On-Demand SSRI Treatment of Premature Ejaculation: Pharmacodynamic Limitations for Relevant Ejaculation Delay and Consequent Solutions

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Abstract
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‐HT1A 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‐HT1A 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‐HT1A 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.