Abstract
Screening, diagnosis, and management of hypoactive sexual desire disorder (HSDD) and research into the condition have been challenging due to its biopsychosocial complexity and lack of consensus on relevant measures. Although physician interviews yield much clinically valid information, self-reported questionnaires appear more acceptable to patients and physicians. Consequently, validated patient-reported outcome (PRO) tools are essential for evaluation and management of HSDD, including any therapeutic intervention. The US Food and Drug Administration (FDA) has issued guidance on the use of appropriate endpoints and associated measures for female sexual dysfunction, including HSDD. Although many of the available measures were not designed specifically for HSDD assessment, as per FDA guidelines, most clinical studies have used individual domains or items from established tools, such as the Female Sexual Function Index-desire domain and Item 13 of the revised Female Sexual Distress Scale. For clinical practice, several professional societies recommend the Decreased Sexual Desire Screener and/or a sexual history as tools to diagnose HSDD. This review discusses frequently used PRO tools as well as the newly developed and validated Elements of Desire Questionnaire, which may be appropriate for clinical trials or clinical practice.
Introduction
Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction among women and is defined as persistent or recurrent deficiency or absence of sexual fantasies/thoughts and/or desire for, or receptivity to, sexual activity that causes personal distress and is not explained by another mental disorder, medical condition, or substance use. 1 –3 HSDD affects general well-being and quality of life. 4 –6 A significantly greater number of women with HSDD reported dissatisfaction with their sex life and marriage or partner compared with women without decreased sexual desire. 4 Women who suffer from HSDD also complained of several psychological consequences, including personal feelings of concern, unhappiness, hopelessness, and anger, as well as loss of femininity and altered self-esteem. 5 Due to the biopsychosocial complexity of female sexual desire and its impact on the quality of patients' lives, validated patient-reported outcome (PRO) instruments are required to assess the efficacy of potential treatments. 7
There are currently two drugs approved by the US Food and Drug Administration (FDA) for the treatment of generalized acquired HSDD in premenopausal women. Flibanserin, approved by the FDA in 2015, has demonstrated efficacy in this population in a phase 3 clinical trial. 8 Bremelanotide, a melanocortin receptor agonist, received FDA approval in 2019 and has also demonstrated robust and consistent efficacy. 9
Historically, the development of appropriate measures of female sexual dysfunction (FSD) has been hampered by inappropriate attempts to align it with a male paradigm in addition to a lack of consensus on relevant symptoms/diagnostic classification. 10 In 2000, the FDA first released draft guidelines for the design of trials for FSD, including decreased sexual desire. 11 This guidance document noted that new scales, questionnaires, and other instruments were required to diagnose FSD and its components and that these should be tested and validated as well as be able to measure minimal clinically meaningful differences. 11 The ability to define minimal important differences (MIDs) derived from patient-based and clinical anchors that correlate with the reported outcome is crucial for an effective PRO tool. MIDs are also informed by clinical trial experiences, but may vary by population and context. 12 Previous guidance from the FDA noted that clinical endpoints should be based on successful and satisfying sexual events (SSEs) and encounters over time and that PRO instruments were not acceptable as primary endpoints. 11 However, it is important to note that the definitions for disorders of low sexual interest or desire include associated distress, but do not encompass satisfaction related to sexual events. Feedback received from an FDA-sponsored patient workshop in 2014–2015 led to the new draft guidance in 2016, in which measures of associated distress replace SSEs as coprimary efficacy endpoints for clinical trials of drugs intended to treat low sexual interest and desire disorders; SSEs were relegated to secondary endpoints. 7
An International Consensus Conference on FSD sought to define sexual desire disorders based on the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, nomenclature system. HSDD was characterized as persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts and/or desire for or receptivity to sexual activity, which causes personal distress. 13,14 The limitations of the DSM-IV criteria for HSDD as eligibility requirements for clinical trials evaluating treatments for low sexual desire in women have been discussed previously. 15 Most importantly, DSM-IV did not distinguish between HSDD in men and women. DSM-5 merged HSDD in women and female sexual arousal disorder (FSAD) as female sexual interest/arousal disorder. 16 However, this latest revision has no published data to support or validate this definition. Additionally, most research on women with HSDD utilizing PROs, such as the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R), has been based on the DSM-IV definition. 1 As a result, the International Classification of Diseases, 11th edition, defines HSDD and FSAD separately. 17
Most recently, the International Society for the Study of Women's Sexual Health (ISSWSH) developed revised nomenclature and definitions for desire, arousal, and orgasm dysfunctions. 1 They recommended a broadening and simplification of the diagnostic criteria and a return to the previous diagnostic label due to the large body of clinical and experimental evidence. This nomenclature allows clinicians and researchers to address current and future patient management needs in addition to providing diagnostic entry criteria for clinical trials.
