Column
Dr. Clayton is professor and vice chairin theDepartment of Psychiatric Medicine at the University of Virginia Health Systems in Charlottesville.
Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer. No financial, academic, or other support was received for this work.
Please direct all correspondence to: Anita H. Clayton, MD, Department of Psychiatric Medicine, University of Virginia, 2955 Ivy Rd., Northridge Suite 210, Charlottesville, VA 22908-0623; Tel: 434-924-2241; Fax:?434-924-5149; E-mail: ahc8v@virginia.edu
Abstract
How can the occurrence of antidepressant-associated sexual dysfunction be minimized? In prospective studies, sexual dysfunction has been reported by up to 70% of patients using serotonergic antidepressants, which are associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or minimally affect serotonergic neurotransmission. Three approaches to managing antidepressant-associated sexual dysfunction include reduction or elimination of antidepressant doses suspected of causing sexual dysfunction, use of a second medication to reverse sexual dysfunction, or substitution of a second antidepressant not associated with sexual side effects. The introduction of new antidepressants augments the options for controlling or avoiding sexual dysfunction. For symptoms of depression, the norepinephrine and dopamine reuptake inhibitor bupropion sustained-release and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective as serotonergic antidepressants, but with a much lower incidence of sexual dyfunction.
Introduction
Clinically depressed individuals often suffer from sexual dysfunction, which can arise from numerous causes, including the depression itself, comorbid psychiatric or medical disorders, antidepressant therapy, and concomitant medications.1 A primary role of antidepressant therapy in the etiology of sexual dysfunction has become increasingly recognized since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the late 1980s.2 While SSRIs and other medications that enhance serotonergic function are most strongly associated with orgasm dysfunction,3-6 they may also be associated with disorders of other phases of the sexual response cycle, including desire and arousal.7-9 As data from well-controlled studies on the sexual side effects of SSRIs and other serotonergic antidepressants have accumulated over the last decade and a half, health care providers’ concern about these side effects and interest in exploring treatment strategies that minimize or eliminate sexual side effects have grown. This review, based on MEDLINE searches and systematic review of congress abstracts, considers clinical aspects, prevalence, and possible mechanisms of antidepressant-associated sexual dysfunction with a discussion of strategies to minimize the occurrence of this side effect.
Antidepressant-Associated Sexual Dysfunction
Clinical Consequences
Sexual dysfunction can adversely affect quality of life, self-esteem, and interpersonal relationships. These effects are of particular concern among patients with depression, in whom these issues may already be compromised. Moreover, antidepressant-associated sexual dysfunction may lead to medication noncompliance and premature discontinuation and thereby may increase the risk of relapse or recurrence of depression.10,11
In an open-label study of 1,022 patients with a mean 40 years of age, 59.1% reported antidepressant-associated sexual dysfunction.10 The study analyzed the following antidepressants: citalopram, paroxetine, venlafaxine, sertraline, fluvoxamine, fluoxetine, mirtazapine, nefazodone, amineptine, moclobemide, clomipramine, imipramine, maprotiline, phenelzine, and trazodone. Of those with sexual dysfunction attributed to antidepressants, 38.3% rated themselves as being concerned enough about sexual dysfunction to discontinue antidepressant therapy (Figure 1). Another 34.5% indicated that, although they did not intend to discontinue antidepressant therapy because of it, they and/or their partner were concerned or distressed about sexual dysfunction. That nearly 4 of 10 patients in this study were concerned enough about their sexual dysfunction to discontinue their antidepressant is worrisome in view of the fact that noncompliance with the therapeutic regimen may result in relapse or recurrence of depression.
In a patient survey (N=350) reported in 2001, 60% of patients indicated that they had stopped taking their prescribed antidepressant at one time or another, and 22% of patients indicated that they did not always take their antidepressant medication exactly as prescribed.11 Sexual dysfunction was one of the top five reasons for stopping medication or failing to use medication as prescribed. When asked to rate the impact of specific side effects, one fourth of the patients indicated that it would be extremely difficult to live with the side effects of orgasm dysfunction or erectile dysfunction.
