Pharmacotherapy for Sexual Dysfunction in Women.

PURPOSE OF REVIEW: This review article discusses the controversy in the DSM-5 conceptualization and diagnostic criteria for female sexual dysfunction (FSD). An overview of recent studies on available treatments for hypoactive sexual desire disorder (HSDD), female sexual arousal disorder (FSAD), and genitopelvic pain/penetration disorder (GPPD) is provided. RECENT FINDINGS: Include delineation of the process of care for pre- and postmenopausal women with HSDD; release of global position statement on testosterone therapy in women; updates on efficacy and safety of vaginal estrogen for genitourinary syndrome of menopause and bremelanotide for HSDD; removal of flibanserin alcohol REMS; and development of new technology to enhance bioavailability and brain delivery of treatments. The DSM-5 revision combining HSDD and FSAD into one diagnostic category is a less accurate characterization of these separate disorders and may hinder access to demonstrated effective treatments for the women with these conditions. There are a wide range of pharmacological, other physiological, and psychological treatment options available for women with FSD, which can be offered based on their specific symptoms, potential benefits/risks, and preferences.

The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Including partners in discussions of sexual side effects from breast cancer: a qualitative study of survivors, partners, and providers.

PURPOSE: Ensuring there are clear standards for addressing cancer-related sexual side effects is important. Currently, there are differences in two leading sets of clinical guidelines regarding the inclusion of survivors' romantic partners into clinical discussions between survivors and their providers about this issue. To help refine guidelines, we examine breast cancer survivor, partner, and oncology provider perspectives about including partners in discussions about cancer-related sexual side effects in a secondary analysis of a broader qualitative study. METHODS: Partnered female breast cancer survivors (N = 29) completed online surveys, and intimate partners of breast cancer survivors (N = 12) and breast oncology providers (N = 8) completed semi-structured interviews. Themes were derived from thematic content analysis. RESULTS: Among survivors who reported a discussion with their provider, fewer than half indicated their partner had been present, despite most survivors expressing it was - or would have been - helpful to include their partner. Partners also largely indicated being included was or would have been helpful, when welcomed by the survivor. Providers similarly emphasized the importance of survivors' autonomy in deciding whether to discuss sexual concerns in the presence of a partner. CONCLUSIONS: Partners were infrequently included in conversations about cancer-related sexual side effects, even though survivors, partners, and providers alike expressed value in these discussions occurring with the couple together - when that is the survivor's preference. Findings suggest future clinical guidelines should emphasize that incorporating partners into clinical discussions about sexual concerns is important for many breast cancer patients. Soliciting and enacting patients' preferences is essential for truly patient-centered care.

An Innovative Model of Behavior Management to Address Behavioral Emergencies in the Acute Medical Inpatient Setting: Pilot Data.

Workplace violence in healthcare is a significant and costly problem. The majority of violent events that occur in the medical inpatient setting are perpetrated by patients against staff and occur during a behavioral emergency. The primary purpose of this study was to evaluate the impact of an innovative model of behavior management on occurrence of behavioral emergencies and staff comfort and competence in managing difficult patient behaviors. This model consists of primary, secondary, and tertiary interventions provided by a clinical psychologist which include proactive training for hospital staff and consultation-liaison services for behavior management. Forty-six staff at the University of Virginia Medical Center completed a 1-h training on preventing and managing difficult patient behavior. Self-report data on comfort and competence in managing challenging patient behaviors was collected at baseline, immediately following the intervention, and one and three months post-intervention. Behavioral emergencies were tracked for the intervention unit and a comparison unit. The occurrence of behavioral emergencies decreased by 50% in the three months following the intervention compared to a 142% increase on the comparison unit. Staff reported the greatest increase in confidence from baseline to three months post-intervention on caring for patients with psychiatric illnesses, managing verbal abuse, being supported by medical center leadership, having clear roles and responsibilities, and effectiveness of the skills and strategies used to manage difficult patient behavior. The results of this study provide preliminary support for the use of a comprehensive model for managing the behavioral needs of medical inpatients.

Addressing sexual concerns of female breast cancer survivors and partners: a qualitative study of survivors, partners, and oncology providers about Internet intervention preferences.

