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CPD Article: Antidepressant-induced sexual dysfunction Antidepressant-induced sexual dysfunction Outhoff K, MBChB, MFPM(UK)
Department of Pharmacology, University of Pretoria, South Africa Correspondence to: Dr Kim Outhoff, e-mail: kim.outhoff@up.ac.za
Keywords: depression; sexual dysfunction; antidepressants
Depression and sexual dysfunction are both common in the general population. When they co-exist they have the potential to impact negatively on each other in a bidirectional manner. Medication used to treat depression may cause additional problems with the sexual response cycle; although no drug is completely innocent, serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are most frequently implicated in antidepressant-induced sexual dysfunction. Adherence to long-term treatment may be compromised, which may have serious consequences. Various psychological and pharmacological strategies, including the ad hoc use of sildenafil, may offer some respite.
SA Fam Pract 2009;51(4):298-302
Approximately 34% of men and 41% of women in the general population experience some form of sexual problem, which may range from Perhaps not since Masters and Johnson1 published their pioneering work decreased libido, vaginal dryness (28%) and erectile problems (26%) to on the physiology of the human sexual response in 1966 has there been premature ejaculation (14%) and anorgasmia (27%).5,6 such lively interest in sexual functioning. The recent unabashed flaunting of sildenafil (Viagra®) and other phosphodiesterase type 5 inhibitors by Many aetiologies have been linked to the disruption of the normal pharmaceutical giants has greatly facilitated changing attitudes to sexual sexual response cycle. These include psychological causes (psychiatric health globally. Erectile dysfunction in particular is no longer taboo and is illness, particularly anxiety and depression), pathological states (vascular increasingly viewed and treated as a medical issue.
disease, diabetes, neurological disease) and pharmacological effects of drugs.6 It has long been recognised that certain antihypertensive agents, The physiology of sexual functioning
notably centrally acting sympatholytic agents, beta antagonists, and diuretics, have an adverse effect on sexual functioning.7 Antidepressants, The normal sexual response cycle is general y divided into four antipsychotics, anticonvulsants, drugs with antimuscarinic effects, successive phases (desire, arousal, orgasm, resolution) and is controlled steroids, proton pump inhibitors, histamine receptor blockers and by a multifaceted interplay between the hypophyseal-pituitary-adrenal chemotherapeutic agents have also been implicated.8 (HPA) axis, the autonomic nervous system, circulating sex hormones (testosterone, oestrogens and progesterones), neurotransmitters Increasing age, poor physical health, smoking more than six to (serotonin, dopamine, noradrenaline, GABA and acetylcholine) and 20 cigarettes a day, recreational drugs including alcohol and opioid use, vasoactive peptides such as nitric oxide.2 loss of or low income and distressing previous sexual experiences may increase the likelihood or risk of encountering sexual problems.6,9 It has been postulated that desire is facilitated mostly by a combination of hormonal factors and noradrenaline, desire and arousal by dopamine, Sexual dysfunction and depression
and orgasm by oxytocin and acetylcholine. Prolactin's role might be to deter arousal and studies have shown serotonin to hinder desire and Depression is a common, serious and disabling illness. Besides arousal, possibly by indirect means (by inhibiting noradrenaline and depressed mood and reduced energy, it is characterised by loss of dopamine) as well as by influencing peripheral effects (decreasing interest, diminished self-esteem and the inability to experience pleasure, sensation, and inhibiting the vasodilator, nitric oxide). It may thus play a which may often impede the establishment or maintenance of intimate role in the resolution phase of the sexual cycle.3 relationships.10 It is hardly surprising therefore that depression may negatively impact on sexual function. Equally, it is plausible that sexual Sexual dysfunction
dysfunction may impact adversely on depression. It has even been suggested that these two disorders may share a common aetiology.11 Whilst a sexual complaint is an expression of discontent or pain associated The causal relationship is far from clear and the precise effects of with the sexual experience, sexual dysfunction is pain associated with depression on sexuality are variable.
