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Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression.
To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors.
In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks.
Safety assessment included adverse events and symptoms of depression and anxiety.
73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology–Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients receiving placebo; remission of anxiety based on the Beck Anxiety Inventory was noted in 16.4% and 2.7% of patients, respectively.
The results of this study support the safety of flibanserin in premenopausal women being treated with a serotonergic antidepressant. No increased risks were observed when adding flibanserin to a stable selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor treatment regimen.
Strengths and Limitations
This was a well-designed, randomized, placebo-controlled trial. The primary limitation was the early study discontinuation by the sponsor, which decreased the sample size and duration of treatment.
In this small trial, flibanserin 100 mg qhs was generally safe and well tolerated in premenopausal women with mild or remitted depression taking a serotonergic antidepressant.
Clayton AH, Croft HA, Yuan J, et al. Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study. J Sex Med 2018;15:43–51.
As defined by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), HSDD is a persistent or recurrent deficiency (or absence) of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty and is neither better accounted for by another psychiatric condition nor due exclusively to the direct physiologic effects of a substance, medication, or general medical condition.
Flibanserin is a postsynaptic 5-hydroxytryptamine (5-HT)1A agonist and 5-HT2A antagonist that decreases serotonin activity and enhances dopamine and norepinephrine activity in certain regions of the cerebral cortex.
In this meta-analysis, study participants with sexual dysfunction had a 130% to 210% increased risk of developing depression, and those with depression had a 50% to 70% increased risk of developing sexual dysfunction. Because pharmacologic treatment for HSDD can be considered in women who are already receiving treatment for depression, and information on concomitant use of depression treatments was not available from previous studies of flibanserin (major depressive disorder and antidepressant medication use were exclusion criteria),
the FDA required a study to evaluate the safety of concomitant use of flibanserin with antidepressant medications.
This placebo-controlled study evaluated the safety of flibanserin in women with symptoms of HSDD (ie, decreased sexual desire and related distress) who were being treated for depression with a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).
Potential study participants were identified from new or existing patients who were receiving treatment for depression at investigative sites, referred by other physicians, or recruited through advertising. Eligible patients were women 18 to 50 years of age who were not postmenopausal (ie, did not meet the criterion of 12 consecutive months of amenorrhea) and had been taking the same SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline) or SNRI (duloxetine, desvenlafaxine, or venlafaxine) for at least 3 months (with a stable dose for ≥2 months). All patients had mild or remitted depressive disorder (with or without concurrent mild anxiety disorder or premenstrual dysphoric disorder) for at least 12 weeks based on medical records or other documentation and supported by scores lower than 11 on the 16-item Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR16)
and supported by scores of at least 15 on the Female Sexual Distress Scale–Revised (FSDS-R) and no higher than 9 on the Changes in Sexual Functioning Questionnaire–14-item self-report (CSFQ-14) desire/interest items. Investigators were required to determine, by history taken at screening, whether HSDD symptoms predated the depressive disorder and/or SSRI or SNRI use; however, a diagnosis of HSDD made before the onset of depressive symptoms was not required for participation in this safety study. All patients were required to be in a stable, communicative, monogamous, heterosexual relationship of at least 1 year’s duration with a sexually functional partner who was expected to be physically present for at least 50% of every month during the study.
Exclusion criteria included other sexual dysfunction (eg, lifelong history of decreased sexual desire, arousal disorder, or orgasm disorder; sexual aversion disorder; substance-induced sexual dysfunction other than SSRI- or SNRI-induced sexual dysfunction; and sexual dysfunction from a general medical condition other than depression); current suicidal ideation or history of suicidal behavior; history of drug abuse or dependence (including alcohol) in the past 12 months; and history of another psychiatric disorder that could affect sexual function. Women were excluded if they had pelvic inflammatory disease, urinary tract or vaginal infection or vaginitis, cervicitis, interstitial cystitis, vulvodynia, or significant vaginal atrophy; were currently pregnant or had a pregnancy within the past 6 months; had a history of cancer within the past 5 years; or had electrocardiographic or blood abnormalities. The use of certain medications within the previous 4 weeks was prohibited, including sex hormones (except for hormonal contraceptives), anticoagulants, central nervous system stimulants, dopamine agonists, antidepressants (other than SSRIs or SNRIs), antipsychotics, benzodiazepines, prescription hypnotics, mood stabilizers, antiepileptics, triptans, St John’s wort, metoclopramide, or narcotics (except for short-term use in acute situations).
