CNS Agents Emerge as Frontrunners in FDA-Approved Treatments for Low Libido in Women
February 1, 2020
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By Nicole Cirino, MD, CST, IF
Reproductive Psychiatrist, Associate Professor of Psychiatry and OB/GYN, Oregon Health & Science University, Portland
Dr. Cirino reports no financial relationships relevant to this field of study.
Low libido is the most common sexual complaint, affecting up to 38.7% of women, with up to 12.3% also reporting significant distress associated with this condition.1 Debate continues in the scientific and clinical communities about how female desire disorders are characterized, diagnosed, and treated. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) categorized this common female condition in women as hypoactive sexual desire disorder (HSDD). HSDD is characterized by deficient or absent sexual fantasies and desire for sexual activity lasting at least six months. Women must report significant distress and no other identifiable cause for HSDD, such as substance abuse or general medical conditions (that may affect sexual function).2
HSDD occurs in 8% to 19% of women and is associated with lower health-related quality of life, psychosocial distress, depression, anxiety, and increased total healthcare expenditures.3 In the updated DSM-5, HSDD has been removed and replaced with an amalgamation of female sexual arousal disorder diagnoses termed female sexual interest/arousal disorder (FSIAD).3 However, even though HSDD has been removed from the updated DSM-5, FSIAD has failed to gain clinical traction among the sexual medical community. HSDD remains the diagnosis used for studying new treatment modalities and developing algorithms of care. In the past five years, for the first time in history, we now have two Food and Drug Administration (FDA)-approved medications specifically for treating HSDD in women.
Thus far, FDA approval is for a specific population of HSDD: women who are premenopausal and have a generalized (vs. situational), acquired (vs. lifelong) form of the condition. Of note, both medications are central nervous system (CNS) agents. According to the FDA, both have pre- and post-menopausal designations, as is typical for sex steroids but atypical for CNS agents. The FDA Bone, Reproductive, and Urologic Drugs Advisory Committee (formerly Reproductive Health Drugs Advisory Committee), not a neuroscience committee,4 approved the drug.
In fact, CNS-acting agents have emerged in sex-specific sexual medicine research as the newest treatment for this condition in women. The three main neurotransmitters in the brain implicated in sexual function are dopamine, serotonin, and norepinephrine. We have just recently begun to define how these neurotransmitters can inhibit or promote sexual desire. Generally speaking, both dopamine and norepinephrine are considered pro-sexual, while serotonin has anti-sexual properties and is considered to be a “sexual satiety” agent.5 Because they are CNS agents, caution must be used in prescribing them to women already taking CNS medications for psychiatric or neurologic conditions.
It is fairly universally agreed upon that interventions for low libido start with a full medical and psychosexual evaluation. The first line of treatment is office-based counseling, as well as addressing modifiable factors such as untreated health conditions, medications, or relationship issues.3 When this approach does not prove helpful, both physicians and patients alike start to wonder, “Is there a pill for this?” In 2020, it turns out, there are two — and perhaps three. Although two novel CNS agents have captured the elusive FDA approval for HSDD, one longtime antidepressant with wide use has led to three possible options for patients with HSDD: flibanserin, bremelanotide, and bupropion. (See Table 1, available at: http://bit.ly/2QTatO9.)
In 2015, flibanserin was approved by the FDA for HSDD in premenopausal women with generalized, acquired HSDD. It came with both controversy (since it failed twice to be approved) and some trepidation, as it initially required a risk evaluation and mitigation strategies (REMS) certification and a black box warning limiting all alcohol consumption during the duration of the daily treatment because of concerns about hypotension and syncope. Recent updates have refined the limitation for alcohol and removed the REMS. Specifically, as of 2019, the boxed warning, contraindication, warnings and precautions, and adverse reactions sections of labeling are updated to reflect that women should discontinue drinking alcohol at least two hours before taking flibanserin at bedtime or skip the flibanserin dose that evening.6
Flibanserin is a CNS agent acting as a serotonin receptor agonist and antagonist that results in a transient decrease in serotonin with a downstream increase in dopamine and norepinephrine in certain regions of the brain. Initially, it was studied as a potential antidepressant, and although it was ineffective for depression, it appeared to increase sex drive.
A 2016 systematic review of flibanserin in pre- and post-menopausal women in the Journal of the American Medical Association found five published and three unpublished studies that included 5,914 women. Overall, the quality of evidence for efficacy was rated as “very low.” The mean differences in sexually satisfying events (SSE) involved a 0.49-point increase in SSE per month with flibanserin vs. placebo and a 0.27-point increase in Female Sexual Function Index desire domain (FSFI-D). Women’s mean global impression of improvement scores indicated minimal improvement to no change.7 Although serious adverse effects were rare, adverse events in pre- and post-menopausal women included dizziness, nausea, fatigue, and somnolence in 29.9% to 36.5% for flibanserin vs. 12.7% to 15.8% for placebo.7
Bremelanotide, a melanocortin receptor agonist, was approved by the FDA in June 2019, also for treatment of generalized, acquired HSDD in premenopausal women.8 The medication is administered as a subcutaneous injection (1.75 mg) at least 45 minutes before anticipated sexual activity. Bremelanotide works as a pre-melanocortin, accidentally discovered by experimenting with self-tanning agents. Its mechanism of action is considered to be a downstream increase in dopamine in the CNS system.
