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Savvy Psychopharmacology


Sildenafil for SSRI-induced sexual dysfunction in women

Vol. 12, No. 04 / April 2013
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Practice Points

  • Sexual dysfunction can arise from environmental, social, medical, or drug effects and requires a multifaceted approach to treatment.
  • When possible, take a baseline sexual dysfunction measurement to assess if selective serotonin reuptake inhibitor use is correlated with onset or worsening of sexual dysfunction.
  • Nonpharmacologic options should be considered before and during pharmacotherapy.
  • Sildenafil may be useful for treating anorgasmia in women taking serotonergic antidepressants.
  • Phosphodiesterase type 5 inhibitors are not FDA-approved for sexual dysfunction in women.

Mrs. L, age 27, has a history of major depressive disorder with symptoms of anxiety. She was managed successfully for 2 years with bupropion XL, 300 mg/d, but was switched to venlafaxine, titrated to 225 mg/d, after she developed seizures secondary to a head injury sustained in a car accident. After the switch, Mrs. L’s mood deteriorated and she was hospitalized. Since then, she’s received several medication trials, including paroxetine, 30 mg/d, a selective serotonin reuptake inhibitor (SSRI), and the tricyclic antidepressant (TCA) nortriptyline, 75 mg/d, but she could not tolerate these medications because of severe xerostomia.

After taking sertraline, 150 mg/d, for 8 weeks, Mrs. L improves and has a Patient Health Questionnaire score of 6, indicating mild depression. Her initial complaints of diarrhea and nausea have resolved, but Mrs. L now reports that she and her husband are having marital difficulties because she cannot achieve orgasm during sexual intercourse. She did not have this problem when she was taking bupropion. Her husband occasionally takes the phosphodiesterase type 5 (PDE5) inhibitor sildenafil before intercourse, and Mrs. L asks you if this medication will help her achieve orgasm.

DSM-IV-TR defines sexual dysfunction as disturbances in sexual desire and/or in the sexual response cycle (excitement, plateau, orgasm, and resolution) that result in marked distress and interpersonal difficulty.1 Sexual dysfunction can occur with the use of any antidepressant with serotonergic activity; it affects an estimated 50% to 70% of patients who take SSRIs.2 Sexual dysfunction can occur with all SSRIs; however, higher rates of sexual dysfunction are found with citalopram, fluoxetine, paroxetine, and sertraline.3 Studies have suggested there may be a dose-side effect relationship with SSRI-induced sexual dysfunction.4

Several factors can increase a patient’s risk of sexual dysfunction and should be considered before prescribing an antidepressant or when a patient presents with new or worsening sexual dysfunction (Table 1).5 In general, nonserotonergic agents such as bupropion, mirtazapine, and nefazodone are associated with lower rates of sexual dysfunction. The pharmacology of these agents explains their decreased propensity to cause sexual dysfunction. These agents increase levels of dopamine in the mesolimbic dopaminergic system either by blocking reuptake (bupropion) or antagonizing the serotonin subtype-2 receptor and facilitating disinhibition of decreased dopamine downstream (nefazodone and mirtazapine).

Table 1

Risk factors for sexual dysfunction

Sex

Risk factors

Women

History of sexual, physical, or emotional abuse, physical inactivity

Men

Severe hyperprolactinemia, smoking

Both sexes

Poor to fair health, genitourinary disease, diabetes mellitus, cardiovascular disease, hypertension, increasing age, psychiatric disorders, relationship difficulties

Source: Reference 5

One option for treating antidepressant-induced sexual dysfunction in women is PDE5 inhibitors, which are used to treat erectile dysfunction (ED). These medications ameliorate ED by inhibiting degradation of cyclic guanosine monophosphate by PDE5, which increases blood flow to the penis during sexual stimulation. Although these medications are not FDA-approved for treating sexual dysfunction in women, adjunctive PDE5 inhibitor treatment may be beneficial for sexual dysfunction in females because similar mediators, such as nitric oxide and cyclic guanosine monophosphate, involved in the nonadrenergic-noncholinergic signaling that controls sexual stimulation in men also are found in female genital tissue.6

When treating a woman with SSRI-induced sexual dysfunction, consider nonpharmacologic treatments both before and during pharmacotherapy (Table 2).7,8 See Table 3 for a comparison of pharmacokinetics, side effects, and drug interactions of the 4 FDA-approved PDE5 inhibitors—avanafil, sildenafil, tadalafil, and vardenafil.

