Sexual dysfunction during treatment with serotonergic and
noradrenergic antidepressants: Clinical description and
the role of the 5-HTTLPR
JANA STROHMAIER 1 , STEFAN W Ü ST 1 , RUDOLF UHER 2 , NEVEN HENIGSBERG 3 ,
OLE MORS 4 , JOANNA HAUSER 5 , DANIEL SOUERY 6 , ASTRID ZOBEL 7 ,
MOJCA Z. DERNOVSEK 8 , FABIAN STREIT 1,9 , CHRISTINE SCHM Ä L 1 ,
DEJAN KOZEL 10 , ANNA PLACENTINO 11 , ANNE FARMER 2 , PETER MCGUFFIN 2 ,
KATHERINE J. AITCHISON 2,12 & MARCELLA RIETSCHEL 1
1 Central Institute of Mental Health, Division of Genetic Epidemiology in Psychiatry, Mannheim, Germany, 2 Medical Research
Council (MRC) Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King ’ s College London,
UK, 3 Croatian Institute for Brain Research, Medical School, University of Zagreb, Croatia, 4 Aarhus University Hospital,
Risskov, Denmark, 5 Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences,
Poland, 6 Laboratoire de Psychologie M é dicale, Universit é Libre de Bruxelles and Psy Pluriel – Centre Europ é en de Psychologie
M é dicale, Belgium, 7 Department of Psychiatry, University of Bonn, Germany, 8 Educational and Research Institute Ozara,
Ljubljana, Slovenia, 9 Institute of Psychobiology, University of Trier, Germany, 10 Institute of Public Health, Ljubljana, Slovenia,
11 Psychiatric Unit 23, Department of Mental Health, Spedali Civili Hospital and Biological Psychiatry Unit, Centro San
Giovanni di Dio IRCCS-FBF, Brescia, Italy, and 12 Division of Psychological Medicine and Psychiatry, Institute of Psychiatry,
King ’ s College London, UK
Objectives . Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective
serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based
Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on
sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant).
Methods. A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with
escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery –
Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the
Sexual Functioning Questionnaire. Results . The incidence of reported SD after 12 weeks of treatment was relatively low,
and did not differ signifi cantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no signifi cant
interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age
were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR. Conclusions.
In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no
apparent effect of the 5-HTTLPR on the observed decline in SD.
Key words: Sexual dysfunction , 5-HTTLPR , selective serotonin uptake inhibitors , escitalopram , nortriptyline
Patients who receive antidepressants frequently
report sexual dysfunction (SD), which may affect all
phases of the sexual response cycle, i.e. desire, arousal,
and orgasm. Estimates of medication-induced SD
vary widely. Rates of between 10 and 90% have been
reported, with higher rates for antidepressants which
act on the serotonergic system (Werneke et al. 2006;
Correspondence (current affi liation): Jana Strohmaier, MS Psych, Central Institute of Mental Health, Department of Genetic Epidemiology
in Psychiatry, J 5, 68159 Mannheim, Germany. Tel: ? 49 621 1703 6067. Fax: ? 49 621 1703 6055. E-mail: jana.strohmaier@
(Received 20 August 2010 ; accepted 20 January 2011 )
The World Journal of Biological Psychiatry, 2011; 12: 528–538
ISSN 1562-2975 print/ISSN 1814-1412 online © 2011 Informa Healthcare
Sexual dysfunction, antidepressants and the 5-HTTLPR 529
In a study of the treatment of premature ejaculation,
long allele homozygotes showed a better SSRI treat-
ment response than short allele carriers (Safarinejad
Pharmacologically, SSRIs reduce the binding of
serotonin to the serotonin transporter – a protein
responsible for the transport of serotonin from the
synaptic cleft into presynaptic serotonergic neurons –
thereby increasing the concentration of synaptic
serotonin (5-HT) and facilitating the modulation of
post-synaptic receptors (Stahl 1998). This SSRI
effect may additionally decrease the concentrations
of dopamine and noradrenaline in the mesolimbic
system by activating serotonin 5-HT 2 receptors
(Meltzer et al. 1979; Baldessarini and Marsh 1990;
Done and Sharp 1992). Dopamine release within the
mesolimbic system has been implicated as a major
mechanism in sexual function (Bitran et al. 1988;
Segraves 1989; Hull et al. 1999). Noradrenaline
regulates sexual arousal (Lee and Pfaff 2008) and
bup ropion, a dopamine and noradrenaline reuptake
in hibitor, has been reported to decrease SSRI-in-
duced SD (Zisook et al. 2006; Safarinejad 2010b,c).
