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Sexual Side Effects
Of Antidepressants Common,
But Still Seriously Underestimated By Physicians

from The Brown University Psychopharmacology Update

Assessing the prevalence of sexual side effects of antidepressants is a difficult but important task. Treatment-emergent sexual dysfunction (SD) may be a major factor leading to noncompliance with antidepressant pharmacotherapy and may also contribute to or complicate the patient's depression. Due in part to the different methodologies used for collecting such information, the reported incidence of sexual dysfunction with various antidepressants varies quite markedly.

A recently published study has attempted to close the information gap by using a validated scale -- the Changes in Sexual Functioning Questionnaire (CSFQ) -- in a large sample of primary care patients receiving newer antidepressants. The researchers note that the reported incidence of sexual side effects in the product labeling for the newer antidepressants is around 15 percent, but when asked directly, up to 70 percent of patients report SD.

Anita H. Clayton, M.D., of the department of Psychiatric Medicine, University of Virginia, and colleagues conducted an observational study of the prevalence of sexual dysfunction at 1,101 primary care clinics in the United States. Primary care physicians were asked to enroll the first five patients who were receiving antidepressant monotherapy for depression with one of the following medications: bupropion immediate- or sustained-release (Wellbutrin IR or SR), citalopram (Celexa), fluoxetine (Prozac), mirtazapine (Remeron), nefazodone (Serzone), paroxetine (Paxil), sertraline (Zoloft), venlafaxine or venlafaxine extended-release (Effexor or Effexor XR). To be included, patients had to have experienced sexual intercourse, masturbation, sexual fantasies or other sexual activity over the previous 12 months.

Within the larger sample of 6,297 patients (the overall clinical population), the researchers identified a target population subgroup consisting of those patients least likely to experience SD for any reason other than antidepressant use. This group of 802 patients was 18 to 40 years of age, had never used antidepressants before, had been treated for at least three months, were taking no other medications that could be expected to cause SD and reported at least some sexual enjoyment in the past.

Clayton et al. found the prevalence of SD in the overall clinical population to be 37 percent (95% CI=36% to 38%), ranging from 22 (bupropion SR) to 43 (paroxetine) percent for various medications. The lowest rates of SD were reported in the bupropion IR and SR and nefazodone groups (22, 25 and 28%, respectively), while the highest rates were reported for paroxetine (43%) and mirtazapine (41%). Patients taking bupropion SR or nefazodone were significantly less likely to experience SD than patients taking fluoxetine, paroxetine, sertraline or venlafaxine XR. Patients taking bupropion SR also had a significantly lower incidence of SD than patients taking citalopram or mirtazapine, while patients taking bupropion IR had a significantly lower incidence than patients taking paroxetine, sertraline or venlafaxine XR. The only other significant difference in the overall clinical population favored patients taking fluoxetine over those taking paroxetine.

In the target population, the overall prevalence of SD was 24 percent (95% CI=22% to 28%), ranging from seven (bupropion SR) to 30 (citalopram and venlafaxine XR) percent. In this subgroup, patients taking bupropion SR were significantly less likely to experience SD than patients taking citalopram, paroxetine, sertraline or venlafaxine XR. (Sample sizes for bupropion IR, mirtazapine, nefazodone and venlafaxine were too small to conduct individual analyses, although they were included in the overall analysis of the target population group.)

Clayton et al. also report that the overall incidence of SD (37%) was almost twice the estimation made by physicians prior to participation in the study (20%). Patients may not report SD, especially if physicians do not inform them that it may be caused by their medication. Clayton et al. suggest that the CSFQ may facilitate patient-physician dialogue concerning SD.

With the exception noted above, the prevalence of sexual dysfunction was similar among the SSRIs in both the overall clinical population and target population, ranging from 36 to 43 percent in the latter. Combined with the significantly lower rates for non-SSRI antidepressants bupropion (IR and SR) and nefazodone, these findings suggest that sexual dysfunction is a particular concern with SSRIs. Many researchers have hypothesized that serotonin plays a role in the etiology of sexual dysfunction.

While this study benefits from the large sample size, without random assignment to treatment, comparisons between specific antidepressants must be considered preliminary. More specifically, physicians are likely to have considered the risk of sexual dysfunction when prescribing antidepressants for individual patients and patients may have already been switched from one antidepressant to another due to SD prior to enrollment. Also, the researchers note that physicians in primary care settings may use lower doses of antidepressants than psychiatrists, resulting in a lower incidence of SD than with random assignment.

