Sexual dysfunctions (SD) and selective serotonin reuptake inhibitors (SSRIs): from preclinical studies to intervention strategies

Abstract

In the light of existing literature, we reviewed the causes, management and potential therapeutic benefits of SSRI (Selective serotonin reuptake inhibitor) agents regarding sexual functions. (SSRIs) are the most commonly used medications for the treatment of depression, based on their effectiveness and safety profile. Sexual dysfunctions (SD) caused by SSRIs are one of the most important reasons for discontinuation of treatment in both genders. Knowing the intervention strategies in patients who develop SD is pivotal for the proper management of sexual side effects and the treatment adherence of patients. The effects of SSRIs on sexual functions can also be used to treat certain disorders. SSRIs have a high success rate in the treatment of premature ejaculation and their off-label use for this purpose is widely recognized.

Keywords

• selective serotonin reuptake inhibitors
• sexual dysfunctions
• ejaculation disorders

References

1. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(Suppl):1-45.
2. Edinoff AN, Akuly HA, Hanna TA, et al. Selective serotonin reuptake inhibitors and adverse effects: a narrative review. Neurol Int. 2021;13:387-401.
3. Olie´JP, ElomariF, Spadone C, Le´pine JP. Antidepressants consumption in the global population in France. L’ Encephale. 2002; 28:411-417.
4. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Güneş Tıp Kitabevi, Ankara. 2022;2:3155-3160.
5. Ekselius L, von Knorring L. Effect on sexual function of long- term treatment with selective serotonin reuptake inhibitors in depressed patients treated in primary care. J Clin Psychopharmacol. 2001;21(2):154-160.
6. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34–38 years. J Affect Disord. 2002;68:167-181.
7. Fava M, Rankin M. Sexual functioning and SSRIs. J Clin Psychiatry. 2002;63(Suppl 5):13-16.
8. Montejo-González AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176-194.

