sign in sign up
<<
Home , Granisetron, Vardenafil

Web audio at CurrentPsychiatry.com Savvy Psychopharmacology Dr. Burghardt: Treating SSRI-induced in men

Sildenafil for SSRI-induced sexual dysfunction in women

Kyle J. Burghardt, PharmD, and Kristen N. Gardner, BS

rs. L, age 27, has a history of major with activity; it depressive disorder with symptoms affects an estimated 50% to 70% of patients Mof anxiety. She was managed suc­ who take SSRIs.2 Sexual dysfunction can cessfully for 2 years with XL, 300 occur with all SSRIs; however, higher rates mg/d, but was switched to venlafaxine, titrat­ of sexual dysfunction are found with citalo- ed to 225 mg/d, after she developed seizures pram, , , and sertraline.3 secondary to a head injury sustained in a car Studies have suggested there may be a dose- Vicki L. Ellingrod, accident. After the switch, Mrs. L’s mood dete­ side effect relationship with SSRI-induced PharmD, BCPP, FCCP riorated and she was hospitalized. Since then, sexual dysfunction.4 Series Editor she’s received several medication trials, includ­ Several factors can increase a patient’s ing paroxetine, 30 mg/d, a selective risk of sexual dysfunction and should be reuptake inhibitor (SSRI), and the anti­ considered before prescribing an antidepres- depressant (TCA) , 75 mg/d, but sant or when a patient presents with new or she could not tolerate these medications be­ worsening sexual dysfunction (Table 1, page cause of severe xerostomia. 30).5 In general, nonserotonergic agents such After taking sertraline, 150 mg/d, for 8 as bupropion, , and weeks, Mrs. L improves and has a Patient Health are associated with lower rates of sexual dys- Questionnaire score of 6, indicating mild de­ pression. Her initial complaints of diarrhea and have resolved, but Mrs. L now reports Practice Points that she and her husband are having marital • Sexual dysfunction can arise from environmental, social, medical, or drug difficulties because she cannot achieve orgasm effects and requires a multifaceted during . She did not have this approach to treatment. problem when she was taking bupropion. Her husband occasionally takes the phosphodies­ • When possible, take a baseline sexual dysfunction measurement to assess if terase type 5 (PDE5) inhibitor before selective serotonin reuptake inhibitor use intercourse, and Mrs. L asks you if this medica­ is correlated with onset or worsening of tion will help her achieve orgasm. sexual dysfunction. • Nonpharmacologic options should DSM-IV-TR defines sexual dysfunction as be considered before and during disturbances in sexual desire and/or in the pharmacotherapy. sexual response cycle (excitement, plateau, • Sildenafil may be useful for treating orgasm, and resolution) that result in marked anorgasmia in women taking serotonergic 1 distress and interpersonal difficulty. Sexual . dysfunction can occur with the use of any •  type 5 inhibitors are Dr. Burghardt is Psychiatric Pharmacogenomics Research not FDA-approved for sexual dysfunction Fellow and Ms. Gardner is a PharmD candidate, University of in women. Current Psychiatry Michigan College of Pharmacy, Ann Arbor, MI. Vol. 12, No. 4 29 Savvy Psychopharmacology

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

function. The pharmacology of these agents trial (RCT) have evaluated sildenafil as an explains their decreased propensity to cause adjunctive treatment for serotonergic anti- Clinical Point sexual dysfunction. These agents increase depressant-associated sexual dysfunction 6,9 6 Although not FDA- levels of in the mesolimbic dopa- in women. Nurnberg et al examined the minergic system either by blocking reuptake efficacy of adjunctive sildenafil in women approved for treating (bupropion) or antagonizing the serotonin with SSRI-induced sexual dysfunction. This sexual dysfunction in subtype-2 receptor and facilitating disinhi- 8-week, placebo-controlled, double-blind, women, adjunctive bition of decreased dopamine downstream RCT used a flexible dose (50 or 100 mg), PDE5 inhibitor (nefazodone and mirtazapine). intention-to-treat design to assess the effect One option for treating antidepressant- of sildenafil on 98 premenopausal women treatment may be induced sexual dysfunction in women is whose depression was in remission. Ten beneficial PDE5 inhibitors, which are used to treat patients were taking the serotonin-norepi- (ED). These medications nephrine inhibitor venlafaxine, 1 was taking ameliorate ED by inhibiting degradation of the TCA , and 87 were receiv- cyclic guanosine monophosphate by PDE5, ing an SSRI. Patients were instructed to take which increases blood flow to the penis dur- sildenafil or placebo 1 to 2 hours before sex- ing sexual stimulation. Although these med- ual activity. The primary outcome was mean ications are not FDA-approved for treating change from baseline on the Clinical Global sexual dysfunction in women, adjunctive Impression-Sexual Function (CGI-SF) scale. PDE5 inhibitor treatment may be beneficial Women taking sildenafil showed sig- for sexual dysfunction in females because nificant improvement compared with those similar mediators, such as nitric oxide and taking placebo, with a treatment difference cyclic guanosine monophosphate, involved between groups of 0.8 (95% CI, 0.6 to 1.0; in the nonadrenergic-noncholinergic signal- P = .001). Additionally, 23% of sildenafil- ing that controls sexual stimulation in men treated patients reported no improvement also are found in female genital tissue.6 with the intervention, compared with 73% of When treating a woman with SSRI- patients receiving placebo. Secondary out- induced sexual dysfunction, consider non- comes using 3 validated scales that evalu- pharmacologic treatments both before and ated specific phases of sexual function found during pharmacotherapy (Table 2).7,8 See that patients’ orgasmic function significantly this article at CurrentPsychiatry.com for a benefited from sildenafil treatment, while Discuss this article at table that compares , side desire, arousal, and overall satisfaction were www.facebook.com/ effects, and drug interactions of the 4 FDA- not significantly different. CurrentPsychiatry approved PDE5 inhibitors—, silde- Although these findings seem to sup- nafil, , and vardenafil. port sildenafil for treating serotonergic antidepressant-associated sexual dysfunc- Limited evidence for sildenafil tion in women, the study had a relatively Case reports, a few small open-label trials, small treatment effect in a well-defined pa- Current Psychiatry 30 April 2013 and 1 prospective, randomized controlled tient population; therefore, replication in Savvy Psychopharmacology