This multicenter, randomized, double-blinded, placebo-controlled, 12-week, phase 3 safety study (ClinicalTrials.gov, NCT01040208) was conducted from January 2010 through January 2011 at 40 sites in the United States. Eligible patients were stratified by antidepressant medication (SSRI or SNRI) and randomly assigned centrally through an interactive voice response system in a 1:1:1 ratio to receive flibanserin 50 mg once daily at bedtime (qhs) for 2 weeks and then up-titration to flibanserin 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo. Each patient’s SSRI or SNRI dose was to remain stable for the duration of the study. Study medication was provided in blister cards of identically matched flibanserin 50 mg or placebo tablets. Medication cards were labeled with individual patient numbers by study staff so that investigators and patients were blinded to treatment allocation. The study was carried out in compliance with the principles of the Declaration of Helsinki (1996 version) in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines. The study was approved by an institutional review board at each investigational site, and all participants provided written informed consent before initiation of study procedures.
Main outcome measures
The primary study end point was the incidence of adverse events (AEs). Patients were asked to report spontaneously any AEs at each clinic visit, which occurred at baseline, after 2, 4, 8, and 12 weeks of treatment, and 1 week after treatment discontinuation. AEs were defined as on treatment (occurred from the day of randomization through 1 day after the final dose of the study medication) or after treatment (occurred 2 to 7 days after the final dose of the study medication). Other safety outcomes assessed at each clinic visit included signs or symptoms of depression (QIDS-SR16
), and vital signs. Clinical laboratory tests were conducted and 12-lead electrocardiograms were obtained at screening and the final study visit.
This safety study included no primary or secondary efficacy end points. Exploratory efficacy outcome measures included scales commonly used in studies of sexual dysfunction: Female Sexual Function Index (FSFI), FSDS-R, CSFQ-14, Patient Global Impression–Improvement, and Clinical Global Impression–Improvement.
The FSFI is a self-report questionnaire that consists of 19 items across 6 domains of sexual functioning: desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSDS-R is a self-report questionnaire that consists of 13 items designed to assess sex-related personal distress; item 13 assesses how frequently the respondent is bothered by low sexual desire.
The CSFQ-14 is a sex-specific, self-report questionnaire that consists of 14 items designed to measure change in sexual functioning across 5 domains: desire/frequency, desire/interest, pleasure, arousal/excitement, and orgasm/completion.
Compliance with study medication (flibanserin or placebo) was evaluated at each study visit, based on tablet counts of unused medication. Patients were considered compliant if the number of doses taken was within 80% to 120% of their prescribed dose.
The planned sample size was 200 patients randomly assigned across treatment groups. No formal sample size determination was conducted, because this study was designed as a safety study. The safety population consisted of patients who received at least 1 dose of the study medication. Statistical analyses were conducted using SAS software (SAS Institute, Cary, NC, USA). Safety outcomes were tabulated for the flibanserin and placebo groups using descriptive statistics.
The study sponsor (Boehringer Ingelheim, Ingelheim, Germany) terminated the study early for administrative reasons (discontinuation of the clinical development of the product), resulting in 111 randomized patients: 73 patients who were treated with flibanserin (45 patients in the up-titration group and 28 patients who received 100 mg qhs from the day of randomization) and 38 patients who received placebo (1 patient did not have any post-baseline efficacy assessments, so 37 patients were included in the exploratory efficacy population). Because of the smaller-than-planned sample, the flibanserin dose groups were combined (Figure 1). Overall, 26.0% of patients who received flibanserin and 7.9% of patients who received placebo discontinued the study; discontinuation because of AEs was the reason for 2.7% of patients in the flibanserin group (constipation and fibrocystic breast disease, 1 patient each) and 5.3% of patients in the placebo group (headache and weight gain, 1 patient each).
Demographic and baseline clinical characteristics were similar in the flibanserin and placebo groups (Table 1). Average age was 37.5 years and the vast majority of patients (90.1%) were white. Alcohol use of 1 to 3 drinks per day was reported by 16.4% and 18.4% of patients in the flibanserin and placebo groups, respectively. SSRIs were used by 83.6% and 81.6% of patients in the flibanserin and placebo groups, respectively, and SNRIs were used by 16.4% and 18.4% of patients, respectively (Table 2).