However, the mechanisms through which SSRIs
cause SD remain poorly understood (Segraves 2007;
Perlis et al. 2009). SSRIs are currently the most
commonly prescribed antidepressants. They have
been reported to be highly effective in the treatment
of depression and to cause fewer severe side effects
than TCAs (Degner et al. 2004; Grohmann et al.
1999). It is therefore important to elucidate the
association between SSRIs and SD.
The aim of the present study was to assess SD rates
during treatment with escitalopram and nortriptyline,
and to determine the possible infl uence of 5-HTTLPR
genotype on sexual function. The study was conducted
within the context of a large European Commission
funded multicentre study (Genome-based Therapeutic
Drugs for Depression – GENDEP). Given previous
fi ndings of an association between 5-HTTLPR
genotype, SD, and treatment response during anti-
depressant treatment, we hypothesised that carriers
of the 5-HTTLPR long allele would experience a
higher degree of SD during SSRI treatment than
either short allele homozygotes or patients receiving
Study design and sample
The GENDEP project is a multicentre pharmacoge-
netic study designed to compare the clinical and
genetic determinants of therapeutic response to two
antidepressants with contrasting primary modes
of action – nortriptyline and escitalopram (http://
Serretti and Chiesa 2009; Williams et al. 2010). SD
rates of around 40% have been reported for the
selective serotonin reuptake inhibitor (SSRI) escit-
alopram (Clayton et al. 2006b, 2007), although
lower rates were reported in a review published in
2004 (Hirschfeld and Vornik 2004). Only one previ-
ous report has compared rates of SD during treat-
ment with tricyclics and SSRIs. This retrospective
study included a small male sample and compared
SD rates during treatment with fi ve tricyclic antide-
pressants (including nortriptyline) and three SSRIs
(not including escitalopram). A higher rate of treat-
ment-associated SD was observed during treatment
with SSRIs (Hsu and Shen 1995). Research suggests
that SSRIs cause dysfunction in all phases of the
sexual response cycle, predominantly in the phases
of desire and orgasm in males and arousal in females
(Clayton et al. 2006a; Corona et al. 2009; Serretti
and Chiesa 2009). TCAs have been found to have
particular effects on desire and orgasm, although
they may also affect other phases of the sexual
cycle since they modify several neurotransmitters
(Werneke et al. 2006). SD is known to decrease
compliance with antidepressant treatment, and
effective strategies for its management are therefore
essential (Rothschild 2000; Montejo et al. 2001;
Werneke et al. 2006).
Pharmacogenetic research has only recently
begun to identify genetic markers that may predict
response to antidepressant treatment (Lin and
Chen 2008; Drago et al. 2009; Ising et al. 2009;
Schosser and Kasper 2009; Uher et al. 2009b, 2010;
Kato and Serretti 2010). These markers may facili-
tate the prediction of adverse events such as SD dur-
ing antidepressant treatment (Bishop et al. 2009). It
has been hypothesised that the development of SD
during treatment with serotonergic antidepressants
is moderated by variations in the serotonin trans-
porter gene ( SLC6A4 ), which encodes the serotonin
transporter protein (5-HTT; Bishop et al. 2009).
The polymorphism in SLC6A4 which has been most
studied for association with SD to date is the
5-HTTLPR , an insertion/deletion of 44 base pairs
(bp) within the promoter region. An association has
been reported between 5-HTTLPR genotype and
response to antidepressant treatment, in which car-
riers of the long allele show a better response than
short allele homozygotes (Serretti et al. 2007; Huezo-
Diaz et al. 2009). Long allele homozygotes have also
been shown to experience more SD during SSRI
treatment for depression (Bishop et al. 2009).
Furthermore, an association has been found between
the short allele and premature ejaculation (Ozbek
et al. 2009), whereas Janssen et al. (2009) reported
in s-carriers with premature ejaculation longer ejac-
ulation times compared to long allele homozygotes.
530 J. Strohmaier et al.
mild, moderate, severe). Each study participant was
asked to complete the ASEC before commencing the
study medication, and then weekly for 12 weeks. The
ASEC item 12 was selected as the main outcome
measure due to its weekly application and low rate
of missing data. The UKU Side Effects Rating Scale
(UKU) is a comprehensive semi-structured inter-
view which assesses psychic and physical adverse
reactions to psychotropic drugs (Lingjaerde et al.
1987). Five of the 48 UKU items (desire, erection,
ejaculation, vaginal lubrication, orgasm) enquire
specifi cally about SD according to a four-point scale.
