The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

Evaluation of safety for flibanserin.

Introduction: Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction in women, previously managed with off-label therapies. Indicated for premenopausal women, flibanserin is the first FDA-approved medication to treat HSDD.Areas covered: This review summarizes flibanserin's pharmacokinetics, proposed mechanism of action, and safety data in clinical trials with a focus on sedation- and hypotension-related adverse events, and drug interactions with alcohol and antidepressants. Sources included peer-reviewed publications and internal data from the manufacturer.Expert opinion: Flibanserin is a well-tolerated and effective treatment that decreases distress and restores sexual desire to a level that is normative for the individual patient with HSDD. Simplification of a risk mitigation program for flibanserin in the US is likely to increase the number of prescribing clinicians if accompanied with educational efforts to clarify flibanserin's risk-benefit profile. As flibanserin is dosed daily and may be used for a decade or more in the typical premenopausal patient, long-term pharmacovigilance data will be essential. Over time, HSDD will be treated by more nonspecialist health care professionals and flibanserin will likely become established as a significant treatment option along with other medications approved for this indication in the context of a holistic biopsychosocial treatment paradigm.

Lumping, Splitting, and Treating: Therapies Are Needed for Women With Overlapping Sexual Dysfunctions.

INTRODUCTION: Phase-specific diagnoses, such as hypoactive sexual desire disorder, are the norm in sexual medicine. Epidemiologic surveys and clinical trials show the value of this structure for understanding and treating premenopausal sexual dysfunction; however, postmenopausal women have sexual dysfunction in >1 phase, for example, in desire and arousal. OBJECTIVE: To evaluate the evidence for mixed or global sexual dysfunction in women, identify associated comorbidities, and determine the best available treatment. METHODS: Literature review of epidemiologic surveys and clinical trials to quantitate overlap in sexual dysfunction and render conclusions about treatments. MAIN OUTCOME MEASURES: The main outcome measures were the Changes in Sexual Functioning Questionnaire and the Female Sexual Function Index. RESULTS: Overlap of sexual dysfunction in women is low to moderate before menopause, but it is high after menopause. Data suggest that clinical trials of postmenopausal women diagnosed with hypoactive sexual desire disorder actually entered patients with mixed or global sexual dysfunction and that benefits were pan-phasic rather than concentrated on desire. Whether local/vaginal products for the genitourinary syndrome of menopause impact all phases of sexual dysfunction is under study. Women treated for breast or gynecologic cancer or taking antidepressants also have global sexual dysfunction. Treatment options are limited but support mindfulness-based cognitive behavioral therapy and others. Other strategies include adding or switching to a serotonin 1A receptor agonist (eg, buspirone, flibanserin), a serotonin 2A receptor antagonist (eg, flibanserin, trazodone), or a norepinephrine-dopamine reuptake inhibitor (eg, bupropion). Elimination of hormonal contraception in premenopausal women and adding hormonal therapies in postmenopausal women may be necessary. CONCLUSIONS: Practitioners should be alert to overlap of sexual dysfunction in women. Focusing diagnostics and treatment on individual phases of sexual function is appropriate in premenopausal patients, but global sexual dysfunction is more likely in women taking antidepressants or cancer chemotherapy or during and after the menopausal transition. More safe, broadly effective treatments for mixed sexual dysfunction are needed for these populations of women. Pyke RE, Clayton AH. Lumping, Splitting, and Treating: Therapies Are Needed for Women With Overlapping Sexual Dysfunctions. Sex Med Rev 2019;7:551-558.

Effect Size in Efficacy Trials of Women With Decreased Sexual Desire.

BACKGROUND: 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. AIM: 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. METHODS: 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. OUTCOMES: Cohen d was used to determine effect sizes. RESULTS: 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). CLINICAL TRANSLATION: 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. CONCLUSIONS: 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.

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.

Symptoms related to the menstrual cycle: diagnosis, prevalence, and treatment.

Menstrual cycle-related symptoms are associated with the intrinsic hormonal fluctuations of the menstrual cycle. These symptoms can be physical, behavioral, or emotional and include problems such as dysmenorrhea, premenstrual syndrome (PMS), and premenstrual dysphoric disorder (PMDD). Because of the emotional and behavioral aspects of menstrual cycle-related symptoms, it is likely that clinical psychiatrists will encounter these symptoms in their daily practice and should therefore be familiar with their diagnosis, prevalence, etiology, and treatment. As many as 2.5 million women are affected by menstrual disorders each year, which can have a profound impact on their quality of life. Although a definitive etiology has yet to be established, fluctuations in estrogen and progesterone as well as genetic factors are thought to contribute to the occurrence of menstrual disorders. Current treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs) (for dysmenorrhea), lifestyle changes, selective serotonin reuptake inhibitors (SSRIs), and ovulation suppression (e.g., with oral contraceptives). Treatment with oral contraceptives (OCs), particularly extended or continuous use, may significantly reduce the incidence of menstrual cycle-related symptoms.