Copyright  2006 The Authors

Journal Compilation  2006 Blackwell Munksgaard

Acta Psychiatr Scand 2006: 114: 384397

All rights reserved
DOI: 10.1111/j.1600-0447.2006.00890.x

ACTA PSYCHIATRICA
SCANDINAVICA

Review article

Antidepressants and sexual dysfunction

Werneke U, Northey S, Bhugra D. Antidepressants and sexual
dysfunction.

U. Werneke1,2, S. Northey3,
D. Bhugra4,5
1

Objective: Many patients with depression suer from sexual

dysfunction and sexual dysfunction is a recognized side-eect of
antidepressants. The aim of this review was to examine the prevalence
of psychosexual dysfunction associated with antidepressants, and to
review treatment options which are specic to the aected component
of sexual functioning and antidepressants.
Method: Comprehensive literature review using Medline and
Cochrane databases.
Results: Up to 70% of patients with depression may have sexual
dysfunction. Tricyclic antidepressants, selective-serotonin reuptake
inhibitors and venlafaxine are most and the non-serotonergic
antidepressants and duloxetine least likely to produce sexual
dysfunction. Pharmacological treatment options include
antidepressants less likely associated or antidotes to reverse sexual
dysfunction.
Conclusion: Sexual dysfunction may be a preventable or treatable sideeect of antidepressants. Patients need routinely to be asked about
sexual function to identify problems early. If sexual dysfunction is
ignored it may maintain the depression, compromise treatment
outcome and lead to non-compliance.

Department of Psychiatry, Homerton University

Hospital, London, 2Barts and The London Queen Mary
School of Medicine and Dentistry, London, 3Department
of Psychology, University of Surrey, Surrey, 4Section of
Cultural Psychiatry, Health Services Research
Department, Institute of Psychiatry (KCL) and 5Couple
and Sexual Therapy Clinic, Maudsley Hospital, London,
UK

Key words: sexual dysfunction; antidepressive agents;

adverse effects; receptor; serotonin; review
Ursula Werneke, Department of Psychiatry, Homerton
University Hospital, East Wing, Homerton Row, London
E9 6SR, UK.
E-mail: uwernecke@easynet.co.uk
Accepted for publication July 3, 2006

Summations

The likelihood of developing and maintaining sexual dysfunction is determined by the balance of
serotonergic, noradrenergic and dopaminergic properties of individual antidepressant agents.
Substitution of a possible suspect offending agent by using an alternative antidepressant with less
impact on sexual function may be the rst line of pharmacological treatment.
Alternatively, antidotes can be tried, aiming at reversing specic neurotransmitter activities known
to mediate sexual dysfunction.
Considerations

With a high baseline prevalence of sexual dysfunction in cases of depression, it may be difcult to
identify and quantify the adverse effects of individual antidepressants.
Measuring the prevalence of sexual dysfunction is difcult because research methods and reporting
thresholds vary widely.
For many pharmacological treatment options the evidence is still limited to small trials or case
reports.

Introduction

Many patients with depressive disorders suer

from disturbance of sexual function which can
aect all three domains: sexual interest (libido);
384

arousal; and orgasm/ejaculation (13). Establishing the cause of sexual dysfunction in depressed
patients can be dicult, and dierential diagnosis
must include a primary sexual dysfunction, sexual
dysfunction associated with general medical and

Antidepressants and sexual dysfunction

psychiatric disorders, and sexual dysfunction associated with treatments for psychiatric disorders (4).
Physical factors may account for primary sexual
dysfunction, i.e. absence of normal sexual function
ever, and for secondary sexual dysfunction, which
develops after a period of normal sexual function.
Conditions associated with depression and sexual
dysfunction include most chronic ailments including Parkinsons disease, diabetes, chronic pain,
cancer and ischaemic heart disease (5). Anatomical
abnormalities can also impair sexual function. For
instance, Peyronies disease, by leading to signicant penile deformity impairing penetration, may
discourage sexual activity and cause signicant
psychological distress (6). Women who have suffered circumcision may experience similar problems, but do not wish to talk about them (7).
Sexually transmitted diseases and harmful use of
alcohol or illicit substances may also play a role.
Finally, increasing age is an independent risk
factor for both depression and sexual dysfunction
(5, 8). Equally, many drugs, apart from antidepressants, are associated with sexual dysfunction.
These include antipsychotics, lithium and mood
stabilizers, thiazide and potassium-sparing diuretics, beta-blockers and histamine-2 receptor (H2)
blocking anti-ulcer drugs (9).
Psychological symptoms associated with depression such as low mood, anhedonia, i.e. the inability
to experience pleasure, fatigue and low energy
levels can aect all aspects of sexual functioning
(1013). A restricted emotional receptiveness and
reactivity, and emotional withdrawal can lead to
relationship problems. Low self-esteem may result
in performance anxiety and, nally, excessive guilt
feelings may lead to avoidance of sexual activity or
aect sexual intercourse at any stage (1418).
Previous unwanted and unpleasant sexual experiences (or sexual abuse) may also be associated with
depression and sexual dysfunction (1923).
Conversely, sexual dysfunction may result in
psychological symptoms such as low mood, poor
self-esteem, performance anxiety and guilt. In this
way, sexual problems can also contribute to and
possibly even cause depression (2427). The bidirectional aetiological relationship is dicult to
assess as the studies are mostly cross-sectional, and
rely on samples of patients presenting to health
services with either sexual dysfunction or depression. However, the link could only be further
explored in suciently large cohort studies following a population-based sample from adolescence.
Thus at present, the cause of sexual dysfunction in
depressed patients may be dicult to determine in
some cases. This then warrants a search for
common and often mutually reinforcing factors,

which could underlie both depression and sexual

dysfunction (27). For a subgroup of depressed
patients it may suce only to treat the presenting
sexual problem (28, 29).
Equally, it is important to assess the role of
antidepressive agents in the genesis of sexual
dysfunction in depressed patients. Many antidepressants have been associated with sexual
dysfunction in all three domains depending on
receptor prole including type and number of
receptors targeted and the overall net eect on all
receptors involved. The overall impact may also be
dose dependent and a net eect of the neurotransmitters known to be modulated by antidepressive
agents including serotonin, noradrenaline, dopamine, histamine and acetylcholine.
Tricyclic antidepressants (TCAs) have at least
ve mechanisms of action. These include serotonin
(5HT) and noradrenaline reuptake inhibition, a1
antagonism, acetylcholine antagonism at the muscarinic receptor (ACh M1) and histamine (H1)
blockade (30). The balance between serotonergic
and noradrenergic neurotransmission of the individual substance and its active metabolites seems
important. Clomipramine is at the serotonergic end
of the TCA spectrum, and should therefore be
more likely to cause disturbance of desire and
orgasm. Conversely, nortriptyline, a metabolite of
amitriptyline, preferentially blocks the reuptake of
noradrenaline (31), and should be less associated
with orgasmic problems. However, as nortriptyline
is more anticholinergic than amitriptyline and
clomipramine, a higher incidence of erectile dysfunction may result (30). Dothiepine and amitriptyline are equipotent serotonin and noradrenaline
reuptake inhibitors, but additionally dothiepin is a
5HT2 antagonist (31). This suggests that dothiepin
may cause less sexual problems than amitriptyline.
Monoamineoxidase inhibitors (MAOIs) prevent
the breakdown of monoamines. MAO-A metabolizes serotonin, noradrenaline and dopamine.
MAO-B only targets dopamine. The non-selective
inhibitors, such as phelzine and tranylcyclopromine, block both isoenzymes, whereas the selective
inhibitors bind to and block only one of the two
isoenzymes. Only selective MAO-A inhibitors,
specically moclobemide, are used as antidepressants (32). The greater availability of dopamine
will enhance sexual function in all domains; however, serotonergic eects may disrupt desire and
orgasmic function including ejaculation.
Selective-serotonin reuptake inhibitors (SSRIs)
specically target the serotonin system, but they
dier in potency. Sertraline and paroxetine seem to
be most potent and citalopram is the most selective, whereas uoxetine is the least selective reup385