PURPOSE: Sexual side effects after breast cancer treatment are common and distressing to both survivors and their intimate partners, yet few receive interventions to address cancer-related sexual concerns. To direct intervention development, this qualitative study assessed the perceptions of female breast cancer survivors, intimate partners of breast cancer survivors, and breast cancer oncology providers about how an Internet intervention for couples may address breast cancer-related sexual concerns. METHODS: Survivors (N = 20) responded to online open-ended surveys. Partners (N = 12) and providers (N = 8) completed individual semi-structured interviews. Data were inductively coded using thematic content analysis. RESULTS: Three primary intervention content areas were identified by the key stakeholder groups: (1) information about and strategies to manage physical and psychological effects of cancer treatment on sexual health, (2) relationship and communication support, and (3) addressing bodily changes and self-image after treatment. Survivors and partners tended to express interest in some individualized intervention private from their partner, although they also emphasized the importance of opening communication about sexual concerns within the couple. Survivors and partners expressed interest in an intervention that addresses changing needs across the cancer trajectory, available from the time of diagnosis and through survivorship. CONCLUSION: Internet intervention for couples to address cancer-related sexual concerns, particularly one that provides basic education about treatment side effects and that evolves with couples' changing needs across the cancer trajectory, was perceived as a valuable addition to breast cancer care by survivors, partners, and providers.

Effect of Brexpiprazole on Prolactin and Sexual Functioning: An Analysis of Short- and Long-Term Study Data in Major Depressive Disorder.

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.

Effects of Alcohol Administered With Flibanserin in Healthy Premenopausal Women: A Randomized, Double-Blind, Single-Dose Crossover Study.

INTRODUCTION: Flibanserin is approved in the United States and Canada for the treatment of hypoactive sexual desire disorder in premenopausal women. AIM: The purpose of this trial was to evaluate the safety of concomitant administration of flibanserin with alcohol. METHODS: In this single-center, randomized, double-blind, single-dose, crossover study, participants were randomly assigned to 1 of 12 sequences to receive each of 7 treatments: flibanserin 100 mg or placebo with ethanol 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg, or flibanserin 100 mg only. Treatments were administered using a worst-case approach that included morning dosing and consumption of alcohol within 10 minutes. MAIN OUTCOME MEASURE: The primary end point was the proportion of participants who experienced dizziness, syncope, or hypotension. Safety end points included orthostatic vital signs. RESULTS: The study included 96 premenopausal women (mean age 31 ± 8 years). The incidence of dizziness for ethanol + flibanserin was 39.8% for ethanol 0.6 g/kg, 34.1% for 0.4 g/kg, and 27.4% for 0.2 g/kg compared with 31.1% for flibanserin without ethanol. Based on the available vital signs data, there was no effect of ethanol concentration on orthostatic blood pressure, vertigo, or hypotension; no instances of syncope were observed. The overall incidence of adverse events (AEs) was similar when flibanserin was administered alone (96.7%) or with ethanol (90.5-97.6%). CLINICAL IMPLICATIONS: Consumption of the tested amounts of alcohol (0.2-0.6 g/kg) does not have an additive effect on the AE profile of flibanserin 100 mg in healthy premenopausal women. STRENGTHS & LIMITATIONS: Strengths include the study population (premenopausal women, as indicated for flibanserin) and range of ethanol doses. Limitations include the morning dosing of study medication, which is inconsistent with the bedtime dosing recommended for flibanserin, and the method of handling missing vital sign measurements. CONCLUSION: Co-administration of flibanserin 100 mg with varying doses of ethanol resulted in few AEs of special interest, with no notable alcohol dose response. However, a significantly greater percentage of participants administered flibanserin with 0.6 g/kg and 0.4 g/kg of alcohol were characterized as "Participants in Whom Standing Blood Pressure Was Not Obtained" compared with participants administered flibanserin alone. Simon JA, Clayton AH, Parish SJ, et al. Effects of Alcohol Administered With Flibanserin in Healthy Premenopausal Women: A Randomized, Double-Blind, Single-Dose Crossover Study. J Sex Med 2020;17:83-93.

Dose-Finding Study of Lorexys for Hypoactive Sexual Desire Disorder in Premenopausal Women.

