ArticleLiterature Review

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

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Abstract

Flibanserin is a novel pharmacologic agent in late-stage clinical testing for hypoactive sexual desire disorder (HSDD) in premenopausal women. The aim of this article is to review the hypothetical mechanism of action of flibanserin in HSDD. A literature review was conducted of all published works on flibanserin and on related studies of serotonin (5-HT)(1A) receptors and 5-HT(2A) receptors, including their actions on monoamines and on sexual function. The main outcome measures are preclinical pharmacologic actions, especially changes in regional monoamines following treatment with flibanserin. At clinically relevant doses, flibanserin acts predominantly at 5-HT(1A) receptors as an agonist and secondarily at 5-HT(2A) receptors as an antagonist. Additional binding actions within an order of magnitude of its 5-HT(1A) affinity, which are not likely to be clinically relevant, include weaker antagonist actions at 5-HT(2C) and 5-HT(2B) receptors, and less defined activity at dopamine (DA) D4 receptors. The 5-HT(1A) actions of flibanserin are only seen postsynaptically, which is unlike other agents such as buspirone that act at presynaptic 5-HT(1A) 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. 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.

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... The mechanism of action of flibanserin has been comprehensively reviewed by Stahl et al. [33]. Flibanserin is primarily an agonist at serotonin 5HT 1A receptors and an antagonist at 5HT 2A/2B receptors [34]. ...
... Instead, the parsimonious view is that (at least) all mammals engage in sex for the pleasurable/rewarding consequences. Neurobiologically, this view focuses on the mesolimbic system as the hub integrating external stimuli and experiences into subjective reward and pleasure [33]. Others have effectively reviewed the underlying neurobiology of female sexual behavior in rodents. ...
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Hypoactive sexual desire disorder (HSDD) in women is a condition of low sexual desire that develops over time. Sexual desire normally diminishes over long-term relationships, but is also negatively affected by a demanding lifestyle, poor self-esteem and body image, and loss of intimacy in a relationship. HSDD elevates to a disorder when it is a concern for the woman, arising from conflict with a partner who is interested in a greater frequency of sexual interaction. Two drugs have been marketed (Addyi and Vyleesi) to treat HSDD. Neither drug was originally developed for this purpose, nor is either drug particularly effective. The lack of rational development of drugs to treat sexual disorders in women is due to the mistaken belief that components of female sexuality, such as sexual desire, cannot be effectively modeled in animals. To the contrary, sexual interest, desire, arousal, and reward are measurable aspects of sexual behavior in female rodents. Going forward, basic research using these pre-clinical models should be the starting point for drug development. At the same time, it is not clear that drug development represents the primary therapeutic approach to the problem, with behavioral therapies providing good options for first line of treatments for HSDD.
... Flibanserin differs considerably from SSRIs and SNRIs in serotonergic effects. Flibanserin targets cortical 5-HT 1A and 5-HT 2A receptors, 6 whereas medications that block serotonin reuptake exert more generalized effects across the serotonin system. 38 Agonist activity at 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors, as demonstrated by flibanserin, serve to inhibit glutamate release that in turn decreases 5-HT activity in the prefrontal cortex. ...
... 38 Agonist activity at 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors, as demonstrated by flibanserin, serve to inhibit glutamate release that in turn decreases 5-HT activity in the prefrontal cortex. 6 Flibanserin has demonstrated efficacy in the treatment of HSDD in a number of studies. 14e18 The present safety study was conducted as 1 aspect of the extensive clinical development program for flibanserin in HSDD. ...
Article
Background: Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression. Aim: To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. Methods: In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks. Outcomes: Safety assessment included adverse events and symptoms of depression and anxiety. Results: 73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology-Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients receiving placebo; remission of anxiety based on the Beck Anxiety Inventory was noted in 16.4% and 2.7% of patients, respectively. Clinical implications: The results of this study support the safety of flibanserin in premenopausal women being treated with a serotonergic antidepressant. No increased risks were observed when adding flibanserin to a stable selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor treatment regimen. Strengths and limitations: This was a well-designed, randomized, placebo-controlled trial. The primary limitation was the early study discontinuation by the sponsor, which decreased the sample size and duration of treatment. Conclusion: In this small trial, flibanserin 100 mg qhs was generally safe and well tolerated in premenopausal women with mild or remitted depression taking a serotonergic antidepressant. Clayton AH, Croft HA, Yuan J, et al. Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study. J Sex Med 2018;15:43-51.
... to the biological etiology of sexual dysfunction (SD). Or from a subjective perspective, for a person to maintain sexual arousal, anti-sexual thoughts (believed to reside in the cortical section) must be inhibited for optimal sexual response [21,22]. Despite its clinical underpinnings, it is understandable that the STP model has been aligned with the dual control theories of others given its similar emphasis on excitation and inhibition. ...
... The reverse can of course contribute to the biological etiology of sexual dysfunction (SD). Or from a subjective perspective, for a person to maintain sexual arousal, anti-sexual thoughts (believed to reside in the cortical section) must be inhibited for optimal sexual response [21,22]. ...
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The Sexual Tipping Point® Variable Control model illustrates whether a man or woman is “turned on or turned off,” with simultaneous capability of depicting all the complex multifaceted factors intrinsic to understanding sexual response. The Sexual Tipping Point® or STP, depicts the moment to moment interaction of a person’s constitutional sexual capacity with the biomedical- psychosocial and cultural factors that determine sexual their response. A person’s STP differs from one experience to another, based on the proportional impact of one factor dominating, as others recede in importance. The STP model can illustrate both the intra and inter-individual variability characterizing sexual response and its disorders for both men and women. Previously, the STP was labeled as one of a number of “Dual Control” models. Instead, it should be thought of as a “Variable Control” model. The above key will familiarize you with the STP model's graphic representations and its fundamental elements are summarized below. Two pans labeled “Excitation” and “Inhibition” respectively each hold two pairs of interconnected containers. The containers are labeled “M” (Mental) and “P” (Physical), but are bridged together by an “A” (And), recognizing that the line between mental and physical has become progressively more porous with greater understanding of how thoughts become translated into biochemical/electrical components. The Mental And Physical containers hold all known exciting (+) and inhibiting (-) factors that influence a sex positive or sex negative response. Dimmer switches illustrate each of these billions of factors that are variably charged and with variable valence. Some additional factors may be neutral (=) and others are not yet discovered (?). The STP is the net sum of all Mental And Physical factors, displayed on a balance scale labeled with a Gaussian (normal) distribution curve that spans from excitation to inhibition (or Hot to Not). So, each factor's dimmer switch setting contributes to the STP’s dynamic representation of any individual’s manifest sexual response at any moment in time. The STP is easily used to explain etiology and highlight treatment targets for patients. It helps healthcare clinicians disabuse patient’s erroneous binary beliefs. Clinicians can then instill hope through a simple explanation of how the problem’s causes can be diagnosed, parsed, and fixed.
... Flibanserin is a 5-HT 1A agonist and 5-HT 2A antagonist. [19][20][21][22] It is the only U.S. Food and Drug Administration (FDA)approved treatment for acquired, generalized HSDD in premenopausal, but not postmenopausal women. 23 It works by increasing dopamine and norepinephrine and reducing serotonin in specific areas of the cerebral cortex. ...
... 23 It works by increasing dopamine and norepinephrine and reducing serotonin in specific areas of the cerebral cortex. [19][20][21][22] Serotonergic pathways in the brain also impact metabolism and weight. 24,25 Certain selective serotonin reuptake inhibitors (SSRIs) are associated with weight gain, 26 whereas lorcaserin, a 5-HT 2C agonist, is an FDA-approved medication for weight loss. ...
... Flibanserin has two principal pharmacological actions in neural microcircuits: it acts as a full agonist at postsynaptic 5HT1A receptors and an antagonist at postsynaptic 5HT2A receptors. [12,15] Exclusive binding at these receptors differentiates flibanserin from buspirone and bupropion. [4] This action in the prefrontal cortex causes the downstream release of dopamine and norepinephrine and reduction of serotonin, consistent with sites of abnormal neuroimaging described in patients with reduced sexual interest and desire. ...
... [12,16,17] Flibanserin acts selectively on pyramidal neurons that excite brainstem 5HT neurons yet also selectively on pyramidal neurons that inhibit brainstem Norepinephrine and Dopamine neurons. [15] PHARMACOKINETICS Flibanserin shows linear and dose proportional kinetics following a single oral dose (5-150 mg) and multiple oral doses (total daily dose ranging from 60 to 300 mg). [4] It is 90% absorbed and has mean half-life of ~ 11 h. ...
Article
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Sexual functioning is an integral part of human life. Female sexual dysfunction (FSD) adversely affects quality of life and general well-being. The Food and Drug Administration recently approved flibanserin, for treatment of female hypoactive sexual desire disorder (HSDD), regarded as the most common FSD, amid great controversy. A novel multifunctional serotonin agonist and antagonist, flibanserin, has been shown to be efficacious in treating HSDD but with a rather tenacious side effect profile. We review this interesting drug in its entirety. Data for the article were collected by reviewing articles on PubMed, the drug (Addyi) website, and related websites on the internet
... Flibanserin (postsynaptic 5-hydroxytryptamine 1A agonist and 2A antagonist) was the first agent approved by the FDA for the treatment of HSDD [53]. Flibanserin functions by decreasing serotonin levels and increasing both dopamine and norepinephrine levels [13,54]. Flibanserin has a high affinity for 5-HT 1A receptors in the hippocampus and the prefrontal cortex [55]. ...
... Flibanserin was initially rejected for approval by the FDA in 2010 due to concerns over efficacy and safety data [53,65]. The most common adverse events included somnolence and dizziness, which researchers have explored with alcohol use [54,62]. Finally, Bremelanotide, which is the main focus of this paper, is a melanocortin receptor agonist and has been recently approved by the FDA for the treatment of HSDD [10,66] ...
Article
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Hypoactive sexual desire disorder (HSDD) is a persistent deficiency or absence of sexual fantasies and desire resulting in significant distress or interpersonal difficulty. Women with this disorder may display a lack of motivation for sexual activity, reduced responsiveness to erotic cues, a loss of interest during sexual activity, and avoidance of situations that could lead to sexual activity. The pathophysiology of HSDD is thought to be centered around inhibitory and excitatory hormones, neurotransmitters, and specific brain anatomy. Due to the multifactorial nature of HSDD, treatment can be complex and must attempt to target the biological and psychosocial aspects of the disorder. Bremelanotide is a melanocortin receptor agonist and has been recently approved by the FDA to treat HSDD. Bremelanotide is administered intranasally or as a subcutaneous injection. The recommended dosage of bremelanotide is 1.75 mg injected subcutaneously in the abdomen or thigh at least 45 min before sexual activity. Studies showed improvements in desire, arousal, and orgasm scores when 1.75 mg of bremelanotide was administered before sexual activity compared to a placebo. Bremelanotide is a promising way to treat HSDD.
... The therapeutic mechanism of FLB is not fully understood in HSDD. It has been reported to reduce synthesis and extracellular levels of 5-HT in the cortex, where it enhances extracellular levels of norepinephrine and dopamine [9][10][11]. The concerns of its non-regulated usage have been increased significantly due to adulteration in unauthenticated nutritional supplements [12,13]. ...
