An update on the pharmacology of serotoninergic appetite-suppressive drugs.

D-Fenfluramine, fluoxetine and sertraline are considered to be serotoninergic appetite-suppressive drugs. These three agents have been compared in fasted mice, rats and guinea pigs for their activity as food intake inhibitors. D-Fenfluramine is the most effective drug in the three animal species followed by fluoxetine and then sertraline. All three compounds are metabolized to N-dealkylated metabolites which accumulate in the brain and are themselves effective in reducing food intake. At anorectic doses the brain levels of the drugs and their metabolites are compatible with the concentrations able to block serotonin (5-HT) uptake and to release brain 5-HT from brain synaptosomes. However only the anorectic activity of D-fenfluramine is antagonized by the previous administration of 5-HT antagonists. These results cast some doubts on the role of brain 5-HT in explaining the anorectic activity of fluoxetine and sertraline.