Werneke et al.
take inhibitor (31). Although SSRIs are selective,
some also have an impact on other monoamines.
For instance, sertraline blocks dopamine reuptake
at higher doses (33). This, theoretically, should
result in less sexual side-eects as dosage increases.
Paroxetine has D2 blocking properties, thereby
affecting the dopaminergic mesolimbic reward
system (34). At the same time, this increases the
risk of hyperprolactenaemia (35, 36). In addition,
nitric oxidase activity, which is required for penile
vasodilatation (37), may be impaired (38).
Serotonin noradrenaline reuptake inhibitors
increase the availability of serotonin and noradrenaline at the synapse. Two substances are available: venlafaxine and duloxetine. Venlafaxine at
low dose only blocks serotonin reuptake, whereas
at higher dose noradrenaline reuptake is also
inhibited. At very high dose, dopamine reuptake
is also blocked (30). Thus, theoretically, sexual
side-eects should decrease as the venlafaxine dose
increases. Duloxetine had been licensed for the
treatment of urinary incontinence and was only
recently approved as an antidepressant. The equilibrium between serotonin and noradrenaline reuptake suggests a relative absence of sexual sideeects (39).
Of the noradrenergic serotonergic antidepressants, mirtazepine is an a2 antagonist, facilitating
serotonin and noradrenaline neurotransmission.
However, the 5HT2 blocking properties reduce
the potential for sexual dysfunction, particularly
anorgasmia. Mirtazepine also blocks 5HT3 receptors, which may further promote orgasm. Due to
the increased noradrenaline availability, erectile
dysfunction remains a possibility, and a prevalence
of 14% has been reported (40).
Serotonin antagonist reuptake inhibitors include
two drugs: nefazodone, which is no longer available, and trazodone. Nefazodone selectively blocks
5-HT2A receptors and moderately inhibits serotonin and noradrenaline reuptake (41). A related
drug is trazodone, which blocks 5HT2A and 5HT2C
receptors. It has also some D2 blocking properties,
but at the same time may release the nigrostriatal
dopaminergic neurones from the tonic inhibition
caused by serotonin (42). Once serotonin levels are
high, trazodone enhances GABA release (43). In
both drugs, 5HT2 blockade reduces the likelihood
of serotonin-associated sexual dysfunction. They
also have moderate anti-adrenergic properties,
which may contribute to, but not fully explain,
the risk of priapism (44).
Non-serotonergic antidepressants include reboxetine, not licensed in the USA, and bupropion.
Reboxetine selectively blocks noradrenaline reuptake (45). Its lack of serotonergic eects explains
386

the relative absence of sexual side-eects. As a1

neurotransmission may lead to detumescence,
erectile dysfunction would be theoretically possible. Bupropion is another novel antidepressant
with dopaminergic and noradrenergic properties,
but the exact mechanisms of action are not clear.
Bupropion is a weak inhibitor of noradrenaline
and dopamine reuptake, but noradrenaline release
may play a bigger role (46, 47). Its lack of
serotonergic activity and its noradrenergic and
dopaminergic actions suggest a lower incidence of
sexual dysfunction. A further D2 agonist is pramipexole, which is currently licensed for Parkinsons
disease, but may be an effective antidepressant on
its own (48) or augment other antidepressants (49).
Aims of the study

The aim of this review was to examine evidence on

the prevalence of psychosexual dysfunction associated with antidepressants, and to review treatment options which are specic to the aected
component of sexual functioning and antidepressants.
Material and methods

We searched the Medline and Cochrane databases

for depression and sexual dysfunction.
For the review of prevalence of antidepressantassociated dysfunction, the search terms included
antidepressant including all types of antidepressants, prevalence, incidence, adverse eect,
sexual function/dysfunction including desire,
libido, arousal, erectile function/dysfunction,
orgasm, anorgasmia and ejaculation, as well as
receptor, dopamine, noradrenalin, serotonin
and re-uptake inhibition/inhibitor. All recovered
papers were reviewed for further relevant references. Where available, we used reviews summarizing the proposed mechanism of action and
eectiveness of antidepressants, as presenting all
the evidence in detail would have been beyond the
scope of this paper and duplicating existing work.
For the review of treatment options, we searched
according to potential pharmacological antidotes
for antidepressant-induced sexual dysfunction
identied by their purported mechanism of
action. We combined the identied drugs with the
dierent antidepressants and all aspects of sexual
dysfunction such as desire, sexual interest, sex
drive, arousal, erection, orgasm and ejaculation.
We also distinguished between studies using substitution and those using combination therapies.
Whenever possible, we gave meta-analyses (MAs),
systematic reviews (SRs) and double blind rand-

Antidepressants and sexual dysfunction

omized trials priority. To MAs and SRs, we added
those randomized controlled trials (RCTs), which
had been published thereafter. We also included
other evidence such as open trials and case reports,
when the evidence otherwise was limited to single
small trials (Fig. 1). Due to the small number of
studies in each substance category and the heterogeneity of the data, no attempt at meta-analysis of
other trials was made. Figure 1 illustrates the
method followed in selection of studies.

Results
Prevalence of sexual dysfunction

Sexual dysfunction is common in the general

population but prevalence gures vary considerably between studies depending on study population and design (25, 50). Women may be more
aected than men (25). It is important to establish

the risk of sexual dysfunction directly attributable

to depression compared to treatment with antidepressants. The overall prevalence of sexual dysfunction in patients hospitalized for depression
may be as high as 70% (13). The probability of
sexual dysfunction varies by antidepressant
(Table 1ac), and such eects may be dose dependent (25, 51).
Tricyclic antidepressants were reported with the
widest prevalence range estimates (25, 5254).
Problems may occur in up to 90% of patients
and clomipramine has the highest prevalence (25).
TCA-associated sexual dysfunction may particularly aect sexual desire and experience of
orgasm. However, as TCAs can modify a broad
range of neurotransmitters, all aspects of sexual
dysfunction have been reported as associated. As
predicted, amitriptyline and doxepin, which are
relatively more noradrenergic, had a lower incidence of sexual dysfunction (25, 53). For MAOIs,
Targets
Noradrenaline:

Papers and documents possibly eligible: 2061

Excluded: 2012
Exclusion criteria:
Higher ranking evidence
available
Combination of different
interventions
Diagnosis other than
depression
Qualitative reviews
Special patient groups
Healthy volunteer studies

147

Serotonin:

219

Dopamine:

110

Acetylcholine:
Histamine:
Nitric oxide:

33
3
1549

Studies included: 49

Target:
Noradrenaline: 10

Target:
Serotonin: 22

Target:
Dopamine: 9

Target: other
Acetylcholine,
and Histamine: 5

Target: Nitric
oxide: 3

Reboxetine: 2 RCTs
Brupropion: 2MAs,
1 SR, 1 RCT
High dose
Venlafaxine: 0
Mirtazepine: 1 RCT,
2 open label studies
Yohimbine: 1RCT

Buspirone: 2 RCTs
Mirtazapine: 1 RCT, 2
open label studies
Nefazodone: 2 RCTs
Trazoodone: 1 MA, 1
case-report
Cyprheptadine: 9 case
reports/ small case
series
Olanzapine: 1 RCT
Sumatriptan/
Granisetron: 2 RCTs, 1
open label trial

Brupropion: 2MAs,
1 SR, 1 RCT
Apomorphine: 0
Pramipexole: 0
Amantadine: 1RCT,
3 case reports
Methylphenidate /
Dextroamphet amine: 1 case report

Neostigmine/
Physostigmine: 0
Bethanecol
(urecholine):
1 RCT, 1 case
series, 1 case
report
Rivastgmine,
Donezepil,
galantamine: 0
Loratidine:
1open label
study, 1 case
series

Sldenafil: 1 MA
Tadalafil:: 1 RCT
Vardenafil: 1 case
report

Fig. 1. Selection of efcacy studies.

