Among 25 to 30 million Americans in whom depression is diagnosed annually, 18 to 25 million are treated with antidepressants, of which 90% are SSRI or non-selective serotonin reuptake inhibitor (SRI) antidepressants, the most frequently prescribed medications for all outpatients aged 18 to 65 years.^1,2 Treatment-emergent adverse effects (eg, sexual dysfunction [SD], weight gain, sleep disturbance) account for 75% of premature treatment terminations and place patients at significantly increased risk for relapse, recurrence, morbidity, and mortality.³ With treatment-associated SD reported to occur in 40% to 70% of patients using SRIs,⁴ an iatrogenic SD may develop in 10 to 15 million patients annually. If this issue is not addressed, as many as 87% of these patients will become noncompliant.^5,6

SRI-associated SD usually occurs early in treatment, is persistent, and rarely remits spontaneously. It is frequently overlooked or misattributed to major depressive disorder (MDD). Despite an up to 80% potential response rate to the first or second SRI prescribed, up to 68% withdrawal rates within the first 3 months of treatment indicate that patients do not continue their prescribed medication for a sufficient period.^7,8 SRI-associated SD is a major factor responsible for this.^3,5 It is interesting, however, to note that although physicians underestimate the occurrence of iatrogenic SD, it significantly influences their selection or switching of antidepressant agents.⁹

Only a small number of double-blind, randomized, placebo-controlled trials (RCTs) have studied management of SRI-associated SD, and most of these found the agents tested no better than placebo. The only agents that have shown broad-based efficacy and effectiveness are selective type 5 phosphodiesterase inhibitors (PDE5Is).¹⁰ Without evidence-based treatments of SRI-associated SD, physicians have relied on clinical wisdom, anecdotal reports, case reports, and open-label studies to manage SD, which has left patients exposed to excessive random drug interventions aimed at mitigating the adverse sexual effects of SRIs.

Finding effective treatments for SRI-associated SD would be a significant advance for improving MDD treatment outcomes. In addition, SRI-associated SD can serve as a model for understanding relationships between treatment-emergent adverse effects in other conditions in which SD may be both a symptom of the primary disorder and an adverse effect of the medication used to treat it. Advances in nonadrenergic-noncholinergic novel signal transduction and the development of PDE5Is offer new evidence-based treatments for SD of different etiologies, for improving depression management with antidepressant-associated SD, and for developing treatments in other conditions in which medication causes SD. This article reviews the comparative effectiveness of treatment options for SRI-associated SD.

Classification and prevalence of sexual dysfunction

The DSM-IV classification system for SD is based on a modified triphasic model and categorizes patients according to etiology, gender, and domain: interest, response, and orgasm. A separate category, sexual pain disorders, includes dyspareunia, vaginismus, and priapism. Premature ejaculation in men and premature orgasm in women are residual categories. DSM-IV has a separate category for cases that are secondary to medical treatment or substance use; antidepressant-associated SD is classified as substance-induced.

Epidemiological surveys of SD report rates of approximately 40% in women and 30% in men. These rates may be somewhat overreported, depending on whether a "significant distress" criterion is required.¹¹ The most common complaints in women are low sexual desire (32%), inability to achieve orgasm (26%), and sex not being pleasurable (23%). Premature ejaculation (31%), performance anxiety (18%), and low sexual desire (15%) are the most common in men. With increasing age, men and women report lower frequencies of sexual intercourse;increased rates of erectile dysfunction; and decreased lubrication, orgasm, and enjoyment of sexual activity.^13,14

Patients with MDD should be systematically evaluated for SD. De-creased libido is reported in about 70% of patients with depression but is not a reliable indicator because it is easily confused with anhedonia¹⁴; 49% of women and 26% of men with MDD reported no sexual activity in the preceding month.¹⁵ Patients with MDD report decreased genital sensitivity, decreased sexual interest, decreased sexual arousal, and orgasm difficulties. Overall, 48% of women and 60% of men reported delayed or absent orgasm.¹⁶ SD severity appears to be correlated with depression severity.^12,13

