levetiracetam and zonisamide are approved for patients with focal epilepsy, limited data are available on the recommended first-line treatment for newly diagnosed patients. The objective of the current study was to determine the long-term efficacy and cost-effectiveness of lamotrigine, compared with levetiracetam and zonisamide.

This randomized, open-label, controlled trial included adults and children aged 5 years and older from neurology services across the UK with 2 or more unprovoked focal seizures. The patients were randomly assigned 1:1:1 to receive lamotrigine, levetiracetam, or zonisamide.

All participants were included in the intention-to-treat analysis, but the per-protocol analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. The trial was designed to assess noninferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission.

The study sample included 990 patients (mean age, 39.3 years; 57% boys and men). Of these, 330 patients were randomly assigned to receive lamotrigine, 332 were treated with levetiracetam, and 328 received zonisamide.

In the intention-to-treat analysis, levetiracetam did not meet noninferiority criteria for 12-month remission compared with lamotrigine (hazard ratio [HR], 1.18; 97.5% CI, 0.95-1.47; noninferiority margin, 1.314), but zonisamide did meet the criteria (HR, 1.03; 97.5% CI, 0.83-1.28). In per-protocol analysis, 12-month remission was better with lamotrigine than either levetiracetam (HR, 1.32; 97.5% CI, 1.05-1.66) or zonisamide (HR, 1.37; 97.5% CI, 1.08-1.73). In cost-utility analyses, based on differences between treatment groups in costs and quality-adjusted life years, lamotrigine was superior to both drugs.

Study researchers observed adverse reactions to have been reported by 33% of patients treated with lamotrigine, 44% of those who started levetiracetam, and 45% of patients who initiated zonisamide. During the trial there were 37 deaths: 15 among those treated with lamotrigine, 12 among levetiracetam-treated patients, and 10 in participants who initiated zonisamide.

The study had several limitations, including using seizure diaries to collect data with potential bias, a relatively small number of patients younger than 18 years of age, potential systematic bias due to the maintenance doses chosen, low return rate for quality of life questionnaires, and no data on the impact of newer antiepileptic drugs.

“Our results support the continued use of lamotrigine as first-line treatment for patients with focal epilepsy and its use as a standard comparator in future comparative trial,” concluded the study researchers.

Disclosure: Some study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021 Apr 10;397(10282):1363-1374. doi:10.1016/S0140-6736(21)00247-6