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.

Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials.

BACKGROUND: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function. AIM: To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains. METHODS: Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set. OUTCOMES: Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials. RESULTS: Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men. CLINICAL IMPLICATIONS: The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T. STRENGTHS & LIMITATIONS: Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity. CONCLUSION: Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997-1009.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD. STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201-216.

Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF).

BACKGROUND: The Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF) is a patient-reported outcome measurement designed to evaluate the symptoms of hypogonadism. The HIS-Q-SF is an abbreviated version including17 items from the original 28-item HIS-Q. AIM: To conduct item analyses and reduction, evaluate the psychometric properties of the HIS-Q-SF, and provide guidance on score interpretation. METHODS: A 12-week observational longitudinal study of hypogonadal men was conducted as part of the original HIS-Q psychometric evaluation. Participants completed the original HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12, and the PROMIS Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change scales and a clinical form. MAIN OUTCOME MEASURES: Item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed. RESULTS: One hundred seventy-seven men participated (mean age = 54.1 years, range = 23-83). Similar to the full HIS-Q, the final abbreviated HIS-Q-SF instrument includes five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For key domains, test-retest reliability was very good, and construct validity was good for all domains. Known-groups validity was demonstrated for all domain scores, subdomain scores, and total score based on the Clinical Global Impression-Severity. All domains and subdomains were responsive to change based on patient-rated anchor questions. CLINICAL IMPLICATIONS: The HIS-Q-SF could be a useful tool in clinical practice, epidemiologic studies, and other academic research settings. STRENGTHS AND LIMITATIONS: Careful consideration was given to the selection of the final HIS-Q-SF items based on quantitative data and clinical expert feedback. Overall, the reduced set of items demonstrated strong psychometric properties. Testosterone levels for the participating men were not as low as anticipated, which could have limited the ability to examine the relations between the HIS-Q-SF and testosterone levels. Further, the analyses used data collected through administration of the full HIS-Q, and future studies should administer the standalone HIS-Q-SF to replicate the psychometric analyses reported in the present study. CONCLUSION: Similar to the original HIS-Q, the HIS-Q-SF has evidence supporting reliability, validity, and responsiveness. The short form includes a smaller set of items that might be more suitable for use in clinical practice or academic research settings. Gelhorn HL, Roberts LJ, Khandelwal N, et al. Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF). J Sex Med 2017;14:1046-1058.

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

INTRODUCTION: A nomenclature is defined as a classification system for assigning names or terms in a scientific discipline. A nosology more specifically provides a scientific classification system for diseases or disorders. Historically, the nosologic system informing female sexual dysfunction (FSD) has been the system developed by the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-III through DSM-5). Experts have recognized limitations of its use in clinical practice, including concerns that the DSM-5 system does not adequately reflect the spectrum and presentation of FSD. AIM: To review the central considerations and issues that underlie the development of a new evidence-based nomenclature that reliably and validly defines the categories of FSD and will effectively function in clinical and research settings, serve as a basis for International Classification of Diseases (ICD) codes, and provide regulatory guidance for interventions designed as FSD treatments. METHODS: The International Society for the Study of Women's Sexual Health conducted a 2-day conference on nomenclature for FSD in December 2013. Key opinion leaders representing diverse areas of expertise discussed ideal characteristics, existing DSM definitions, and current and future ICD coding to develop consensus for this new nomenclature. MAIN OUTCOME MEASURE: A comprehensive appreciation of the parameters and characteristics essential to a new FSD nomenclature and terminology that will serve as the principal nosology for the description and diagnosis of FSD. RESULTS: A critical appraisal of the essential elements of a classification system for diagnosing FSD was accomplished. The applicability of DSM-5 FSD definitions was challenged; and the considerations for developing a new nomenclature were discussed, including comorbidities, clinical thresholds, alternative etiologies, and validity. CONCLUSION: The essential elements for developing a valid, reliable, credible, and clinically applicable nosology for FSD were enumerated as a preamble to constructing the actual nosologic system (Part II).

Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire.

INTRODUCTION: The Hypogonadism Impact of Symptoms Questionnaire (HIS-Q) is a patient-reported outcome measurement designed to comprehensively evaluate the symptoms of hypogonadism and to detect changes in these symptoms in response to treatment. AIM: To conduct item analysis and reduction, evaluate the psychometric properties of the HIS-Q, and provide guidance on interpreting the instrument score. METHODS: A 12-week observational, longitudinal study of hypogonadal men was conducted. Participants completed the HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants also completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12 Health Survey, and the Patient-Reported Outcomes Measurement Information System Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (at baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change measurements and a clinical form. MAIN OUTCOME MEASURES: Individual item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed. RESULTS: In total, 177 men participated in the study (mean age = 54.1 years, range = 23-83). The original 53-item draft HIS-Q was reduced to 28 items; the final instrument included five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For all domains, test-retest reliability was acceptable (intraclass correlation coefficients > 0.70), construct validity was good (|r > 0.30| for all comparisons). Known-groups validity was demonstrated for all HIS-Q domain scores, subdomain scores, and the total score as measured by the Clinical Global Impression of Severity, and total testosterone level at baseline (P < .05 for all comparisons). All domains and subdomains were responsive to change based on patient-rated anchor questions (P < .05 for all comparisons). CONCLUSION: The final 28-item HIS-Q is reliable, valid, and responsive. The HIS-Q is suitable for inclusion in future clinical trials to help characterize the effects of testosterone replacement therapy.

Psychometric properties of the Iranian version of the female sexual distress scale-revised in women.

INTRODUCTION: Several tools for the assessment of sexuality-related distress are now available. The Female Sexual Distress Scale (FSDS) and its revised version (FSDS-R) are extensively validated and among the most widely used tools to measure sexually related personal distress. AIM: The aim of the study was to determine the psychometric properties of the Iranian version of the FSDS-R in a population sample of Iranian women. METHODS: A total of 2,400 married and potentially sexually active women were recruited and categorized into three groups including (i) a healthy control group; (ii) a group of women with hypoactive sexual desire disorder (HSDD); and (iii) a group of women suffering from other female sexual dysfunction (FSD). Participants were asked to complete a set of questionnaires including the Iranian version of the Female Sexual Function Index (FSFI-IV), the FSDS-R, and the Hospital Anxiety and Depression Scale. MAIN OUTCOME MEASURES: Sexuality-related distress and FSD as assessed by the Iranian version of the FSDS-R and the FSFI-IV are the main outcome measures. RESULTS: Internal consistencies and test-retest reliability of the FSDS-R across the three assessments points for the three groups were >0.70. The FSDS-R correlated significantly with anxiety, depression, and the FSFI total score. Significant differences in the FSDS-R scores were found between healthy women, women with HSDD, and women with other types of FSD. Factor analysis of the FSDS-R yielded a single-factor model with an acceptable fit. CONCLUSIONS: The Persian version of the FSDS-R is a valid and reliable instrument for the assessment of sexuality-related distress in Iranian women and can be used to screen patients with HSDD.

Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial.

INTRODUCTION: Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. AIM: 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. METHODS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSION: 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.

Association of major depression with sexual dysfunction in men.

The effect of type and severity of depression on sexual functioning was examined before treatment in 591 men with Major Depression (MDD) or Atypical Depression, as determined by percentage of subjects meeting Diagnostic and Statistical Manual, 4th Edition (DSM-IV) sexual dysfunction criteria (A and B only), and percentage with Derogatis Inventory of Sexual Function (DISF) scores greater than 1 standard deviation below normal. Sexual dysfunction rates were higher for MDD than for Atypical Depression. Depression affected DISF domains differently: orgasm was most impaired, whereas sexual desire was preserved. More severe depression resulted in greater sexual dysfunction.