Article
Flibanserin (FLB) is the first FDA approved drug showed to have significant activity against sexual desire disorder of premenopausal and postmenopausal women. Unfortunately, FLB is used as an adulterant in dietary supplement products as a performance enhancer in sports. Identification of FLB and its metabolites in the biological samples requires an authenticated analytical technique. The aim of this study was to identify N-oxide metabolite of FLB in microsomal and S9 human liver enzyme fractions, rat urine and feces. There are several N-oxide reported as genotoxic impurity or reactive metabolites based on position of N-oxide in piperazine ring. This study also describes the strategy to utilize degradation chemistry for isolation of N-oxide and its step-wise characterization. An LC-MS method has been developed and employed for identifying the N-oxide metabolite of FLB. The targeted N-oxide metabolite in the extracted ion chromatogram of the in vitro and in vivo samples has been confirmed by analyzing the changes in observed mass at m/z 407.1693. Major distinguished abundant ions at m/z 243.1104, 190.0974, 161.0705, 119.0601 confirmed the structure of the metabolite. This study will help to understand the oxidative potential of FLB in toxicokinetic study. The developed method can be useful to identify FLB or its N-oxide metabolite in dope testing in future. This is the first time to report a strategy to utilize degradation chemistry for N-oxide metabolite characterization. In this study, isolated N-oxidative degradation product was used to confirm N-oxide metabolite which was characterized by LC-MS through H/D exchange and structure was ensured by NMR spectroscopy (1H, COSY).
... Thus, this action on the serotonin receptors in the prefrontal cortex (PFC) is hypothesized to enhance sexual desire through increasing downstream release of dopamine and norepinephrine, while decreasing serotonin release. 4,6 However, FLB suffers from limited oral bioavailability of about 33%, which could be attributed mainly to the drug's considerable first-pass metabolism. 1 In addition, FLB is a weakly basic drug with a pH-dependent solubility; it is soluble in 0.1N HCL and insoluble in phosphate buffer at pH 6.8. 6 This solubility feature may be a challenging factor for drug dissolution in the body neutral fluid, and subsequently, absorption via mucosal barriers. ...
Article
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Background and aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X1), liquid lipid % (LL%, X2), and sonication time (ST, X3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.
... To date, flibanserin is the only drug that has received approval for treatment of low sexual desire in women in the United States and Canada. While this drug, which has pharmacological effects on serotonin and dopamine receptors [10], was being tested on patients with major depressive disorder, its positive effect on women's sexual functioning was discovered [11]. So far, 3 systematic reviews or meta-analyses have found modest positive effects on women's low sexual desire [12][13][14], while also acknowledging its side effects (eg, nausea, dizziness, fatigue). ...
Preprint
BACKGROUND Psychological therapies are effective treatments for Hypoactive Sexual Desire Disorder (HSDD), a common sexual dysfunction among women. Access to evidence-based treatments, however, remains difficult. Internet-based interventions are effective for a variety of psychological disorders and may be a promising means to close the treatment gap for HSDD. OBJECTIVE This article describes the treatment protocol and study design of a randomized controlled trial, aiming to study the efficacy of cognitive-behavioral and mindfulness-based interventions delivered via the Internet for women with HSDD to a waitlist control group. METHODS A mindfulness-based and a cognitive-behavioral self-help intervention for HSDD will be provided online. Overall, 266 women with HSDD will be recruited and assigned either to one of the intervention groups, or to a waitlist control group (2:2:1). Outcome data will be assessed at baseline, at 12 weeks, and at 6 and 12 months after inclusion. Intention to treat and completer analyses will be conducted. RESULTS We expect improvements in sexual desire and sexuality-related distress in both intervention groups compared to the waitlist control. Recruitment has begun in January 2019 and is expected to be completed in August 2021. Results will be published in 2022. CONCLUSIONS This study aims to contribute to the improvement and dissemination of psychological treatments for women with HSDD and to clarify whether mindfulness-based and/or cognitive-behavioral treatments for HSDD are feasible and effective when delivered via the Internet. CLINICALTRIAL Clinical Trials Gov NCT03780751
... Warto wspomnieć o badaniach Modica i wsp., którzy otrzymali ligandy 5-HT1A w grupie pochodnych tieno [2,3d]pirymidynonu (42) [93]. Wyniki tych badań dały początek całej grupie nowych LCAP. ...
Article
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Choroby afektywne są grupą zaburzeń psychicznych, wyróżniającą się złożoną patogenezą i etiologią. Jednym z głównych biologicznych czynników wywołujących depresję są zaburzenia w neuroprzekaźnictwie katecholamin w mózgu. Związki wpływające na poziom serotoniny wytyczają bardzo obiecujący kierunek poszukiwania nowych leków przeciwdepresyjnych. Poniższa praca stanowi przegląd i analizę modyfikacji struktury ligandów receptora serotoninowego 5-HT1A. Receptor 5-HT1A występuje jako receptor presynaptyczny (autoreceptor), ale także jako receptor postsynaptyczny. Za jego pośrednictwem, w zależności od lokalizacji, może dojść do zahamowania sekrecji endogennej serotoniny do przestrzeni synaptycznej, bądź do zwiększenia przekaźnictwa w neuronach serotoninergicznych. Receptor 5-HT1A uważany jest za istotny czynnik w patogenezie i leczeniu depresji. Najważniejszymi ligandami dla tego receptora są pochodne arylopiperazyny, tetraliny i indoloalkiloaminy. W tej pracy szczególną uwagę zwrócono na modyfikacje struktury, które zwiększały powinowactwo i selektywność wymienionych związków względem receptora 5-HT1A.
... Modulation of the level of neurochemicals like dopamine, norepinephrine or serotonin in the hypothalamus and limbic system of the brain is the primary cause of female hypoactive sexual desire disorder (HSDD) (1,2). In 2015, USFDA approved flibanserin (FLB) as a serotonin modulator for the treatment of acquired generalized HSDD (3,4). ...
Article
Flibanserin (FLB) is the first USFDA approved serotonin modulator recently marketed to treat acquired generalized women hypoactive sexual desire disorder. The scope of this study was to develop and validate a sensitive, selective and reliable ultra-performance-liquid chromatography-mass spectroscopy/mass spectroscopy based quantification method for FLB in rat plasma as well as brain tissue samples. The method includes a simple liquid-liquid sample extraction procedure. FLB was subjected to chromatographic separation using a poroshell C18 column with the mobile phase comprising a mixture of acetonitrile, 10 mM ammonium acetate and acetic acid (90:10:0.1, v/v/v). Detection and quantification of FLB after positive electrospray ionization was carried out in selective ion monitoring mode. The fragment ion (m/z) of FLB (parent ion: 391.1741) and IS (parent ion: 448.1550) were monitored at 161.0704 and 285.0917, respectively. A linear response of FLB was observed over a concentration range of 2.5 to 600 ng/mL in plasma and 5 to 500 ng/mL in brain tissue homogenate. The intra and inter-day precision and accuracy of the method was met the acceptable limits specified in the USFDA bioanalytical method validation guideline. The analyte was found to be stable in benchtop, freeze-thaw, auto-injector, and dry extract stability studies. The developed method was used to quantitate FLB in the plasma and brain tissue of a single dose oral pharmacokinetic and brain tissue distribution study in female rats. Maximum FLB concentration in plasma and brain were achieved within an hour, however the total amount of the drug that reached the brain was significantly less than in plasma. Rate of elimination of FLB from brain was also faster resulting in a lesser half-life in brain compared to the plasma.
... The mechanism of action of flibanserin is not fully understood. A post-synaptic serotonin 5HT 1A agonist and serotonin 5HT 2A antagonist, one theory is that it may improve sexual desire by modulating a transient decrease in serotonin and increase in dopamine and epinephrine in certain areas of the brain [19]. ...
Article
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Purpose of Review Several new modalities for treatment of female sexual function problems have been approved by the US Food and Drug Administration (FDA). This review summarizes current evidence about recently approved medications to inform treatment of sexual function problems in women older than 65 years. Recent Findings Published studies leading to FDA approval of treatment modalities were efficacy trials not widely applicable to the general population. The clinical effectiveness of these modalities remains unknown. Although some studies have included post-menopausal women, few have included women older than 65 years. Summary Health care providers need current information about safety and effectiveness of these new treatments for all women, including the fast-growing population of older post-menopausal women. Exclusion of older women from studies of treatments for female sexual function problems presents a barrier to treatment.
... 6 Preclinical studies suggest that flibanserin activates 5-HT 1A receptors and blocks 5-HT 2A receptors in the prefrontal cortex that ultimately stimulate dopaminergic and noradrenergic neural circuits to restore sexual desire. [7][8][9][10] Consistent with its activity at serotonin receptors, the most common side effects associated with flibanserin are dizziness, somnolence, and nausea, affecting !10% of premenopausal women with HSDD in placebo-controlled studies. 2 The original prescribing information for flibanserin included a boxed warning regarding risk of severe hypotension and syncope with concomitant alcohol use. 2,3 Although previous alcohol interaction studies have examined the effects of daytime dosing of flibanserin and ethanol intake, 11À13 the effects of alcohol on flibanserin safety in a real-world context when alcoholic beverages are consumed in the evening and in moderation, and flibanserin is taken at bedtime, have not been adequately evaluated. ...
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Introduction: Flibanserin, a treatment for hypoactive sexual desire disorder, carries warnings for increased risk of severe hypotension and syncope when used with alcohol. However, these warnings are not informed by studies that used flibanserin's recommended bedtime dosing because previous alcohol studies assessed flibanserin's safety during the day. Aim: The aim of this study was to assess the effects of ethanol in a real-world context in premenopausal women taking flibanserin at bedtime. Methods: In a randomized, placebo-controlled, double-blind study, 24 healthy premenopausal women (mean age = 34.5 ± 9.9 years; mean body mass index = 25.2 ± 3.4 kg/m2) were dosed with flibanserin or placebo for 3 days to achieve steady-state plasma levels. In a clinical research unit, subjects (n = 22) were provided 2 units of wine (150 mL/unit; 12% ethanol content) or a nonalcoholic beverage with a standardized 3-course evening meal. Flibanserin 100 mg or placebo was administered at bedtime 2.5 hours after the end of the evening meal. On a separate day, subjects were provided the alternative beverage (± alcohol) with the same evening meal and dosed with the same treatment (flibanserin or placebo) at bedtime. After a 5-day washout period, subjects crossed over to the other treatment arm and the protocol was repeated. Main outcome measure: Adverse events (AEs) and vital signs were monitored. Results: In the absence of ethanol, headaches and hypotension were the only AEs that occurred in ≥2 subjects after flibanserin dosing (placebo corrected rates were 17.4% and 8.7%, respectively). After ethanol consumption, the rate of hypotension after flibanserin dosing was no greater than with flibanserin or placebo after nonalcoholic beverage consumption. There were no instances of orthostatic hypotension or syncope and no serious AEs or AEs leading to study discontinuation. Conclusion: Flibanserin dosed at bedtime after moderate amounts of alcohol with an evening meal was well-tolerated with no evidence of clinically significant hypotension or syncope. Millheiser L, Clayton AH, Parish SJ, et al. Safety and Tolerability of Evening Ethanol Consumption and Bedtime Administration of Flibanserin in Healthy Premenopausal Female Subjects. Sex Med 2019;7:418-424.
... Flibanserin is a non-hormonal oral medication that affects neurotransmitter levels in the CNS, leading to their normalization and restoration of sexual function. In previous research, it was demonstrated that flibanserin behaves as a 5-HT2A antagonist, and a 5-HT1A agonist, as well as having an affinity to 5-HT2B, 5-HT2C, and the dopamine receptors of D4 [8] Flibanserin inhibits serotonin and elevates the number of dopamine receptors. This is believed to promote dopaminergic effects while inhibiting 'anti-sexual' serotonergic effects, which is associated with enhanced sexual desire. ...