sexual activity (vaginusmus or dyspareunia) or a disturbance (either psychogenic or organic) in sexual functioning, involving one or more From a patho-physiological perspective, a significant percentage of of the phases of the physiological sexual response cycle. When this is depressed patients exhibit overactivity of the autonomic system and accompanied by marked distress, it becomes a sexual disorder.4 dysregulation of the neuroendocrine hypothalamic-pituitary-adrenal SA Fam Pract 2009 CPD Article: Antidepressant-induced sexual dysfunction (HPA) axis. This is accompanied by changes in corticotropin-releasing Table I: Crude estimate of antidepressant-induced sexual dysfunction
hormone (CRH), adrenocorticotropic hormone (ACTH), beta-endorphins Prevalence
and catecholamines, which could increase the risks for not only Class* Drug
Author / Year
cardiovascular disease, but also for sexual dysfunction.12 Reimherr 1991; Montgomery 2002 In the 1980s, Derogatis13 and Schreiner-Engel11 established a link between sexual dysfunction and mood disorders. They found that patients presenting with desire disorders had a strikingly elevated Kennedy 2008; Gregorian 2002 lifetime prevalence of psychopathology, particularly of depression, and Clayton 2007; Delgado 2005 that the mood disturbances almost always preceded or coincided with Hirschfield 2004; Clayton 2007 the development of inhibited sexual desire. Clayton 2002; Montejo 2001 A decade or so later the Massachusetts Male Aging Study (MMAS)14 Clayton 2002; Kennedy 2000 revealed that depression and anger were highly correlated with erectile dysfunction. In other words, depressive symptoms were regarded as a Reimherr 1991; Montejo 2001 strong predictor for erectile dysfunction.
Montejo 1997; Montejo 2001 Studies comparing the prevalence of sexual dysfunction in depressed Zajecka 1991; Montejo 2001 patients and non-depressed controls have consistently shown higher NaSSA mirtazapine Behnke 2003; Montejo 2001 levels of dysfunction (most commonly loss of interest or arousal) in Mucci 1997; Clayton 2003 the former group.15,16 Perlman and colleagues17 found that depression, co-morbidity (especially cardiopulmonary illness) and the use of Phillip 2000; Montejo 2001 antidepressants were all powerful risk factors for developing sexual MASSA agomelatine** Rouillon 2006; Kennedy 2008 dysfunction in the psychiatric inpatient setting. Moreover, both Casper18 Others nefazodone** Zajecka 2002; Modell 1997 and Osvath19 estimated the prevalence of sexual dysfunction in depressed Thase 2006; Clayton 2006 patients to be in excess of 70%. It has proved difficult to discern whether the prevalence of sexual TCA: tricyclic antidepressant MAOI: monoamine oxidase inhibitor dysfunction is related to, amongst others, depression itself or to the SNRI: serotonin and noradrenaline reuptake inhibitor adverse effects of antidepressant treatment. Kennedy and colleagues20 SSRI: selective serotonin reuptake inhibitor NaSSA: noradrenergic and specific serotonergic antidepressant attempted to establish the baseline prevalence in an unmedicated NARI: noradrenaline reuptake inhibitor sample of patients with major depressive disorder. Prior to initiating RIMA: reversible inhibitor of monoamine oxidase type AMASSA: melatonin agonist and selective serotonin antagonist antidepressant medication, more than 40% men and 50% women ** not currently available in South Africa reported decreased sexual desire and arousal, with 15–20% reporting ejaculatory or orgasm difficulties. No correlation with the severity of The mechanism of SSRI- and SNRI-induced sexual dysfunction is thought depression was found in the small sample. to involve indiscriminate stimulation of post synaptic 5HT-2 and 5HT-2 receptors by the increased synaptic levels of serotonin.27 Antidepressants that antagonise these particular serotonin receptor subtypes, e.g. In the 1960s and 1970s, sporadic cases appeared in the literature of mirtazapine, nefazodone and agomelatine, have a lower propensity to TCA- (tricyclic antidepressant) and MAOI- (monoamine oxidase inhibitor) cause sexual dysfunction. The reversible inhibitor of monoamine oxidase, induced erectile dysfunction, anorgasmia and retrograde ejaculation.21,22 moclobemide, although showing an increased incidence of sexual It wasn't until the introduction of selective serotonin reuptake inhibitors arousal, has a very low incidence of sexual dysfunction per se, whilst the (SSRIs) in the latter half of the 1980s, however, that attention became noradrenaline reuptake inhibitor, reboxetine, and the noradrenaline and more focused on the problem of antidepressant-induced sexual dopamine reuptake inhibitor, bupropion, have little or no effect. dysfunction. Widespread and first-line use of these agents highlighted Gender, race and duration of treatment do not appear to predict sexual their adverse effects on sexual functioning, and their negative impact on dysfunction. However, prior history of antidepressant-induced sexual patients' quality of life (QOL) could not be ignored.10 dysfunction increases the risk of developing it again.28 The epidemiology of treatment-induced sexual dysfunction has been a thorny issue, due in part to confounding factors such as mental illness Management of antidepressant-induced sexual
itself, cultural influences and co-morbidity.23,24 Efforts to establish the true prevalence of antidepressant-induced sexual dysfunction, to eke out Antidepressant-induced sexual dysfunction impacts heavily on diagnostic significant differences and to compare vastly disparate trials may leave issues, treatment planning and prescribing practices, patients' quality methodology purists justifiably distressed. (See Table I.) of life and their ultimate adherence to long-term medication. Non- Nonetheless, the general consensus is, firstly, that there is a high adherence may lead to persistence, relapse or recurrence of depression, incidence of sexual dysfunction attributable to SSRI and SNRI usage – which may have serious consequences.