The objective of this review is to discuss available instruments for the screening, diagnosis, and assessment of patients with HSDD for clinical trials and in clinical practice. This is done in light of the recent FDA guidelines regarding PRO instruments, other recent pronouncements by professional societies, and in consideration of the two FDA-approved pharmacologic interventions for HSDD that potentially allow for additional effective treatment for this condition.
Screening Tools and the Structure of Assessments
The first step in the assessment of HSDD should include both a brief, diagnostic screening questionnaire and collection of a more detailed patient history. 2 A patient's sexual medical history should include both psychosocial and medical issues. 18 Based on the patient's medical history, if appropriate, a basic gynecological examination should also be conducted. 18
A number of screening tools, including self-report questionnaires and structured interviews, have been developed over the past 20 years, but many of these were not specific to HSDD and were developed in the absence of effective treatments. As a result, they may only be valid for diagnosis and assessment of the severity of the disorder. Until 2000, when the first draft FDA guidance was published, there were few scales that provided relevant information on HSDD. 19,20 Further complicating the issue is the fact that although structured or semistructured interviews are generally considered to yield more clinically valid information, it has been suggested that a self-report questionnaire may be more acceptable to both patients and physicians with regard to this sensitive topic. 21 The most commonly used of these screeners and questionnaires are reviewed below.
Assessment of Overall Sexual Function
Female Sexual Function Index
The FSFI is generally regarded as the gold standard self-reporting instrument for assessment of FSD. 22 It is a validated 19-item questionnaire that assesses six domains of FSD: desire, subjective arousal, lubrication, orgasm, satisfaction, and pain/discomfort. 23 This form of the FSFI is used mainly for clinical trials. Originally, the FSFI consisted of five domains, combining desire and subjective arousal; however, the authors determined that desire and arousal should be assessed independently and subsequently separated them into two distinct measurable dimensions. 23 The content validity of FSFI, especially the desire domain, has been demonstrated and it meets the criteria for clarity, relevance, and completeness in both pre- and postmenopausal women with HSDD. 24
A shorter 6-item FSFI has also been validated, with each item covering one of the six domains. 25 This short-form version of the FSFI may be more practical for use in clinical practice and research when limited time availability is a consideration.
Although the FSFI was first developed for assessment of women with FSAD, it has also been validated in women with female orgasmic disorder and in women with HSDD. 26 It has been further validated by assessing the following: (i) correlations between FSFI scores and quantitative scores generated from clinical interviews; (ii) the specificity of FSFI subscale scores in reflecting corresponding aspects of sexual function; and (iii) sensitivity to therapeutically induced change (i.e., responsiveness). 22
While some have suggested limitations of the FSFI with regard to nonlinear scoring and measurement of desire, 27,28 or distinguishing between arousal and desire, 22,27 some of this latter difficulty may be due to the evolving definitions of sexual desire over time. In response to criticism that the two brief desire questions (assessing frequency and intensity of desire) on the FSFI may be insufficient to gauge the complexity of female sexual desire, 26,27 most women in a validation study felt that the FSFI-desire domain (FSFI-D) adequately conveyed their feelings on sexual desire, with no need for additional questions. 29 While the FDA has also noted content validity and response scale concerns with the FSFI-D in the past, the FDA has issued guidance on how to use the FSFI as a study endpoint, suggesting the inclusion of a supplemental monthly desire recall with a subset of patients using daily recall or use of secondary endpoints to further assess desire. 7 Another criticism of FSFI is that some FSFI item response scales include zero, while others do not, which raises statistical concerns. As a result, Meyer-Bahlburg and Dolezal have proposed amendments to the FSFI to address some of these issues. 28 Although the FSFI is a scale based on self-reported information and is not highly detailed, it remains a valid and simple tool for tracking patients over time and evaluating treatment response. Most importantly, the FSFI-D remains the gold standard for evaluating low sexual desire in HSDD as it was demonstrated and utilized in several clinical studies, including the recent phase 3 clinical trials investigating the efficacy of flibanserin and bremelanotide. 8,9,30,31