Assessment
Across studies in which sexual dysfunction is a prospectively defined endpoint, the condition has been reported in up to 70% of patients using antidepressants such as SSRIs.9,12 Lower frequencies of sexual dysfunction are reported in studies in which sexual function was not objectively assessed or patients were not specifically queried.3,9 Variance in estimates of the prevalence of sexual dysfunction arises primarily from the fact that some studies specifically queried patients regarding sexual dysfunction whereas other studies relied on patients’ spontaneous reports. Because patients are usually reticent to initiate discussion about sexual dysfunction with their health care provider, reliance on spontaneous report of sexual dysfunction underestimates the commonality of the condition. This fact is illustrated by the results of a study (N=344) that assessed sexual dysfunction both via patients’ spontaneous reports and with a questionnaire. Whereas only 14% (28 of 200) of patients spontaneously reported sexual dysfunction, 58% (200 of 344 patients) subsequently reported sexual dysfunction when specifically asked.13
From a practical perspective, these results emphasize the importance of having health care providers discuss sexual function with their patients both before antidepressant therapy is initiated (to obtain a baseline measure) and during antidepressant therapy. Normalizing the issue by opening with an explanation of the frequency of sexual disorders in the general population and among depressed patients, as well as the frequency of sexual disorders associated with specific treatments for depression, can help remove the barriers to discussing sexual functioning with patients.1
Using the medical model to evaluate each stage of the sexual response cycle (desire, arousal, orgasm, resolution) or employing an assessment tool such as the Arizona Sexual Experiences (ASEX) Scale14 or the Changes in Sexual Functioning Questionnaire-Clinical version (CSFQ-C)15 is also important in identifying and assessing sexual dysfunction. Once the presence of sexual dysfunction is confirmed, further evaluation is necessary to differentiate antidepressant-associated sexual dysfunction from sexual dysfunction that may be attributed to other causes.1 This evaluation should compare a sexual history with the current level of sexual functioning and should eliminate other contributing factors including comorbid medical or psychiatric conditions, medications, or substances of abuse. Because both erectile dysfunction and decreased libido commonly occur as symptoms of depression, it is important to determine the patient’s level of sexual functioning prior to the onset of depression to determine the relative contributions of depression and antidepressant therapy.1
Besides reliance on spontaneous reports, other factors that explain variability in estimates of the prevalence of sexual dysfunction include misattribution of depression-associated sexual dysfunction to antidepressant use, failure to account for other established correlates of decreased sexual function such as advancing age and physical illness, and variation among studies in the definition and measurement of sexual dysfunction. Moreover, many studies reporting on sexual dysfunction did not prospectively define it as an endpoint and were often not sufficiently powered to assess the influence of specific variables or interventions.
Several recent studies that have controlled for these methodological problems provide useful data on the prevalence of antidepressant-associated sexual dysfunction.4-6,16-18 The data from these recent studies are consistent in showing that the prevalence of sexual dysfunction differs by physiologic mechanism of the antidepressant: antidepressants affecting serotonergic neurotransmission are reliably associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or only minimally affect serotonergic neurotransmission. For example, in the first study to employ a validated rating scale to assess the effects of the 10 new-generation antidepressants on sexual dysfunction in a large population of patients, 37% of 6,297 patients consulting 1,100 primary care physicians in the United States, reported sexual problems associated with antidepressant use.18 The lowest rates of sexual dysfunction across all antidepressant groups were in patients treated with bupropion (22% and 25%, for the immediate-release and sustained-release [SR] forms, respectively) and nefazodone (28%). Patients treated with bupropion SR or nefazodone had a statistically significantly lower prevalence rate of sexual dysfunction than patients taking SSRIs (citalopram, fluoxetine, paroxetine, sertraline), or venlafaxine extended-release. The mean prevalence rate of presumed antidepressant-associated sexual dysfunction was 24.4% among a prospectively defined subpopulation of patients free from other probable causes of sexual dysfunction (ie, patients were 18–40 years of age, had no history of sexual side effects on previous antidepressants, had used their current antidepressant for at least 3 months, were not taking concomitant medications affecting sexual functioning, had no comorbid illness that would affect sexual functioning, and had a history of at least some sexual enjoyment). Patients treated with bupropion SR had the lowest prevalence (6.7%) of sexual dysfunction (Table 1).
Manifestations
The four phases of the sexual response cycle are desire, arousal (erection in men, engorgement and lubrication in women), orgasm, and resolution. The aspect of sexual functioning most often affected by serotonergic antidepressants is the ability to achieve orgasm, which is either delayed or does not occur in many patients treated with antidepressants.7 Because orgasm dysfunction, unlike other sexual problems such as decreased libido, rarely occurs as a manifestation of depression per se, it is more easily attributed to pharmacotherapy than are sexual symptoms that frequently occur as manifestations of depression.3 In addition to orgasm dysfunction, the serotonergic antidepressants have been linked to erectile dysfunction and decreased libido, although the data associating these sexual side effects with antidepressant therapy are less consistent.7
Mechanisms of Action
The mechanism of antidepressant-associated sexual dysfunction has not been determined. The range of possible mechanisms includes (1) nonspecific neurologic effects (eg, sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function.8 It is probable that antidepressants impact several of these physiologic substrates of sexual function.