The Sexual Functioning Questionnaire (SFQ; Smith
et al. 2002) is a 38-item self-rating questionnaire that
measures current sexual functioning across various
domains (libido, arousal, erection, ejaculation, vagi-
nal lubrication, orgasm) according to a two-point
scale. Higher scores indicate greater sexual dysfunc-
tion in the respective domain. In GENDEP, the
UKU and the SFQ were administered at baseline
and at study weeks 8 and 12 (Uher et al. 2009a).
Genotyping and quality control
Blood samples were collected in ethylenediamine
tetra-acetic acid and frozen. DNA was extracted using
a standard procedure (Freeman et al. 2003). Short
and long alleles of the 5-HTTLPR were determined
using polymerase chain reaction (PCR) with a previ-
ously described method (de Bakker et al. 2005).
A repeated measures ANOVA was used to compare
differences in the main outcome measure ( ASEC
item 12) at baseline and all subsequent study weeks
between drop-outs and subjects who completed the
entire protocol. In this analysis, study week was a
within-subject factor and drop-out vs. non-drop-out
and sex were between-subject factors. All subsequent
ANOVAs were computed with study week as a with-
in-subject factor and sex as a between-subject factor.
For the infl uence of study medication, a repeated
measures ANOVA was computed with study medi-
cation as a between-subject factor. In a subsequent
step, change in depressive symptoms during the
course of treatment (difference in MADRS sum-
mary scores and depressive symptom dimensions
between baseline and week 12), age, and genotype
status at the 5-HTTLPR locus (s/s vs. s/l vs. l/l) were
added to the model as further predictors.
To limit the number of statistical analyses, only the
genetic association between the 5-HTTLPR and the
main outcome measure (ASEC item 12) was tested.
A further reason for focusing the genetic association
analysis on ASEC item 12 was the high rate of missing
gendep.iop.kcl.ac.uk/results.php). The study was
partly randomised, i.e. patients were only randomised
to treatment in the absence of any contraindication
to either of the two study drugs. All subjects met
ICD-10/DSM-IV criteria for a major depressive epi-
sode. Patients were treated with nortriptyline or esci-
talopram for a period of 12 weeks. Escitalopram was
initiated at a dose of 10 mg daily, and this was
increased to a target dose of 15 mg daily within the
fi rst 2 weeks. The dose could be further increased to
20 mg daily, or up to 30 mg when there was clinical
agreement that a higher dose was indicated. Nortri-
ptyline was initiated at 50 mg daily and titrated to a
target dose of 100 mg daily within the fi rst 2 weeks.
The dose could be increased to 150 mg daily, or up
to 200 mg when there was clinical agreement that a
higher dose was indicated. Adjunct psychotropic
medication was not allowed, with the exception of
occasional hypnotics. Compliance was monitored
weekly by self-reported pill count, and antidepres-
sant plasma levels were measured at week 8. Written
informed consent was obtained from all participants
prior to inclusion. A detailed description of the
GENDEP sample and treatment outcomes is pro-
vided elsewhere (Uher et al. 2009c). Only subjects
who had been randomly allocated to treatment were
included in the present study to exclude possible
confounding between pre-treatment SD and treat-
ment allocation. The fi nal sample included 176 males
(mean age 41.7 ? 12.5 years) and 318 females
(mean age 42.4 ? 11.0 years). Forty-six males and
70 females discontinued the study medication before
week 12 and were thus considered study drop-outs.
Depression severity was measured weekly using three
established scales: (i) the clinician-rated 10-item
Montgomery – Asberg Depression Rating Scale
(MADRS); (ii) the clinician rated 17-item Hamilton
Rating Scale for Depression (HRSD-17); and (iii)
the self-report 21-item Beck Depression Inventory
(BDI). The MADRS provides the most accurate and
internally valid refl ection of depression severity
(Uher et al. 2008). Joint factor analysis of the items
of all three depression scales revealed three depressive
symptom dimensions that provide a more detailed
description of depression severity: (i) observed mood
and anxiety, (ii) cognitive symptoms, and (iii)
neurovegetative symptoms (Uher et al. 2008).
Sexual function was measured weekly with the
Antidepressant Side-Effect Checklist (ASEC; Uher
et al. 2009a). The ASEC is a self-report instrument
that was designed to measure 21 adverse reactions
to antidepressants. Item 12 rates problems with sex-
ual function according to a four-point scale (absent,
Sexual dysfunction, antidepressants and the 5-HTTLPR 531
decrease over time was observed (main effect Time
F 4.477;158 ? 2.037, P ? 0.08). Separate analyses for
males and females revealed a signifi cant main effect
for Time in females only ( F 5.437;98 ? 2.963, P ? 0.01),
with not even a trend being identifi ed in males
( F 2.466;60 ? 0.908, P ? 0.423). The highest SD rates
were reported at baseline, i.e. when the subjects were
still medication free. On a descriptive level, this trend
was more pronounced in females than in males, with
20.3% of females reporting severe SD at baseline and
only 5.8% of males (see Discussion). There was no
evidence that study medication infl uenced the overall
severity or the time course of SD (main effect Medica-
tion F 1;156 ? 0.027, P ? 0.869, interaction Time ?