Intended or unintended consequences? The likely implications of raising the bar for sexual dysfunction diagnosis in the proposed DSM-V revisions: 2. For women with loss of subjective sexual arousal.

INTRODUCTION: Brotto proposes to combine female sexual desire and arousal disorders in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. AIM: We provide evidence that the proposed criteria could potentially exclude from diagnosis or treatment a large number of women with distressing dysfunction in sexual arousal. METHODS: Rating scale data from nontreatment validation studies of patient-reported outcome measures including almost 500 women in North America and Europe, including 49 women diagnosed with arousal disorder only, were compared with the proposed criteria. MAIN OUTCOME MEASURES: The main measures were an early version of the eDiary (an electronic diary on sexual activity) and four previously validated measures of female sexual dysfunction (FSD), the clinician-rated Sexual Interest and Desire Inventory-Female and the self-rated Female Sexual Function Index, Changes in Sexual Functioning Questionnaire, and Female Sexual Distress Scale. Results. The women with female sexual arousal disorder (FSAD) scored as manifestly sexually dysfunctional and significantly sexually distressed. They had fewer satisfying sexual events (SSEs) vs. women with no FSD, with a lower proportion of SSEs, and significantly fewer orgasms. CONCLUSION: Despite evidence presented that women with FSAD have clinically disordered sexual function, our data also suggest that the majority of these women with FSAD would meet none of the six proposed "A" criteria for Sexual Interest/Arousal Disorder, raising new validity and utility concerns for the proposed diagnostic classification. Suggestions are made to modify the proposed new criteria so as to include such distressed women.

How to evaluate the efficacy of the phosphodiesterase type 5 inhibitors.

INTRODUCTION: Several methods have been so far proposed to compare the effectiveness of the three available phosphodiesterase type 5 inhibitors (PDE5Is). METHODS: Two urologists (E.C. and G.B.B.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of erectile dysfunction (ED) present the various perspectives on the evaluation of PDE5Is in ED. The use of the most popular psychometric tool, the International Index of Erectile Function, is presented by an expert psychologist (L.R.D.). MAIN OUTCOME MEASURES: Expert opinion supported by the critical review of the currently available literature. RESULTS: Trials have demonstrated that the PDE5Is are excellent drugs with a great specificity of action and an almost perfect tolerance profile. Some instruments for comparison of clinical efficacy have to be considered subjective (psychometry, patient's preference, changes in quality of general, or sexual life). Some others are more objective (hardness, hormonal levels, and local circulation). An evidence-based comparison of the three PDE5Is should in the future be rooted in both subjective and objective methods. This will be of paramount importance in the drug trial design of new, forthcoming PDE5Is. CONCLUSIONS: Comparison between PDE5Is using both subjective and objective parameters will permit to individuate, on the basis of the evidence, the subset of couples where one drug, or one dose, or dose regimen, is to be considered of first choice.

Intended or unintended consequences? The likely implications of raising the bar for sexual dysfunction diagnosis in the proposed DSM-V revisions: 1. For women with incomplete loss of desire or sexual receptivity.

