A selective serotonin reuptake inhibitor, citalopram, inhibits collagen-induced platelet aggregation and activation

Tseng, Yung Zu; Chiang, Meng-Ling; Huang, Tur-Fu; Su, Kuan‐Pin; Lane, Hsien‐Yuan; Lai, Yanhao

doi:10.1016/j.thromres.2010.09.017

Cited by 54 publications

(53 citation statements)

References 35 publications

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“…It is possible that 4 weeks was an insufficient treatment period; previous research showing FMD improvement with SSRI treatment used a treatment period of 20 weeks. 22 Unlike previous research, [40][41][42] we did not observe an impact of SSRI treatment on platelet aggregation. However, our results indicated that another marker of platelet function, platelet NO production, decreased considerably with SSRI treatment, with a significant 21% drop from pre-to posttreatment.…”

Section: Discussioncontrasting

confidence: 98%

Selective Serotonin Reuptake Inhibitors and Endothelial Function in Women

Hantsoo

Czarkowski

Child

et al. 2014

Journal of Women's Health

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Background: Among women worldwide, major depression (MDD) and heart disease rank first and second, respectively, in burden of disease. Although selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed, possible inhibition of nitric oxide (NO) function has caused concerns about their effects on protective vascular mechanisms. Our study aimed to determine the effect of SSRIs on flow-mediated vascular dilatation (FMD), platelet aggregation, and platelet NO production among women. Methods: Women (n = 28) without known cardiovascular disease were recruited prior to undergoing SSRI treatment for MDD, postpartum depression (PPD), or premenstrual dysphoric disorder (PMDD). Symptoms were quantified using the Hamilton Depression/Anxiety and Beck Depression scales. FMD, platelet aggregation, and platelet NO production were measured before and after 1 month of SSRI (sertraline, fluoxetine, or paroxetine) therapy. Results: Depression and anxiety symptoms decreased significantly with SSRI treatment ( ps < 0.01). FMD and platelet aggregation did not differ between pre-and posttreatment, although FMD rose to the normal range ( ‡ 8%) in two of three women with abnormal FMD prior to SSRI treatment. We observed a 21% decrease ( p = 0.024) in platelet NO production. Conclusions: SSRI treatment had little effect on FMD or platelet aggregation. The health impact of decreased NO production is unclear, particularly in this relatively young group of women without cardiovascular disease, but should be considered in future studies focusing on SSRI safety in patients with cardiovascular disease.

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Section: Discussioncontrasting

confidence: 98%

Selective Serotonin Reuptake Inhibitors and Endothelial Function in Women

Hantsoo

Czarkowski

Child

et al. 2014

Journal of Women's Health

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“…However, these studies utilized SSRIs at high concentrations (Ͼ10 M) that are known to exert off-target effects (e.g. the 1 receptor) (11,24). Comparatively, our study uses concentrations of SSRIs that block platelet-mediated SERT uptake but are far below the reported concentrations resulting in off-target effects (10 nM; Fig.…”

Section: Discussionmentioning

confidence: 99%

“…citalopram and paroxetine) leads to dramatically reduced platelet 5-HT granule content (5,6), altering peripheral 5-HT homeostasis and potentially modifying multiple physiological processes including hemostasis (7)(8)(9)(10). Clinically, increased bleeding risk has been observed in patients taking SSRIs, and platelet aggregation is disrupted (5,11). Here, we have characterized a similar effect in two distinct mouse models of lost SERT function, suggesting that sustained loss of SERT function influences hemostasis.…”