Medication F 4.491;156 ? 0.226, P ? 0.939; Figure 1).
An analysis was then performed to investigate
whether the change in depressive symptoms (i.e. the
difference between MADRS summary scores at base-
line and at week 12) had any impact on SD. The
ANOVA revealed a signifi cant interaction effect of
Time ? MADRS ( F 4.780;154 ? 5.016, P ? 0.001). This
effect was controlled for medication and sex, although
it was virtually identical without controlling for these
variables. To provide a graphical illustration (Figure 2),
a median split was performed for the MADRS differ-
ence. Subjects with a more pronounced decrease in
depressive symptoms over time also reported a more
pronounced reduction in SD (Time ? MADRS
Median Split F 4.665;157 ? 3.544, P ? 0.004). Further-
more, all available information on depression was used
to explore the impact on SD of the change in depres-
sive symptoms as indexed by the following three
dimensions: (i) observed mood and anxiety, (ii) cogni-
tive symptoms, and (iii) neurovegetative symptoms.
The decrease in depressive symptoms between base-
line and week 12 was most pronounced for observed
mood and anxiety symptoms (mean difference ? 1.69,
SD ? 0.87), followed by cognitive symptoms (mean
difference ? 1.42, SD ? 0.87). The smallest decrease
was observed for neurovegetative symptoms (mean
difference ? 1.13, SD ? 0.91). All differences were
signifi cant ( P ? 0.001). In a supplementary analysis,
the ANOVA was repeated using the differences in the
scores of these three depressive symptom dimensions
data for the UKU and SFQ, which resulted in very
low statistical power.
For the fi ve individual UKU items and the SFQ
subscales, similar repeated measures ANOVAs were
performed as those carried out for the main outcome
measure (ASEC item 12). Study week was entered
as a within-subject factor and sex as a between-sub-
ject factor. The stepwise inclusion of study medica-
tion, age, and the change in depressive symptoms
during the course of treatment (difference between
MADRS summary score at baseline and week 12)
were considered as further predictors. Due to a high
rate of missing data for the SFQ, this analysis was
restricted to data from baseline and study week 12.
All analyses were performed in SPSS version 17.0.
Greenhouse – Geisser corrections were applied where
appropriate, and only adjusted results are reported.
Genotype data were available for 473 subjects. Gen-
otype frequencies for the 5-HTTLPR variant were
192 l/l (0.41), 211 l/s (0.45), and 70 s/s (0.14). These
are consistent with previously reported frequencies,
and did not deviate signifi cantly from Hardy – Wein-
berg equilibrium ( P ? 0.33).
Results obtained from the various sexual function
Antidepressant Side-Effect Checklist. Subjects who
dropped out of the study did not differ signifi cantly
from those who completed the protocol in terms of
the main outcome measure (ASEC item 12; main
effect Group F 1;156 ? 0.064, P ? 0.801; interaction
Sex ? Group F 1;156 ? 0.112, P ? 0.738). The data
of study drop-outs were therefore included in the
analyses. The drop-out rate was linear, with around
10% of running subjects dropping out each week.
In both treatment groups, the majority of patients
reported no, or only mild, SD according to ASEC item
12 (see Table I). Furthermore, a trend towards a
Table I. Percentage of reported SD according to ASEC item 12.
SDBaseline SW 1SW 2SW 3SW 4 SW 5SW 6 SW 7SW 8 SW 9SW 10 SW 11 SW 12
SW, study week.
532 J. Strohmaier et al.
The fi nal analysis tested for an association
between 5-HTTLPR genotype and SD. No main
effect was detected for Genotype ( F 2;142 ? 0.057,
P ? 0.945). Similarly, no main effect was detected
for any of the following interactions: Time ? Gen-
otype ( F 9.726;142 ? 0.812, P ? 0.614); Medica-
tion ? Genotype ( F 2;142 ? 0.293, P ? 0.747); or
three-way Time ? Medication ? Genotype
( F 9.726;142 ? 0.872, P ? 0.557). To test for a pos-
sible interaction between age and genotype on
reported SD, the continuous variable age was con-
verted into a categorical variable by performing a
median split (Median Split ? 42 vs. ? 42). The sub-
sequent ANOVA revealed a signifi cant interaction
for Age Median Split ? Genotype ( F 2;131 ? 3.559,
P ? 0.031), with younger s/s subjects reporting less
SD than older s/s subjects (see Figure 3). Again,
this effect was not signifi cantly modifi ed by medica-
tion (Medication ? Age Median Split ? Genotype
F 2;131 ? 0.004, P ? 0.996).
