How do SSRIs cause sexual dysfunction? Understanding key mechanisms can help improve patient adherence, prognosis lthough selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed1 and are better Atolerated 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 im- pairment 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 assess- ments of depressed patients receiving ongoing treatment with results of a standardized side effects questionnaire and found that even though psychiatrists regularly in- quired about sexual side effects, on the questionnaire © 2010 PHOTOS.COM patients reported higher rates of almost all sexual dys- Deepak Prabhakar, MD, MPH functions. The incidence of SSRI-induced sexual dysfunc- Chief Resident, Outpatient Department tion also can be difficult to ascertain because some sexual Richard Balon, MD dysfunctions frequently accompany a primary psychiat- Professor ric disorder5 or physical illness. Balon6 suggested that the • • • • incidence of SSRI-associated sexual dysfunction is 30% to Department of Psychiatry and Behavioral 50%, although others have reported higher incidences. Neurosciences Few quality studies have focused on identifying the ex- Wayne State University act nature and causes of SSRI treatment-emergent sexual Detroit, MI dysfunction. This article describes mechanisms that may be fundamental to SSRI-associated sexual dysfunction. Not just serotonin Although SSRIs are relatively selective for the serotoner- Current Psychiatry 30 December 2010 gic system, they affect other neurotransmitter systems Table 1 Sexual dysfunction and the sexual response cycle Phase Description Dysfunction/disorder Desire Characterized by sexual Hypoactive sexual desire disorder fantasies and the desire Sexual aversion disorder to have sex Hypoactive sexual desire disorder due to a general medical condition Substance-induced sexual dysfunction with impaired desire Excitement Subjective sense Female sexual arousal disorder of sexual pleasure Erectile disorder and accompanying physiologic changes Erectile disorder due to a general medical condition Dyspareunia due to a general medical condition Substance-induced sexual dysfunction with impaired arousal Clinical Point Orgasm Peaking of sexual Female orgasmic disorder pleasure with release Although SSRIs are Male orgasmic disorder of sexual tension relatively selective Premature ejaculation Other sexual dysfunction due to a general medical for serotonin, they condition also affect other Substance-induced sexual dysfunction with impaired neurotransmitter orgasm systems Resolution A sense of general Postcoital dysphoria relaxation, well-being, Postcoital headache and muscle relaxation Source: References 2,3 as well (Table 2, page 32).7 For example, at imal studies of the impact of serotonin ago- high dosages paroxetine is believed to block nist and antagonist agents on mounting and norepinephrine reuptake, and it has a clini- ejaculation have reported inconsistent re- cally significant anticholinergic effect. Also, sults.10 Differential roles of 5-HT1 and 5-HT2 sertraline is a potent reuptake inhibitor of receptor activation on sexual behavior may dopamine.8 Therefore, our discussion will explain some of these inconsistencies.8 How- include these neurotransmitters. ever, 1 study found that antiserotonergic In their dual control model of male sex- pharmacologic agents enhance sexual exci- ual response, Bancroft et al9 discuss the in- tation in laboratory animals,11 and a separate terplay between excitatory and inhibitory study showed that severing serotonergic mechanisms at the central and peripheral axons in the medial forebrain bundle in male levels. For example, they describe the role rats facilitated ejaculation.12 of norepinephrine mediation in the cen- Monteiro et al13 found a high incidence of tral arousal system via the disinhibition of anorgasmia in previously orgasmic patients dopaminergic and a possible testosterone after they received clomipramine, which mechanism. They also point to possible in- may be partially attributed to the drug’s se- hibition of central sexual arousal by neuro- rotonergic action. This prompted research- peptidergic and serotonergic mechanisms. ers to hypothesize that central serotonergic Evidence linking serotonin to sexual dys- tone inhibits sexual behavior. However, function is inconclusive because there are no based on current evidence, it would be best exclusively serotonergic agents. Drugs fre- to consider serotonin as having a modulat- quently used to test these hypotheses often ing effect10—as opposed to a complete in- affect other