Selective Serotonin Reuptake Inhibitors And Sexual Dysfunction: A Historical Review Of The Development Of Evidence For An Adverse Effect
Anita K. Wagner, Pharm.D., M.P.H.
Under the headline "Viagra and Prozac, strange bedfellows", The Buffalo News recently published the following readerĺs question: "I take Prozac and Wellbutrin for depression. As you may know, Prozac affects a man's ability to perform sexually. I don't know if I can blame this completely on the medication; some may be due to the job stress that made me depressed to start with. Would Viagra be an appropriate treatment for this problem? If I took it, would there be any dangerous interaction?" The pharmacologistĺs answer was "Prozac can have a profound impact on sexuality. It can delay ejaculation or lead to impotence in men, and can lower libido or interfere with orgasm in both sexes. Viagra cannot improve sexual desire or speed ejaculation. While it might improve erections, we do not know whether it would interact with your antidepressants in a dangerous way. Such experiments have not been conducted."(1) Around that time also, Eli Lilly and Company, manufacturer of the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine (Prozacâ ), announced a joint venture with Icos to develop a new impotence drug, a "product [that] is being talked about as a next-generation Viagra." The companies indicated that they also intend to develop treatments for women who have sexual dysfunction.(2)
These excerpts from the general news media reflect several of the insights patients, clinicians, researchers, and drug manufacturers have gained over the 12 years since FDA approval of fluoxetine into one of the SSRIĺs disturbing adverse effects: SSRI affect different aspects of menĺs and womenĺs sexual functioning, at higher rates than originally detected; these effects are not easily separated from the underlying disorders for which they are prescribed; patients prefer not to suffer from adverse sexual effects; identification of drugs to counteract them have provided additional evidence for the drug-associated sexual effects and contributed to further understanding of the neurophysiology of sexual dysfunction.
In this paper, I will attempt to chronicle the development of evidence for SSRI-induced sexual dysfunction. Published reports were identified in January 1999 through a search of citations in the National Library of Medicineĺs Medlineâ database from 1966 to 1999. Keywords used were SSRIs (in any field) and sexual dysfunction (as MeSH term or text word). The search yielded 31 citations; another search using fluoxetine and sexual dysfunction yielded 78 records. Pertinent publications are reviewed here.
In their 1988 review of drug-induced sexual dysfunction, McWaine and Procci discussed the reports of sexual function disturbances attributed to the then available two major groups of antidepressants, heterocyclic antidepressants and monoamine oxidase inhibitors.(3) The authors point out the major caveat to the interpretation of the available data, that depression itself is associated with various forms of sexual dysfunction. Several reports were available at that time of decreased libido, erectile dysfunction, inhibited, painful ejaculation and anorgasmia in males. Less evidence pointed to female sexual dysfunction. Case reports of antiserotonergic (cyproheptadine)(4) and cholinergic (bethanechol)(5) agents' successful use to treat antidepressant-associated sexual dysfunction supported the hypothesis that the antidepressants' serotonergic and anticholinergic properties may be responsible for their impairment of sexual function.
Fluoxetine was available in the US in January 1988. By 1990, it had become the most widely prescribed antidepressant ever, attributed to its perceived lack of side effects and lack of toxicity in overdose. At that time, the manufacturer cited a 1.9% incidence of sexual dysfunction associated with fluoxetine treatment in controlled clinical trials of its efficacy and safety.(6) The first case reports after the drug was available, however, indicated higher incidences of sexual dysfunction. In 1990, Dr. Musher began a letter to the American Journal of Psychiatry saying "I have noticed over the past 15 months that my patients who were taking fluoxetine were experiencing anorgasmia as a side effect at a much higher rate than that described by the manufacturer."(7) He observed that 5 of the 32 (16%) patients he had treated with fluoxetine spontaneously reported new-onset anorgasmia as a side effect, temporally related to the start of fluoxetine therapy. In other case series published in the same and the following year, 5 of 60 (8.3%)(8) and 6 of 77 (7.8%)(9) patients treated with various doses of fluoxetine spontaneously reported delayed orgasm or anorgasmia.
