Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder

Abstract

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.

Flibanserin for the treatment of hypoactive sexual desire disorder in premenopausal women

“…Finding the normal female testosterone range posttreatment can be complicated because delivery systems are marketed for men, and accurate testosterone laboratory measurements are often unavailable. Side effects of excess testosterone may include virilization (including hoarsening of the voice and excess hair growth) and acne [7,9] Pivotal trial(s) Phase III, double-blind placebo-controlled efficacy and safety trials [12,13,15].…”

“…Based on the observed effects of flibanserin on these three monoamine neurotransmitters that are involved in sexual excitation and inhibition, a mechanism of action for flibanserin has been proposed that involves normalization of CNS neurotransmitter levels (increased DA and NE, reduced 5-HT) to enhance sexual desire. Information on dopaminergic circuits was derived from studies done on animals and the known sexual side effects of medications in humans [13].…”

The pharmacodynamic effects of combined administration of flibanserin and alcohol

“…17 The pathophysiology of HSDD is hypothesized to result from a hypoactive excitatory response, a hyperactive inhibitory response, or both 17,18 ; the effects of flibanserin may counteract this imbalance, resulting in the restoration of sexual desire. 19 The safety and efficacy of flibanserin were examined across multiple phase 1, 2 and 3 studies in pre-and post-menopausal women with HSDD (and safety in healthy men); more than 1500 premenopausal women with HSDD received the recommended dose of flibanserin 100 mg daily at bedtime for ≥6 months. 20 The most commonly reported adverse events (AEs) were dizziness, somnolence, nausea, fatigue and insomnia, consistent with the classification of flibanserin as a central nervous system (CNS) depressant; 5-HT 1A agonism promotes wakefulness and inhibits sleep, 21 whereas 5-HT 2A antagonism causes sedation.…”

Interest, Arousal, and Shifting Diagnoses of Female Sexual Dysfunction, or: How Women Learn About Desire

“…In 2010, the drug Flibanserin went through FDA trials but was ultimately not approved (Wilson, 2010), in part due to protest by a critical outpouring of members of Tiefer's New View Campaign among other antimedicalization activists (http://www.newviewcampaign.org/ flibanserin.asp). Flibanserin is a neurotransmitter drug that works on the central nervous system, specifically on serotonin receptors, purportedly enhancing libido in women (Stahl, Sommer, and Allers, 2011). The newest addition to the neuropharmaceutical lineup is Lybrido, which was undergoing field tests at the time of this writing (Bergner, 2013).…”