Sildenafil Studied in Women With Antidepressant-Associated Sexual Dysfunction
The objective of our current trial was to use a protocol—similar to our previous RCT11 involving men with sexual dysfunction associated with SRI treatment—to assess the efficacy of sildenafil in the treatment of women, specifically women whose major depressive order is in remission while taking a stable dose of SRI antidepressants and who did not have a preexisting sexual dysfunction but due to the treatment had sexual dysfunction manifest as dysfunction of orgasm (delay) or arousal (lubrication).5 Recognizing the importance of the hormonal variability on nitric oxide signaling in sexual function in women20 and depression on hypothalamic-pituitary–adrenal axis regulation,21 we also examined endocrine measures.
What special precautions should I follow?
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The following were our specific aims: (1) to compare the efficacy of sildenafil with placebo for treatment of sexual dysfunction associated with SRI treatment in women with remitted major depressive disorder; (2) to determine whether sildenafil treatment is associated with change in depression severity; and (3) to compare adverse events occurring with sildenafil and placebo treatment.
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This prospective, parallel group, randomized, double-blind, placebo-controlled, 8-week trial to test the efficacy of a flexible dose of between 50 mg and 100 mg of sildenafil for sexual dysfunction in women was conducted from September 2003 to January 2007, at 7 US outpatient clinic medical centers. Each center's institutional review board approved the protocol. Before enrollment, each woman provided written informed consent to the investigator, who had explained the nature, purpose, and risks of the trial and who provided her with a copy of the information sheets. The study received an investigational new drug approvable letter from the FDA. Women were eligible if they (1) were between 18 and 50 years, (2) were premenopausal, (3) had a diagnosis of major depressive disorder in remission, (4) were taking an antidepressant with a selective or nonselective SRI mechanism for at least 8 weeks (at a stable dose for at least 4 weeks), and (5) were experiencing persistent sexual dysfunction for at least 4 weeks. Other eligibility criteria were good health, some form of regular sexual activity (ie, masturbation, oral sex, intercourse) at least twice monthly before the antidepressant treatment, willingness to continue efforts at sexual activity at least once weekly for the duration of the study, and satisfactory sexual function before onset of depression or antidepressant treatment.
Other Treatments for Low Libido
In addition to an assessment of medical history with detailed sexual history and recording of last menstrual period, all patients received a physical examination including blood pressure, 12-lead electrocardiogram, standard biochemistry and hematological laboratory tests, and pelvic examination with Papanicolaou test (unless documented within the last 12 months). Blood samples for determination of plasma concentrations of free testosterone, thyroid-stimulating hormone, tetraiodothyronine thyroxin, follicle-stimulating hormone, luteinizing hormone, cortisol, progesterone, estradiol, sex hormone–binding globulin, total testosterone, and prolactin were sildenafil 100mg blue pill collected at the first and eighth week before 11 AM on days 1 to 10 of the menstrual period. Using SPSS version 10 (SPSS Inc, Chicago, Illinois), an unrestricted, computer-generated randomization schedule was developed by the study statistician (S.P.) and given to the independent pharmacy. The randomization assigned 49 patients to receive active sildenafil and 49 to receive identical placebo. The only restriction to this randomization was that the groups be of equal size.
Female sexual response: the role of drugs in the management of sexual dysfunction
The largest difference in numbers assigned to the 2 groups at any point in the trial was 4 (excludes completions). At baseline, patients were allocated to the next available number that randomly assigned them to receive sildenafil or matching placebo (50-mg starting dose). Medications were sealed in sequentially numbered identical containers according to allocation sequence, and all study personnel and participants were blinded to treatment assignment for the duration of the study. Patients were instructed to take 1 tablet of trial medication approximately 1 to 2 hours before anticipated sexual activity, not more than once daily over the 8-week trial period and were required to make at least 1 attempt but were asked to try to make at least 2 attempts at sexual activity per week. The dose of study drug could be adjusted from 1 (50 mg) to 2 (100 mg) tablets based on investigator judgment of efficacy and tolerability, including the recording of the findings that resulted in any study drug dosage change and adverse events.
Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernousum smooth muscle
Patients were given diaries with instructions for recording trial medication use and sexual activity. Sildenafil and placebo were provided by Pfizer Inc, New York, New York. Drug accountability, concomitant antidepressant treatment, vital signs, and self-rated and physician-rated symptom reports were assessed at each visit (weeks 2, 4, and 8), which included diary review and return of unused medication. A urine pregnancy test was administered to all women of childbearing potential at each visit. Investigators monitored, collected, and followed up on any spontaneous reports of adverse events, and they assessed and categorized the severity of the events and their relationship to the study drug throughout the trial. In addition, any prior sexual dysfunction must have been limited to previous episodes of depression or antidepressant treatment and must have remitted on clinical improvement and discontinuation of medication.
