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Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism
Author(s) -
ABDELMALIK N.,
RUHÉ H. G.,
BARWARI K.,
VAN DEN DOOL E.J.,
MEIJERS J. C.M.,
MIDDELDORP S.,
BÜLLER H. R.,
SCHENE A. H.,
KAMPHUISEN P. W.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.03196.x
Subject(s) - paroxetine , serotonin transporter , serotonin , serotonin reuptake inhibitor , pharmacology , reuptake inhibitor , serotonin plasma membrane transport proteins , medicine , platelet , transporter , norepinephrine transporter , chemistry , receptor , gene , biochemistry
Summary. Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. Objectives: To prospectively quantify the dose‐response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5‐HTTLPR) on platelet function. Methods: Nineteen drug‐free psychiatric outpatients (44.5 ± 10.8 years) were tested before and after 6 weeks of paroxetine treatment (20 mg day −1 ). Based on clinical symptoms, paroxetine dosages were increased (40–50 mg day −1 ) for 6 more weeks in 11 patients. Parameters related to platelet function were assessed by bleeding time, platelet function analyzer (PFA), platelet serotonin, platelet factor 4 (PF4), β‐thromboglobulin (β‐TG), and aggregation tests. Results: Paroxetine 20 mg day −1 increased mean bleeding time by 1.2 min (95% confidence interval (95% CI) −0.2–2.7) and reduced median platelet serotonin level (463 ng 10 −9 platelets; inter quartile range (IQR) 361–666), and platelet ß‐TG concentration (3.1 IU 10 −6 platelets; IQR 0.3–6.0). Other platelet parameters did not change significantly. Serial platelet aggregation tests did not become abnormal. Paroxetine dose‐escalation did not further influence platelet function. However, 5‐HTTLPR polymorphisms modified these effects: in L A /L A ‐carriers, bleeding times did not change (−0.2 min; 95% CI −0.6 to 0.9), while bleeding times significantly increased in <2L A ‐allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L A ‐alleles (868 ng 10 −9 platelets; IQR 585 to 1213) than in ≥1 L A ‐allele carriers (457 ng 10 −9 platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L A ‐alleles. Conclusions: Paroxetine 20 mg day −1 does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ß‐TG. These paroxetine effects appear to be mediated by 5‐HTTLPR, with most pronounced effects in patients without L A ‐alleles.