How Important IS Sex, Anyway?

Abstract & Commentary

By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips reports no financial relationship to this field of study.

Synopsis: Women who had sexual dysfunction that was believed to be a side effect of antidepressants were more likely to report improved sexual function if they were assigned to the sildenafil, rather than to the placebo arm of a placebo-controlled trial.

Source: Nurnberg HG, et al. Sildenafil Treatment of Women With Antidepressant-Associated Sexual Dysfunction: A Randomized Controlled Trial. JAMA. 2008;300(4):395-404.

This study is the result of an 8-week, prospective, parallel-group, randomized, double-blind, placebo-controlled trial. Investigators at four different institutions (including the famous Kinsey Institute in Bloomington, IN), recruited women between the ages of 18-50 years who developed sexual dysfunction while taking a selective or nonselective serotonin reuptake inhibitor (SRI) for major depressive disorder. To be included in this industry-supported study, the participants had to have had satisfactory sexual function prior to the onset of depression or antidepressant treatment. The definition of sexual dysfunction is worth examining, and is taken from the DSMIV. To meet criteria for antidepressant-associated sexual dysfunction in this study, women had to have 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, represented 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, interfered with her sexual function (compared with before taking antidepressant medication).1

There were also many, many exclusion criteria for this study, including any of the following: 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, change in SRI antidepressant agent or prescribed dose during the study, 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, infectious condition, or clinical estrogen deficiency; amenorrhea over 1 year; or situational sexual dysfunction.

Over a 40-month period, 145 women (recruited from outpatient clinic, newspaper ads and referrals) were assessed for eligibility. One hundred met criteria, and 98 were randomized to either placebo or sidenafil (50mg) 1 to 2 hours prior to sexual activity, optimally at least twice a week. Participants could increase the dose to 2 tablets in consultation with a study investigator. Outcome measures were the changes in four different questionnaires: the Clinical Global Impression (CGI) Scale of sexual function, the Sexual Function Questionnaire, the Arizona Sexual Experience Questionnaire, and the University of New Mexico Sexual Function Inventory-female version. The latter two questionnaires, which have been validated in patients with psychiatric disorders, were used for concurrent validity. The study participants were seen at baseline, 2, 4, and 8 weeks and these questionnaires were given each time. In addition, a variety of biochemical hormone measures were assayed during the study.

The baseline cohort had a mean age of about 36 years, most were married, and they had an average of 3 sexual problems apiece. Only 76 of the 98 women completed the study. Several variables improved for participants in each group. There was a statistically significant difference in the CGI score improvement for the active drug vs placebo drug, and 73% of those taking placebo compared with 28% of those taking active drug reported no improvement (as defined by a CGI score > 3). Women in the sildenafil group were more likely to report improvement in orgasm attainment on 3 of the questionnaires. There were no significant differences in depression over the course of the study, based on the Hamilton depression inventory. Except for increased free testosterone levels and thyoxine among the treatment responders, there were no differences in hormone levels over the course of the study. Most participants, placebo and sildenafil alike, increased the dose to 2 tablets (100mg). No serious adverse events were reported, but women on active drugs were statistically more likely to report flushing, dyspepsia, nasal congestion, and visual disturbances. However, those in the placebo group were more likely to report nausea. The authors concluded, "By treating this bothersome treatment-associated adverse effect in patients who have been effectively treated for depression, but need to continue on their medication to avoid relapse or recurrence, patients can remain antidepressant-adherent, reduce the current high rates of premature medication discontinuation, and improve depression disease management outcomes."


This article came to my attention because it was heavily publicized in the lay press. And it got published in JAMA. This work extends previous work demonstrating that phosphodiesterase type 5 inhibitor treatment improves sexual function in men who experience antidepressant-associated sexual dysfunction.2 How big a problem is this in women? Depression is a serious, deadly illness, and its treatment is important. Women are about twice as likely as men to experience depression, and antidepressant-associated sexual dysfunction is estimated to occur in 30% to 70% of those who are treated with first- or second-generation SRI's.3 Further, antidepressant-associated sexual dysfunction is believed to be a reason for antidepressant nonadherence and subsequent depression relapse.4 This first-ever study of the use of a phosphodiesterase type 5 inhibitor to treat antidepressant-associated sexual dysfunction in women has the potential to greatly expand the already huge market for these agents (though it should be noted that use of phosphodiesterase type 5 inhibitors for women with antidepressant-related sexual dysfunction is most definitely an off-label use, at present). On the other hand, it took investigators at 4 centers more than 3 years to accumulate 100 appropriate candidates for this study, which suggests that women may not be as preoccupied with sexual function or dysfunction as men are.


1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

2. Nurnberg HG, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003;289(1):56-64.

3. Montejo AL, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62(Suppl 3):10-21.

4. Lin EHB, et al. The role of the primary care physician in patients' adherence to antidepressant therapy. Med Care. 1995;33(1):67-74.