Two randomized, phase III trials involving a total of 1,247 premenopausal women with HSDD found that 24 weeks of bremelanotide compared with placebo resulted in more women with a meaningful increase in sexual desire using the FSFI-D (51% vs. 21%, P < 0.001) and improvement in sexual satisfaction using the Female Sexual Distress Scale desire/arousal/orgasm domain (FSDS-DAO) (57% vs. 26 %, P < 0.001). Women in the bremelanotide group showed an increase in FSFI-D scores of 0.35 points (P < 0.001) over placebo. Changes in the primary endpoint were observed at four weeks, which was the earliest evaluated time point. There was no statistically significant improvement in SSEs between treatment groups (bremelanotide 0.0 vs. placebo -0.1, P = 0.630) from baseline to the end of the study. The most common treatment-emergent adverse events, occurring in more than 10% of patients compared with placebo, are nausea, flushing, and headache.9 Eighty-seven percent of participants rated administering the medication as “easy.”10
Subsequently, a 52-week open label extension looked at the safety and efficacy of bremelanotide. The study concluded that no new safety signals were observed, and premenopausal women exhibited sustained improvements in HSDD with a higher reduction in distress over time (FSDS-DAO -1.7 and -1.4) from baseline to the end of open label testing, suggesting improvements in distress may lag behind improvements in desire.11
Bupropion is an antidepressant, known for a low sexual side effect profile, that has been widely used for depression and selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction since its market release in 2006. Because it is widely used and has been on the market the longest, it has significantly more safety profile data and costs significantly less. Therefore, it is worth considering as an off-label CNS agent to treat HSDD. It is one of the few antidepressants that increases dopamine as well as norepinephrine. For HSDD, there is a single, randomized, placebo-controlled trial of four months duration in nondepressed women with HSDD. There were 75 premenopausal participants, with an average age of 36.1 years.
Statistically significant self-reported improvements in pleasure, arousal, and orgasm, according to the Changes in Sexual Functioning Questionnaire (CSFQ), occurred in the bupropion group.12 Secondarily, blinded raters measured several sexual health variables, and although they showed improved “sexual responsiveness” in all rater-measured variables, many of them were not statistically significant. The effect was seen starting at 28 days of treatment.12
We now have two FDA-approved medications, and one off-label antidepressant, that can be considered in treating the most common sexual complaint in women — low libido. On one hand, this is groundbreaking, as we are beginning to see more research on how CNS agents may indeed be key in addressing sex-specific sexual dysfunction. However, each agent did not consistently show more than a modest improvement (if any) in the measurements used to assess sexual desire in their respective studies. Flibanserin, for instance, may increase SSEs by half an event a month, while no increase in SSEs was seen with bremelanotide. (SSEs were not studied with bupropion.)
Regarding the improvement in FSFI-D score, this was a statistically significant improvement in both the flibanserin and bremelanotide trials (0.27 points vs. 0.35 points). However, in the bremelanotide studies, this change in score did not transfer to significantly increase the women’s global impression of improvement of their sexual function. While these medications may be options for some patients after behavioral approaches fail, it is unlikely that our current available medications for HSDD will change significantly the current landscape in our approach to the treatment of low libido. However, the press coverage (both positive and negative) that these medications have received may bring the often-overlooked conversation on female sexual function back to the doctor’s office to be addressed in a comprehensive way.
REFERENCES
- Shifren JL, Monz BU, Russo PA, et al. Sexual problems and distress in United States women: Prevalence and correlates. Obstet Gynecol 2008;112:970-978.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 2008, Washington, DC.
- Goldstein I, Kim NN, Clayton AH, et al. Hypoactive sexual desire disorder: International Society for the Study of Women's Sexual Health (ISSWSH) expert consensus panel review. Mayo Clin Proc 2017;92:114-128.
- FDA. Reproductive Health Drugs Advisory Committee Meeting Announcement. June 18, 2010. Available at: https://wayback.archive-it.org/7993/20170404150118/https://www.fda.gov/AdvisoryCommittees/Calendar/ucm210886.htm. Accessed Dec. 17, 2019.
- Clayton AH. Epidemiology and neurobiology of female sexual dysfunction. J Sex Med 2007;4 Suppl 4:260-268.
- FDA. FDA orders important safety labeling changes for Addyi. April 11, 2019. Available at: https://www.fda.gov/news-events/press-announcements/fda-orders-important-safety-labeling-changes-addyi. Accessed Dec. 17, 2019.
- Jaspers L, Feys F, Bramer WM, et al. Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: A systematic review and meta-analysis. JAMA Intern Med 2016;176:453-462.
- FDA. FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women. June 21, 2019. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women. Accessed Dec. 17, 2019.
- Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the treatment of hypoactive sexual desired disorder: Two randomized phase 3 trials. Obstet Gynecol 2019;134:899-908.
- Koochaki P, Revicki D, Wilson H, et al. 146 conversations with participants in the RECONNECT studies about their experiences with bremelanotide for treatment of hypoactive sexual desire disorder. J Sex Med 2019;16:S75.
- Simon JA, Kingsberg SA, Portman D, et al. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder. Obstet Gynecol 2019;134:909-917.
- Segraves RT, Clayton A, Croft H, et al. Bupropion sustained release for the treatment of hypoactive sexual desire disorder in premenopausal women. J Clin Psychopharmacol 2004;24:339-342.
- GoodRX. Comparison of Drug Prices. 2019. Available at: https://www.goodrx.com/. Accessed Jan. 8, 2020.
Low libido is the most common sexual complaint, affecting up to 38.7% of women, with up to 12.3% also reporting significant distress associated with this condition. In the past five years, for the first time in history, there are two Food and Drug Administration-approved medications specifically for treating hypoactive sexual desire disorder in women. Of note, both medications are central nervous system agents.
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