Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Clinical features and management

INTRODUCTION — Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat many psychiatric disorders, including depressive disorders, anxiety disorders, obsessive compulsive and related disorders, and posttraumatic stress disorder. However, SSRIs can interfere with different aspects of sexual functioning, including desire, arousal, and orgasm, which can lead to nonadherence [1,2]. Although sexual side effects can also occur with other types of antidepressants, including serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, there are more studies of sexual dysfunction secondary to SSRIs due to their widespread use.

SSRI-induced sexual dysfunction occurs in both males and females [1,2], and most patients with antidepressant-associated sexual dysfunction have unipolar depression, which can also impair sexual functioning [3]. Conversely, treating depression with an SSRI can improve sexual impairment [4,5].

This topic reviews the clinical features and management of sexual dysfunction caused by SSRIs. Sexual dysfunction in the general population is discussed separately, as are the pharmacology, administration, and other side effects of SSRIs.

●(See "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation".)

●(See "Overview of sexual dysfunction in females: Management".)

●(See "Epidemiology and etiologies of male sexual dysfunction".)

●(See "Evaluation of male sexual dysfunction".)

●(See "Treatment of male sexual dysfunction".)

●(See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

INCIDENCE OF SEXUAL DYSFUNCTION — Establishing the incidence of adverse sexual effects secondary to SSRIs is difficult due to methodologic problems in some studies, such as the absence of baseline assessments and comparison groups [2,4,6]. In addition, studies vary in how they define and assess sexual dysfunction, and the level of impairment required to meet the threshold for dysfunction. Other differences across studies include the time frame examined and how dysfunction was ascertained and reported. Also, embarrassment may cause patients and clinicians to not discuss the problem [5,7].

Nevertheless, sexual dysfunction appears to be one of the most common adverse effects of SSRIs [1,8]. Based upon relatively large studies in the United States and Europe, it is estimated that sexual impairment occurs in approximately 50 percent of patients treated with SSRIs [7]:

●A 14-week, prospective observational study (Sequenced Treatment Alternatives to Relieve Depression [STAR*D]) of 1473 patients treated with citalopram found that [9]:

•Decreased libido occurred in 54 percent

•Difficulty achieving orgasm occurred in 36 percent

•Erectile dysfunction (n = 574 males) occurred in 37 percent

●A cross-sectional survey of 704 patients who had started SSRIs or serotonin-norepinephrine reuptake inhibitors estimated that treatment-emergent sexual dysfunction occurred in approximately 50 percent [10].

Other studies suggest SSRI-induced sexual dysfunction my occur in as many as 80 percent of patients [1,4,6,8,11].

The risk of sexual difficulties secondary to SSRIs, such as decreased libido and difficulty with orgasm, is greater in patients who are younger (eg, age 30 to 50 years), male, and married [3,5,9,12]. In addition, onset of depression at an earlier age (eg, age 20 years), relatively long episodes of depression (eg, 12 months), recurrent depression, and comorbidities such as anxiety disorders are associated with SSRI-induced sexual dysfunction.

Incidence with different SSRIs — The SSRI drug class includes citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, each of which can cause sexual dysfunction [1,7]. Although few head-to-head randomized trials have compared sexual dysfunction among different SSRIs, limited data suggest that the incidence of sexual dysfunction may be lowest with fluoxetine and highest with citalopram-escitalopram and paroxetine:

●A network meta-analysis of 37 randomized trials (n >14,000 depressed patients) evaluated sexual dysfunction with SSRIs by pooling results from head-to-head trials that directly compared SSRIs, along with results from indirectly comparing the drugs through their relative effect with a common comparator (typically placebo) [6]. Sexual dysfunction was three to four times less likely to occur with fluoxetine than escitalopram or paroxetine.

●A prospective observational study of 789 patients who were treated with SSRIs found that the frequency of sexual dysfunction was as follows [3]:

•Fluoxetine – 58 percent

•Fluvoxamine – 62 percent

•Sertraline – 63 percent

•Paroxetine – 71 percent

•Citalopram – 73 percent

PATHOGENESIS — Although it is not known how SSRIs impair sexual functioning, some studies suggest that genetic polymorphisms may be involved [9,13]. In addition, sexual dysfunction may be the result of central and peripheral mechanisms that increase serotonin at receptors that affect hormones such as testosterone and other neurotransmitters such as dopamine [4,7]. Another hypothesized cause is inhibition of nitric oxide [13].