387

Werneke et al.
Table 1. Frequency of antidepressant-associated sexual dysfunction: (a) TCAs and MAOIs, (b) SSRIs and (c) newer antidepressants
Substance class
(a) TCAs and MAOIs
TCAs

Antidepressant

Amitriptyline
Imipramine
Clomipramine

MAOIs

Doxepin
Phenelzine
Moclobemide

(b) SSRIs
SSRIs

Fluoxetine

Fluvoxamine

Sertraline

Citalopram

Escitalopram
Paroxetine

(c) Newer antidepressants

SNRIs

Venlafaxine

NaSSAs

Duloxetine
Mirtazepine

SARIs

Nefazodone

Non-serotonergic antidepressants

Trazodone
Reboxetine
Bupropion

Prevalence/incidence of sexual dysfunction

Overall up to 10% (25)

Decreased libido 14% men and 6% women (25)
Delayed orgasm in 21% of men and 27% in women (54)
Anorgasmia 96% (54)
Anorgasmia in 15%92% in both sexes (52)
Unspecified complaint 15%33% (25)
Abnormal ejaculation in 424% and erectile dysfunction in 15% (25)
Increased sexual desire 6% (53)
Delayed orgasm in 30% of men and 36% in women (54)
Overall 40% (25)
Increased sexual desire 18% (53)
Overall 3.9% (40)
Overall 24% (51)
Decreased libido 2% (25)
Anorgasmia 2075% (54)
Overall 58%: decreased libido 50%, delayed orgasm/ejaculation 49%, anorgasmia/no
ejaculation 39%, erectile dysfunction/decreased vaginal lubrication 22% (40)
Abnormal ejaculation 918%, erectile dysfunction 14% (25)
Overall 62%: decreased libido 48%, delayed orgasm/ejaculation 54%, anorgasmia/no
ejaculation 38%, erectile dysfunction/decreased vaginal lubrication 21% (40)
Overall 27% (51)
Anorgasmia 2067% (54)
Ejaculatory failure or delay 1119% and decreased libido 1014% (25)
Overall 63%: decreased libido 48%, delayed orgasm/ejaculation 54%, anorgasmia/no
ejaculation 38%, erectile dysfunction/decreased vaginal lubrication 21% (40)
Overall 30% (51)
Anorgasmia 210% (60)
Overall 73%: decreased libido 62%, delayed orgasm/ejaculation 63%, anorgasmia/no
ejaculation 51%, erectile dysfunction/decreased vaginal lubrication 35% (40)
Ejaculatory disorder 9% (56)
Overall 27% (51)
Decreased libido 312%, abnormal ejaculation 1036 %, erectile dysfunction 4%-21% (25)
Anorgasmia 20%30% (54)
Overall 71%: decreased libido 48%, delayed orgasm/ejaculation 54%, anorgasmia/no
ejaculation 38%, erectile dysfunction/decreased vaginal lubrication 21% (40)
Overall 30% (51)
Erectile dysfunction 44% (61)
Decreased libido 2%, abnormal orgasm 12% (25)
Anorgasmia 2030% (54)
Overall 67%: decreased libido 60%, delayed orgasm/ejaculation 62%, anorgasmia/no
ejaculation 42%, erectile dysfunction/decreased vaginal lubrication 40% (40)
At placebo level (56)
Overall 40% (51)
Decreased libido 6% in men and 6% in women (25)
Overall 24%: decreased libido 20%, delayed orgasm/ejaculation 18%, anorgasmia/no
ejaculation 8%, erectile dysfunction/decreased vaginal lubrication 14% (40)
Overall 30% (51)
Decreased libido 1% and abnormal ejaculation/orgasm <1% (25)
Anorgasmia 30% (54)
Overall 8%: decreased libido 6%, delayed orgasm/ejaculation 2%, anorgasmia/no ejaculation
2%, erectile dysfunction/decreased vaginal lubrication 0% (40)
Several case reports of priapism (59) and increased libido in women (62) and men (63)
At placebo level (57)
One case report of prolonged orgasm with reduced intensity and pain (64)
Overall 22% (51)
Increase in libido possible (54)
Orgasmic delay 7% (54)

TCAs, tricyclic antidepressants; MAOIs, monoamineoxidase inhibitors; SSRIs, selective-serotonin reuptake inhibitors; SNRIs, serotonin noradrenaline reuptake inhibitors;
NaSSAs, noradrenergic serotonergic antidepressants; SARIs, serotonin antagonist reuptake inhibitors.

388

Antidepressants and sexual dysfunction

possibly, the prevalence of sexual dysfunction also
varied, but no prevalences in excess of 40% were
found (25, 40, 53). Moclobemide was much less
implicated than phenelzine, possibly because
increases in serotonin are less marked and reversible (55) (Table 1a).
Among the SSRIs, prevalence estimates also
diered, and it was dicult to establish a dysfunction pattern for the individual compounds. In the
study of Montejo et al. comparing all ve antidepressants, paroxetine and citalopram had the
highest overall prevalence (40). For escitalopram,
only one study was available, which reported a
substantially lower prevalence of ejaculatory problem compared with the other SSRIs (56)
(Table 1b).
Among the newer antidepressants, venlafaxine is
the most serotonergic agent, and was most likely to
cause sexual dysfunction in all domains (40).
Duloxetine, achieving an equilibrium between
serotonin and noradrenaline reuptake performed
at placebo level (56). The non-serotonergic antidepressants, reboxetine and bupropion also were
substantially less associated with sexual dysfunction (25, 51, 54, 57, 58) (Table 1c). Mirtazepine was
associated with sexual dysfunction in about a
quarter of patients (40). For nefazodone, the
estimates varied from virtual absence of sexual
problems (25, 58) to a prevalence of anorgasmia of
30% (54). Finally, trazodone was not associated
with major sexual dysfunction, but cases of priapism have been reported (59). Table 1ac illustrates
the frequency of associated sexual dysfunction with
specic antidepressant categories.
Treatment of antidepressant-induced sexual dysfunction

Treatment of sexual dysfunction, like any other

condition, must begin with clarication of aetiological factors. It is important to exclude alternative
and contributing factors such as diabetes mellitus,
thyroid function disorders and certain neurological, urological and gynaecological conditions (9).
Weight gain associated with many psychotropic
drugs may lead to insulin resistance, which may
shift the oestrogen/androgen balance resulting in
virilization and dys- or amenorrhea (6568). This
has been reported for sodium valproate, which is
associated with polycystic ovaries (6870). Similar
mechanisms of action may apply to antidepressants associated with weight gain, such as mirtazepine (71, 72).
In patients for whom sexual function is important the choice should be made carefully. Where
available, non-serotonergic antidepressants such as
bupropion and reboxetine, or mirtazepine or tra-

zodone, may be used rst line. Patients who are on

other antidepressants may be switched to these
agents, but stopping and swapping has to be done
carefully to avoid drug interactions such as serotonin syndrome in the transition phase (73).
It may be possible to wait for adaptation to
occur (74), possibly through downregulation of the
prospective receptors. Improvement in mood may
lead to better sexual relationships. However, it
seems that this strategy is only helpful in a minority
of patients. For instance, in a study of 1022 outpatients only 10% achieved total improvement,
11% partial improvement and 79% did not achieve
any improvement of their sexual dysfunction (40).
The evidence for the eectiveness of drug holidays is sparse, may not apply to all antidepressants
and may depend on drug half-lives (74). Positive
results have been reported for sertraline, paroxetine and uvoxamine but not for uoxetine (75,
76). Patients may experience recurrence of depression or psychological and physical discontinuation
symptoms, all of which could also compromise
sexual function.
Pharmacological reversal of antidepressantinduced sexual dysfunction involves targeting the
respective receptors. Receptor anities of the
dierent antidepressants point towards suitable
antidotes. The less receptor specic an antidepressant is, the more likely sexual dysfunction is
mediated through dierent pathways and aects
several domains. This is reected in the range of
reported prevalence (Table 1ac) and can make
pharmacological reversal more dicult. Many
substances targeting specic neurotransmitters
have been tried; however, for most substances the
evidence relies on small randomized studies, usually using cross-over design.
Table 2ae illustrates pharmacological reversal
related to antidepressant-induced sexual dysfunction. The rst target is the noradrenaline system.
Potential antidotes include reboxetine, bupropion,
mirtazepine and yohimbine, an a2 blocker, which
had commonly been used for the treatment of
erectile dysfunction before phosphodiesterase 5
(PD5) inhibitors became available (77) (Table 2a).
Reboxetine performed better than paroxetine in
direct comparison (78) and better than placebo
when combined with uoxetine (79). The evidence
for bupropion remains conicting as some studies
demonstrated improved sexual function, whereas
others failed to demonstrate any eectiveness
above the placebo level (8082). The discrepancies
in nding may be associated with the bupropion
dose chosen, i.e. bupropion may not be suciently
eective for the reversal of sexual dysfunction at a
dose of 150 mg per day (80). Equally inconsistent
389

