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Antidepressants

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DOI: 10.1007/978-3-319-59531-3_4-1

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A
Antidepressants
Tierney Lorenz
Department of Psychology, University of
Nebraska, Lincoln, TX, USA
Synonyms
Sexual adverse events; Medication-associated
sexual dysfunction
Definition
Antidepressants are associated with sexual side
effects: clinically significant disturbances in sex-
ual desire, arousal, orgasm, or other aspects of
sexual wellbeing that develop on starting or stop-
ping antidepressant medications. When sexual
side effects are significant (appearing in at least a
quarter of all sexual events) and distressing, they
meet criteria for “substance-induced sexual dys-
function,” a significant clinical disorder (Ameri-
can Psychiatric Association, 2013).
Introduction
Sexual wellbeing depends on the complex inter-
play between multiple neurotransmitters and hor-
mones, including those targeted by
antidepressants. The most commonly prescribed
© Springer Nature Switzerland AG 2019
A. D. Lykins (ed.), Encyclopedia of Sexuality and Gender,
https://doi.org/10.1007/978-3-319-59531-3_4-1
antidepressants include selective serotonin reup-
take inhibitors (SSRIs), selective serotonin and
norepinephrine reuptake inhibitors (SNRIs), and
atypical agents such as bupropion and
mirtazapine. Commonly reported sexual side
effects include decreased sexual desire, lower sex-
ual arousal, and problems having an orgasm
(termed “anorgasmia”). This entry outlines the
prevalence of sexual side effects, impact on treat-
ment adherence and patient’s wellbeing, demo-
graphic predictors of sexual side effects,
scientific models of side effect etiology, and treat-
ments for sexual side effects.
Prevalence of Sexual Side Effects of
Antidepressants
Approximately, 25–80% of individuals taking
antidepressants will experience significant change
in sexual function within 2–6 weeks of beginning
treatment (Schweitzer, Maguire, & Ng, 2009). Of
these, about 30% will experience recovery of sex-
ual function by week 12 (Clayton, Kornstein,
Prakash, Mallinckrodt, & Wohlreich, 2007;
Thase et al., 2006).
Medications with primarily serotoninergic
mechanisms of treatment (e.g., sertraline,
citalopram, venlafaxine) are associated with sig-
nificantly higher rates of sexual side effects than
medications with predominantly noradrenergic,
dopaminergic, or other mechanisms (e.g.,
mirtazapine, bupropion, duloxetine). While
2 Antidepressants
medication class appears to be related to risk for
sexual side effects, several meta-analyses have not
found any specific antidepressant type to be sig-
nificantly superior or inferior to others in terms of
impact on sexual wellbeing (Reichenpfader et al.,
2014; Serretti & Chiesa, 2009). Lithium and anti-
convulsants (which are often used as mood stabi-
lizers and thus potentially termed
“antidepressants”) have also been associated
with decreased sexual desire (Aizenberg, Sigler,
Zemishlany, & Weizman, 1996).
Impact of Antidepressant Sexual Side Effects
on Quality of Life and Treatment Efficacy
Antidepressant side effects significantly contrib-
ute to treatment nonadherence (Burra et al., 2007).
Importantly, onset of sexual side effects occurs
within about 1–3 weeks of starting a new antide-
pressant, while the treatment effects do not con-
sistently appear until about 2–4 weeks (Gelenberg
et al., 2013). During this “critical window,” many
patients suffer side effects without benefits of
symptom reduction, and not surprisingly, drop
out of treatment prematurely. One of the best pre-
dictors of risk for developing sexual side effects is
sexual function prior to starting medication (Perlis
et al., 2009), and thus clinical best practices sup-
port careful assessment of patient’s sexual func-
tion before starting antidepressants and
counseling regarding the critical window men-
tioned above (Lorenz, Rullo, & Faubion, 2016).
