Anita H. Clayton, MD

Attention to sex and gender differences has been a long time coming. In 1986, the National Institutes of Health required that women and minorities be included in clinical research; this initiative was strengthened with the 1993 FDA Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, which reversed the 1977 directive that women with childbearing potential be excluded from early clinical studies and explicitly called for data to be analyzed for sex differences.

Why Men and Women May Respond Differently to Psychological Trauma

Miranda Olff, PhD; and Willemien Langeland, PhD

Disentangling the Web: Comorbidity Issues in Gender-Diverse Youth

Christy L. Olezeski, PhD; and Nicolas Meade, MS

Sex refers to genetic and biological differences, and gender reflects the impact of social constructs/expectations on roles and relationships, behaviors, expression of emotions, and power dynamics. Advancements in personalized medicine that utilize genetic or other biomarker information to make treatment decisions have demonstrated 

 with some treatments. We now know that the interaction of the genome and the environment or experience can result in epigenetic changes—alterations in gene expression rather than mutations of DNA sequences, which can lead to the formation of inherited phenotypic changes in addition to the traditional genetic basis for inheritance. This increases the complexity of parsing out whether a problem is genome or sex based, related to experienced social constructs and stressors, driven by environmental events impacting a parent that manifested in the offspring, or all of the above.

Thus, some conditions are specific to those born with female sex (eg, ovarian disorders). Some may manifest similarly but are more likely to occur in one gender than the other (eg, 

 being twice as likely to occur in women than in men). In some cases, gender differences influence the expression of similar characteristics such as dramatic or erratic features, emotional dysregulation, and interpersonal conflict, diagnosed as 

 in women and narcissistic or antisocial personality disorder in men. Furthermore, gender differences increase the risk of various environmental stressors such as childhood trauma/victimization in girls and in 

Unfortunately, nearly 30 years after mandating evaluation of sex differences, the US Food and Drug Administration has not followed through on requirements for meaningful analysis for sex-related differences in clinical trials. Tracking of menses in premenopausal women in clinical trials is rare, as are comparisons of results in premenopausal women versus postmenopausal women or men. Very little has been done to evaluate 

 in symptoms and treatments for conditions such as posttraumatic stress disorder (eg, military sexual trauma and/or childhood sexual trauma affecting women versus combat-related trauma in men). Additionally, priority has not been given to finding treatments for conditions disproportionately affecting women, minorities, and LGBTQ+ individuals.

Until gender-sensitive evaluating of clinical presentation, acquiring necessary history, making the correct diagnosis(es), assessing comorbidities, and individualizing treatment are the responsibility of all providers, and assessment of sex and gender differences is ingrained in all research, the needs of our patients will not be met.

The focus of this Special Report will be on how sex and gender, influenced by genetics, epigenetics, and environmental/social stressors, must be considerations in evaluating every patient. Specifically, we must anticipate the potential effect of traumas, understand the impact of gender-based environmental bias/stressors, intervene early, and consider how sex steroids determine the timing of various symptoms, especially in women. Our patients deserve nothing less.

™ World CME Conference™. Register now: 

is the David C. Wilson Professor and chair of the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, with a secondary appointment as professor of clinical obstetrics and gynecology. She is the author of

Satisfaction: Women, Sex, and the Quest for Intimacy

published by Ballantine Books in 2007, and an editor of the 2005

Women’s Mental Health: A Comprehensive Textbook

Articles

Sex and gender, influenced by genetics, epigenetics, and environmental/social stressors, must be considerations in evaluating every patient. 

Evaluating Every Patient

May is Maternal Mental Health Month, and moms around the world could probably use a break. During the COVID-19 pandemic, they have done even more of the childcare and housework, while also, in many cases, 

. How has the pandemic affected their mental health—either by creating new problems or by exacerbating 

, Anita H. Clayton, MD, explores the wide and varied field of maternal mental health. Along with the effects of the pandemic, Clayton discusses prenatal mental health care, new and emerging treatments for postpartum depression and psychosis, and how what she saw in a courtroom set her on a path to becoming a renowned expert on maternal wellness.

Dr Clayton will speak further on these issues at the 

Annual Psychiatric TimesTM World CME Conference.

is the David C. Wilson Professor and chair of the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, with a secondary appointment as professor of clinical obstetrics and gynecology. She is the author of 

 published by Ballantine Books in 2007, and an editor of the 2005 

. She is also a program co-chair of the Annual 

Podcasts

What are the implications of maternal mental health not only for mothers, but also for children, families, and society as a whole?   