Table 2

Management strategies for SSRI-induced sexual dysfunction

Intervention

Comments

Nonpharmacologic

Lifestyle modifications

Encourage healthy eating, weight loss, smoking cessation, substance abuse treatment, or minimizing alcohol intake to improve patient self-image and overall health

Cognitive-behavioral therapy

Patients can identify coping strategies for reducing symptom severity and preventing worsening sexual dysfunction

Sex therapy

May benefit patients with relationship difficulties

‘Watch and wait’

Spontaneous resolving (or ‘adaptation’) of sexual dysfunction with antidepressants can take ≥6 months. Studies have found adaptation rates generally are low (~10%)

Pharmacologic

Drug holiday

May be an option for patients taking antidepressants with shorter half-lives and patients taking lower doses. Be cautious of empowering patients to stop their own medications as needed

Dosage reduction

Serotonergic antidepressant-induced sexual dysfunction may be related to dose. Little research has been conducted on this method and the patient’s clinical status must be considered

Dose timing

Instructing a patient to take the antidepressant after his or her usual time of sexual activity (eg, patients who engage in sexual activity at night should take the antidepressant before falling asleep). This may allow the drug level to be lowest during sexual activity

Switching medications

Case reports, retrospective studies, and RCTs suggest switching to a different antidepressant with less serotonergic activity may be appropriate, particularly if the patient has not responded to the current antidepressant

Adjunctive therapy

RCTs support adjunctive bupropion (≥300 mg/d) or olanzapine (5 mg/d) as treatment for SSRI-induced sexual dysfunction in women Studies have found no improvement in sexual functioning with adjunctive buspirone, granisetron, amantadine, mirtazapine, yohimbine, ephedrine, or ginkgo biloba in women

RCTs: randomized controlled trials; SSRI: selective serotonin reuptake inhibitor
Source: Reference 7,8

Table 3

Phosphodiesterase type 5 inhibitors: A comparison

Medication

Dose rangea

Pharmacokinetics

Side effects

Significant drug interactions

Avanafil

50 to 200 mg, 30 minutes before sexual activity

Bioavailability: N/A (high-fat meal delays Tmax by 60 minutes and reduces Cmax by 24% to 39%; clinically insignificant) Half life: 5 hours Metabolism: CYP3A4

Headache, flushing, nasal congestion, nasopharyngitis, backache

Strong CYP3A4 inhibitors (increased avanafil levels) Contraindicated within 12 hours of nitrate use (eg, nitroglycerin)

Sildenafil

25 to 100 mg, 1 to 2 hours before sexual activity

Bioavailability: 41% (food/high-fat meal delays Tmax by 60 minutes and reduces Cmax by 29%) Half life: 4 hours Metabolism: CYP3A4

Headache, flushing, erythema, indigestion, insomnia, visual disturbances (blue vision)

Strong CYP3A4 inhibitors (increased sildenafil levels) Contraindicated within 24 hours of nitrate use

Tadalafil

10 to 20 mg, 30 minutes before sexual activity

Bioavailability: N/A (not affected by food) Half life: 17.5 hours (duration of action up to 36 hours) Metabolism: CYP3A4

Headache, flushing, indigestion, nasal congestion, dizziness, myalgia, and back pain

Strong CYP3A4 inhibitors (increased tadalafil levels) Contraindicated within 48 hours of nitrate use

Vardenafil

5 to 20 mg, 30 minutes to 2 hours before sexual activity

Bioavailability: 15% for film-coated tablet (high-fat meal reduces Cmax by 18% to 50%) Half life: 4 to 5 hours Metabolism: CYP3A4

Headache, flushing, indigestion, nasal congestion, dizziness, visual disturbances (blue vision)

Strong CYP3A4 inhibitors (increased vardenafil levels) Contraindicated within 24 hours of nitrate use

aTypical dose range for treatment of erectile dysfunction
Cmax: maximum concentration; CYP: cytochrome P450; Tmax: time to maximum concentration
Source: Micromedex® Healthcare Series [Internet database]. Greenwood Village, CO: Thomson Healthcare. Accessed October 10, 2012

Limited evidence for sildenafil

Case reports, a few small open-label trials, and 1 prospective, randomized controlled trial (RCT) have evaluated sildenafil as an adjunctive treatment for serotonergic antidepressant-associated sexual dysfunction in women.6,9 Nurnberg et al6 examined the efficacy of adjunctive sildenafil in women with SSRI-induced sexual dysfunction. This 8-week, placebo-controlled, double-blind, RCT used a flexible dose (50 or 100 mg), intention-to-treat design to assess the effect of sildenafil on 98 premenopausal women whose depression was in remission. Ten patients were taking the serotonin-norepinephrine inhibitor venlafaxine, 1 was taking the TCA clomipramine, and 87 were receiving an SSRI. Patients were instructed to take sildenafil or placebo 1 to 2 hours before sexual activity. The primary outcome was mean change from baseline on the Clinical Global Impression-Sexual Function (CGI-SF) scale.

