Table of Contents
Flibanserin
After previous denial, in 2015, the American Food and Drug Administration (FDA) approved flibanserin (brand name Addyi) for the treatment of low sexual desire in premenopausal women. Flibanserin has mixed effects on the serotonergic and dopaminergic neurotransmitter systems and was initially developed as an anti-depressant, and later tested for pro-sexual effects. In a number of large trials in women with a diagnosis of hypoactive sexual desire disorder, it was shown that the use of flibanserin (compared to placebo) resulted in a significantly larger increase in the number of monthly so-called “satisfying sexual events” (SSEs) [21, 22, 23].
Although statistically significant, the effects of flibanserin were small; across the phase 3 studies, an increase relative to placebo of 1 to 1.5 SSEs a month was observed [24••]. Also, it is a drug that has to be used daily, with side effects such as dizziness, somnolence, nausea, and fatigue and it should not be used in combination with alcohol.
The effects of long-term use are yet unknown. Based on the limited pro-sexual effect, the side effects, and the lack of data on safety with long-term use, there has been a vehement discussion about the approval of the drug [25].
Testosterone plus Sildenafil (Lybrido) and Testosterone plus Buspiron (Lybridos)
Inspired by the dual control model of sexual response [26], Tuiten and colleagues reasoned that low sexual desire in women may be due to either a relative insensitive brain system for sexual cues, or to enhanced activity of sexual inhibitory mechanisms [27•]. This distinction was taken into account in the design of pharmacotherapies for low sexual desire in women. A combination of testosterone (T, 0.5 mg sublingual) plus a phosphodiesterase type 5 inhibitor (sildenafil, 50 mg) was developed for women with low sensitivity to sexual cues [28].
In addition, a combination of T with a serotonin1A receptor agonist (buspiron, 10 mg), intended to decrease sexual inhibition, was developed for women more inclined to sexual inhibition [29]. Both drugs are meant to be used on demand, 4 h before the wanted effects an advantage because it addresses the potential safety concerns of prolonged use of androgens in women.
In the first test of the drugs, 56 pre- and postmenopausal women with hypoactive sexual desire disorder (HSDD, based on DSM-IV-TR) participated in a complex, randomized, doubleblind, placebo-controlled cross-over design [30]. All women underwent three medication regimes: placebo, T + sildenafil, and T + buspiron, each for 4 weeks and completed an emotional Stroop task to measure preconscious attentional bias for sexual cues.
During this task, sexual or neutral words were presented in color, very briefly (only 26 ms), and were immediately followed by randomly cut and reassembled letters in the same color (the masking stimuli).
The initial results with these drugs seem promising. However, the study groups were small, and—although crucial—the validity and reliability of making accurate distinctions between women with high and low sexual sensitivity or between those with high and low sexual inhibition have not been established.
At the company’s website, it is stated that an innovative classification system based on genetic markers has been developed and that a phase III study is being prepared. However, to date, no further publications on this classification system or on further drug trials have appeared.
Bremelanotide
In the reported analyses, the data of the two groups receiving the highest doses were pooled and compared with placebo. Apparently, the lowest dose of BMT showed no effect at all. The mean change in SSEs was 0.7 in the BMT group, which was significantly higher than 0.2 in the placebo group. Also, sexual function and sexual distress scores showed stronger improvement in the BMT group compared to placebo. The most common reported side effects were nausea, flushing, and headache.
Nausea was reported in 22% of BMT users, compared to 3% in placebo users, but very few BMT users ended participation in the study because of this side effect. Also, 24% of the BMT group reported injection-site reactions, such as irritation, rash, or swelling. No serious BMT-related side effects were reported. Physical examinations showed a small increase in blood pressure and a decrease in heart rate 4 h post BMT dose.
Taken together, the results indicate an increase relative to placebo of 0.5 satisfying sexual event a month. The authors describe this finding as a clinically significant improvement; however, the effect is even smaller than the reported effect of flibanserin.
Testosterone Intranasal Gel
A new drug under investigation is TBS-2, a testosterone intranasal gel [33]. Effects of the gel on genital and subjective sexual arousal in response to an erotic film were tested in women with HSDD or anorgasmia. Effects of the gel were compared with the Intrinsa (testosterone) patch in the HSDD group and with placebo in the anorgasmia group.
In women with HSDD, significantly stronger feelings of sexual arousal, sensuality, and positive affect were observed in those receiving TBS-2 compared to the Intrinsa patch. In women with anorgasmia, a significantly stronger genital response (measured with vaginal photoplethysmography) compared to placebo was observed 30 min after administration in the TBS-2 high-dose group and 4.5 h after administration in the TBS-2 low-dose group. No safety concerns were reported and plasma testosterone levels did not exceed the upper limit of normal levels. In a subsequent study, the effect of the gel was tested in women with anorgasmia [34].
Effects on genital and subjective sexual response and occurrence of orgasm during clitoral vibrotactile stimulation in combination with an erotic film were tested. Relative to placebo participants, TBS-2-treated participants reported significantly stronger feelings of sexual arousal and showed stronger genital response as measured by vaginal photoplethysmography.
Four women in the TBS-2 group and 2 in the placebo group experienced orgasm; this difference was, however, not significant. Whether TBS-2 will undergo further study is not reported.
BP101
Another new drug under investigation is BP101, a synthetic peptide molecule. The structure has not been disclosed for commercial reasons. The effect of the drug on sexual behavior was tested in three experiments in female rats [35], one experiment on the acute effects of a single intranasal administration, one on the effects of long-term (16 days) daily intranasal administration, and one on the effects of administration directly into the brain, more specifically into the olfactory bulb, the ventral medial hypothalamus, the MPOA, or the ventral tegmental area.
Effects on solicitation, lordosis, and social approach behaviors, as well as genital sniffing, were studied. In experiments 1 and 2, an effect of BP101 was observed for solicitation behavior only. In experiment 3, it was observed that administration of BP101 in the MPOA and not in other brain areas increased solicitation behaviors.
BP101 is currently undergoing randomized, double-blinded, placebo-controlled phase II studies. Safety, tolerability, pharmacokinetics, pharmacodynamics, and effects on sexual function will be studied after multiple-dose administration of BP101 nasal spray in healthy volunteers (https://clinicaltrials.gov/ct2/show/NCT03102489) and in women with HSDD (https://clinicaltrials.gov/ct2/show/NCT03080298).
D-cycloserine
A potentially interesting new approach to psychopharmacological treatment of FSIAD may be the use of memory-enhancing medication in combination with cognitive behavioral therapy (CBT). The combination of CBT with d-cycloserine (DCS), a partial agonist of the NMDA receptor which is essential in learning and memory, has already been investigated in the context of anxiety disorders and indicates that DCS can facilitate effectiveness of extinction-based therapy [36].
Besides extinction of fear responses, there is also evidence that DCS can enhance extinction learning of responses to appetitive stimuli, such as drugs [37, 38]. In contrast to the compounds described in the previous sections, which aim is to increase neurobiological sensitivity to sexual cues, the aim of DCS will be to facilitate the basic learning processes underlying CBT interventions in the treatment of sexual dysfunctions.
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