Total number for individual medications exceeds that for the medication class because 2 patients received more than 1 SSRI (1 patient in the flibanserin group [citalopram, fluoxetine], 1 patient in the placebo group [citalopram, escitalopram]).
∗ Total number for individual medications exceeds that for the medication class because 2 patients received more than 1 SSRI (1 patient in the flibanserin group [citalopram, fluoxetine], 1 patient in the placebo group [citalopram, escitalopram]).
Mean duration of exposure to study medication was 72.9 days (10 weeks) in the flibanserin group and 82.4 days (almost 12 weeks) in the placebo group. Exposure duration was at least 8 weeks (56 days) for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. Compliance with study medication was 98.6% and 95.0% of patients taking flibanserin and placebo, respectively.
AEs were reported by 65.8% and 71.1% of patients in the flibanserin and placebo groups, respectively (Table 3). The most common AEs (incidence ≥ 2% in the flibanserin group) occurring in a larger proportion of flibanserin-treated patients compared with patients in the placebo group, respectively, were dry mouth (5.5% vs 2.6%), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), dizziness (4.1% vs 0.0%), constipation (2.7 vs 0.0%), hot flushes (2.7% vs 2.6%), hyperhidrosis (2.7% vs 2.6%), and sinus congestion (2.7% vs 0.0%). AEs (incidence ≥ 2% in the flibanserin group) more common with placebo than with flibanserin, respectively, were headache (18.4% vs 5.5%), nasopharyngitis (10.5% vs 2.7%), anxiety (5.3% vs 2.7%), fatigue (5.3% vs 4.1%), increased appetite (5.3% vs 2.7%), sedation (5.3% vs 4.1%), diarrhea (5.3% vs 2.7%), and sinusitis (5.3% vs 2.7%).
Table 3AEs occurring during double-blinded treatment in at least 2% of flibanserin-treated patients
In the 2 treatment groups, most AEs were mild or moderate in intensity. Severe AEs were reported by 2.7% of patients in the flibanserin group (lower abdominal pain and soft tissue injury in 1 patient each) and 2.6% of patients in the placebo group (headache and vomiting in 1 patient). AEs were considered by the investigator to be drug related in 39.7% and 36.8% of patients in the flibanserin and placebo groups, respectively. AEs leading to study discontinuation included constipation (n = 1) and fibrocystic breast disease (n = 1) in the flibanserin group (n = 73) and headache (n = 1) and weight gain (n = 1) in the placebo group (n = 38). AEs occurring during the 7-day post-treatment period were dysphagia (n = 1) in the flibanserin group and insomnia (n = 1) and ovarian cyst (n = 1) in the placebo group. The incidence of expected AEs (based on previous studies of flibanserin) was generally low in this study: dizziness (4.1% with flibanserin vs 0.0% with placebo, respectively), fatigue (4.1% vs 5.3%), nausea (0.0% vs 5.3%), somnolence (1.4% vs 7.9%), and insomnia (5.5% vs 2.6%). No deaths or serious AEs were reported during the study.
Most patients (68.5% and 73.7% in the flibanserin and placebo groups, respectively) entered the study in remission from depression, and 31.5% of patients who were randomly assigned to receive flibanserin and 26.3% of patients who were randomly assigned to receive placebo experienced mild symptoms. At study baseline, symptoms of anxiety were minimal (80.8% and 86.8% of patients in the flibanserin and placebo groups, respectively) or mild (19.2% and 13.2%, respectively). Changes in depression and anxiety symptoms were evaluated as part of the safety assessment. Categorical shifts in symptom severity are presented for depression (Table 4) and anxiety (Table 5). Worsening of depression symptoms was noted in 6.9% of patients in the flibanserin group and 21.6% of patients in the placebo group; worsening of anxiety symptoms occurred in 1.4% and 2.7% of patients, respectively. Remission of depression at study end point, as measured by the QIDS-SR16, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients receiving placebo; remission of anxiety based on the Beck Anxiety Inventory was noted in 16.4% and 2.7% of patients, respectively. Notably, in patients with mild depression at baseline, remission was achieved in 63.6% of flibanserin-treated patients compared with 44.4% of patients in the placebo group. In patients with remitted depression at baseline, symptom worsening was noted in 6.0% and 25.0% of flibanserin- and placebo-treated patients, respectively. No instances of suicidal ideation or behavior were reported spontaneously or elicited on the C-SSRS during the study.