neurotransmitters, which means hibitory effect—on human sexual behavior. Current Psychiatry conclusions are not specific to serotonin. An- Regarding the parasympathetic system, Vol. 9, No. 12 31 Table 2 structurally similar to cytochrome P450 (CYP450). Paroxetine is a strong CYP2D6 in- Neurotransmitters affected hibitor, which contributes to low nitric oxide by SSRIs levels in patients taking the drug.16 SSRI Neurotransmitters Citalopram 5-HT Escitalopram 5-HT SSRIs and sexual response SSRIs and Fluoxetine 5-HT, NE, DA Because decreased libido is part of depres- sexual dysfunction Fluvoxamine 5-HT sive psychopathology,5 it is difficult to attri- Paroxetine 5-HT, NE, Ach bute loss of sexual desire directly to SSRIs. Sertraline 5-HT, NE, DA Nonetheless, SSRIs are associated with a 5-HT: serotonin; Ach: acetylcholine; DA: dopamine; risk of clinically significant loss of sexual NE: norepinephrine; SSRIs: selective serotonin reuptake inhibitors desire that may resemble moderate to se- Source: Reference 7 vere hypoactive sexual desire disorder.17 Reduced mesolimbic dopaminergic activity as a result of inhibitory serotonergic mid- Clinical Point it was long believed that cholinergic inner- brain raphe nuclei projections is 1 possible SSRIs may reduce vations mediate penile erection. However, cause.18 This hypothesis has lead investi- levels of nitric oxide, a more plausible hypothesis may be that gators to examine drug targets in the CNS parasympathetic cholinergic transmission for hypoactive sexual desire disorder that which is necessary at best has a modulating effect when other would inhibit serotonergic tone and lead to for mediating penile neurotransmitters—primarily the adrener- brain dopaminergic system stimulation. vasculature changes gic system—are affected by concomitant Another putative hypothesis for SSRI- 10 needed for erection pharmacologic interventions. Segraves induced loss of sexual desire is the role of proposed that cholinergic potentiating of 5-HT1A receptor-mediated norepinephrine adrenergic activity may be primarily re- neurotransmission. Because the sympathetic sponsible for bethanechol-induced rever- nervous system is believed to be involved sal of SSRI-induced sexual dysfunction. in genital arousal in women, a small study The adrenergic system is believed to play analyzed the effect of sympathetic activa- a role in penile erection and ejaculation.10 tion on SSRI-induced sexual dysfunction.19 Adrenergic fibers innervate the vas deferens, Women who received paroxetine and sertra- seminal vesicles, trigone of the urinary blad- line—both are highly selective for 5-HT1A— der, and proximal urethra.14 Penile contrac- showed improvement in sexual arousal and tile and erectile tissue is richly innervated by orgasm after taking ephedrine before sex- the adrenergic nerve fibers.10 Ejaculation is ual activity.19 Women who took fluoxetine, 10 mediated by α1-adrenergic receptors. which is less selective for 5-HT1A, show no change or decreased sexual function. SSRIs are associated with reduced noc- The role of nitric oxide synthase turnal penile erections and severe erectile The advent of sildenafil underscored the im- dysfunction, but the relationship is not ro- portance of nitric oxide-mediated relaxation bust.17 SSRI-induced suppression of rapid pathways in treating erectile dysfunction. eye movement sleep20 may partially explain Nitric oxide plays an important role in me- reduced nocturnal and early morning erec- ONLINE ONLY diating the penile vasculature changes es- tions. Supraspinal areas and preganglionic sential for erection and also is hypothesized sacral neurons involved in sexual excite- Discuss this article at to promote penile smooth muscle relaxation ment also are reported to have substantial http://CurrentPsychiatry. blogspot.com via cyclic guanosine monophosphate, there- serotonergic activity, which suggests that by contributing to physiologic erection.15 serotonin has a direct role in erectile dys- Paroxetine is known to inhibit nitric oxide function at a comparative peripheral level.21 synthase, which reduces nitric oxide levels. However, a recent study17 found no differ- The exact mechanism of this interaction re- ence in flaccid and peak systolic velocity mains unclear; however, it is hypothesized when comparing patients taking SSRIs with Current Psychiatry 32 December 2010 that 3 nitric oxide synthase isoenzymes are those who do not. This indicates that SSRIs’ affect on spontaneous and sexually aroused Table 3 erections may be mediated at both central and peripheral levels. Other than SSRIs, which medications