The association of some antidepressants and of depression itself with sexual dysfunction is not surprising in view of the fact that many of the neurotransmitter systems implicated in depression, including the serotonin, dopamine, and norepinephrine systems, are also implicated in control of sexual function. Animal research and data from studies in human subjects suggest that sexual behavior and function are enhanced by increases in brain dopaminergic function and inhibited by increases in brain serotonergic function.2,8,19,20 The latter observation is consistent with the association of serotonergic antidepressants with sexual dysfunction.
Management Strategies for Antidepressant-Associated Sexual Dysfunction
Four general approaches to managing antidepressant-associated sexual dysfunction have been adopted (Table 2). The first approach is deciding not to intervene for antidepressant-associated sexual dysfunction in the hope that spontaneous remission will occur. The second approach is to reduce or eliminate doses of the antidepressant suspected of causing sexual dysfunction. The third approach involves use of a second medication as an antidote to reverse sexual dysfunction. Finally, the fourth approach involves substitution of a second antidepressant unlikely to cause sexual side effects. Each of these strategies for managing antidepressant-associated sexual dysfunction is reviewed below.
No Intervention
Some health care providers decide not to intervene in the case of antidepressant-associated sexual dysfunction in the hope that sexual side effects may spontaneously remit over time.4 Spontaneous remission of antidepressant-associated sexual dysfunction has been reported in case studies.21,22 However, recent research suggests that it infrequently occurs within the first 6 months of initiation of therapy. In a prospective, open-label study of 1,022 outpatients taking antidepressants, 59% reported antidepressant-associated sexual dysfunction.10
Of the patients reporting sexual dysfunction, only 9.7% of them reported total improvement or spontaneous remission at the end of 6 months of antidepressant therapy; 79% of them reported no improvement. These data, suggesting that antidepressant-associated sexual dysfunction does not promptly remit, are consistent with data from the 16-week controlled comparison of sertraline and bupropion SR.16 In that study, sertraline-associated sexual dysfunction was observed at the end of the first treatment week (the initial assessment following the start of treatment) and was maintained throughout the 16-week treatment period. If spontaneous remission does not occur, failure to intervene may increase the likelihood of noncompliance with the antidepressant regimen—particularly among patients to whom sexual dysfunction is a significant concern.
Reducing or Eliminating Antidepressant Doses
Reducing the dose of antidepressant medication has been tried in attempts to ameliorate antidepressant-associated sexual dysfunction.8 This strategy has not been systematically assessed in controlled clinical studies but has been reported effective with an SSRI and a monoamine oxidase inhibitor.23,24 Depressive symptoms may reemerge with dose reduction.
Antidepressant drug holidays have also been employed as a strategy for reducing antidepressant-associated sexual dysfunction. Like the dose-reduction strategy, the efficacy of drug holidays in reducing antidepressant-associated sexual dysfunction has not been systematically studied. Positive results were obtained in one open-label, 30-patient study in which patients discontinued sertraline or paroxetine, but not fluoxetine, for the weekend. Discontinuation was associated with significant improvement in sexual functioning without a worsening of depressive symptoms.25
As drug holidays may result in antidepressant discontinuation syndrome and may provide a risk for relapse of depression, they are not an ideal strategy for most patients. Drug holidays may also limit patients’ spontaneity with respect to the timing of sexual activity. Furthermore, advising drug holidays for improvement of sexual dysfunction may encourage patients to be noncompliant with the treatment regimen during times when drug holidays are not advised or appropriate. Finally, in cases in which a drug holiday is effective in reducing sexual side effects, reinstatement of antidepressant therapy is likely to result in the reemergence of sexual dysfunction.