CLINICAL MANIFESTATIONS — SSRIs may worsen pre-existing sexual impairment due to major depression or a primary sexual disorder, or cause new onset of impairment [5,7,13,14]. Sexual dysfunction caused by depression may be more likely to take the form of decreased interest (libido) and arousal, whereas SSRIs often cause orgasmic difficulties. Nevertheless, sexual dysfunction secondary to depression or SSRIs can arise in any aspect of sexual activity and manifest with decreased or impaired:

●Libido

●Frequency of sexual activity

●Arousal

•Erectile dysfunction (difficulty achieving and maintaining penile erection)

•Insufficient vaginal lubrication

●Orgasm

•Delayed orgasm

•Anorgasmia

●General satisfaction

Some patients present with multiple, concurrent types of dysfunction, such as decreased libido and difficulty achieving orgasm [9].

Among patients who present with SSRI-induced sexual dysfunction, approximately 40 to 50 percent report the adverse effect greatly bothers them [3,15]. These effects can decrease quality of life and lead to nonadherence with treatment [5,7,14].

However, for some males with premature ejaculation that predates starting an SSRI, delayed ejaculation induced by the SSRI is beneficial [5]. (See "Treatment of male sexual dysfunction", section on 'Premature ejaculation'.)

Onset and duration — Onset of sexual dysfunction after starting an SSRI usually occurs within the first two weeks [15]. With continued treatment, sexual dysfunction may endure for at least three months in more than 80 percent of patients. After the medication is discontinued, sexual side effects resolve within a few weeks [16]. As an example, a small prospective study in healthy male volunteers (n = 35) found that sexual side effects induced by SSRIs ended within one month of stopping the medication [17].

However, hundreds of case reports describe adverse sexual effects secondary to SSRIs that persist after discontinuing the drug, termed “post-SSRI sexual dysfunction” [18-23]. In addition to symptoms such as genital numbness (reduced sensitivity), decreased libido, delayed orgasm, and anorgasmia, nonsexual symptoms have been attributed to post-SSRI sexual dysfunction, including anhedonia, apathy, blunted affect, cognitive impairment, diminished functioning and quality of life, and suicidal behavior. Onset has been observed after short- or long-term exposure to SSRIs, and the reports describe a variable time course; in some cases, the syndrome may persist indefinitely.

The European Medicines Agency has acknowledged the existence of case reports describing persistent sexual dysfunction after drug withdrawal [24]. However, the prescribing information for SSRIs, as determined by the US Food and Drug Administration, does not mention post-SSRI sexual dysfunction [25], and the existence of this syndrome is uncertain due to the lack of more compelling evidence. An alternative explanation for adverse sexual effects following discontinuation of the drug is that they may be caused by the underlying depressive disorder that prompted treatment with the SSRI and has not resolved.

ASSESSMENT — Embarrassment may cause patients with sexual dysfunction secondary to depression or pharmacotherapy to not spontaneously report the problem [5]. Thus, prior to administering SSRIs, it is incumbent upon clinicians to establish a baseline and ask about all aspects of sexual functioning [5,26,27]. Subsequently, monitoring of treatment with SSRIs should include questions about sexual dysfunction and its severity if present, including the type of impairments and intensity of each. (See 'Clinical manifestations' above.)

Several validated screening or severity questionnaires are available for assessing SSRI-induced sexual dysfunction at baseline and during treatment [4,14,26,28,29]. These include the Arizona Sexual Experience Scale, Changes in Sexual Functioning Questionnaire, International Index of Erectile Functioning, and Psychotropic-Related Sexual Dysfunction Questionnaire, as well as other questionnaires that assess sexual dysfunction along with side effects in other domains or organ systems. However, these questionnaires are generally not part of standard clinical practice and are reserved for research settings. Only a minority of experts in sexual dysfunction secondary to antidepressants routinely use questionnaires [28].

Detailed information about the general evaluation of sexual dysfunction is discussed separately. (See "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation" and "Evaluation of male sexual dysfunction".)

MANAGEMENT

Overview — We suggest that management of sexual dysfunction caused by SSRIs proceed according to the sequence described in the algorithm (algorithm 1) and the sections below. Patients first receive initial treatment and progress through each subsequent step until they respond [4,27]:

●Initial treatment

•Watchful waiting; if sexual impairment persists:

•Decrease the dose of the SSRI within the therapeutic range.