References (17)
The objective of our current trial was to use a protocol—similar to our previous RCT11 involving men with sexual dysfunction associated with SRI treatment—to assess the efficacy of sildenafil in the treatment of women, specifically women whose major depressive order is in remission while taking a stable dose of SRI antidepressants and who did not have a preexisting sexual dysfunction but due to the treatment had sexual dysfunction manifest as dysfunction of orgasm (delay) or arousal (lubrication).5 Recognizing the importance of the hormonal variability on nitric oxide signaling in sexual function in women20 and depression on hypothalamic-pituitary–adrenal axis regulation,21 we also examined endocrine measures. The following were our specific aims: (1) to compare the efficacy of sildenafil with placebo for treatment of sexual dysfunction associated with SRI treatment in women with remitted major depressive disorder; (2) to determine whether sildenafil treatment is associated with change in depression severity; and (3) to compare adverse events occurring with sildenafil and placebo treatment. This prospective, parallel group, randomized, double-blind, placebo-controlled, 8-week trial to test the efficacy of a flexible dose of between 50 mg and 100 mg of sildenafil for sexual dysfunction in women was conducted from September 2003 to January 2007, at 7 US outpatient clinic medical centers. Each center's institutional review board approved the protocol. Before enrollment, each woman provided written informed consent to the investigator, who had explained the nature, purpose, and risks of the trial and who provided her with a copy of the information sheets.
Study design:
The study received an investigational new drug approvable letter from the FDA. Women were eligible if they (1) were between 18 and 50 years, (2) were premenopausal, (3) had a diagnosis of major depressive disorder in remission, (4) were taking an antidepressant with a selective or nonselective SRI mechanism for at least 8 weeks (at a stable dose for at least 4 weeks), and (5) were experiencing persistent sexual dysfunction for at least 4 weeks. Other eligibility criteria were good health, some form of regular sexual activity (ie, masturbation, oral sex, intercourse) at least twice monthly before the antidepressant treatment, willingness to continue efforts at sexual activity at least once weekly for the duration of the study, and satisfactory sexual function before onset of depression or antidepressant treatment. In addition, any prior sexual dysfunction must have been limited to previous episodes of depression or antidepressant treatment and must have remitted on clinical improvement and discontinuation of medication. Major depressive disorder in remission was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria.22 Women had to score no more than 10 points on the Hamilton Rating Scale for Depression, which consists of 17 items that are clinician rated on a 5-point scale from 0 (absent) to 4 (severe).23 The remission threshold score of 10, rather than 7, was selected to adjust for sexual dysfunction associated with SRI treatment potentially inflating the score.24 In addition, women had to score no more than 10 on the Hamilton Rating Scale for Anxiety, indicating absence of significant symptomatic anxiety.25 Sexual dysfunction associated with SRI antidepressant treatment is defined by DSM-IV criteria for substance-induced sexual dysfunction,22 which includes impaired desire, arousal (lubrication), and orgasm and sexual pain.
A note about sex and gender
Women had to have substantial impaired sexual function defined by at least 1 of the following criteria that caused significant distress: (1) inability to have an orgasm (anorgasmia), according to the woman's opinion; (2) clinically significant orgasm delay with masturbation or intercourse that, according to the woman's opinion, represents a meaningful delay compared with her usual time to achieve orgasm in response to sexual stimulation before antidepressant medication interfered with her sexual function; or (3) inability to attain or maintain until completion of sexual activity an adequate lubrication or swelling response of sexual excitement that, according to the woman's opinion, interferes with her sexual function (compared with before taking antidepressant medication). Women were excluded for any of the following reasons: diagnosis of a sexual disorder other than one associated with SRI treatment or onset of major depressive disorder, genital anatomical deformity, hysterectomy with or without oophorectomy, and at least 6 months of established normal sexual function after the procedure and before onset of depression and antidepressant treatment, uncontrolled psychiatric disorder, diabetes mellitus, cardiovascular disease, alcohol or substance abuse or dependence, stroke, unstable cardiac condition, arrhythmia, or myocardial infarction within the last 6 months, current or anticipated use of nitrate or nitric oxide donor in any form, major relationship changes, proliferative retinopathy, investigational drug use within 3 months, current use of other therapies or medications to treat sexual dysfunction, a sexual partner who has or is receiving treatment for sexual dysfunction, or change in SRI