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Evidence-Based Reviews


Sex and antidepressants: When to switch drugs or try an antidote

Help patients stay on depression treatment by reducing sexual side effects

Vol. 3, No. 11 / November 2004

Antidepressants’ sexual side effects can often be managed—while preserving the antidepressant effect—by altering dosages, switching to another drug class, or adding an “antidote.” Understanding the benefits and risks of each strategy can help you:

  • base treatment choices on your patient’s history and side-effect experience
  • improve long-term compliance with antidepressant regimens.

EFFECTS VARY BY ANTIDEPRESSANT CLASS

Antidepressants may affect one or more phases of sexual functioning:

  • desire (libido)
  • arousal (erection or vaginal lubrication)
  • orgasm/ejaculation.

Sexual symptoms linked to antidepressants range from diminished interest/arousal and delayed orgasm to heightened sexual functioning (Table 1). Resulting sexual dysfunction can impair quality of life and intimate relationships and discourage patients from taking antidepressants (Box) 1,2

Table 1

Sexual side effects linked to antidepressants

Most common effects

Shown by these drugs

Decreased desire

TCAs, MAOIs, SSRIs

Delayed or absent ejaculation/orgasm

TCAs, MAOIs, SSRIs

Impaired erection

TCAs, MAOIs, SSRIs

Less common effects

Increased desire

Bupropion

Spontaneous/prolonged erections

SSRIs, CMI,bupropion, trazodone, nefazodone

Premature/retrograde/painful ejaculations

TCAs, trazodone, nefazodone

Priapism

SSRIs, CMI, bupropion, trazodone, nefazodone

Spontaneous orgasms (associated with yawning)

SSRIs, CMI, bupropion

Altered sexual sensation and sensitivity

SSRIs, CMI, bupropion

TCAs: tricyclics

MAOIs: monoamine oxidase inhibitors

SSRIs: selective serotonin reuptake inhibitors

CMI: clomipramine

Although most reports have focused on SSRIs, all antidepressant classes have been associated with sexual dysfunction, with prevalence likely influenced by differences in neurotransmitter modulation (Table 2).1,3,4 The highest rates of sexual side effects have been reported with SSRIs, certain tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

A recent study reported similarly high rates with mirtazapine, but its small sample size limits conclusions about side effect prevalence with this drug.1 Other studies have found significantly lower rates with bupropion and nefazodone.

TCAs’ sexual side-effect rates and types depend on how much each drug inhibits serotonin reuptake. Clomipramine appears to have the highest rates of sexual dysfunction—particularly anorgasmia—probably because it inhibits the serotonin transporter more than do other TCAs.5 In TCAs with lesser effects on serotonergic neurotransmission, alpha-adrenergic and cholinergic receptor blockade may cause sexual side effects—particularly erectile dysfunction (ED).

Cholinergic agonists such as bethanechol, 10 to 50 mg/d, may reverse sexual dysfunction caused by anticholinergic effects.6 Cyproheptadine—a nonselective serotonin receptor antagonist—has also shown benefit at 4 to 12 mg/d in treating TCA-related sexual side effects.7

MAOIs. Sexual side effects appear to be more prevalent with MAOIs than with TCAs,4 perhaps similar to the rate seen with SSRIs. MAOIs directly increase serotonergic neurotransmission, and their substantial alpha-adrenergic antagonist effects may also produce sexual side effects.

Waiting for symptoms to subside may be appropriate, as anorgasmia caused by MAOIs may remit spontaneously. Sildenafil8 and cyproheptadine9 may reverse MAOI sexual side effects, although serious toxicity has been reported in a patient taking cyproheptadine and an MAOI.10

SSRIs. Increased serotonergic neurotransmission is widely believed to cause SSRI sexual side effects. Resulting secondary effects—such as inhibited central dopamine release, increased prolactin secretion, and inhibited nitric oxide synthesis—may also play important roles.

In general, SSRIs appear to alter sexual functioning in 40% to 60% of patients—both men and women. Anorgasmia is the most commonly reported sexual symptom.

Although all SSRIs are associated with sexual dysfunction, some studies have found higher rates with paroxetine. One study associated paroxetine with significantly higher rates of ED compared with other SSRIs. The authors attributed this finding to paroxetine’s greater anticholinergic effects or to its directly decreasing nitric oxide synthesis.3

SSRI MANAGEMENT STRATEGIES

Waiting. The simplest, safest way to manage SSRI-related sexual dysfunction is to wait and see if side effects resolve spontaneously. Sexual side effects improve without treatment in approximately 20% of cases,3 although improvement is often incomplete. Moreover, several months may pass before symptoms diminish adequately, making this strategy impractical for patients with substantial sexual dysfunction.