More Than Postpartum Depression: Addressing Maternal Mental Health Through the Life Cycle

[[{"type":"media","view_mode":"media_crop","fid":"41962","attributes":{"alt":"Â©Marimaria/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_7024378268862","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4500","media_crop_rotate":"0","media_crop_scale_h":"150","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Â©Marimaria/Shutterstock.com","typeof":"foaf:Image"}}]]Attention spans are shorter than ever, so maybe it was to be expected that the media would try to tell the entire story of the FDA’s approval of Sprout Pharmaceuticals’ flibanserin on August 18, 2015, for generalized, acquired hypoactive sexual desire disorder (HSDD), with 2 words: “Pink Viagra.”

 Unfortunately, while one of those words is technically correct-the pill is pink-put together they don’t tell the story at all. Flibanserin, to be marketed beginning October 17, 2015, as Addyi, is nothing like sildenafil (Viagra). Flibanserin’s goal is different. Its administration is different. And its mechanism of action is different. Not only is the phrase misleading, but it does a disservice to our understanding of HSDD, to the newly approved treatment for it, and to the potentially millions of women across the country whose lives have been disrupted by the condition.

HSDD has been in the scientific literature since 1977.

 And while it affects 6% to 10% of US women, it still has not received the sort of attention from the scientific community as erectile dysfunction (ED) treatment, which began with the FDA approval of sildenafil 17 years ago and today includes 3 other phosphodiesterase-5 (PDE-5) inhibitors.

 low sexual desire-distressing being the operative word.

 In the women I see, this is usually an acquired condition. That is, they had what they considered an adequate level of desire, and for some reason unknown to them, it is now diminished or completely absent. As a result, they feel significant distress. They don’t feel like themselves as a sexual being, they’re concerned about the impact of the loss of desire on their relationship, and they’re frustrated with this loss. For these women, increasing the number of “date nights” with their partners, romantic weekend getaways, or other such “cures” are useless. HSDD is biological-it is a daily state of being, is consistent, and persists for years.

There are 2 primary ways that HSDD affects a woman. First, she feels bad about herself, which can carry over into every aspect of her life-in her relationship with her partner, of course, but also in her relationship with her children, her friends, and her colleagues, because it changes her view of herself. Second, her behaviors change. Because she’s not interested in sex, she avoids her partner, so she doesn’t have to make a decision about whether to participate in sex if approached. Some women will say yes, usually out of obligation, every time their partner tries to initiate sex; others decline their partner routinely. Loss of sexual desire changes their relationship, as these women avoid the circumstances in which their partners might approach them. And their partners often respond by blaming themselves or believing she is no longer in love with or attracted to them.

Unlike PDE-5 inhibitors-ED treatments that enhance performance by increasing blood flow to the penis-flibanserin acts to correct the imbalance in the function of neurotransmitters in the brain that affect sexual desire.

 While the exact mechanism of action for flibanserin remains unclear, flibanserin has been found to stimulate postsynaptic 5-HT

 This decreases serotonin activity, which is responsible for sexual inhibition, and indirectly increases the availability of dopamine and norepinephrine, which are responsible for sexual excitement.

 In other words, flibanserin seems to reduce inhibitory effects at the same time as it enhances excitatory effects in reward circuits, leading to the generation of sexual desire. Because of these effects, flibanserin is administered as 100 mg daily at bedtime, with a gradual effect over 2 to 8 weeks.

As the first-ever FDA-approved treatment for HSDD, flibanserin is a breakthrough. It’s going to make a real difference for women because it has the potential to affect them on a daily basis. And it’s going to change my practice, as well as those of many others, since we’ve been using off-label treatments, reassurance, and other unproven interventions-the truth is, these treatments have not been effective. We will finally be able to talk to women with HSDD about a treatment that has FDA approval.

Approval from the FDA also means that patients will be bringing up the topic of their sexuality, and providers will need to understand HSDD and this new treatment option. While flibanserin is not appropriate for all patients, approval opens the door to a bigger discussion between every woman and her health care provider about sexuality and sexual health.

FDA approval also means that an accurate diagnosis of HSDD is more important than ever. More physicians will become familiar with the Decreased Sexual Desire Screener (DSDS), a highly reliable tool that was developed to provide clinicians with easy-to-use screening for the diagnosis of HSDD in women. The DSDS comprises 4 simple yes/no questions:

1. In the past, was your level of sexual desire or interest good and satisfying to you?

2. Has there been a decrease in your level of sexual desire or interest?

3. Are you bothered by your decreased level of sexual desire or interest?

4. Would you like your level of sexual desire or interest to increase?

A fifth question asks about potential factors that might be contributing to the loss of desire, such as medications, recent childbirth, a partner’s sexual problems, or dissatisfaction with one’s relationship.