UKU Side Effects Rating Scale
Table II shows the frequency of SD for each UKU
item. Desire dysfunction decreased signifi cantly over
time (main effect Time F 1.888;211 ? 24.219,
P ? 0.001). Women reported more severe desire dys-
function than men (main effect Sex F 1;211 ? 10.100,
P ? 0.002). This gender effect did not change over
time (Time ? Sex F 1.888;211 ? 0.048, P ? 0.947).
The decrease over time showed a trend towards
being more pronounced in the escitalopram group
(interaction Time ? Medication F 1.896;209 ? 2.746,
P ? 0.068). The change in depressive symptoms had
a signifi cant impact on desire dysfunction (interac-
tion Time ? MADRS F 1.909;205 ? 4.691, P ? 0.011).
Subjects with a more pronounced decrease in depres-
sive symptoms also reported a more pronounced
between baseline and week 12 rather than the differ-
ence in the MADRS score. The impact on SD of the
change in depressive symptoms was most pronounced
for the cognitive (Time ? Cognitive Symptoms
F 4.647;155 ? 4.305, P ? 0.001, η ² ? 0.027) and neu-
rovegetative symptoms (Time ? Neurovegetative
Symptoms F 4.568;155 ? 4.150, P ? 0.001, η ² ? 0.026).
The smallest impact on SD was observed for change
in mood and anxiety symptoms (Time ? Observed
Mood and Anxiety Symptoms F 4.630;155 ? 3.541,
P ? 0.005, η ² ? 0.022).
Tests were then performed to assess the impact of
age on SD. A trend towards a main effect for Age
was observed ( F 1;153 ? 3.039, P ? 0.083), with older
age being positively correlated with SD score.
Figure 1. Time course of reported sexual dysfunction (ASEC item
12) over the 12-week study period for escitalopram and
Figure 3. Interaction effect of the 5-HTTLPR genotype (s/s, s/l,
l/l) and age on reported sexual dysfunction (ASEC item 12).
Figure 2. Time course of reported sexual dysfunction ( ASEC item
12) over the 12-week study period according to the change in
MADRS (Montgomery – Asberg Depression Rating Scale) in
subjects with scores ? 18 points and ? 18 points.
Sexual dysfunction, antidepressants and the 5-HTTLPR 533
Erectile dysfunction was more common in subjects
who showed a less pronounced decrease in depressive
symptoms (main effect MADRS F 1;63 ? 4.396,
P ? 0.040), and in subjects who were older (main
effect Age F 1;62 ? 4.274, P ? 0.043). Both effects were
independent of time (interaction Time ? MADRS
F 1.629;63 ? 0.468, P ? 0.588; interaction Time ? Age
F 1.625;62 ? 0.194, P ? 0.778). Ejaculation dysfunction
showed a trend towards a decrease over time (main
effect Time F 1.832;63 ? 3.120, P ? 0.052), and no asso-
ciation was found with study medication, change in
depressive symptoms, or age. For vaginal lubrication
dysfunction, all possible effects were non-signifi cant.
Orgasmic dysfunction showed a trend towards a
decrease over time (main effect Time F 1.497;151 ? 2.856,
P ? 0.075). Women reported more severe orgasmic
dysfunction than men (main effect Sex F 1;151 ? 3.490,
P ? 0.064). This trend did not reach signifi cance and
did not change over time (interaction Time ? Sex
F 1.497;151 ? 0.034, P ? 0.930). Subjects with a more
pronounced decrease in depressive symptoms over
time also reported a more pronounced reduction in
orgasmic dysfunction (interaction Time ? MADRS
F 1.522;146 ? 4.061, P ? 0.028). No association was
found with study medication or age.
Sexual Functioning Questionnaire
Table III shows the frequency of SD for each of
the SFQ subscales. Desire dysfunction signifi cantly
decreased over time (main effect Time F 1.000;52 ? 7.028,
P ? 0.011). Women reported more severe desire dys-
function than men (main effect Sex F 1;52 ? 4.239,
P ? 0.045). This difference between women and men
did not change over time (interaction Time ? Sex
reduction in desire dysfunction. Older subjects
reported more severe desire dysfunction (main effect
Age F 1;204 ? 5.248, P ? 0.023).
