european urology 50 (2006) 454–466 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review – Sexual Medicine Serotonin and Premature Ejaculation: From Physiology to Patient Management Franc¸ois Giuliano a,b,*, Pierre Cle´ment a a b PELVIPHARM Laboratories, Gif-sur-Yvette, France AP-HP, Neuro-Urology unit, Department of Physical Medicine and Rehabilitation, Raymond Poincare´ 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 Poincare´ Hospital, 104 bd Raymond Poincare´, 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) . 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) ; its prevalence is higher than that of ED, and varies from 9% and up to 31% of the male population . PE recently has been reported to be associated with significant effects on sexual functioning and satisfaction . 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 . 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’’ . 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 . 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 . Accordingly from a scientific perspective, it is fair to state that PE pathophysiology is largely unknown. Since the first publications of clomipramine  and paroxetine  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 ) 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 . The presence of these cells, named lumbar spinothalamic (LSt) 456 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 , 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 . In addition, LSt cells send a direct projection to the parvocellular subparafascicular nucleus of the thalamus . 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 , 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) , the periaqueductal grey (PAG) , and the paragigantocellular nucleus (nPGi) . 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 . 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 . 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  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 . 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 . 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 . 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 . 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 . 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 . 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 . 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  and possibly also to desensitisation of 5-HT1B autoreceptors , 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 . Alternatively, as this mechanism of action was proposed to explain the delayed antidepressant activity of SSRIs , 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 . The increased 5-HT levels activate 5-HT1A autoreceptors and consequently lead to lower 5-HT release into the synaptic cleft within minutes . 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 . 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 460 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 . 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 . 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 . 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 naı¨ve rats or in sexually experienced animals in their first ejaculatory series . 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 . 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 . 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 . 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.  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  or 10 mg  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 . According to McMahon  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  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 . 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 . 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 . 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 . These symptoms are typically reversible upon reintroduction of the SSRI . 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 . [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 . 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 . 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? 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