Table 4Categorical shift from baseline to week 12 (LOCF) in QIDS-SR16 scores
No clinically important findings were observed in electrocardiographic parameters, and no notable changes were detected in heart rate or systolic blood pressure. 1 patient on citalopram in the flibanserin group, who was taking amlodipine for hypertension and had a history of obesity and anxiety, experienced a clinically relevant increase in diastolic blood pressure (from 92 mm Hg at baseline to 110 mm Hg at week 4). Hypertension was reported as an AE in 1 patient in the placebo group. No clinically relevant decreases in blood pressure were observed, and no episodes of hypotension or syncope occurred as an AE in either treatment group.
Clinically significant changes in laboratory parameters noted in flibanserin-treated and placebo-treated patients, respectively, were 3.6% vs 5.9% for increased total cholesterol (>240 mg/dL), 3.8% vs 2.9% for increased prolactin (>30 ng/mL), and 3.7% vs 3.0% for low absolute neutrophil count (<2 × 109/L). Weight gain of at least 7% was experienced by 0.0% of patients in the flibanserin group and 2.6% of patients in the placebo group; weight loss of at least 7% was experienced by 4.1% and 7.9% of patients, respectively.
No significant differences between the flibanserin and placebo groups were found regarding exploratory efficacy outcome measures. Numerically, mean change from baseline in standard measures of female sexual dysfunction (FSFI total score and FSDS-R total score) favored flibanserin over placebo. However, mean change scores on other measures of efficacy were comparable or favored the placebo group.
In this randomized, placebo-controlled, safety study, the AE profile in flibanserin-treated patients was generally similar to that in the placebo group. Of the common AEs (ie, dizziness, fatigue, nausea, somnolence, and insomnia) reported in the pivotal phase 3 trials of flibanserin in the treatment of women with HSDD,
dizziness, fatigue, nausea, and somnolence were less frequent during treatment with flibanserin in this population of women with HSDD symptoms and remitted or mild depression. In addition, no withdrawal effects were indicated after the abrupt discontinuation of flibanserin in this study. Also, symptoms of depression or anxiety did not appear to worsen in the flibanserin group compared with those experienced by the placebo group. In fact, a larger proportion of flibanserin-treated patients experienced remission of depression symptoms than women taking placebo. No serious AEs, no instances of suicidality, and no deaths were reported during this study.
Flibanserin was originally investigated as an antidepressant but did not demonstrate significantly better efficacy than placebo in phase 2 studies.
Changes in symptoms of depression and anxiety were assessed in the present study to evaluate the safety of flibanserin (ie, possible symptom recurrence in patients with mild or remitted depression). The observed improvements in mood in women who received flibanserin compared with placebo in this study could be related to activity at 5-HT1A and 5-HT2A receptors. Buspirone, a presynaptic full agonist and a postsynaptic partial agonist of 5-HT1A receptors approved for the management of anxiety disorders, was found in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to augment the antidepressant effects of citalopram (an SSRI).
Trazodone, a serotonin 5-HT2A and 5-HT2C receptor antagonist and 5-HT transporter inhibitor, is an approved antidepressant with known anxiolytic effects and is often used in combination with SSRIs or SNRIs to improve sleep in patients with depression.
The relatively small number of patients who reported alcohol use at study baseline precluded a subgroup analysis that compared alcohol users with non-users. Based on the available data, there was no increased incidence of safety issues associated with alcohol use in the flibanserin group compared with the placebo group. Specifically, no clinically relevant decreases in blood pressure and no AEs of hypotension or syncope were observed in either group. Also, although the incidence of dizziness was greater in flibanserin-treated patients compared with patients receiving placebo, rates of fatigue, sedation, and somnolence were lower with flibanserin compared with placebo.
In this study, there was no evidence of serotonin syndrome, as indicated by autonomic or behavioral symptoms. Flibanserin differs considerably from SSRIs and SNRIs in serotonergic effects. Flibanserin targets cortical 5-HT1A and 5-HT2A receptors,
Agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors, as demonstrated by flibanserin, serve to inhibit glutamate release that in turn decreases 5-HT activity in the prefrontal cortex.
The present safety study was conducted as 1 aspect of the extensive clinical development program for flibanserin in HSDD. In the exploratory efficacy analysis in this study, improvement on standard measures of female sexual dysfunction was not statistically different for flibanserin compared with placebo. The small sample and relatively brief duration of treatment (12 weeks) in this study precluded our ability to draw conclusions on the efficacy of flibanserin for women with HSDD and depression.