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Background: In this work, we aim to develop and validate a fast, simple, and sensitive method for the quantitative determination of flibanserin and the exploration of its pharmacokinetics. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was the method of choice for this investigation and carbamazepine was selected as an internal standard (IS). The plasma samples were processed by one-step protein precipitation using acetonitrile. The highly selective chromatographic separation of flibanserin and carbamazepine (IS) was realised using an Agilent RRHD Eclipse Plus C18 (2.1 × 50 mm, 1.8 µ) column with a gradient mobile phase consisting of 0.1% formic acid in water and acetonitrile. The analytes were detected using positive-ion electrospray ionization mass spectrometry via multiple reaction monitoring (MRM). The target fragment ions were m/z 391.3 → 161.3 for flibanserin and m/z 237.1 → 194 for carbamazepine (IS). The method was validated by linear calibration plots over the range of 100-120,000 ng/mL for flibanserin (R2 = 0.999) in rat plasma. Results: The extraction recovery of flibanserin was in the range of 91.5-95.8%. The determined inter- and intra-day precision was below 12.0%, and the accuracy was from - 6.6 to 12.0%. No obvious matrix effect and astaticism was observed for flibanserin. The target analytes were long-lasting and stable in rat plasma for 12 h at room temperature, 48 h at 4 °C, 30 days at - 20 °C, as well as after three freeze-thaw cycles (from - 20 °C to room temperature). The proposed method has been fully validated and successfully applied to the pharmacokinetic study of flibanserin.
... ' Although indirect comparisons between drugs should be performed with caution, this difference could possibly be explained by brexpiprazole being more potent at 5-HT 1A/2A receptors than aripiprazole. The 5-HT 2A antagonist effects of brexpiprazole, similar to those of flibanserin (approved for the treatment of hypoactive sexual desire disorder in women 34 ), and possibly also the 5-HT 1A partial agonist effects, might potentially attenuate the effects of serotonin reuptake inhibition from selective serotonin reuptake inhibitor antidepressants on desire and arousal by decreasing serotonin activity, 35 and thereby contribute to the positive effect on the item 'sexually aroused. ' As for the differences in magnitude of improvements in sexual functioning between women and men in our analysis, serotonin inhibition of sexual functioning may exert a greater impact in women due to the mitigating effects of testosterone in men. ...
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Purpose/background: Evidence supports use of adjunctive atypical antipsychotics in major depressive disorder (MDD). Impaired sexual functioning is common in MDD and may be worsened by antipsychotic adverse effects. We evaluated the effect of brexpiprazole on prolactin and sexual functioning in patients with MDD. Methods/procedures: In short-term studies, patients received adjunctive brexpiprazole 1, 2, or 3 mg or placebo. The long-term study was a flexible-dose (0.5-3 mg/d) open-label extension (OLE). Change from baseline and shifts in prolactin status and prolactin-related treatment-emergent adverse events (TEAEs) were assessed. Sexual functioning was assessed by the Massachusetts General Hospital Sexual Functioning Questionnaire. Findings/results: Median changes in prolactin levels from baseline to week 6 in short-term studies were as follows: brexpiprazole, 5.99 ng/mL (females) and 1.61 ng/mL (males); placebo, -0.15 ng/mL (females) and -0.08 ng/mL (males).Median changes from baseline to week 52 in the OLE were as follows: 0.27 ng/mL (females) and 0.27 ng/mL (males). Prolactin levels in patients with baseline prolactin greater than 1× upper limit of normal values tended to decrease over time.The proportion of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies for both sexes was low (0%-0.3%) and did not differ from placebo: OLE, 0.5% (females) and 0.8% (males).In short-term studies, the incidence of prolactin-related TEAEs was 3.1% for brexpiprazole and 0.7% for placebo (OLE, 3.1%). There were overall numerical improvements from baseline in sexual functioning for females and males after short- and long-term brexpiprazole treatment, with statistically significant improvements for brexpiprazole versus placebo in females on the items 'interest in sex' (-0.19; 95% confidence interval [CI], -0.33 to -0.05; P = 0.0074), 'sexually aroused' (-0.17; 95% CI, -0.30 to -0.03; P = 0.0154), and 'overall sexual satisfaction' (-0.16; 95% CI, -0.30 to -0.03; P = 0.0184). Implications/conclusions: There were small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, low incidences of prolactin-related TEAEs, and modest improvements in sexual functioning with adjunctive brexpiprazole in MDD.
... This hypothesis is consistent with studies demonstrating neuroplastic alterations regulating neurogenesis, synaptic plasticity, and synaptic activity associated with all of the recommended interventions: mindfulness and cognitive behavioral therapy, [189][190][191][192] steroid hormones, 193,194 and CNS-active drugs that modulate the neurotransmitter systems mediating HSDD. [195][196][197] Given the unmet need of women with HSDD, developmental efforts are continuing for new safe and effective treatments. However, cost of development and regulatory requirements remain substantial obstacles. ...
Article
The International Society for the Study of Women's Sexual Health process of care (POC) for management of hypoactive sexual desire disorder (HSDD) algorithm was developed to provide evidence-based guidelines for diagnosis and treatment of HSDD in women by health care professionals. Affecting 10% of adult females, HSDD is associated with negative emotional and psychological states and medical conditions including depression. The algorithm was developed using a modified Delphi method to reach consensus among the 17 international panelists representing multiple disciplines. The POC starts with the health care professional asking about sexual concerns, focusing on issues related to low sexual desire/interest. Diagnosis includes distinguishing between generalized acquired HSDD and other forms of low sexual interest. Biopsychosocial assessment of potentially modifiable factors facilitates initiation of treatment with education, modification of potentially modifiable factors, and, if needed, additional therapeutic intervention: sex therapy, central nervous system agents, and hormonal therapy, guided in part by menopausal status. Sex therapy includes behavior therapy, cognitive behavior therapy, and mindfulness. The only central nervous system agent currently approved by the US Food and Drug Administration (FDA) for HSDD is flibanserin in premenopausal women; use of flibanserin in postmenopausal women with HSDD is supported by data but is not FDA approved. Hormonal therapy includes off-label use of testosterone in postmenopausal women with HSDD, which is supported by data but not FDA approved. The POC incorporates monitoring the progress of therapy. In conclusion, the International Society for the Study of Women's Sexual Health POC for the management of women with HSDD provides a rational, evidence-based guideline for health care professionals to manage patients with appropriate assessments and individualized treatments.
... 49,50 This agent (postsynaptic 5-hydroxytryptamine 1A agonist and 2A antagonist) decreases serotonin levels and increases dopamine and norepinephrine levels, which are neurotransmitters that affect sexual desire. 18,51 Flibanserin is believed to work on brain function by enhancing excitatory elements and lessening the inhibitory response to sexual cues. 52 ...
Article
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Introduction: Hypoactive sexual desire disorder (HSDD) often has a negative impact on the health and quality of life of women; however, many women do not mention-let alone discuss-this issue with their physicians. Providers of gynecologic services have the opportunity to address this subject with their patients. Aim: To review the diagnosis and evidence-based treatment of low sexual desire in women with a focus on strategies that can be used efficiently and effectively in the clinic. Methods: The Medline database was searched for clinically relevant publications on the diagnosis and management of HSDD. Results: HSDD screening can be accomplished during an office visit with a few brief questions to determine whether further evaluation is warranted. Because women's sexual desire encompasses biological, psychological, social, and contextual components, a biopsychosocial approach to evaluating and treating patients with HSDD is recommended. Although individualized treatment plan development for patients requires independent medical judgment, a simple algorithm can assist in the screening, diagnosis, and management of HSDD. Once a diagnosis of HSDD has been made, interventions can begin with office-based counseling and progress to psychotherapy and/or pharmacotherapy. Flibanserin, a postsynaptic 5-hydroxytryptamine 1A agonist and 2A antagonist that decreases serotonin levels and increases dopamine and norepinephrine levels, is indicated for acquired, generalized HSDD in premenopausal women and is the only agent approved in the United States for the treatment of HSDD in women. Other strategies to treat HSDD include using medications indicated for other conditions (eg, transdermal testosterone, bupropion). Bremelanotide, a melanocortin receptor agonist, is in late-stage clinical development. Conclusions: Providers of gynecologic care are uniquely positioned to screen, counsel, and refer patients with HSDD. Options for pharmacotherapy of HSDD are currently limited to flibanserin, approved by the US Food and Drug Administration, and off-label use of other agents. Clayton AH, Kingsberg SA, Goldstein I. Evaluation and Management of Hypoactive Sexual Desire Disorder. Sex Med 2018;X:XXX-XXX.
... These properties translate to important functions that act on the serotonin and dopamine pathways within the brain ( Figure 1). 44,45 Flibanserin has been shown to activate the serotonin-1A receptor but inhibit the serotonin-2A receptor. Serotonin is an important monoamine neurotransmitter in the human body and is implicated in several vital functions. ...
Article
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Background: Female sexual dysfunction (FSD) affects as many as 1 in every 3 women, with a significant portion of these with hypoactive sexual desire disorder (HSDD). These figures alone present significant psychological and pharmacologic challenges. Partly in response to this situation, in 2015 the US Food and Drug Administration approved flibanserin for the treatment of HSDD. This approval has drawn criticism on the grounds of efficacy and necessity. Aim: To better inform potential consumers about FSD, flibanserin and other interventions for the treatment of HSDD, the importance of understanding the mechanism of FSD, and the efficacy of flibanserin and to review existing relevant knowledge. Methods: A literature review of extant clinic studies and theoretical discussion articles was performed. Outcomes: Efficacy of flibanserin for addressing symptoms associated with HSDD in premenopausal women. Results: Extant literature and empirical evidence suggest that the efficacy of flibanserin for the treatment of HSDD in premenopausal women is at least questionable. Clinical translation: Clinicians considering the prescription of flibanserin would be well advised to appreciate some of the controversies concerning the efficacy of the drug. Strengths and limitations: The prohibitive usage guidelines, tenuous risk-benefit profile, and considerable cost of use of flibanserin are each worthy of consideration. Flibanserin thus far has been trialed in only a narrow patient range: premenopausal women in long-term relationships with acquired or generalized HSDD. Conclusions: Although we acknowledge that the discovery and use of flibanserin constitute a compelling narrative, we conclude by questioning the specific efficacy and necessity of flibanserin in providing a treatment for HSDD in women. Anderson R, Moffatt CE. Ignorance Is Not Bliss: If We Don't Understand Hypoactive Sexual Desire Disorder, How Can Flibanserin Treat It? Commentary: J Sex Med 2018;XX:XXX-XXX.
... To date, flibanserin is the only drug that has received approval for treatment of low sexual desire in women in the United States and Canada. While this drug, which has pharmacological effects on serotonin and dopamine receptors [10], was being tested on patients with major depressive disorder, its positive effect on women's sexual functioning was discovered [11]. So far, 3 systematic reviews or meta-analyses have found modest positive effects on women's low sexual desire [12][13][14], while also acknowledging its side effects (eg, nausea, dizziness, fatigue). ...
Article
Full-text available
Background: Psychological therapies are effective treatments for hypoactive sexual desire dysfunction (HSDD; formerly hypoactive sexual desire disorder), a common sexual dysfunction among women. Access to evidence-based treatments, however, remains difficult. Internet-based interventions are effective for a variety of psychological disorders and may be a promising means to close the treatment gap for HSDD. Objective: This article describes the treatment protocol and study design of a randomized controlled trial, aiming to study the efficacy of cognitive behavioral and mindfulness-based interventions delivered via the internet for women with HSDD to a waitlist control group. Outcomes are sexual desire (primary) and sexual distress (secondary). Additional variables (eg, depression, mindfulness, rumination) will be assessed as potential moderators or mediators of treatment success. Methods: A cognitive behavioral and a mindfulness-based self-help intervention for HSDD will be provided online. Overall, 266 women with HSDD will be recruited and assigned either to one of the intervention groups, or to a waitlist control group (2:2:1). Outcome data will be assessed at baseline, at 12 weeks, and at 6 and 12 months after randomization. Intention-to-treat and completer analyses will be conducted. Results: We expect improvements in sexual desire and sexuality-related distress in both intervention groups compared to the waitlist control. Recruitment has begun in January 2019 and is expected to be completed in August 2021. Results will be published in 2022. Conclusions: This study aims to contribute to the improvement and dissemination of psychological treatments for women with HSDD and to clarify whether cognitive behavioral and/or mindfulness-based treatments for HSDD are feasible and effective when delivered via the internet.
