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european urology 50 (2006) 454–466
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Review – Sexual Medicine
Serotonin and Premature Ejaculation: From Physiology to
Patient Management
François Giuliano a,b,*, Pierre Clément a
a
b
PELVIPHARM Laboratories, Gif-sur-Yvette, France
AP-HP, Neuro-Urology unit, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France
Article info
Abstract
Article history:
Accepted May 31, 2006
Published online ahead of
print on June 19, 2006
Introduction: Premature ejaculation (PE), whose pathophysiology is still not clearly
identified, is the most common male sexual dysfunction, yet it remains underdiagnosed and undertreated. The aims of this paper are to provide a scientific and
pharmacologic rationale, and to discuss to what extent selective serotonin reuptake
inhibitors (SSRIs) can help patients with PE.
Materials and Methods: A comprehensive evaluation of available published data
included analysis of published full-length papers that were identified with Medline
and Cancerlit from January 1981 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed.
Results: The central ejaculatory neural circuit comprises spinal and cerebral areas
that form a highly interconnected network. The sympathetic, parasympathetic, and
somatic spinal centers, under the influence of sensory genital and cerebral stimuli
integrated and processed at the spinal cord level, act in synergy to command
physiologic events occurring during ejaculation. Experimental evidence indicates
that serotonin (5-HT), throughout brain descending pathways, exerts an inhibitory
role on ejaculation. To date, three 5-HT receptor subtypes (5-HT1A, 5-HT1B, and 5HT2C) have been postulated to mediate 5-HT’s modulating activity on ejaculation.
Pharmacologic manipulation of the serotonergic system has been performed in rats,
with the antidepressant selective serotonin reuptake inhibitors (SSRIs) exhibiting
the greatest efficacy in delaying ejaculation. The mechanism of action by which
SSRIs modulate central 5-HT tone has been studied in depth, but gaps in this
knowledge prevent an explanation of the efficacy of acute treatment in delaying
ejaculation. Emerging clinical evidence indicates chronic and on-demand dosing of
SSRIs has a beneficial effect for the treatment of men with PE, at least for paroxetine.
On-demand dapoxetine, and SSRI with a short half-life, recently has been shown to
significantly increase intravaginal latency time and PE patient-related outcomes in
phase 3 clinical trials.
Conclusions: Nowadays there is no doubt that PE can be treated effectively by SSRIs.
Nevertheless their mechanism of action is not yet well understood and deserves
more research. In particular it is not understood why all the SSRIs are not equal in
terms of their ability to delay ejaculation. Therefore, there is a need for more
research to better characterize the mechanism of action of SSRIs as well their
clinical benefit in patients affected by PE.
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords:
Dapoxetine
Neurophysiology of
ejaculation
Selective serotonin reuptake
inhibitor
Serotonin receptors
* Corresponding author. Department of Physical Medicine and Rehabilitation, Raymond
Poincaré Hospital, 104 bd Raymond Poincaré, 92380 Garches, France. Tel. +33 147107072;
Fax: +33 147107615.
E-mail address: [email protected] (F. Giuliano).
0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2006.05.055
european urology 50 (2006) 454–466
1.
Introduction
Sexual medicine has evolved greatly in the past
several years, to a large extent because of the
introduction of the phosphodiesterase-5 inhibitor
sildenafil followed by tadalafil and vardenafil as
highly effective oral therapies for erectile dysfunction (ED) [1]. Conversely, despite some substantial
progress in medical and scientific knowledge in
other areas of sexual medicine including ejaculation
disorders and female sexual dysfunctions, there is
still a need for the development of a clinically
effective treatment for these sexual symptoms.
According to the epidemiologic studies conducted
so far, premature ejaculation (PE) is the most
common male sexual dysfunction in younger men
(<30 years) [2]; its prevalence is higher than that of
ED, and varies from 9% and up to 31% of the male
population [3]. PE recently has been reported to be
associated with significant effects on sexual functioning and satisfaction [4]. Nevertheless according
to the National Health and Social Life Survey
conducted in the United States, it is noteworthy
that men with ED and low sexual desire experienced
diminished quality of life, but those with premature
ejaculation were not affected [5]. Accordingly it must
be kept in mind that the level of bother attributable
to PE is likely less than that caused by ED, and the
number of men currently seeking medical assistance for PE is likely less than that for ED. Another
striking difference between PE and ED is the fact
that, conversely to ED, PE patients have no impairment of the physiologic process that leads to the
forceful expulsion of sperm at the urethral meatus.