INTRODUCTION: Prior medication treatment for hypoactive sexual desire disorder (HSDD) in women has left about half the subjects without benefit. Lorexys (LOR), a proprietary combination of the stimulating/excitatory dopamine-norepinephrine reuptake inhibitor bupropion (BUP) and the sedating/inhibitory serotonergic agonist-antagonist trazodone (TRZ), was developed as a multifunctional solution for this problem. AIM: Test efficacy, safety, and tolerability of LOR in a range of doses in a combined phase IB/IIA study in premenopausal outpatients with HSDD. METHODS: Otherwise healthy premenopausal women from 25-50 years of age with HSDD were tested in an open-label, active-control, one-way crossover study, with three 4-week treatments of extended-release TRZ and/or sustained-release BUP. Evaluations were made before and after each treatment. A washout of at least a week followed each treatment. The order of treatments was a standard dose of BUP; a subtherapeutic dose of BUP and TRZ (LOR-low); and a threshold-therapeutic dose of BUP and TRZ (LOR-mod). A midpoint interim analysis was planned to consider adapting doses for efficacy or safety. MAIN OUTCOME MEASURE: The primary efficacy measure was the Female Sexual Function Index, Desire domain; the main secondary efficacy measures included the Female Sexual Distress Scale-Revised 13th item, on bother about low desire, and a Patient's Global Impression of Change. The main outcome comparison was the proportions of responders. Safety measures were elicited adverse events, Epworth Sleepiness Scale, Columbia Suicide Severity Rating Scale 6-item SCREEN version, vital signs, electrocardiograms, and standard laboratory tests. RESULTS: Interim analysis did not require altering doses. Most evaluable subjects responded to LOR-mod (at the standard thresholds for response based on minimum clinically relevant difference from baseline, 79% on Female Sexual Function Index, Desire domain, 87% on Female Sexual Distress Scale-Revised Item 13, and 79% on Patient's Global Impression of Change; each P < .05 vs BUP). As expected, close to half responded to BUP (38%, 45%, and 52%, respectively). Response to LOR-low was intermediate (not significant vs BUP). Sensitivity analyses to compensate for carryover effects supported the efficacy of LOR-mod. Elicited adverse events showed the expected profile of TRZ, but led to no sedative-type dropouts or worsening on the Epworth Sleepiness Scale. CLINICAL IMPLICATIONS: The open-label 1-way crossover design of this phase IB/IIA study limits conclusions, but the consistency of responder analyses showing superiority of LOR-mod dose over control, and the lack of central depressant dropouts, favor further development in double-blind placebo-control trials. STRENGTH & LIMITATIONS: Strengths include large margins of efficacy over control agent, rapid onset of action, and rigorous safety assessment. Limitations are open-label, cross-over design/lack of placebo control and 1-month duration of exposure. CONCLUSION: Moderate-dose LOR was generally well-tolerated and was significantly more effective than BUP (active control). The results seem highly favorable compared to previously tested agents. Pyke RE, Clayton AH. Dose-Finding Study of Lorexys for Hypoactive Sexual Desire Disorder in Premenopausal Women. J Sex Med 2019;16:1885-1894.

Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study.

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.

Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide.

BACKGROUND: Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful. AIM: To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD). METHODS: The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD. OUTCOMES: MCIDs based on the ROC curves for changes in Female Sexual Function Index-desire domain, Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events. RESULTS: Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P ≤ .03). CLINICAL IMPLICATIONS: These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD. STRENGTHS & LIMITATIONS: MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial. CONCLUSION: Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD. Althof S, Derogatis LR, Greenberg S, et al. Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide. J Sex Med 2019;16:1226-1235.

Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part III.

INTRODUCTION: In 2016 the International Society for the Study of Women's Sexual Health (ISSWSH) published an expert consensus report on new nomenclature that addressed the need for comprehensive, evidence-based criteria for new diagnoses in desire, arousal, and orgasm, with the definition on arousal focusing exclusively on female genital arousal disorder (FGAD). AIM: A new expert panel solely focused on mechanisms of arousal disorders convened to revise the nomenclature to include female cognitive arousal disorder (FCAD) and FGAD. METHODS: The ISSWSH co-chairs identified experts on arousal disorders in women. The 10 participants included clinicians, researchers, and educators, representing a diverse, multidisciplinary group. Pre-meeting preparation included evidence-based literature review as the basis of presentations panelists made at the meeting on the current knowledge in cognitive arousal. Consensus was reached using a modified Delphi method. Writing assignments were made as a basis of manuscript development. MAIN OUTCOME MEASURES: The new definition of FCAD is characterized by distressing difficulty or inability to attain or maintain adequate mental excitement associated with sexual activity, as manifested by problems with feeling engaged and mentally turned on or sexually aroused for a minimum of 6 months. RESULTS: Female sexual arousal disorder encompasses both FGAD (revised definition) and FCAD (new definition). Recommendations regarding diagnosis include a clinical interview to assess for FCAD using targeted questions. Patient-reported outcomes that contain questions to assess FCAD are described, including limitations for differentiating between cognitive arousal, genital arousal, and sexual desire. Laboratory measures of cognitive and genital arousal are discussed, including the relationships between genital and cognitive arousal patterns. Biopsychosocial risk factors for FCAD and FGAD, as well as exclusionary conditions, are presented. CLINICAL IMPLICATIONS: The revision of the ISSWSH nomenclature regarding the criteria for the 2 arousal categories, FCAD and FGAD, and the recommended diagnostic strategies offers a framework for management of women with arousal disorders. STRENGTHS & LIMITATIONS: This nomenclature allows for basic science and clinical research in subtypes of arousal in order to develop better diagnostic and treatment options for use by clinicians, scientists, and regulatory agencies. There are limited validated measures of cognitive arousal, including the Female Sexual Function Index, the most commonly used measure, which does not effectively distinguish between cognitive excitement, genital sensations, and event-related desire. CONCLUSION: Future directions include the refinement of FCAD and FGAD and development and validation of patient-reported outcomes that distinguish between the cognitive processes and genital responses to enhance clinical care and research in this area. Parish SJ, Meston CM, Althof SE, et al. Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part III. J Sex Med 2019;16:452-462.