... Modulation of the level of neurochemicals such as dopamine, norepinephrine or serotonin in the hypothalamus and limbic system of the brain is the primary cause of female hypoactive sexual desire disorder (HSDD) (1,2). In 2015, the United States Food and Drug Administration (USFDA) approved flibanserin (FLB) as a serotonin modulator for the treatment of acquired generalized HSDD (3,4). ...
Article
Flibanserin (FLB) is the first USFDA approved serotonin modulator recently marketed to treat acquired generalized women hypoactive sexual desire disorder. The scope of this study was to develop and validate a sensitive, selective and reliable ultra-performance-liquid chromatography-mass spectroscopy/mass spectroscopy based quantification method for FLB in rat plasma as well as brain tissue samples. The method includes a simple liquid-liquid sample extraction procedure. FLB was subjected to chromatographic separation using a poroshell C18 column with the mobile phase comprising a mixture of acetonitrile, 10 mM ammonium acetate and acetic acid (90:10:0.1, v/v/v). Detection and quantification of FLB after positive electrospray ionization was carried out in selective ion monitoring mode. The fragment ion (m/z) of FLB (parent ion: 391.1741) and IS (parent ion: 448.1550) were monitored at 161.0704 and 285.0917, respectively. A linear response of FLB was observed over a concentration range of 2.5 to 600 ng/mL in plasma and 5 to 500 ng/mL in brain tissue homogenate. The intra and inter-day precision and accuracy of the method was met the acceptable limits specified in the USFDA bioanalytical method validation guideline. The analyte was found to be stable in benchtop, freeze-thaw, auto-injector, and dry extract stability studies. The developed method was used to quantitate FLB in the plasma and brain tissue of a single dose oral pharmacokinetic and brain tissue distribution study in female rats. Maximum FLB concentration in plasma and brain were achieved within an hour, however the total amount of the drug that reached the brain was significantly less than in plasma. Rate of elimination of FLB from brain was also faster resulting in a lesser half-life in brain compared to the plasma.
... It acts either as a serotonin 5-HT 1A receptor agonist to decrease serotonin level in the brain or as a 5-HT 2A receptor antagonist to increase dopamine and norepinephrine levels. Upon balancing between these neurotransmitters, FLN regulates the sexual response [2]. Many liquid chromatographic methods using different detectors have been reported for determination of FLN in pharmaceuticals and biological matrices [3][4][5][6][7][8][9][10][11][12][13][14][15]. ...
Article
A specific and sensitive thin layer chromatographic method coupled with fluorescence detection for determination of flibanserin (FLN) that treats woman hypoactive sexual desire disorder was developed. The proposed method depends on the enhancement of FLN native fluorescence intensity via the exposure of the developed TLC plate to concentrated hydrochloric acid vapors. Herein, an evaporation setup needed for HCl vapors exposure step was designed for the first time to ensure a uniform distribution of the vapors throughout the developed bands on the plate. Chloroform: methanol (9.5: 0.5, v/v) was the optimum mobile phase that gave a compact band (Rf= 0.44 ± 0.02) using TLC aluminium plates precoated with silica gel G 60F254 as a stationary phase. After exposure of the developed TLC plate to HCl vapors, the FLN bands emission intensities were measured after excitation at 275 nm. Conferring ICH guidelines, the linearity range was 20.0 – 1500.0 ng/band with a good linear relationship (r= 0.9998). Detection and quantitation limits were 5.12 and 15.50 ng/band, respectively. Also, the method was validated for accuracy, precision, robustness, specificity and selectivity. Statistical analysis verified the suitability of the proposed method for estimation of FLN in tablets and in human plasma with acceptable recoveries (98.07-101.45%).
... Flibanserin (FLB) (Fig. 1) was first approved by USFDA in 2015 for use in sexual desire deficiency in women [8]. FLB produce pharmacological action by enhancing extracellular levels of norepinephrine and dopamine as well as by inhibiting serotonin [9,10]. A literature survey revealed that only a few quantitative methods and LC-MS/MS studies were published for the analysis of FLB [11][12][13][14][15]. Ahmed et al. published a study on the determination of oxidative DPs by a third derivative emission spectrofluorometric method. ...
Article
Sprout Pharmaceuticals (USA) recently got marketing approval for Flibanserin (FLB) from USFDA. It is a well-known fact that post-marketing research on impurity profiling significantly contributes to the improvement of quality, safety and efficacy of a drug. In this study, we performed a comprehensive forced degradation of FLB to identify and characterize its degradation impurities and establish the degradation pathways. All the potential degradation impurities were chromatographically separated and identified. Five new potential degradation products (DPs) were characterized using LC-DAD/ESI/APCI-Q-TOF-MS/MS. The plausible structure for all the DPs has been established employing their mass fragmentation pattern. Elemental compositions of the DPs were derived from accurate mass measurements and mass error in ppm. A probable mechanistic explanation has been established for formation of the DPs. Till date, no study has been reported on the degradation behavior of FLB before this. The degradation profiling of FLB reported in this study will provide a complete understanding of the entire possible degradation impurities of FLB. One or more identified degradation impurities can be recommended by the regulatory bodies as the marker for stability study of FLB. The analytical method we have developed can be used for routine quality control of this molecule to quantitate it in presence of their potential impurities. In continuation to this research, degradation kinetic study of FLB to establish the degradation behavior in different stress conditions, mass balance study to correlate the amount loss of parent drug with formation of DPs and evaluation of toxicity potential of the DPs are recommended to be conducted in future.
... Others have turned to neurotransmitters, like the drug Flibanserin (Jaspers et al., 2016). Flibanserin increases levels of dopamine and norepinephrine, which are thought to increase sexual arousal, and decreases serotonin, which is thought to inhibit sexual arousal (Pfaus, 2009;Stahl et al., 2011). However, there is little evidence to support these biomedical factors as effective treatments or as causes of low sexual desire. ...
Article
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Low sexual desire in women partnered with men is typically presumed to be a problem—one that exists in women and encourages a research agenda on causation and treatment targeting women. In this paper, we present a distinct way forward for research on low sexual desire in women partnered with men that attends to a more structural explanation: heteronormativity. A heteronormative worldview assumes that relationships and structures are heterosexual, gender (usually conflated with sex) is binary and complementary, and gender roles fit within narrow bounds including nurturant labor for women. We propose the heteronormativity theory of low sexual desire in women partnered with men, arguing that heteronormative gender inequities are contributing factors. We outline four hypotheses and their predictions related to: inequitable divisions of household labor, blurring of partner and mother roles, objectification of women, and gender norms surrounding sexual initiation. We discuss some mechanisms—social, physiological, and otherwise—for the heteronormativity theory, especially related to stress, objectification, and nurturance. We close by noting some limitations of our paper and the ways that the heteronormativity theory of low sexual desire in women partnered with men provides a rigorous, generative, and empirical way forward.
... FBS acts either as a serotonin 5-HT 1A receptor agonist or as a 5-HT 2A receptor antagonist. By decreasing serotonin level in the brain or increasing dopamine and norepinephrine levels, FBS regulates the sexual response [28]. ...
Article
A novel electrochemical sensor based on the electro-deposition of silver nanoparticles (AgNPs) on Tropaeolin OO (poly-TO) layers on pencil graphite electrode (PGE) surface was fabricated for the first time for voltammetric determination of flibanserin (FBS) that enhances female sexual performance. Further characterization studies using cyclic voltammetry (CV), square wave voltammetry (SWV), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM) were conducted. The AgNPs synergistic effect on poly-TO layer facilitates the FBS electro-oxidation in phosphate buffer solution (pH 6.0) and its determination in bulk form, tablets and in human plasma. Following ICH guidelines, the validation of the proposed SWV method for FBS analysis was successfully achieved using the fabricated sensor ([email protected]/PGE). Under the optimal instrumental and experimental conditions, the anodic oxidation peak current was directly proportional to FBS concentration in the range of 0.1 × 10⁻⁶ to 8.5 × 10⁻⁶ mol L⁻¹ with low detection and quantitation limits (0.0286 × 10⁻⁶ and 0.0867 × 10⁻⁶ mol L⁻¹, respectively). High sensitivity, selectivity as well as the easiness of fabrication are the main advantages of the modified sensor.
... 1-PP is pharmacologically active and opposes the antidepressant-like properties of 5-HT 1A receptor agonists (Abe et al., 1996). Flibanserin (Addyi ®), a drug prescribed for female pre-menopausal hypoactive sexual desire disorder, binds to receptors of the 5-HT2 family and DA D4 receptors (Stahl, Sommer, & Allers, 2011). Eltoprazine and sarizotan, two compounds that have been clinically tested for indications including aggressivity, dyskinesia in Parkinson's disease and respiratory deficits in Rett syndrome (Abdala et al., 2014;de Koning et al., 1994;Goetz et al., 2007;Svenningsson et al., 2015), bind to other serotonergic and/or DA receptors in addition to 5-HT 1A . ...
Article
Biased agonism (or “functional selectivity”) at G-protein-coupled receptors has attracted rapidly increasing interest as a means to improve discovery of more efficacious and safer pharmacotherapeutics. However, most studies are limited to in vitro tests of cellular signaling and few biased agonists have progressed to in vivo testing. As concerns 5-HT1A receptors, which exert a major control of serotonergic signaling in diverse CNS regions, study of biased agonism has previously been limited by the poor target selectivity and/or partial agonism of classically available ligands. However, a new generation of highly selective, efficacious and druggable agonists has advanced the study of biased agonism at this receptor and created new therapeutic opportunities. These novel agonists show differential properties for G-protein signaling, cellular signaling (particularly pERK), electrophysiological effects, neurotransmitter release, neuroimaging by PET and pharmacoMRI, and behavioral tests of mood, motor activity and side effects. Overall, NLX-101 (a.k.a. F15599) exhibits preferential activation of cortical and brain stem 5-HT1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT1A autoreceptors in Raphe nuclei and in regions associated with motor control. Accordingly, NLX-101 is potently active in rodent models of depression and respiratory control, whereas NLX-112 shows promising activity in models of Parkinson's disease across several species – rat, marmoset and macaque. Moreover, NLX-112 has also been labeled with ¹⁸F to produce the first agonist PET radiopharmaceutical (known as [¹⁸F]-F13640) for investigation of the active state of 5-HT1A receptors in rodent, primate and human. The structure-functional activity relationships of biased agonists have been investigated by receptor modeling and novel compounds have been identified which exhibit increased affinity at 5-HT1A receptors and new profiles of cellular signaling bias, notably for β-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms.
... It has been shown to have region-specific effects on monoamine levels in the human brain 15 and it has been proposed that flibanserin may enhance sexual desire by reducing serotonergic activity and increasing dopaminergic and noradrenergic activity within the prefrontal cortex on the basis of these findings. 13 Fig. 2 explains the mechanism of action of Flibanserin. However, the precise mechanism of action or the treatment of HSDD has yet to be determined. ...
Article
Full-text available
Hypoactive sexual desire disorder (HSDD) is a widely known type of female sexual dysfunction that could also cause emotional distress and relationship problems. Flibanserin, a benzimidazole, was being studied as a treatment for premenopausal women with hypoactive sexual desire disorder because there was no accurate drug therapy available at the time (HSDD). The US Food and Drug Administration (FDA) approved Flibanserin in 2015 for the treatment of generalised acquired HSDD in premenopausal women. It has a high affinity for postsynaptic 5-HT-1A receptors (agonist) and 5-HT-2A receptors (antagonist), and it tends to work by increasing dopamine and noradrenaline levels in the brain while decreasing serotonin levels. This review was to assess Flibanserin efficacy and safety and it is found the drug Flibanserin benefits did not outweigh the risks in premenopausal and postmenopausal women.
