mdl-100907 and Sexual-Dysfunctions--Psychological

Regarding hypoactive sexual desire disorder (HSDD) in women, some reviewers judge the effect size small for medications vs placebo, but substantial for cognitive behavior therapy (CBT) or mindfulness meditation training (MMT) vs wait list. However, we lack comparisons of the effect sizes for the active intervention itself, for the control treatment, and for the differential between the two.. For efficacy trials of HSDD in women, compare effect sizes for medications (testosterone/testosterone transdermal system, flibanserin, and bremelanotide) and placebo vs effect sizes for psychotherapy and wait-list control.. We conducted a literature search for mean changes and SD on main measures of sexual desire and associated distress in trials of medications, CBT, or MMT. Effect size was used as it measures the magnitude of the intervention without confounding by sample size.. Cohen d was used to determine effect sizes.. For medications, mean (SD) effect size was 1.0 (0.34); for CBT and MMT, 1.0 (0.36); for placebo, 0.55 (0.16); and for wait list, 0.05 (0.26).. Recommendations of psychotherapy over medication for treatment of HSDD are premature and not supported by data on effect sizes. Active participation in treatment conveys considerable non-specific benefits. Caregivers should attend to biological and psychosocial elements, and patient preference, to optimize response.. Few clinical trials of psychotherapies were substantial in size or utilized adequate control paradigms. Medications and psychotherapies had similar, large effect sizes. Effect size of placebo was moderate. Effect size of wait-list control was very small, about one quarter that of placebo. Thus, a substantial non-specific therapeutic effect is associated with receiving placebo plus active care and evaluation. The difference in effect size between placebo and wait-list controls distorts the value of the subtraction of effect of the control paradigms to estimate intervention effectiveness. Pyke RE, Clayton AH. Effect Size in Efficacy Trials of Women With Decreased Sexual Desire. Sex Med Rev 2018;6:358-366.

Topics: alpha-MSH; Androgens; Benzimidazoles; Biomedical Research; Cognitive Behavioral Therapy; Female; Humans; Libido; Meditation; Mindfulness; Peptides, Cyclic; Placebos; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological; Testosterone

Flibanserin was approved by the Food and Drug Administration in the USA in August 2015 as the first drug for the treatment of American women with the dysfunction hypoactive sexual desire disorder (HSDD) and is a 5-HT1A agonist and 5-HT2A antagonist. The neurophysiological effects of flibanserin on these receptors are consistent with the clinical effects, i.e. significantly increasing sexual desire and frequency of satisfying sexual experiences. As such, shifting the balance between inhibitory and excitatory neurotransmitters of importance to sexual desire, flibanserin pharmacologically broaches a possible new approach to the treatment of HSDD.

Topics: Benzimidazoles; Female; Humans; Libido; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Sexual Dysfunctions, Psychological

Flibanserin is a postsynaptic 5-HT-1A agonist and 5-HT-2A antagonist for the treatment of generalized acquired hypoactive sexual desire disorder in premenopausal women.. To review and evaluate the efficacy and safety of flibanserin.. We review and critique the appropriateness of the co-primary and secondary end points used in the flibanserin pivotal trial research program. We review the efficacy and safety parameters of this drug based on the published literature and related sources.. Pivotal trial primary and secondary end points and safety profile data from the flibanserin development program.. Our review identified instances of poor fit of two primary trial pivotal trial end points with the hypoactive sexual desire disorder construct: satisfying sexual events and electronic daily diary assessments of the most intense level of sexual desire experienced each day. Efficacy findings of the flibanserin pivotal trials program were positive for satisfying sexual events, not positive for electronic daily diary assessments of the most intense level of sexual desire experienced, and positive for secondary end points of the Female Sexual Function Index desire domain and overall measurements and the Female Sexual Distress Scale-Revised desire-specific and overall measurements. Safety data from the clinical trial program showed a reasonable safety profile.. Flibanserin has demonstrated efficacy on appropriate measurements of the hallmarks of hypoactive sexual desire disorder-experience of absent or decreased sexual desire that is persistent over time and distressing-and the safety profile of flibanserin is acceptable. Fisher WA, Pyke RE. Flibanserin Efficacy and Safety in Premenopausal Women With Generalized Acquired Hypoactive Sexual Desire Disorder. Sex Med Rev 2017:5;445-460.