Women taking sildenafil showed significant improvement compared with those taking placebo, with a treatment difference between groups of 0.8 (95% CI, 0.6 to 1.0; =.001). Additionally, 23% of sildenafil-treated patients reported no improvement with the intervention, compared with 73% of patients receiving placebo. Secondary outcomes using 3 validated scales that evaluated specific phases of sexual function found that patients’ orgasmic function significantly benefited from sildenafil treatment, while desire, arousal, and overall satisfaction were not significantly different.

Although these findings seem to support sildenafil for treating serotonergic antidepressant-associated sexual dysfunction in women, the study had a relatively small treatment effect in a well-defined patient population; therefore, replication in future trials and different patient populations is warranted. Overall, sildenafil was well tolerated, despite patient reports of headaches, flushing, visual disturbances, dyspepsia, nasal congestion, and palpitations. Finally, cost vs benefit should be considered; PDE5 inhibitors may not be covered by insurance or may require prior authorization.

CASE CONTINUED: Symptoms resolve

Bupropion is not an appropriate choice for Mrs. L because of her seizure risk. Mirtazapine is ruled out because in the past she experienced excessive somnolence that impaired her ability to function. You are not comfortable prescribing nefazodone because of its risk of hepatotoxicity or suggesting that Mrs. L take a “drug holiday” (stop taking any antidepressants for a short period) because of the risk of depressive relapse. You suggest that Mrs. L continue to take sertraline because sometimes antidepressant-induced sexual dysfunction resolves after ≥6 months of treatment with the same agent, but she is adamant that her relationship with her husband will deteriorate if she waits that long. She also declines cognitive-behavioral therapy because her job doesn’t allow the time or flexibility to commit to the sessions.

You prescribe sildenafil, 50 mg, and instruct Mrs. L to take 1 tablet 1 to 2 hours before sexual activity. This treatment improves her ability to achieve orgasm. She tolerates the drug well and after 8 weeks of treatment her CGI-SF score improves from 6 at baseline, indicating extreme dysfunction, to 2, indicating normal function. Ten months into her sertraline treatment, Mrs. L discovers she no longer requires sildenafil to achieve orgasm.

Related Resources

  • Nurnberg HG. An evidence-based review updating the various treatment and management approaches to serotonin reuptake inhibitor-associated sexual dysfunction. Drugs Today (Barc). 2008;44(2):147-168.
  • NIH Medline Plus. Sexual problems in women. www.nlm.nih.gov/medlineplus/sexualproblemsinwomen.html.
  • Sturpe DA, Mertens MK, Scoville C. What are the treatment options for SSRI-related sexual dysfunction? J Fam Pract. 2002;51(8):681.

Drug Brand Names

  • Amantadine • Symadine, Symmetrel
  • Avanafil • Stendra
  • Bupropion • Wellbutrin, Zyban
  • Buspirone • BuSpar
  • Citalopram • Celexa
  • Clomipramine • Anafranil
  • Fluoxetine • Prozac
  • Granisetron • Kytril
  • Mirtazapine • Remeron
  • Nefazodone • Serzone
  • Nitroglycerin • Nitrostat
  • Nortriptyline • Pamelor
  • Olanzapine • Zyprexa
  • Paroxetine • Paxil
  • Sertraline • Zoloft
  • Sildenafil • Viagra
  • Tadalafil • Cialis
  • Vardenafil • Levitra
  • Venlafaxine • Effexor

Disclosures

Dr. Burghardt receives grant or research support from the University of Michigan Depression Center.

Ms. Gardner reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

SSRI-induced sexual dysfunction
Dr. Burghardt: Treating SSRI-induced sexual dysfunction in men

References

1. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.

2. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62(suppl 3):10-21.

3. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29(3):259-266.

4. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.

5. Lewis RW, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk factors of sexual dysfunction. J Sex Med. 2004;1(1):35-39.

6. Nurnberg HG, Hensley PL, Heiman JR, et al. Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial. JAMA. 2008;300(4):395-404.

7. Taylor MJ, Rudkin L, Hawton K. Strategies for managing antidepressant-induced sexual dysfunction: systematic review of randomised controlled trials. J Affect Disord. 2005;88(3):241-254.

8. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163(9):1504-1509.

9. Brown DA, Kyle JA, Ferrill MJ. Assessing the clinical efficacy of sildenafil for the treatment of female sexual dysfunction. Ann Pharmacother. 2009;43(7):1275-1285.

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