**Background:** Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of rare neurodevelopmental disorders characterized by early-onset, often intractable seizures, developmental delay/regression, and electroencephalographic abnormalities. The International League Against Epilepsy (ILAE) defines 'epileptic encephalopathy' as a condition where epileptic activity itself contributes to severe cognitive and behavioral impairments beyond the underlying pathology. DEEs include West syndrome, Dravet syndrome, Lennox–Gastaut syndrome (LGS), and others, with an estimated cumulative incidence of 169/100,000 children. Many DEEs have genetic aetiologies, but structural, metabolic, and immune causes also occur. Conventional antiseizure medications (ASMs) are often ineffective, and patients frequently experience comorbidities including intellectual disability, movement disorders, and increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). This review focuses on the mechanisms of action, pharmacokinetics, and clinical trial findings of five ASMs specifically approved for DEEs (rufinamide, fenfluramine, stiripentol, cannabidiol, ganaxolone) and emerging ASMs in development.
**Methods:** This is a narrative review article summarizing the pharmacology, preclinical evidence, and clinical trial data for approved and emerging ASMs for DEEs. The review synthesizes information from published literature, including phase III randomized controlled trials, open-label extension studies, and preclinical studies. Key pharmacokinetic parameters (bioavailability, half-life, metabolism, drug interactions) and mechanisms of action are described for each drug. Clinical trial outcomes include seizure frequency reduction, responder rates, and adverse events.
**Key Results:** Five ASMs with diverse mechanisms have been approved for specific DEEs: rufinamide (voltage-gated sodium channel blocker) for LGS; fenfluramine (serotonin receptor agonist and sigma-1 receptor positive modulator) for Dravet syndrome and LGS; stiripentol (positive allosteric modulator of GABA-A receptors) for Dravet syndrome; cannabidiol (TRPV1 agonist, GPR55 antagonist, adenosine reuptake inhibitor) for Dravet syndrome, LGS, and tuberous sclerosis complex; and ganaxolone (positive allosteric modulator of GABA-A receptors) for CDKL5 deficiency disorder. Clinical trial results include: rufinamide significantly reduced drop attack frequency in LGS (p<0.001); fenfluramine 0.7 mg/kg/day reduced monthly convulsive seizure frequency in Dravet syndrome by a mean of 74.9% vs. placebo (p<0.001) and in LGS reduced drop seizure frequency by a median of 26.5% vs. placebo (p=0.001); stiripentol added to valproate and clobazam resulted in significantly greater reduction in clonic/tonic-clonic seizures in Dravet syndrome (p<0.001); cannabidiol reduced convulsive seizure frequency in Dravet syndrome by a median of 38.9% vs. placebo (p=0.01) and drop seizures in LGS by a median of 43.9% vs. placebo (p=0.01); ganaxolone reduced 28-day motor seizure frequency in CDKL5 deficiency disorder by a median of 30.7% vs. 6.9% for placebo (p=0.0036). Emerging ASMs in development include soticlestat (cholesterol 24-hydroxylase inhibitor), carisbamate, verapamil, radiprodil, clemizole, and lorcaserin, with phase II/III trials ongoing.
**Clinical Implications:** The pharmacological diversity of approved and emerging ASMs for DEEs represents a significant advance in treating these challenging conditions. The availability of drugs with novel mechanisms (e.g., fenfluramine's serotonergic/sigma-1 action, cannabidiol's multi-target effects) expands treatment options beyond conventional sodium channel or GABAergic agents. However, many drugs have complex pharmacokinetic profiles with significant drug-drug interactions, requiring careful management. The low prevalence of DEEs necessitates collaborative trial designs and standardized endpoints. While these drugs rarely render patients seizure-free, they provide meaningful seizure reduction and improved quality of life. The repurposing of existing drugs (e.g., fenfluramine, verapamil, lorcaserin) offers faster clinical translation. Future research should focus on elucidating precise mechanisms, particularly for cannabidiol, and developing precision therapies targeting specific genetic aetiologies.