How do SSRIs cause sexual dysfunction?

The advent of sildenafil underscored the importance of nitric oxide-mediated relaxation pathways in treating erectile dysfunction. Nitric oxide plays an important role in mediating the penile vasculature changes essential for erection and also is hypothesized to promote penile smooth muscle relaxation via cyclic guanosine monophosphate, there-by contributing to physiologic erection.¹⁵ Paroxetine is known to inhibit nitric oxide synthase, which reduces nitric oxide levels. The exact mechanism of this interaction remains unclear; however, it is hypothesized that 3 nitric oxide synthase isoenzymes are structurally similar to cytochrome P450 (CYP450). Paroxetine is a strong CYP2D6 inhibitor, which contributes to low nitric oxide levels in patients taking the drug.¹⁶

SSRIs and sexual response

Because decreased libido is part of depressive psychopathology,⁵ it is difficult to attribute loss of sexual desire directly to SSRIs. Nonetheless, SSRIs are associated with a risk of clinically significant loss of sexual desire that may resemble moderate to severe hypoactive sexual desire disorder.¹⁷ Reduced mesolimbic dopaminergic activity as a result of inhibitory serotonergic midbrain raphe nuclei projections is 1 possible cause.¹⁸ This hypothesis has lead investigators to examine drug targets in the CNS for hypoactive sexual desire disorder that would inhibit serotonergic tone and lead to brain dopaminergic system stimulation.

Another putative hypothesis for SSRI-induced loss of sexual desire is the role of 5-HT1A receptor-mediated norepinephrine neurotransmission. Because the sympathetic nervous system is believed to be involved in genital arousal in women, a small study analyzed the effect of sympathetic activation on SSRI-induced sexual dysfunction.¹⁹ Women who received paroxetine and sertraline—both are highly selective for 5-HT1A—showed improvement in sexual arousal and orgasm after taking ephedrine before sexual activity.¹⁹ Women who took fluoxetine, which is less selective for 5-HT1A, show no change or decreased sexual function.

SSRIs are associated with reduced nocturnal penile erections and severe erectile dysfunction, but the relationship is not robust.¹⁷ SSRI-induced suppression of rapid eye movement sleep²⁰ may partially explain reduced nocturnal and early morning erections. Supraspinal areas and preganglionic sacral neurons involved in sexual excitement also are reported to have substantial serotonergic activity, which suggests that serotonin has a direct role in erectile dysfunction at a comparative peripheral level.²¹ However, a recent study¹⁷ found no difference in flaccid and peak systolic velocity when comparing patients taking SSRIs with those who do not. This indicates that SSRIs’ affect on spontaneous and sexually aroused erections may be mediated at both central and peripheral levels.

Delayed ejaculation frequently is associated with SSRIs¹⁷ and usually is not caused by depressive psychopathology.²² Animal studies show that increased serotonergic tone predicts ejaculatory latency by acting as an inhibitor at the hypothalamus level.²³ In contrast, noradrenergic tone enhances ejaculation.²⁴ Antidepressants that increase noradrenaline levels and serotonin levels—such as serotonin-norepinephrine reuptake inhibitors—induce milder ejaculatory delay.¹⁷

A recent study¹⁷ found impaired climax and reduced libido in partners of patients using SSRIs. Patients receiving SSRIs report less frequent sexual intercourse and heightened guilt associated with masturbation, and SSRIs are associated with psychosocial factors such as higher stress at work and increased risk of conflicts with partners and other family members.¹⁷ In addition to biologic mechanisms, these psychosocial and intra-couple factors might contribute to SSRI-associated sexual dysfunction. However, because the temporal association between SSRI use and psychosocial dysfunction is ambiguous, this hypothesis should be interpreted with caution.

SSRIs have been associated with lower serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone.²⁵ However, these findings need to be replicated before drawing firm conclusions on intermediary role of hormones in SSRI-emergent sexual dysfunction.

Be aware that other medications may contribute to sexual dysfunction experienced by a patient receiving an SSRI (Table 3).²⁶

Table 3

Other than SSRIs, which medications can cause sexual dysfunction?

SSRIs for premature ejaculation?

Because SSRIs can cause delayed ejaculation, they have been used off-label to treat premature ejaculation.²⁷ For this purpose, paroxetine and sertraline have been prescribed with daily or on-demand dosing before sexual intercourse²⁸ and daily fluoxetine has been used.²⁹ However, none of these SSRIs is FDA-approved for treating premature ejaculation, daily dosing of SSRIs exposes patients to undesirable side effects, and inconsistent use of paroxetine can lead to discontinuation syndrome.

These concerns have lead researchers to seek an SSRI that could be used on as-needed basis and would not cause some of the deleterious side effects associated with current SSRIs. The short-acting SSRI dapoxetine is in FDA review for treating premature ejaculation; the drug is approved for this use in several countries outside the United States.³⁰