Expert opinion on existing and developing drugs to treat female sexual dysfunction.

INTRODUCTION: Female sexual dysfunction (FSD) is a highly prevalent, yet commonly underdiagnosed and undertreated condition. This paper reviews the diagnostic terminology for FSD, and basic sexual physiology in women. The Food and Drug Administration (FDA) approved drugs for FSD are discussed, followed by investigational drugs for FSD currently in phase 2 or 3 clinical trials, reasons for failure of drug development, and potential future drug targets. Areas covered: A literature review was conducted for available treatments for FSD: flibanserin, estrogen, ospemifene and prasterone. Potential treatments are assessed, as was the Pharmaprojects database which includes clinical trial information. Testosterone, bremelanotide, bupropion-trazodone, PDE-5 inhibitors, prostaglandins, tibolone and combination therapies, and the theoretical basis of potential drug targets are discussed. Expert opinion: The lack of established endpoints for phase 3 studies of FSD has impeded approval of new treatments, and required additional studies for validation, resulting in proposed changes to the FDA draft guidance for FSD clinical trials in October 2016. Current DSM-5 diagnostic nosology also fails to capture the full range of symptomology. Several promising compounds have shown no movement for several years limiting women's options. Overcoming socio-cultural bias against women's sexual and reproductive health will be critical in the approval of new treatments for FSD.

Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study.

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.

Sex Differences in the Treatment of Sexual Dysfunction.

PURPOSE OF REVIEW: Sex differences in the treatment of sexual dysfunction are partly due to neurobiological differences, as well as, the central and peripheral physiological effects of hormones and neurotransmitter actions on reproductive systems in men and women. Differences in epidemiology of complaints and diagnostic considerations, variance in medical comorbidities, and interference from related medications also contribute to the need for different strategies for treatments of sexual dysfunction according to gender. RECENT FINDINGS: Flibanserin and ospemifene are new medication treatment options that may help some women with symptoms of sexual dysfunction. Various therapies are available to address sexual dysfunction and sex differences are relevant to consider, in terms of diagnosis, effectiveness of treatments, and side effect profiles that may help determine indication, safety, and outcomes for specific treatments.

Quantitative and Qualitative Research in HSDD: The Difference Between Testing Theory and Generating New Theories.

Tiefer (2017) criticized our recent analysis of psychological treatment trials for HSDD (Pyke & Clayton, 2015) on what she claims to be scientific and "political" grounds. In the same letter, she alleged that we, and, by extension, the U.S. Food and Drug Administration, promoted drugs to the detriment of psychological treatment of female sexual problems. Such accusations require a serious response.

Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part II.