Werneke et al.
Table 2. Pharmacological reversal of antidepressant-induced sexual dysfunction: target (a) noradrenaline, (b) serotonin, (c) dopamine, (d) acetylcholine and histamine, and (e)
nitric oxide
Mechanism of action
(a) Noradrenaline
NA reuptake
inhibition
NA reuptake
inhibition
NA release

Substance

Reboxetine

Venlafaxine
(higher dose)
Bupropion

a2 blockade

Mirtazepine

Yohimbine

(b) Serotonin*
5HT1A agonism

5HT2 & 5HT3

blockade
5HT2 blockade

Buspirone

Mirtazepine
Nefazodone

Trazodone

Cyproheptadine

Olanzapine
5HT3 blockade

(c) Dopamine
DA reuptake
inhibition
DA agonists

Comments

RCT (n 70): compared with paroxetine: sexual excitement (78)

RCT (n 450): compared with fluoxetine and placebo overall
sexual function (79)
None available for combination

Tachycardia, insomnia (73)

MA of 7 RCTs: prevalence of sexual desire disorder compared

to SSRIs and equivalent to placebo (81)
SR of 2 RCTs combined with SSRI: desire in 1 of 2 RCTs (82)
RCT combined with SSRI (n 41): not better than placebo (80)
(preliminary report indicated some effect (82), which was not
confirmed in the final study
Effect of bupropion may be dose dependent
RCT (n 75): combined with SSRI: no improvement of female
sexual dysfunction (77)
Open label study of substitution in patients with SSRI induced sexual
dysfunction (n 19): of sexual function in 13 patients (83)
Open label study of substitution in patients with SSRI induced sexual
dysfunction (n 11): no patient reported sexual dysfunction (84)
Efficacy has been demonstrated for the treatment of erectile
dysfunction (85), but remains unlicensed for this indication in the UK
RCT (n 74): combined with SSRI: no improvement of female sexual
dysfunction (77)

seizures (87); one case report of serotonin syndrome in

combination with other serotonergic antidepressants of
bupropion (86)

hypertension at higher doses, nausea, agitation (73)

weight gain, sedation,

2 case reports of serotonin syndrome in combination
therapy with venafaxine & tramadal and venlafaxine
only (117, 118)

anxiety, QT interval

RCT (n 39): combined with fluoxetine: no difference to placebo

in overall sexual function (91)
RCT (n 119): combined with SSRI: 58% improvement vs. 30%
in placebo in overall sexual function (92)
Cf. above a2 blockade. Table 3a

hypertension with MAOIs,

liver enzymes in combination with trazodone (119)

RCT (n 681): compared with cognitive behavioural therapy and

combination treatment sexual interest and satisfaction; effect
equivalent to cognitive behavioural therapy (88)
RCT (n 105) compared with sertraline: re-emergence of
ejaculatory/orgasmic difficulties (89)
MA of 6 RCTs: ED: effect greatest for non-organic ED and higher
doses of trazodone; effects not significant (90)
Case series of 3 men: sexual interest (63)
9 case reports/small case series reporting reversal of anorgasmia/
overall sexual dysfunction in patients treated with TCAs (9597),
SSRIs (98102) and MAOI (103)
RCT (n 77): combined with SSRI: not effective (77)

Significant CYP 3A4 inhibition

Cf. above a2 blockade. Table 3a

Sedation, several cases reports of priapism (120)

Reversal of antidepressant effect of fluoxetine (54)

Weight gain (121)
Weight gain, hyperglycaemia, shift of oestrogen/
androgen balance (67)
Usually well tolerated

Granisetron/
sumatriptan

RCT (n 12) antidepressants not listed: no difference in overall

sexual function to placebo (93)
RCT (n 31): combined with SSRI or venlafaxine: no difference
in overall sexual function to placebo (94)
Open label crossover trial with granisetron and sumatriptan (n 35):
combined with SSRI: significant improvement in overall sexual
function with granisetron but not with sumatriptan (122)

Bupropion

Cf. above a2 blockade. Table 3a

Cf. above a2 blockade. Table 3a

Apomorphine

Licensed for treatment of erectile dysfunction, but no specific

evidence for men on antidepressants available
General success rates between 35% and 54% (123125)
No evidence available

Sublingual administration, start with low dose to prevent

dose dependent side-effects such as headaches, nausea, somnolence and yawning (104, 105)
Nausea, excessive somnolence, 4 case reports of mania
(126)
Psychiatric side-effects include depression, agitation,
delirium, psychosis and visual hallucinations. May
affect performance of skilled tasks (127) rash in up to
30%. Associated with livedo reticularis (128)

Pramipexole
Amantadine

390

Evidence

RCT (n 38): combined with fluoxetine: no difference in overalls

sexual function in women compared with placebo (91)
3 case reports on reversal of anorgasmia (106108)

Antidepressants and sexual dysfunction

Table 2. Continued
Mechanism of action

Substance
Methylphenidate/
Dextroamphetamine

(d) Acetylcholine and histamine

ACh: cholinesterase
Neostigmine/Physiostigmine
inhibition
ACh: cholinesterase
inhibition,
additionally cGMP
(Lambertine & Anotnelli)

Bethanechol (Urecholine)

ACh: cholinesterase
inhibition
H1

Rivastigmine, Donezepil,
Galantamine
Loratidine

(e) Nitric oxide

NO: PD5 inhibition

Sildenafil

Tadalafil

Vardenafil

Evidence

Comments

Case series (n 5): women reported orgasm

and men firmer erections (109)

Potential for harmful use and addiction

Based on case reports of men with spinal cord

injuries: treatment of ejaculatory failure/
anorgasmia (110112)
RCT (n 12): combined with clomipramine: of
ejaculatory delay (129)
Case series (n 3): combined with TCA: reversal
of erectile dysfunction in 2 men and anorgasmia
in one woman treated with TCAs (130)
Case report: combined with imipramine: reversal
erectile and ejaculatory failure (131)
None available

Rarely used
Neostigmine requires intra-thecal administration,
physiostigmine is used sub-cutaneously (111)
Reversal of TCA induced anticholinergic side-effects

Open label study combined with SSRIs (n 10):

erectile function (113)
Case series combined with fluoxetine (n 10):
of sexual function (114)

Licensed anti-histamine. Mechanism of action

unclear, H1 antagonism may relax the penile
corpora cavernosa (115), but histamine in itself
leads to vasodilation (116)

General success rate for the treatment of erectile

dysfunction between 60% and 91%, dose
dependent (132134); may also postorgasmic
refractory time (135)
MA of 3 RCTs: ED (82)
General success rate for the treatment of erectile
dysfunction between 62% and 84%, dose
dependent (136, 137)
RCT (n 111) combined with antidepressants:
erectile function (82)
General success rate for the treatment of erectile
dysfunction up to 91%, dose dependent (105)
Case report: combined with sertraline: complete
reversal achieved of female anorgasmia (138)

Nitrates including amylnitrate (poppers)

contraindicated
Absorption delayed after ingestion of a meal
with >30% fat (105)
Not licensed for female sexual dysfunction
As above, long half life extends erectile potential
to 24 h, thus more attempts possible (105)
No interaction with food or alcohol on absorption
(105)

Licensed anti-dementia drugs

As above. Absorption delayed after ingestion of a

meal with >30% fat (105)

*All combinations have an increased risk of serotonin syndrome.

are the ndings for mirtazepine. One RCT failed to

demonstrate any improvement of sexual dysfunction (77) whereas two preceding open-label studies
had suggested an eect (83, 84). Yohimbine has
been used for the treatment of erectile dysfunction
(85), but did not show any benet in women taking
SSRIs (77). As noradrenaline modulates serotonin
release and transmission, serotonin syndrome is
possible even with non-serotonergic antidepressants such as bupropion (86). In addition, bupropion lowers the seizure threshold (87).
Drugs targeting the serotonin system include
buspirone, a 5HT1A agonist, mirtazepine, a 5HT2
and 5HT3 antagonist, nefazodone and trazodone,
serotonin reuptake inhibitors with additional 5HT2
blocking properties and 5HT3 blockers, such as
granisetrone and sumatriptan (Table 2b). Of these,
nefazodone was shown to improve sexual interest
and orgasmic experience in two trials (88, 89). The
eects for trazodone, a related substance, did not
reach signicance in the one meta-analysis available (90). For buspirone, two trials gave conicting
results (91, 92). Equally for 5HT3 blockers, the

evidence was inconsistent (93, 94). Cyproheptadine

was found to improve sexual dysfunction in several
case series or small studies (95103), but no larger
studies were available. Olanzapine was tried in one
study without success (77).
Bupropione, apomorphine, pramipexole, amantadine and amphetamines including detroamphetamine and methylphenidate target dopamine
(Table 2c). As outlined above, the eect for
bupropione was inconsistent. Apomorphine is
licensed for treatment of erectile dysfunction.
However, patients have to be reminded not to
swallow the tablet but to dissolve it under the
tongue (104, 105). Nausea and yawning are
common side-eects. All the other dopaminergic
drugs had limited evidence (91, 106109) and may
lead to potentially serious adverse reactions. Pramipexole is associated with excessive somnolence,
amantadine can lead to psychiatric disturbances
and rashes, and amphetamines are addictive
(Table 2c).
Another neurotransmitter target for TCAinduced sexual dysfunction is acetylcholine.
391

