Explanations of the causes and mechanisms of MDD and SRI treatment-emergent SD were essentially post hoc to assumptions that elevated central serotonin levels were causal. With the development of PDE5Is and the awareness of the role of nitric oxide and other novel signaling transmitters, the involvement of dopamine(Drug information on dopamine), adrenergic, cholinergic, and many other neu- rohormonal, neurotransmitter, and other peripheral agents (eg, N-methyl- d-aspartate, neuropeptides, hormones, g-aminobutyric acid) in the complex sequencing of events that constitute biological and behavioral sexual function became better understood. An explanatory model, that could be empirically tested, was needed that recognized the extensive cross-talk and direct/indirect dynamic interactions occurring among various central, autonomic, and peripheral neurotransmitter and neuroendocrine systems.Management of antidepressant-associated sexual dysfunction
In almost 5 decades of antidepressant use, treatment recommendations for antidepressant-associated SD have increased. They fall into 4 general categories: (1) use of antidotes by agonists, partial agonists, or antagonist agents; (2) avoidance by use of nonserotonergic antidepressants with neutral or proactive pharmacokinetics for sexual function; (3) augmentation with or switching to primarily nonserotonergic antidepressants after the emergence of treatment-associated SD; and (4) adaptation or tolerance by waiting, dose adjustment, or drug holiday.
Most of the evidence for antidotes comes from single case reports or open-treatment case series. Initially promising antidotes failed to separate from placebo in RCTs. Reports for the use of mianserin(Drug information on mianserin), cyproheptadine(Drug information on cyproheptadine), Ginkgo biloba, amantadine(Drug information on amantadine), loratadine(Drug information on loratadine), and other agents have not demonstrated significant improvement for antidepressant-associated SD over placebo. The conclusions in these trials are also limited by their methodological shortcomings.4,10,24,26,27 For example, buspirone(Drug information on buspirone) was reported to be effective for SSRI-induced SD as a post hoc secondary finding in a treatment-augmentation study of refractory depression.29 Another prospective buspirone RCT for treatment of antidepressant-associated SD showed no significant effect with higher doses than in the augmentation study.27,28
Another approach and variant of antidote approaches is to select an antidepressant agent with a receptor profile that is less likely to be associated with the development of SD (eg, bupropion, nefazodone(Drug information on nefazodone), mirtazapine(Drug information on mirtazapine), reboxetine(Drug information on reboxetine)). There are data showing that when prescribed as initial agents, these antidepressants may be associated with lower rates of antidepressant-associated SD compared with some SSRIs.29 However, despite its widespread promotion and perception of efficacy, bupropion has not been shown to be significantly better than placebo as a treatment for SSRI-associated SD in RCTs.30
Switching antidepressants in a patient with MDD who has SRI-associated SD and is responding to the antidepressant adds the risk that the patient may be switched from an effective agent to an agent that may not be effective, as well as the risk for potential relapse or recurrence.31
Waiting for adaptation may be the most frequently used approach. Placebo-controlled studies, or those following patients over time, have shown that spontaneous remission occured in only 6% to 20% of patients.26,27 Dose reduction to reestablish sexual function is not a practical strategy, since it may result in a subtherapeutic level with consequent relapse or recurrence of depression. There is no evidence to support the use of a drug holiday, although one uncontrolled study found favorable results after patients discontinued their SSRI for up to 3 days and then restarted medication at the usual dose.32
Improvement in sexual functioning during a drug holiday cannot be expected with a longer-acting drug such as fluoxetine(Drug information on fluoxetine), presumably because of the metabolite's long half-life. In addition, intermittent dosing puts patients at risk for serotonergic discontinuation syndrome and promotes noncompliance with medication.
With the exception of PDE5Is (sildenafil, tadalafil(Drug information on tadalafil), vardenafil(Drug information on vardenafil)), the data on current SRI-associated SD management approaches with other antidotes, augmentation, switching antidepressants, or waiting for tolerance to develop, are without evidence and rely on clinical wisdom.10,21,22 Psychiatrists will need to familiarize themselves further with these PDE5I agents, which can offer effective management for SRI-associated SD.Selective phosphodiesterase-5 inhibitors
The currently available PDE5Is are competitive and selective inhibitors of cyclic guanosine monophosphate [cGMP] specific phosphodiesterase-type five [PDE-5]. They have been shown to be effective in treating erectile dysfunction (ED) with a diverse etiological spectrum in men and are well-tolerated oral agents that enable a natural response to sexual stimulation by acting at the end organ to permit vascular engorgement and penile erection.33,34 PDE5Is distributed in smooth muscle cells of the corpus cavernosum, blood vessels, and circulating platelets enhance the signal transduction of nitric oxide--cGMP on smooth-muscle relaxation in the corpus cavernosum by inhibiting PDE-5 catabolism of cGMP.35 PDE5Is have advanced the understanding of physiological mechanisms of SD and offer a new approach for the treatment of medication-associated SD.
The efficacy of PDE5Is for the treatment of ED in men with comorbid depression was first reported in a retrospective analysis of data from 3414 men with diverse etiologies, including current or past history of depression from 11 double-blind, placebo-controlled clinical trials.36 Sildenafil(Drug information on sildenafil) 25 to 100 mg taken approximately 1 to 2 hours before sexual activity showed significant efficacy on the erectile function domain of the International Index of Erectile Function (IIEF). Mean improvement in baseline ED scores was significantly higher in those treated with sildenafil than in those treated with placebo (P < .001).PDE5I efficacy for ED with comorbid mild to moderate or major depression was demonstrated in 3 RCTs: in men with depression in remission, in men with untreated mild or major depression,and in men with residual ED and treated MDD.37-39 Improvement from baseline in IIEF erectile function scores was significantly greater with a PDE5I than with placebo (P < .0001). In addition, regardless of whether treatment was with PDE5I or placebo, the mean score on the Hamilton Rating Scale for Depression (HAM-D) improved to a greater extent in treatment responders than in nonresponders, suggesting that the relationship between ED and depression is complex and multidirectional.
The efficacy of sildenafil in the treatment of antidepressant-associated SD was first noted in several case reports and small open-label studies.4,10,22 A retrospective subanalysis of several double-blind, placebo-controlled trials showed significantly greater improvement in mean scores for erectile function, orgasm, and satisfaction domains of the IIEF (P < .01), suggesting the effectiveness of sildenafil for antidepressant-associated SD.40
The strongest evidence supporting PDE5I efficacy in the treatment of antidepressant-associated ED is provided by 3 prospective, double-blind RCTs in men with MDD in remission and SRI-associated SD. The men were enrolled on the basis of treatment with a selective or nonselective SRI for a minimum of 12 weeks (last 6 weeks stable), antidepressant-associated SD for at least 4 weeks, and no history of SD before the onset of depression or antidepressant treatment.21,41,42 Sildenafil was taken before sexual activity, initially at 50 mg, with the dose increased to 100 mg if needed. Sildenafil-assigned patients reported much/very much improved sexual function, including erectile function, ejaculation, orgasm, and satisfaction compared with those on placebo.
All patients maintained remission of depression, supporting the importance of maintaining medication adherence by managing treatment-emergent adverse effects to improve treatment outcomes. In addition, antidepressant- associated SD responders showed significant additional improvement in depression severity, even though in remission (HAM-D score of 7 or greater) at baseline. Although the FDA indication is specific to ED, as a whole, the empirical data for these studies are consistent with those showing that sildenafil provides significant improvements in SRI-associated SD, not limited to ED but including desire, delayed ejaculation/ orgasm, and satisfaction, which can directly or indirectly improve with treatment.