Table 2 Management strategies for SSRI-induced sexual dysfunction Intervention Comments Nonpharmacologic Lifestyle Encourage healthy eating, weight loss, smoking cessation, substance abuse modifications treatment, or minimizing intake to improve patient self-image and overall health Cognitive-behavioral Patients can identify coping strategies for reducing symptom severity and therapy 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%) Clinical Point Pharmacologic Drug holiday May be an option for patients taking antidepressants with shorter half-lives In one small RCT, and patients taking lower doses. Be cautious of empowering patients to stop their own medications as needed women’s orgasmic Dosage reduction Serotonergic antidepressant-induced sexual dysfunction may be related to function significantly dose. Little research has been conducted on this method and the patient’s benefited from clinical status must be considered sildenafil, while 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 desire and arousal take the antidepressant before falling asleep). This may allow the drug level to be lowest during sexual activity were not different Switching Case reports, retrospective studies, and RCTs suggest switching to a medications 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 (5 mg/d) as treatment for SSRI-induced sexual dysfunction in women Studies have found no improvement in sexual functioning with adjunctive , granisetron, , mirtazapine, , ephedrine, or ginkgo biloba in women RCTs: randomized controlled trials; SSRI: selective serotonin reuptake inhibitor Source: Reference 7,8

future trials and different patient populations her ability to function. You are not comfort­ is warranted. Overall, sildenafil was well tol- able prescribing nefazodone because of its erated, despite patient reports of headaches, risk of hepatotoxicity or suggesting that flushing, visual disturbances, dyspepsia, Mrs. L take a “drug holiday” (stop taking any nasal congestion, and palpitations. Finally, antidepressants for a short period) because cost vs benefit should be considered; PDE5 of the risk of depressive relapse. You suggest See this article at inhibitors may not be covered by insurance that Mrs. L continue to take sertraline because CurrentPsychiatry.com or may require prior authorization. sometimes antidepressant-induced sexual for a table that compares dysfunction resolves after ≥6 months of treat­ 4 FDA-approved PDE5 inhibitors CASE CONTINUED ment with the same agent, but she is adamant Symptoms resolve that her relationship with her husband will Bupropion is not an appropriate choice for deteriorate if she waits that long. She also de­ Mrs. L because of her seizure risk. Mirtazapine clines cognitive-behavioral therapy because is ruled out because in the past she experi­ her job doesn’t allow the time or flexibility to Current Psychiatry enced excessive somnolence that impaired commit to the sessions. Vol. 12, No. 4 31 continued Savvy Psychopharmacology