Diagnostic assessment by a non–sexual medicine expert using the DSDS versus administration of a standard diagnostic interview by a sexual medicine expert demonstrated agreement in 85.2% of cases, with sensitivity of 83.6% and specificity of 87.8%.

 Providers will also need to complete online training about the risks and prescribing of flibanserin before their prescriptions will be filled by certified pharmacies, which is not currently required for use of medications to treat ED despite similar drug interactions.

Flibanserin can improve a woman’s sexual desire so that she becomes interested in sex again-50% of women who received flibanserin responded to treatment during clinical trials. Specifically, the studies showed a 53% improvement in women’s desire for sex as measured by the Female Sexual Function Index-Desire subscale; flibanserin may even restore a woman’s desire to her previously satisfying level.

Avoidant behaviors also change. The woman feels better about herself as a woman and as a sexual being, and her distress decreases (29% decrease in distress evaluated with the Female Sexual Distress Scale); she might even start initiating sexual activity again. And responders report more and better sex as measured by satisfying sexual events, which doubled with flibanserin. On every endpoint, flibanserin was statistically superior to placebo. And those changes matter: 60% of women in the clinical trials indicated the improvement they experienced was clinically meaningful to them.

The power of an established diagnosis, and of having an approved treatment, is that it empowers a woman to decide what’s right for her. She makes the decision whether her distress is high enough to take a medication, and she’s the one who decides through her own experience whether the medication has been effective for her in a way that has changed her life. While we know flibanserin has been shown to be effective in half the women who take it, not all who take it will, in the end, decide it’s right for them.

What are the adverse effects with flibanserin? As with most CNS drugs, there are adverse effects such as nausea, dizziness, and sedation. These adverse effects are generally mitigated by the bedtime dosing of flibanserin; fewer than 13% of women who took flibanserin in the 6-month registration trials discontinued use due to adverse effects.

Ultimately, FDA approval of flibanserin not only will help women living with HSDD in the short run, but over the long term it will open up opportunities for a deeper, richer dialogue between physicians and patients (and perhaps on a societal/cultural level). It is a first step that can lead to more research and new drugs to address this very real, very distressing condition experienced by so many women.

Dr Clayton is David C. Wilson Professor and Interim Chair of the department of psychiatry and neurobehavioral sciences at the University of Virginia Health Systems in Charlottesville, VA. She reports that she has received grants from Auspex Pharmaceuticals, Forest Research Institute, Inc, and Palatin Technologies; she is on the Advisory Board/a consultant for Forest Labs, Lundbeck, Naurex, Otsuka, Palatin Technologies, Roche, S1 Biopharmaceuticals, and Sprout Pharmaceuticals; she receives royalties/holds copyright from Ballantine Books/Random House, Changes in Sexual Function Questionnaire, and Guilford Publications; she has shares/restricted stock units in Euthymics and S1 Biopharmaceuticals, Inc. She does not stand to benefit from the approval of any drug under consideration by the FDA; and she has no promotional relationships to declare.

 US Food and Drug Administration. FDA approves first treatment for sexual desire disorder. August 18, 2015. 

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm

 Jutel A. Framing disease: the example of female hypoactive sexual desire disorder. 

 Shifren JL, Monz BU, Russo PA, et al. Sexual problems and distress in United States women: prevalence and correlates. 

 Johannes CB, Clayton, AH, Odom DM, et al. Distressing sexual problems in United States women revisited: prevalence after accounting for depression. 

 Caplan A. Ethical implications of drugs for erectile dysfunction. 

 Brotto LA. The DSM diagnostic criteria for hypoactive sexual desire disorder in women. 

How does VIAGRA® (sildenafil citrate) work? 

 Reviriego C. Flibanserin for female sexual dysfunction. 

 Stahl S. Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. 

 Clayton AH, Goldfischer ER, Goldstein I, et al. Validation of the decreased sexual desire screener (DSDS): a brief diagnostic instrument for generalized acquired female hypoactive sexual desire disorder (HSDD). 

Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Premenopausal Women Advisory Committee Briefing Document; 2015

 Addyi [package insert]. Raleigh, NC: Sprout Pharmaceuticals; 2015.

Flibanserin is a breakthrough. We will finally be able to talk to women with hypoactive sexual desire disorder about a treatment that has FDA approval.

Anita H. Clayton, MD

Articles

Evaluating Every Patient

More Than Postpartum Depression: Addressing Maternal Mental Health Through the Life Cycle

Flibanserin: More Than Just a “Pink Viagra”