INTRODUCTION: Combining female sexual desire and arousal disorders is proposed for the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Brotto et al. challenged our findings that the proposed criteria could potentially exclude from diagnosis or treatment a large number of women with distressing loss of function or in sexual desire, because (i) our samples were insufficiently severe; (ii) we sought to retain the current diagnostic criteria, whereas they contend that "the bar should be raised"; and (iii) the current sexual function diagnostic criteria are unreliable. AIM: Here we provide additional data to support our view suggesting that the proposed criteria would potentially exclude large numbers of women from diagnosis or treatment if they have moderate-to-marked (rather than severe) hypoactive sexual desire disorder (HSDD), or HSDD with incomplete loss of receptivity. METHODS: In nontreatment validation studies of 481 women in North America and Europe, 231 women diagnosed with HSDD only were compared to women with no female sexual desire. MAIN OUTCOME MEASURES: Clinicians experienced in sexual medicine determined the severity of HSDD using the standard Clinical Global Impression of Severity. Rating scale data were also used, including the clinician-rated Sexual Desire and Interest Inventory-Female and the self-rated Female Sexual Function Index, Changes in Sexual Functioning Questionnaire, Female Sexual Distress Scale, and an e-Diary about desire during sexual events. RESULTS: The severity of the HSDD was rated by clinicians as generally moderate-to-marked, not mild. The women with HSDD scored as manifestly sexually dysfunctional and significantly sexually distressed, and reported markedly fewer satisfying sexual events compared to age-matched, non-dysfunctional controls, even for those with moderate or milder degrees of severity, providing compelling evidence that our sample of women with HSDD had clinically disordered sexual function. Yet the proposed criteria would apparently allow diagnosis (and therefore treatment) of only severe desire dysfunction. CONCLUSION: It would be counterproductive to combine the two disorders, to make individual criteria for the disorders more stringent or to require more such criteria for a diagnosis because such disorders tend to be distinct in presentation, in treatability with currently available therapies, and in logical approaches to be tested to improve therapy.

The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men.

INTRODUCTION: Sexual dysfunction is common in patients with major depressive disorder (MDD). Antidepressant medications especially the selective serotonin reuptake inhibitors (SSRIs) may improve depressive symptoms but further decrease sexual function. Gepirone extended release (gepirone-ER) differs from the SSRIs in only affecting the 5-HT(1A) receptor and has demonstrated efficacy in treatment of depression and sexual dysfunction in depressed women. This report describes the effect of gepirone-ER on sexual function in depressed men. AIM: The aims of this article were to study the effects of gepirone-ER on sexual function in men with MDD and to determine if positive effects are independent of antidepressant or anxiolytic activity. MAIN OUTCOME MEASURES: The main outcome measures of this article were Hamilton depression rating scale (HAMD-17), and changes in sexual functioning questionnaire (CSFQ). METHODS: In an 8-week study, gepirone-ER, placebo, or fluoxetine were administered in a double-blind fashion to 181 depressed men. The CSFQ results were used to determine quality of sexual function. To test for an antidepressant or anxiolytic effect, a 50% reduction in HAMD-17 score separated antidepressant responders from nonresponders, and item 12 of the HAMD scale (psychic anxiety) scores of 0 or 1 separated anxiolytic responders from nonresponders. RESULTS: Gepirone-ER treatment improved total sexual function compared with placebo measured by the CSFQ at weeks 4 (P=0.012) and 8 (P=0.046). At 4 weeks, almost every CSFQ domain is improved. The orgasm domain was especially improved, 67% by week 4. Gepirone-ER antidepressant and anxiolytic nonresponders showed significant improvement in sexual function. Fluoxetine treatment did not produce improvement. In fact, fluoxetine-treated subjects had lower scores on the total CSFQ, less than placebo, and significantly less than gepirone-ER. CONCLUSION: Gepirone-ER improves sexual dysfunction in depressed men. All domains of sexual function improved. Gepirone-ER has a pro-sexual effect independent of antidepressant or anxiolytic activity.

Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study.

INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is the most common form of female sexual dysfunction and is characterized by low sexual desire that causes distress. AIM: The aim of this study was to assess the efficacy and safety of flibanserin, a postsynaptic 5-HT(1A) agonist/5-HT(2A) antagonist, in premenopausal women with HSDD. METHODS: North American premenopausal women with HSDD were randomized to 24 weeks' treatment with placebo (N = 295), flibanserin 50 mg (N = 295), or flibanserin 100 mg (N = 290), once daily at bedtime. MAIN OUTCOME MEASURES: Coprimary endpoints were change from baseline to study end in number of satisfying sexual events (SSE) and sexual desire score measured daily using an electronic diary (eDiary). Secondary endpoints included change from baseline to study end in female sexual function index (FSFI) desire domain and total scores, female sexual distress scale-revised (FSDS-R) Item 13 and total scores, and patient's global impression of improvement. RESULTS: Flibanserin 50 mg and 100 mg led to increases in SSE (P < 0.05 and P < 0.01 vs. placebo, respectively). There was a numerical trend toward improvement in eDiary desire score on flibanserin 100 mg, but statistical significance was not reached (P = 0.07 vs. placebo). FSFI desire domain and total scores increased with both flibanserin regimens (P < 0.05). FSDS-R total and Item 13 scores decreased with flibanserin 100 mg (P < 0.001), indicating reduced sexual distress. More women receiving flibanserin 50 mg and 100 mg considered their HSDD to have improved than women receiving placebo (39.6% and 50.0% vs. 30.3%, respectively) (P < 0.05). CONCLUSION: In premenopausal women with HSDD, flibanserin 50 mg and 100 mg once daily at bedtime were well tolerated and associated with statistically significant improvements in SSE, sexual desire (FSFI desire domain score but not eDiary desire score) and overall sexual function, and reduction of sexual distress, vs. placebo.

Gepirone-ER treatment of low sexual desire associated with depression in women as measured by the DeRogatis Inventory of Sexual Function (DISF) fantasy/cognition (desire) domain--a post hoc analysis.

INTRODUCTION: Gepirone-extended release (ER) is effective in treating hypoactive sexual desire disorder (HSDD), as measured by the percent of females with HSDD that no longer met criteria for HSDD treatment. Another approach is to determine treatment effect on sexual desire using a recognized rating scale for sexual function. Because gepirone-ER has antidepressant and anxiolytic effects, investigation of these effects on sexual desire is appropriate. AIM: The aim of this study was to determine whether gepirone-ER has positive effects on sexual desire as measured by the DeRogatis Inventory of Sexual Function (DISF) in a post hoc analysis of 8- and 24-week studies and if this gepirone effect is independent of its antidepressant or anxiolytic activity. MAIN OUTCOME MEASURES: The main outcome measures used for this study were the Hamilton Depression Rating Scale (HAMD-25), change from baseline (CFB), and DISF CFB. METHODS: Three hundred thirty-four women selected for depressive symptoms, not sexual dysfunction, received gepirone-ER (40-80 mg/day) in a controlled study of atypical depression using the HAMD-25 to measure antidepressant efficacy and a DISF subscale (domain I) to measure sexual cognition/fantasy (desire). After treatment, a 50% reduction from baseline HAMD-25 score identified antidepressant responders. Item 12 of HAMD scale (psychic anxiety) was used to define anxiolytic response scores of 0, 1 as responders, and scores of 2, 3, and 4 as nonresponders. RESULTS: Gepirone-ER had no significant antidepressant or an anxiolytic effect in study 134006; however, DISF results demonstrate that gepirone-ER improves sexual desire in short term (P=0.043) and long term (P=0.006). Both gepirone-ER antidepressant and anxiolytic responders have statistically significant improved sexual desire. Gepirone-ER antidepressant and anxiolytic nonresponders also show statistically significant improvement. CONCLUSIONS: In depressed women, gepirone-ER has three mechanisms of action affecting sexual desire: an antidepressant effect, an anxiolytic effect, and a pro-sexual effect. Gepirone-ER improves sexual desire from the 24th to the 50th percentile according to population norms for the DISF.

Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women.