●Treatment-resistant patients – Management is determined by the severity of depression and sexual dysfunction:

•Ongoing depression – For patients with a limited response to an SSRI (eg, reduction of baseline symptoms <50 percent), we suggest switching to a different antidepressant.

•Improved depression but severe sexual dysfunction – For patients whose depression has responded to an SSRI (eg, reduction of baseline symptoms ≥50 percent), but suffer severe sexual dysfunction, we suggest switching antidepressants.

•Improved depression and mild to moderate sexual dysfunction – For patients whose depression has responded to an SSRI and whose sexual dysfunction is mild to moderate, we suggest augmenting the SSRI with a second drug.

Each treatment step is described in greater detail in the sections below.

Most treatments for SSRI-induced sexual dysfunction have not been compared in head-to-head trials. In addition, the results of some studies are difficult to interpret because it is not clear whether sexual dysfunction began prior to onset of treatment with the SSRI and represents a symptom of the depressive syndrome or a primary sexual disorder (either of which may be exacerbated by an SSRI), or began after the SSRI was started and represents an adverse effect.

Initial treatment of sexual dysfunction — For depressed patients who receive an SSRI and develop sexual dysfunction, we suggest initially waiting a limited time (eg, two to eight weeks) for spontaneous remission of the adverse effect (algorithm 1). If sexual impairment persists, we then decrease the dose within the therapeutic range. Although not well studied, these interventions are two of the most frequently used strategies [4,5,27,28,30]. A reasonable alternative to watchful waiting and decreasing the dose is to switch antidepressants.

●Watchful waiting – For SSRI-induced sexual dysfunction, two randomized trials by the same investigator suggest that watchful waiting may be useful [31,32]. Each trial enrolled patients with depression or another psychiatric disorder, who had been successfully treated with fluoxetine, but developed sexual dysfunction. The trial began with a four-week baseline assessment, after which patients were assigned to acute add-on treatment for six or eight weeks with study drugs, including placebo (n = 39 and 20); all patients continued fluoxetine throughout the trial. On average, patients receiving placebo demonstrated moderate improvement of sexual functioning.

Nevertheless, multiple observational studies suggest that watchful waiting alone is typically not effective, despite relatively long observation [8,11,27]. As an example, a prospective observational study included 156 patients with major depression or another psychiatric disorder, and normal sexual function at baseline, who were treated with different SSRIs and developed sexual problems [16]. After waiting four to six months, moderate to complete improvement of sexual dysfunction occurred in only 19 percent [16]. However, it is not clear whether the baseline psychiatric disorder had responded to the SSRI.

One review suggested that watchful waiting may work best for patients with mild SSRI-induced sexual dysfunction [33].

●Decreasing the dose – SSRI-induced sexual impairment appears to be dose-dependent; thus, reducing the dose may be helpful [4,5,7,13,26]. Decreasing the dose is one of the initial strategies used most frequently by experts in managing sexual dysfunction caused by antidepressants [5,28]. However, reducing the dose is reserved for remitted patients who are stable for at least several weeks and are taking doses that exceed the minimum therapeutic dose [4,5].

Given that dose reductions can precipitate relapse of depression, the dose is decreased slowly in small increments and should generally not be reduced below the minimum therapeutic dose [4,27]. As an example, sertraline 200 mg per day can be reduced by 25 to 50 mg per day every two to four weeks, with patients interviewed prior to each decrease. The minimum therapeutic dose for sertraline is typically 50 mg per day (table 1).

Nevertheless, for some patients, if a minimum therapeutic dose (eg, fluoxetine 20 mg/day) has resolved the depressive syndrome but is causing sexual side effects, it is reasonable to lower the dose below the minimum therapeutic dose, because a “subtherapeutic” dose (eg, fluoxetine 10 mg/day) may maintain the clinical response while improving the adverse effects. One reason is that slow metabolizers may have therapeutic serum concentrations at subtherapeutic doses.

Support for decreasing the dose as a means of mitigating SSRI-induced sexual dysfunction includes a small prospective observational study (n = 30 patients) in which the dose was decreased by 50 percent; at least moderate improvement of sexual dysfunction occurred in 77 percent [16].

