Serotonin and sudden death: differential effects of serotonergic drugs on seizure-induced respiratory arrest in DBA/1 mice

Epilepsy Behav. 2014 Aug;37:198-203. doi: 10.1016/j.yebeh.2014.06.028. Epub 2014 Jul 26.


In the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP), administration of a selective serotonin (5-HT) reuptake inhibitor (SSRI), fluvoxamine, completely suppressed seizure-induced respiratory arrest (S-IRA) at 30 min after administration (i.p.) in a dose-related manner without blocking audiogenic seizures (AGSz), but another SSRI, paroxetine, reduced S-IRA but with a delayed (24 h) onset and significant toxicity. A serotonin-norepinephrine reuptake inhibitor, venlafaxine, reduced S-IRA incidence, but higher doses were ineffective. A selective 5-HT7 agonist, AS-19, was totally ineffective in reducing S-IRA. In developing DBA/1 mice that had not previously experienced AGSz, administration of a nonselective 5-HT antagonist, cyproheptadine, induced a significantly greater incidence of S-IRA than that of saline. This study confirms that certain drugs that enhance the activation of 5-HT receptors are able to prevent S-IRA, but not all serotonergic drugs are equally effective, which may be relevant to the potential use of these drugs for SUDEP prevention. Serotonergic antagonists may be problematic in patients with epilepsy.

Keywords: Cyproheptadine; Fluvoxamine; Paroxetine; SNRI; SSRI; SUDEP; Serotonin; Venlafaxine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / adverse effects
  • Adrenergic Uptake Inhibitors / therapeutic use
  • Animals
  • Cyclohexanols / adverse effects
  • Cyclohexanols / therapeutic use
  • Cyproheptadine / adverse effects
  • Cyproheptadine / therapeutic use
  • Death, Sudden / etiology
  • Death, Sudden / prevention & control*
  • Dose-Response Relationship, Drug
  • Epilepsy, Reflex / physiopathology
  • Female
  • Heart Arrest / etiology
  • Heart Arrest / mortality
  • Heart Arrest / prevention & control
  • Male
  • Mice
  • Mice, Inbred DBA
  • Seizures / epidemiology
  • Seizures / mortality
  • Seizures / prevention & control*
  • Serotonin / physiology*
  • Serotonin Agents / adverse effects
  • Serotonin Agents / therapeutic use*
  • Serotonin Antagonists / adverse effects
  • Serotonin Antagonists / therapeutic use
  • Serotonin Uptake Inhibitors / adverse effects
  • Serotonin Uptake Inhibitors / therapeutic use
  • Venlafaxine Hydrochloride


  • Adrenergic Uptake Inhibitors
  • Cyclohexanols
  • Serotonin Agents
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors
  • Cyproheptadine
  • Serotonin
  • Venlafaxine Hydrochloride