Product inserts for antidepressants significantly underestimate the risk of SD (0% to 14%) because they are derived from spontaneous reports instead of systematic assessments that would reveal rates as high as 70%.^17-19 A causal connection is clear because SD develops in healthy volunteers over a 2- to 4-week period when taking SRIs; this remits on drug discontinuation.²⁰

Most patients with SRI-associated SD present with similar rates of multiple complaints, including orgasm (delayed or anorgasmia), decreased satisfaction, arousal disturbance (lubrication/erection), and decreased interest.^21,22 Figure 1 presents the distribution of men and women with SRI-associated SD in our trials. To determine which is primary, secondary, or a halo effect requires a systematic and comprehensive evaluation that must take into account:

• Preexisting SD not associated with depression or anxiety (with or without treatment), relationship problems, risk factors (eg, obesity, hypertension, alcohol(Drug information on alcohol)/drug abuse), and other external factors or lifestyle conditions.
• SD associated with depression.
• SD associated with antidepressant treatment in the context of treatment response (remission), dose, other concurrent Axis I to Axis III conditions, and psychosocial (relationship, work, stress, financial) factors.

Over time, some patients with depression-associated SD will improve with treatment, while some will experience an exacerbation when taking an antidepressant. In other patients, antidepressant-associated SD will develop de novo.⁴ Women appear to experience a higher base rate of depression-associated SD than men; men experience antidepressant-associated SD more frequently but with less severity and improve less than women with effective antidepressant treatment.²³

Although SSRIs replaced tricyclic antidepressants as first-line agents because of their improved side-effect profile, more efficient dosing, and overall safety and efficacy, the initial enthusiasm was dampened as more attention was paid to their adverse effects on sexual function. Although the effects on sexual function suggest a link to serotonergic mechanisms, this is not the full explanation because different serotonin receptors have different influences on sexual function. For example, 5HT-2 and 5HT-3 receptor stimulation is inhibitory to sexual function compared with 5HT-1 stimulation, which is facilitory.^4,24 The final expression of antidepressant-associated SD is a cumulative effect, derived from factors such as receptor selectivity, receptor binding, potency, and other properties of the specific antidepressant (Table 1).

	TABLE 1 Pharmacokinetic profiles of some antidepressants4,25
	Antidepressant		Associated with
	Citalopram		Persistence of heightened prolactin levels
	Paroxetine		M3 cholinergic receptor blockade; potential nitric  oxide synthase inhibition with P-450 isozyme  inhibition
	Fluoxetine and paroxetine(Drug information on paroxetine)		Potential nitric oxide synthase inhibition with P- 450 isozyme inhibition
	Bupropion and nefazadone		Direct serotonergic 2C agonist affects by the  mCPP metabolite of nefazodone(Drug information on nefazodone);  dopamine/norepinephrine reuptake inhibition and  potential sexual dysfunction–sparing effects
	1-pyriminylpiperazine metabolite of buspirone(Drug information on buspirone)		α2-Adrenergic antagonist
	Dual action venlafaxine at increasing doses		Noradrenergic effects (α-adrenergic agonist)
	Fluoxetine		Prolonged active metabolite accumulation  prolongs effects

This variability was demonstrated in a study of more than 6000 patients using standardized instruments to evaluate SD in a primary care setting. The study found the following rates of antidepressant- associated SD with various agents: bupropion IR (22%), bupropion SR (25%), nefazodone (28%), SSRIs (39% to 43%), venlafaxine (42%), and mirtazapine(Drug information on mirtazapine) (41%), which were lower when patients with comorbidities and concurrent risk factors were factored out.²⁵ However, while differences between SRIs and other antidepressants suggest differential effects, their clin-ical significance needs to be better understood.