Actually in such patients, there is an inadequate
timing for ejaculation to occur as well as a selfreported lack of voluntary control associated more
or less with personal distress. It is currently
unknown whether peripheral and/or central
mechanisms are involved in the pathophysiology
of PE.
The Diagnostic and Statistical Manual of Psychiatry,
Fourth Edition (DSM-IV) defines PE as ‘‘persistent or
recurrent ejaculation with minimal sexual stimulation before, on or shortly after penetration and
before the person wishes it,’’ which is associated
with ‘‘marked distress or interpersonal difficulty’’
[6]. More recently during the 2nd International
Consultation on Sexual Dysfunctions, premature
ejaculation, also referred to as rapid or early
ejaculation, was defined according to three essential
criteria: (1) brief ejaculatory latency, (2) loss of
control, and (3) psychologic distress in the patient
and/or partner. Ejaculatory latency of 2 minutes or
less may qualify a man for the diagnosis of PE, which
455
should include consistent inability to delay or
control ejaculation and marked distress about the
condition. All three components should be present
to qualify for the diagnosis [7].
The aetiology of PE is uncertain in almost all
cases, and might include a combination of organic
and psychogenic factors. Negative conditioning and
penile hypersensitivity are the most frequently cited
aetiological factors in PE, although neither mechanism has received adequate experimental support to
date [7]. Accordingly from a scientific perspective, it
is fair to state that PE pathophysiology is largely
unknown.
Since the first publications of clomipramine [8]
and paroxetine [9] for the treatment of PE, numerous
other studies have confirmed the efficacy of
selective serotonin reuptake inhibitors (SSRIs) antidepressants as well as clomipramine in the treatment of lifelong PE [10–12].
The rat is the most widely used animal for the
study of sexual behaviour, and the data presented
below refer to this animal species unless specified
otherwise. At first glance, human copulatory behaviour does not resemble the copulatory behaviour in
rats. However, when looking at greater details, some
common features emerge (for review see [13]) that
allow animal studies-based development of relevant
strategies for the treatment of sexual dysfunctions
in human.
The aims of this paper are to provide a scientific
and pharmacologic rationale, and to discuss to what
extent SSRIs can help patients with PE.
2.
Neurophysiology of ejaculation
2.1.
Spinal network
The thoracolumbar sympathetic as well as the
sacral parasympathetic and somatic (Onuf’s
nucleus) spinal ejaculatory centres play a pivotal
role in ejaculation, because they integrate peripheral and central signals, and send coordinated
outputs to pelviperineal anatomic structures that
allow a normal ejaculatory process to occur.
Integrity of these spinal nuclei is necessary and
sufficient for the expression of ejaculation as
demonstrated by the induction of the ejaculatory
reflex after peripheral stimulation in animals with
spinal cord transection and in patients after spinal
cord lesion [14,15]. The conversion of sensory
information into secretory and motor outputs
involves spinal interneurones that have been
recently characterised in rats [16]. The presence
of these cells, named lumbar spinothalamic (LSt)
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european urology 50 (2006) 454–466
Fig. 1 – Schematic representation of the control of the seminal tract and the bulbospongiosus (BS) muscle by the spinal
ejaculation generator (LSt cells) in rats. The spinal ejaculation generator projects to the parasympathetic (sacral
parasympathetic nucleus [SPN]) and sympathetic (dorsal grey commissure [DGC] and intermediolateral cell column [IML])
preganglionic neurons, and BS muscle motoneurones (Onuf’s nucleus). The parasympathetic centre projects to the seminal
tract via the pelvic nerve (PN) and the major pelvic ganglion (MPG). The sympathetic centre innervates the seminal tract by
sending projections through the lumbar sympathetic chain (LSC) to the superior hypogastric plexus (SHP) and then via the
hypogastric nerve (HN), which joins the MPG. The motoneurones of the BS muscle project to the muscle through the motor
branch of the pudendal nerve (PudN).
cells, has been demonstrated in laminae X and VII
of the third and fourth spinal lumbar segments. In
the rat spinal cord, fibres of the sensory branch of
the pudendal nerve terminate close to LSt cells
[17], although a direct connection has not been
revealed yet. LSt neurones project to the sympathetic and parasympathetic preganglionic neurones innervating the pelvis and particularly the
prostate as well as the motoneurones innervating
the bulbospongiosus muscles [18]. In addition, LSt
cells send a direct projection to the parvocellular
subparafascicular nucleus of the thalamus [19]. All
these data support a crucial role for LSt cells in
coordinating the spinal control of ejaculation
(Fig. 1).
