The pivotal role of
5-HT in the control of appetite was formally proposed nearly 30 years ago. In particular endogenous hypothalamic
5-HT has been implicated in the processes of within meal satiation and the end state of post meal satiety. Of the numerous
5-HT receptor subtypes currently identified, 5-HT(1B) and 5-HT(2C) receptors are believed to mediate the
5-HT induced satiety.
5-HT drugs such as d-
fenfluramine, selective serotoninergic reuptake inhibitor (
SSRIs) and
5-HT(2C) receptor agonists have all been shown to significantly attenuate rodent
body weight gain, an effect strongly associated with marked hypophagia. D-
Fenfluramine,
sibutramine,
fluoxetine and the
5-HT(2C) receptor agonist mCPP have also all been shown to reduce caloric intake by modifying appetite in both lean and obese humans. Specifically,
5-HT drugs reduce appetite prior to and after the consumption of fixed caloric loads, and reduce pre meal appetite and caloric intake at ad libitum meals. Clinically significant
weight loss over a year or more can be produced by both d-
fenfluramine and
sibutramine treatment, but apparently not by the SSRI
fluoxetine. Treatment with the preferential
5-HT(2C) receptor agonist mCPP and the
serotonin precursor
5-HTP has also been shown to produce
weight loss in the obese. Issues around the actual and possible side effects of these compounds, and in the case of d-
fenfluramine toxicity, have led to a search for drugs that act selectively on the CNS
5-HT receptors critical to the satiety response. Currently, a new generation of 5-HT(2C) selective agonists have been developed (including
Ro 60-0175, Org 12962, VER-3323, BVT-933 and
YM348) and at least one, ADP356, is currently undergoing clinical trials. Hopefully, such drugs will be as or even more effective at regulating appetite and controlling
body weight, and will also be free of their predecessors' side effect.