The negative effects of antidepressants on sex-
uality should be considered alongside the poten-
tial for improvements in sexual desire and
relationship satisfaction associated with treating
depression. Meta-analyses and representative
population-level studies in the US consistently
show that depression is a significant risk factor
for sexual dysfunction, and vice versa (Atlantis &
Sullivan, 2012; Laumann, Paik, & Rosen, 1999;
Laumann et al., 2004). In one meta-analysis of
over 14,000 patients, patients with diagnoses of
depression had a 50–70% risk of developing sex-
ual dysfunction, even after adjusting for common
factors (Bonierbale, Lancon, & Tignol, 2003).
Depression may impair sexual wellbeing by
reducing motivation for engaging in pleasurable
activities more generally (Admon & Pizzagalli,
2015), interfering with romantic or sexual rela-
tionships (Althof et al., 2005; Rosen et al., 2004),
increasing the likelihood of substance misuse
(Shifren, Monz, Russo, Segreti, & Johannes,
2008), or suppressing physiological factors that
support sexual function (Goldstat, Briganti, Tran,
Wolfe, & Davis, 2003).
Thus, for many patients, the benefits of reduc-
ing the negative effects of depression on their
mood and relationships far outweigh the specific
effects of medication on sexual function
(O’Mullan, Doherty, Coates, & Tilley, 2015).
Accordingly, depressed patients taking antide-
pressants are significantly less likely to report
distress regarding low sexual desire than those
not taking antidepressants (Hayes et al., 2008;
Rosen et al., 2009). And, even some disturbances
in sexual function can sometimes be perceived as
positive such as how antidepressant-induced
increased orgasm latency can improve rapid ejac-
ulation (Balon, 1996; Waldinger, Berendsen,
Blok, Olivier, & Holstege, 1998).
Predictors of Sexual Side Effects of
Antidepressants
Gender/sex. Men report antidepressant sexual
side effects at a higher rate (Serretti & Chiesa,
2009), but as there are far more women taking
antidepressants (Nolen-Hoeksema, 2001;
Piccinelli & Wilkinson, 2000), the number of
men and women who experience sexual side
effects is approximately equal. Also, women
report higher severity of side effects than do men
(Montejo, Llorca, Izquierdo, & Rico-
Villademoros, 2001). Across antidepressant
types, men are significantly more likely to report
problems with sexual desire and orgasm, while
women are significantly more likely to report
problems with arousal and lubrication (Serretti &
Chiesa, 2009).
Age. Although there is an association between
increased age and incidence of sexual problems
(Avis et al., 2017), older adults (age 60+) are
generally at no increased risk for sexual side
effects of antidepressants (Garfield et al., 2014;
Modell, Katholi, Modell, & DePalma, 1997;
Read, Cartwright, & Gibson, 2014) and in fact
may be protected relative to younger patients
Antidepressants
(Hughes, Lacasse, Fuller, & Spaulding-Givens,
2017). However, the effects of untreated depres-
sion on sexual function appear to be greater for
older adults (Laumann, Glasser, Neves, &
Moreira Jr, 2009; Leiblum, Koochaki,
Rodenberg, Barton, & Rosen, 2006; Wang et al.,
2015), suggesting greater possible benefits of anti-
depressant use in this population. Of note, antide-
pressants are often prescribed to women during
menopause to manage vasomotor symptoms;
these patients appear to be at no increased risk of
sexual dysfunction relative to unmedicated men-
opausal women (Portman et al., 2014).
The data on sexual side effects in children and
adolescents are extremely limited, despite calls
from researchers and pediatric care providers for
more research (Scharko, 2004). One study of 235
adolescents with depression found no significant
difference in sexual function among medicated
versus unmedicated patients; however, the doses
were low and time on antidepressants was rela-
tively short (M = 25 days; Deumic et al., 2016).
Studies in nonhuman animals suggest that antide-
pressant use during development can impair adult
sexual function (de Jong et al., 2006), suggesting
the need for more research on long-term develop-
mental effects of antidepressant use in young
people.