Managing Sexual Dysfunction

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Even when the sexual side effects of antidepressants are recognized, the practical problem of managing them remains a challenge to clinicians. The most common sexual side effects reported with antidepressant treatment are erectile dysfunction, diminished libido and delayed/attenuated or absent orgasm (dysorgasmia or anorgasmia). One of the major challenges for clinicians is distinguishing between sexual dysfunction associated with depression, treatment-emergent SD and preexisting SD exacerbated by treatment. The practical implications may be great. For example, one strategy for treating sexual dysfunction associated with depression -- raising the antidepressant dose -- would be particularly inappropriate for treating treatment-emergent SD, in which case the dose often should be lowered.

In a recent review, Maurizio Fava, M.D., and Meredith Rankin, B.A., described the main approaches to managing antidepressant-induced sexual dysfunction. First, clinicians may attempt to alleviate the sexual side effects of a drug by reducing the dose or switching to an alternative therapy that may be less likely to cause sexual side effects. Both of these strategies risk sacrificing the therapeutic benefit of treatment and are more likely to be used in patients who are not responding fully to treatment.

Second, nonpharmacologic interventions -- such as behavioral and cognitive-behavioral techniques employed by sex therapists -- have been used extensively, but studies evaluating their success in patients taking antidepressants are needed.

Lastly,a number of medications have been reported to be useful in the treatment of sexual dysfunction associated with antidepressants, but few placebo-controlled trials have been conducted. According to Fava and Rankin, the most common medications for antidepressant-induced sexual dysfunction fall into three categories:

• a2-adrenergic receptor antagonists such as yohimbine.
• Serotonin 5-HT2 or 5-HT3 receptor antagonists, including nefazodone, cyproheptadine and granisetron.
• Dopaminergic agents, such as amantadine and pramipexole.

Some agents that fall into more than one of these categories include mirtazapine (an 2 and serotonin receptor antagonist) and bupropion (a dopaminergic/noradrenergic agent). Other agents that may be useful are gingko biloba and sildenafil, note Fava and Rankin. The potential for new side effects and drug-drug interactions is one concern with this approach. The lack of research for treatment-emergent SD is common to all of these pharmacotherapies.

Sildenafil (Viagra) for Sexual Dysfunction

The introduction of sildenafil (Viagra) as a treatment for erectile dysfunction has increased interest in the pharmacotherapy of treatment-emergent SD. Fava and Rankin also report on an open trial with sildenafil that found significant improvement in nine out of a group of ten men with antidepressant-induced sexual dysfunction. Adverse effects were only reported in one patient.

Although sildenafil is indicated for treatment of erectile dysfunction, there has been increasing interest in its potential use in treating SD in women as well as men. However, even less research has been done in this area. A letter-to-the-editor in the American Journal of Psychiatry reported success in using sildenafil in 10 women who experienced anorgasmia as a consequence of antidepressant treatment. Nine of the ten patients reported complete or very significant reversal of their SD.

More recently, researchers conducted a retrospective study of sildenafil in 31 women and 61 men with psychotropic-induced sexual dysfunction (PISD). Seven psychiatrists who prescribed sildenafil for PISD collected information on 92 patients, the majority of whom were receiving an antidepressant (see Table 1). The primary outcome measure was the Salerian Sexual Satisfaction Survey (S4), which addresses questions of arousal, libido, orgasm and overall sexual satisfaction. The S4 also contains one gender-specific item addressing erection in men and lubrication in women.

Patients received between 12.5 and 100 mg of sildenafil, with 84.4 percent receiving 50 mg. There were significant differences before and after treatment for each of the topics (arousal, libido, orgasm, overall sexual satisfaction and lubrication or erectile function) on the S4, indicating the potential usefulness of sildenafil in this patient population.

A secondary analysis found no significant differences between men and women in improvement in any area of the S4 with the exception of arousal, where the mean improvement favored men (P<0.05). Interestingly, patients taking SSRIs demonstrated significantly less improvement compared with all other classes of psychotropic medications in the areas of arousal (P<0.05), libido (P<0.05) and overall sexual satisfaction (P<0.01).

Acknowledging the need for randomized, double-blind trials in this area, the researchers noted that their sample included twice as many men as women, perhaps due to sociocultural factors including differences in reporting style.

Source: The Brown University Psychopharmacology Update 13(6):1, 6, 2002. © 2002 Manisses Communications Group, Inc

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