Erectile dysfunction did not change over time, and
no association with study medication was found.
Table III. Mean and standard deviation of reported SD according to the SFQ subscales.
BaselineSW 8SW 12
SW, study week.
Table II. Percentage of reported SD according to the UKU
Baseline SW 8 SW 12
SW, study week.
534 J. Strohmaier et al.
nortriptyline group reported SD at week 8; and 14.9%
in the escitalopram group and 19.7% in the nortrip-
tyline group reported SD at week 12.
A supplementary analysis of the two more in-depth
measures (UKU and SFQ) indicated that lack of
desire was the most prominent SD in both men and
women. This decreased over time, and escitalopram
may have had a more positive effect than nortrip-
tyline. Desire and orgasmic dysfunction were more
frequent and severe in women than in men. Sexual
diffi culties in the other phases of the sexual cycle
showed no change, or only a slight decrease, over
time. This fi nding is plausible, since previous reports
have suggested that SSRIs and TCAs cause reduced
sexual desire and orgasmic dysfunction (Clayton
et al. 2006a; Corona et al. 2009; Rosen et al. 1999;
Serretti and Chiesa 2009; Werneke et al. 2006); how-
ever, it could also be due to the depressive disorder.
Lack of sexual desire and orgasmic dysfunction are
also more prevalent in women than in men in the
general population (Laumann et al. 1999).
The SD rates in the present prospective and ran-
domised sample are substantially lower than those
found in two previous studies by Clayton et al.
(2006b, 2007) which reported rates of 34 to 48.7%
following eight weeks treatment with escitalopram. In
comparison to the present study, the above reports
had narrower inclusion criteria. Clayton et al. (2006b)
only included subjects with (self-reported) normal
sexual functioning at baseline, who had agreed to
report any changes in sexual functioning, and who
reported that they were sexually active at least once
every 2 weeks. The authors excluded subjects with
pre-existing SD, anorexia nervosa, bulimia, seizure
disorders, brain injury, panic disorder, obsessive-
compulsive disorder, post-traumatic stress disorder,
acute stress disorder or a history of attempted suicide
within the previous 6 months. The impact of these
differences in study protocol on reported SD rates is
unknown. It is plausible, however, that the patients ’
knowledge of the explicit aim to assess SD may have
enhanced their awareness of such symptoms.
The results of a multinational study that compared
escitalopram with paroxetine are consistent with
those of the present study (Baldwin et al. 2006). In
both treatment groups, reported SD declined over
the course of treatment, and differences between
treatment groups were not signifi cant, although
reported SD rates were higher than in the present
study. Again, the inclusion criteria were more nar-
rowly defi ned. The authors argued that the decline
may have been due to the dropping-out of patients
with more severe SD (Baldwin et al. 2006). However,
drop-outs in the present study did not differ subs-
tantially from subjects who completed the protocol in
terms of reported SD. Moreover, a lower prevalence
F 1.000;52 ? 0.257, P ? 0.614). The decrease in desire
dysfunction was marginally more pronounced in the
escitalopram group (interaction Time ? Medication
F 1.000;50 ? 2.561, P ? 0.116). Subjects with a more
pronounced decrease in depressive symptoms also
reported less severe desire dysfunction (main effect
MADRS F 1;48 ? 11.259, P ? 0.002). Older subjects
reported more severe desire dysfunction than younger
subjects (main effect Age ( F 1;47 ? 6.421, P ? 0.015).
Arousal dysfunction signifi cantly decreased over
time (main effect Time F 1.000;51 ? 12.641, P ? 0.001).
Subjects with a more pronounced decrease in depres-
sive symptoms over time also reported a more pro-
nounced reduction in arousal dysfunction (interaction
Time ? MADRS F 1.000;47 ? 7.450, P ? 0.009). No
signifi cant effects were found for study medication,
sex, or age.
Erectile dysfunction decreased over time (main
effect Time F 1.000;21 ? 5.469, P ? 0.029) and older
subjects reported more severe erectile dysfunction
( F 1;18 ? 6.157, P ? 0.023). No infl uence was observed
for study medication or change in depressive symp-
toms. No signifi cant effects were observed for ejacula-
tion dysfunction or vaginal lubrication dysfunction.