2.2.
Brain network
As a centrally integrated and highly coordinated
process, ejaculation involves cerebral sensory areas
and motor centres that are tightly interconnected
(Fig. 2). Recent findings, based on studies investigating Fos protein’s pattern of expression, have
revealed, in distinct species, brain structures that
are specifically activated when the animals displayed ejaculation [20,21], suggesting the existence
of a cerebral network that is specifically related to
ejaculation and is activated no matter what sexual
activity precedes ejaculation. The brain structures
belonging to this cerebral network comprise discrete
regions lying within the posteromedial bed nucleus
of stria terminalis (BNSTpm), the posterodorsal
medial amygdaloid nucleus (MeApd), the posterodorsal preoptic nucleus (PNpd), and the parvicellular part of the subparafascicular thalamus (SPFp).
Reciprocal connections between those substructures and the medial preoptic area (MPOA) of the
hypothalamus, a brain area known to be essential in
controlling sexual behaviour [22], have been
reported in anatomic and functional studies
[21,23]. Neuroanatomic studies failed to reveal the
existence of direct connections between the MPOA
and the spinal ejaculatory centres. However, it was
shown that MPOA projects to other brain regions
involved in ejaculation such as the paraventricular
thalamic nucleus (PVN) [24], the periaqueductal grey
(PAG) [25], and the paragigantocellular nucleus
(nPGi) [26]. Parvocellular neurones of the PVN
directly innervate autonomic preganglionic neurones in the lumbosacral spinal cord [27,28] and
pudendal motoneurones located in the L5–L6 spinal
segment in rats [17]. Retrograde and antegrade
axonal tracing studies have shown that SPFp sends
projections to BNST, MeA, and MPOA [29,30] and
receives inputs from LSt cells [19]. These data
suggest a pivotal role for SPFp in the control of
european urology 50 (2006) 454–466
457
Fig. 2 – Diagram of brain structures and putative central pathways involved in ejaculation. Structures containing serotonin
auto/heteroreceptors are indicated in grey. BNSTpm: posteromedial bed nucleus of stria terminalis; MeApd: posterodorsal
medial amygdaloid nucleus; MPOA: medial preoptic area; PAG: periaqueductal grey; nPGi: paragigantocellular nucleus;
PNpd: posterodorsal preoptic nucleus; PVN: paraventricular thalamic nucleus; SPFp: parvicellular part of the
subparafascicular thalamus.
ejaculation, although functional investigations are
lacking.
In the brainstem, nPGi and PAG have received
increasing attention. NPGi projects to pelvic efferents and interneurones in the lumbosacral spinal
cord [31,32]. A strong inhibitory role for NPGi on
ejaculation in rats has been suggested from investigations using an experimental model, namely
urethrogenital reflex, developed in anaesthetised
rats by McKenna’s group [33] and considered a
spinal expulsion-like reflex. The same experimental
paradigm was used to demonstrate the important
role of PAG in controlling expulsion reflex. In
addition, as established in neuroanatomical studies,
PAG constitutes a relay between MPOA and nPGi
[23,34]. Clearly, midbrain structures exert a regulating function on ejaculation, but further investigations are required for revealing the details of the
mechanism. Recently, a study using positron emission tomography (PET) to investigate increases in
regional cerebral blood flow in humans during
ejaculation showed that the strongest activation
occurs in the mesodiencephalic transition zone
including ventral tegmental area (VTA), medial
and ventral thalamus, and SPFp [35]. Regarding
the role of the neocortex in ejaculation, several
studies have shown the intense activation of the
parietal cortex and cerebellum during ejaculation by
PET and functional magnetic resonance imaging
(fMRI) techniques [35–37]. This brain area is considered a site that receives sensory information
from pudendal sensory fibres [38].
3.