Dosing changes. Because SSRIs’ sexual side effects appear to be dose-related,11 carefully reducing the dosage may reduce sexual dysfunction without compromising antidepressant efficacy. This strategy is most likely to sustain remission when you avoid dosages that have proven ineffective. For example, consider a patient who achieves remission of depressive symptoms when fluoxetine is increased from 20 to 40 mg/d. If sexual side effects emerge at 40 mg/d, relapse may be less likely at 30 mg/d than at 20 mg/d.

Box

Talking to patients about sexual function

Sexual side effects are common in patients taking selective serotonin reuptake inhibitors.1 Sexual side effects diminish patients’ quality of life and significantly decrease adherence to antidepressant regimens,2 which in turn diminishes depression treatment efficacy.

Hidden problem. Drug-related sexual side effects often go undetected because:

  • patients are too embarrassed to discuss sexual problems with their physicians
  • onset is often later and more insidious than that of other antidepressant side effects
  • they may be difficult to distinguish from pre-existing sexual dysfunction caused by depression, other medical reasons, or psychosocial factors
  • physicians often fail to educate patients about them.

Clinical tips. These problems point out the importance of obtaining a sexual history before starting antidepressant therapy, educating patients about the potential for sexual side effects with antidepressants (including when they occur and what may be done to manage them), and directly asking patients about specific sexual side effects at follow-up visits.

Other strategies that lessen sexual side effects for some patients include:

  • dividing the dosage
  • delaying dosing until after sexual activity
  • allowing 2- to 3-day “drug holidays” over weekends, when sexual activity is more likely to occur.12

Drug holidays probably would not help patients taking fluoxetine, as plasma concentrations would not drop sufficiently in 2 to 3 days to alleviate sexual side effects. Also, drug holidays are presumably safest for patients who are in maintenance treatment, are asymptomatic, and have no history of rapid symptom recurrence or withdrawal effects when discontinuing SSRIs.12

Switching medications. When sexual side effects do not resolve spontaneously or with dose reduction, consider switching to an antidepressant with a lower incidence of sexual dysfunction.

Table 2

Prevalence of antidepressant sexual side effects

SSRIs

% of patients affected

Citalopram

38 to 731,3

Fluoxetine

36 to 581,3

Fluvoxamine

623

Paroxetine

42 to 711,3

Sertraline

40 to 631,3

Other antidepressants

Bupropion

20 to 241

Mirtazapine

24 to 401,3

MAO inhibitors

404

Nefazodone

8 to 291,3

Tricyclics (excluding clomipramine)

30 4

Venlafaxine

40 to 671,3

SSRI: selective serotonin reuptake inhibitor

Bupropion has been shown to improve sexual functioning in patients treated for depression. One study reported improved sexual functioning in patients with SSRI-induced sexual side effects who were switched to bupropion.13 Similar studies have shown benefits with substituting nefazodone or mirtazapine for an SSRI.

These uncontrolled studies suggest that switching some patients to a non-SSRI antidepressant may diminish sexual side effects while continuing antidepressant efficacy. Bupropion or nefazodone may be more effective for this purpose, as mirtazapine showed a high rate of sexual side effects in a large observational study.1

Use caution when switching from an SSRI to nefazodone, as cytochrome P-450 2D6 isoenzyme inhibition may increase levels of mCPP—a nefazodone metabolite with anxiogenic properties. To avoid this interaction, taper the SSRI before starting nefazodone.

Switching medications may not be ideal for patients with an unacceptable depression relapse risk, characterized by severe dysfunction, suicidal ideation, or past treatment resistance.

USING AN ANTIDOTE

Adding a second medication to antidepressant therapy is another strategy to consider. An antidote seems most practical when:

  • a patient clearly benefits from an antidepressant regimen
  • the risk of losing efficacy with a new medication is high
  • reducing the dosage or waiting for sexual dysfunction to resolve spontaneously are impractical or have failed.

Most reports of sexual side effect antidotes have been open-label trials of drugs thought to:

  • improve some aspect of sexual functioning as with dopamine or noradrenergic agonists)
  • or block antidepressant mechanisms suspected of contributing to sexual side effects (as with serotonin receptor antagonists or cholinergic agonists).

Unfortunately, controlled trials with many of these strategies have been less than promising (Table 3).5,14-28 Several trials reported high placebo-response rates—which may complicate assessment of any sexual side effect treatment—and most produced negative results. Two notable exceptions have been sildenafil and bupropion.

