The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis

Abstract

While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.

Association between depression and macrovascular disease: a mini review

“…The pivotal contribution of 5-HT to the onset of depression has been well established ( 89 ). As a prominent neurotransmitter, 5-HT is capable of binding with 5-HT receptors located on the platelet surface, augmenting their aggregation process, which requires the participation of the 5-HT transporter protein ( 83 , 93 , 94 ). Therefore, the potential utility of serotonin as a promising pharmacological target for treating depression has been established, notably through the use of selective serotonin reuptake inhibitors (SSRIs) ( 94 – 96 ), which have been confirmed to effectively curtail platelet activation, consequently alleviating the risk of myocardial infarction ( 97 ).…”

Duloxetine, Gabapentin, and the Risk for Acute Myocardial Infarction, Stroke, and Out-of-Hospital Death in Medicare Beneficiaries With Non-Cancer Pain

“…Through its effects on serotonin, duloxetine has antiplatelet and antithrombotic activity, as demonstrated in antiplatelet function tests and in vivo animal models. 10 Consequently, duloxetine could decrease the risk of acute myocardial infarction (AMI) and stroke. Indeed, stronger inhibitors of serotonin reuptake among antidepressants have been associated with decreased risk for ischemic stroke, which may be attributable to this effect.…”

“…Duloxetine has pharmacologic properties that could either decrease or increase cardiovascular risk. Through its effects on serotonin, duloxetine has antiplatelet and antithrombotic activity, as demonstrated in antiplatelet function tests and in vivo animal models 10. Consequently, duloxetine could decrease the risk of acute myocardial infarction (AMI) and stroke.…”