The role of central 5-HT in ejaculation
A great body of evidence indicates that the overall
effect of 5-HT on ejaculation is inhibitory [39,40]. The
role of 5-HT and the 5-HT system on sexual reflexes
was investigated by using the urethrogenital reflex
paradigm. As a conclusion of several series of
experiments, it was suggested that 5-HT, released
at L3–L5 spinal segments from terminals of axons
descending from the rostral region of the nPGi,
exerts an inhibitory role on ejaculation [31,41].
However the above data are contradicted by experi-
458
european urology 50 (2006) 454–466
mental results reporting the proejaculatory effect of
systemic injection of p-chloroamphetamine (PCA),
an amphetamine derivative that liberates catecholamines and 5-HT from monoaminergic nerve
terminals, in both conscious and anaesthetised rats.
Pharmacologic investigations showed that the primary role in mediating the activity of PCA on
ejaculation is played by 5-HT, whereas noradrenaline appears of secondary importance [42]. The
proejaculatory effect of PCA was also observed in
rats with acute spinal transection at the T8 level,
indicating a spinal site of action for this drug [43].
Accordingly further studies are required to determine the precise role of spinal 5-HT in the
ejaculatory process.
Cerebral action of 5-HT on ejaculation has been
described in a number of behavioural studies that
led to similar conclusions [44–46]. Indeed, microinjection of 5-HT into serotonergic projection field
within the forebrain and MPOA resulted in prolongation of the ejaculation latency in rats. Conversely,
facilitation of male rat ejaculatory behaviour was
reported after delivery of 5-HT onto raphe nuclei
containing serotonergic cell bodies [47]. At this site,
stimulation of somatodendritic autoreceptors (5HT1A) by 5-HT reduces the firing of 5-HT neurones,
which results in decreased 5-HT release within
projection areas. It seems to be clear that 5-HT,
acting on brain postsynaptic receptors, exerts an
inhibitory control on the ejaculatory process.
3.1.
Role of 5-HT1A receptors
5-HT1A somatodendritic autoreceptors are present in
the mesencephalic and medullary raphe nuclei. The
facilitator effect of 8-OH-DPAT, a selective agonist of
5-HT1A receptors, on ejaculation has been evidenced
by decreasing the number of intromissions before
ejaculation and the ejaculation latency in rats after
systemic delivery [48,49]. This proejaculatory effect
was observed after microinjection of 8-OH-DPAT in
brain areas such as the median raphe nucleus or
nucleus accumbens [44,45]. Consistent with the
findings that 5-HT in general inhibits ejaculation,
8-OH-DPAT likely blocks this inhibitory effect by
decreasing the release of 5-HT in the synaptic cleft. In
this favour, stimulation of 5-HT1A autoreceptors,
located on 5-HT cell bodies in the raphe nuclei, by
microinjection of 8-OH-DPAT decreased 5-HT cell
firing and consequently 5-HT release in projection
areas [50,51]. However these results have to be
interpreted with some caution because of recent
evidence that strongly suggests brain dopamine D2like receptors mediate the proejaculatory effect of 8OH-DPAT [52,53]. In addition to their cerebral loca-
tion, 5-HT1A receptors have also been found in the
spinal cord within the dorsal horn (laminae I–IV),
sacral parasympathetic nucleus, and dorsal grey
matter commissure at the lumbosacral level. However the functional implication of those spinal 5-HT1A
receptors in regulation of the ejaculatory process is
still unknown.
3.2.
Role of 5-HT1B receptors
It has been shown in several studies that subcutaneous administration of the 5-HT1B receptor agonists (anpirtoline, TFMPP) impaired ejaculation in
rats [44,48]. Further investigations reported that the
5-hydroxytryptophan (5-HTP)–induced inhibition of
male rat ejaculatory behaviour was antagonised by
cotreatment with the 5-HT1B receptor antagonist
isomoltane [54]. Expression of 5-HT1B receptors has
been detected in the hypothalamus and, at the
lumbosacral level of the spinal cord, in the sacral
parasympathetic nucleus, the dorsal grey matter
commissure, and the dorsomedial nucleus.
Whether brain or spinal 5-HT1B receptors are
involved in 5-HT’s inhibiting activity on ejaculation
remains to be clarified.
3.3.