Sildenafil, a phosphodiesterase-5 inhibitor, showed greater benefit than placebo in a prospective trial of 90 depressed men (mean age 45) diagnosed with sexual dysfunction caused by an SSRI.28 The men took sildenafil, 50 to 100 mg, 1 hour before sexual activity.

After 6 weeks, 55% of sildenafil-treated patients were rated as much/very much improved on the Clinical Global Impression Scale adapted for Sexual Function, compared with 4% of those taking placebo, a statistically significant difference. Measures used to assess sexual function showed that arousal, erectile function, and orgasm improved significantly, with a lesser effect on desire. This suggests that adjunctive sildenafil reduces SSRIs’ sexual side effects, and this benefit may extend beyond improving ED.

Table 3

Evidence for antidotes used to treat antidepressant sexual side effects

Drug/dosage Dopaminergic agents

Study designs and outcomes

Amantadine, 100 to 400 mg/d14

Open-label (+)

Placebo-controlled (−)

Bupropion SR, 75 to 300 mg/d15

Open-label (+)

Placebo-controlled (+)

Ephedrine16

Placebo-controlled (−)

Methylphenidate, 10 to 30 mg/d14

Open-label (+)

Pramipexole, 0.125 to 2.0 mg/d18

Open-label (+)

Ropinirole, 1 to 4 mg/d19

Open-label (+)

5-HT antagonists

Cyproheptadine, 2 to 16 mg/d20

Open-label (+)

Granisetron, 1 to 1.5 mg/d21

Open-label (+)

Placebo-controlled (−)

Mianserin, 30 mg/d22

Open-label (+)

Mirtazapine, 15 to 45 mg/d23

Open-label (+)

Placebo-controlled (−)

Nefazodone, 50 to 150 mg/d24

Open-label (+)

Noradrenergic agent

Yohimbine, 5.4 mg/d25

Open-label (+)

Placebo-controlled (−)

Others

Bethanechol, 10 to 50 mg/d6

Open-label (+)

Buspirone, 15 to 60 mg/d26

Placebo-controlled (+)(−)

Ginkgo biloba, 60 to 240 mg/d27

Open-label (+)

Placebo-controlled (−)

Sildenafil, 25 to 200 mg28

Open-label (+)

Placebo-controlled: (+)

(+) = evidence supports effectiveness

(−) = evidence does not support effectiveness

Source: Prepared from references 6 and 14-28.

Sildenafil improves peripheral vasodilatation due to smooth muscle relaxation caused by enhanced nitric oxide release. Other sexual side effects—such as delayed orgasm/ejaculation—may improve because of indirect effects of increased penile and clitoral blood flow caused by vasodilatation.29

Sildenafil treatment was well-tolerated; the most common side effects were headache (40.5%), flushing (16.7%), dyspepsia (7.1%), nasal congestion (11.9%), and transient visual disturbances (11.9%).

Bupropion has also shown therapeutic efficacy for SSRI-related sexual dysfunction in a 4-week, placebo-controlled trial of 55 patients (mean age 39) diagnosed with SSRI-induced sexual dysfunction.15 Compared with the placebo group, those receiving add-on bupropion SR, 150 mg bid, improved significantly more in sexual desire and frequency of sexual activity, as measured by the Changes in Sexual Functioning Questionnaire.

Measures of arousal, orgasm, and global sexual functioning did not differ significantly between the two groups. Bupropion added to SSRI treatment was well-tolerated; most-commonly reported side effects were irritability (12%), dry mouth (12%), and headache (15%).

Other ED treatments. Two additional phosphodiesterase-5 inhibitors have become available in the past year. Like sildenafil, tadalafil and vardenafil are indicated for treating ED. They may be useful as alternatives for patients who do not respond to or tolerate sildenafil, although no published studies have examined their use in antidepressant-induced sexual dysfunction.

Recommendation. Based on the evidence, it seems reasonable to start with bupropion or sildenafil when considering an antidote for sexual side effects caused by SSRIs or other medications with strong serotonergic effects. Determining which agent would be “first-line” depends on patient factors, as summarized in Table 130,31For example:

  • Bupropion has been reported to augment SSRIs’ antidepressant effects32 and thus may provide added benefit in patients with residual depressive symptoms.
  • Bupropion is more effective than sildenafil for improving sexual desire and thus would be preferred for patients in whom this sexual dysfunction symptom is prominent.
  • Sildenafil appears to be more effective than bupropion for improving overall sexual satisfaction for men experiencing substantial erectile dysfunction.

Table 4

Bupropion vs. sildenafil as antidote therapy for antidepressant sexual side effects

Continued...
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