9. van Geffen EC, van der Wal SW, van Hulten R, de Groot MC, Egberts AC, Heerdink ER. Evaluation of patients’ experiences with antidepressants reported by means of a medicine reporting system. Eur J Clin Pharmacol. 2007; 63(12):1193-1199.
10. Perlis RH, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ. Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients. Neuropsychopharmacology. 2009;34:1819-1828.
11. Keltner NL, McAfee KM, Taylor CL. Mechanisms and treatments of SSRI-induced sexual dysfunction. Perspect Psychiatr Care. 2002;38:111-116.
12. Sramek JJ, Murphy MF, Cutler NR. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin Neurosci. 2016;18:447-457.
13. Sramek JJ, Cutler NR. The impact of gender on antidepressants. Curr Top Behav Neurosci. 2011;8:231-249.
14. Shalimova A, Babasieva V, Chubarev VN, Tarasov VV, Schiöth HB, Mwinyi J. Therapy response prediction in major depressive disorder: current and novel genomic markers influencing pharmacokinetics and pharmacodynamics. Pharmacogenomics. 2021;22:485-503.
15. Clayton AH, McGarvey EL, Abouesh AI. Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction. Prim Care Companion J Clin Psychiatry. 2001;3(2):89.
16. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29(3):259-266.
17. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish working group for the study of psychotropic-related sexual dysfunction. J Clin Psychiatry. 2001;62(Suppl 3):10-21.
18. O’Mullan C, Doherty M, Coates R, Tilley PJ. Women’s experiences of coping with the sexual side effects of antidepressant medication. Psychol Health. 2014;29:1388-1406.
19. Modell J, Katholi C, Modell J, De-Palma R. Comparative sexual side effects of bupropion, fuloxetine, paroxetine and sertraline. Clin Pharmacol Ther. 1997;61:476-487.
20. Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91:27-32.
21. Werneke U, Northey S, Bhugra D. Antidepressants and sexual dysfunction. Acta Psychiatr Scand. 2006;114(6): 384-397.
22. Thibaut F, Cosyns P, Fedoroff JP, Briken P, Goethals K, Bradford JMW. WFSBP task force on paraphilias. the world federation of societies of biological psychiatry (WFSBP) 2020 guidelines for the pharmacological treatment of paraphilic disorders. World J Biol Psychiatry. 2020;21:412-490.
23. McMahon CG, Abdo C, Incrocci L et al. Disorders of orgasm and ejaculation in men. J Sex Med. 2004;1:58-65.
24. Atan A, Aslan Y. Premature ejaculation: the new definition and place of dapoxetine in current treatment. Turkish J Urol. 2010;36(2):149-154.
25. Incesu C. Sexual functions and sexual dysfunctions. Clin Psychiatry. 2004;3:3-13.
26. Althof SE, McMahon CG, Waldinger MD et al. An update of the International Society of Sexual Medicine’s guidelines for the diagnosis and treatment of premature ejaculation (PE). J Sex Med. 2014;11(6):1392-1422.
27. DSM 5 diagnostic and statistical manual of mental disorder. American Psychiatry Association (APAA), 2013.
28. Waldinger MD. The neurobiological approach to premature ejaculation. J Urol. 2002;168:2359-2367.
29. Waldinger MD, Zwinderman AH, Olivier B. Antidepressants and ejaculation: a double-blind, randomized, placebo-controlled, fixed- dose study with paroxetine, sertraline, and nefazodone. J Clin Psychopharmacol. 2001;21(3): 293-297.
30. Giuliano F, Clément P. Serotonin and premature ejaculation: from physiology to patient management. Eur Urol. 2006;50(3):454-466.
31. Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res. 2004;16:369-381.
32. Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system. Behav Brain Res. 1998; 92:111-118.
33. Martin-Tuite P, Shindel AW. Management options for premature ejaculation and delayed ejaculation in men. Sex Med Rev. 2020;8:473-485.
34. Zhang D, Cheng Y, Wu K, Ma Q, Jiang J, Yan Z. Paroxetine in the treatment of premature ejaculation: a systematic review and meta-analysis. BMC Urol. 2019;3;19:22.
35. Arafa M, Shamloul R. A randomized study examining the effect of 3 SSRI on premature ejaculation using a validated questionnaire. Ther Clin Risk Manag. 2007;3:527-531.
36. McMahon CG, Jannini E, Waldinger M, Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation. J Sex Med. 2013;10:204-229.
37. Russo A, Capogrosso P, Ventimiglia E et al. Efficacy and safety of dapoxetine in treatment of premature ejaculation: an evidence-based review. Int J Clin Pract. 2016;70:723-733
38. Aversa A, Pili M, Francomano D, et al. Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation. Int J Impot Res. 2009;21:221-227.
39. Kirby EW Tramadol for the management of premature ejaculation: a timely systematic review Int J Import Res. 2015; 27:121-127.
40. Hull EM, Muschamp JW, Sato S. Dopamine and serotonin: influences on male sexual behavior. Physiol Behav. 2004; 83:291-307.
41. de Jong TR, Veening JG, Olivier B, Waldinger MD. Oxytocin involvement in SSRI-induced delayed ejaculation: a review of animal studies. J Sex Med. 2007;4(1):14-28.
42. Nutt DJ, Forshall S, Bell C et al. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur Neuropsychopharmacol 1999;9 (suppl 3):81-86.
43. Giuliano F, Clèment P. Pharmacology for the treatment of premature ejaculation. Pharmacol Rev. 2012;64:621-644.
44. Hillegaart V, Ahlenius S, Larsson K. Region-selective inhibition of male rat sexual behavior and motor performance by localized forebrain 5-HT injections: a comparison with effects produced by 8-OH-DPAT. Behav Brain Res. 1991;42:169-180.
45. Fernandez-Guasti A, Escalante AL, Ahlenius S, Hillegaart V, Larsson K. Stimulation of 5-HT1A and 5-HT1B receptors in brain regions and its effects on male rat sexual behaviour. Eur J Pharmacol. 1992;210:121-129.
46. Foreman MM, Hall JL, Love RL. The role of the 5-HT2 receptor in the regulation of sexual performance of male rats. Life Sci. 1989;45:1263-1270.
47. de Jong TR, Pattij T, Veening JG, et al. Citalopram combined with WAY 100635 inhibits ejaculation and ejacu- lation-related Fos immunoreactivity. Eur J Pharmacol. 2005;509:49-59.