fore sexual activity. This treatment improves Related Resources her ability to achieve orgasm. She tolerates • Nurnberg HG. An evidence-based review updating the vari­ the drug well and after 8 weeks of treatment ous treatment and management approaches to serotonin her CGI-SF score improves from 6 at baseline, reuptake inhibitor-associated sexual dysfunction. Drugs Today (Barc). 2008;44(2):147-168. indicating extreme dysfunction, to 2, indi­ • NIH Medline Plus. Sexual problems in women. www.nlm. cating normal function. Ten months into her nih.gov/medlineplus/sexualproblemsinwomen.html. sertraline treatment, Mrs. L discovers she no • Sturpe DA, Mertens MK, Scoville C. What are the treatment longer requires sildenafil to achieve orgasm. options for SSRI-related sexual dysfunction? J Fam Pract. 2002;51(8):681. References Drug Brand Names 1. Diagnostic and statistical manual of mental disorders, 4th ed, Amantadine • Symadine, Nefazodone • Serzone text rev. Washington, DC: American Psychiatric Association; 2000. Symmetrel Nitroglycerin • Nitrostat Avanafil • Stendra Nortriptyline • Pamelor 2. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a Bupropion • Wellbutrin, Olanzapine • Zyprexa prospective multicenter study of 1022 outpatients. Spanish Clinical Point Zyban Paroxetine • Paxil Working Group for the Study of Psychotropic-Related Sexual Buspirone • BuSpar Sertraline • Zoloft Dysfunction. J Clin Psychiatry. 2001;62(suppl 3):10-21. Overall, sildenafil Citalopram • Celexa Sildenafil • Viagra 3. Serretti A, Chiesa A. Treatment-emergent sexual Clomipramine • Anafranil Tadalafil • Cialis dysfunction related to antidepressants: a meta-analysis. J was well tolerated, Fluoxetine • Prozac Vardenafil • Levitra Clin Psychopharmacol. 2009;29(3):259-266. despite patient Granisetron • Kytril Venlafaxine • Effexor 4. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual Mirtazapine • Remeron dysfunction among newer antidepressants. J Clin Psychiatry. reports of 2002;63(4):357-366. Disclosures 5. Lewis RW, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk headaches, flushing, Dr. Burghardt receives grant or research support from the factors of sexual dysfunction. J Sex Med. 2004;1(1):35-39. University of Michigan Depression Center. 6. Nurnberg HG, Hensley PL, Heiman JR, et al. Sildenafil treatment visual disturbances, of women with antidepressant-associated sexual dysfunction: a Ms. Gardner reports no financial relationship with any com­ randomized controlled trial. JAMA. 2008;300(4):395-404. pany whose products are mentioned in this article or with and other effects 7. Taylor MJ, Rudkin L, Hawton K. Strategies for managing manufacturers of competing products. 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. You prescribe sildenafil, 50 mg, and in­ 9. Brown DA, Kyle JA, Ferrill MJ. Assessing the clinical efficacy of sildenafil for the treatment of female sexual dysfunction. Ann struct Mrs. L to take 1 tablet 1 to 2 hours be­ Pharmacother. 2009;43(7):1275-1285.

Current Psychiatry 32 April 2013 Savvy Psychopharmacology

Table Phosphodiesterase type 5 inhibitors: A comparison Significant drug Medication Dose rangea Pharmacokinetics interactions Avanafil 50 to 200 mg, : N/A Headache, flushing, Strong CYP3A4 30 minutes (high-fat meal delays nasal congestion, inhibitors (increased before sexual Tmax by 60 minutes nasopharyngitis, avanafil levels) activity and reduces Cmax by backache Contraindicated 24% to 39%; clinically within 12 hours insignificant) of use Half life: 5 hours (eg, nitroglycerin) Metabolism: CYP3A4 Sildenafil 25 to 100 mg, Bioavailability: 41% (food/ Headache, Strong CYP3A4 1 to 2 hours high-fat meal delays flushing, erythema, inhibitors (increased before sexual Tmax by 60 minutes and indigestion, sildenafil levels) activity reduces Cmax by 29%) insomnia, visual Contraindicated Half life: 4 hours disturbances (blue within 24 hours of vision) Metabolism: CYP3A4 nitrate use Tadalafil 10 to 20 mg, Bioavailability: N/A Headache, flushing, Strong CYP3A4 30 minutes (not affected by food) indigestion, nasal inhibitors (increased before sexual Half life: 17.5 hours congestion, tadalafil levels) activity (duration of action up dizziness, myalgia, Contraindicated to 36 hours) and back pain within 48 hours of Metabolism: CYP3A4 nitrate use Vardenafil 5 to 20 mg, Bioavailability: 15% Headache, flushing, Strong CYP3A4 30 minutes for film-coated tablet indigestion, inhibitors (increased to 2 hours (high-fat meal reduces nasal congestion, vardenafil levels) before sexual Cmax by 18% to 50%) dizziness, visual Contraindicated activity Half life: 4 to 5 hours disturbances (blue within 24 hours of vision) Metabolism: CYP3A4 nitrate use aTypical dose range for treatment of erectile dysfunction Cmax: maximum concentration; CYP: ; Tmax: time to maximum concentration Source: Micromedex® Healthcare Series [Internet database]. Greenwood Village, CO: Thomson Healthcare. Accessed October 10, 2012

Current Psychiatry Vol. 12, No. 4 A