the best estimate probably in the region of 30 to 50% – and that this The overall treatment approach should be cognisant of the normal is a dose-related class effect,25 secondly, consensus is that drugs with fluctuation of sexual functioning. Risk factors (co-morbid psychiatric, different pharmacological actions are less inclined to affect sexual endocrine, vascular and neurological conditions and recreational drug, alcohol and nicotine use) should be noted and, if possible, addressed. SSRIs have demonstrated an effect on all phases of the sexual cycle, It has been suggested that the promotion of a healthy lifestyle may causing decreased libido, impaired arousal and erectile dysfunction. lead to improved self-image, sense of well-being and general health, However, they are most commonly associated with delayed ejaculation and consequently to a better physiological functioning of the sexual and delayed orgasm.26 response cycle (thereby rendering the drug-induced sexual dysfunction SA Fam Pract 2009 CPD Article: Antidepressant-induced sexual dysfunction more manageable). Cognitive behaviour therapy, couple therapy and Delayed ejaculation and orgasm are most frequently associated with counselling may help the patient cope with the dysfunction, reduce SSRIs and SNRIs, whereas diminished sexual desire is more commonly symptom severity or help prevent symptom worsening. However, in associated with either depression itself or with various psychological the absence of psychogenic causes or relationship factors contributing factors such as sorrow, relationship difficulties and anxiety. to the sexual dysfunction, the impact of psychological treatment is currently unknown; no randomised studies assessing the benefits of Adjuvant supportive psychological therapy and the promotion of a healthy psychological interventions in antidepressant-induced sexual dysfunction lifestyle may prove useful management options. Switching to a non-SSRI have been identified. drug or augmenting with bupropion appear to be the best supported pharmacological strategies for managing antidepressant-induced sexual Validated screening tools such as the Arizona Sexual Experience Scale dysfunction, although they may be encumbered by the potential for (ASEX) and the Changes in Sexual Functioning Questionnaire (CSFQ) may discontinuation reactions and drug-drug interactions. be useful for evaluating baseline sexual functioning prior to initiating antidepressant medication as well as at intervals to determine the Finally, the liaison between PDE-5 inhibitors and SSRIs, the only two presence of adverse drug effects.24 classes of pharmacological agents to have achieved superstar status Evidence-based recommendations for the pharmacological management (with their prototypes Viagra® and Prozac®) in their eminent fields of of antidepressant-induced sexual dysfunction are in short supply.29 erectile dysfunction and depression, appears promising. However, Prescribers' intuition, experience and personal comfort zones therefore unforeseen incompatibility issues or the introduction of more alluring generally dictate their strategies. Some recommend initiating therapy effective antidepressants that are untroubled by sexual dysfunction may with an antidepressant that has a lower propensity to cause sexual ultimately determine whether this particular partnership is able to flourish dysfunction, e.g. mirtazapine, reboxetine, nefazodone, bupropion or or whether it is brought to an emotional, celebrity-style conclusion.
agomelatine. Others advocate awaiting spontaneous remission of sexual dysfunction or development of drug tolerance. The effectiveness of this "wait and see" strategy is considered low. Reducing the dose of the 1. Masters WH, Johnson VE. Human sexual response. Boston: Little, Brown & Co; 1966:189–91.
offending agent requires careful monitoring of the patient for relapse 2. Raina R. Female sexual dysfunction: classification, pathophysiology, and management. Fertility and and recurrence of depression. Two to three-day drug holidays for agents 3. Meston CM, Frohlich PF. The neurobiology of sexual function. Arch Gen Psychiatry 2000;57:1012–30. with short half lives (paroxetine and sertraline) may elicit discontinuation 4. Basson R., Berman J, Derogatis L, et al. Report of the international consensus development conference reactions and encourage non-adherence.
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8. Yang B, Donatucci C. Drugs that affect male sexual function. In: Mulcahy JJ, Totowa NJ (eds). Current clinical urology: male sexual function: a guide to clinical management. 2nd edition. 9. Clayton AH, Pradko J, Croft H. Prevalence of sexual dysfunction among newer antidepressants. J Clin Many augmenting agents have been described as useful, including the addition of bupropion, mirtazapine, nefazodone, granisetron (serotonin 10. Baldwin DS. Sexual dysfunction associated with antidepressant drugs. Expert Opin Drug Safety antagonist), yohimbine (alpha-1 agonist and alpha-2 antagonist), 11. Schreiner-Engel P, Schiavi RC. Lifetime psychopathology in individuals with low sexual desire. J Nerv cyproheptadine (antihistamine with 5HT-2 blocking activity), amantadine Ment Dis 1986;174:646–51.