The FSFI has been used broadly and has been adapted for use in 20 languages, including Spanish, Arabic, Farsi, Japanese, and Chinese. 32 –36 Overall, it has been translated and linguistically validated in over 30 countries. 37 The FSFI can also now be used reliably in lesbian women with HSDD after an adaptation to replace heterosexual language with more inclusive language. 38 Furthermore, the FSFI has also been validated to monitor sexual dysfunction and cancer-related dysfunction in female cancer survivors. 39
Changes in Sexual Functioning Questionnaire
The Changes in Sexual Functioning Questionnaire (CSFQ) was initially designed to assess sexual function associated with psychiatric illness and medication effects. 40 The original version of the CSFQ is a validated 35-item questionnaire consisting of five subscales (desire/interest, frequency/desire, arousal, orgasm, and sexual pleasure). This long-form of the CSFQ has been used for clinical trials. The CSFQ has demonstrated concurrent validity with the Derogatis Interview for Sexual Function–Self-Report, internal consistency, and test–retest reliability over 1 month in a sample population of normal subjects and measures sexual experiences that parallel categories in DSM-IV. 41 The CSFQ has also been used to measure changes in sexual functioning over time in other populations, including women with premenstrual complaints, 42 following changes in antidepressants, 43 adjunct therapy for sexual dysfunction, 44 and treatment of primary sexual disorders. 45 Moreover, the CSFQ is sensitive to bidirectional changes. 46
A shorter self-report version—CSFQ-14—that maintains the five subscales has also been developed and validated to help overcome some of the barriers that clinicians face when assessing sexual function, including patient embarrassment, patient lack of confidence in the professional's knowledge of the issue, time constraints, and physician discomfort in talking about sex. 21
The CSFQ has been translated for and validated in a Spanish population 46 and has been validated in postmenopausal women, 47 Taiwanese patients with depression, 48 and Spanish patients with mental disorders. 49
Assessment of Desire
Decreased Sexual Desire Screener
The Decreased Sexual Desire Screener (DSDS) is a 5-item self-report questionnaire that has been validated as a screening tool to assist internists, family physicians, gynecologists, nurse practitioners, and other providers in clinical practice who lack expertise in sexual medicine in making an accurate diagnosis of HSDD. 50 The tool can also be used as a semistructured, clinician-administered interview guide. 1 Similar to the two brief desire questions assessing frequency and intensity of sexual desire from the FSFI (FSFI-D), the first four questions of the DSDS establish the presence of decreased sexual desire and indicate whether further assessment is required; a yes response to all four questions indicates the presence of HSDD. 50 A yes response to any part of question 5, which lists possible causes, may help establish the etiology and/or modifiable factors of HSDD. 50
The DSDS was validated for use as a brief diagnostic instrument for generalized acquired HSDD. The sensitivity and specificity of the DSDS are 0.84 and 0.88, respectively, as measured by comparing it with a standardized diagnostic interview. 50 The validity of the DSDS was further confirmed in two large clinical trials of flibanserin. 51 In these trials, a comparison of diagnoses by nonexpert clinicians using the DSDS followed by an extensive interview by expert clinicians trained in diagnosis of female sexual disorders showed that the tool has a sensitivity of 0.95–0.96. 51 In the ORCHID trial, which took place across 11 European countries (Austria, Belgium, Czech Republic, France, Germany, Hungary, Italy, The Netherlands, Spain, Sweden, and the United Kingdom), women completed the DSDS in their local language. 52 Therefore, the DSDS is a sensitive, specific, easy-to-use, and brief diagnostic instrument for use by nonexpert clinicians in English and other languages to aid in the diagnosis of generalized acquired HSDD. 50,51
Sexual Interest and Desire Inventory-Female
The Sexual Interest and Desire Inventory-Female (SIDI-F) is a validated, 13-item clinician-administered instrument designed to measure the severity of HSDD and, in particular, to monitor the disorder over time and evaluate therapeutic interventions. 53,54 One advantage of this instrument is that it is better able to distinguish between HSDD and FSAD than other established instruments (such as the FSFI and CSFQ-14), which were not specifically designed to assess the severity of HSDD. 54 Another benefit of SIDI-F is that it provides greater depth related to the impact of changes in sexual desire since it considers the frequency of initiation of sex, receptivity, avoidance behavior, affection, and orgasm, as well as desire and arousal. 54 A Persian version of the SIDI-F has been validated in a study of 40 Iranian married women of reproductive age (15–49 years). 55 The SIDI-F has also been utilized in evaluating HSDD in breast cancer patients. 56 This tool is designed mainly for clinical trials.