Reemergence of sexual dysfunction due to antidepressants was evaluated in a double-blind rechallenge study enrolling depressed patients who reported impairment in sexual function upon initiation of therapy with sertraline 100 mg OD.26 Patients discontinued sertraline for a 2-week period, and if their sexual functioning normalized during the 2-week period, were assigned to 8 weeks of double-blind treatment with sertraline 50 mg OD or the mixed serotonin antagonist/reuptake inhibitor nefazodone 100 mg BID. Beginning with the first week of reinstatement of sertraline therapy, sexual dysfunction reemerged. Whereas approximately 15% of patients were dissatisfied with sexual function before reinstatement of sertraline therapy, 50% were dissatisfied at week 1 of sertraline reinstatement. When doses were increased to 100 mg/day sertraline and 150 mg nefazodone BID during the second week of therapy, the proportion of sertraline-treated patients dissatisfied with sexual function increased to approximately 80%, which was consistently maintained through the remainder of the 8-week treatment period. These data suggest that drug holidays are not a viable long-term strategy for controlling antidepressant-associated sexual side effects, particularly for a chronic disease such as depression, which often requires life-long pharmacotherapy.
Adding an Antidote
Daily administration of pharmacotherapies that reverse sexual dysfunction and administration of antidotes acutely before sexual activity have also been tried. Agents used for this application are listed in Table 3.27-52 Although addition of an antidote can be successful in reducing the incidence of sexual side effects, it entails polytherapy, which relative to monotherapy increases the overall risk of side effects and drug interactions.
Of all of the agents administered as antidotes, only bupropion SR and buspirone have been demonstrated effective in placebo-controlled trials as well as open-label studies involving both sexes.27,32-37,51 Unlike some of the other augmentation therapies that have been tried, both bupropion SR and buspirone added to SSRI regimens appear to be well-tolerated. None of the other possible antidotes to antidepressant-associated sexual dysfunction have been evaluated in placebo-controlled studies. Evidence for their use is derived primarily from case reports and small, open-label investigations as follows:
• Several authors have reported that amantadine used for at least 2 days before sexual activity or on a regular basis reverses SSRI-associated sexual dysfunction.28-31 In a retrospective chart-review study involving records from 594 patients, amantadine was less effective than yohimbine at reversing SSRI-associated sexual dysfunction.52
• Sildenafil, which is currently approved only for management of erectile dysfunction in men, was reported in an open-label investigation to work as an antidote to antidepressant-induced sexual dysfunction in both men and women.38 Sildenafil is one of the only antidotes that can be taken on an as-needed basis shortly prior to sexual activity.
• Psychostimulants used intermittently or on a daily basis have been reported to be effective at reversing SSRI-associated sexual dysfunction.27,49 Possible drawbacks
of the use of psychostimulants include impairment of sexual function with increasing dose, the potential for abuse, and cardiovascular side effects.
• Ginkgo biloba has been reported in case reports and one uncontrolled study to counter SSRI-induced sexual dysfunction.27,46 As it is an over-the-counter herbal extract, its safety profile has not been assessed with the rigor that is applied to prescription medicines.
• Serotonin (5-HT)2 antagonists such as nefazodone and mirtazapine, as well as the 5-HT2 antagonist and antihistamine cyproheptadine, have been reported to be effective antidotes to antidepressant-associated sexual dysfunction.42-45,47,48 Cyproheptadine administered as daily therapy can interfere with the antidepressant efficacy of SSRIs.42,53 Administered acutely or chronically, it may also cause sedation, which can interfere with sexual function.
Substitution With an Antidepressant Unlikely to Cause Sexual Dysfunction
The development of new antidepressants with little or no adverse effects on sexual function has provided new opportunities for managing antidepressant-associated sexual dysfunction. Health care providers increasingly manage antidepressant-associated sexual dysfunction by starting new patients on an antidepressant shown to cause less sexual dysfunction than the SSRIs and venlafaxine. Similarly, in patients with antidepressant-associated sexual dysfunction, the sexually impairing antidepressant may be replaced with an antidepressant not associated with negative sexual side effects. These strategies have been shown to be effective with the nonserotonergic antidepressant bupropion SR as well as with the mixed serotonin antagonist/reuptake inhibitor nefazodone.7
Feiger and colleagues17 conducted a randomized, double-blind, parallel-group study to compare 6 weeks of treatment with nefazodone (n=71; mean modal end-of-treatment dose of 456 mg/day) and sertraline (n=72; mean modal end-of-treatment dose of 148 mg/day) with respect to efficacy, tolerability, and effects on sexual function. Sexual function was evaluated weekly via questionnaire. The results show that sertraline, but not nefazodone, significantly impaired sexual function, particularly among men. The following was noted among men during the last treatment week:
(1) 100% of those receiving nefazodone reported that they “fully enjoyed” or “sometimes enjoyed” sex compared with 57% of those receiving sertraline;
(2) 89% of those receiving nefazodone were at least moderately satisfied with sex compared with 50% of men receiving sertraline (Figure 2);
(3) 19% of those receiving nefazodone compared with 67% of those receiving sertraline reported difficulty with ejaculation; and
(4) 18% of those receiving nefazodone compared with 67% of those receiving sertraline indicated that they frequently, usually, or always took a long time to ejaculate.