antidepressant agent or prescribed dose during the study. Additional exclusion criteria were use of hormone therapy; pregnancy; lactation; planning to become pregnant during the trial; of child-bearing potential and unwilling, unprepared, or judged unreliable to use an acceptable and verifiable form of contraception during the trial; Papanicolaou test results indicating further assessment; dyspareunia due to anatomical, inflammatory, infection condition, or clinical estrogen deficiency; amenorrhea over 1 year; or situational sexual dysfunction. Women were recruited and enrolled from outpatient settings, newspaper advertisements, postings, and referrals. One hundred forty-five patients were assessed for eligibility at screening (Figure). Major depressive disorder in remission was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria.22 Women had to score no more than 10 points on the Hamilton Rating Scale for Depression, which consists of 17 items that are clinician rated on a 5-point scale from 0 (absent) to 4 (severe).23 The remission threshold score of 10, rather than 7, was selected to adjust for sexual dysfunction associated with SRI treatment potentially inflating the score.24 In addition, women had to score no more than 10 on the Hamilton Rating Scale for Anxiety, indicating absence of significant symptomatic anxiety.25 Sexual dysfunction associated with SRI antidepressant treatment is defined by DSM-IV criteria for substance-induced sexual dysfunction,22 which includes impaired desire, arousal (lubrication), and orgasm and sexual pain. Women had to have substantial impaired sexual function defined by at least 1 of the following criteria that caused significant distress: (1) inability to have an orgasm (anorgasmia), according to the woman's opinion; (2) clinically significant orgasm delay with masturbation or intercourse that, according to the woman's opinion, represents a meaningful delay compared with her usual time to achieve orgasm in response to sexual stimulation before antidepressant medication interfered with her sexual function; or (3) inability to attain or maintain until completion of sexual activity an adequate lubrication or swelling response of sexual excitement that, according to the woman's opinion, interferes with her sexual function (compared with before taking antidepressant medication). Women were excluded for any of the following reasons: diagnosis of a sexual disorder other than one associated with SRI treatment or onset of major depressive disorder, genital anatomical deformity, hysterectomy with or without oophorectomy, and at least 6 months of established normal sexual function after the procedure and before onset of depression and antidepressant treatment, uncontrolled psychiatric disorder, diabetes mellitus, cardiovascular disease, alcohol or substance abuse or dependence, stroke, unstable cardiac condition, arrhythmia, or myocardial infarction within the last 6 months, current or anticipated use of nitrate or nitric oxide donor in any form, major relationship changes, proliferative retinopathy, investigational drug use within 3 months, current use of other therapies or medications to treat sexual dysfunction, a sexual partner who has or is receiving treatment for sexual dysfunction, or change in SRI antidepressant agent or prescribed dose during the study. Additional exclusion criteria were use of hormone therapy; pregnancy; lactation; planning to become pregnant during the trial; of child-bearing potential and unwilling, unprepared, or judged unreliable to use an acceptable and verifiable form of contraception during the trial; Papanicolaou test results indicating further assessment; dyspareunia due to anatomical, inflammatory, infection condition, or clinical estrogen deficiency; amenorrhea over 1 year; or situational sexual dysfunction. Women were recruited and enrolled from outpatient settings, newspaper advertisements, postings, and referrals. One hundred forty-five patients were assessed for eligibility at screening (Figure). In addition to an assessment of medical history with detailed sexual history and recording of last menstrual period, all patients received a physical examination including blood pressure, 12-lead electrocardiogram, standard biochemistry and hematological laboratory tests, and pelvic examination with Papanicolaou test (unless documented within the last 12 months).
- Sildenafil's effect duration in women may range from 4 to 6 hours.
- It may help women experiencing low libido linked to blood flow issues.
- The drug’s efficacy in women is less predictable than in men.
- Female sexual dysfunction has multiple causes beyond blood flow.
Blood samples for determination of plasma concentrations of free testosterone, thyroid-stimulating hormone, tetraiodothyronine thyroxin, follicle-stimulating hormone, luteinizing hormone, cortisol, progesterone, estradiol, sex hormone–binding globulin, total testosterone, and prolactin were sildenafil 100mg blue pill collected at the first and eighth week before 11 AM on days 1 to 10 of the menstrual period.
- Sildenafil is primarily approved for erectile dysfunction in men.
- Some studies explore its potential to treat female arousal disorder.
- Its use for women remains off-label in many regions.
- Long-term safety data for women is limited.