Werneke et al.
Several cholinesterase inhibitors such as neostigmine, physiostigmine and bethanechol (urecholine)
have been suggested (Table 2d). The evidence is
limited to only small studies or case reports.
Neostigmine and physiostigmine have only been
used to treat ejaculatory failure in men with severe
spinal cord injuries (110112). Theoretically, the
new anti-dementia drugs donezepil, rivastigmine
and galantamine could also be used, but no data
are available. Loratidine, a tricyclic antihistamine,
has been reported to revert erectile dysfunction in
two small studies (113, 114). It has been suggested
that changes in histamine availability may lead to
vasodilation in the penile corpora cavernosa (115).
However, the mechanism of action remains unclear
as conversely stimulation of the H1 receptor may
lead to increased nitric oxide availability and
vasodilation (116).
Finally agents enhancing the availability of nitric
oxide have been shown to be eective in the
treatment of erectile dysfunction (Table 2e). Three
oral drugs are available: sildenal, tadalal and
vardenal, which are eective in about 80% of men
with erectile dysfunction. Sildenal and vardenal
are shorter acting whereas tadalal has a half-life
of 36 h (105). Sildenal and tadalal have been
reported signicantly to improve erections in men
taking serotonergic antidepressants and been
found signicantly to improve erections (82).
Vardenal, a related drug, is likely to be equally
eective.
Hormone therapies

Both oestrogens and androgens such as testosterone have been suggested for treatment of sexual
dysfunction. In men, symptoms of testosterone
deciency include loss of energy, depressed mood,
decreased libido and erectile dysfunction, but
evidence is inconclusive and limited to small
trials. Potential risks, such as the need for
invasive treatment of benign prostate hyperplasia,
development of a clinical prostate cancer, or
cardiovascular events require further assessment
(139).
In women, these types of treatments have been
shown to lead to increased frequency of sexual
activity and improved interest and arousal. Longterm safety, optimal types, doses and routes of
therapy, however, remain unclear (140). However, such treatments are not without risks.
Currently, hormone replacement therapy is only
recommended for short-term use as it is associated with an excess risk of breast cancer and
stroke (141), and risks may outweigh potential
benets.
392

Discussion

Antidepressant-induced sexual dysfunction is an

important issue in the clinical management of
depression. However, the problem is highly complex because sexual dysfunction may be independently associated with the depressive illness or with
other non-psychiatric factors. All factors can
inuence each other, so that often it may be
impossible to work out the contribution of each
component. Our ndings suggest that with a
baseline prevalence of 70% of sexual dysfunction
in depression, it may be indeed dicult to identify
and quantify a potential adverse eect, an antidepressant may have. Moreover, patients are likely to
dier in the prevalence of other, e.g. somatic,
factors and in their therapeutic response as well as
their metabolic characteristics. Measuring the prevalence of sexual dysfunction is dicult because
research methods vary widely. Some of the measurement tools in use have not been validated,
others are only applicable to either men or women
or only address one specic aspect of sexual
dysfunction. Besides, cultural and social factors
may lead to dierent expectations of normality,
and availability of acceptable treatment may
change a patients willingness to seek help. Accordingly, reporting thresholds vary (50). The more
recently developed antidepressants have been associated with less sexual side-eects. Although this
may be an expression of improved pharmacodynamic properties, this may be also a reection of
their relative novelty, and updated prevalence
studies will become available in future. This
particularly applies to escitalopram, the l-enantiomer of the racemate citalopram, because it
remains pharmacologically implausible that escitalopram should lead to signicantly less sexual
side-eects because the receptor prole is essentially the same. The great variation in methodological approaches makes it extremely dicult to
systematically review the literature on the prevalence and incidence of antidepressant-associated
dysfunction. Ultimately, researchers in the eld
may need to nd a consensus on standardized
methods for reporting of such adverse events.
As it is dicult to establish the contribution of
antidepressants to sexual dysfunction, it can
become dicult to formulate suitable treatments.
However, knowledge of the dierent receptor
anities of the various antidepressants may help
predict potential diculties. This was conrmed in
our review. For instance, TCAs are the least
selective antidepressants and receptor anities
vary within the substance class. Hence, it is not
surprising that prevalence rates uctuate widely.

Antidepressants and sexual dysfunction

Equally, substances with a mainly serotonergic
mechanism of action consistently yielded relatively
high prevalence rates of sexual dysfunction
between 50% and 70%. The prevalence could be
expected to be less in those substances with HT2
blocking properties, such as mirtazepine, trazodone and nefazodone. This was conrmed by our
ndings, which, apart from one study, did not
report prevalence rates in excess of 30%. As
could be expected, the lowest level of sexual
dysfunction was found in the non-serotonergic
antidepressants.
Thus although sexual dysfunction is a feature of
depression in its own right, it is likely that this can
be aggravated or in some cases even be induced by
some antidepressants. This suggests that antidepressant-associated sexual dysfunction can be
treated or possibly even prevented. Patients, male
and female, need to be routinely asked about
sexual function to identify problems early. It is
important to grade depressive episodes in their
severity to establish whether antidepressants are
required or psychological treatments, such as
cognitive behavioural therapy, should be attempted rst (142). Once the decision is taken to use
antidepressants, patients should be presented with
a choice of substances whenever possible, and the
side-eect proles should be matched with the
patients preferences. If sexual function is important, it may be best to choose antidepressants that
are less likely to cause this. If this is not possible
and sexual dysfunction has occurred, a suitable
antidote can be suggested, where indicated. However, as antidotes often reverse only one specic
action, sexual dysfunction may persist when mediated through dierent receptors. Many of these
antidotes have only been tested in small trials, and
management of lack of sexual interest and orgasmic disturbance may be most dicult to treat.
With the advent of PD5 inhibitors, treatment of
erectile dysfunction has become highly successful,
and the current evidence suggests equally good
treatment results for men taking antidepressants.
Sound pharmacological knowledge will help clinicians to choose the appropriate treatment strategies.
In conclusion, recognition of antidepressantinduced sexual dysfunction and appropriate management are of paramount importance for those
patients who value sexual function highly and
whose depression may be maintained through
failure to restore sexual function. Increasingly,
treatment strategies have become available to
target this important feature of depression and
antidepressant-associated side-eects. Our review
shows that knowledge of the various mechanisms

