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Home , Anorgasmia, Dapoxetine, Fluoxetine, Libido, Serotonin, Sexual arousal disorder

How do SSRIs cause ?

Understanding key mechanisms can help improve patient adherence, prognosis

lthough selective inhibitors (SSRIs) are frequently prescribed1 and are better Atolerated than older , such as sexual dysfunction limit patient acceptance of these . DSM-IV-TR categorizes -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 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 systems Table 1 Sexual dysfunction and the sexual response cycle

Phase Description Dysfunction/disorder Characterized by sexual Hypoactive 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 disorder of sexual pleasure Erectile disorder and accompanying physiologic changes Erectile disorder due to a general medical condition due to a general medical condition Substance-induced sexual dysfunction with impaired arousal Clinical Point Peaking of sexual Female orgasmic disorder pleasure with release Although SSRIs are Male orgasmic disorder of sexual tension relatively selective Premature 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 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 is believed to block nist and antagonist agents on mounting and reuptake, and it has a clini- ejaculation have reported inconsistent re- cally significant effect. Also, sults.10 Differential roles of 5-HT1 and 5-HT2 is a potent of activation on sexual behavior may .8 Therefore, our discussion will explain some of these inconsistencies.8 How- include these . 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 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 in previously orgasmic patients and a possible after they received , which mechanism. They also point to possible in- may be partially attributed to the ’s se- hibition of central 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. 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 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 (CYP450). Paroxetine is a strong CYP2D6 in- Neurotransmitters affected hibitor, which contributes to low by SSRIs levels in patients taking the drug.16 SSRI Neurotransmitters 5-HT 5-HT SSRIs and sexual response SSRIs and 5-HT, NE, DA Because decreased is part of depres- sexual dysfunction 5-HT sive ,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: ; 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- projections is 1 possible SSRIs may reduce vations mediate penile . 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 -induced rever- 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 is richly innervated by orgasm after taking 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 turnal penile and severe erectile The advent of 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 . 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 involved in sexual excite- Discuss this article at to promote penile 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 can cause frequently is associ- sexual dysfunction? 17 ated with SSRIs and usually is not caused Psychotropics by depressive psychopathology.22 Animal studies show that increased serotonergic Anticonvulsants tone predicts ejaculatory latency by acting as Antidepressants an inhibitor at the level.23 In • serotonin-norepinephrine reuptake inhibitors contrast, noradrenergic tone enhances ejacu- • antidepressants • inhibitors lation.24 Antidepressants that increase nor- levels and serotonin levels—such as serotonin-norepinephrine reuptake inhib- Nonpsychotropics 17 itors—induce milder ejaculatory delay. Antihypertensives 17 A recent study found impaired climax • alpha blockers and reduced libido in partners of patients • beta blockers Clinical Point • diuretics using SSRIs. Patients receiving SSRIs report Loss of sexual desire in less frequent and height- Digoxin blockers patients taking SSRIs ened guilt associated with , -lowering agents and SSRIs are associated with psychosocial may be the result of Narcotics factors such as higher at work and reduced mesolimbic Oral contraceptives increased risk of conflicts with partners SSRIs: selective serotonin reuptake inhibitors dopaminergic activity 17 and other family members. In addition to Source: Reference 26 biologic mechanisms, these psychosocial and intra-couple factors might contribute to SSRI-associated sexual dysfunction. SSRIs exposes patients to undesirable side However, because the temporal associa- effects, and inconsistent use of paroxetine tion between SSRI use and psychosocial can lead to discontinuation syndrome. dysfunction is ambiguous, this hypothesis These concerns have lead researchers to should be interpreted with caution. seek an SSRI that could be used on as-needed SSRIs have been associated with low- basis and would not cause some of the del- er serum levels of luteinizing , eterious side effects associated with current follicle-stimulating hormone, and testos- SSRIs. The short-acting SSRI is in terone.25 However, these findings need to FDA review for treating premature ejacula- be replicated before drawing firm conclu- tion; the drug is approved for this use in sev- sions on intermediary role of in eral countries outside the United States.30 SSRI-emergent sexual dysfunction. Be aware that other medications may contribute to sexual dysfunction experienced Sexual health education by a patient receiving an SSRI (Table 3).26 Because sexual dysfunction can be caused by underlying psychopathology or physical ill- ness, it is essential to obtain a detailed sexual SSRIs for ? history at your patient’s initial assessment Because SSRIs can cause delayed ejacula- and at every follow-up visit. Patients and tion, they have been used off-label to treat providers may be guarded when discussing premature ejaculation.27 For this purpose, sexual health, which can be a barrier to pro- paroxetine and sertraline have been pre- viding comprehensive health care. The orga- scribed with daily or on-demand dos- nizations listed in Related Resources (page ing before sexual intercourse28 and daily 34) can provide information and materials fluoxetine has been used.29 However, none to help patients and health care providers of these SSRIs is FDA-approved for treat- better understand sexual health. Addressing Current Psychiatry ing premature ejaculation, daily dosing of the importance of sexual health in a com- Vol. 9, No. 12 33 erectile dysfunction. Neurosci Biobehav Rev. 2000;24(5): 571-579. Related Resources 10. Segraves RT. Effects of psychotropic drugs on human erection • American Association of Sexuality Educators, Counselors, and ejaculation. Arch Gen Psychiatry. 1989;46(3):275-284. and Therapists. www.aasect.org. 11. Tagliamonte A, Tagliamonte P, Gessa GL, et al. Compulsive sexual activity induced by p-chlorophenylalanine in normal • Sexual and Wellness Center. www. and pinealectomized male rats. Science. 1969;166(911): methodistsexualwellness.com. 1433-1435. • The Sexual Health Network. www.sexualhealth.com. 12. Rodriguez M, Castro R, Hernandez G, et al. Different roles of catecholaminergic and serotoninergic neurons of the medial • International Society for the Study of Women’s Sexual forebrain bundle on male rat sexual behavior. Physiol Behav. SSRIs and Health. www.isswsh.org. 1984;33(1):5-11. Drug Brand Names 13. Monteiro WO, Noshirvani HF, Marks IM, et al. Anorgasmia sexual dysfunction from clomipramine in obsessive-compulsive disorder. A Bethanechol • Urecholine Fluoxetine • Prozac controlled trial. Br J Psychiatry. 1987;151:107-112. Citalopram • Celexa Fluvoxamine • Luvox 14. Kleeman FJ. The of the internal urinary Clomipramine • Anafranil Paroxetine • Paxil sphincter. J Urol. 1970;104(4):549-554. Dapoxetine • Priligy Sertraline • Zoloft 15. Stahl SM. How psychiatrists can build new therapies for Digoxin • Lanoxin Sildenafil • Viagra impotence. J Clin Psychiatry. 1998;59(2):47-48. Escitalopram • Lexapro 16. Bredt DS, Hwang PM, Glatt CE, et al. Cloned and expressed nitric oxide synthase structurally resembles cytochrome Disclosure P-450 reductase. Nature. 