Bromides, the drug of choice for decades, was introduced in 1850 as the first effective seizure treatment based on the theory that epilepsy was caused by excessive sexual desire. There have been several PHB-like drugs developed, including primidone.
The Journal of the American Medical Association published a 1938 report by Houston Merrit and Tracy Putnam describing an animal model for screening multiple compounds for anti-epileptic activity. Phenytoin (PHT) was discovered to be effective for treating epilepsy in 1940, and it has since been the first choice of anti-epileptic drugs (AEDs) for partial and secondary generalized seizures.
First approved for the treatment of trigeminal neuralgia in 1968, carbamazepine (CBZ) was later approved for partial seizures in 1974. The use of ethosuximide for the treatment of absence seizures without generalized tonic-clonic seizures has been prevalent since 1958. In 1960, valproate (VPA) was approved in the European Union, and in 1978 in the United States. In the mid-1990s, it was approved for the treatment of partial seizures and was the drug of choice for primary generalized epilepsy.
These anticonvulsants were the mainstay of seizure management until the 1990s when newer AEDs were developed with good efficacy, fewer toxicities, better tolerability, and without the need for blood level monitoring. The new generation AEDs, lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam in the first trimester were not associated with an increased risk of serious birth defects.
The new AEDs are only approved as add-on therapy in the USA, except topiramate and oxcarbazepine (OXC); Lamotrigine (LTG) is approved for conversion to monotherapy. A meta-analysis of 70 randomized clinical trials confirms the clinical impression that the effectiveness of AEDs used in refractory partial epilepsy does not differ significantly.