Serotonin Associated Mechanisms in Sudden Unexpected Death in Epilepsy: A Review

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of death in patients with epilepsy (PWE), although the mechanisms are unclear. Early studies have shown that abnormal cardiopulmonary function plays a key role in SUDEP. Cardiopulmonary activity is regulated by the autonomic nervous system. Serotonin (5-hydroxytryptamine or 5-HT) neurons significantly influence respiration and are also closely related to epilepsy. Therefore, serotonin is hypothesized to be involved in SUDEP, and a substantial amount of research has focused on it. Notably, serotonin signals through at least 14 known receptor subtypes, with preclinical data suggesting a particular involvement of the 5-HT₂, 5-HT₃, and 5-HT₄ receptors in SUDEP. Dilute Brown Non-Agouti (DBA)/1 and DBA/2 mice, which often die of seizure-induced respiratory arrest (S-IRA) following audiogenic seizures (AGS), are the most commonly used animal models for studying SUDEP. Increased serotonin reduces S-IRA, activating serotonin neurons prevents SUDEP, abnormalities in serotonin receptors are associated with SUDEP, and selective serotonin reuptake inhibitors (SSRIs) affect electroencephalogram (EEG) activity. Other studies have found that serotonin protects against S-IRA in PWE. Pathological studies in patients with SUDEP have also revealed that, in comparison with controls, the axonal length (AL) of serotonin transporter (SERT)-positive axons is longer and the level of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis, is lower. Consequently, serotonin is possibly a potential target for preventing SUDEP. However, most of the results are from animal studies, while the experimental data in PWE are limited. More human studies are needed in the future.