Treatment-resistant sexual dysfunction

Overview — Sexual dysfunction caused by SSRIs may not respond to watchful waiting and lower doses. Treatment options for these patients depends upon whether the depressive syndrome has responded to the SSRI and if so, the severity of the SSRI-induced sexual impairment:

●Ongoing depression – The response of the depressive syndrome to the SSRI is limited (eg, reduction of baseline symptoms <50 percent)

●Improved depression – The depressive syndrome has responded to the SSRI (eg, reduction of baseline symptoms ≥50 percent)

•Sexual dysfunction is severe (eg, impairment occurs almost always during sexual activity)

•Sexual dysfunction is mild to moderate (eg, impairment occurs no more often than half the time)

Managing patients with SSRI-induced sexual dysfunction is summarized in the algorithm (algorithm 1). Each treatment step is described in greater detail in the sections below.

Among experts in managing sexual dysfunction caused by antidepressants, the two strategies used most frequently for treating SSRI-induced sexual dysfunction are [28]:

●Switching antidepressants – Switching antidepressants is often preferable to augmentation because adherence may be better with monotherapy than combination treatment [34]. In addition, monotherapy may cause fewer adverse effects, cost less, and present fewer risks of drug interactions in patients taking medications for other conditions.

●Add-on pharmacotherapy – Conversely, augmentation with a second drug maintains the benefit derived from the SSRI, whereas switching antidepressants may lead to relapse of depression or new adverse effects [33].

No head-to-head trials in patients with SSRI-induced sexual dysfunction have compared switching with augmentation.

Ongoing depression — Some patients with SSRI-induced sexual dysfunction may also have ongoing depression, such that their response to the SSRI is limited (eg, reduction of baseline depressive symptoms <50 percent), despite treatment at a sufficient dose for a sufficient length of time. For these patients, we suggest switching to a non-SSRI antidepressant, based upon studies that indicate several antidepressants cause fewer adverse sexual effects than SSRIs (table 2) [1,5,35,36]. This approach addresses both the depressive syndrome and the sexual dysfunction. However, one potential problem in switching antidepressants is the antidepressant discontinuation syndrome. Information about switching antidepressants and avoiding the syndrome is discussed separately. (See "Switching antidepressant medications in adults".)

Multiple options are suitable for patients who decide to switch antidepressants [26]. Given that few head-to-head trials have compared the alternatives with SSRIs that are listed below, the choice is based upon the quality of evidence that the drug does not cause adverse sexual side effects. Additional factors to consider include the antidepressant’s availability, other potential side effects, and cost, as well as the patient’s past treatment history (eg, comorbidities) and preference. The different options, listed in order of preference, are as follows:

●Bupropion – Several randomized trials have demonstrated that bupropion does not impair sexual functioning and that sexual dysfunction occurs less often with bupropion than SSRIs [5,37-39]:

•A meta-analysis of patient level data from five randomized trials, lasting 6 to 16 weeks, compared bupropion sustained release, SSRIs (fluoxetine or sertraline), and placebo in 1228 patients with unipolar major depression who did not meet criteria for sexual desire disorder [40]. Treatment-emergent sexual desire disorder occurred in fewer patients who received bupropion than SSRIs (6 versus 17 percent) and was identical with bupropion and placebo (6 percent). The incidence of sexual arousal disorder and orgasmic dysfunction were also less with bupropion than SSRIs, and comparable for bupropion and placebo.

•A meta-analysis of patient level data from two randomized trials, each lasting eight weeks, compared bupropion extended release (300 or 450 mg per day), escitalopram (10 or 20 mg per day), and placebo in 830 patients with unipolar major depression and normal sexual functioning [41]. Worsened sexual functioning occurred in fewer patients who received bupropion than escitalopram (20 versus 36 percent), and was comparable with bupropion and placebo (20 and 15 percent).

•A network meta-analysis of 37 randomized trials (n >14,000 depressed patients) evaluated sexual dysfunction with SSRIs by pooling results from head-to-head trials that directly compared SSRIs, along with results from indirectly comparing the drugs through their relative effect with a common comparator (typically placebo) [6]. The study found that sexual dysfunction was two to three times less likely to occur with bupropion than escitalopram, paroxetine, or sertraline. However, the credible intervals were wide; this, along with the indirect comparisons, led the investigators to conclude that the quality of the evidence was low.

In addition, bupropion is used to treat females with sexual interest/arousal disorder. (See "Overview of sexual dysfunction in females: Management", section on 'Bupropion'.)

The pharmacology, administration, and side effects of bupropion are discussed separately, as is switching antidepressants. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion' and "Switching antidepressant medications in adults".)