Role of 5-HT2C receptors
There are very few experimental results in favour of
a role for 5-HT2C receptors in ejaculation. Systemic
acute administration of the 5-HT2A/2C agonist DOI
has been shown to suppress ejaculation in rats [55].
In these experiments, ejaculation was restored with
pretreatment with a 5-HT2C antagonist. High density
of 5-HT2C receptors has been detected in the
hypothalamus as well as in the sacral parasympathetic nucleus and dorsal grey matter in the
lumbosacral spinal cord; here again, the site of
action for 5-HT2C agonists is not established.
4.
Regulation of the activity of central 5-HT
transmission
Serotonergic neurones regulate their own activity by
three mechanisms (Fig. 3). Any acute increase of 5HT release is immediately followed by activity of the
neurone to diminish the extracellular 5-HT level.
Under normal physiologic conditions, 5-HT activates (presynaptic) 5-HT1A autoreceptors on the cell
bodies of serotonergic neurones. Activation of these
5-HT1A autoreceptors decreases firing of the 5-HT
neurone and consequently lowers the 5-HT release
from the presynaptic neurone into the synaptic cleft
(mechanism 1). After release of 5-HT in the synapse,
european urology 50 (2006) 454–466
459
autoreceptors over the course of a few weeks [56]
and possibly also to desensitisation of 5-HT1B
autoreceptors [57], and consequently to less inhibition on 5-HT release into the synapse. The net effect
of chronic versus acute SSRI administration is more
5-HT release into the synapse, stronger enhancement of 5-HT neurotransmission, and consequently
stronger activation of postsynaptic 5-HT receptors
[58]. Alternatively, as this mechanism of action was
proposed to explain the delayed antidepressant
activity of SSRIs [59], long-term adaptive changes
in the plethora of biologic substrates, receptors, and
pathways under the influence of 5-HT tone may be
the cause of the more-pronounced biologic effects of
chronic administration of SSRIs. At the molecular
level, the adaptive responses to chronic exposure to
SSRIs include decrease in the function and expression of monoamine and gamma amino-butyric acid
receptors, increase in the cyclic adenosine monophosphate (cAMP) signal transduction and expression of cAMP response element-binding protein, as
well as an increase in brain-derived neurotrophic
factor [59,60].
Fig. 3 – Schema of the three inhibitory feedback
mechanisms that exist in serotonin (5-HT) neurones, and
control 5-HT release and concentration in the synaptic
cleft. These mechanisms include (1) 5-HT1A
somatodendritic autoreceptors whose stimulation lowers
5-HT neurone firing (mechanism 1), (2) 5-HT1B presynaptic
autoreceptors whose stimulation reduces 5-HT release
(mechanism 2), and (3) 5-HT transporters (5-HTT), which
remove 5-HT from the synaptic cleft (mechanism 3).
presynaptic 5-HT1B autoreceptors become activated,
which in turn inhibits 5-HT release from the
presynaptic neurone into the synaptic cleft
(mechanism 2). This feedback mechanism of the
neurone probably prevents overstimulation of
(post)synaptic 5-HT receptors. Another automechanism to prevent overstimulation of postsynaptic
5-HT receptors is the immediate removal of 5-HT in
the synapse back into the presynaptic neurone by 5HT transporters (5-HTT) at the presynaptic endings
and at the serotonergic cell bodies (mechanism 3).
5.
Mechanism of action of chronic SSRIs
The blockade of 5-HTTs by chronic administration of
SSRIs results in a persistent increase of 5-HT levels
in the synapse and in the space around the cell
bodies, which leads to desensitisation of 5-HT1A
6.
Mechanism of action of acute SSRIs
All 5-HT transporters are blocked after acute
administration of an SSRI, leading to higher 5-HT
levels in the synaptic cleft and in the space around
the cell bodies [61]. The increased 5-HT levels
activate 5-HT1A autoreceptors and consequently
lead to lower 5-HT release into the synaptic cleft
within minutes [62]. The diminished release of 5-HT
in the synaptic cleft compensates (completely or
partially) the initially increased 5-HT concentrations
as the result of the SSRI-induced blockade of the 5HT reuptake by transporters from the synapse into
the presynaptic neurone. Higher 5-HT concentrations in the synapse will strongly activate presynaptic 5-HT1B autoreceptors, which alone will
attenuate 5-HT release. The net effect of acute SSRI
administration, under physiologic conditions, is
only a mild or no increase of 5-HT neurotransmission and mild or no stimulation of the various
postsynaptic 5-HT receptors [63]. In other words, on
the basis of these data, it is predicted that ondemand SSRI treatment will not lead to acute (i.e.,
within 1–2 h) relevant stimulation of 5-HT postsynaptic receptors, because there is hardly any 5-HT
increase in the synapse and hardly any stimulation
of postsynaptic 5-HT receptors. If postsynaptic 5-HT
receptors are not activated or are weakly activated,
clinically relevant physiologic effects will not occur.
