Sex and antidepressants: When to switch drugs or try an antidote
Help patients stay on depression treatment by reducing sexual side effects
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.