●Mirtazapine – Ongoing depression and sexual dysfunction that emerges during treatment with SSRIs may persist despite switching to bupropion. For these patients, we suggest discontinuing bupropion and switching to mirtazapine, based upon the following [5,8,38,39,42]:

•A meta-analysis of four randomized trials (n = 907 patients with major depression) compared mirtazapine with SSRIs (fluoxetine, paroxetine, or sertraline), and found that sexual dysfunction was less likely with mirtazapine (odds ratio 0.3, 95% CI 0.1-0.7) [43].

•A network meta-analysis of 37 randomized trials (n >14,000 depressed patients) found that mirtazapine was three times less likely to cause sexual dysfunction than escitalopram, and six times less likely than paroxetine [6]. However, the credible intervals were wide.

However, mirtazapine-induced drowsiness and weight gain may limit its acceptability. The side effects, pharmacology, and administration of mirtazapine are discussed separately, as is switching antidepressants. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine' and "Switching antidepressant medications in adults".)

●Vortioxetine – Ongoing unipolar major depression and sexual dysfunction that emerges during treatment with SSRIs, may persist despite sequential switches to bupropion and mirtazapine. For these patients, we suggest switching to vortioxetine, based upon multiple randomized trials [5,26,27,38]:

•One trial evaluated switching to vortioxetine in patients who responded to their SSRI (rather than patients with ongoing depression) [44]. The investigators enrolled patients (n = 447) who were successfully treated with an SSRI for unipolar major depression, but also developed sexual dysfunction as a side effect. Patients were randomly assigned to switch to vortioxetine (10 or 20 mg/day) or escitalopram (10 or 20 mg/day) for eight weeks. Antidepressant efficacy was maintained with each drug, but improvement of sexual dysfunction was somewhat greater with vortioxetine than escitalopram. Discontinuation of treatment due to adverse effects with vortioxetine and with escitalopram occurred in nine and six percent of patients.

•In addition, randomized trials indicate that the incidence of sexual dysfunction is similar with vortioxetine and placebo.

-A pooled analysis included seven trials in patients with unipolar major depression or generalized anxiety disorder (n = 889) who did not have sexual dysfunction at baseline, and assigned them to vortioxetine 5, 10, 15, or 20 mg/day, or placebo for eight weeks [45]. The risk of treatment-emergent sexual dysfunction in each of the five groups was comparable.

-In a six-week randomized trial that compared vortioxetine (10 mg/day) with placebo in patients with acute unipolar major depression (n = 205), the incidence sexual dysfunction in the two groups was comparable [46].

The pharmacology, administration, and side effects of vortioxetine are discussed separately, as is switching antidepressants. (See "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Vortioxetine' and "Switching antidepressant medications in adults".)

●Other non-SSRI antidepressants – Patients with ongoing depression and SSRI-induced sexual dysfunction may not respond sufficiently to sequential switches to bupropion, mirtazapine, and then vortioxetine. For these patients, reasonable options include selegiline and vilazodone [5,38]. Other choices include agomelatine, amineptine, and moclobemide, which are not available in the United States. Extra caution is required if patients are switched from SSRIs to monoamine oxidase inhibitors such as moclobemide or selegiline. (See "Switching antidepressant medications in adults", section on 'Switching to or from MAOIs'.)

A pooled analysis of randomized trials and prospective and retrospective observational studies found that sexual impairment was comparable for agomelatine, moclobemide, selegiline, and placebo [1]. Other randomized trials indicate that sexual dysfunction secondary to depression often improves during acute treatment with vilazodone, and that the incidence of sexual dysfunction secondary to vilazodone is relatively low [47,48].

When switching from SSRIs to non-SSRIs to relieve sexual dysfunction in patients with ongoing depression, another option is nefazodone, based upon randomized trials [5,6,49]. However, some clinicians avoid nefazodone because of concerns about hepatic toxicity. (See "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Side effects'.)

●Different SSRI – Switching to a different SSRI (eg, fluoxetine) may ameliorate sexual impairment. However, the degree of sexual dysfunction may be so substantial that patients insist upon switching to a non-SSRI.

Although few head-to-head trials have compared sexual dysfunction among different SSRIs, some data suggest that the incidence of sexual dysfunction may perhaps be greater with escitalopram or paroxetine than fluoxetine, but the evidence is considered weak [37]. A network meta-analysis of 37 randomized trials (n >14,000 depressed patients) evaluated the adverse effects of 13 second-generation antidepressants by using results from direct comparisons between the drugs, as well as indirectly comparing drugs through their relative effect with a common comparator (typically placebo) [6]. The likelihood of sexual dysfunction was three to four times greater with escitalopram or paroxetine than fluoxetine. However, the credible intervals were wide; this, along with the indirect comparisons, led the investigators to conclude that the quality of the evidence was low.