INTRODUCTION: There is currently no Food and Drug Administration (FDA)-approved treatment for hypoactive sexual desire disorder (HSDD). FDA approval of products utilizing testosterone has been delayed due to possible safety concerns. Flibanserin, a 5-HT(1A) agonist, 5-HT(2) antagonist, and gepirone-ER, a 5-HT(1A) agonist, have been shown to have activity in treatment of HSDD. However, more recently, the FDA issued a non-approval letter for flibanserin. AIM: To study the effect of gepirone-ER on HSDD in women with major depressive disorder (MDD). METHODS: At baseline and post-treatment visits, a trained psychiatrist made diagnoses of HSDD based on Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria. Subjects meeting criteria for HSDD were followed to observe the effect of gepirone-ER (20-80 mg/day), comparator antidepressants (fluoxetine, 20-40 mg/day or paroxetine, 10-40 mg/day), or placebo in reversing DSM-IV diagnosis. A subpopulation of women with Hamilton Depression Rating Scale (HAMD-17) entry scores of 18 or less was evaluated. Adverse events (AEs) of sexual dysfunction were also collected. MAIN OUTCOME MEASURE: Number (%) of patients who no longer met criteria for HSDD (percent resolved). RESULTS: Eight hundred seventy-five women (18-64 years of age, average 38 years old, ∼80% premenopausal) entered three studies; 668 (72.5%) completed. Only 161 (18.4%) met DSM-IV criteria for HSDD. Cumulatively, 63% of gepirone-ER-treated patients reversed their diagnosis of HSDD compared to 40% of placebo-treated patients at end point (8 weeks) (P = 0.007). Selective serotonin reuptake inhibitor-treated patients were not different from placebo. Significant results for gepirone-ER occurred by week 2 (P = 0.0001). Patients who were mildly depressed (HAMD scores of 18 or less) also improved at week 2 (P = 0.01) and week 8 (P = 0.07). Sexual dysfunction AEs were significantly less in gepirone-ER-treated patients than placebo (P = 0.013). CONCLUSIONS: Gepirone-ER may have efficacy in the treatment of HSDD among depressed and possibly nondepressed women. Efficacy occurs by week 2, and does not seem to be purely an antidepressant effect.

Content validity of the Female Sexual Function Index (FSFI) in pre- and postmenopausal women with hypoactive sexual desire disorder.

INTRODUCTION: The Female Sexual Function Index (FSFI) has consistently been shown to have discriminant validity, test-retest reliability, and internal consistency as a measure of female sexual function. However, the content validity (relevance, clarity, comprehensiveness) of the instrument in women with hypoactive sexual desire disorder (HSDD) must also be established. AIM: The aim of this study were to assess the content validity of the FSFI, specifically the FSFI desire domain, in pre- and postmenopausal women with HSDD. METHODS: Two single-visit content validation studies were conducted in the United States. Eligible premenopausal (both studies) and postmenopausal (second study only) women with HSDD completed the FSFI followed by one-on-one, face-to-face cognitive debriefing interviews including open-ended questions to capture information on their perceptions of the instrument. Information on women's experiences of decreased sexual desire was also captured. MAIN OUTCOME MEASURES: The main outcome measures of this study were the women's ratings of the clarity, ease of understanding, comprehensiveness, and relevance of the 19 items of the FSFI. RESULTS: Interviews with 15 premenopausal women (first study), and 30 pre- and 31 postmenopausal women (second study), were analyzed. Across the whole sample, most women (80-100%) found every item of the FSFI clear and easy to understand. The majority (53-70%) felt that the FSFI captured all their feelings about decreased sexual desire and other sexual problems, and most (84-90%) indicated that additional questions were unnecessary. Most women in both studies (93-100%) reported that the two items comprising the FSFI desire domain were clear, easy to understand, and were relevant to them. The majority of women thought that a recall period of ≥7 days is most relevant for recall of their sexual desire. CONCLUSIONS: These studies establish the content validity of the FSFI in pre- and postmenopausal women with HSDD, supporting the use of this instrument as a measure of sexual function in women with this condition.

Psychometric validation of the Female Sexual Distress Scale-Desire/Arousal/Orgasm.

