Does Flibanserin Have a Future?

TABLE. Factors that affect female sexual desire to consider in diagnosing HSDD2

Hypoactive sexual desire disorder (HSDD) first appeared in DSM-III-R, and it has been argued that this diagnosis is largely founded on an androcentric view of sexuality with little basis in actual female sexual experience.¹ DSM-III-R criteria included “persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity.” DSM-IV added the requirement of “marked distress or interpersonal difficulty” as a result of this “disturbance” to make a diagnosis. Clinicians were to make the determination of “deficiency or absence” of sexual desire by “taking into account factors that affect sexual functioning, such as age and the context of the person’s life.” In the development of DSM-5, experts argued for changes to language and criteria; HSDD was replaced by female sexual interest/arousal disorder (FSIAD), which also absorbed and replaced female arousal disorder and sexual aversion.

The biggest change resulting from this polythetic approach was the combination of arousal and desire disorders, which recognized the interrelationship between desire and arousal.¹ Changes to the criteria included the addition of a 6-month duration requirement and options for variability in the manifestation of the disorder (ie, 4 indicators out of a possible 6, lifelong or acquired, generalized or situational, level of distress). However, on October 1, 2015, DSM-5 diagnoses were replaced by ICD-10, which includes HSDD but not FSIAD.

CASE VIGNETTE

Sally is a heterosexual woman in her mid-thirties. She has been married for 8 years and has no children. She and her husband, Joe, have sought treatment to “improve communication” and increase the frequency of sex in their marriage. When asked if she thinks about, wants, or looks forward to sex with her husband, she states matter-of-factly that “no sex ever again would be my dream.” Joe is understandably displeased to hear this assertion.

HSDD with distress

Despite the ongoing controversies surrounding the conceptualization of female sexual functioning and desire, research clearly demonstrates that low desire is common and that approximately 26% to 53% of women struggle with this issue.^2,3 However, the prevalence of both low desire and distress is much smaller: approximately 7% to 16%, depending on age and menopausal status.^3,4 The prevalence of low desire increases with age, although distress about low desire does not.¹

CASE VIGNETTE CONT’D

Further assessment of Sally and Joe’s sexual relationship includes discussions of how sex is negotiated between them, how often each of them would prefer to have sex, and whether sex is enjoyable when it occurs. “I could take it or leave it,” she says and reports that she “never” feels a physical urge to engage in sexual behavior.

Sally also expresses frustration about her husband’s complaints of infrequent sexual activity and the arguments that result. She goes on to assert that “he doesn’t talk to me” and that she does not feel emotionally connected to her husband. As a result, she believes that it is “weird for him to expect me to want to have sex when we don’t even talk about how our day was.”

Assessment

In clinical practice, low or absent desire is the most common sexual complaint among women of all ages, although their distress is often associated with a desire to be more emotionally connected to their partners rather than concern about the absence of a physical drive or urge.5 This difference highlights the importance of approaching problematic low desire as a biopsychosocial phenomenon and conducting a thorough mental health and relationship assessment before making a diagnosis and selecting a treatment.^6,7

CASE VIGNETTE CONT’D

Joe says that he finds discussion of emotions to be “pointless” because they “aren’t actionable.” He grew up in a family that rarely displayed emotions openly, and he finds it difficult and uncomfortable to communicate with his wife in that way. He states matter-of-factly that he has “nothing to talk about” and does not understand the relationship between sharing his emotions and having sex with his wife. “She’s always been like this; isn’t there something she can take?”

Treatment of HSDD

Psychotherapy has been used for decades to treat low sexual desire, although few outcome studies have evaluated its efficacy. Sex therapy (eg, sensate focus) has been found to be modestly effective for the treatment of HSDD, and mindfulness-based cognitive-behavioral therapy has been successful in improving sexual desire and arousal in cancer survivors.⁷ Psychotherapy (individual and/or couples) is likely to produce more positive outcomes when HSDD is acquired or situational, as opposed to a lifelong problem. When psychological factors (eg, relationship conflict, poor body image, abuse history, depression, anxiety) are the cause of low desire, psychotherapy should focus on these difficulties prior to or in conjunction with addressing low desire.

CASE VIGNETTE CONT’D

A history of each partner’s sexual experience reveals that this is one of the few sexual relationships Sally has ever had. Attempts to explore her thoughts and feelings about sexual behavior and her views of herself as a sexual being lead to acknowledgments that she has “never felt comfortable” discussing, thinking about, or engaging in sexual behavior. She has never enjoyed sex. She has never masturbated and does not know how to communicate what feels good. Her discomfort is visible. Later, she says that she feels “dirty” and “guilty” when engaging in sexual behavior and connects this to her religious upbringing. She asks, “Isn’t there something I can take?”