Improved depression but severe sexual dysfunction — For patients whose depression has responded to an SSRI (eg, reduction of baseline depressive symptoms ≥50 percent), but who suffer severe sexual dysfunction (eg, impairment during sexual activity occurs almost always), we suggest switching antidepressants.

In selecting a new drug, the choice is based upon factors such as availability, past treatment history, other potential side effects, cost, and patient preference. The specific antidepressants that we use for switching are described in the section immediately above and are listed in order of preference. (See 'Ongoing depression' above.)

Improved depression and mild to moderate sexual dysfunction — For patients who obtain at least moderate relief of depressive symptoms with an SSRI (eg, reduction of baseline depressive symptoms ≥50 percent), and whose sexual dysfunction is mild to moderate (eg, impairment during sexual activity occurs half the time) , we suggest augmenting the SSRI with a second drug. However, a reasonable alternative to augmentation is to switch antidepressants; choosing a new antidepressant is described elsewhere in this topic. (See 'Ongoing depression' above.)

Choosing add-on pharmacotherapy for SSRI-induced sexual dysfunction depends upon the patient’s sex:

Males — For males who are treated with an SSRI that improves their depression but induces sexual dysfunction, we recommend adjunctive treatment with a phosphodiesterase-5 inhibitor, based upon multiple randomized trials in patients who are and who are not prescribed antidepressants. Information about prescribing phosphodiesterase-5 inhibitors is discussed separately in the context of treating sexual dysfunction in the general population of males. (See "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)

Reasonable alternatives to phosphodiesterase-5 inhibitors include add-on bupropion or switching antidepressants.

Evidence supporting the use of a phosphodiesterase-5 inhibitor in patients taking SSRIs includes the following trials:

●A meta-analysis of two trials compared adjunctive sildenafil (50 or 100 mg before sexual activity) with placebo for six or eight weeks in 112 euthymic males with sexual dysfunction caused by ongoing antidepressant treatment (primarily SSRIs), and found that improvement was greater with sildenafil [2].

The larger of the two trials included 89 patients with remitted unipolar major depression who were continuing to receive antidepressants (largely SSRIs) and were experiencing sexual dysfunction, including low libido (64 percent), erectile dysfunction (87 percent), delayed ejaculation (70 percent), and anorgasmia (21 percent) [50]. Overall sexual dysfunction was much improved or very much improved in more patients who received sildenafil than placebo (55 versus 4 percent). In addition, libido, erectile function, and orgasmic function each improved more with sildenafil than placebo. However, headache occurred in more patients who received sildenafil than placebo (40 and 10 percent). None of the patients suffered a relapse of major depression.

●A pooled analysis of 19 trials (lasting 12 weeks) compared tadalafil with placebo in males with erectile dysfunction [51]. In the subgroup (n = 205) who were taking antidepressants (SSRIs or other types), successful intercourse occurred in more patients treated with tadalafil 10 or 20 mg per day, compared with patients who received placebo (54 and 59 versus 29 percent). This finding was consistent with the demonstrated efficacy of tadalafil for the general treatment of erectile dysfunction. In addition, tadalafil was well tolerated in the subgroup taking antidepressants.

●A subsequent 12-week randomized trial compared tadalafil (20 mg) with placebo in 50 males with SSRI-induced sexual impairment who completed the study (out of 54 enrolled) [52]. Erections and sexual activity improved in more males who received tadalafil than placebo (92 versus 8 percent). In addition, improvement of each domain of sexual functioning (libido, erectile function, orgasm, intercourse satisfaction, and overall satisfaction) was greater with tadalafil than placebo, and active treatment was well tolerated.

It is likely that other phosphodiesterase-5 inhibitors (eg, avanafil and vardenafil) are beneficial for males with SSRI-induced sexual dysfunction.

Few if any interactions between an SSRI and a phosphodiesterase-5 inhibitor have been identified; interactions may be determined by using the UpToDate drug interactions program.

Evidence supporting add-on bupropion in males with SSRI-induced sexual dysfunction includes randomized trials, which are discussed in the section immediately below. (See 'Females' below.)