Elements of Desire Questionnaire (EDQ)
Recent phase 3 controlled trials of bremelanotide in premenopausal women with HSDD have employed the newly developed and validated Elements of Desire Questionnaire (EDQ), a 9-item PRO instrument 57 (Revicki et al., manuscript in preparation). The EDQ was developed to measure areas of desire that current instruments do not capture, such as intensity of sexual thoughts or fantasies about sex and receptivity to sexual requests. It is intended to be used not only in clinical trials to assess treatment benefits of interventional pharmacotherapies that may improve sexual desire in women with HSDD but it may also be used in clinical practice to assess HSDD. The EDQ was developed based on input from clinical experts and the content validity was explored through qualitative research with women with HSDD 57 (Revicki et al., manuscript in preparation).
The EDQ was developed as both daily (24-hour) and monthly (28-day) recall versions. 58 Importantly, the EDQ, in particular the daily recall version, was developed to be consistent with FDA guidelines for PROs. 57 There was a significant correlation between the monthly and daily recall versions, which is noteworthy given the inherent issues with daily data collection (i.e., missing data and poor fit with the sexual desire construct); the monthly recall version of the EDQ appears to be more appropriate for both clinical trials and clinical practice. In addition to providing excellent correlation with the FSFI-D, the EDQ also measures different elements of desire and behavior associated with HSDD, 59 which along with distress are the defining hallmarks for the diagnosis and evaluation of HSDD treatments. 58,59
Assessment of Distress
FSDS and FSDS-R
The FSDS is a 7-day recall self-report tool first introduced and validated in 2002 to report sexual distress relating to all categories of female sexual function and is therefore not specific to HSDD. 60 The instrument was demonstrated to be highly reliable and discriminating in diagnosing sexual functional versus dysfunctional status and is sensitive to therapeutically induced change. The updated and revised FSDS-R added a question to measure personal distress related specifically to low desire (Item 13), which allowed for differentiation between HSDD and FSD. 61 The authors suggested that this question be incorporated into an eDiary and demonstrated that distress due to low sexual desire was highly variable from day to day. 62 Additionally, this distress measure, with its longer 7-day recall period, showed a high frequency of distress and moderate variability, potentially making it useful in both clinical practice and clinical trials. 62 In agreement with this assessment, the FDA indicated that this single item on distress related to sexual desire (Item 13) was an acceptable measure of sexual distress for clinical trials in the 2016 guidance. 7 The FSDS and FSDS-R have been translated and independently validated in studies in Egypt and Poland. 63,64
A second revision of the FSDS, the FSDS-Desire/Arousal/Orgasm (FSDS-DAO) instrument, has also been developed and validated. 65 The FSDS-DAO is a 15-item instrument based on the validated 13-item FSDS-R. The additional two items relate specifically to concerns (related to arousal and frustration) related to orgasm. This latest version was developed using a 30-day recall period. The tool has demonstrated internal consistency, test–retest reliability, and construct and discriminant validity (Derogatis et al., manuscript in preparation).
Sexual Desire Relationship Distress Scale
The Sexual Desire Relationship Distress Scale (SDRDS) was designed specifically to measure distress due to decreased sexual desire. 66,67 This tool has been validated in women with HSDD and provides a comprehensive and reliable assessment of distress. The 17-item PRO tool measures not only personal distress but also distress relating to the woman's relationship. An observational study of 260 pre- and postmenopausal women demonstrated excellent internal consistency and test–retest reliability, concurrent validity, and known group validity for the SDRDS. Mean SDRDS scores at baseline were higher in women with HSDD compared with women who did not have sexual dysfunction (p < 0.00001). 66 The SDRDS may be of value in measuring distress in clinical trials in women with HSDD and in assessing the degree of distress before and after treatment.