Genetic factors. Individuals with genotypes
associated with inefficient serotonin transport (e.
g., 5HTTLPR) have been shown to have signifi-
cantly higher risk of experiencing antidepressant
sexual side effects (Bishop, Moline, Ellingrod,
Schultz, & Clayton, 2006; Clark et al., 2012;
Huezo-Diaz et al., 2009). Women with the short
form of this allele are at even higher risk if they
also take hormonal contraceptives (Bishop,
Ellingrod, Akroush, & Moline, 2009), suggesting
possible interactions with endocrine factors. Sim-
ilarly, older adults (60+) with high-expressing
genotypes for serotonin transporter and auto-
receptors are at particular risk of diminished sex-
ual desire following antidepressant treatment
(Garfield et al., 2014).
Possible Causes of Sexual Side Effects
Serotonergic inhibition of sexual desire,
arousal, and orgasm. As noted above, there is
3
significantly increased incidence of sexual side
effects among medications with greater serotoner-
gic effects. Serotonin plays a largely inhibitory
role in sexual function (Pfaus, 2009), particularly
in the suppression of spinal cord reflexes associ-
ated with orgasm (Zajecka, Fawcett, Schaff,
Jeffriess, & Guy, 1991) and suspension of genital
vasocongestion (the vascular responses associated
with lubrication and erection; Frohlich & Meston,
2000). Serotonin inhibits attention to and activa-
tion by sexual cues, increasing the threshold for
sexual excitation and interest and lowering both
spontaneous and responsive sexual desire (Croft,
2017). Moreover, serotonin is a key neurotrans-
mitter in satiety, which (generally) acts as a
countervailing force opposing motivation. In
other words, by signaling sexual satiety, seroto-
nergic medications may suppress desire for fur-
ther sexual activity (Pfaus, 2009).
Inhibition of dopamine and norepinephrine.
In addition to their direct effects on serotonin,
antidepressants can inhibit the action of dopamine
on reward pathways, which in turn may impair
sexual pleasure and interest (Bijlsma et al., 2014).
Dopaminergic inhibition may also play a role in
antidepressant-associated emotional blunting,
including blunted romantic or loving feelings
towards a sexual partner (Marazziti et al., 2014;
Opbroek et al., 2002). Finally, SSRIs may also
blunt the activation of the sympathetic nervous
system via inhibition of norepinephrine activation
in response to arousing stimuli (Lorenz & Meston,
2012). As female – but not male – sexual arousal
is facilitated by sympathetic activation (Lorenz,
Harte, Hamilton, & Meston, 2012); this may par-
tially explain why females are more likely to
report sexual arousal side effects of SSRI use
than are males (Montejo et al., 2001) and why
females report lower arousal side effects to
SNRIs (Serretti & Chiesa, 2009).
Endocrine effects. There is crosstalk between
estrogenic and serotonergic systems in the brain,
with each modulating the activity of the other
(Bethea, Lu, Gundlah, & Streicher, 2002; Biegon
& McEwen, 1982). There is some evidence that
SSRIs can impair estrogen synthesis (Thibeault et
al., 2017), which in turn may impact sexual desire,
particularly among females (Cappelletti &
4 Antidepressants
Wallen, 2016). Similarly, SSRI use may alter
androgen production via disruption of aromatase
activity (Hansen, Larsen, Sørensen, Halling-
Sørensen, & Styrishave, 2017). Finally, certain
antidepressants (such as those that act on dopa-
mine) can increase prolactin secretion via inhibi-
tion of hypothalamic dopamine pathways that
normally suppress production of prolactin
(Lyons, Ammari, Hellysaz, & Broberger, 2016).
High levels of prolactin are associated with lower
sexual desire and reduced enjoyment of orgasm in
both men and women (Corona et al., 2014;
Krysiak, Drosdzol-Cop, Skrzypulec-Plinta, &
Okopien, 2016; Weizman et al., 1983).
