New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System

**Background**: GABA is the predominant inhibitory neurotransmitter in the mammalian brain, and its interaction with GABA_A receptors mediates chloride ion influx leading to neuronal hyperpolarization. Disruption of GABAergic transmission contributes to seizure initiation and propagation. Many antiseizure medications (ASMs) enhance GABAergic inhibition through various mechanisms. This review discusses the role of GABA in seizure modulation and profiles two recently approved ASMs: cenobamate and ganaxolone.

**Methods**: The authors conducted a literature search on PubMed for studies published from January 1, 2005 to June 30, 2023 using search terms 'GABA AND seizures OR epilepsy'. Additional searches for cenobamate and ganaxolone were performed without language or time limitations. US and European prescribing information and clinical trials registered on ClinicalTrials.gov were also reviewed.

**Key Results**: Cenobamate is a carbamate derivative approved in 2019 (USA) and 2021 (Europe) for focal seizures in adults. It acts via dual mechanism: positive allosteric modulation of synaptic and extrasynaptic GABA_A receptors (independent of benzodiazepine site) and preferential inhibition of persistent sodium currents. In a pivotal double-blind trial (n=437), cenobamate 200 mg/day produced median seizure frequency reduction of 55.6% vs 21.5% for placebo (p<0.0001), with responder rate 50.4% vs 22.2% (p<0.0001). Seizure freedom rates during maintenance were 11% (p<0.01) for 200 mg/day and 21% (p<0.001) for 400 mg/day (conservative assessment: 9% and 14% respectively). Common adverse events included somnolence (22% at 200 mg), dizziness (18%), and fatigue (12%). Three cases of drug rash with eosinophilia and systemic symptoms (DRESS) occurred with rapid titration; slow titration (starting 12.5 mg/day) is now recommended.

Ganaxolone is a synthetic neurosteroid, a methyl analogue of allopregnanolone, approved in March 2022 (USA) for seizures associated with CDKL5 deficiency disorder. It acts as a positive allosteric modulator at both synaptic and extrasynaptic GABA_A receptors, including δ-subunit-containing receptors that do not internalize during prolonged seizures. In the MARIGOLD trial (n=101, ages 2-19 years), ganaxolone (up to 63 mg/kg/day or 1800 mg/day) reduced major motor seizure frequency by median 30.7% vs 6.9% for placebo (p=0.004). Responder rate (≥50% reduction) was 24% vs 10% (p=0.064). Common adverse events included somnolence (38% vs 20% placebo), pyrexia (18% vs 8%), and upper respiratory tract infection (10% vs 6%). In a phase III trial for focal epilepsy (n=359), ganaxolone 1800 mg/day did not significantly reduce seizure frequency vs placebo (21.3% vs 10.2%, p=0.15).

**Clinical Implications**: Cenobamate offers robust efficacy for drug-resistant focal epilepsy, with seizure freedom rates higher than those reported for other second-generation ASMs. Its use requires slow titration to mitigate DRESS risk and careful monitoring for pharmacokinetic interactions (e.g., increases phenytoin, phenobarbital, N-desmethylclobazam levels; decreases carbamazepine, lamotrigine). Ganaxolone is the first approved therapy for CDKL5 deficiency disorder, an ultra-rare epileptic encephalopathy. It is generally well tolerated, but somnolence is common. Enzyme-inducing ASMs reduce ganaxolone exposure and should be avoided if possible. Both drugs are under investigation for additional indications: cenobamate for generalized tonic-clonic seizures and pediatric populations; ganaxolone for tuberous sclerosis complex-related epilepsy and refractory status epilepticus. Their differing mechanisms highlight the diversity of GABA-targeting therapies and the potential for improved outcomes in hard-to-treat epilepsies.