Utility of selective serotonin reuptake inhibitors in premature ejaculation.

The introduction of selective serotonin reuptake inhibitors (SSRIs) has revolutionized our understanding of the treatment of premature ejaculation. Lifelong premature ejaculation may be a neurobiological phenomenon, namely part of a biological variability of the intravaginal ejaculation latency time in men. Animal studies support this view, and an animal model for premature and delayed ejaculation has recently been developed. It is proposed that drug treatment of premature ejaculation should consist of 5-hydroxytryptamine (5-HT)2c receptor stimulation and/or 5-HT1A receptor inhibition. A meta-analysis of 35 daily treatment studies with selective serotonin reuptake inhibitors (SSRIs) and clomipramine demonstrated comparable efficacy of clomipramine with the SSRIs sertraline and fluoxetine in delaying ejaculation, whereas the efficacy of the SSRI paroxetine was greater than all other SSRIs and clomipramine. It is postulated that acute treatment with SSRIs, including those with short half-lives, will not produce an ejaculation delay equivalent to that induced by daily treatment of SSRIs.

Waldinger MD ，Olivier B 《Current Opinion in Investigational Drugs》

Emerging drugs for premature ejaculation.

Lifelong premature ejaculation (PE) is a frequent male sexual dysfunction and is thought to be mediated in part by disturbances of serotonergic (5-hydroxytryptamine; 5-HT) neurotransmission and ejaculation-mediating 5-HT receptors in the CNS. The aetiology of the dysfunction is unclear, but probably includes neurobiological and environmental factors. Lifelong PE is a syndrome characterised by a cluster of symptoms. Rapid ejaculations become manifest around the first sexual encounters in puberty or adolescence. Intravaginal ejaculation latency time usually occurs within 30-60 s, or maximally within 2 min after vaginal penetration, is present with nearly every sexual partner, and remains similar throughout life or may aggravate during ageing. The syndrome may lead to secondary psychological, sexual and relationship problems. Daily treatment with some selective serotonin re-uptake inhibitors (SSRIs) leads to strong ejaculation delay, but may be accompanied by side effects. New treatment with SSRIs with a short half-life (if approved) for on-demand use 1-2 h prior to coitus exerts less ejaculation-delaying effects than daily SSRI strategies. Animal studies have shown that strong, immediate ejaculation delay may be induced by the combination of an SSRI with a 5-HT(1A) receptor antagonist. The combination of an SSRI and any other compound that immediately strongly raises 5-HT neurotransmission may form the basis for the development of new on-demand drugs to treat PE.

Waldinger MD 《-》

On-demand SSRI treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions.

Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation. To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration. We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT(1A) receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation. Intravaginal ejaculation latency time (IELT). Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT(1A) receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration. On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT(1A) receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.

Waldinger MD ，Schweitzer DH ，Olivier B 《Journal of Sexual Medicine》

Serotonin and premature ejaculation: from physiology to patient management.

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. 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. 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 5-HT2C) 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. 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.

Giuliano F ，Clément P 《EUROPEAN UROLOGY》

Lifelong premature ejaculation: definition, serotonergic neurotransmission and drug treatment.

The ejaculation distribution theory (EDT) postulates a biological continuum of the intravaginal ejaculation latency time (IELT) in men. Such an continuum has recently been found in two epidemiological stopwatch studies. In addition, a continuum of ejaculation latency time has also been demonstrated in laboratory rats. It is suggested that the invariable parts of ejaculation, i.e. premature and retarded ejaculation are highly influenced by genetic and neurobiological factors. In contrast, superimposed on biological roots, ejaculation of men, in the middle part of the continuum, is probably more easily influenced by environmental and psychological factors. A meta-analysis of 35 daily SSRI and clomipramine treatment studies demonstrated a similar efficacy for paroxetine, clomipramine, sertraline and fluoxetine, with paroxetine exerting the strongest effect on ejaculation. Based on fundamental insights into serotonergic neurotransmission, it is suggested that on-demand conventional SSRI treatment will not lead to similarly impressive ejaculation delay as that found after daily conventional SSRI treatment. Future studies with SSRIs with short half-lives, short T(max) and high C(max )should elucidate whether these pharmacokinetic properties are able to affect the pharmacodynamics of 5-HT neurons in such a way that immediate clinically relevant ejaculation delay occurs.

Waldinger MD 《WORLD JOURNAL OF UROLOGY》