Assessment of Sexual Encounters
Female Sexual Encounter Profile
The original versions of the Female Sexual Encounter Profile (FSEP) included a 6- or 7-item diary record used to assess sexual functioning in the context of female sexual arousal and FSAD. 68,69 The patient-completed diary questionnaire asks questions relating to conditions for intercourse, details about sexual activity, arousal and lubrication levels, and achievement of orgasm. 68 Although it has been used in a number of clinical studies, little has been published on its psychometric properties 70 ; as such, this questionnaire has little applicability to HSDD.
While Item 10 of the revised 10-item questionnaire, which is based on SSEs, has been used as a primary endpoint in clinical trials evaluating efficacy of agents for FSD (e.g., testosterone and flibanserin), 7,71 some experts have argued that this is a narrow metric too far downstream from desire to capture changes in the symptoms of HSDD. 71,72 When measuring changes in desire for women with HSDD, use of SSEs as endpoints has also been criticized on methodological grounds. 59 These shortcomings include the lack of a defined improvement score, 73 the subjective nature of satisfaction for women, the individualized criteria applied given the vague definition of an SSE, and the lack of specificity of SSEs to HSDD. 71 Furthermore, a higher count of sexual encounters does not correlate with more satisfaction, as is the case in men. 71
Recommendations for HSDD Screening Tools by Professional Societies
Screening tools for diagnosing HSDD recommended in the Handbook on Female Sexual Health and Wellness, published by the Association of Reproductive Health Professionals, include the Brief Hypoactive Sexual Symptom Checklist, FSFI, DSDS, SIDI-F, and FSDS-R (Table 1). 18,23,50,53,54,61,71,74 Consistent with these recommendations, several professional societies, including the ISSWSH, the American College of Obstetricians and Gynecologists, and the Sexual Medicine Society of North America, suggest the use of the DSDS and a sexual history as tools to diagnose HSDD (Fig. 1). 75,76
International Society for the Study of Women's Sexual Health recommendations for HSDD screening algorithm. 75 From Clayton et al., 75 with permission. Copyright© 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier, Inc. *To detect sexual problems, it is recommended to simply ask a question such as “Are you sexually active?” during the patient visit. To follow-up, whether the patient answers yes or no, a health care professional is recommended to ask a direct screening question such as “Are there sexual concerns you wish to discuss?” †If a woman responds no to at least one of the first four questions on the DSDS, she does not meet the criteria for generalized acquired HSDD, but could meet criteria for either situational or lifelong low sexual desire/interest. HSDD, hypoactive sexual desire disorder; DSDS, Decreased Sexual Desire Screener.
Recommendations From the Association of Reproductive Health Professionals
HSDD, hypoactive sexual desire disorder.
Application of PRO Instruments in Clinical Trials for Treatments in Women with HSDD
FDA guidance
For drugs intended to treat decreased sexual interest or desire, the 2016 FDA draft guidance stated that it is acceptable to use change from baseline in sexual interest or desire scores as coprimary endpoints with associated distress. 7 For the FSFI-D to be used as the assessment of desire, the FDA has made recommendations requiring additional evaluation: assessment of components of desire on a daily basis with subsequent validation, comparing the 28-day recall results with results from a subset of subjects providing daily recall results, removing the multibarreled instructions on the FSFI, and adding secondary endpoints assessing aspects of desire beyond frequency and intensity of desire (the two items on the FSFI-D).
