Options for Management of Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction
By H. George Nurnberg, MD |
August 1, 2007
Dr Nurnberg is professor and executive vice chair in the department of psychiatry, Health Sciences Center, University of New Mexico School of Medicine, Albuquerque. He reports that he is on the speakers' bureaus of Pfizer Pharmaceuticals, Eli Lilly and Company, Glaxo Inc, and Wyeth; a consultant to Pfizer, Eli Lilly, and Glaxo; and has received grants/research support from Pfizer, Eli Lilly, Bristol-Myers Squibb Com-pany, and Wyeth.
With continuation open-label treatment of SRI-associated SD in partial responders and nonresponders, 81% became full responders (75% of partial and nonresponders to double-blind sildenafil(Drug information on sildenafil); and 85% of partial and nonresponders to blind placebo) (Figure 2). Significant improvement occurred in measures of erectile function and ejaculatory delay, with overall satisfaction in both groups with persisting remission of MDD in all patients who continued stable-dose SRI antidepressant treatment. Sildenafil was well tolerated, with no discontinuations attributed to adverse events in both open and blind phases.43 Similar studies with tadalafil(Drug information on tadalafil) and vardenafil(Drug information on vardenafil) treatment of depression-associated or antidepressant-associated ED showed similar results, with patients attaining successful intercourse during double-blind38 (58%) and open-label (77%) treatment.44,45
The use of sildenafil and other PDE5Is for antidepressant-induced SD in women is off-label. With women exibiting a higher prevalence of MDD, greater severity of treatment-emergent SD, and greater use of SSRIs, it was expected that interest regarding the potential effectiveness of selective PDE5Is in women would occur. Mechanisms analogous to male sexual function apply in female sexual (dys)function. PDE5 and not-otherwise-specified isoforms are present in human genital tissue and can respond to the enhancement of the NO-cGMP axis.46-48
Sildenafil treatment for female sexual disorder (FSD) is associated with clitoral erection, labial swelling, and vaginal lubrication upon sexual stimulation, but these reports are more discordant between subjective experience and physiological arousal. Initial reports of PDE5I-treatment of FSD described potential efficacy, but other reports in FSD of various etiologies were equivocal and raised important questions needing further study.48-50
Open-label reports show improvements with SRI-associated SD treatment.49,50 In a study by Nurnberg and colleagues,50 9 of 10 women with MDD in remission, without preexisting SD and serotonergic antidepressant-induced anorgasmia, had effective reversal of delayed orgasm.
Reports from a study of flexible-dose sildenafil for serotonergic antidepressant-associated SD in 100 women following the same protocol as in the study in men indicate that SRI-associated SD in women improved with sildenafil treatment while the patients continued their prescribed antidepressant.21,22 The women with MDD in remission, without preexisting SD, and SRI-associated SD randomly assigned to sildenafil or placebo (50 or 100 mg) as needed before sexual activity reported significant improvement in SD; 67% of all SRI-associated SD treatment responders were treated with sildenafil and 33% with placebo (P < .001).
The domains with the most significant improvement were orgasm delay and overall satisfaction. Female treatment responders had higher initial hormone levels of free testosterone and thyroxine. That suggests that PDE5I-treatment responders may have different hormone profiles than nonresponders, and hormonal status is an important marker associated with sildenafil treatment outcomes.51 This trial allowed female patients with SRI-associated SD to maintain treatment adherence and depression remission. The decision by industry to terminate trials pursuing an indication for PDE5I use in women may have been premature, and further studies are needed.
The evidence reviewed here suggests that the PDE5Is may effectively manage SRI-associated SD and support antidepressant treatment adherence in men and women. The message to physicians prescribing antidepressants or other medications with associated SD is to tell their patients not to stop the primary drugs if sexual adverse effects occur, but instead, encourage the patient to discuss these effects, and further assure them that these adverse effects can often be addressed without stopping medication. Table 2 summarizes recommended clinical guidelines for patients stabilized on a dose of prescribed antidepressant or other medication with sexual adverse effects.
Initial work has been promising, but further study is needed to determine whether PDE5I reversal of adverse medication effects on sexual function can be extended to women, and to other disease states or conditions in which treatment-associated adverse effects are likely to develop. The evidence-based literature for PDE5Is is compelling, particularly when compared with former expert-opinion-driven folk treatments. With the current emphasis on treatment effectiveness, active treatment of treatment-emergent adverse effects would seem to be essential and should be incorporated into efficacy studies. Keeping patients treatment-adherent is a direct and cost-effective way of improving disease management outcomes.
- Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003; 289:56-64.
- Rudkin L, Taylor MJ, Hawton K. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2004;(4):CD003382.
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