Almost simultaneously, the first case reports of treatment of the drug-induced sexual dysfunction with the antiserotonergic agent cyproheptadine(10,11,12,13,14) suggested the SSRI's serotonergic activity as the main mechanism of fluoxetineĺs effect on sexual function. Results of these treatments were mixed. In some cases, cyproheptadine, as was expected, also abolished the antidepressant effect of fluoxetine,(11,12) while in others, patients regained orgasmic capabilities without diminished antidepressant effects.(10,13,14) Balogh and colleagues discovered incidentally that amantadine, a mild dopamine agonist, resolved fluoxetine-associated anorgasmia and successfully treated three men and two women.(15) They proposed that effects of fluoxetineĺs serotonin agonism on dopamine activity were responsible for delayed orgasm and anorgasmia.
Clinicians and researchers were aware that patientsĺ depressed mood could well contribute to their reported sexual problems. Depression-associated sexual effects were usually not assessed in the case reports which documented spontaneous reports only and were not based on systematic inquiry about sexual performance of each patient. Lack of systematic inquiry also prohibited an assessment of which of the aspects of sexual function, desire, erection and ejaculation for men, lubrication for women, and/or orgasm were affected. Following studies targeted these issues.
In 1992, Jacobson and colleagues published a survey of 160 patients who had fulfilled DSM-III-R criteria for major depression and fully responded to treatment with fluoxetine.(16) Over two years during monthly follow-up visits, they asked patients open-ended questions about changes in libido, ability to get/maintain an erection (males only), and orgasm, compared to before the onset of depression. Fifty-four of 160 patients (34%) reported the onset of sexual dysfunction after the successful treatment of depression. Sixteen patients (10% of all fluoxetine-treated patients) reported decreased libido alone, 21 (13%) reported decreased sexual response alone, and 17 (11%) reported both. Sexual dysfunction occurred in all patients within the first two months of therapy, did not decrease throughout treatment, often responded to decreases in the fluoxetine dose, and reversed 1-3 weeks after fluoxetine was discontinued. Following their discovery of fluoxetineĺs impact on sexual desire, they enrolled nine of the patients (2 women and 7 men) into an open trial of yohimbine. Yohimbine is believed to act as an aphrodisiac through presynaptic alpha-2-adrenergic blockade. Eight patients reported complete or partial response of their sexual dysfunction, one patient failed to respond.
One may question these results based on the likely unreliability of patientsĺ recall of sexual functioning prior to the onset of depression and the variability in duration of treatment among study patients at the time of study initiation. However, the author stated that the significantly higher (34%) than previously reported incidence of fluoxetine-associated sexual dysfunction detected in his study is credible for the following reasons: It is consistent with previously reported rates of sexual dysfunction with clomipramine which has significant serotonergic effects; contrary to previous reports, it includes diminished libido as a form of sexual dysfunction; and it is based on repeated questioning of patients about sexual functioning, rather than relying on spontaneous reports.
Since fluoxetine's approval, three more SSRI antidepressants have become available to clinicians and patients in the US. With those, the question of differential adverse sexual effects among the SSRI antidepressants arose. In 1997, Modell and colleagues compared the sexual side effects of fluoxetine, paroxetine, and sertraline and those of the new non-SSRI antidepressant bupropion.(17) Of 320 patients of their outpatient clinic who had been taking one of the study medications for at least one week and met the inclusion criteria, 107 (49 men, 57 women, 1 unspecified; 22 on bupropion; 37 on fluoxetine; 21 on paroxetine; 27 on sertraline) returned a questionnaire about possible medication-induced effects on libido, sexual arousal, duration of time from arousal to orgasm and duration and intensity of orgasm. The questionnaire instructed patients to answer the questions comparing their current sexual experiences with those prior to the onset of symptoms for which they were treated and prior to beginning the medication under study. Similar proportions of patients on the three SSRI experienced one or more adverse sexual effects: 73% of fluoxetine-, 86% of paroxetine-, and 67% of sertraline-treated patients. Differences among the SSRI were not significant. In contrast, 14% of bupropion-treated patients experienced adverse sexual effects. Twenty-seven percent of SSRI-treated patients reported no adverse sexual effects at all, and 77% of bupropion-treated patients reported at least one improvement in sexual functioning. Self-selection into the study of only one third of the invited patients may have resulted in substantial overestimation of the sexual side effects of the SSRI. It should however not be associated with the type of SSRI taken and thus not affect the relative incidence estimates for the three SSRI. The authors concluded that SSRI-induced adverse sexual effects are far more common than initially reported, and that their incidence does not differ among the three SSRI evaluated.