As discussed above, the change from baseline in SSEs as a primary endpoint for clinical trials is a flawed measure since the definitions of disorders such as HSDD do not include mention of SSEs. As a result, the FDA has accepted decrease in associated distress as a replacement for SSEs as a coprimary endpoint. With regard to secondary endpoints for clinical trials, the FDA has agreed to accept assessments of improvement in SSEs, interest, desire, arousal, or distress among responders. 7
Along with the FSFI-D, Item 13 of the FSDS-R is considered an acceptable measurement of distress related to decreased sexual desire, the other key aspect of HSDD. However, since FSFI and FSDS-R total scores are not directly specific to outcome measures related to HSDD, the FDA does not regard these metrics as acceptable for any labeling claim. 7 The definition of a responder for these secondary endpoints must be prospectively defined based on trial data that establish clinically important changes and are derived using anchor-based methods. That said, while not specific to low sexual desire, the FSFI total score encompasses issues related to low sexual desire and provides additional insight to patients and prescribers around overall sexual health; it is a marker of the impact of low desire, and the score is often impacted beyond the FSFI-D by treating low desire. Similarly, the FSDS-DAO total score highlights improvement in overall distress and parallels the overall improvement in the FSFI total score, reflecting the downstream impact of improving desire. This is arguably a better marker than the downstream change in SSEs for premenopausal women with HSDD. 59
Recommendations Regarding the Use of PRO Instruments in Clinical Trials and Clinical Practice
Although sexual medicine experts from ISSWSH generally agreed with the recent FDA guidelines that relegated SSEs to secondary endpoints and accepted a measurement of sexually associated distress as a coprimary endpoint, they believed that a considerable portion of the guidance on the PROs could be further improved. The FDA questioned the adequacy and validity of the FSFI and called on sponsors to develop new validated PROs. While ISSWSH agreed with the need for the development of additional instruments to better assess desire and arousal disorders, they disagreed that there is insufficient evidence for FSFI validation as the FSFI is supported by robust reliability and validity. 77
With regard to the recall period of a PRO, shorter recall periods (ideally within 24 hours) are strongly encouraged by the FDA with the presumption that recall beyond a few days is inaccurate and subject to greater variation. However, an examination of daily affect and sexual function over a 2-week period demonstrated considerable fluctuation in daily sexual desire. 78 Moreover, chronic conditions such as HSDD are best evaluated by a longer recall period, as shown by several clinical validation studies. 24,79 Thus, ISSWSH supports the use of PROs with longer recall periods to accurately measure the multidimensional/contextual nature and/or sexual desire/arousal domains of sexual dysfunction in clinical trials.
Multidimensional and single-dimensional measures of sexual function are both relevant for understanding treatment outcomes. Multidimensional measures, such as the FSFI, are relatively short and assess several different domains. A single-domain scale, such as the DSDS, may be more useful when there is interest in more comprehensively assessing a specific sexual function domain. Nevertheless, a multidimensional instrument may be useful in clinical practice to confirm a diagnosis and monitor changes following an intervention. We recommend that the selection of sexual function measures should be based on the objectives of the study.
Conclusions
Conceptions of sexual desire have progressed over the past few decades along with new regulatory guidance on the use of PROs in clinical trials. Although there has been significant interest in development of instruments for assessment of FSD over the past 20 years, the methodology for assessment of female HSDD has evolved slowly. The DSDS has proven to be a useful and reliable tool for the diagnosis of HSDD for all types of providers, and assessment of the hallmark symptoms of HSDD can be achieved with the FSFI-D (desire) and FSDS-R (distress) scales. However, especially since there are now two FDA-approved pharmacotherapies for HSDD, flibanserin and bremelanotide, there remains a continuing need for additional validated PRO measures that are specific to HSDD and can be used in clinical trials to appropriately evaluate specific outcome measurements. The EDQ, a new measure that was recently developed to specifically assess additional dimensions of desire, could be used in current and future clinical trials and warrants further evaluation and validation. Moreover, since there are PROs that were previously validated and recommended by several professional societies for clinical practice, ongoing education emphasizing the use of the instruments among health care providers will further assist in accurate diagnosis, determination of optimal treatment options, and individualized management for women who suffer from HSDD. The continued evolution and development of PROs should not impede future scientific and clinical progress on development of new therapies, whether drug, behavioral, or otherwise. Optimally, these two pathways should move forward in concert as knowledge of biology and origins of HSDD become better established.
Footnotes
Author Contributions
All authors contributed to the research, writing, and reviewing of all drafts of the manuscript and approved the final version.
Acknowledgment
Editorial support in preparation of the manuscript was provided by Phase Five Communications, funded by AMAG Pharmaceuticals, Inc.
Author Disclosure Statement
L.R.D. has received research funding support or consulting fees from Palatin Technologies, Inc. D.A.R. has served as a consultant and has received research funding support from AMAG Pharmaceuticals, Inc., Palatin Technologies, Inc., and Viveve. A.H.C. has served on advisory boards or has been a consultant for Alkermes, AMAG Pharmaceuticals, Inc., Fabre Kramer, Ivix, Palatin Technologies, Inc., S1 Biopharma, Sprout, Takeda, and Valeant; she has received grants from Axsome, Endoceutics, Janssen, Palatin Technologies, Inc., Sage, and Takeda; and she has shares or restricted stock units in Euthymics and S1 Biopharma.
Funding Information
The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this article.