by which antidepressants mediate their adverse

eects can guide rational therapy.
Funding

None.
Declaration of interest

Ursula Werneke has previously received a grant

from Pzer Ltd, and honoraria and speaker fees
from Ely Lilly Ltd.
Sara Northey has previously been funded as a
researcher using a grant from Pzer Ltd.
Dinesh Bhugra has received speaker fees and
hospitality from Eli Lilly, Janssen-Cilag, Astra
Zeneca and Lundbeck, but not in the context of the
present work.
References
1. Nicolosi A, Moreira ED Jr, Villa M, Glasser DB. A
population study of the association between sexual function, sexual satisfaction and depressive symptoms in men.
J Affect Disord 2004;82:235243.
2. Roose SP. Depression: links with ischemic heart disease
and erectile dysfunction. J Clin Psychiatry 2003;64(suppl.
10):2630.
3. Araujo AB, Durante R, Feldman HA, Goldstein I, Mckinlay
JB. The relationship between depressive symptoms and
male erectile dysfunction: cross-sectional results from the
Massachusetts Male Aging Study. Psychosom Med
1998;60:458465.
4. Hirschfeld RM. Care of the sexually active depressed patient. J Clin Psychiatry 1999;60(suppl. 17):3235.
5. Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in
men with erectile dysfunction. J Urol 2004;171:23412345.
6. Briganti A, Salonia A, Deho F et al. Peyronies disease: a
review. Curr Opin Urol 2003;13:417422.
7. Toubia N. Female circumcision as a public health issue. N
Engl J Med 1994;331:712716.
8. Seidman SN. The aging male: androgens, erectile dysfunction, and depression. J Clin Psychiatry 2003;64(suppl.
10):331337.
9. Werneke U, Crowe M. Review of patients with erectile
dysfunction attending the Maudsley psychosexual clinic
in 1999: the impact of sildenal. Sex Relation Ther
2002;17:171185.
10. Mallis D, Moysidis K, Nakopoulou E, Papaharitou S,
Hatzimouratidis K, Hatzichristou D. Psychiatric morbidity
is frequently undetected in patients with erectile dysfunction. J Urol 2005;174:19131916.
11. Cyranowski JM, Frank E, Cherry C, Houck P, Kupfer DJ.
Prospective assessment of sexual function in women
treated for recurrent major depression. J Psychiatr Res
2004;38:267273.
12. Gracia CR, Sammel MD, Freeman EW, Liu L, Hollander L,
Nelson DB. Predictors of decreased libido in women
during the late reproductive years. Menopause
2004;11:144150.
13. Moore TM, Strauss JL, Herman S, Donatucci CF. Erectile
dysfunction in early, middle, and late adulthood: symp-

393

Werneke et al.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.
24.

25.

26.

27.

28.

29.

30.

31.

394

tom patterns and psychosocial correlates. J Sex Marital

Ther 2003;29:381399.
Latini DM, Penson DF, Colwell HH et al. Psychological
impact of erectile dysfunction: validation of a new health
related quality of life measure for patients with erectile
dysfunction. J Urol 2002;168:20862091.
Dunn KM, Croft PR, Hackett GI. Association of sexual
problems with social, psychological, and physical
problems in men and women: a cross sectional population survey. J Epidemiol Community Health
1999;53:144148.
Brien SE, Smallegange C, Gofton WT, Heaton JP, Adams
MA. Development of a rat model of sexual performance
anxiety: eect of behavioural and pharmacological hyperadrenergic stimulation on APO-induced erections. Int
J Impot Res 2002;14:107115.
Rosen RC, Leiblum SR, Spector IP. Psychologically based
treatment for male erectile disorder: a cognitive-interpersonal model. J Sex Marital Ther 1994;20:6785.
Davidson JK Sr, Darling CA. Masturbatory guilt and
sexual responsiveness among post-college-age women:
sexual satisfaction revisited. J Sex Marital Ther
1993;19:289300.
Bergmark K, Avall-Lundqvist E, Dickman PW, Steineck G,
Henningsohn L. Synergy between sexual abuse and cervical
cancer in causing sexual dysfunction. J Sex Marital Ther
2005;31:361383.
Whiffen VE, Macintosh HB. Mediators of the link between
childhood sexual abuse and emotional distress: a critical
review. Trauma Violence Abuse 2005;6:2439.
Arnow BA. Relationships between childhood maltreatment, adult health and psychiatric outcomes, and medical
utilization. J Clin Psychiatry 2004;65(suppl. 12):1015.
Roesler TA, Mckenzie N. Eects of childhood trauma on
psychological functioning in adults sexually abused as
children. J Nerv Ment Dis 1994;182:145150.
Lunde I, Ortmann J. Prevalence and sequelae of sexual
torture. Lancet 1990;336:289291.
Shabsigh R, Zakaria L, Anastasiadis AG, Seidman AS.
Sexual dysfunction and depression: etiology, prevalence,
and treatment. Curr Urol Rep 2001;2:463467.
Montgomery SA, Baldwin DS, Riley A. Antidepressant
medications: a review of the evidence for drug-induced
sexual dysfunction. J Affect Disord 2002;69:119140.
Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the
United States: prevalence and predictors. JAMA
1999;281:537544.
Goldstein I. The mutually reinforcing triad of depressive
symptoms, cardiovascular disease, and erectile dysfunction. Am J Cardiol 2000;86:41F45F.
Rosen RC, Seidman SN, Menza MA et al. Quality of life,
mood, and sexual function: a path analytic model of
treatment eects in men with erectile dysfunction
and depressive symptoms. Int J Impot Res 2004;16:334
340.
Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen
RC. Treatment of erectile dysfunction in men with
depressive symptoms: results of a placebo-controlled
trial with sildenal citrate. Am J Psychiatry
2001;158:16231630.
Stahl SM. Basic psychopharmacology of antidepressants,
part 1: Antidepressants have seven distinct mechanisms of
action. Clin Psychiatry 1998;59(suppl. 4):514.
Sanchez C, Hyttel J. Comparison of the eects of antidepressants and their metabolites on reuptake of biogenic
amines and on receptor binding. Cell Mol Neurobiol
1999;19:467489.

32. Yamada M, Yasuhara H. Clinical pharmacology of MAO

inhibitors:
safety
and
future.
Neurotoxicology
2004;25:215221.
33. Damsa C, Bumb A, Bianchi-Demicheli F et al. Dopaminedependent side eects of selective serotonin reuptake
inhibitors: a clinical review. J Clin Psychiatry
2004;65:10641068.
34. Stahl SM. The psychopharmacology of sex, Part 1:
Neurotransmitters and the 3 phases of the human sexual
response. J Clin Psychiatry 2001;62:8081.
35. Goodnick PJ, Chaudry T, Artadi J, Arcey S. Womens issues in mood disorders. Expert Opin Pharmacother
2000;1:903916.
36. Nadeem HS, Attenburrow MJ, Cowen PJ. Comparison of
the eects of citalopram and escitalopram on 5-Htmediated neuroendocrine responses. Neuropsychopharmacology 2004;29:16991703.
37. Boolell M, Allen MJ, Ballard SA et al. Sildenal: an
orally active type 5 cyclic GMP-specic phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996;8:4752.
38. Angulo J, Peiro C, Sanchez-Ferrer CF et al. Dierential
eects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase
expression in rat corpus cavernosum tissue. Br J Pharmacol 2001;134:11901194.
39. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG et al.
Comparative anity of duloxetine and venlafaxine for
serotonin and norepinephrine transporters in vitro and in
vivo, human serotonin receptor subtypes, and other
neuronal
receptors.
Neuropsychopharmacology
2001;25:871880.
40. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F.
Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022
outpatients. Spanish Working Group for the Study of
Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry 2001;62(suppl. 3):1021.
41. Davis R, Whittington R, Bryson HM. Nefazodone. A review of its pharmacology and clinical ecacy in the
management of major depression. Drugs 1997;53:608
636.
42. Balsara JJ, Jadhav SA, Gaonkar RK, Gaikwad RV, Jadhav
JH. Eects of the antidepressant trazodone, a 5-HT(2A/
2C) receptor antagonist, on dopamine-dependent behaviors in rats. Psychopharmacology (Berl) 2005;179:597
605.
43. Luparini MR, Garrone B, Pazzagli M, Pinza M, Pepeu G. A
cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:11171127.
44. Betti L, Botta M, Corelli F et al. alpha(1)-Adrenoceptor
antagonists. Rational design, synthesis and biological
evaluation of new trazodone-like compounds. Bioorg
Med Chem Lett 2002;12:437440.
45. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for
the treatment of depression. Lancet 2000;355:911918.
46. Gobbi G, Slater S, Boucher N, Debonnel G, Blier P.
Neurochemical and psychotropic eects of bupropion in
healthy
male
subjects.
Clin
Psychopharmacol
2003;23:233239.
47. Learned-Coughlin SM, Bergstrom M, Savitcheva I et al. In
vivo activity of bupropion at the human dopamine
transporter as measured by positron emission tomography. Biol Psychiatry 2003;54:800805.
48. Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans
DL. Comparison of pramipexole, uoxetine, and placebo

Antidepressants and sexual dysfunction

49.

50.

51.

52.

53.

54.
55.

56.

57.

58.

59.

60.

61.

62.
63.
64.
65.

66.

67.