The present study included women who had depression that was reasonably well controlled with SSRI or SNRI treatment, and there was no evidence of suicidal ideation or behavior. No data are available for women with depression and HSDD who were only treated with flibanserin. Thus, depressive symptoms should be adequately treated before considering flibanserin.
In women with depression and low sexual desire, HSDD can be difficult to distinguish from sexual dysfunction associated with depression or from antidepressant-related sexual dysfunction.
However, depression and/or SSRI or SNRI treatment were identified as contributing factors to the observed sexual dysfunction in most patients.
This study had several limitations. The percentage of patients with a diagnosis of HSDD was relatively small. Early termination of the study by the sponsor restricted the sample size. The small sample and relatively brief duration of treatment could have limited the detection of infrequently occurring AEs. Because this study included only women with remitted or mild depression who were not postmenopausal, the generalizability of these findings is limited. Also, efficacy measures were exploratory in this study, which was designed to assess the safety of flibanserin in women taking an SSRI or an SNRI for the treatment of depression. Therefore, no firm conclusions can be drawn regarding the efficacy of flibanserin in this population.
In this small placebo-controlled trial, flibanserin 100 mg qhs was generally safe and well tolerated in premenopausal women with mild or remitted depression who were taking a serotonergic antidepressant. No increased risks were observed when adding flibanserin to a stable SSRI or SNRI treatment regimen.
Statement of authorship
Conception and Design
Anita H. Clayton; Harry A. Croft; James Yuan; Louise Brown
Acquisition of Data
Anita H. Clayton; Harry A. Croft
Analysis and Interpretation of Data
Anita H. Clayton; Harry A. Croft; James Yuan; Louise Brown; Robert Kissling
Drafting the Article
Anita H. Clayton; Harry A. Croft; James Yuan; Louise Brown; Robert Kissling
Revising It for Intellectual Content
Anita H. Clayton; Harry A. Croft; James Yuan; Louise Brown; Robert Kissling
Final Approval of the Completed Article
Anita H. Clayton; Harry A. Croft; James Yuan; Louise Brown; Robert Kissling
Technical editorial and medical writing assistance was provided under the direction of the authors by Nancy Holland, PhD, Synchrony Medical Communications, LLC (West Chester, PA, USA). Funding for this support was provided by Valeant Pharmaceuticals North America LLC.
Hypoactive sexual desire disorder: a review of epidemiology, biopsychology, diagnosis, and treatment.
Conflicts of Interest: Dr Clayton reports receiving research and grant support from Auspex Pharmaceuticals, Axsome Therapeutics, Forest Research Institute, Inc, Genomind, Inc, Janssen Pharmaceuticals, Inc, Palatin Technologies, Pfizer, Inc, SAGE Therapeutics, and Takeda; serving as a consultant to Fabre-Kramer Pharmaceuticals, Inc, Palatin Technologies, S1 Biopharma, Sprout, a division of Valeant Pharmaceuticals North America LLC, and Takeda Global Research and Development; being a stock shareholder of Euthymics and S1 Biopharma; and having royalties from and copyrights at Ballantine Books/Random House, the Changes in Sexual Functioning Questionnaire, and Guilford Publications. Dr Croft reports receiving research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Company, Cephalon, Inc, Clinical Data, Elan, Eli Lilly and Company, Forest, GlaxoSmithKline, Labopharm, Lundbeck, Merck & Co, Inc, Otsuka, Pfizer Inc, Sarnoff, Sepracor Inc, Shire, Takeda, and Trimel; serving as a consultant to Boehringer Ingelheim, Clinical Data, Forest, and GlaxoSmithKline; serving on the speakers’ bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Forest, Pfizer Inc, and Takeda; and testifying at the 2015 FDA Advisory Committee meeting regarding flibanserin. Dr Yuan and Dr Kissling are employees of Valeant Pharmaceuticals North America LLC. Ms Brown was an employee of Valeant Pharmaceuticals North America LLC at the time the analyses were conducted.
Funding: This study was supported by Boehringer Ingelheim. Boehringer Ingelheim was involved in study design, data collection, and data analysis. Boehringer Ingelheim had no involvement in interpretation of data, writing of the report, or the decision to submit the report for publication. Funding for technical editorial and medical writing assistance was provided by Valeant Pharmaceuticals North America LLC. Valeant Pharmaceuticals North America LLC was involved in the interpretation of data and writing of the report.