Introduction. Flibanserin is a novel pharmacologic agent in late-stage clinical testing for hypoactive sexual desire disorder (HSDD) in premenopausal women.
Aim. The aim of this article is to review the hypothetical mechanism of action of flibanserin in HSDD.
Methods. A literature review was conducted of all published works on flibanserin and on related studies of serotonin (5-HT)1A receptors and 5-HT2A receptors, including their actions on monoamines and on sexual function.
Main Outcome Measures. The main outcome measures are preclinical pharmacologic actions, especially changes in regional monoamines following treatment with flibanserin.
Results. At clinically relevant doses, flibanserin acts predominantly at 5-HT1A receptors as an agonist and secondarily at 5-HT2A receptors as an antagonist. Additional binding actions within an order of magnitude of its 5-HT1A affinity, which are not likely to be clinically relevant, include weaker antagonist actions at 5-HT2C and 5-HT2B receptors, and less defined activity at dopamine (DA) D4 receptors. The 5-HT1A actions of flibanserin are only seen postsynaptically, which is unlike other agents such as buspirone that act at presynaptic 5-HT1A receptors. Furthermore, the postsynaptic actions of chronic flibanserin administration appear to demonstrate a preference for some populations of postsynaptic 5-HT receptors, particularly those that are located on the prefrontal cortex (PFC) pyramidal neurons, which regulate monoamine release in certain selective brain regions.
Conclusions. The regional selectivity of flibanserin results in a unique pattern of monoamine modulation. Sustained increases in baseline of DA and norepinephrine (NE) are observed in the PFC, and flibanserin dosing increases DA and NE levels above the basal changes. Conversely, flibanserin induces transient decreases in 5-HT levels in some brain areas such as the PFC, nucleus accumbens, and hypothalamus, but not in other brain areas such as the hippocampus. Therefore, since DA and NE are excitatory and 5-HT is inhibitory to sexual desire and arousal, it is tempting to postulate that the actions of flibanserin on serotonin receptors at the PFC pyramidal neurons, resulting in increased DA and NE yet reduced 5-HT in the PFC, are the mechanistic underpinnings of enhancing sexual desire in HSDD. Stahl SM, Sommer B, and Allers KA. Multifunctional pharmacology of flibanserin: Possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med 2011;8:15–27.