This complex feedback mechanism in the central serotonergic system is meant to sustain homeostasis [47]. However, it has also consequences for drug treatment of PE. Particularly, for on-demand treatment with SSRIs [47].
19.14.1 Acute SSRI Administration
All 5-HT transporters are blocked after acute SSRI administration, leading to higher 5-HT levels in the synaptic cleft and in the space around the cell bodies [49]. The increased 5-HT levels activate 5-HT1A autoreceptors and consequently lead to lower 5-HT release into the synaptic cleft within minutes [50]. 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 5-HT reuptake by transporters from the synapse into the presynaptic neuron. Higher 5-HT concentrations in the synapse will increase the activation of presynaptic 5-HT1B autoreceptors that by itself will attenuate 5-HT release. The net effect of acute SSRI administration, under physiological conditions, is only a mild or no increase of 5-HT neurotransmission and mild or no stimulation of all postsynaptic 5-HT receptors (Fig. 19.2 ).
In other words, based on these data, it follows that on-demand SSRI treatment will acutely (i.e., within 1–2 h) not lead to relevant stimulation of 5-HT postsynaptic receptors, as 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 or hardly activated clinically relevant ejaculation delay will not occur [47].
Indeed, animal studies have shown that acute administration of the five SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram) has no significant effects on ejaculation time and number of ejaculations [51]. And also human studies indicate that on-demand use of the classical SSRIs do not lead to a similar strong ejaculation delay as can be induced by daily treatment with SSRIs.
19.14.2 Chronic SSRI Administration
In contrast to acute administration, chronic administration of SSRIs leads to a number of adaptations that are pivotal for inducing relevant ejaculation delay. The ongoing blockade of 5-HTTs results in a persistent increase of 5-HT levels in the synapse and in the space around the cell bodies. This leads to desensitization of 5-HT1A autoreceptors over the course of a few weeks [52], possibly also to desensitization of 5-HT1B autoreceptors [53], and consequently to less inhibition on 5-HT release into the synapse. The net effect of chronic 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 compared with acute SSRI administration [54] (Fig. 19.3).
Based on these insights into serotonergic neurotransmission, it appears that daily SSRI treatment leads to very relevant stimulation of 5-HT postsynaptic receptors and consequent clinically very relevant ejaculation delay after 1–2 weeks of continuous intake [47].
Indeed, animal studies have shown that chronic administration of fluoxetine and paroxetine results in increased values of ejaculation latency time [55–57]. Moreover, human studies have repeatedly shown the clinically very relevant ejaculation delay induced by daily treatment of paroxetine, sertraline and clomipramine.
19.15 Conclusion
Of the SSRIs, daily treatment with paroxetine, sertraline, fluoxetine, and citalopram gives rise to a clinically relevant ejaculation delay within 2–3 weeks. On-demand use of SSRIs gives rise to much less ejaculation delay. Both treatment strategies with the classical SSRIs are off-label but are recommended as one of the treatment options of PE by the ISSM guideline for the treatment of PE. Before prescribing an SSRI, patients should be informed about the SSRI-induced side effects, the SSRI-discontinuation syndrome, and the very rare known side effects.
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