In vitro effects of risperidone and 9-hydroxy-risperidone on human platelet function, plasma coagulation, and fibrinolysis

Background: Thrombotic events have been reported with the use of antipsychotic compounds, although the incidence, predisposing factors, and biological mechanisms associated with these events in psychiatric patients are subject to debate. Objective: The in vitro actions of risperidone and its active metabolite 9-hydroxy-risperidone (9-OH-risperidone) on human platelet function, plasma coagulation, and fibrinolysis were examined to explore whether hematologic effects might be a mechanism for thrombotic events with these compounds. Methods: Blood was donated by healthy white male subjects who were free of medications (particularly acetylsalicylic acid and nonsteroidal anti-inflammatory compounds). Platelet shape change and adhesion/aggregation reactions to risperidone and 9-OH-risperidone induced by adenosine diphosphate (ADP), collagen, epinephrine, and 5-hydroxytryptamine (5-HT) were tested in human platelet-rich plasma. Arachidonic acid metabolism was assessed in human platelets and rat aortic rings. Plasma coagulation was tested in human platelet-poor plasma. Fibrinolysis was measured in human whole blood. Results: The 12 study subjects ranged in age from 20 to 40 years (median age, 30 years). At concentrations of 1 X 10(-5) mol/L (similar to4180 ng/mL), neither risperidone nor 9-OH-risperidone induced platelet shape change or aggregation, amplified reactions to ADP or modified platelet adhesion/aggregation induced by collagen or ADP but they did attenuate epinephrine-induced platelet aggregation (-50% in the case of 9-OH-risperidone P < 0.05) and 5-HT-induced platelet aggregation (drug concentrations yielding 50% inhibition of 5-HT-induced platelet aggregation, 0.5 and 0.2 ng/mL, respectively). Cyclooxygenase, thromboxane A(2) synthase, 12-lipoxygenase, prostacyclin synthase, plasma coagulation, and fibrinolysis were unaffected. Conclusions: Risperidone and 9-OH-risperidone reduced epinephrine- and 5-HT-induced human platelet aggregation but did not significantly alter other measures of platelet function, plasma coagulation, or fibrinolysis in vitro. (Clin Ther. 2004;26:1261-1273) Copyright (C) 2004 Excerpta Medica, Inc.