... Flibanserin (a postsynaptic 5-hydroxytryptamine 1A agonist and 2A antagonist) decreases serotonin levels and increases dopamine and norepinephrine levels, neurotransmitters that affect sexual desire. 15,32 It is believed that flibanserin affects brain function through enhancement of excitatory elements and decreasing inhibitory responses to sexual cues. 29 Bremelanotide (Vyleesi Ò ; AMAG Pharmaceuticals), a novel cyclic 7-amino acid melanocortin-receptor agonist with high affinity for the melanocortin-4-receptor, was ap-proved by the FDA in June 2019 and is also indicated for the treatment of premenopausal women with acquired generalized HSDD. ...
Article
Background: Hypoactive sexual desire disorder (HSDD), which affects ∼10% of women in the United States, is defined as the persistent or recurrent deficiency/absence of sexual desire accompanied by personal distress. Although HSDD impacts patient quality of life and interpersonal relationships, the disorder often goes unaddressed or untreated. Recent studies of the burden of illness in women with HSDD, especially premenopausal women, are limited. Materials and Methods: A 45-minute web-based survey was designed to investigate the experience of women seeking treatment for HSDD and the impact of this disorder on several psychosocial aspects of women's lives. Women were recruited from an online panel of patients who participated in research studies for compensation. Validated questionnaires assessed sexual function (Female Sexual Function Index) and health-related quality of life (12-Item Short Form Survey [SF-12]), including mental and physical component scores. Results: A total of 530 women, aged ≥18 years, diagnosed with acquired generalized HSDD were included in the study. Premenopausal women indicated greater overall HSDD symptom burden compared with postmenopausal women. Patients with HSDD reported lower SF-12 scores compared with the general population. A multivariable regression analysis demonstrated that psychosocial factors influencing the burden of HSDD, including interference with their relationship with their partner (β = -0.18; p < 0.005), mental and emotional well-being (β = -0.23; p < 0.005), and household and personal activities (β = -0.23; p = 0.02), negatively affected SF-12 mental component scores. Conclusions: HSDD symptom burden was found to be negatively and statistically significantly associated with patients' mental health; the impact was greater among premenopausal women compared with postmenopausal women.
... Its mechanism of action is exerted through serotonin 1A (5HT1A) receptor agonism and serotonin 2A (5HT2A) receptor antagonism. This process reduces serotonin inhibition of excitatory neurotransmitters and thus indirectly increases release of dopamine and norepinephrine (33,34). ...
Article
Hypoactive sexual desire disorder (HSDD) is a persistent or recurrent absence of sexual fantasies and desire for sexual activity, causing marked personal distress or interpersonal difficulties. HSDD affects 10% of U.S. women and is associated with depression and other negative emotional states. It is imperative that psychiatrists are competent to make this diagnosis and are aware of available treatment options. A full psychiatric and medical history are necessary to identify potential causes or contributing factors that may need to be addressed first. The authors discuss the diagnostic tools available as well as general diagnostic considerations for psychiatrists. Given its importance in the understanding of the available treatments for this disorder, the pathophysiology behind HSDD is reviewed. The authors emphasize the treatment of HSDD, including general treatment considerations, treatment in the context of depression, and psychotherapy and medications that have been approved by the U.S. Food and Drug Administration.
... But a few years later, in August 2015, flibanserin was finally passed by the FDA, due in part to a purportedly "grassroots" movement of women advocating gender equality in regard to pharmaceutical treatments for sexual problems-many of whom had been paid by Sprout Pharmaceuticals, the company that then bought the rights to the drug. Flibanserin, now brand name Addyi, is a neurotransmitter drug that works on the central nervous system, specifically by decreasing serotonin uptake while increasing dopamine and norepinephrine, purportedly enhancing libido in women (Stahl, Sommer, & Allers, 2011). Newer additions to the neuro-pharmaceutical lineup are Lybrido and Lybridos, which are currently still undergoing field trials (Bergner, 2013a). ...
Chapter
The consequences of estrogen deprivation and therapeutic interventions such as radiation, chemotherapy and surgery have a significant negative impact on libido, sexual arousal, orgasmic function and the ability to have pleasurable intercourse. Evaluation and treatment of female sexual dysfunction is a significant unmet need in the breast cancer survivor in spite of the availability of safe and effective treatments.
Chapter
Sexual functioning is complex, and sexual dysfunction may involve any component of the sexual response cycle including libido, arousal, or orgasm. The etiology of most forms of sexual dysfunction is multifactorial and may be physical or psychological. Those suffering from depression may note a change in sexual functioning secondary to their underlying psychiatric condition or quite often, to the antidepressants prescribed to treat their depression. In such situations, patients often become noncompliant with their antidepressant treatment, potentially increasing their risk for serious complications of untreated depression. It is therefore of great importance for clinicians to recognize this side effect and treat it appropriately.
Article
Erectile dysfunction (ED), defined as the inability to develop or maintain an erection firm enough for satisfactory sexual intercourse, is a common urologic condition that increases in prevalence with age but can affect men of any age. As the discovery of the role of the nitric oxide pathway in inducing and maintaining erections, there have been numerous pharmacologic advancements for the treatment of ED. Here, we will review the mainstays of the pharmacologic treatment of ED: OTC/herbal supplements, phosphodiesterase type V inhibitors (PDE5I), intraurethral suppositories (MUSE), and intracorporal injections (ICI).
Article
This commentary serves to raise awareness for health care professionals about the potential risks of accidental ingestion of flibanserin tablets by children. Flibanserin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acquired generalized hypoactive sexual desire disorder in premenopausal women. Since its approval in 2015, the FDA has identified five reports of serious accidental ingestion by toddlers. All five children, boys with ages ranging from 18 months to 2 years, presented with central nervous system and respiratory depression, and two of them required intubation. A combination of hypertension, hyperthermia, and seizure-like activity was also seen in four of the five children. The clinical manifestation resembles serotonin syndrome (eg, tachycardia, hypertension, and muscle stiffness). As flibanserin use increases, greater awareness by health care professionals regarding the risk of accidental pediatric ingestion is needed to facilitate preventative counseling for patients with young children.
Article
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Introduction: Sexual dysfunction (SD) is a symptom of depression in ≈70% of patients presenting with major depressive disorder (MDD). Antidepressant medications (AD) and adjunctive treatments may further contribute to SD and complicate evaluation and management. Areas covered: A systematic literature search of PubMed, Ovid MEDLINE and Cochrane databases for MDD, SD, classes of antidepressants, etc. was performed with a focus on 2014 to June 2021. SSRIs are associated with 70% treatment-emergent sexual dysfunction (TESD), SNRIs and tricyclics have rates of TESD of 40 - 45%, and antidepressant medications without SRI effects or with additional unique mechanisms of action have rates similar to placebo (<10%). Appropriate assessment at baseline and throughout treatment, consideration of patient preferences in prescribing, addressing modifiable factors (comorbid medical/psychiatric conditions, substances, relationship difficulties), and utilizing management strategies of switching to an AD with less SD, adding an antidote/adjunctive therapy or lowering the dose are discussed. Expert opinion: MDD and antidepressant treatment contribute to SD in a high percentage of patients. Treating to remission reduces SD as a symptom of depression. Frequent assessment and targeted management strategies may be effective in preventing or addressing SD. Secondary outcomes like impact on adherence, relationships and self-image should also be considered.
Chapter
Many medications are used nowadays to improve male and female sexual function. But, it is known that such drugs that are appropriate for some aspects of sexual function in turn may be deleterious leading to the development of a different kind of sexual dysfunction. Moreover, drugs adopted for comorbid psychiatric symptoms of sexual dysfunction, as antidepressant, may cause sexual side effects. Again, there are quite a number of medicines used to treat systemic conditions, as hypertension, that may impair some domains of sexual function, as erectile capability. Finally some psychotropic drugs may be used as an off-label treatment for sexual dysfunctions. In this chapter all these issues are reviewed.
Chapter
Alcohol and other drugs have actions in limbic-hypothalamic hedonic motivational pathways that subserve basic biological functions including sexual behaviors. They may also have a range of other physiological and psychological effects on sexual function. Psychoactive drugs are often used to facilitate or enhance sexual behaviors, but they can also cause sexual dysfunction. Their use can be associated with risky or harmful sexual behaviors. Pharmacotherapies commonly used in addiction treatment, including opioid pharmacotherapies, sedative/hypnotics, antidepressants, and antipsychotics, can negatively affect sexual function, with implications for treatment adherence and effectiveness. Further, common psychological and physical comorbidities in people with substance use disorders may cause sexual dysfunction. An understanding of these issues can help clinicians working in the field of addiction better to appreciate motivations for continuing or reducing drug use, can inform motivational and harm reduction interventions, and can improve understanding of issues around treatment adherence. While there are challenges for clinicians in speaking about sexuality with their patients, this may be an important part of comprehensive assessment and treatment planning. The clinical benefits of addressing these issues, ranging from reducing sexual risk behavior to improving the quality of life of people receiving pharmacotherapies, can be substantial.
Article
Introduction: Flibanserin, a multifunctional serotonin agonist and antagonist, is approved by the U.S. Food and Drug Administration (FDA) for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. During the FDA's review of flibanserin, concerns were raised about the risks of hypotension, syncope, and sedation-related adverse events, which increase with alcohol use. Based on the results of an alcohol challenge study, the FDA required a boxed warning and alcohol contraindication in the flibanserin prescribing information, as part of a risk evaluation and mitigation strategy program. Aim: To evaluate the adverse event profile of flibanserin in the context of that seen with other medications that affect serotonin in the brain and are commonly prescribed for women. Methods: This was a review of data provided in the product prescribing information for flibanserin, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, other serotonergic antidepressants, and triptans. Main outcome measures: The incidence of adverse events was assessed. Results: The incidences of hypotension, syncope, and sedation-related adverse events (eg, dizziness, somnolence, fatigue) in studies of flibanserin were within the ranges observed for serotonergic antidepressants; the rates of these adverse events were generally lower with triptan medications. Other flibanserin-associated adverse events (eg, nausea, insomnia, dry mouth) occurred more commonly in patients taking antidepressant medications. Conclusion: Although medications that affect the serotonin system have varying adverse event profiles (likely mediated by differences in serotonin-related mechanisms of action, specific brain structures affected, and effects on other neurotransmitter systems), the occurrence of central nervous system-related adverse events was not dissimilar between flibanserin and serotonergic antidepressants. Kingsberg SA, McElroy SL, Clayton AH. Evaluation of Flibanserin Safety: Comparison with Other Serotonergic Medications. Sex Med Rev 2019;7:380-392.
Article
Background: Bremelanotide, a melanocortin receptor agonist, is Food and Drug Administration (FDA)-approved for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Methods: Review of bremelanotide's safety profile from the clinical development program (phases 1 through 3). Results: The clinical development program comprised 3500 subjects in 43 completed studies. In the phase 3 studies, subjects took bremelanotide for up to 18 months. The most common adverse events (AEs) were nausea (40.0% vs. 1.3%), flushing (20.3% vs. 1.3%), headache (11.3% vs. 1.9%), and injection site reactions (5.4 vs. 0.5), bremelanotide versus placebo groups, respectively, in the integrated double-blind portion of the phase 3 studies (N = 1247). Nausea was the most common reason for bremelanotide discontinuation. There were no deaths; a few subjects experienced serious AEs. Focal hyperpigmentation was rare when bremelanotide was dosed in accordance with label recommendations, but it occurred in more than one-third of subjects following up to 16 consecutive daily dosings. Small and transient but statistically significant blood pressure increases were observed during ambulatory blood pressure monitoring. Most drug-drug interactions were not clinically significant, except for interactions that lowered plasma concentrations of indomethacin and naltrexone. In the double-blind portion of the integrated phase 3 studies, 70% of the bremelanotide group proceeded to the open-label phase of the studies versus 87% of those on placebo. Conclusions: The AEs associated with bremelanotide are mostly mild to moderate. Although not deemed clinically important, bremelanotide should be used with caution in patients at risk of cardiovascular disease, and blood pressure should be well controlled during treatment. Clinical Trial Registration number: NCT02333071 [Study 301] and NCT02338960 [Study 302].
