How does stiripentol's effect on seizures in dravet differ from fenfluramine?

Short answer: they work through different targets, so they tend to affect seizures in Dravet in different ways and with different safety considerations.

Key differences

- Mechanism of action
- Stiripentol: a GABAergic drug. It enhances GABAergic inhibition (positive allosteric effect at GABA-A receptors) and increases brain GABA levels by interfering with GABA metabolism. It also raises levels of the antiseizure medication clobazam (and its active metabolite) by inhibiting certain liver enzymes, which can amplify sedation and other effects.
- Fenfluramine: a serotonergic agent. It increases serotonin (5-HT) signaling in the brain (through serotonin release and receptor activity, mainly 5-HT receptors). Its antiseizure effect is thought to come from modulation of neuronal circuits via serotonin rather than GABA.

- What kind of seizure reduction you see
- Stiripentol: generally used as an add-on to other drugs (notably valproate and clobazam) in Dravet. It reduces overall seizure frequency across the spectrum of seizures seen in Dravet, but its strongest clinical signal is as part of a broader, multi-drug regimen.
- Fenfluramine: has shown a particularly robust effect on convulsive seizures in Dravet, with large reductions in monthly convulsive seizures in randomized trials (and useful reductions in total seizures as well). It is often highlighted for its strong impact on convulsive events.

- Safety and monitoring
- Stiripentol: common side effects include drowsiness/sedation, ataxia, and GI upset. It interacts with many drugs by inhibiting liver enzymes, which can raise levels of clobazam and other meds (increasing sedation and other effects).
- Fenfluramine: common effects include reduced appetite/weight loss, diarrhea, and somnolence. It carries a notable risk of valvular heart disease with long-term use, so patients typically undergo cardiac monitoring (echocardiograms) as part of therapy. It can also interact with other serotonergic drugs (watch for serotonin syndrome in combined therapy).

- Where and how it’s used
- Stiripentol: approved as an add-on therapy for Dravet syndrome, especially in patients already taking valproate and clobazam.
- Fenfluramine (Fintepla): approved for Dravet (and Lennox-Gastaut) and can be used as add-on or stand-alone therapy; comes with cardiac monitoring requirements due to valvular risks.

Bottom line
- Stiripentol boosts GABAergic inhibition and can enhance the effects of other antiseizure meds, with a safety profile centered on sedation and drug interactions.
- Fenfluramine boosts serotonergic signaling and tends to produce a strong reduction in convulsive seizures, but carries a risk of valvular heart disease and requires cardiac monitoring.

If you’re evaluating them for a Dravet patient, the choice and sequencing often depend on the individual seizure pattern (especially convulsive seizures), current medication list (to manage interactions), and tolerance of potential cardiac risks with fenfluramine.