68.

in patients with major depression. Depress Anxiety

2000;11:5865.
Cassano P, Lattanzi L, Soldani F et al. Pramipexole in
treatment-resistant depression: an extended follow-up.
Depress Anxiety 2004;20:131138.
Dunn KM, Jordan K, Croft PR, Assendelft WJ. Systematic
review of sexual problems: epidemiology and methodology. J Sex Marital Ther 2002;28:399422.
Clayton AH, Pradko JF, Croft HA et al. Prevalence of
sexual dysfunction among newer antidepressants. J Clin
Psychiatry 2002;63:357366.
Monteiro WO, Noshirvani HF, Marks IM et al. Anorgasmia from clomipramine in obsessive-compulsive disorder.
A controlled trial. Br J Psychiatry 1987;151:107112.
Philipp M, Kohnen R, Benkert O. A comparison study of
moclobemide and doxepin in major depression with special reference to eects on sexual dysfunction. Int Clin
Psychopharmacol 1993;7:149153.
Segraves RT. Antidepressant-induced sexual dysfunction.
J Clin Psychiatry 1998;59(suppl. 4):4854.
Da Prada M, Kettler R, Keller HH, Burkard WP, MuggliManiglio D, Haefely WE. Preclinical proles of the novel
reversible MAO-A inhibitors, moclobemide and brofaromine, in comparison with irreversible MAO inhibitors. J Neural Transm 1989;28(suppl.):520.
Hirschfeld RM, Vornik LA. Newer antidepressants: review
of ecacy and safety of escitalopram and duloxetine. J
Clin Psychiatry 2004;65(suppl. 4):4652.
Clayton AH, Zajecka J, Ferguson JM et al. Lack of
sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major
depressive disorder. Int Clin Psychopharmacol
2003;18:151156.
Preskorn SH. Comparison of the tolerability of bupropion, uoxetine, imipramine, nefazodone, paroxetine,
sertraline, and venlafaxine. J Clin Psychiatry
1995;56(suppl. 6):1221.
Warner MD, Peabody CA, Whiteford HA, Hollister LE.
Trazodone and priapism. J Clin Psychiatry 1987;48:244
245.
Wade AG, Lepola U, Koponen HJ, Pedersen V, Pedersen T.
The eect of citalopram in panic disorder. Br J Psychiatry
1997;170:549553.
Pollack MH, Worthington JJ 3rd, Otto MW et al. Venlafaxine for panic disorder: results from a double-blind,
placebo-controlled
study.
Psychopharmacol
Bull
1996;32:667670.
Gartrell N. Increased libido in women receiving trazodone. Am J Psychiatry 1986;143:781782.
Sullivan G. Increased libido in three men treated with
trazodone. J Clin Psychiatry 1988;49:202203.
Haberfellner EM. Sexual dysfunction caused by reboxetine. Pharmacopsychiatry 2002;35:7778.
Elsenbruch S, Hahn S, Kowalsky D et al. Quality of life,
psychosocial well-being, and sexual satisfaction in women
with polycystic ovary syndrome. J Clin Endocrinol Metab
2003;88:58015807.
Linne Y. Eects of obesity on womens reproduction and
complications during pregnancy. Obes Rev 2004;5:137
143.
Werneke U, Taylor D, Sanders TA. Options for pharmacological management of obesity in patients treated with
atypical antipsychotics. Int Clin Psychopharmacol
2002;17:145160.
Rasgon N. The relationship between polycystic ovary
syndrome and antiepileptic drugs: a review of the evidence. J Clin Psychopharmacol 2004;24:322334.

69. Nelson-Degrave VL, Wickenheisser JK, Cockrell JE et al.

Valproate potentiates androgen biosynthesis in
human
ovarian
theca
cells.
Endocrinology
2004;145:799808.
70. Luef G, Abraham I, Haslinger M et al. Polycystic ovaries, obesity and insulin resistance in women with
epilepsy. A comparative study of carbamazepine
and valproic acid in 105 women. J Neurol
2002;249:835841.
71. Chen JL, Spinowitz N, Karwa M. Hypertriglyceridemia,
acute pancreatitis, and diabetic ketoacidosis possibly
associated with mirtazapine therapy: a case report.
Pharmacotherapy 2003;23:940944.
72. Fisfalen ME, Hsiung RC. Glucose dysregulation and mirtazapine-induced weight gain. Am J Psychiatry
2003;160:797.
73. Taylor D, Kerwin R, Paton C. Maudsley prescribing
guidelines, 7th edn. London: Taylor and Francis, A
Martin Dunitz book, 2003.
74. Zajecka J. Strategies for the treatment of antidepressantrelated sexual dysfunction. Clin Psychiatry 2001;62(suppl.
3):3543.
75. Nemeth A, Arato M, Treuer T, Vandlik E. Treatment of
uvoxamine-induced anorgasmia with a partial drug
holiday. Am J Psychiatry 1996;153:1365.
76. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: ecacy of a drug holiday. Am J
Psychiatry 1995;152:15141516.
77. Michelson D, Kociban K, Tamura R, Morrison MF. Mirtazapine, yohimbine or olanzapine augmentation therapy
for serotonin reuptake-associated female sexual dysfunction: a randomized, placebo controlled trial. J Psychiatr
Res 2002;36:147152.
78. Baldwin D, Bridgman K, Buis C. Resolution of sexual
dysfunction during double-blind treatment of major
depression with reboxetine or paroxetine. J Psychopharmacol 2006;20:9196.
79. Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK,
Brown MT, Schwartz GE. Lack of sexual dysfunction with
the selective noradrenaline reuptake inhibitor reboxetine
during treatment for major depressive disorder. Int Clin
Psychopharmacol 2003;18:151156.
80. Debattista C, Solvason B, Poirier J, Kendrick E, Loraas E.
A placebo-controlled, randomized, double-blind study of
adjunctive bupropion sustained release in the treatment of
SSRI-induced sexual dysfunction. J Clin Psychiatry
2005;66:844848.
81. Thase ME, Haight BR, Richard N et al. Remission rates
following antidepressant therapy with bupropion or
selective serotonin reuptake inhibitors: a meta-analysis of
original data from 7 randomized controlled trials. J Clin
Psychiatry 2005;66:974981.
82. Taylor MJ, Rudkin L, Hawton K. Strategies for managing
antidepressant-induced sexual dysfunction: systematic
review of randomised controlled trials. J Affect Disord
2005;88:241254.
83. Gelenberg AJ, McGahuey C, Laukes C et al. Mirtazapine
substitution in SSRI-induced sexual dysfunction. J Clin
Psychiatry 2000;61:356360.
84. Koutouvidis N, Pratikakis M, Fotiadou A. The use of mirtazapine in a group of 11 patients following poor compliance to selective serotonin reuptake inhibitor treatment
due to sexual dysfunction. Int Clin Psychopharmacol
1999;14:253255.
85. Ernst E, Pittler MH. Yohimbine for erectile dysfunction:
a systematic review and meta-analysis of randomized
clinical trials. J Urol 1998;159:433436.

