Risperidone counteracts lethality in an animal model of the serotonin syndrome

Psychopharmacology (Berl). 2000 May;150(1):9-14. doi: 10.1007/s002130000397.


Rationale: The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and pharmacologic treatment should be offered in severe cases.

Objective: In the present study, the effects of risperidone, ketanserin, and haloperidol on an animal model of the serotonin (5-HT) syndrome were evaluated.

Methods: Intraperitoneal administration of 100 mg/kg 5-hydroxy-L-tryptophan (5-HTP) (a precursor of 5-HT) and 2 mg/kg clorgyline (a monoamine oxidase type-A inhibiting antidepressant) induced the 5-HT syndrome in rats. The rectal temperature of the rats was measured, and the microdialysis method was used to measure noradrenaline (NA) levels in the anterior hypothalamus.

Results: In the group pre-treated with saline, the NA concentration increased to 13 times the pre-administration level, rectal temperature increased to more than 40 degrees C, and all of the animals died 75 min later. In the group pre-treated with risperidone (0.5 mg/kg), the 5-HT syndrome was completely inhibited, and the NA level increased to 6.5 times the pre-administration level. Ketanserin, a selective 5-HT2A antagonist (5 mg/kg) also inhibited the 5-HT syndrome. In contrast, all of the rats in the group pre-treated with haloperidol (0.5 mg/kg) died earlier than in the saline group.

Conclusions: These results suggest that strong 5-HT2A antagonists such as risperidone, but not dopamine D2 antagonists, counteract lethality due to 5-HT syndrome, and that not only does enhancement of 5-HT activity occur in the 5-HT syndrome, but NA activity also increases.

MeSH terms

  • 5-Hydroxytryptophan / adverse effects
  • Animals
  • Antidepressive Agents / adverse effects
  • Body Temperature / drug effects
  • Clorgyline / adverse effects
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Hypothalamus, Anterior / drug effects*
  • Hypothalamus, Anterior / metabolism
  • Male
  • Norepinephrine / metabolism*
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin / drug effects
  • Risperidone / pharmacology*
  • Risperidone / therapeutic use
  • Serotonin Antagonists / pharmacology*
  • Serotonin Antagonists / therapeutic use
  • Serotonin Syndrome / drug therapy*
  • Serotonin Syndrome / metabolism
  • Serotonin Syndrome / mortality


  • Antidepressive Agents
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin
  • Serotonin Antagonists
  • 5-Hydroxytryptophan
  • Risperidone
  • Clorgyline
  • Norepinephrine