Topics: Benzimidazoles; Female; Humans; Premenopause; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological

The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD.. To review the role of serotonin in female sexual function and the effects of pharmacologic interventions that target the serotonin system in the treatment of HSDD.. Searches of the Medline database for articles on serotonin and female sexual function.. Relevant articles from the peer-reviewed literature were included.. Female sexual response is regulated not only by the sex hormones but also by several neurotransmitters. It is postulated that dopamine, norepinephrine, oxytocin, and melanocortins serve as key neuromodulators for the excitatory pathways, whereas serotonin, opioids, and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Serotonin appears to be a key inhibitory modulator of sexual desire, because it decreases the ability of excitatory systems to be activated by sexual cues. Centrally acting drugs that modulate the excitatory and inhibitory pathways involved in sexual desire (eg, bremelanotide, bupropion, buspirone, flibanserin) have been investigated as treatment options for HSDD. However, only flibanserin, a multifunctional serotonin agonist and antagonist (5-hydroxytryptamine [5-HT]. The central serotonin system is 1 biochemical target for medications intended to treat HSDD.. This narrative review integrates findings from preclinical studies and clinical trials to elucidate neurobiological underpinnings of HSDD but is limited to 1 neurotransmitter system (serotonin).. Serotonin overactivity is a putative cause of sexual dysfunction in patients with HSDD. The unique pharmacologic profile of flibanserin tones down inhibitory serotonergic function and restores dopaminergic and noradrenergic function. Croft HA. Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options. J Sex Med 2017;14:1575-1584.

Topics: Animals; Dopamine; Female; Humans; Male; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Sexual Behavior; Sexual Dysfunctions, Psychological

Flibanserin (Addyi™) is chemically described as a benzimidazole and is being developed by Sprout Pharmaceuticals for the treatment of hypoactive sexual desire disorder (HSDD). The drug has a high affinity for serotonin 5-HT1A and 5-HT2A receptors (5-HT1A agonist/5-HT2A antagonist) and is believed to treat HSDD by increasing levels of dopamine and noradrenaline and lowering levels of serotonin in the brain. Flibanserin has been approved in the USA for the treatment of premenopausal women with acquired, generalized HSDD. Earlier phase III development of the agent for HSDD in the EU and Canada had been discontinued by Boehringer Ingelheim, following regulatory feedback. Boehringer Ingelheim had also evaluated flibanserin for the treatment of depression but, due to displaying very mild antidepressant activity, its development in this indication was discontinued. This article summarizes the milestones in the development of flibanserin leading to its first approval for HSDD.

Topics: Aged; Benzimidazoles; Clinical Trials, Phase III as Topic; Drug Approval; Female; Humans; Libido; Middle Aged; Postmenopause; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological

Flibanserin, is a postsynaptic agonist of serotonin receptor 1A and an antagonist of serotonin receptor 2A, has been shown to increase sexual desire and reduce distress in women with hypoactive sexual desire disorder (HSDD).. We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug in women with HSDD.. A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of flibanserin for the treatment of HSDD. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated.. Four publications involving a total of 3,414 patients were used in the analysis, including four randomized controlled trials that compared flibanserin with placebo.. For the comparison of flibanserin with placebo, primary efficacy endpoints: satisfying sexual events (the standardized mean difference [SMD] = 0.59, 95% confidence interval [CI] = 0.37-0.80, P < 0.00001); sexual desire score (the SMD = 1.91, 95% CI = 0.21 to 3.60, P = 0.03) and Female Sexual Function Index (FSFI) desire domain score (the SMD = 0.32, 95% CI = 0.19-0.46, P < 0.00001) and key secondary efficacy endpoints: FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, FSDS-R Item 13 score, Patient's Global Impression of Improvement score and Patient Benefit Evaluation indicated that flibanserin was more effective than the placebo. Safety assessments included the proportion of women who experienced an adverse event (odds ratio = 1.54, 95% CI =  .34 to 1.76, P < 0.00001), nervous system disorders and fatigue indicated that flibanserin was well tolerated.. This meta-analysis indicates that flibanserin to be an effective and safe treatment for HSDD in women.