Article
Background: Flibanserin, a 5-hydroxytryptamine 5-HT1A agonist and 5-HT2A antagonist, is indicated for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. This post hoc analysis assessed pooled efficacy and safety data for flibanserin in premenopausal women with HSDD. Materials and methods: Data for flibanserin 100 mg once daily at bedtime (qhs) and placebo were pooled from three pivotal 24-week, randomized, placebo-controlled, multicenter studies (VIOLET, DAISY, and BEGONIA) of premenopausal women with HSDD. Pooled efficacy endpoints included the change from baseline to study end (i.e., 24 weeks) in the number of satisfying sexual events (SSEs) over 28 days, the Female Sexual Function Index desire domain (FSFI-d) score, and the Female Sexual Distress Scale-Revised Item 13 (FSDS-R-13) score. Results: The analysis included 2465 women (flibanserin, n = 1227; placebo, n = 1238) with a mean age of 36 years and a mean HSDD duration of 56.5 months. The mean ± standard error (SE) change from baseline to study end in SSEs over 28 days for flibanserin versus placebo was 2.1 ± 0.14 versus 1.2 ± 0.11, respectively (p < 0.0001). The least-squares mean ± SE changes from baseline to study end in FSFI desire domain score and FSDS-R-13 score were also significantly greater for flibanserin versus placebo (FSFI desire domain: 0.9 ± 0.04 vs. 0.6 ± 0.04, p < 0.0001; FSDS-R-13: -0.9 ± 0.04 vs. -0.6 ± 0.04, p < 0.0001). Patients in the flibanserin group generally had significantly greater improvements, compared with placebo, in SSEs, FSFI-d score, and FSDS-R-13 in subgroup analyses based on selected demographic and baseline clinical characteristics. Adverse events occurring in ≥10% of patients included dizziness and somnolence. Conclusions: This pooled analysis of three pivotal trials demonstrated that flibanserin 100 mg qhs was well tolerated, improved sexual desire, and reduced sexual distress associated with HSDD in premenopausal women, and these improvements were generally consistent across various subgroups based on demographic and baseline characteristics.
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5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
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More than 300 million people are suffering from depression, one of the civilization diseases in the 21st century. Serotonin 5-HT1AR and dopamine D2R play an important role in the treatment and pathogenesis of depression. Moreover, in recent years, the efficacy of dual 5-HT1A/D2 receptors ligands has been demonstrated in the fight against depression. In this work the new bulky arylpiperazine derivatives (LCAP) were synthesized in microwave radiation field. The affinities for the selected serotonin (5-HT1A,5-HT2A,5-HT6,5-HT7) and dopamine (D2) receptors have been evaluated in vitro. Compounds 5.3a,5.4,5.1c,5.3d,5.2a are promising dual 5-HT1AR/D2R ligands. The SAR analysis were additionally supported with molecular docking studies.
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With the range of psychotropic drugs expanding and the usages of existing medications diversifying, we are pleased to present the Seventh Edition of the world's best-selling formulary in psychopharmacology. The new edition features nine new compounds as well as information about several new formulations of existing drugs. Many important new indications are covered for existing drugs, as are updates to the profiles of the entire content and collection, including new injectable and transdermal formulations, as well as updated warnings and indications. The Pearls have all been refreshed and the antipsychotics section has been completely revised. With its easy-to-use, full-colour template-driven navigation system, Prescriber's Guide combines evidence-based data with clinically informed advice to support everyone who is prescribing in the field of mental health.
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Flibaserin is a drug for the treatment of hypoactive sexual desire disorder in pre-menopausal women. Four solid forms of flibanserin were discovered, including form A, form I, form II, and form III. The properties of these forms were characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and Fourier transform infrared spectroscopy. Single-crystal structures of form A and form I were identified by single-crystal X-ray diffraction. The host molecule conformations, H-bonding interactions, as well as packing arrangements of these single crystals were analyzed. Besides, stability and solid-state transition of these forms were investigated.
Article
Introduction: Flibanserin is approved in the United States and Canada for the treatment of acquired, generalized, hypoactive sexual desire disorder in premenopausal women. Sedation-related side effects are among the most prevalent adverse events. Although infrequent, hypotension and syncope remain safety concerns because of possible interaction of flibanserin with alcohol. Aim: To evaluate the impact of the timing of alcohol consumption on flibanserin safety and tolerability. Methods: In this single-center, randomized, double-blind, placebo-controlled, 4-treatment crossover study, 64 healthy premenopausal women (mean age 32.5 ± 8.7 years; range 20‒52 years) received once-daily flibanserin 100 mg or placebo during each of two 10-day treatment periods. Study medication was administered on days 1-3 to achieve steady state. On days 4, 6, 8, and 10, after a standard breakfast, participants consumed 0.4 g/kg ethanol (approximately equivalent to two 5-oz glasses of wine) administered with orange juice 2, 4, or 6 hours before taking study medication or orange juice alone (no ethanol) 2 hours before taking study medication. Outcomes: The primary endpoint was percentage of participants experiencing syncope or orthostatic hypotension-associated adverse events requiring medical intervention. Secondary endpoints included the incidence of hypotension, the incidence of orthostatic hypotension, and rates of adverse events of special interest (syncope, orthostatic hypotension, dizziness, and somnolence). Results: 1 participant experienced a primary endpoint event (syncope) during treatment with placebo taken 4 hours after ethanol consumption. Within each ethanol dose-timing treatment, there were no statistically significant differences for flibanserin compared with placebo. Rates of hypotension were 53.3-66.7% after flibanserin dosing and 57.4-63.3% after placebo dosing. Rates for orthostatic hypotension were 0.0-5.0% after flibanserin dosing and 1.7-6.6% after placebo dosing. Clinical implications: Ethanol interaction with flibanserin was not observed in this study. Strengths & limitations: This study provides information regarding the use of flibanserin after the consumption of moderate amounts of ethanol (0.4 g/kg). However, daytime administration of flibanserin is not consistent with the drug's indicated bedtime dosing. Conclusion: Flibanserin, at steady state taken 2, 4, or 6 hours after 0.4 g/kg of ethanol intake did not increase the incidence of hypotension, orthostatic hypotension, or syncope compared with either flibanserin alone or ethanol alone. Simon JA, Clayton AH, Kingsberg SA, et al. Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study. J Sex Med 2019;16:1779-1786.
Article
Introduction: Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss. Aim: To understand possible mechanisms by which flibanserin may produce weight loss. Methods: A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management. Main outcome measures: Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss. Results: Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT2A receptors and factors such as improved mood and improved sleep. Conclusion: Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586.
Article
Introduction: Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction in women, previously managed with off-label therapies. Indicated for premenopausal women, flibanserin is the first FDA-approved medication to treat HSDD. Areas covered: This review summarizes flibanserin’s pharmacokinetics, proposed mechanism of action, and safety data in clinical trials with a focus on sedation- and hypotension-related adverse events, and drug interactions with alcohol and antidepressants. Sources included peer-reviewed publications and internal data from the manufacturer. Expert Opinion: Flibanserin is a well-tolerated and effective treatment that decreases distress and restores sexual desire to a level that is normative for the individual patient with HSDD. Simplification of a risk mitigation program for flibanserin in the US is likely to increase the number of prescribing clinicians if accompanied with educational efforts to clarify flibanserin’s risk-benefit profile. As flibanserin is dosed daily and may be used for a decade or more in the typical premenopausal patient, long-term pharmacovigilance data will be essential. Over time, HSDD will be treated by more non-specialist health care professionals and flibanserin will likely become established as a significant treatment option along with other medications approved for this indication in the context of a holistic biopsychosocial treatment paradigm.
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Herein, poly (dopamine- Cr³⁺) nanocubes functionalized reduced graphene oxide ((poly (DAQ-Cr³⁺) @ rGO)) nanohybrid was proposed for electrochemical determination of flibanserin (FLBN). The poly (DAQ-Cr³⁺) and poly (DAQ-Cr³⁺)@ rGO nanohybrids were characterized via different morphological and spectroscopic techniques such as scanning electron microscope (SEM), transmission electron microscope (TEM), energy dispersive X-ray spectroscopy (EDX), Fourier transform infrared (FTIR) spectroscopy, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The modified electrode exhibited high electro- catalytic activity towards the electrochemical oxidation of FLBN in phosphate buffer solution (PBS, pH 6.0). Using DPV technique, the anodic oxidation peak current (Ipa) was increased with the increase of FLBN concentration in the range of 0.05-25.0×10⁻⁷ M with LOD of 0.016×10⁻⁷ M. Moreover, the poly (DAQ-Cr³⁺) @ rGO/GCE was successfully applied for analysis of FLBN in human plasma and urine samples.
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Hypoactive sexual desire disorder (HSDD) in women is defined as the persistent or recurrent absence of sexual thoughts or fantasies and/or lack of desire for sexual activity that is associated with marked personal distress and/or interpersonal difficulties, and cannot be better attributed to another primary disorder, medication, or general medical condition. Notably, HSDD shares some similarity with depression, as its etiology can be explained using a biopsychosocial model that includes biological, psychological, and sociocultural factors, as well as interpersonal influences. Due to its high prevalence and negative impact on the overall health and well-being of women, primary care health professionals and women's health practitioners need to be actively aware of HSDD, particularly because patients may be reluctant or unwilling to initiate a discussion about their sexual concerns during routine visits. HSDD is well established as a valid and treatable clinical entity. Even for those inexperienced in treating sexual problems, there are simple and validated screening tools such as the Decreased Sexual Desire Screener that can help identify HSDD and a need for further evaluation and treatment. There have been few established pharmacologic treatments for HSDD. Flibanserin was the first drug approved for the treatment of HSDD by the U.S. Food and Drug Administration (FDA). Bremelanotide, a novel melanocortin receptor agonist, was recently approved by the FDA for the treatment of acquired, generalized HSDD in premenopausal women. Increased awareness and recognition of HSDD as a medical condition should provide an incentive for further clinical development of effective treatments for HSDD.
Article
Objectives: Spontaneous orgasm is characterized by a spontaneous onset of orgasm without any preceding sexual or nonsexual trigger. It sheds insight on the mechanisms underlying orgasms and the sexual response cycle in humans. Methods: We report a male patient of repetitive spontaneous orgasm under trazodone treatment and systematically review the literature on drug-associated spontaneous orgasm (DASO). Results: A total of 25 patients (18 women and 7 men), including our reported case, experienced 27 DASO events. Over half of them were under 50 years of age during the DASO event. Depression was the leading morbidity for these patients, and a limited list of antidepressants and antipsychotics were involved in 92.5% of all DASO events. Although offending drugs possess variable pharmacological properties, their common effect is an augmentation of serotonin-1A (5HT1A) neurotransmission. Offending drugs seemingly increase personal susceptibility to DASO. Over half of the patients, especially men, did not concurrently experience sexual arousal or desire during the DASO event. In the remaining patients, the orgasm was accompanied by or ensued with arousal or desire. A reduction of dose or discontinuation of the offending drug usually abolished DASO. Conclusions: It appears that 5HT1A has a key role in generating orgasm. Orgasms may be activated through arousal-independent or arousal-dependent pathways, and both orgasms and sexual arousal are bidirectionally activated. This double-bidirectional model of sexual response cycle may promote the success of sexual procreation and recreation, and further research on this pathway could offer an innovative method to manage anorgasmia in the future.