Orgasmic dysfunction decreased over time in
men but not in women (interaction Time ? Sex
F 1.000;42 ? 6.402, P ? 0.015), and men reported less
severe orgasmic dysfunction than women (main
effect Sex F 1;42 ? 14.680, P ? 0.001). All other SFQ
main and interaction effects failed to reach statistical
The primary aim of the present study was to inves-
tigate the association between the 5-HTTLPR and
SD during treatment with antidepressants with
contrasting modes of action within the context of
the large pharmacogenetic GENDEP study. We
hypothesised that there would be a signifi cant asso-
ciation with SD during treatment with the SSRI
escitalopram but not during treatment with the
Our most prominent fi nding was that the majority
of subjects reported no, or only mild, SD despite
explicit and frequent assessment. The highest rates of
SD were reported at baseline, when subjects were still
medication-free, particularly in females. Over the
course of treatment, reported SD showed a slight
decrease. After 12 weeks of treatment, 16% of males
and 24% of females reported moderate or severe SD.
The decrease over time was only statistically signifi cant
in females, and was based on a pronounced decrease
in reported SD within the fi rst study week, i.e. between
baseline and week 1. Of those subjects with no SD at
baseline, 15.1% in the escitalopram and 16.4% in the
Sexual dysfunction, antidepressants and the 5-HTTLPR 535
risk factor for SD (Phanjoo 2000; Derogatis and
Burnett 2008; Corona et al. 2010).
Finally, we found no infl uence of 5-HTTLPR gen-
otype on reported SD on average, over the time
course of treatment, or in interaction with the study
medication. However, our data suggest a possible
infl uence of age on the association between the
5-HTTLPR genotype and reported SD. The infl u-
ence of age on sexual function may be more pro-
nounced in s/s subjects than in patients with the
genotype s/l or l/l. One previous report found that
the s/s genotype was associated with less SD than the
l/l genotype during SSRI treatment, although this
study did not report any infl uence of age (Bishop et
al. 2009). However, the age distribution of the Bishop
et al. sample (2009) differed signifi cantly ( t ? 11.70,
P ? 0.01) from that of the present study. In the
present sample, subjects with genotype data were
between 19 and 72 years of age, and the mean age
was 42.11 years. The study by Bishop et al. (2009)
included relatively young patients of between 18 and
40 years of age (mean of 29.2 years) in order to
minimise the confounding effect of age on the pres-
ence of SD. The lower proportion of older subjects
may explain why Bishop et al. (2009) found no
infl uence of age on the association between the
5-HTTLPR genotype and reported SD.
The present study met several of the methodolog-
ical quality criteria for the evaluation of antidepres-
sant related SD (Montgomery et al. 2002; Schweitzer
et al. 2009). These included: (i) a randomised and
prospective design; (ii) comparisons between differ-
ent treatments; (iii) a baseline assessment; (iv) the
use of defi ned diagnostic criteria for depression; (v)
the application of reliable and validated rating scales
for the assessment of SD in men and women; (vi)
direct assessment of depression and sexual function
before and during treatment; and (vii) consideration
of the possible effects of degree of remission and
gender on the outcome variables. However, the study
had several limitations. Firstly, we did not control for
comorbid illness or concomitant medications that
might affect normal sexual function. A previous
study, which involved neither random assignment
nor baseline control, controlled for these factors and
compared several different antidepressants. This
found the highest prevalence rates for SD during
treatment with the SSRI citalopram (Clayton et al.
2002). We did, however, exclude individuals who had
a contraindication to both study medications, who
were currently being treated for a somatic disease
using potentially depressogenic medications, or who
were using other psychotropic medications, with the
exception of the occasional use of hypnotics. A
second very important limitation is that patients
of ejaculatory problems has been reported for
escitalopram compared with other SSRIs following
8 weeks of treatment (Hirschfeld and Vornik
2004). A small study ( N ? 47) reported a reduction
in SD in the majority of subjects who switched from
other SSRIs or serotonin-norepinephrine reuptake
inhibitors to escitalopram (Ashton et al. 2005). Esci-
talopram is associated with lower rates of treatment-
withdrawal, and fewer discontinuation symptoms,
than paroxetine (Baldwin et al. 2006, 2007).
It is important to acknowledge that SD is wide-
spread in the general population. Estimates of 11%
for frequent or severe SD and 69% for infrequent or
mild diffi culties have been reported. Men predomi-
nantly report ejaculatory problems, with overall rates
of between 10 and 20%, whereas lack of sexual desire
is most prevalent in women, with rates of between
20 and 25%. Women also report higher rates of
orgasm dysfunction than
et al. 1999; Montgomery et al. 2002; Derogatis and
Burnett 2008; Laumann et al. 2009; Christensen
et al. 2010). In the present study, the SD rates
reported after 12 weeks of antidepressant treatment
(16% in males and 24% in females) only slightly
exceed the SD rates in the general population.