Topics: Benzimidazoles; Double-Blind Method; Female; Humans; Libido; Randomized Controlled Trials as Topic; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological; Treatment Outcome

Flibanserin is a serotonin 5-HT. In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC. In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use.. Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

Topics: Adult; Alcohol Drinking; Area Under Curve; Benzimidazoles; Double-Blind Method; Drug Interactions; Fatigue; Female; Humans; Male; Middle Aged; Premenopause; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological; Syncope; Young Adult

Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty.. The aim of this study was to assess the efficacy and safety of the 5-HT1A agonist/5-HT2A antagonist flibanserin in premenopausal women with HSDD.. This was a randomized, placebo-controlled trial in which premenopausal women with HSDD (mean age: 36.6 years) were treated with flibanserin 100 mg once daily at bedtime (qhs) (n = 542) or placebo (n = 545) for 24 weeks.. Coprimary end points were the change from baseline to study end in Female Sexual Function Index (FSFI) desire domain score and in number of satisfying sexual events (SSE) over 28 days. Secondary end points included the change from baseline in FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, and FSDS-R Item 13 score.. Compared with placebo, flibanserin led to increases in mean (standard deviation) SSE of 2.5 (4.6) vs. 1.5 (4.5), mean (standard error [SE]) FSFI desire domain score of 1.0 (0.1) vs. 0.7 (0.1), and mean (SE) FSFI total score of 5.3 (0.3) vs. 3.5 (0.3); and decreases in mean (SE) FSDS-R Item 13 score of -1.0 (0.1) vs. -0.7 (0.1) and mean (SE) FSDS-R total score of -9.4 (0.6) vs. -6.1 (0.6); all P ≤ 0.0001. The most frequently reported adverse events in the flibanserin group were somnolence, dizziness, and nausea, with adverse events leading to discontinuation in 9.6% of women receiving flibanserin vs. 3.7% on placebo.. In premenopausal women with HSDD, flibanserin 100 mg qhs resulted in significant improvements in the number of SSE and sexual desire (FSFI desire domain score) vs. placebo. Flibanserin was associated with significant reductions in distress associated with sexual dysfunction (FSDS-R total score) and distress associated with low sexual desire (FSDS-R Item 13) vs. placebo. There were no significant safety concerns associated with the use of flibanserin for 24 weeks.

Topics: Adult; Aged; Benzimidazoles; Dizziness; Double-Blind Method; Female; Humans; Libido; Middle Aged; Motivation; Nausea; Outcome Assessment, Health Care; Personal Satisfaction; Placebos; Premenopause; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Behavior; Sexual Dysfunctions, Psychological

Flibanserin is a 5-HT(1A) agonist/5-HT(2A) antagonist that has been shown to increase sexual desire and reduce distress in premenopausal women with Hypoactive Sexual Desire Disorder (HSDD).. To assess the efficacy and safety of flibanserin over 24 weeks of double-blind treatment vs. placebo in premenopausal women with HSDD who showed a predefined response after 24 weeks of open-label treatment with flibanserin.. Women (N = 738) were treated with open-label, flexible-dose flibanserin (50 mg or 100 mg/day) for 24 weeks. At week 24, women who showed a predefined response, measured using an eDiary, were randomized to 24 weeks of continued flibanserin therapy at optimized dosage (N = 163) or placebo (N = 170). The criteria for entering the double-blind phase were an increase from baseline to weeks 21-24 of ≥2 satisfying sexual events (SSE) and/or ≥4 "desire days." A "desire day" was one in which a woman reported more than "no" desire.. Coprimary endpoints were change from randomization to study end in SSE and desire score. Secondary measures included change in Female Sexual Function Index (FSFI) total and desire domain scores and Female Sexual Distress Scale-Revised (FSDS-R) total and Item 13 scores.. During the open-label period, mean SSE and desire score approximately doubled, and FSFI, FSDS-R total, and Item 13 scores improved. At the end of the double-blind period, flibanserin was superior to placebo in change from randomization in SSE, desire score, FSFI desire domain and total scores, and FSDS-R total and Item 13 scores (P < 0.05, for all). Flibanserin was well tolerated, and withdrawal reactions were not observed.. At the end of the 24-week randomized withdrawal phase of a 48-week trial in premenopausal women with HSDD, flibanserin was superior to placebo on measures of SSE, sexual desire, overall sexual function, and sexual distress. Flibanserin was well tolerated, and no withdrawal reactions were observed following discontinuation.