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Flibanserin, a novel 5-HT(1A) agonist and 5-HT(2A) antagonist, has the potential to treat sexual dysfunction. Provide historical perspective on the rationale for development of flibanserin to treat sexual dysfunction, based on post hoc analyses of data. The Arizona Sexual Experiences (ASEX) scale and the Hamilton depression rating scale (HAMD) Genital Symptoms item. Sexual function outcomes are presented from four double-blind, randomized controlled studies involving a total of 369 men and 523 women diagnosed with Major Depressive Disorder. Each study had an active treatment arm to confirm assay sensitivity on the primary antidepressive endpoint. Two studies placebo, flibanserin (50mg bid), or fluoxetine (20mg qd) for 6 weeks and two involved placebo, flibanserin (50-100mg bid), or paroxetine (20-40mg qd) for 8 weeks. Individual study completion rates were 77-80%. At baseline, 38% of men and 67% of women reported sexual dysfunction. Assay sensitivity was not demonstrated in the fluoxetine trials and sexual function outcomes were inconsistent. Flibanserin and placebo were associated with low rates of treatment-emergent sexual dysfunction in women during the paroxetine studies. In one study, 70% of flibanserin-treated women with baseline sexual dysfunction reported improvement in sexual function, compared with 30% of placebo-treated women. Mean change from baseline on the HAMD "Genital Symptoms" item in one paroxetine study was significantly better among flibanserin- than placebo-treated women at weeks 4, 6, and 8 (P<0.05). Sexual function adverse events across flibanserin groups were generally comparable to placebo. Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.
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Flibanserin, a 5-HT(1A) receptor agonist and 5-HT(2A) receptor antagonist, is being developed for the treatment of hypoactive sexual desire disorder (HSDD) in pre-menopausal women. Here, we investigated the effects of acute administration of flibanserin (15 and 45 mg/kg, p.o.) and the selective 5-HT(1A) receptor agonist (+)-8-OH-DPAT (1 mg/kg, i.p.) on neurotransmitter levels in brain areas of female rats. Specifically, levels of dopamine (DA) and serotonin (5-HT) and neurotransmitter metabolites were examined in prefrontal cortex (PFC), nucleus accumbens, hypothalamus and brain stem using high performance liquid chromatography coupled to electrochemical detection. In addition, spontaneous motor activity was determined in an automated motor activity system. Flibanserin (45 mg/kg) but not (+)-8-OH-DPAT significantly reduced motor activity, when compared to vehicle controls. Specifically, the DA turnover was significantly increased (279%) in the PFC after flibanserin treatment but less pronounced (159%) after 8-OH-DPAT administration. Serotonin tissue levels were not altered in any of the investigated brain regions upon flibanserin treatment. However, flibanserin produced a significant decrease of the major serotonin metabolite 5-hydroxyindoleacetic acid and 5-HT turnover in the PFC, nucleus accumbens, hypothalamus and brain stem similar to (+)-8-OH-DPAT. In conclusion, the present study indicates that flibanserin is able to modulate dopaminergic and serotonergic activity in distinct brain areas. The observed effects in the PFC on dopaminergic markers are different from those induced by (+)-8-OH-DPAT and may contribute to its therapeutic efficacy in HSDD. The effects of flibanserin on spontaneous motor behaviour are in agreement with its receptor profile and underscore that flibanserin is devoid of any locomotor hyperactivity inducing properties.
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5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal raphe nucleus, we studied their activation by two agonists with a different profile of efficacy [(+)8-OH-DPAT and buspirone], addressing simultaneously the identification of the specific Galpha subtypes ([35S]GTPgammaS labelling and immunoprecipitation) involved and the subsequent changes in cAMP formation. A significant increase (32%, p<0.05) in (+)8-OH-DPAT-induced [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 antibodies but not with anti-Galphao, anti-Galphai1, anti-Galphai2, anti-Galphaz or anti-Galphas antibodies. In contrast, in the presence of buspirone, significant [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 (50%, p<0.01), anti-Galphao (32%, p<0.01) and anti-Galphai2 (29%, p<0.05) antibodies, without any labelling with anti-Galphai1, anti-Galphaz or anti-Galphas. The selective 5-HT1A antagonist WAY 100635 blocked the labelling induced by both agonists. Furthermore, (+)8-OH-DPAT failed to modify forskolin-stimulated cAMP accumulation, while buspirone induced a dose-dependent, WAY 100635-sensitive, inhibition of this response (Imax 30.8+/-4.9, pIC50 5.95+/-0.46). These results demonstrate the existence of an agonist-dependency pattern of G-protein coupling and transduction for 5-HT1A autoreceptors in native brain tissue. These data also open new perspectives for the understanding of the differential profiles of agonist efficacy in pre- vs. post-synaptic 5-HT1A receptor-associated responses.
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Anatomical evidence indicates that medial prefrontal cortex (mPFC) neurons project to the dorsal raphe nucleus (DR). In this study, we functionally characterized this descending pathway in rat brain. Projection neurons in the mPFC were identified by antidromic stimulation from the DR. Electrical stimulation of the mPFC mainly inhibited the activity of DR 5-HT neurons (55 of 66). Peristimulus time histograms showed a silence of 150 +/- 9 msec poststimulus (latency, 36 +/- 1 msec). The administration of WAY-100635 and picrotoxinin partly reversed this inhibition, indicating the involvement of 5-HT(1A) and GABA(A) receptors. In rats depleted of 5-HT with p-chlorophenylalanine, the electrical stimulation of mPFC mainly activated 5-HT neurons (31 of 40). The excitations (latency, 17 +/- 1 msec) were antagonized by MK-801 and NBQX. Likewise, MK-801 prevented the rise in DR 5-HT release induced by electrical stimulation of mPFC. The application of 8-OH-DPAT in mPFC significantly inhibited the firing rate of DR 5-HT neurons and, in dual-probe microdialysis experiments, reduced the 5-HT output in mPFC and DR. Furthermore, the application of WAY-100635 in mPFC significantly antagonized the reduction of 5-HT release produced by systemic 8-OH-DPAT administration in both areas. These results indicate the existence of a complex regulation of DR 5-HT neurons by mPFC afferents. The stimulus-induced excitation of some 5-HT neurons by descending excitatory fibers releases 5-HT, which inhibits the same or other DR neurons by acting on 5-HT(1A) autoreceptors. Afferents from the mPFC also inhibit 5-HT neurons through the activation of GABAergic interneurons. Ascending serotonergic pathways may control the activity of this descending pathway by acting on postsynaptic 5-HT(1A) receptors.
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We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.
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The mode of action of antidepressant drugs may be related to mechanisms of receptor adaptation, involving overall the serotonin 1A (5-HT1A) receptor subtype. However, so far, the clinical effectiveness of selective compounds acting at this level has proved disappointing. This could be explained by the heterogeneity of 5-HT1A receptors within the central nervous system. In animals, two 5-HT1A agonists, flibanserin and buspirone, have shown different pharmacological properties, depending on the brain region. Since no evidence supports this observation in humans, this study sought to investigate whether these two drugs exert different effects on 5-HT1A receptor activation in three different human brain areas: the prefrontal cortex, hippocampus and raphe nuclei. 5-HT1A-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) was taken as an index of 5-HT1A receptor activation. Flibanserin significantly reduced the activity of AC post-synaptically, i.e. in the prefrontal cortex [EC50 (mean +/- S.E.M.), 28 +/- 10.2 nM; Emax, 18 +/- 2.3%] and in the hippocampus (EC50, 3.5 +/- 3.1 nM; Emax, 20 +/- 4.0%), but had no effect in the raphe nuclei, i.e. at pre-synaptic level. Vice versa, buspirone was only slightly but significantly effective in the raphe (EC50, 3.0 +/- 2.8 nM; Emax, 12 +/- 1.9%). Agonist effects were sensitive to the 5-HT1A antagonists WAY-100135 and pindobind 5-HT1A in the cortex and raphe nuclei, whereas buspirone antagonized flibanserin in the hippocampus. These findings suggest a region-related action of flibanserin and buspirone on forskolin-stimulated AC activity in human brain.
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The prefrontal cortex (PFC) is enriched in several serotonin receptors, including 5-HT1A-R, 5-HT2A-R, and 5-HT3-R. These receptors modulate PFC activity due to their expression in large neuronal populations (5-HT1A-R, 5-HT2A-R) or in selected GABAergic populations (5-HT3-R). They are also relevant for antidepressant and antipsychotic drug action. Less is known about the localization of 5-HT2C-R, for which atypical antipsychotics show high affinity. Here, we report on the cellular distribution of 5-HT2C-R in rat PFC and striatum, using double in situ hybridization histochemistry. In PFC, 5-HT2C-R are expressed in pyramidal (VGLUT1-positive) and GABAergic (GAD-positive) neurons, including parvalbumin-positive neurons. There is a marked dorso-ventral gradient in the proportion of VGLUT1-positive cells expressing 5-HT2C-R (9% in the cingulate cortex, 61% in the tenia tecta and 66% in the piriform cortex), less marked for GABAergic neurons (13–27%). There is also a laminar gradient, with more cells expressing 5-HT2C-R in deep (V–VI) than in intermediate (II–III) layers. In common with 5-HT3-R, layer I GABAergic cells express 5-HT2C-R. The proportion of 5-HT2C-R-expressing striatal neurons was 23% (dorsolateral caudate-putamen), 37% (ventromedial caudate-putamen), 53% (nucleus accumbens-core), and 49% (nucleus accumbens-shell). These results help to better understand the serotonergic modulation of PFC-based networks, including basal ganglia circuits, and atypical antipsychotic drug action.
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Essential Pain Pharmacology: The Prescriber's Guide expertly reviews the most important medications used to relieve pain, now considered by many physicians as the fifth vital sign. The catalogue of analgesics has expanded rapidly, and this text presents the most up-to-date, comprehensive array of agents available for prescribing. Each clear and concise drug entry covers the range of indications, advantages and disadvantages, and tips for appropriate dosing and avoiding adverse effects. A separate section covers nutraceuticals, a class of drug increasingly used to manage chronic pain, yet little discussed in medical literature. The detailed description of each medication enables the user to make quick and informed decisions, confident that they are best serving the needs of their patients. Practical ‘pearls’ for each entry provide a quick go-to reference for the key information to consider before prescribing. This concise user-friendly reference is a must-have on the shelf of every physician.
Conference Paper
The prefrontal cortex guides behaviours, thoughts, and feelings using representational knowledge, i.e., working memory. These fundamental cognitive abilities subserve the so-called executive functions, the ability to inhibit inappropriate behaviours and thoughts, regulate our attention. monitor our actions and plan and organize for the future. Neuropsychological and imaging studies indicate that these prefrontal cortex functions are weaker in patients with attention-deficit/hyperactivity disorder and contribute substantially to attention-deficit hyperactivity disorder symptomology. Research in animals indicates that The prefrontal cortex is very sensitive to its neurochemical environment and that small changes in catecholamine modulation of prefrontal cortex cells can have profound effects on the ability of the prefrontal cortex to guide behaviour. Optimal levels norepinephrine acting at postsynaptic α-2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine α-2-adrenoceptors in prefrontal cortax markedly impairs prefrontal cortex function and mimics most of the symtoms of attention-deficit/hyperactivity disorder, including impulsivity and locomotor hyperactivity. Conversely, stimulation of α-2-adrenoceptors in prefrontal cortex strengthens prefrontal cortex regulation of behavior and reduces distractibility. Most effective treatments for attention-deficit/hyperactivity disorder facilitate catecholamine transmission and likely have their therapeutic actions by optimizing catecholamine actions in prefrontal cortex.
Article
5-HT1A receptor agonists reduce the neuronal release of 5-hydroxytryptamine (5-HT) by activation of raphe 5-HT1A autoreceptors. Using in vivo microdialysis in unanesthetized rats, we show that the local application of the selective 5-HT1A receptor agonist 8-OH-DPAT decreased the 5-HT output to similar to 50% of controls in medial prefrontal cortex (mPFC) but not in dorsal hippocampus. The decrease in 5-HT output was counteracted by the concurrent application of the selective 5-HT1A receptor antagonist WAY-100635. This agent also reversed the decrease in 5-HT output-elicited by the novel 5-HT1A receptor agonist BAY x 3702 (30 mu M) in mPFC and dorsal raphe nucleus. These results indicate that postsynaptic 5-HT1A receptors in mPFC also participate in the control of serotonergic activity. NeuroReport 10:1441-1445 (C) 1999 Lippincott Williams & Wilkins.
