Korean J Urol.  2014 Sep;55(9):599-607. 10.4111/kju.2014.55.9.599.

Nonresponders to Daily Paroxetine and Another SSRI in Men With Lifelong Premature Ejaculation: A Pharmacokinetic Dose-Escalation Study for a Rare Phenomenon

• Janssen PK
• Touw D
• Schweitzer DH
• Waldinger

• KMID: 2069778
• DOI: http://doi.org/10.4111/kju.2014.55.9.599

Abstract

PURPOSE
Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs.
MATERIALS AND METHODS
Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations.
RESULTS
Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively.
CONCLUSIONS
Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.

Keyword

5-HT1A (C-1019G) polymorphism; CYP2D6; Leptin; Lifelong premature ejaculation; Paroxetine hemihydrate

MeSH Terms

Adolescent
Adult
Aged
Body Mass Index
Cytochrome P-450 CYP2D6/genetics
Humans
Leptin/blood
Male
Middle Aged
Mutation
Paroxetine/*administration & dosage/blood
Polymorphism, Genetic
Premature Ejaculation/*drug therapy/genetics
Receptor, Serotonin, 5-HT1A/genetics
Risk Factors
Serotonin Uptake Inhibitors/*administration & dosage
Time Factors
Treatment Outcome
Young Adult
Cytochrome P-450 CYP2D6
Leptin
Paroxetine
Receptor, Serotonin, 5-HT1A
Serotonin Uptake Inhibitors

Figure

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  FIG. 1 The fold increase of the geometric mean intravaginal ejaculatory latency time as a function of the paroxetine plasma level.

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  FIG. 2 Fold increase (FI) of the geometric mean intravaginal ejaculatory latency time (Y axis) as a function of the serum paroxetine dosage (X axis). The second horizontal line represents a fold increase of 2. In the current study, nonresponse was defined as a FI of less than 2, and response was defined as a FI of more than 2. On the left side are the FIs of the paroxetine nonresponders (GC genotype for the 5-HT1A receptor C-1019 G). On the right side, are the FIs of the paroxetine responders (CC genotype for the 5-HT1A receptor C-1019 G).

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  FIG. 3 Paroxetine-induced serum prolactin concentration changes in men with lifelong premature ejaculation. In the paroxetine nonresponders, prolactin concentrations tend to reduce, whereas in paroxetine responders, prolactin concentrations increased.

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