12. Goldstein I. The mutually reinforcing triad of depressive symptoms, cardiovascular disease and erectile and other dopamine agonists such as ropinirole. The evidence for dysfunction. Am J Cardiol 2000;86:41F–44F.
bupropion augmentation is the most compelling.31 13. Derogatis LR, Meyer JK, King KM. Psychopathology in individuals with sexual dysfunction. Am J 14. Araujo AB, Durante R, Feldman HA, Goldstein I, McKinlay JB. The relationship between depressive Finally, there is firm evidence that remedial drug therapy with sildenafil, symptoms and male erectile dysfunction: cross-sectional results from the Massachusetts Male Aging the selective and competitive inhibitor of phosphodiesterase type 5 Study. Psychosomatic Medicine 1998;60:458–65.
15. Matthew RJ, Weinmann ML. Sexual dysfunctions in depression. Arch Sex Behav 1982;11:323–8. (PDE-5), has proved effective in men for antidepressant-induced erectile 16. Thase ME, Reynolds CF, Jennings JR, et al. Diminished nocturnal penis tumescence in depression: a dysfunction,32 and more recently – although not licensed for this group replication study. Biol Psychiatry 1992;31:1136–42.
17. Perlman CM, Martin L, Hirdes JP, et al. Prevalence and predictors of sexual dysfunction in psychiatric – in women with SSRI- and SNRI-induced sexual adverse effects.33 inpatients. Psychosomatics 2007;48:309–18.
Its characteristics of peripheral site of action, high efficacy, good 18. Casper RC, Redmond E, Katz MM, et al. Somatic symptoms in primary affective disorder: presence and relationship to the classification of depression. Arch Gen Psychiatry 1985;42:1098–104. tolerability, relatively short duration of action and administration only if 19. Osvath P, Fekete S, Vörös V, et al. Sexual dysfunction among patients treated with antidepressants: a and when required make this agent in some ways the ideal antidote. Hungarian retrospective study. Eur Psychiatry 2003;18:412–4.
20. Kennedy SH, Dickens SE, Eisfeld BS, et al. Sexual dysfunction before antidepressant therapy in major Common adverse effects include dyspepsia and those attributable to depression. Journal of Affective Disorders 1999;56:201–8.
vasodilatation (headache and flushing). As with the routine prescription 21. Monteiro WO, Noshirvani HF, Marks IM, et al. Anorgasmia from clomipramine in obsessional compulsive disorder: a controlled trial. Br J Psychiatry 1987;151:107–12.
of sildenafil, a detailed medical and drug history should be undertaken 22. Segraves RT. Treatment emergent sexual dysfunction in affective disorder: a review and management strategies. J Clin Psychiatry Monograph 1993;11:57–63.
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23. Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug- induced sexual dysfunction. J Affect Disord 2002;69(1–3):119–40.
Conclusions and recommendations
24. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry 2006;163:1504–9.
25. Williams VSL, Baldwin DS, Hogue SL, Fehnel SE, Hollis KA, Edin HM. Estimating the prevalence and impact of antidepressant-induced sexual dysfunction in two European countries: a cross sectional patient When initiating therapy, prescribers should be aware that antidepressant survey. J Clin Psychiatry 2006;62(2):204–10.
26. Rosen RC, Marin H. Prevalence of antidepressant-associated erectile dysfunction. J Clin Psychiatry drugs may cause sexual dysfunction and that this is particularly true of the SSRI and SNRI classes. Agents such as mirtazapine, reboxetine 27. Mir S, Taylor D. Sexual adverse effects with new antidepressants. Psychiatric Bulletin 1998;22:438–41.
28. Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. J Clin and the newcomer, agomelatine (not yet licensed in South Africa), do Psychiatry 2006;67(6):33–7. not currently enjoy the broad familiarity of the SSRI class. However, they 29. Rudkin L, Taylor MJ, Hawton K. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003382.
are far less inclined to cause sexual side-effects and may be considered 30. Labbate LA, Croft HA, Oleshansky MA. Antidepressant-related erectile dysfunction: management via appropriate alternative first-line drug options for patients where normal avoidance, switching antidepressants, antidotes, and adaptation. J Clin Psychiatry 2003;64(10):11–9.
31. Labbate LA, Grimes JB, Hines A, Pollack MH. Bupropion treatment of serotonin reuptake antidepressant- sexual functioning is a priority.
associated sexual dysfunction. Ann Clin Psychiatry 1997;(4)24–5.
32. Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S. Treatment of antidepressant- The diagnosis of antidepressant-induced sexual dysfunction may be associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA 2003;289(1):56–64.
33. Nurnberg HG, Hensley PL, Heiman JR. Sildenafil treatment of women with antidepressant-associated aided by baseline and periodic clinical monitoring of sexual function. sexual dysfunction: a randomized controlled trial. JAMA 2008;300(4):395–404.
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