Article
Introduction: Hypoactive sexual desire disorder (HSDD) is defined as persistent lack of sexual fantasies or desire marked by distress. With a prevalence of 10% it is the most common form of female sexual dysfunction. Recently, the serotonin-1A (5-HT(1A)) receptor agonist and the serotonin-2A (5-HT(2A)) receptor antagonist flibanserin were shown to be safe and efficacious in premenopausal women suffering from HSDD in phase III clinical trials. Aim: The current study aims to assess the effect of flibanserin on neurotransmitters serotonin (5-HT), norepinephrine (NE), dopamine (DA), glutamate, and gamma-aminobutyric acid (GABA) in brain areas associated with sexual behavior. Methods: Flibanserin was administered to female Wistar rats (280-350 g). Microdialysis probes were stereotactically inserted into the mPFC, NAC, or MPOA, under isoflurane anesthesia. The extracellular levels of neurotransmitters were assessed in freely moving animals, 24 hours after the surgery. Main outcome measures: Dialysate levels of DA, NE, and serotonin from medial prefrontal cortex (mPFC), nucleus accumbens (NAC), and hypothalamic medial preoptic area (MPOA) from female rats. Results: Acute flibanserin administration decreased 5-HT and increased NE levels in all tested areas. DA was increased in mPFC and MPOA, but not in the NAC. Basal levels of NE in mPFC and NAC and of DA in mPFC were increased upon repeated flibanserin administration, when compared to vehicle-treated animals. The basal levels of 5-HT were not altered by repeated flibanserin administration, but basal DA and NE levels were increased in the mPFC. Glutamate and GABA levels remained unchanged following either repeated or acute flibanserin treatment. Conclusions: Systemic administration of flibanserin to female rats differentially affects the monoamine systems of the brain. This may be the mechanistic underpinning of flibanserin's therapeutic efficacy in HSDD, as sexual behavior is controlled by an intricate interplay between stimulatory (catecholaminergic) and inhibitory (serotonergic) systems.
Article
We recently reported the cloning of a new member of the serotonin 5-HT2 family, the 5-HT2B receptor. We now report the production and characterisation of a specific antiserum directed against the C-terminal portion of the mouse 5-HT2B receptor. After affinity purification, this polyclonal antibody recognises specifically the mouse 5-HT2B receptor. Immunohistochemical analysis of cryosections from various adult mouse tissues reveals a major 5-HT2B receptor expression in stomach, intestine and pulmonary smooth muscles as well as in myocardium. Furthermore, the antiserum recognises specific areas of the mouse brain, including cerebellar Purkinje cells and their projection areas.
Article
Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [(3)H]serotonin ([(3)H]5-HT), superfused and the release of [(3)H]5-HT was determined at rest and in response to electrical stimulation. Compartmental analysis of [(3)H]5-HT taken up by raphe tissue indicated various pools where the neurotransmitter release may originate from these stores differed both in size and rate constant. 5-HT release originates not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process establishing synaptic and non-synaptic neurochemical transmission in the serotonergic somatodendritic area. Manipulation of 5-HT transporter function modulates extracellular 5-HT concentrations in the raphe nuclei: of the SSRIs, fluoxetine was found 5-HT releaser, whereas citalopram did not exhibit this effect. Serotonergic projection neurons in the raphe nuclei possess inhibitory 5-HT(1A) and 5-HT(1B/1D) receptors and facilitatory 5-HT(3) receptors, which regulate 5-HT release in an opposing fashion. This observation indicates that somatodendritic 5-HT release in the raphe nuclei is under the control of several 5-HT homoreceptors. 5-HT(7) receptors located on glutamatergic axon terminals indirectly inhibit 5-HT release by reducing glutamatergic facilitation of serotonergic projection neurons. An opposite regulation of glutamatergic axon terminals was also found by involvement of the inhibitory 5-HT(7) and the stimulatory 5-HT(2) receptors as these receptors inhibit and stimulate glutamate release in raphe slice preparation, respectively, Furthermore, postsynaptic 5-HT(1B/1D) heteroreceptors interact with release of GABA in inhibitory fashion in raphe GABAergic interneurons. Serotonergic projection neurons also possess glutamate and GABA heteroreceptors; NMDA and AMPA receptors release 5-HT, whereas both GABAA and GABAB receptors inhibit somatodendritic 5-HT release. Evidence was found for reciprocal interactions between serotonergic and glutamatergic as well as serotonergic and GABAergic innervations in the raphe nuclei. Serotonergic neurons in the raphe nuclei also receive noradrenergic innervation arising from the locus coeruleus and alpha-1 and alpha-2 adrenoceptors inhibited [(3)H]5-HT release in our experimental conditions. The close relation between 5-HT transporter and release-mediating 5-HT autoreceptors was also shown by addition of L-deprenyl, a drug possessing inhibition of type B monoamine oxidase and 5-HT reuptake. L-Deprenyl selectively desensitizes 5-HT(1B) but not 5-HT(1A) receptors and these effects are not related to inhibition of 5-HT metabolism but rather to inhibition of 5-HT transporter.
Article
Hypoactive Sexual Desire Disorder (HSDD) is defined as a persistent or recurrent deficiency of sexual fantasies and desire for sexual activity, which causes marked personal distress or interpersonal difficulty, and is not better accounted for by another psychiatric disorder or the direct physiological effects of a substance (e.g., a medication) or medical condition. HSDD is believed to be the most common form of Female Sexual Dysfunction and is associated with emotional distress and relationship problems. No pharmacologic therapy is approved for the treatment of HSDD in premenopausal or naturally postmenopausal women. Flibanserin is a 5-HT(1A) agonist/5-HT(2A) antagonist that is under investigation as a treatment for HSDD in women. The aim of this article is to present an overview of the pharmacology, clinical efficacy and safety of flibanserin. Flibanserin is an investigational drug that is not licensed for any indication in any country.
Article
Sexual desire is controlled by brain systems involved in sexual excitation and inhibition. Hypoactive sexual desire disorder (HSDD) may result from hypofunctional excitation, hyperfunctional inhibition, or some mix of the two. This study aimed to identify neurochemical and neuroanatomical systems involved in sexual excitation and inhibition, their role during normal, and hypoactive sexual expressions. A comprehensive review of the human and animal literature is made, and a theory surrounding the ways that HSDD can be manifested and treated is presented. Drug effects and neural systems derived largely from rat studies that are involved in the stimulation of sexual desire (excitatory system) vs. the stimulation of sexual reward, sedation, and satiety (inhibitory system). Brain dopamine systems (incertohypothalamic and mesolimbic) that link the hypothalamus and limbic system appear to form the core of the excitatory system. This system also includes melanocortins, oxytocin, and norepinephrine. Brain opioid, endocannabinoid, and serotonin systems are activated during periods of sexual inhibition, and blunt the ability of excitatory systems to be activated. Drugs that stimulate the activation of hypothalamic dopamine or that blunt endocannabinoid or serotonin release and/or postsynaptic binding may be effective in stimulating sexual desire in animals and humans. The characterization of how those drugs work will help generate a rational approach to drug development in the treatment of HSDD.
Article
Beginning this month and appearing periodically in future columns, "Trends in Psychopharmacology" will cover a new concept and hot topic in the field, namely, that of "multifunctional drugs." The concept is presented in overview here. Future installments will cover specific drugs in greater depth. Multifunctional drugs include those agents with more than one putative therapeutic mechanism of action.
Article
Activation of post-synaptic 5-HT(1A) receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT(1A) receptor agonist. F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. F15599 was highly selective for 5-HT(1A) receptors in binding experiments and in [(35)S]-GTPgammaS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT(1A) receptors. In cell lines expressing h5-HT(1A) receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT(1A) receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [(35)S]-GTPgammaS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated G(alphai) than G(alphao) activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT(1A) receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT(1A) receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT(1A) receptors in vivo almost as potently as F13714. F15599 showed a distinctive activation profiles for 5-HT(1A) receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT(1A) receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.
Article
Lack of sexual interest is the most common sexual complaint among women. However, factors affecting sexual desire in women have rarely been studied. While the role of the brain in integrating the sensory, attentional, motivational, and motor aspects of sexual response is commonly acknowledged as important, little is known about specific patterns of brain activation and sexual interest or response, particularly among women. We compared 20 females with no history of sexual dysfunction (NHSD) to 16 women with hypoactive sexual desire disorder (HSDD) in a functional magnetic resonance imaging (fMRI) study that included assessment of subjective sexual arousal, peripheral sexual response using a vaginal photoplethysmograph (VPP), as well as brain activation across three time points. Video stimuli included erotic, sports, and relaxing segments. Subjective arousal to erotic stimuli was significantly greater in NHSD participants compared with HSDD. In the erotic-sports contrast, NHSD women showed significantly greater activation in the bilateral entorhinal cortex than HSDD women. In the same contrast, HSDD females demonstrated higher activation than NHSD females in the medial frontal gyrus (Brodmann area (BA) 10), right inferior frontal gyrus (BA 47) and bilateral putamen. There were no between group differences in VPP-correlated brain activation and peripheral sexual response was not significantly associated with either subjective sexual response or brain activation patterns. Findings were consistent across the three experimental sessions. The results suggest differences between women with NHSD and HSDD in encoding arousing stimuli, retrieval of past erotic experiences, or both. The findings of greater activation in BA 10 and BA 47 among women with HSDD suggest that this group allocated significantly more attention to monitoring and/or evaluating their responses than NHSD participants, which may interfere with normal sexual response.
Article
Agonist activity at recombinant human dopamine D4.4 receptors was compared in stably transfected CHO cells using two functional readouts: G protein activation by [35S]GTPgammaS binding and phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Results with a large series of agonists reveal markedly higher relative agonist efficacy in the pERK1/2 assay compared with [35S]GTPgammaS binding, while potencies were generally higher in the latter readout. Whereas efficacies were highly correlated when comparing both tests, potencies determined using the pERK1/2 assay were neither correlated with those for G protein activation nor with binding affinities. In order to examine if these differences may be attributable to distinct assay conditions (5 min incubation for pERK1/2 compared with binding equilibrium conditions for [35S]GTPgammaS), selected compounds were tested in a modified short-duration [35S]GTPgammaS binding assay. In these experiments, potencies were generally reduced; however, compounds exhibiting comparably high potency in the pERK1/2 assay were not affected by this duration-dependent potency shift. We conclude that assay parameters such as signal amplification and incubation time have to be considered with respect to the appropriate choice of experimental approaches that best reflect agonist activity at dopamine D4 receptors in vivo.
Article
This study quantitatively addresses the hypothesis that there is a systematic relationship between the morphologic characteristics of locus neurons and the particular target regions they innervate. Following horseradish peroxidase injections into selected terminal fields, locus coeruleus cell bodies are heavily labeled by retrograde transport so that somata size and shape, and in many cases primary dendritic pattern can be observed. This allows the classification of neurons as one of six cell types: large multipolar cells within ventral locus coeruleus, large multipolar cells in the anterior pole of locus coeruleus, fusiform cells in dorsal LC, posterior pole cells, medium-sized multipolar cells (termed core cells in this report), and small round cells. It was found that while core cells contribute to the innervation of all terminal fields examined, other cell types project to more restricted sets of targets. The contributions of each type to selected efferents are presented in detail. In particular, fusiform cells project to hippocampus and cortex, large multipolar cells in ventral locus coeruleus project to spinal cord and cerebellum, and small round cells in central and anterior locus coeruleus, as well as large multipolar cells in anterior locus coeruleus, project to hypothalamus. These results, in conjunction with those described in the preceding report, indicate that locus coeruleus is intrinsically organized with respect to efferent projections with much more specificity than has previously been evident. This high degree of organization is consistent with other recent demonstrations of functional specificity exhibited by locus coeruleus neurons.