Among women, 74% of those receiving nefazodone compared with 59% of those receiving sertraline were at least moderately satisfied with sex (Figure 2). Nefazodone-treated women achieved orgasm more easily and were more satisfied with the ability to achieve orgasm than were sertraline-treated women.
The effects on sexual function of bupropion SR have also been assessed in double-blind, head-to-head comparisons with SSRIs in patients with depression.4-6,16 In the first study, patients with moderate or severe depression received bupropion SR (100–300 mg/day) or sertraline (50–200 mg/day) for 16 weeks.16 To be included in the study, patients had to have normal sexual function (defined as absence of sexual arousal disorder, orgasm dysfunction, premature ejaculation, dyspareunia, or vaginismus) at baseline prior to the initiation of treatment, although sexual desire disorder associated with the depression could be present. The results demonstrate that the cumulative incidence of orgasm delay or failure was significantly (P<.001) greater among sertraline-treated patients (52%) than among bupropion SR-treated patients (8%), as was the overall incidence of sexual desire disorder (34% of sertraline-treated patients, 21% of bupropion-treated patients; P<.05) and the cumulative incidence of sexual arousal disorder (16% of sertraline-treated patients, 4% of bupropion SR-treated patients; P<.05). Consistent with these data, the percentage of patients satisfied with their sexual function at the end of the study increased substantially for bupropion SR (57% to 79%) but did not change for sertraline (57% to 58%). While bupropion SR had a better sexual tolerability profile than did sertraline, it conferred comparable efficacy for depressive symptoms measured with the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions Scale for Severity, and the Clinical Global Impressions Scale for Improvement.54
These data were substantiated by two double-blind, placebo-controlled, 8-week studies that replicated the findings of the first study.4,5 The placebo-controlled studies also extended the earlier findings by demonstrating that the effects of bupropion SR on the incidence of orgasm dysfunction, sexual desire disorder, and sexual arousal disorder did not differ from those of placebo (with the exception of sexual arousal disorder on day 56 of treatment in one study4) in patients with major depression. In both of these studies as in the first one, differences between bupropion SR and sertraline were most marked for orgasm delay or failure, which of the sexual problems assessed was the most common one reported with sertraline therapy (Figure 3).
In a similar placebo-controlled study prospectively designed to compare the effects of bupropion SR (100–400 mg/day) with those of fluoxetine (10–60 mg/day) on sexual dysfunction, significantly more fluoxetine-treated patients experienced orgasm dysfunction beginning by the second treatment week and continuing throughout the study compared with bupropion SR- or placebo-treated patients (P<.001, Figure 4).6 This effect was observed both in patients defined as clinical responders (ie, those with a 50% decrease in total HAM-D scores during treatment) and in patients experiencing remission (ie, those with total HAM-D scores improved to less than 8). Worsened sexual functioning, decreased sexual desire, sexual arousal disorder, and dissatisfaction with sexual functioning were more often associated with fluoxetine than with bupropion SR or placebo.
Similar differences between treatments were reported in two prospective clinical trials in which patients with antidepressant-associated sexual dysfunction were switched from an SSRI to bupropion.55,56 Sexual side effects resolved while antidepressant efficacy was maintained in both studies. In one study, bupropion SR was initiated prior to discontinuation of paroxetine, sertraline, fluoxetine, or venlafaxine while in the other, bupropion was initiated 2 weeks after discontinuation of fluoxetine. Both of these methods of switching from an SSRI to bupropion were generally well tolerated.
Conclusion
Health care providers increasingly recognize antidepressant-associated sexual dysfunction as a significant problem among some patients. Sound sexual function is important in maintaining the patient’s quality of life and self-esteem, preserving interpersonal relationships, and ensuring compliance with the antidepressant regimen. The introduction of new antidepressants augments the range of options for controlling or avoiding sexual dysfunction. In particular, the norepinephrine and dopamine reuptake inhibitor bupropion SR and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective at controlling depressive symptoms as are antidepressants associated with sexual dysfunction,57,58 but with a low incidence of this undesirable side effect. PP
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