Given the rather low rates of reported SD, it is not
surprising that we failed to detect a major infl uence
of study medication or the 5-HTTLPR on reported
SD or its time course in the analysis of the main
outcome measure. No signifi cant differences in
reported SD were observed between patients receiv-
ing escitalopram and those receiving nortriptyline.
A more pronounced decrease in reported SD was
found in subjects whose depression improved sub-
stantially. This is consistent with previous fi ndings
for escitalopram, duloxetine, nortriptyline, and ser-
traline, and suggests that SD is infl uenced by the
remission of depression and may not be a side-effect
of antidepressant treatment (Lanza di Scalea et al.
2009). The effect was similar for the three depressive
symptom dimensions “ observed mood and anxiety ” ,
“ cognitive symptoms ” , and “ neurovegetative symp-
toms ” . This may be due to the high correlation
between the changes in depressive symptoms over
time across the three dimensions. Observed mood
and anxiety symptoms showed the most pronounced
improvement and neurovegetative symptoms the
least. The effects of study medication on the improve-
ments in each of these three symptom dimensions
have been described and discussed elsewhere (Uher
et al. 2009c).
We also observed an infl uence of age on reported
SD. Younger subjects reported less SD than older
subjects particularly for desire and erection diffi culties.
This fi nding is plausible, since age is an established
536 J. Strohmaier et al.
additional funding from the Biomedical Research
Centre for Mental Health at the South London and
Maudsley NHS Foundation Trust and the Institute of
Psychiatry, King ' s College London (grant from the
National Institute for Health Research, Department of
Health, UK). The funding bodies had no infl uence on
the design, analysis, or interpretation of the study
results. Author JS was supported by the German
Research Foundation (GRK 793).
Statement of Interest
Strohmaier, W ü st, Uher, Mors, Hauser, Souery, Zobel,
Dernovsek, Streit, Schm ä l, Kozel, Placentino, and
Rietschel have no confl icts of interests. Henigsberg has
participated in clinical trials sponsored by pharmaceu-
tical companies including GlaxoSmithKline and Lun-
dbeck; Henigsberg has received honoraria for
participating in expert panels from pharmaceutical
companies including Lundbeck. Souery is a member
of national advisory boards for Astra-Zeneca, Bristol-
Myers Squibb, Eli Lilly, and Lundbeck. Aitchison,
Farmer, and McGuffi n have received consultancy fees
and honoraria for participating in expert panels for
pharmaceutical companies including Lundbeck,
GlaxoSmithKline, and Bristol-Myers Squibb and
Otsuka Pharmaceuticals Limited. EudraCT clinical
trials registry number, 2004 – 001723-38 (http://eudract.
emea.europa.eu) and International Standard Random-
ized Controlled Trials registry number, ISRCTN
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were not asked whether they had a sexual partner or
questioned about their actual sexual activity during
the course of the study (sexual intercourse, sexual
fantasies, or other sexual activities). As already men-
tioned, Clayton et al. (2006b) only included subjects
who had normal orgasmic function and who were
sexually active. Future comparative well-designed
randomised controlled trials of SD during antide-
pressants treatment for depression should include
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about sexual activity, to determine the clinical sig-
nifi cance of differences in SD (Schweitzer et al.
2009). Thirdly, the study was not double-blind, with
in most cases in fact both the treating psychiatrist
and the patient knowing which medication was being
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In summary, the present study of a large multi-
centre European sample found no interaction effect
for 5-HTTLPR genotype and two antidepressants
with contrasting primary modes of action on reported
SD. In addition, no differential infl uence of study
medication per se was found, with the exception of
a possible benefi cial effect on desire dysfunction for
escitalopram compared to nortriptyline. The rate of
reported SD was rather low, with only minor changes
or improvements being reported during the course
of treatment, despite the application of three differ-
ent measurement tools. We identifi ed an infl uence of
change in depressive symptoms and age on reported
SD. The unexpectedly low rate of SD reported dur-
ing treatment with both medications is a noteworthy
fi nding of the present study, which may have impor-
tant implications for clinical practice.
We thank all of the study participants, researchers, and
clinicians who contributed to this study. GENDEP
was funded by a European Commission Framework
6 grant (contract number LSHB-CT-2003-503428).
We thank Lundbeck for supplying the study medica-
tion (escitalopram and nortriptyline). We also thank
GlaxoSmithKline and the Medical Research Council
(UK) for contributing to the funding of the sample
collection at the Institute of Psychiatry, London,
though add-on projects. The London centre received
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