Indirect effects. In addition to direct effects on
neurochemical pathways associated with sexual
response, there are a number of other effects that
may contribute indirectly to sexual wellbeing.
Other side effects such as weight gain, nausea,
or insomnia could contribute to poorer sexual
function (Gafoor, Booth, & Gulliford, 2018;
Hughes et al., 2017). Finally, treating depression
can change patient’s sexual habits or relationship
dynamics in ways that may impact sexual func-
tion. For example, there is some evidence that
depressed women are more likely to masturbate
than their nondepressed peers (Frohlich &
Meston, 2002); insofar as masturbation is associ-
ated with higher rates of orgasm function
(Heiman, & LoPiccolo, 1988), it is possible that
antidepressant treatment may lead to lower
orgasm function via decreased rates of
masturbation.
Treatments for Antidepressant Sexual Side
Effects
There are few scientifically tested interventions to
improve antidepressant sexual side effects. Clini-
cians are advised to start patients on medications
with lower side effect risk to begin with (Clayton,
Croft, & Handiwala, 2014; Lorenz et al., 2016),
and to move patients who are on problematic
medications to another antidepressant with lower
side effect burdens when possible (de Boer,
Castelein, Wiersma, Schoevers, & Knegtering,
2015; Nurnberg et al., 2003). In most cases, sex-
ual function will return when the problematic
antidepressant is removed but there are occasional
reports of persistent sexual disturbance following
withdrawal (Healy, Le Noury, & Mangin, 2018).
Other treatments include augmentation with
other medications such as phosphodiesterase
inhibitors (e.g., sildenafil (Nurnberg et al., 2008)
or androgens (e.g., transdermal testosterone
(Fooladi et al., 2014), or supplements such as
ginkgo biloba (Meston, Rellini, & Telch, 2008;
Wheatley, 2004) or maca root (Dording et al.,
2008). However, augmentation strategies are
often problematic, as they increase the cost and
complexity of care, and generally only address a
portion of the concern. For example, sildenafil
improves orgasm dysfunction in women taking
antidepressants, but has no significant effect on
decreased desire or satisfaction (Nurnberg et al.,
2008).
Finally, a few behavioral interventions have
been developed for antidepressant side effects,
such as exercise (Lorenz & Meston, 2012, 2014)
and vibratory stimulation (Lorenz et al., 2016;
Rullo et al., 2018). One previously popular behav-
ioral strategy was the “drug holiday,” in which the
patient is directed to stop taking the drug for a
specified time; however, although this sometimes
reduces side effects, it also reduces therapeutic
efficacy and thus is no longer recommended
(Clayton et al., 2014).
Conclusion
Antidepressants are associated with a variety of
effects on sexual function, including decreased
sexual desire and arousal, increased latency to
orgasm, and lower enjoyment of sexual activity.
Many patients treated with antidepressants will
experience some sexual side effects: estimates
range from 25 to 80% of all patients notice a
change in sexual function for at least some of the
time they take these medications. The majority of
these patients will improve over time
(Reichenpfader et al., 2014), but for a noteworthy
subset (10–30%), side effects will persist and
require separate clinical attention (Serretti &
Chiesa, 2009). Side effects have a significant
impact on patient’s quality of life and relation-
ships, and can interfere with taking the medication
Antidepressants
as prescribed (aka treatment adherence). The eti-
ology of antidepressant sexual side effects is mul-
tifactorial, including neurochemical, endocrine,
and behavioral effects. The best recommended
treatment for antidepressant-associated sexual
problems is prevention by avoiding medications
known to have high side effect risk; other treat-
ments such as supplementation and drug holidays
have limited efficacy.
Cross-References
▶ Effects of Substances on Sexual Behavior,
Interest, and Arousal
▶ Influence of Hormones, Neurotransmitters, and
Neural Activity on Sexual Behavior and
Motivation
▶ Sexual Behavior Across the Life Cycle
▶ Sexual Dysfunctions
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