Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction

Labos, Christopher; Dasgupta, Kaberi; Nedjar, Hacene; Turecki, Gustavo; Rahme, Elham

doi:10.1503/cmaj.100912

Cited by 131 publications

(120 citation statements)

References 31 publications

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“…[1][2][3][4] The bleeding risk increases further when SSRIs/SNRIs are used concomitantly with NSAIDs, anticoagulants, and antiplatelet agents. 1,[5][6][7][8] Potential mechanisms that underlie the bleeding risk associated with medications that affect the serotonergic system may include inhibition of serotonin uptake by platelets, SRI-induced increases in gastric acid secretion, and modulation of the CYP450 metabolism. 9,10,26 Certain SSRIs and SNRIs with high protein binding (eg, fluoxetine, duloxetine), when coadministered with another highly bound drug (eg, warfarin), may also increase the free plasma drug concentrations via displacement of proteinbound drug, potentially increasing the risk of adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…The study also evaluated the effects of vortioxetine coadministration on the pharmacokinetics of aspirin and vice versa. In period 1, 28 subjects were randomized to 1 of the 2 sequences in which vortioxetine 10 mg or matching placebo was administered once daily in the morning for 14 days (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14], followed by coadministration with aspirin 150 mg once daily for 6 days (days [15][16][17][18][19][20]. Following a 21-day washout, in period 2, subjects received the alternative treatment.…”

Section: Designmentioning

confidence: 99%

“…[1][2][3][4] This bleeding risk increases further with concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, and antiplatelet agents. 1,[5][6][7][8] This effect is thought to be related to platelet serotonin depletion. …”

mentioning

confidence: 99%

“…25 SSRIs and SNRIs are reported to potentially increase the risk of bleeding events, and concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants with these drugs may potentiate this risk. [1][2][3][4][5][6][7][8] The objectives of the current studies were to evaluate the effects of multiple vortioxetine doses on the pharmacokinetics and pharmacodynamics of aspirin/salicylic acid and the (R)-and (S)-warfarin enantiomers.…”

mentioning

confidence: 99%

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Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin

Chen

Zhang

Serenko

2015

The Journal of Clinical Pharmacology

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Vortioxetine is an antidepressant with multimodal activity approved for the treatment of major depressive disorder. Two separate randomized, placebo-controlled trials evaluated the effects of multiple doses of vortioxetine (10 mg/day) on the pharmacokinetics and pharmacodynamics of aspirin and warfarin in healthy volunteers. In the aspirin study, subjects received vortioxetine 10 mg or placebo once daily for 14 days, followed by coadministration with aspirin 150 mg once daily for 6 days, in 2 periods with a crossover design. In the warfarin study, subjects were randomized after reaching target international normalized ratio (INR) values on warfarin to receive vortioxetine 10 mg or matching placebo once daily for 14 days, with all subjects receiving a maintenance dose of warfarin (1-10 mg). Vortioxetine had no effect on the steady-state pharmacokinetic parameters of aspirin or its metabolite salicylic acid, and no statistically significant effect on the inhibition of arachidonic acid-, adenosine-5 0 -diphosphate-, or collageninduced platelet aggregation at any time points. Coadministration of vortioxetine did not alter the pharmacokinetics of (R)-and (S)-warfarin enantiomers, or the mean coagulation parameters of warfarin treatment alone. Coadministration of vortioxetine doses in healthy volunteers had no effect on aspirin or warfarin pharmacokinetics or pharmacodynamics. Vortioxetine was well tolerated when coadministered with aspirin or warfarin. Keywords vortioxetine, platelet, bleeding, coagulation, pharmacokinetics, drug-drug interactionVarious case reports and epidemiologic studies indicate that selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) may be associated with an increased risk of bleeding. [1][2][3][4] This bleeding risk increases further with concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, and antiplatelet agents. 1,[5][6][7][8] This effect is thought to be related to platelet serotonin depletion. 9Based on the observation that serotonin reuptake inhibitor (SRI)-related bleedings most commonly occur in upper gastrointestinal sites, increased gastric acidity associated with some SRIs could be another important mechanism of drug-drug interaction.10 Because warfarin is highly protein-bound, coadministration with other SSRIs or SNRIs with high protein binding, such as fluoxetine and duloxetine, may result in increased levels of free drug, which could contribute to bleeding-related complications. 11Vortioxetine was approved by FDA and European Union (EU) in 2013 for the treatment of major depressive disorder (MDD). 12,13 The pharmacokinetic profile of vortioxetine is linear and dose-proportional with moderate oral bioavailability, extensive tissue distribution, and a long elimination half-life.14 Vortioxetine is extensively metabolized primarily through oxidation via multiple CYP450 isozymes and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine...