However, this view is contradicted by several lines of
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european urology 50 (2006) 454–466
evidence supporting the ability of a single systemic
administration of SSRI (fluoxetine and sertraline) to
markedly increase 5-HT levels in extracellular and
cerebrospinal fluids [64–66]. In a recent study aimed
at determining the time course of sertraline effects
on 5-HT concentrations in cerebrospinal fluid,
which is considered a good index of functionally
active 5-HT, it was shown that the 5-HT level
increase occurring after the first oral delivery of
sertraline (20 mg/kg) to monkey was comparable
with that measured throughout 28-day chronic
treatment [67]. An experimental approach combining electrophysiology and neurochemistry indicated
that the increase in extracellular levels of 5-HT
induced by acute intravenous injection of fluoxetine
was sufficient to alter postsynaptic excitability and
that this accumulation of synaptic 5-HT and the
subsequent activation of postsynaptic 5-HT1A receptors were achievable despite loss of firing-dependent 5-HT release [64].
7.
Mechanism by which SSRIs delay
ejaculation: preclinical data
7.1.
Chronic treatment
The delaying effect of chronic administration of
SSRIs on ejaculation has been demonstrated in
several behavioural studies carried out in rats [68–
70]. Despite some minor discrepancies that may be
due to interstudy technical differences, we can
conclude that chronic SSRIs (at least fluoxetine and
paroxetine) substantially inhibit copulatory behaviours without affecting sexual motivation. More
particularly, ejaculation latency and postejaculatory
interval were found to have a dose-dependent
increase after daily SSRI treatment, although drug
to drug differences in the amplitude of changes were
reported [70]. Various to-be-challenged hypotheses
that have been suggested to explain such a
differential activity of SSRIs include differences in
pharmacokinetic properties, direct interaction with
5-HT receptors, and direct and/or indirect interaction with other neurotransmitter systems [69,70].
7.2.
Acute treatment
Whereas there is no doubt that daily administration
of some antidepressant SSRIs significantly delay
ejaculation, conflicting results exist regarding the
efficacy of acute regimens. Acute systemic delivery
of SSRIs (fluoxetine, paroxetine) has been shown to
increase ejaculatory latency significantly in rats as
they approach sexual exhaustion (i.e., in sexually
experienced male rats, an average of 5–6 ejaculations
within an experimental period of 1.5–2 hours) [71,72].
However, such an effect was not observed in sexually
naı̈ve rats or in sexually experienced animals in their
first ejaculatory series [71]. The recent results from
behavioural studies testing the activity of acute
subcutaneous and oral delivery of dapoxetine indicate that this compound significantly prolongs
latency to ejaculation in rats with baseline ejaculatory latencies of less than 10 min [73].
7.3.
Conclusion for SSRI Treatment
The hypothesis that chronic treatment with SSRIs
leads to higher synaptic 5-HT levels than acute
treatment and results in a clinical relevant delay of
ejaculation has to be reevaluated with regard to the
experimental data (presented in section 6), which
support that acutely or chronically administered
SSRIs activate serotonergic transmission to the
same degree. In addition, this hypothesis comes
into contradiction with the above-mentioned data
on the efficacy of SSRI acute treatment to delay
ejaculation. Clearly, the inhibiting effect of SSRIs on
ejaculatory behaviour is more evident when administered daily versus acute administration, but one
may suggest that long-term molecular/cellular
adaptative changes take place in neurotransmitter/modulator systems other than the serotonergic
one, which may explain the differential effect
between treatment regimens. Further experimental
investigations focusing on these different elements
may provide new insights into the mechanism of
action by which antidepressant SSRIs affect the
ejaculatory process.
8.