Females — For females with SSRI-induced sexual dysfunction, add-on pharmacotherapy depends upon the specific sexual impairment:

●Low libido – For females with SSRI-induced low libido (female sexual interest/arousal disorder), we suggest augmentation with bupropion titrated to relatively high doses within the therapeutic range (eg, 300 mg/day). The pharmacology, administration, and side effects of bupropion are discussed separately. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion'.)

Reasonable alternatives to add-on bupropion for managing low sexual interest caused by SSRIs include switching antidepressants. Other alternatives include nonpharmacologic interventions, as well as medications such as bremelanotide; however, these approaches were studied in the general population of females with low sexual interest, rather than patients with SSRI-related low sexual interest. (See "Overview of sexual dysfunction in females: Management".)

Randomized trials suggest that in females with SSRI-induced low libido, augmentation with bupropion is efficacious:

•A four-week trial compared add-on bupropion (sustained release 150 mg twice daily) with placebo in 42 patients who had remitted from unipolar major depression, continued the SSRI, and suffered sexual dysfunction, including low libido; 37 (88 percent) of the patients were females [53]. Improvement of desire and frequency of sexual activity was greater with add-on bupropion. However, irritability occurred nearly three times as often with bupropion than placebo (60 and 23 percent of patients).

•A six-week trial compared add-on bupropion (mean dose nearly 200 mg/day) with aripiprazole (mean dose 3 mg/day) in 103 patients (65 percent female) with major depression who had not responded to an SSRI (rather than patients with improved depression); baseline sexual dysfunction in the two groups was comparable [54]. Global improvement of sexual dysfunction, which may have been secondary to depression, the SSRI, or both, was comparable in the two groups.

Two other small, randomized trials found that a relatively low dose of adjunctive bupropion (sustained release 150 mg once daily) was not efficacious for SSRI-induced sexual dysfunction, as did a small prospective observational study [55-57].

●Orgasmic disorder – For females with SSRI-induced orgasmic disorder, we suggest pharmacotherapy or nonpharmacologic interventions, depending upon availability and patient preference. Nonpharmacologic approaches are discussed separately. (See "Treatment of female orgasmic disorder", section on 'Psychosocial interventions' and "Overview of sexual dysfunction in females: Management", section on 'Orgasmic disorder'.)

For females who prefer pharmacotherapy, we suggest a phosphodiesterase-5 inhibitor, based upon one randomized trial. An eight-week trial enrolled females (n = 98) who were successfully treated for major depression with antidepressants (primarily SSRIs), but developed sexual dysfunction, and assigned them to sildenafil (50 or 100 mg) or placebo [58]. Overall improvement of sexual dysfunction occurred in more patients who received sildenafil than placebo (72 versus 27 percent). However, the benefit of sildenafil was limited to delayed orgasm and anorgasmia; the drug provided no advantage for sexual desire or arousal (eg, lubrication). In addition, dyspepsia, flushing, nasal congestion, and visual disturbance each occurred more frequently with sildenafil, and 43 percent of the sildenafil patients reported headaches.

Few if any interactions between an SSRI and a phosphodiesterase-5 inhibitor have been identified. Interactions between an SSRI and bupropion may occur. Interactions between drugs may be determined using the UpToDate drug interactions program.

Treatments with limited to no demonstrated benefit — Among treatments that have been investigated for sexual dysfunction caused by SSRIs, the evidence for the following is at best minimal:

●Augmentation with various drugs – For sexual side effects caused by SSRIs, we suggest not adding amantadine, bethanechol, buspirone, cyproheptadine, ephedrine, ginkgo biloba, granisetron, mirtazapine, olanzapine, or yohimbine; a systematic review of randomized trials found no benefit with these adjunctive drugs [2]. Similarly, we suggest not adding treatment with stimulants such as dextroamphetamine, methylphenidate, and pemoline; although they have been used adjunctively for SSRI-induced sexual dysfunction, support for their effectiveness is limited to case reports [28,33].

In addition, we suggest not adding treatment with flibanserin for females who are taking SSRIs and have low libido. There are no published data regarding the use of flibanserin for antidepressant induced low libido, and the benefits of flibanserin for hypoactive sexual desire disorder are modest. (See "Overview of sexual dysfunction in females: Management", section on 'Flibanserin'.)

●Exercise – A randomized trial compared exercise (30 minutes of moderate strength training and cardiovascular exercise, three times/week) immediately before sexual activity with exercise separate from sexual activity in 52 females who reported antidepressant sexual side effects; nearly half were treated with SSRIs [59]. After three weeks, patients crossed over to the other intervention. Sexual desire and overall sexual function improved more with exercise immediately prior to sexual activity. However, many of the females were not distressed by the antidepressant sexual side effects, and the study was marked by a high rate of attrition (46 percent).