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Section: Discussionmentioning

confidence: 99%

Section: Designmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin

Chen

Zhang

Serenko

2015

The Journal of Clinical Pharmacology

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“…SSRI use has been associated with an increased risk of bleeding (1). Albeit uncommon, sertraline associated gastrointestinal and vaginal bleeding, epistaxis , ecchymosis, purpura, hematuria have been reported in the literature (2,3). We report a case of extensive petechial rash possibly due to sertraline use.…”

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confidence: 86%

Sertalin ile ilişkili peteşiyal döküntü

Yıldız

2016

J Contemp Med

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Dear Editor, Sertraline is a selective serotonin reuptake inhibitor (SSRI) that is widely used in the treatment of various psychiatric disorders with a low adverse side effect profile. SSRI use has been associated with an increased risk of bleeding(1). Albeit uncommon, sertraline associated gastrointestinal and vaginal bleeding, epistaxis , ecchymosis, purpura, hematuria have been reported in the literature (2,3). We report a case of extensive petechial rash possibly due to sertraline use. Petechial rash disappeared after the cessation of sertraline and did not recur with venlafaxine use.A forty eight-year-old female patient presented with anhedonia, lack of energy, feelings of sadness and worthlessness ongoing for three months. Her past psychiatric history revealed that symptoms similar to her present depressive episode started twenty years ago and recurred particularly during the winterseason. She had used many antidepressants before but she only benefited partially from venlafaxine and fluoxetine. For the past six months, she was not on any antidepressants. With a provisional diagnosis of recurrent depression, sertraline50 mg/day was prescribed. After four weeks of sertraline use, her mood improved, and she did not describe any side effects. Six weeks after sertraline use, petechial rash occurred in her body. In her physical examination,pe techial rash was present in her arms, legs, and abdominal region.She didn't have a history of a hematological disorder or a bleeding disorder. She had not experienced any physical trauma that might have caused the lesions. She was not on any drug other than sertraline during this period. Her biochemical profile, and blood count including thrombocytes and bleeding time were all within normal limits. The patient was consulted to dermatology clinic in order to rule out other pathologies. Dermatologic examination revealed no other pathology, and it was stated that sertraline may be responsible for these lesions. After all further examination, the petechial rash was attributed to sertraline use and it was stopped. After a couple of days her petechial rash dimini shed, and it disappeared totally in a week. Three weeks later, venlafaxine 37.5 mg/ day was started for her recurring depressive episodes, and then titrated to 75 mg /day. She has been on venlafaxine 75 mg/day with a good clinical response for the past ten months, and she has not had any similar dermatological complaints during her follow -up.It is well-known that the release of serotonin plays a major role in platelet aggregation. Blockade of serotonin transporters by SSRIs may lead to a lower concentration of serotonin in the platelets, thus causing bleeding (4). Lack of concomitant drug use or a bleeding disorder, normality of the blood tests, and the disappearance of the lesions after cessation of sertraline suggest that sertraline might be the possibl e cause of petechial rash in this case. Although venlafaxine associated bleeding has been reported in the literature, several studies have shown that the risk is speci...

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Selective Serotonin Reuptake Inhibitors and Intracranial Hemorrhage

Hemphill

2017

JAMA Neurol

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Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction

Cited by 131 publications

References 31 publications

Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin

Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin

Sertalin ile ilişkili peteşiyal döküntü

Selective Serotonin Reuptake Inhibitors and Intracranial Hemorrhage

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