Before flibanserin, there were no FDA-approved treatments for HSDD. In the past, low desire was treated with a variety of investigational therapies: bupropion, testosterone, and dehydroepiandrosterone. Bupropion, a norepinephrine and dopamine reuptake inhibitor, has been used off-label on the hypothesis that increasing the concentration of these neurotransmitters promotes libido. Among hormone therapies, testosterone has the strongest evidence base, but it has adverse effects of masculinization. The FDA did not approve its use in women for this purpose based on the lack of efficacy in its final controlled trials and the unknown long-term effects on the breast.⁸

Mechanism of action of flibanserin. Three monoamine neurotransmitters are of particular interest in considering the action of flibanserin: serotonin, norepinephrine, and dopamine. In general, each monoamine is produced by discrete brainstem nuclei, which then project diffusely across the whole cortex. Serotonin activity in the prefrontal cortex has been associated with a reduction of libido, while norepinephrine and dopamine are associated with an increase.⁹ Understanding these circuits is critical to the current understanding of the mechanism of action of flibanserin.

For each of these 3 monoamine neurotransmitters, a circuit exists between the brainstem nuclei and the cortex. For example, neurons using serotonin as their neurotransmitter project onto and excite cortical neurons. These cortical neurons project back to the brainstem and use glutamate as their neurotransmitter, which excites the serotonin brainstem nuclei. The cortical glutamatergic neurons and the brainstem serotonergic neurons are mutually excitatory, forming a positive feedback loop.

Those nuclei containing dopamine and norepinephrine release neurons that project to the prefrontal cortex in a similar fashion, with one key difference. Rather than projecting directly on these brainstem nuclei to excite them, some glutamatergic cortical neurons synapse on an inhibitory inter-neuron first. This inter-neuron serves to flip the signal, turning a mutually excitatory network into an inhibitory one. Thus, glutamatergic cortical input inhibits, rather than promotes, norepinephrine and dopamine release.

Most antidepressants act directly on monoamine transporters and increase the availability of these neurotransmitters¹⁰; flibanserin has more in common with atypical antipsychotics and buspirone than with classic antidepressants. The proposed mechanism of flibanserin differs from that of other antidepressants in that it acts by indirectly modulating the release of neurotransmitters via its actions on cortical glutamate neurons.¹¹

Flibanserin predominantly binds 2 subtypes of serotonin receptor. The serotonin-1A receptor is a postsynaptic receptor on the cortical glutamate neuron, which in theory serves to inhibit its firing.^9,11 The serotonin-2A receptor is its opposite, a postsynaptic receptor on the cortical glutamate neuron that promotes its firing. As an agonist of the former and an antagonist of the latter, flibanserin should reduce the firing of these neurons at both receptors.

In the reciprocally exciting serotonin-glutamate circuit, serotonin brainstem nuclei are no longer stimulated by the glutamatergic cortical neurons, which decreases the libido-dampening effects of serotonin.⁹ In the reciprocally inhibiting circuits between norepinephrine and dopamine brainstem nuclei and cortical neurons, norepinephrine and dopamine output to the cortex is enhanced as the inhibiting GABAergic neuron’s activity decreases. This, in theory, potentiates the libido-enhancing effects of these neurotransmitters.

Use of flibanserin. Flibanserin is rapidly absorbed: half of the compound is absorbed in 25 minutes, and a maximum concentration is achieved in 45 minutes.¹² Steady state is achieved in 3 days, and the drug must be taken daily. It can be taken with or without food, although fatty meals increase its absorption slightly. Flibanserin is metabolized in the liver, mostly by cytochrome P-450 (CYP) 3A4, and its use is contraindicated in those with liver disease. The current recommended flibanserin dosage-and the lowest dosage found to be effective-is 100 mg daily, at night.^13-15

Studies have shown that women who take flibanserin experience one additional “satisfying sexual event” (ie, intercourse, oral sex, masturbation, or genital stimulation by a partner) every 28 days.¹⁶ The studies were conducted in women with acquired HSDD and those with Beck Depression Scores above 14 (ie, minimal symptoms of depression). The efficacy of flibanserin in women with lifelong HSDD or significant mood symptoms remains to be seen. Like all new pharmacotherapies, it has been studied in a highly selective group of women. Because it will likely be prescribed to women who have comorbid diagnoses, the effectiveness of flibanserin may be diminished.