Topics: Adult; Benzimidazoles; Double-Blind Method; Female; Humans; Libido; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological; Treatment Outcome

Hypersexual behavior can be assumed as a rare side effect of treatment with aripiprazole and is possibly due to partial agonism on dopamine receptors or partial agonism on 5-HT. Das Auftreten einer Hypersexualität bzw. einer sexuellen Enthemmung bei Anwendung von verschiedenen Neuroleptika stellt eine Rarität dar. Bei Anwendung von Aripiprazol häufen sich jedoch Mitteilungen, nach denen es zu einer sexuellen Enthemmung bzw. auch anderen Impulskontrollstörungen wie dem pathologischen Spielen kommt. Verantwortlich dafür ist möglicherweise der Partialagonismus am D2-Rezeptor oder auch die Stimulation am 5-HT

Topics: Antipsychotic Agents; Aripiprazole; Germany; Humans; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Sexual Behavior; Sexual Dysfunctions, Psychological

Flibanserin is a mixed 5-HT1A agonist and 5-HT2A antagonist for treatment of premenopausal women with hypoactive sexual desire disorder. It is the first FDA-approved treatment for this disorder and can improve the number of satisfying sexual events. The drug has been associated with hypotension and syncope.

Topics: Adult; Benzimidazoles; Female; Humans; Premenopause; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological; Treatment Outcome

Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that has been developed for the treatment of hypoactive sexual desire disorder in women.. To assess the acute and chronic dose-response effects of flibanserin on measures of sexual desire and copulation in ovariectomized rats primed with estradiol benzoate (EB) alone or in combination with progesterone (P).. In Experiment 1, sexually experienced ovariectomized (OVX) rats at one testing site were rendered fully sexually receptive with EB + P priming and tested weekly with a sexually active male in bi-level pacing chambers following daily flibanserin treatment for 28 days. In Experiment 2, sexually experienced OVX rats at a different testing site received EB alone and were tested weekly with sexually active males following daily flibanserin treatment.. Female appetitive behaviors (solicitations, hops and darts, anogenital investigations), defensive behaviors, pacing, lordosis, and male copulatory responses (intromissions and ejaculations) were measured during each 30-minute copulation test.. Acute flibanserin or 1 week of chronic flibanserin treatment did not modify sexual responses in fully (EB + P) or partially (EB-alone) primed females. After 2 weeks of chronic treatment, fully primed females displayed significantly more solicitations than the three other groups. After 3 weeks of chronic treatment, a significant increase in female solicitations was observed in both hormone-treatment groups.. This study shows the first evidence that chronic, but not acute, flibanserin treatment augments appetitive sexual behaviors in OVX female rats primed with EB + P or EB alone. Given the positive effect of flibanserin in clinical trials, these results confirm previous reports that solicitations in the female rat are a predictive animal model of human female sexual desire.

Topics: Animals; Benzimidazoles; Copulation; Drug Combinations; Ejaculation; Estradiol; Female; Humans; Male; Motivation; Progesterone; Rats; Rats, Inbred LEC; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Behavior, Animal; Sexual Dysfunctions, Psychological

Topics: alpha-MSH; Benzimidazoles; Contraceptives, Oral, Hormonal; Female; Humans; Peptides, Cyclic; Receptors, Melanocortin; Reproductive Health; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological; Testosterone; Women's Health

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.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzimidazoles; Brain Chemistry; Dopamine; Dose-Response Relationship, Drug; Female; Motor Activity; Neurotransmitter Agents; Rats; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Sexual Dysfunctions, Psychological