In 1997 also, the first longitudinal studies of the sexual effects of SSRI in depressed patients were published. Zajecka and colleagues followed 22 women and 20 men treated with fluoxetine, sertraline, or paroxetine.(18) They assessed depressive symptoms and various aspects of sexual function at baseline and eight weeks into SSRI treatment with the Hamilton Depression Rating Scale and the Rush Sexual Inventory, respectively. These authors found that 60% of men and 57% of women reported sexual dysfunction associated with SSRI therapy, most commonly difficulties in orgasm. They did not detect differences in sexual dysfunction between those whose depressive symptoms responded to therapy (Hamilton Depression Rating Scale score less than or equal to 8) and those whose symptoms did not respond. Men, but no women, who took paroxetine, reported a greater number and frequency of adverse sexual effects than those taking fluoxetine or sertraline. Using the Rush Sexual Inventory, the authors also found some improvements in sexual functioning, particularly increased desire, among men and women.
Piazza and colleagues assessed twenty-five patients (4 women and 11 men) who were diagnosed with dysthymia, chronic major depression, or double depression, according to DSM-III-R, with the Arizona Sexual Experience Scale and the Hamilton Depression Rating Scale before and six weeks after treatment with sertraline or paroxetine.(19) These authors found differential baseline sexual dysfunction and differential SSRI-associated sexual dysfunction effects for women and men. Women experienced greater baseline sexual dysfunction than men, and their desire and psychological arousal, as well as global sexual functioning, significantly improved with therapy, without change in physiologic arousal, ease of or satisfaction with orgasm. Men experienced significantly worsened delay of and satisfaction with orgasm and global sexual functioning. They suggested that SSRI-associated sexual side effects may be less frequent in women than men or counterbalanced by the beneficial effects of successful depression therapy on sexual functioning in women.
During the past two years, controlled studies of the successful treatment of premature ejaculation contributed another line of evidence for SSRI-associated sexual effects.(20,21) The results from Waldingerĺs 1998 study point to differences in delaying ejaculation among the three SSRI tested. Paroxetine and fluoxetine showed an ejaculation-delaying effect, while fluvoxamine did not. Subsequently, animals studies have shown different serotonin receptor-subtype effects of a structurally unrelated SSRI, fluvoxamine, compared to fluoxetine and are now prompting exploration of receptor subtype-effects of the SSRI related to their sexual effects.(22)
According to a recent New York Times report, the number of prescriptions written in the US for psychotherapeutics has increased from 130.7 million in 1988 to 232.6 million in 1997. Fluoxetine contributed 1.45 million prescription to the total in 1988, and 9.88 million in 1997.(23) During this decade, evidence from case reports, cross-sectional surveys, and prospective studies of adverse sexual effects, together with reports of therapies to counteract them, and controlled trials of SSRI's use in the treatment of sexual dysfunctions has accumulated. Although the studies reviewed here have many flaws, and no one incidence estimate is available, this overview suggests that different types of sexual side effects exist, and that they are rather the rule than the exception of SSRI treatment. The high prevalence of depression, and its burden on patients, their families and society require that patients receive treatment they can comply with. Thus, alerting patients to and inquiring about the adverse sexual effects of SSRI, and modifying therapy accordingly should be an indispensable part of care.