395

Werneke et al.
86. Munhoz RP. Serotonin syndrome induced by a combination of bupropion and SSRIs. Clin Neuropharmacol
2004;27:219222.
87. Ross S, Williams D. Bupropion: risks and benets. Expert
Opin Drug Saf 2005;4:9951003.
88. Zajecka J, Dunner DL, Gelenberg AJ et al. Sexual function
and satisfaction in the treatment of chronic major
depression with nefazodone, psychotherapy, and their
combination. J Clin Psychiatry 2002;63:709716.
89. Ferguson JM, Shrivastava RK, Stahl SM et al.
Reemergence of sexual dysfunction in patients with
major depressive disorder: double-blind comparison of
nefazodone and sertraline. J Clin Psychiatry 2001;62:24
29.
90. Fink HA, MacDonald R, Rutks IR, Wilt TJ. Trazodone for
erectile dysfunction: a systematic review and meta-analysis. BJU Int 2003;92:441446.
91. Michelson D, Bancroft J, Targum S, Kim Y, Tepner R.
Female sexual dysfunction associated with antidepressant
administration: a randomized, placebo-controlled study
of pharmacologic intervention. Am J Psychiatry
2000;157:239243.
92. Landen M, Eriksson E, Agren H, Fahlen T. Eect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin
Psychopharmacol 1999;19:268271.
93. Jespersen S, Berk M, Van WYK C et al. A pilot randomized, double-blind, placebo-controlled study of granisetron in the treatment of sexual dysfunction in women
associated with antidepressant use. Int Clin Psychopharmacol 2004;19:161164.
94. Nelson EB, Shah VN, Welge JA, Keck PE Jr. A placebocontrolled, crossover trial of granisetron in SRI-induced
sexual dysfunction. Clin Psychiatry 2001;62:469473.
95. Segraves RT. Reversing anorgasmia associated with
serotonin uptake inhibitors. JAMA 1991;266:2279.
96. Riley AJ, Riley EJ. Cyproheptadine and antidepressantinduced anorgasmia. Br J Psychiatry 1986;148:217218.
97. Steele TE, Howell EF. Cyproheptadine for imipramineinduced
anorgasmia.
J
Clin
Psychopharmacol
1986;6:326327.
98. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine
treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol 1995;18:320
324.
99. McCormick S, Olin J, Brotman AW. Reversal of uoxetineinduced anorgasmia by cyproheptadine in two patients. J
Clin Psychiatry 1990;51:383384.
100. Lauerma H. Successful treatment of citalopram-induced
anorgasmia by cyproheptadine. Acta Psychiatr Scand
1996;93:6970.
101. Cohen AJ. Fluoxetine-induced yawning and anorgasmia
reversed by cyproheptadine treatment. J Clin Psychiatry
1992;53:174.
102. Feder R. Reversal of antidepressant activity of uoxetine
by cyproheptadine in three patients. J Clin Psychiatry
1991;52:163164.
103. Decastro RM. Reversal of MAOI-induced anorgasmia
with cyproheptadine. Am J Psychiatry 1985;142:783.
104. Martinez R, Puigvert A, Pomerol JM, Rodriguez-Villalba
R. Clinical experience with apomorphine hydrochloride:
the rst 107 patients. J Urol 2003;170:23522355.
105. Montorsi F, Salonia A, Deho F et al. Pharmacological
management of erectile dysfunction. BJU Int
2003;91:446454.
106. Balon R. Intermittent amantadine for uoxetine-induced
anorgasmia. J Sex Marital Ther 1996;22:290292.

396

107. Shrivastava RK, Shrivastava S, Overweg N, Schmitt M.

Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin
Psychopharmacol 1995;15:8384.
108. Balogh S, Hendricks SE, Kang J. Treatment of uoxetineinduced anorgasmia with amantadine. J Clin Psychiatry
1992;53:212213.
109. Bartlik BD, Kaplan P, Kaplan HS. Psychostimulants
apparently reverse sexual dysfunction secondary to
selective serotonin re-uptake inhibitors. J Sex Marital
Ther 1995;21:264271.
110. Nagai S, Kasai T, Ogawa K et al. Successful treatment of
infertility due to anejaculation with in vitro fertilization
and embryo transfer: a report of two cases. Tohoku J Exp
Med 1998;184:241246.
111. Linsenmeyer TA, Perkash I. Infertility in men with spinal
cord injury. Arch Phys Med Rehabil 1991;72:747754.
112. Chapelle PA, Blanquart F, Puech AJ, Held JP. Treatment of anejaculation in the total paraplegic by subcutaneous injection of Physostigmine. Paraplegia 1983;
21:3036.
113. Aukst-Margetic B, Margetic B. An open-label series
using loratadine for the treatment of sexual dysfunction
associated with selective serotonin reuptake inhibitors.
Prog
Neuropsychopharmacol
Biol
Psychiatry
2005;29:754756.
114. Brubaker RV. Fluoxetine-induced sexual dysfunction reversed by loratadine. J Clin Psychiatry 2002;63:534.
115. Kim YC, Davies MG, Lee TH, Hagen PO, Carson CC 3rd.
Characterization and function of histamine receptors in
corpus cavernosum. J Urol 1995;153:506510.
116. Thomsen LL. Investigations into the role of nitric oxide
and the large intracranial arteries in migraine headache.
Cephalalgia 1997;17:873895.
117. Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine.
Ann Pharmacother 2004;38:411413.
118. Dimellis D. Serotonin syndrome produced by a combination of venlafaxine and mirtazapine. World J Biol
Psychiatry 2002;3:167.
119. MedicineNet.com 1997: Buspirone centre: Buspirone
(Buspar) http://www.medicinenet.com; accessed 11 August
2006.
120. Banos JE, Bosch F, Farre M. Drug-induced priapism. Its
aetiology, incidence and treatment. Med Toxicol Adverse
Drug Exp 1989;4:4658.
121. Daviss WB, Scott J. A chart review of cyproheptadine for
stimulant-induced weight loss. J Child Adolesc Psychopharmacol 2004;14:6573.
122. Berk M, Stein DJ, Potgieter A et al. Serotonergic targets in
the treatment of antidepressant induced sexual dysfunction: a pilot study of granisetron and sumatriptan. Int
Clin Psychopharmacol 2000;15:291295.
123. Bardley I, Wright P, MacDonagh R, Hole J, Edwards A.
An open-label, randomized, exible-dose, crossover study
to assess the comparative ecacy and safety of sildenal
citrate and apomorphine hydrochloride in men with
erectile dysfunction. BJU Int 2004;93:12711275.
124. Dula E, Keating W, Siami PF et al. Ecacy and safety of
xed-dose and dose-optimization regimens of sublingual
apomorphine versus placebo in men with erectile dysfunction. The Apomorphine Study Group. Urology
2000;56:130135.
125. Heaton JP. Apomorphine: an update of clinical trial results. Int J Impot Res 2000;12(suppl. 4):S67S73.
126. Whiskey E, Taylor D. Pramipexole in unipolar and bipolar
depression. Psychiatr Bull 2004;28:438440.

Antidepressants and sexual dysfunction

127. British National Formulary 51/2006: Amantadine
hydrochloride; http://www.bnf.orgbnf/bnf/current/3644.
htm; accessed 11 August 2006.
128. Shulman LM, Minagar A, Sharma K, Weiner WJ. Amantadine-induced
peripheral
neuropathy.
Neurology
1999;53:18631865.
129. Bernik M, Vieira AH, Nunes PV. Bethanecol chloride for
treatment of clomipramine-induced orgasmic dysfunction
in males. Rev Hosp Clin Fac Med Sao Paulo
2004;59:357360.
130. Gross MD. Reversal by bethanechol of sexual dysfunction
caused by anticholinergic antidepressants. Am J Psychiatry 1982;139:11931194.
131. Yager J. Bethanechol chloride can reverse erectile and
ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case. J Clin Psychiatry 1986;47:210
211.
132. Fink HA, Mac Donald R, Rutks IR, Nelson DB, Wilt TJ.
Sildenal for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2002;162:1349
1360.
133. Moore RA, Edwards JE, McQuay HJ. Sildenal (Viagra)
for male erectile dysfunction: a meta-analysis of clinical
trial reports. BMC Urol 2002;2:6.
134. Sairam K, Kulinskaya E, Hanbury D et al. Oral sildenal
(Viagra) in male erectile dysfunction: use, ecacy and

135.

136.
137.

138.
139.

140.

141.

142.

safety prole in an unselected cohort presenting to a

British district general hospital. BMC Urol 2002;2:4.
Mondaini N, Ponchietti R, Muir GH et al. Sildenal does
not improve sexual function in men without erectile dysfunction but does reduce the postorgasmic refractory
time. Int J Impot Res 2003;15:225228.
Carson CC, Rajfer J, Eardley I et al. The ecacy and
safety of tadalal: an update. BJU Int 2004;93:12761281.
Porst H, Padma-Nathan H, Giuliano F et al. Ecacy of
tadalal for the treatment of erectile dysfunction at 24
and 36 hours after dosing: a randomized controlled trial.
Urology 2003;62:121125.
Ashton AK. Vardenal reversal of female anorgasmia. Am
J Psychiatry 2004;161:2133.
Hijazi RA, Cunningham GR. Andropause: is androgen
replacement therapy indicated for the aging male? Annu
Rev Med 2005;56:117137.
Dennerstein L, Alexander JL, Kotz K. The menopause and
sexual functioning: a review of the population-based
studies. Annu Rev Sex Res 2003;14:6482.
Warren MP, Halpert S. Hormone replacement therapy:
controversies, pros and cons. Best Pract Res Clin Endocrinol Metab 2004;18:317332.
NICE. CG23: depression management of depression in
primary and secondary care. London: National Institute
of Clinical Excellence, 2004.

397