Using SPSS version 10 (SPSS Inc, Chicago, Illinois), an unrestricted, computer-generated randomization schedule was developed by the study statistician (S.P.) and given to the independent pharmacy. The randomization assigned 49 patients to receive active sildenafil and 49 to receive identical placebo. The only restriction to this randomization was that the groups be of equal size. The largest difference in numbers assigned to the 2 groups at any point in the trial was 4 (excludes completions). At baseline, patients were allocated to the next available number that randomly assigned them to receive sildenafil or matching placebo (50-mg starting dose). Medications were sealed in sequentially numbered identical containers according to allocation sequence, and all study personnel and participants were blinded to treatment assignment for the duration of the study. Patients were instructed to take 1 tablet of trial medication approximately 1 to 2 hours before anticipated sexual activity, not more than once daily over the 8-week trial period and were required to make at least 1 attempt but were asked to try to make at least 2 attempts at sexual activity per week.
| User Name | Reported Effects | Side Effects Experienced | Usage Frequency | Overall Satisfaction |
|---|---|---|---|---|
| Jenny | Noticed increased sensitivity but mild headaches | Headache, flushes | Weekly | Moderately satisfied |
| Maria | Felt more aroused, no side effects | None | Occasionally | Satisfied |
| Lisa | No significant effect | Nausea, dizziness | Rarely | Dissatisfied |
| Karen | Improved orgasm intensity | Flushing, mild headache | Regular | Satisfied |
The dose of study drug could be adjusted from 1 (50 mg) to 2 (100 mg) tablets based on investigator judgment of efficacy and tolerability, including the recording of the findings that resulted in any study drug dosage change and adverse events. Patients were given diaries with instructions for recording trial medication use and sexual activity. Sildenafil and placebo were provided by Pfizer Inc, New York, New York. Drug accountability, concomitant antidepressant treatment, vital signs, and self-rated and physician-rated symptom reports were assessed at each visit (weeks 2, 4, and 8), which included diary review and return of unused medication. A urine pregnancy test was administered to all women of childbearing potential at each visit.
What should I know about storage and disposal of this medication?
Efficacy was assessed using 4 validated measurements. The primary efficacy outcome measure was the difference between the 2 treatment groups in end point mean improvement scores (ie, lower ordinal score) on the Clinical Global Impression Scale adapted for sexual function.26 Secondary outcome measures were baseline to end point mean scores on the Sexual Function Questionnaire,27 the Arizona Sexual Experience scale–female version,28 and the University of New Mexico Sexual Function Inventory–female version.29 Patient-recorded event logs were reviewed for the frequency and percentage of successful intercourse attempts, the number of satisfactory attempts at orgasm or climax, and used to corroborate ratings. Participants were seen at baseline and at weeks 2, 4, and 8 (or last visit) for assessments that included measures of change from baseline to weeks 2, 4, and 8 (or last visit). The Clinical Global Impression scale is a clinician-rated severity improvement scale derived from a review of the diary and discussion with the patient for measuring sexual function with changes measured from baseline to weeks 2, 4, and 8 (final or last visit) with anchored scores from 1 (normal) to 7 (most extreme sexual dysfunction).26 The sexual function questionnaire is a 34-item, multidimensional, patient-rated, self-report, outcome measure of female sexual function developed and validated in English and several other languages.27 It quantifies sexual function in 7 functional domains (desire, arousal-sensation, arousal-lubrication, orgasm, enjoyment, pain, partner) of the female sexual response cycle to detect change in and distinguish between the presence and absence of female sexual dysfunction consistent with the DSM-IV diagnostic criteria.
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Investigators monitored, collected, and followed up on any spontaneous reports of adverse events, and they assessed and categorized the severity of the events and their relationship to the study drug throughout the trial.
- Sildenafil is being studied for female sexual dysfunction.
- It may improve blood flow to vaginal tissues.
- Not officially approved for women in many countries.
- Side effects can include headaches and flushing.
Efficacy was assessed using 4 validated measurements.
What other information should I know?
The primary efficacy outcome measure was the difference between the 2 treatment groups in end point mean improvement scores (ie, lower ordinal score) on the Clinical Global Impression Scale adapted for sexual function.26 Secondary outcome measures were baseline to end point mean scores on the Sexual Function Questionnaire,27 the Arizona Sexual Experience scale–female version,28 and the University of New Mexico Sexual Function Inventory–female version.29 Patient-recorded event logs were reviewed for the frequency and percentage of successful intercourse attempts, the number of satisfactory attempts at orgasm or climax, and used to corroborate ratings. Participants were seen at baseline and at weeks 2, 4, and 8 (or last visit) for assessments that included measures of change from baseline to weeks 2, 4, and 8 (or last visit). The Clinical Global Impression scale is a clinician-rated severity improvement scale derived from a review of the diary and discussion with the patient for measuring sexual function with changes measured from baseline to weeks 2, 4, and 8 (final or last visit) with anchored scores from 1 (normal) to 7 (most extreme sexual dysfunction).26 The sexual function questionnaire is a 34-item, multidimensional, patient-rated, self-report, outcome measure of female sexual function developed and validated in English and several other languages.27 It quantifies sexual function in 7 functional domains (desire, arousal-sensation, arousal-lubrication, orgasm, enjoyment, pain, partner) of the female sexual response cycle to detect change in and distinguish between the presence and absence of female sexual dysfunction consistent with the DSM-IV diagnostic criteria.