CPD Article: Antidepressant-induced sexual dysfunction
Antidepressant-induced sexual dysfunction
Department of Pharmacology, University of Pretoria, South Africa
Dr Kim Outhoff, e-mail: [email protected]
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
Sexual dysfunction and depression
by oxytocin and acetylcholine. Prolactin's role might be to deter arousal and studies have shown serotonin to hinder desire
Depression is a common, serious and disabling illness. Besides
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
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.
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
and catecholamines, which could increase the risks for not only
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
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
Rouillon 2006; Kennedy 2008
dysfunction in the psychiatric inpatient setting. Moreover, both Casper18
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
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
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offending agent requires careful monitoring of the patient for relapse
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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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the general population. Family Practice 1998;15:519–24.
There is some evidence that switching
to an antidepressant such as
6. Laumann EO, Paik A, Rosen RC, et al. Sexual dysfunction in the United States: prevalence and predictors.
nefazodone or bupropion is effective.30 This may prove troublesome,
7. Ellison KE, Gandhi G. Optimising the use of β-adrenoceptor antagonists in coronary artery disease. Drugs
however, if the offending drug is considered the only effective drug for
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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.
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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.
prior to treatment.
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.
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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
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.
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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
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33. Nurnberg HG, Hensley PL, Heiman JR. Sildenafil treatment of women with antidepressant-associated
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SA Fam Pract 2009
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