title: Nonresponders to daily paroxetine and another SSRI in men with lifelong premature ejaculation: a pharmacokinetic dose-escalation study for a rare phenomenon.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of BetaSciences, Utrecht University, Utrecht, The Netherlands. ; Department of Central Hospital Pharmacy, Viecuri Hospital, Venlo, The Netherlands.
authors.forename: Paddy Kc
authors.initials: PK
authors.lastname: Janssen
authors.affiliation: Apotheek Haagse Ziekenhuizen, HagaZiekenhuis, Den Haag, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: Touw
authors.affiliation: Department of Internal Medicine and Endocrinology, Reinier de Graaf Groep of Hospitals, Delft-Voorburg, The Netherlands.
authors.forename: Dave H
authors.initials: DH
authors.lastname: Schweitzer
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of BetaSciences, Utrecht University, Utrecht, The Netherlands. ; Department of Neurosexology, HagaZiekenhuis, Den Haag, The Netherlands.
authors.forename: Marcel D
authors.initials: MD
authors.lastname: Waldinger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017374:Paroxetine / Q000008:administration & dosage* / Q000097:blood; D011110:Polymorphism, Genetic; D061686:Premature Ejaculation / Q000188:drug therapy* / Q000235:genetics; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D012307:Risk Factors; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D019389:Cytochrome P-450 CYP2D6; D020738:Leptin; D017374:Paroxetine; D044282:Receptor, Serotonin, 5-HT1A; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT1A (C-1019G) polymorphism; CYP2D6; Leptin; Lifelong premature ejaculation; Paroxetine hemihydrate