Pharmacological Management of Dravet Syndrome

Dravet syndrome is a severe developmental and epileptic encephalopathy driven in most cases by loss-of-function variants in the SCN1A gene. Seizures typically begin in the first year of life, are refractory to conventional antiseizure medications and are accompanied by cognitive, behavioural and motor comorbidities. Pharmacological management has evolved from broad-spectrum agents towards targeted approaches that address underlying pathophysiology. First-line therapies often combine valproate, clobazam and stiripentol, but many patients remain drug-resistant. Cannabidiol has provided an adjunctive option with a distinct mechanism, while fenfluramine has been repurposed to deliver profound reductions in seizure frequency through dual serotonergic and sigma-1 receptor modulation. Emerging strategies encompass precision medicine, including antisense oligonucleotides to correct specific sodium-channel mutations, enantiomer-selective formulations of existing compounds to enhance potency and reduce off-target effects, and novel small molecules targeting chaperone proteins or neurotransmitter receptors. These developments aim not only to suppress seizures but also to improve non-seizure outcomes such as cognition, behaviour and risk of sudden unexpected death in epilepsy. The global significance of these advances is underscored by their potential to transform a uniformly severe prognosis into a condition amenable to personalised, mechanism-based therapy.

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Pharmacological Management of Dravet Syndrome publication trend

The graph below shows the total number of articles in pharmacological management of dravet syndrome across all publications each year (not limited to Nature Index journals).

Technical terms

SCN1A: Gene encoding the Nav1.1 voltage-gated sodium channel α subunit; haploinsufficiency leads to impaired inhibitory interneuron firing in Dravet syndrome.

Antisense oligonucleotide: A short, synthetic single-stranded nucleic acid designed to bind complementary mRNA, modulating splicing or inducing degradation to correct genetic defects.

Fenfluramine: A serotonin-releasing agent repurposed for Dravet syndrome that also modulates sigma-1 receptor activity to restore excitatory–inhibitory balance.

Sigma-1 receptor: An endoplasmic reticulum chaperone that regulates calcium signalling and neuronal survival, representing a novel target for antiseizure and neuroprotective therapies.

References

1. Antisense oligonucleotides as a precision therapy for developmental and epileptic encephalopathies. CNS Neuroscience & Therapeutics (2024).
2. Stereoselective Analysis of the Antiseizure Activity of Fenfluramine and Norfenfluramine in Mice: Is l-Norfenfluramine a Better Follow-Up Compound to Racemic-Fenfluramine?. International Journal of Molecular Sciences (2024).
3. Fenfluramine: a plethora of mechanisms?. Frontiers in Pharmacology (2023).
4. An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies. International Journal of Molecular Sciences (2021).