RationaleFenfluramine substantially reduces rates of sudden unexplained death in epilepsy (SUDEP) in Dravet syndrome (Cross JH et al, AES 2020). Fenfluramine reduces respiratory arrest in the DBA/1 SUDEP mouse model (Tupal and Faingold, Epilepsia. 2019). Spreading depolarisation (SD) is a pathophysiologic event linked to cardiorespiratory collapse in SUDEP models. We report that fenfluramine inhibits SD, and explore its potential inhibitory mechanisms.MethodsWe examined the effects of fenfluramine on SD evoked by KCl or oxygen glucose deprivation (OGD) in cortical brain slices of adult C57Bl/6 mice. We also measured the effect on GABAAR-mediated inhibitory postsynaptic currents (sIPSC) in vitro.ResultsFenfluramine increased the threshold for SD events at clinically relevant concentration ranges (~10 µM). Blocking GABAARs with gabazine did not fully occlude SD inhibition by fenfluramine, suggesting that GABAAR potentiation is not involved in the inhibitory SD mechanism of fenfluramine.ConclusionOur results demonstrate that fenfluramine directly inhibits SD generation without acting via a neurovascular mechanism suggesting that SD inhibition could account for the decrease in expected rates of SUDEP in patients treated with fenfluramine.