Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

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Abstract

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 LA/LA-carriers, bleeding times did not change (−0.2 min; 95% CI −0.6 to 0.9), while bleeding times significantly increased in <2LA-allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without LA-alleles (868 ng 10−9 platelets; IQR 585 to 1213) than in ≥1 LA-allele carriers (457 ng 10−9 platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without LA-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 LA-alleles.

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