Adverse drug reactions include those typical of centrally acting agents as well as a few unique to this compound. Adverse effects such as headache, fatigue, nausea, and dizziness occur at rates comparable to other psychoactive medications. Respiration rate, blood pressure, and temperature remain unchanged with flibanserin administration, and no electrocardiographic changes are observed. Somnolence is the most serious adverse effect and affects more than 14% of women.¹⁶ The median onset of this symptom is 2 days, and it lasts for a median duration of 35 days.¹⁰ Alcohol increases sedation, and its use is strongly contraindicated for women who take flibanserin.

Hypotension and syncope are not generally observed but occur when this compound is co-administered with a CYP 3A4 inhibitor (eg, fluoxetine, grapefruit juice, certain antibiotics) or when alcohol is consumed. Providers must take great care to educate and remind patients about the dangers of ignoring this potentially catastrophic adverse effect.

Patients are accustomed to hearing warnings about mixing alcohol and prescription drugs; however, many view these guidelines as suggestions rather than requirements. Women who take flibanserin must be willing and able to commit to forgoing alcohol consumption, potentially for years, depending on how long they receive this medication. Ultimately, some women may be unwilling to make this sacrifice in return for one additional positive sexual experience each month.

CASE VIGNETTE CONT’D

Joe admits that he puts little effort into “seducing” his wife. “I just ask her if ‘tonight is the night’ and usually she says no.” Joe also acknowledges that his wife does “pretty much all” of the housework but argues that he does not “see dirt the way she does.” Joe is unable to connect his behavior to his wife’s lack of desire for him.

Selecting the most appropriate intervention. Mental health and medical providers should consider evaluating and discussing every patient’s sexual history, functioning, and related thoughts and feelings. In evaluating for HSDD and the appropriateness of a pharmacological intervention such as flibanserin, a complete and detailed personal and relationship history is necessary to rule out individual, partner, or relationship variables that may contribute to a lack of interest in sex. Developing this level of understanding is best achieved by meeting with both partners individually and as a couple over several sessions. The Table provides a list of potential factors that influence desire and can be a helpful reference for providers. It is, however, incomplete owing to the myriad of circumstances that accompany and may contribute to low desire in women.

The American Psychiatric Association and the American Foundation for Urologic Disease require the presence of both low sexual desire and sexually related personal distress to make the diagnosis of HSDD. Once low desire has been determined, evaluating distress can be a more complex task. It is useful to determine whether a woman experiences personal distress about her lack of sexual desire or whether her partner’s distress (eg, repeated sexual requests, expressions of anger, frequent conflict about lack of sexual activity) about her disinterest in sex is the main cause for concern. This distinction can help clinicians select the most appropriate intervention (ie, individual or couples; medical or psychotherapeutic).

CASE VIGNETTE CONT’D

Sally rolls her eyes as Joe states his desire to have sex “at least twice a week.” However, when he shares feelings of rejection and sadness when rebuffed by his wife, she begins to tear up. “I want to want to have sex with my husband,” she says. “I don’t want to hurt him.”

Although increased media attention and an impressive advertising strategy will likely result in some women contacting their primary care physician for this issue, it is important to remember that many people-men and women alike-have difficulty discussing sexual concerns with others. Kingsberg and Rezaee⁷ offer strategies for encouraging discussion and incorporating office-based counseling (eg, the PLISSIT model). Primary care physicians may also consider the use of self-report assessment tools such as the Female Sexual Function Index to guide differential diagnosis.¹⁷ In addition, consultation with local mental health and medical professionals who have expertise in this area may be helpful.

Conclusion

To date, a safe and effective pharmacotherapy for HSDD has been elusive. As a result, care has been centered on the treatment of psychiatric and medical comorbidities, re-evaluation of medications that may contribute to decreased libido (eg, SSRIs, oral contraceptives), and individual and/or couples psychotherapy. Undoubtedly, the FDA’s approval of a medication specifically for improving female sexual desire is a watershed moment.

Is flibanserin, erroneously referred to in the media as the “pink Viagra,” the answer to a lack of sexual interest? For some women, possibly. But for others, like Sally, psychotherapy will probably be necessary to help address personal and relationship issues that affect her lifelong lack of desire. More important, with the approval of flibanserin will come renewed attention to understanding the complexities of female sexual functioning and to helping women improve their sexual experiences.

This article was originally posted on 12/01/2015 and has since been updated.

Disclosures:

Dr Cooper is a Psychologist at the Center for Marital and Sexual Health in Cleveland, OH. Dr McBride is a Fourth-Year Resident Physician in University Hospitals Case Medical Center’s Adult Psychiatry program in Cleveland. Dr Levine is Director of the Center for Marital and Sexual Health and is Clinical Professor of Psychiatry at Case Western Reserve University School of Medicine in Cleveland. He was a site investigator for one of the phase III flibanserin trials. Dr Cooper and Dr McBride report no conflicts of interest concerning the subject matter of this article.

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