A brief overview of the data supporting the
use of SSRIs in the treatment of PE
Existence of ejaculatory dysfunctions can be ascribed
to a combination of complex interacting factors
inherent to the disease (depression or anxiety) or
not, such as stress, comorbid medical conditions, and
side-effects of medications to treat concomitant
medical conditions or the disease itself. However
the development of scales to assess drug- or diseaserelated effects on ejaculatory function and their
systematic use in premorbid, baseline, and follow-up
conditions allow one to ascertain the cause of
impaired ejaculation.
A recent review of all drug treatment studies for
PE demonstrated that only a small percentage had
been performed according to evidence-based medicine [74].
european urology 50 (2006) 454–466
8.1.
Chronic dosing
Several authors have evidenced the efficacy of
fluoxetine in delaying ejaculation in PE patients
[75–78]. A double-blind placebo-controlled study of
fluoxetine demonstrated a 7-fold increase in the
ejaculatory interval 1 week after initiation of
treatment [11].
Sertraline at doses of 25–50 mg daily has been
repeatedly reported to improve not only the ejaculation latency time in men with PE but also the control
over ejaculation and sexual satisfaction as evidenced
by open-label and controlled studies that reported
subsequent increased frequency of intercourse
[79–82]. Waldinger et al. [9] first reported a significant
improvement in ejaculatory control with paroxetine
in a double-blind controlled study in PE patients, with
further evidence that improved ejaculatory control
achieved with paroxetine was dose-related. Several
uncontrolled studies of men with PE treated with
20 mg [83] or 10 mg [84] of paroxetine have reported
similar efficacy. In these studies the side-effect
profile was dose-related. Paroxetine, fluoxetine,
sertraline, and clomipramine appear to have similar
efficacy in several short-term and longitudinal
studies [85,86]. Conversely a meta-analysis of 35
daily treatment studies with SSRIs and clomipramine
demonstrated that clomipramine and the SSRIs
sertraline and fluoxetine had comparable efficacy
in delaying ejaculation, whereas the efficacy of the
SSRI paroxetine was greater than all other SSRIs and
clomipramine [10]. According to McMahon [87] SSRIs
are an effective treatment for 80–85% of men with PE.
Most men will notice an increase in their ejaculation
latency time within 2–3 days and will reach a 6- to 8fold increase and plateau after 3–4 weeks treatment.
8.2.
461
On-demand dosing
Similar to what was observed in rats conflicting
results exist in humans, whether for PE or not,
regarding the efficacy of acute SSRIs to delay
ejaculation. Indeed, some authors have reported a
4- to 11-fold increase in ejaculation latency [88,89],
whereas others found only a 1.3-fold increase [90]
when paroxetine 20 mg was taken as needed 3–
4 hours before intercourse. Johnson & Johnson
recently presented data with dapoxetine, an SSRI
structurally related to fluoxetine, for the treatment
of PE. Dapoxetine is the first SSRI with a short halflife specifically developed for the treatment of PE
(Fig. 4). Dapoxetine 30 and 60 mg has been shown to
be effective and generally well tolerated in two
randomised, double-blind, placebo-controlled, multicentre, phase 3 clinical studies for 12 weeks, each
Fig. 4 – Comparative pharmacokinetics of dapoxetine and
other selective serotonin reuptake inhibitor (SSRI)
antidepressant. This figure compares the
pharmacokinetics of dapoxetine with those of three
antidepressant SSRIs that have been used ‘‘off label’’ to
treat premature ejaculation (PE). In each case, the plasma
drug concentrations are expressed as a percentage of the
maximum achieved for that particular drug and dose.
Dapoxetine has the fastest pharmacokinetics profile of all.
The peak for dapoxetine occurs at 1.3 h, earlier than other
SSRIs. After the peak, there is a rapid decline in plasma
concentrations and, 24 h after administration, plasma
concentrations of dapoxetine are less than 4% of peak
(Johnson & Johnson data on file).
in up to 1200 males [91]. In men diagnosed with PE
according to DSM-IV criteria, dapoxetine 30 and
60 mg increased intravaginal ejaculatory latency
time by 3.0- and 3.7-fold, respectively, and significantly improved patient-reported measures of ejaculatory control and sexual satisfaction. The drug
was effective on the first dose and maintained its
efficacy with subsequent administration at both 30and 60-mg doses.