INTRODUCTION: Current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definitions of sexual dysfunction do not identify all sexual problems experienced clinically by women and are not necessarily applicable for biologic or biopsychosocial management of female sexual dysfunction. A unified nomenclature system enables clinicians, researchers, and regulatory agencies to use the same language and criteria for determining clinical end points, assessing research results, and managing patients. AIM: To develop nomenclature with classification systems for female sexual desire, arousal, and orgasm disorders with definitions pertinent to clinicians and researchers from multiple specialties who contribute to the field of sexual medicine. METHODS: Key national and international opinion leaders diverse in gender, geography, and areas of expertise met for 2 days to discuss and agree to definitions of female sexual desire, arousal, and orgasm disorders and persistent genital arousal disorder. The attendees consisted of 10 psychiatrists and psychologists; 12 health care providers in specialties such as gynecology, internal medicine, and sexual medicine; three basic scientists; and one sexuality educator, representing an array of societies working within the various areas of sexual function and dysfunction. MAIN OUTCOME MEASURE: A unified set of definitions was developed and accepted for use by the International Society for the Study of Women's Sexual Health (ISSWSH) and members of other stakeholder societies participating in the consensus meeting. RESULTS: Current DSM-5 definitions, in particular elimination of desire and arousal disorders as separate diagnoses and lack of definitions of other specific disorders, were adapted to create ISSWSH consensus nomenclature for distressing sexual dysfunctions. The ISSWSH definitions include hypoactive sexual desire disorder, female genital arousal disorder, persistent genital arousal disorder, female orgasmic disorder, pleasure dissociative orgasm disorder, and female orgasmic illness syndrome. CONCLUSION: Definitions for female sexual dysfunctions that reflect current science provide useful nomenclature for current and future management of women with sexual disorders and development of new therapies.

Sexual Function Across Aging.

Women experience multiple changes in social and reproductive statuses across the life span which can affect sexual functioning. Various phases of the sexual response cycle may be impacted and can lead to sexual dysfunction. Screening for sexual problems and consideration of contributing factors such as neurobiology, reproductive life events, medical problems, medication use, and depression can help guide appropriate treatment and thereby improve the sexual functioning and quality of life of affected women. Treatment options include psychotropic medications, hormone therapy, and psychotherapy.

Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: a pooled analysis.

OBJECTIVE: Antidepressants are frequently associated with treatment-emergent sexual dysfunction (TESD). Vortioxetine, which was approved for patients with major depressive disorder (MDD), has a receptor profile that suggests limited impact on sexual functioning. METHODS: Arizona Sexual Experiences Scale (ASEX) patient-level data were pooled from 7 short-term vortioxetine trials (6 in MDD, 1 in generalized anxiety disorder) and analyzed for incidence of TESD at any post-baseline visit in patients without sexual dysfunction at baseline (defined as ASEX total score ≥19; individual ASEX item score ≥5; or a score ≥4 on any 3 ASEX items). The primary objective was to confirm the non-inferiority of vortioxetine 5-20 mg/day to placebo on the incidence of TESD. Comparisons were based on the common risk difference (95% confidence interval). Additional analyses compared vortioxetine to duloxetine and duloxetine to placebo. A sensitivity analysis, defined as TESD at 2 consecutive post-baseline visits, was conducted. RESULTS: TESD incidence, relative to placebo, generally increased with vortioxetine dose with vortioxetine 5 mg non-inferior to placebo. Vortioxetine 10, 15, and 20 mg did not meet the non-inferiority criterion, but no dose had a significantly higher risk of developing TESD versus placebo. Changes in ASEX individual item scores supported the similarity of vortioxetine doses to placebo. Significantly higher TESD risk occurred with duloxetine 60 mg/day versus placebo and versus vortioxetine 5 or 10 mg. The sensitivity analysis was generally consistent with the primary analysis. Rates of spontaneously reported sexual adverse events were low. CONCLUSIONS: Vortioxetine was associated with rates of TESD that were not significantly different from placebo in short-term clinical trials.

Psychological Treatment Trials for Hypoactive Sexual Desire Disorder: A Sexual Medicine Critique and Perspective.

INTRODUCTION: Publications claim efficacy for treatment of hypoactive sexual desire disorder (HSDD) in women with cognitive behavior therapy (CBT) and mindfulness meditation training (MMT). However, no review has evaluated the evidence for these therapies from the rigorous perspective of sexual medicine. AIMS: The aim of this study was to evaluate the published controlled trials of CBT and MMT for disorders of sexual desire from the perspective of sexual medicine standards of control paradigms, risk/benefit ratios, and clinical significance. METHODS: MEDLINE was reviewed from the last 10 years. Evaluated study quality via 10 metrics and efficacy as mean change, and proportion of responders and remitters. RESULTS: Three controlled trials support CBT and two controlled trials support MMT. The reports of the trials each lacked several scientific requirements: a hierarchy of endpoints with a planned primary endpoint, sufficient information on the intervention to reproduce it, randomization, adequate control, accepted measures of benefits and harms, compliance data, and/or outcomes of clinical relevance. CONCLUSIONS: Psychological treatments for HSDD are not yet supported by adequate clinical trials. The current scientific and regulatory standards for drug treatment trials should also be applicable to psychological treatment trials.