Flibanserin: Approval of a controversial drug for a controversial disorder

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Byline: T. Sathyanarayana Rao, Chittaranjan. Andrade Flibanserin (BIMT 17; Addyi; Sprout Pharmaceuticals, North Carolina, USA) is an agonist at postsynaptic (but not presynaptic) serotonin (5HT) 5HT1a receptors and an antagonist at 5HT2 receptors; the binding appears preferential for prefrontal cortex (PFC) pyramidal neurons that regulate monoamine release. Thus, flibanserin dosing results in increased release of dopamine (DA) and norepinephrine (NE) in the PFC. Flibanserin is also associated with decreased release of 5HT in the PFC, nucleus accumbens, and hypothalamus, but not hippocampus. Whereas DA and NE putatively increase sexual desire and arousal and 5HT inhibits sexual desire and arousal, this pharmacodynamic profile may explain the suggested benefits of the drug in women with hypoactive sexual desire disorder (HSDD). Weak and probably nonsignificant actions of flibanserin include antagonism at 5HT2b, 5HT2c, and D4 receptor sites.[sup][1],[2] Flibanserin was originally developed as an antidepressant [sup][3] with a potentially rapid onset of action;[sup][4] it was effective in some but not all animal models of depression.[sup][5] Phase 2 randomized controlled trials (RCTs) failed to find it effective against depression; however, interestingly, the drug outperformed placebo on responses to the question“how strong is your sex drive."[sup][3] On September 22, 2015, only 76 hits emerged in a PubMed search with the key word flibanserin, and only 9 hits emerged with the clinical trial search filter applied. The failed antidepressant data are unavailable in PubMed and presumably remain unpublished, but the sexual function findings have been released. Kennedy [sup][6] examined data from 4 RCTs of flibanserin (100–200 mg/day) in men ( n = 369) and women ( n = 523) with major depressive disorder. All RCTs had an active comparison treatment arm, and two RCTs were additionally placebo-controlled. Patients in the RCTs had been assessed using the Arizona Sexual Experiences Scale and the Hamilton Depression Rating Scale (HAM-D) genital symptoms item. In general, it appeared that flibanserin was associated with low or placebo-level risk of treatment-emergent sexual dysfunction. In one RCT, reported improvement in sexual functioning in women with baseline sexual dysfunction was 70% versus 30% for flibanserin versus placebo groups. In another RCT, flibanserin was associated with significantly greater improvement on the genital symptoms HAM-D item at weeks 4, 6, and 8. In the other RCTs, outcomes related to sexual functioning were inconsistent.[sup][6] Thus, there seemed to be a weak signal suggesting that flibanserin carries benefits for sexual functioning in women with depression. Four important RCTs and two long-term studies have now been published on the use of flibanserin for HSDD. HSDD is characterized by low sexual desire as a result of which the individual experiences distress or interpersonal difficulty. The condition is not diagnosed if the low desire is due to medications, substances of abuse, a co-existing medical or psychiatric condition, or relationship problems. HSDD is considered to be acquired when it arises in an individual who had normal sexual desire earlier; it is considered generalized when it is not specific to a type of sexual activity, a situation, or a partner.[sup][7] The four RCTs, with a somewhat sexist slant, were named after flowers: DAISY,[sup][8] VIOLET,[sup][9] BEGONIA,[sup][10] and SNOWDROP.[sup][11] All RCTs were 24 weeks studies, conducted in women with premenopausal HSDD. The mean age of the women was about 36 years, and the mean duration of HSDD was about 5 years. All women in these studies were generally healthy, and so the findings of safety and efficacy cannot be generalized to women with medical and neuropsychiatric conditions, especially those receiving psychotropic drugs. The major outcomes were assessed in the last 4 weeks of treatment relative to baseline. …