1991;351(6329):714-718. The authors report no financial relationship with any 17. Corona G, Ricca V, Bandini E, et al. Selective serotonin reuptake inhibitor-induced sexual dysfunction. J Sex Med. company whose products are mentioned in this article or with 2009;6(5):1259-1269. manufacturers of competing products. Clinical Point 18. Pfaus JG. Pathways of sexual desire. J Sex Med. 2009;6(6):1506-1533. Because SSRIs can 19. Ahrold TK, Meston CM. Effects of SNS activation on SSRI- induced sexual side effects differ by SSRI. J Sex Marital Ther. cause delayed 2009;35(4):311-319. prehensive, culturally sensitive manner can 20. Hirshkowitz M, Schmidt MH. -related erections: ejaculation, they have substantially improve our patients’ medica- clinical perspectives and neural mechanisms. Sleep Med Rev. 2005;9(4):311-329. been used off-label tion compliance and prognosis. 21. Miner MM, Seftel AD. Centrally acting mechanisms for the treatment of male sexual dysfunction. Urol Clin North Am. to treat premature References 2007;34(4):483-496, v. ejaculation 1. Olfson M, Marcus SC. National patterns in 22. Labbate LA, Grimes J, Hines A, et al. Sexual dysfunction medication treatment. Arch Gen Psychiatry. 2009;66(8): induced by serotonin reuptake antidepressants. J Sex 848-856. Marital Ther. 1998;24(1):3-12. 2. Diagnostic and statistical manual of mental disorders, 23. Waldinger MD. The neurobiological approach to premature 4th ed, text rev. Washington, DC: American Psychiatric ejaculation. J Urol. 2002;168(6):2359-2367. Association; 2000. 24. Meston CM, Frohlich PF. The neurobiology of sexual 3. Sadock BJ, Sadock VA. Abnormal sexuality and sexual function. Arch Gen Psychiatry. 2000;57(11):1012-1030. dysfunctions. In Sadock BJ, Sadock VA. Kaplan & Sadock’s 25. Safarinejad MR. Evaluation of endocrine profile and synopsis of psychiatry: behavioral sciences/clinical hypothalamic-pituitary-testis axis in selective serotonin psychiatry. 10th ed. Philadelphia, PA: Lippincott Williams & reuptake inhibitor-induced male sexual dysfunction. J Clin Wilkins; 2007:689-705. Psychopharmacol. 2008;28(4):418-423. 4. Zimmerman M, Galione JN, Attiullah N, et al. 26. Sajith SG, Morgan C, Clarke D. Pharmacological Underrecognition of clinically significant side effects in management of inappropriate sexual behaviours: a depressed outpatients. J Clin Psychiatry. 2010;71(4):484- review of its evidence, rationale and scope in relation to 490. men with intellectual disabilities. J Intellect Disabil Res. 5. Casper RC, Redmont DE Jr, Katz MM, et al. Somatic 2008;52(12):1078-1090. symptoms in primary affective disorder: presence and 27. Giuliano F, Hellstrom WJ. The pharmacological treatment of relationship to the classification of . Arch Gen premature ejaculation. BJU Int. 2008;102(6):668-675. Psychiatry. 1985;42:1098-1104. 28. Kim SW, Paick JS. Short-term analysis of the effects of 6. Balon R. SSRI-associated sexual dysfunction. Am J as needed use of sertraline at 5 PM for the treatment of Psychiatry. 2006;163(9):1504-1509; quiz 1664. premature ejaculation. . 1999;54(3):544-547. 7. Schatzberg AF, Nemeroff CB, eds. The American Psychiatric 29. Waldinger MD, Zwinderman AH, Schweitzer DH, et al. Publishing textbook of . 4th ed. Relevance of methodological design for the interpretation Arlington, VA: American Psychiatric Publishing, Inc.; 2009. of of drug treatment of premature ejaculation: 8. Schatzberg AF, Cole JO, DeBattista C. Antidepressants. In: a and meta-analysis. Int J Impot Res. Schatzberg AF, Cole JO, DeBattista C. Manual of clinical 2004;16(4):369-381. psychopharmacology. 6th ed. Arlington, VA: American 30. Kendirci M, Salem E, Hellstrom WJ. Dapoxetine, a novel Psychiatric Publishing, Inc.; 2007:37-168. selective serotonin transport inhibitor for the treatment of 9. Bancroft J, Janssen E. The dual control model of male sexual premature ejaculation. Ther Clin Risk Manag. 2007;3(2): response: a theoretical approach to centrally mediated 277-289. Bottom Line Selective serotonin reuptake inhibitors (SSRIs) can adversely affect all aspects of the human sexual response cycle. Obtaining a detailed sexual history in a culturally sensitive manner may facilitate early detection and accurate estimation of SSRI- related sexual dysfunction and can prompt interventions to enhance patients’ Current Psychiatry 34 December 2010 medication compliance and improve their overall prognosis.