BACKGROUND: For the treatment of female sexual dysfunction, the most relevant outcome measures are patient-reported treatment effects and changes in symptoms, underscoring the need for reliable, validated patient-reported outcome (PRO) instruments. The aim of this study was to evaluate the psychometric characteristics (validity and reliability) of the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) PRO measure, which was adapted from the validated FSDS-Revised (FSDS-R) questionnaire and added 2 questions involving arousal and orgasm. METHODS: Psychometric analyses were based on the data from a multicenter phase 2b dose-finding study that compared the safety and efficacy of bremelanotide versus placebo and were conducted in the evaluable modified intent-to-treat population (N = 325) from that study. Psychometric evaluation of the new items in the FSDS-DAO included confirmatory factor analyses, tests of internal consistency and test-retest reliability, examinations of convergent and discriminant validity, and determination of responsiveness. The validity of the FSDS-DAO was evaluated based on previously developed instruments, including the Female Sexual Function Index (FSFI), General Assessment Questionnaire (GAQ), Women's Inventory of Treatment Satisfaction (WITS-9), and Female Sexual Encounter Profile-Revised (FSEP-R). RESULTS: Confirmatory factor analyses demonstrated that the FSDS-DAO items fit very well (Bentler's comparative fit index of 0.929). Cronbach's α for the FSDS-DAO total score was ≥ 0.91 at Visits 1, 2, 5, and 12, demonstrating adequate internal consistency reliability. Test-retest reliability was acceptable with an intra-class coefficient of 0.61 and a Spearman's correlation coefficient score of 0.62 between Visits 1 and 2 (4 weeks). Acceptable construct validity was demonstrated by significant correlations with related PRO scales in the expected directions and magnitude. For example, participants reporting the worst levels of sexual function on the FSFI also showed the worst FSDS-DAO scores at Visits 5 and 12. The FSDS-DAO total score was responsive to change. CONCLUSIONS: Evidence supports the validity and reliability of the FSDS-DAO for assessing sexually related distress in women with female sexual arousal disorder and/or hypoactive sexual desire disorder; the addition of the arousal and orgasm items did not impact the validity and reliability of the measure. Clinical Trial Registration ClinicalTrials.gov NCT01382719.

Sexual complaints, pelvic floor symptoms, and sexual distress in women over forty.

INTRODUCTION: The American Psychiatric Association recommends considering sexually related personal distress when assessing female sexual dysfunction. Currently, there is little data regarding the impact of sexual complaints on sexual distress. AIM: To investigate the association between sexual complaints and perceived sexual distress in a population of ambulatory adult women. METHODS: Using the short forms of the Personal Experiences Questionnaire and Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire, we assessed sexual complaints among 305 women seeking outpatient gynecologic care. Depressive symptoms were quantified using the Center for Epidemiologic Studies Depression (CESD) score. Sexual distress was measured using the Female Sexual Distress Scale (FSDS). Using multivariable logistic regression, we compared sexual complaints between distressed and nondistressed women. MAIN OUTCOME MEASURES: Sexual distress, defined by FSDS score ≥15. RESULTS: FSDS scores were available for 292/305 participants. Seventy-six (26%) scores reflected distress. Distressed women were more likely to be younger (55.2±1.0 years vs. 56.7±0.8 years, P=0.017); have higher CESD scores (16.6 vs. 9.5, P=0.001); and report decreased arousal (56.8% vs. 25.1%, P=0.001), infrequent orgasm (54% vs. 28.8%, P=0.001), and dyspareunia (39.7% vs. 10.6%, P=0.001). Women with sexual distress were also more likely to report sexual difficulty related to pelvic floor symptoms, including urinary incontinence with sexual activity (9% vs. 1.3%, P=0.005), sexual avoidance due to vaginal prolapse (13.9% vs. 1%, P=0.001), or sexual activity restriction due to fear of urinary incontinence (14.9% vs. 0.5%, P=0.001). After multivariate analysis, sexual distress was significantly associated with dyspareunia (odds ratio [OR] 3.11, P=0.008) and depression score (OR 1.05, P=0.006), and inversely associated with feelings of arousal during sex (OR 0.19, P=0.001). CONCLUSION: Our results indicate that sexually related personal distress is significantly associated with dyspareunia, depressive symptoms, and decreased arousal during sexual activity. This contributes to our understanding of how sexual complaints may adversely affect women's quality of life.