Risperidone counteracts lethality in an animal model of the serotonin syndrome

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

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

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.

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.

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.