mentioning

confidence: 82%

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. In the periphery, serotonin (5-HT) 3 is produced by enterochromaffin cells in the gastrointestinal tract, released into the plasma, and quickly taken up by platelets via the plasma membrane serotonin transporter (SERT). Following uptake, 5-HT is stored in dense granules by the actions of the vesicular monoamine transporter 2 (1-4). Chronic inhibition of SERT through selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram and paroxetine) leads to dramatically reduced platelet 5-HT granule content (5, 6), altering peripheral 5-HT homeostasis and potentially modifying multiple physiological processes including hemostasis (7-10). Clinically, increased bleeding risk has been observed in patients taking SSRIs, and platelet aggregation is disrupted (5, 11). Here, we have characterized a similar effect in two distinct mouse models of lost SERT function, suggesting that sustained loss of SERT function influences hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERTPlatelet dense granules contain 5-HT along with other platelet agonists including adenosine diphosphate (ADP), thromboxane (TXA2), and histamine. Appropriate platelet activation depends on the timely release of these factors (4, 5, 12). Platelet aggregation is crucial early in thrombus formation (4, 5, 13). Aggregation, which is the bridging of platelet-platelet contacts, requires a conformational alteration in the glycoprotein ␣IIb␤3, leading to its activation and fibrinogen binding. 5-HT has been shown to enhance aggregation in a 5-HT 2A receptor (5-HT 2A R)-dependent manner (4, 14 -17). The 5-HT 2A R is the only serotonergic receptor found on platelets and potentiates platelet responses to weak agonists like ADP (18). Subthreshold concentrations of two different platelet agonists can exert a synergistic effect on platelet activation. One example includes dual ADP and 5-HT activation leading to increases in cytosolic [Ca 2ϩ ] (13). However, the role of 5-HT during in vivo hemostasis remains unclear, particularly in the context of chronic SERT inhibition.To elucidate the underlying mechanisms of SSRI effects on platelet aggregation, a better understanding of acute versus chronic inhibition of SERT function during platelet activation is required. Acute and chronic blockage of SERT function results in distinct scenarios regarding the effects on 5-HT homeostasis. Acute inhibition of SERT blocks the amount of

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“…The higher concentrations of circulating serotonin induced by SSRIs could reduce platelet aggregation [49,50] and impair reactivity to vasoconstriction [51] . However, SSRIs do not appear to intervene in the functionality of vitronectin -a fundamental component of glycoprotein IIb/IIIa [48] -or fibrinogen [52] ; but are able to regulate the expression of vascular adhesion molecules such as VCAM-1, ICAM-1, P-selectin and E-selectin [53,54] . Nevertheless, the relative relevance of these effects remains unknown in the context of the chronic inflammatory milieu which SSRIs could promote simultaneously, as does the clinical significance of this antiplatelet activity.…”

Section: Ssri-associated Cardiometabolic Risk: Molecular Pathwaysmentioning

confidence: 99%

Metabolic risk in depression and treatment with selective serotonin reuptake inhibitors: are the metabolic syndrome and an increase in cardiovascular risk unavoidable?

Chávez-Castillo¹,

Ortega²,

Nava³

et al. 2018

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Depression is one of the most common psychiatric disorders, and has become an epidemic in modern medical practice; notorious for frequently co-occurring with multiple comorbidities, especially cardiovascular disease (CVD), type 2 diabetes mellitus (DM2), and its various risk factors comprised in the metabolic syndrome (MS). Selective serotonin reuptake inhibitors (SSRIs) are the most widely used class of psychotropic drugs in this and many other clinical scenarios; yet their impact on cardiometabolic health has not been elucidated. The objective of this review was to summarize current views on the pharmacology of SSRIs and cardiometabolic risk, as well as available epidemiological evidence regarding its clinical significance. SSRIs appear to intervene in cardiometabolic physiology fundamentally by modulating chronic inflammation, a key pathophysiologic phenomenon in MS, DM2 and CVD. However, the dosing necessary to achieve a beneficial impact in this regard, as well as their clinical correlations, remain controversial. Each SSRI displays a particular profile regarding each of the components of the MS: weight gain seems to be the most common effect of SSRIs, more frequent with paroxetine, followed by citalopram and escitalopram. As a drug class, SSRIs also appear to promote hypercholesterolemia rather uniformly, while fluoxetine and citalopram appear to particularly increase triacylglyceride levels. In contrast, fluvoxamine and paroxetine seem to have the greatest impact on dysglycemia. Lastly, most SSRIs appear to be innocuous or even beneficial regarding blood pressure and high-density lipoprotein cholesterol. Nevertheless, many of these effects may vary significantly upon specific clinical circumstances, especially timing. This topic remains rather unexplored in clinical psychopharmacology, and further, larger-scale epidemiological studies are needed in order to offer improved care in this field.

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A selective serotonin reuptake inhibitor, citalopram, inhibits collagen-induced platelet aggregation and activation

Cited by 54 publications

References 35 publications

Selective Serotonin Reuptake Inhibitors and Endothelial Function in Women

Selective Serotonin Reuptake Inhibitors and Endothelial Function in Women

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Metabolic risk in depression and treatment with selective serotonin reuptake inhibitors: are the metabolic syndrome and an increase in cardiovascular risk unavoidable?

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