There is no doubt that safe and effective medications delaying ejaculation will become widely available in the near future, although combining
pharmacologic and psychologic therapies in an
integrative manner will certainly improve drug
treatment satisfaction and compliance [92].
9.
Tolerability of SSRIs for PE
Side-effects have been a major issue reported during
daily treatment with SSRIs in depressive patients.
SSRI adverse effects include psychiatric and neurologic side-effects, dermatologic reactions, anticholinergic side-effects, changes in body weight,
462
european urology 50 (2006) 454–466
cognitive impairment, and drug–drug interactions.
Sexual side-effects, in addition to delayed ejaculation (e.g., ED and loss of libido) may also occur. The
rate and mean duration of each type of adverse
event varies for each of the SSRI agents, and patients
with comorbidities may be predisposed to certain
side-effects [93]. A further limitation of continuous
SSRI therapy is that dose reduction or discontinuation of ongoing SSRI therapy has been associated
with an SSRI discontinuation syndrome. This cluster
of somatic and psychologic symptoms can include
dizziness, nausea and emesis, headache, gait
instability, lethargy, agitation, anxiety, and insomnia [94,95]. Symptoms usually begin within 1–3 days
after drug discontinuation and have a median
duration of more than 1 week [96]. These symptoms
are typically reversible upon reintroduction of the
SSRI [94].
Conventional SSRIs having longer half-lives than
dapoxetine may require a ‘‘wash-out’’ period to
minimize the risk of excessive levels accumulating
after multiple doses. Overdose of SSRIs or—more
commonly—drug–drug interactions between SSRIs
and other agents that enhance central nervous
system 5-HT activity can lead to serotonin syndrome, a cluster of severe and persistent symptoms,
which may include myoclonus, hyperreflexia,
sweating, shivering, uncoordination, and mental
status changes [97,98]. Patients receiving continuous-dose SSRI therapy must be aware of potential
drug–drug interactions between SSRIs and their
concomitant medications and must schedule their
doses accordingly. Because the dosage and schedule
of SSRI administration for PE may vary from the
approved regimens for other indications (e.g.,
clinical depression and anxiety), it must be noted
that the safety and tolerability profiles of SSRIs in
the off-label setting may be altered, compared with
those observed when used for approved indications
[99].
[101,102], the methodology and design of these
studies have been weak and fail to meet the criteria
of evidence-based research. In addition, long-term
maintenance of ejaculatory control induced by
these treatments has been shown to be very low
[103]. Further investigation into the ways in which
pharmacologic and psychologic strategies can combine to achieve optimal outcomes is greatly needed.
In the long run, proven programs of pharmacotherapy combined with brief counseling or coaching
might prove even more effective in helping to
restore sexual confidence in men and enhance their
learning of effective techniques to control ejaculation [104].
11.
Conclusion and perspectives
Over the past decade, clinical evidence has emerged
indicating a beneficial effect of antidepressant SSRIs
for the treatment of men with PE. Nowadays there is
no doubt that PE can be treated effectively by SSRIs.
Nevertheless their mechanism of action is not yet
well understood and deserves more research. In
particular it is not understood why all the SSRIs are
not equal in terms of their ability to delay ejaculation. There is still an ongoing debate regarding the
clinical relevance of on-demand regimens concerning their ability to successfully delay ejaculation and
to improve patient and partner satisfaction, which
must be the primary target outcome. Recent results
with on-demand dapoxetine are encouraging. Additional end points for clinical research are needed to
provide evidence that the pharmacologic activity of
SSRIs translates into patient benefit. Indeed for a
favourable risk–benefit assessment, prolongation in
intravaginal ejaculatory latency time must translate
into a clinically significant benefit. Accordingly in
addition to ‘‘objective’’ outcomes, there is a need for
patient-related outcomes and health-related quality-of-life instruments for evaluating the benefit of
SSRI treatment in PE patients.
10.
Is there still a role for psychotherapy in
the treatment of PE?
A
number
of
different
psychotherapeutic
approaches to, as well as behavioural techniques
for, PE have been described, but their efficacy has
not been evaluated in properly controlled and
adequately powered trials. Furthermore, the different therapeutic modalities have not been compared
in formal studies. Behavioural treatment is distinguished in the ‘‘stop–start’’ and the ‘‘squeeze’’
techniques [100,101]. Although short-term success
rates from 60% to almost 100% have been reported
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