●Drug holiday – Drug holidays (briefly interrupting treatment) may perhaps be useful for sexual dysfunction caused by SSRIs other than fluoxetine, which has a relatively long half-life; however, this approach is supported by limited evidence and is not widely used [5,28]. One small observational study of weekend drug holidays found that in patients taking paroxetine (n = 10) or sertraline (n = 10), libido, orgasm, and sexual satisfaction improved in half of the patients, whereas no benefit occurred in patients taking fluoxetine (n = 10) [60]. However, potential risks with drug holidays include worsening depression and discontinuation syndromes, as well as sending the wrong message about adherence (especially during maintenance treatment) [4,5,61].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Sexual problems in males (Beyond the Basics)" and "Patient education: Sexual problems in females (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Incidence of sexual dysfunction – The estimated incidence of sexual dysfunction in males and females treated with selective serotonin reuptake inhibitors (SSRIs) is approximately 50 percent. Although each SSRI can cause sexual dysfunction, the incidence may be lowest with fluoxetine and highest with citalopram-escitalopram and paroxetine. (See 'Incidence of sexual dysfunction' above.)

●Clinical manifestations – SSRIs may worsen pre-existing sexual impairment due to major depression or cause new onset of impairment. Sexual dysfunction caused by depression may be more likely to take the form of decreased interest (libido) and arousal, whereas SSRIs often cause orgasmic difficulties. Nevertheless, sexual dysfunction secondary to depression or SSRIs can arise in any aspect of sexual activity and manifest with decreased or impaired:

•Libido

•Frequency of sexual activity

•Arousal

•Orgasm

•General satisfaction

●Assessment – Patients with sexual dysfunction secondary to depression or pharmacotherapy may not spontaneously report the problem. Thus, prior to administering SSRIs, it is incumbent upon clinicians to establish a baseline and ask about all aspects of sexual functioning, and to ask about sexual functioning at follow-up. (See 'Assessment' above and "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation" and "Evaluation of male sexual dysfunction".)

●Initial management – Our initial approach for patients with SSRI-induced sexual dysfunction is watchful waiting for a limited time (eg, two to eight weeks); if the impairment persists, we decrease the dose within the therapeutic dose range (algorithm 1). (See 'Initial treatment of sexual dysfunction' above.)

●Treatment-resistant sexual dysfunction – Patients with SSRI-induced sexual dysfunction often do not respond to watchful waiting or lower doses. Management of treatment-resistant sexual dysfunction depends upon the efficacy of the SSRI in treating the depressive syndrome and the severity of sexual dysfunction:

•Ongoing depression – For patients with a limited antidepressant response to an SSRI (eg, reduction of baseline depressive symptoms <50 percent) and sexual dysfunction, we suggest switching to bupropion (Grade 2C). Reasonable alternatives include mirtazapine and vortioxetine. These agents have similar efficacy for depression and lower rates of sexual dysfunction. (See 'Ongoing depression' above.)

•Improved depression but severe sexual dysfunction – For patients who obtain at least moderate relief of depressive symptoms with an SSRI (eg, reduction of baseline symptoms ≥50 percent) but suffer severe sexual dysfunction (eg, impairment nearly always occurs during sexual activity), we suggest switching antidepressants, rather than prescribing a second drug in conjunction with the SSRI (Grade 2C). We typically switch to bupropion. (See 'Improved depression but severe sexual dysfunction' above.)

•Improved depression and mild to moderate sexual dysfunction – For patients who obtain at least moderate relief of depressive symptoms with an SSRI and whose sexual dysfunction is mild to moderate (eg, impairment occurs half the time during sexual activity), we suggest augmenting the SSRI with a second drug to manage the sexual dysfunction:

-Males – We use add-on treatment with a phosphodiesterase-5 inhibitor for males, similar to the general population of males with sexual dysfunction. (See 'Males' above and "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)

-Females – For females with low libido, we suggest add-on bupropion at relatively high doses within the therapeutic range, rather than other drugs (Grade 2C). For females with delayed orgasm or anorgasmia, we suggest add-on treatment with a phosphodiesterase-5 inhibitor (Grade 2B). (See 'Females' above.)

However, a reasonable alternative to augmentation for both males and females is switching antidepressants. (See 'Improved depression and mild to moderate sexual dysfunction' above.)