Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport

Abstract

Citalopram prevents serotonin (5-HT) uptake into platelets by blocking the serotonin reuptake transporter (SERT). Although some clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may affect haemostasis and thrombosis, these poorly-characterised effects are not well understood mechanistically and useful in vitro data is limited. We sought to determine whether the inhibitory effects of citalopram on platelets are mediated via its pharmacological inhibition of 5-HT transport. We quantified the inhibitory potency of (RS)-, (R)- and (S)-citalopram on platelet function. If SERT blockade is the primary mechanism for citalopram-mediated platelet inhibition, these potencies should show quantitative congruence with inhibition of 5-HT uptake. Our data show that citalopram inhibits platelet aggregation, adhesion and thromboxane production with no difference in potency between (R)- and (S)-isomers. By contrast, citalopram had a eudysmic ratio of approximately 17 (S > R) for SERT blockade. Furthermore, nanomolar concentrations of citalopram inhibited 5-HT uptake into platelets but had no effect on other platelet functions, which were inhibited by micromolar concentrations. Our data indicate that citalopram-induced inhibition of platelets in vitro is not mediated by blockade of 5-HT transport. This raises a new question for future investigation: by what mechanism(s) does citalopram inhibit platelets?

Two novel, putative mechanisms of action for citalopram-induced platelet inhibition

“…Citalopram inhibits both collagen- and U46619-induced platelet aggregation 10 . Since aggregation is dependent on Ca 2+ signalling, the effect of citalopram on agonist-induced increases in [Ca 2+ ] cyt was investigated.…”

“…Citalopram not only inhibits platelet SERT, but also platelet aggregation, adhesion, thromboxane A 2 (TxA 2 ) synthesis and dense granule release 8 – 12 . However, this functional inhibition is not caused by blockade of 5-HT uptake and must therefore be mediated by distinct pharmacological mechanisms of action 10 .…”

“…Citalopram inhibits platelet aggregation induced by both collagen and the TxA 2 mimetic, U46619, countering the claim that it is a specific inhibitor of collagen-induced platelet activation 9 . Nevertheless, citalopram is a more potent inhibitor of collagen 10 , which activates platelets predominantly via glycoprotein VI (GPVI), than U46619, a thromboxane prostanoid (TP) receptor agonist, suggesting differential mechanisms of action. Reduced phosphorylation of signalling proteins in the GPVI pathway 10 points to GPVI as a possible site of action for citalopram, which could act as a classical competitive antagonist or allosteric inhibitor.…”

“…Nevertheless, citalopram is a more potent inhibitor of collagen 10 , which activates platelets predominantly via glycoprotein VI (GPVI), than U46619, a thromboxane prostanoid (TP) receptor agonist, suggesting differential mechanisms of action. Reduced phosphorylation of signalling proteins in the GPVI pathway 10 points to GPVI as a possible site of action for citalopram, which could act as a classical competitive antagonist or allosteric inhibitor. For example, citalopram could disrupt GPVI dimers that mediate collagen binding and platelet activation 13 .…”

Severe poisoning with naproxen causing coagulopathy

“…No analysis to detect drug‐dependent antibodies was performed. Roweth et al have shown that citalopram inhibited platelet aggregation, adhesion and thromboxane production . This inhibition is present at high concentration of citalopram.…”