48. de Almeida Kiguti LR, Pacheco TL, Antunes E, Kempinas WG. Lorcaserin administration has pro-ejaculatory effects in rats via 5-HT2C receptors activation: a putative pharmacologic strategy to delayed ejaculation? J Sex Med. 2020;17(6):1060-1071.
49. Looney C, Thor KB, Ricca D, Marson L. Differential effects of simultaneous or sequential administration of paroxetine and WAY-100,635 on ejaculatory behavior. Pharmacol Biochem Behav. 2005;82:427-433.
50. Yells DP, Prendergast MA, Hendricks SE, Nakamura M. Fluoxetine-induced inhibition of male rat copulatory behavior: modification by lesions of the nucleus paragigantocellularis. Pharmacol Biochem Behav. 1994;49:121-127.
51. Cantor JM, Binik YM, Pfaus JG. Chronic fluoxetine inhibits sexual behavior in the male rat: reversal with oxytocin. Psychopharmacology (Berl) 1999;144:355-362.
52. Renner U, Zeug A, Woehler A et al. Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and tracking. J. Cell Sci.2012; 125, 2486-2499.
53. Naumenko VS, Popova NK, Lacivita E, Leopoldo M, Ponimaskin EG. Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS Neurosci Ther. 2014:20:582-590.
54. Esquivel-Franco DC, Olivier B, Waldinger MD, Gutiérrez-Ospina G, Olivier JDA. Tramadol’s inhibitory effects on sexual behavior: pharmacological studies in serotonin transporter knockout rats. Front Pharmacol. 2018;9:676.
55. Homberg JR, Olivier JDA, Smits BMG, et al. Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system. Neuroscience. 2007;146:1662-1676.
56. Chan JSW, Snoeren EMS, Cuppen E, Waldinger MD, Olivier B, Oosting RS. The serotonin transporter plays an important role in male sexual behavior: a study in serotonin transporter knockout rats. J Sex Med. 2011;8:97-108.
57. Arias B, Catalán R, Gastó C, Gutiérrez B, Fañanás L. Evidence for a combined genetic effect of the 5-HT (1A) receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram. J Psychopharmacol. 2005;19:166-172.
58. Westenberg HGM, Sandner C. Tolerability and safety off fluvoxamine and other antidepressants. Int J Clin Pract. 2006;60(4):482-491.
59. Baldwin DS, Foong T. Antidepressant drugs and sexual dysfunction. Br J Psychiatry. 2013;202(6):396–397.
60. Anderson IM, Tomenson BM. Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants: a meta-analysis. BMJ. 1995;310:1433-1438.
61. Croft H, Settle E Jr, Houser T, Batey SR, Donahue RM, Ascher JA. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther. 1999;21:643-658.
62. Luft MJ, Dobson ET, Levine A, Croarkin PE, Strawn JR. Pharmacologic interventions for antidepressant-induced sexual dysfunction: a systematic review and network meta-analysis of trials using the Arizona sexual experience scale. CNS Spectr. 2021;12:1-10.
63. Montejo AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997; 23:176-194.
64. Waldinger MD. Psychiatric disorders and sexual dysfunction. Handb Clin Neurol. 2015; 130:469-489.
65. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holidays. Am J Psychiatry. 1995;152:1514-1516.
66. Alipour-Kivi A, Eissazade N, Shariat SV, et al. The effect of drug holidays on sexual dysfunction in men treated with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine: an 8-week open-label randomized clinical trial. BMC Psychiatry. 2024;24:67.
67. Reichenpfader U, Gartlehner G, Morgan LC, et al. Sexual dysfunction associated with second-generation antidepressants in patients with major depressive disorder: results from a systematic review with network meta-analysis. Drug Safety. 2014;37:19–31.
68. Tripathi A, Agrawal A, Joshi M. Treatment-emergent sexual dysfunctions due to antidepressants: a primer on assessment and management strategies. Indian J Psychiatry. 2024; 66:293-303.
69. Gelenberg AJ, McGahuey C, Laukes C et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry. 2000;61:356-360
70. Ferguson JM, Shrivastava RK, Stahl SM et al. Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline. J Clin Psychiatry. 2001;62:24-29.
71. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of vortioxetine vs. escitalopram on sexual functioning in adults with well-treated major depressive disorder experiencing SSRI-induced sexual dysfunction. J Sex Med. 2015;12:2036-2048.
72. Montejo AL, Perez Urdaniz A, Mosqueira I et al. EPA-1719 – effectiveness of switching to agomelatine in antidepressant-related sexual dysfunction. Eur Psychiatry. 2014;29:1.
73. Rizvi SJ, Kennedy SH. Management strategies for SSRI-induced sexual dysfunction. J Psychiatry Neurosci. 2013; 38:E27-28.
74. Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2013:CD003382.
75. Walker PW, Cole JO, Gardner EA et al. Improvement in fluoxetine- associated sexual dysfunction in patients switched to bupropion. J Clin Psychiatry. 1993;54:459-465.
76. Kennedy SH, McCann SM, Masellis M et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry. 2002; 63:181-186.
77. Aizenberg D, Weizman A, Barak Y. Sildenafil for selective serotonin reuptake inhibitor-induced erectile dysfunction in elderly male depressed patients. J Sex Marital Ther. 2003;29:297–303.
78. Fava M, Nurnberg HG, Seidman SN et al. Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2006;67:240-246.
79. Salerian AJ, Eric Deibler W, Vittone BJ, et al. Sildenafil for psychotropic- induced sexual dysfunction in 31 women and 61 men. J Sex Marital Ther. 2000;26:133-140.
80. Ozmenler NK, Karlidere T, Bozkurt A et al. Mirtazapine augmentation in depressed patients with sexual dysfunction due to selective serotonin reuptake inhibitors. Human Psychopharmacol. 2008;23:321-326.
81. Landén M, Eriksson E, Agren H, Fahlén T. Effect of buspirone on sexual dysfunc- tion in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999;19:268-271.
82. Norden MJ. Buspirone treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. Depression. 1994;2:109-112.