How do SSRIs cause sexual dysfunction?

Although selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed¹ and are better tolerated than older antidepressants, side effects such as sexual dysfunction limit patient acceptance of these medications. DSM-IV-TR categorizes medication-induced sexual dysfunction as a type of substance-induced sexual dysfunction.² These dysfunctions are characterized by impairment of various sexual response phases (Table 1).^2,3

Estimating the true incidence and prevalence of SSRI-related sexual dysfunction can be difficult. Zimmerman et al⁴ compared psychiatrists’ clinical assessments of depressed patients receiving ongoing treatment with results of a standardized side effects questionnaire and found that even though psychiatrists regularly inquired about sexual side effects, on the questionnaire patients reported higher rates of almost all sexual dysfunctions. The incidence of SSRI-induced sexual dysfunction also can be difficult to ascertain because some sexual dysfunctions frequently accompany a primary psychiatric disorder⁵ or physical illness. Balon⁶ suggested that the incidence of SSRI-associated sexual dysfunction is 30% to 50%, although others have reported higher incidences.

Few quality studies have focused on identifying the exact nature and causes of SSRI treatment-emergent sexual dysfunction. This article describes mechanisms that may be fundamental to SSRI-associated sexual dysfunction.

Table 1

Sexual dysfunction and the sexual response cycle

Not just serotonin

Although SSRIs are relatively selective for the serotonergic system, they affect other neurotransmitter systems as well (Table 2).⁷ For example, at high dosages paroxetine is believed to block norepinephrine reuptake, and it has a clinically significant anticholinergic effect. Also, sertraline is a potent reuptake inhibitor of dopamine.⁸ Therefore, our discussion will include these neurotransmitters.

In their dual control model of male sexual response, Bancroft et al⁹ discuss the interplay between excitatory and inhibitory mechanisms at the central and peripheral levels. For example, they describe the role of norepinephrine mediation in the central arousal system via the disinhibition of dopaminergic and a possible testosterone mechanism. They also point to possible inhibition of central sexual arousal by neuropeptidergic and serotonergic mechanisms.

Evidence linking serotonin to sexual dysfunction is inconclusive because there are no exclusively serotonergic agents. Drugs frequently used to test these hypotheses often affect other neurotransmitters, which means conclusions are not specific to serotonin. Animal studies of the impact of serotonin agonist and antagonist agents on mounting and ejaculation have reported inconsistent results.¹⁰ Differential roles of 5-HT1 and 5-HT2 receptor activation on sexual behavior may explain some of these inconsistencies.⁸ However, 1 study found that antiserotonergic pharmacologic agents enhance sexual excitation in laboratory animals,¹¹ and a separate study showed that severing serotonergic axons in the medial forebrain bundle in male rats facilitated ejaculation.¹²

Monteiro et al¹³ found a high incidence of anorgasmia in previously orgasmic patients after they received clomipramine, which may be partially attributed to the drug’s serotonergic action. This prompted researchers to hypothesize that central serotonergic tone inhibits sexual behavior. However, based on current evidence, it would be best to consider serotonin as having a modulating effect¹⁰—as opposed to a complete inhibitory effect—on human sexual behavior.

Regarding the parasympathetic system, it was long believed that cholinergic innervations mediate penile erection. However, a more plausible hypothesis may be that parasympathetic cholinergic transmission at best has a modulating effect when other neurotransmitters—primarily the adrenergic system—are affected by concomitant pharmacologic interventions. Segraves¹⁰ proposed that cholinergic potentiating of adrenergic activity may be primarily responsible for bethanechol-induced reversal of SSRI-induced sexual dysfunction.

The adrenergic system is believed to play a role in penile erection and ejaculation.¹⁰ Adrenergic fibers innervate the vas deferens, seminal vesicles, trigone of the urinary bladder, and proximal urethra.¹⁴ Penile contractile and erectile tissue is richly innervated by the adrenergic nerve fibers.¹⁰ Ejaculation is mediated by α1-adrenergic receptors.¹⁰

Table 2

Neurotransmitters affected by SSRIs

The role of nitric oxide synthase