Psychosomatic Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schins, A.
Right arrow Articles by Hamulyák, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schins, A.
Right arrow Articles by Hamulyák, K.
Related Collections
Right arrow Genetics
Right arrow Depression
Right arrow Psychophysiology
Right arrow Coronary Artery Disease
Right arrow Other Cardiovascular Medicine
Psychosomatic Medicine 65:729-737 (2003)
© 2003 American Psychosomatic Society

REVIEW ARTICLE

Increased Coronary Events in Depressed Cardiovascular Patients: 5-HT2A Receptor as Missing Link?

Annique Schins, MD, Adriaan Honig, MD, PhD, MRC Psych, Harrie Crijns, MD, PhD, Leo Baur, MD, PhD and Karly Hamulyák, MD, PhD

From the Department of Psychiatry, Academic Hospital Maastricht, Maastricht, The Netherlands.

Address reprint requests to: Dr. Adriaan Honig, Academic Hospital Maastricht, Department of Psychiatry, P. Debyelaan 25, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. Email: adriaan.honig{at}spsy.azm.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DISCUSSION
 REFERENCES
 
OBJECTIVE: Major depressive disorder and depressive symptoms have been identified as independent risk factors for cardiac mobidity and mortality in patients with ischemic heart disease. Increased susceptibility to platelet activation has been proposed as one of the mechanisms by which depression acts as a significant risk factor for thrombotic events. In this review, data on platelet activation and platelet aggregation measures in depressed patients with or without concomitant cardiovascular disease are given. Data on the influence of antidepressants on parameters of platelet activation are summarized.

METHODS: A literature search was done by checking MEDLINE Advanced and PsycInfo from 1990 to 2003 and through checking the bibliographies of these sources. The following key words were used for this search: platelet activation, platelet aggregation, depression, depressive disorder, ischemic heart disease, calcium, and serotonin.

RESULTS: There is an indication of enhanced platelet activation and aggregation in depressed patients. Next, patients with a depressive disorder show signs of a hyperactive platelet 5-HT2A receptor signal transduction system as measured by increased platelet calcium mobilization after stimulation of platelets with serotonin.

CONCLUSIONS: Depression appears to be associated with an increased susceptibility for serotonin-mediated platelet activation. Upregulation and/or increased sensitivity of 5-HT2A/1B receptors and downregulated 5-HT transporter receptors in the periphery may contribute to increased risk of thromboembolic events in patients with depression and cardiovascular disease. Increased platelet reactivity based on a hyperreactive 5-HT2A receptor signaling system might be influenced by antidepressive medication that antagonizes platelet 5-HT2A receptors.

Key Words: platelet activation, • myocardial infarction, • 5-HT2A receptor, • depression, • PF4, serotonin.

Abbreviations: post-MI = post myocardial infarction;; IHD = ischemic heart disease;; 5-HT = serotonin;; SSRI = selective serotonin reuptake inhibitor;; PF4 = platelet factor 4;; ßTG = ß-thromboglobulin;; ADP = adenosine diphosphate;; GPCR = G-protein-coupled receptor.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DISCUSSION
 REFERENCES
 
Major depressive disorder and symptoms of depression have been identified as independent risk factors for cardiac morbidity and mortality in patients with ischemic heart disease. Most (1–11) but not all (12, 13) studies found an increased mortality risk in patients with depressive disorder or patients with symptoms of depression. Odds ratios for increased cardiac mortality of post-MI depression range from 4.9 in older studies (1, 2) to 2.3 to 3.0 (3, 10, 11, 14) in more recent ones. This increased risk is independent of other post-MI risk factors such as left ventricular dysfunction, complex arrhythmias, and history of prior MI. Major depression has been associated with serotonergic neurotransmission dysfunction (15, 16). Most postmortem brain studies in suicide victims with a retrospective diagnosis of depression showed decreased hydroxytryptamine (5-HT) transporter binding sites (16, 17). Regarding 5-HT2A receptors, postmortem brain studies showed both an increase in 5-HT2A receptors in the brain of depressed suicide victims (18–21), or no difference (22–24). Recently, support for a decrease in brain 5-HT transporter receptors in depression was found in an in vivo study comparing 15 patients with unipolar depression and 15 controls using single-photon emission computed tomography (25). In vivo imaging studies on 5-HT2A receptors in the brain have shown no difference (26–29), although some also found an increase (30, 31). Less is known about the status of the 5-HT1 receptor in the brain because of paucity of highly selective radiotracers. There are at least five 5-HT1 receptor subtypes, none of which are present on platelet membranes. 5-HT1 receptors may, however, have a role in thrombotic processes because of their presence in the vascular system. There is evidence that 5-HT1B and 5-HT2A receptors are present in smooth muscle cells of human coronary arteries (32). Serotonin has been shown to promote proliferation of vascular endothelial cells, probably through the 5-HT2A receptor (33, 34), and mediating vasoconstriction through 5-HT2A (35, 36) and 5-HT1B receptors (32). Because of similarity in the pharmacologic and biochemical characteristics of platelet 5-HT transporter receptors and platelet 5-HT2A receptors with those in the brain, it is hypothesized that the platelet receptor status may be analog to the brain receptor status. Indeed, there is considerable evidence of decreased platelet 5-HT transporter binding sites, as measured by [3H]imipramine binding (16, 37, 38), and increased platelet 5-HT2A receptor binding in drug-free patients with major depression (38–40). When binding was assessed with a more selective ligand [3H]paroxetine, a decrease in platelet 5-HT transporter binding sites was not found, however (25). The reasons for this negative result are unclear. Thus, although the status of the 5-HT transporter and the 5-HT2A receptor has not been conclusively shown and the correlation between the status of platelet and central serotonergic neurons needs further investigation, robust evidence for a serotonin dysregulation in mood disorders makes it plausible that 5-HT2A receptors and 5-HT transporters may play a role in the etiology of depression. In addition, changes in 5-HT2A and 5-HT1B receptor status may mediate atherogenic and pro-thrombotic mechanisms in the periphery (41–43). One mechanism accounting for increased serotonin-mediated thrombosis could be upregulation or downregulation of peripheral 5-HT receptors. Another mechanism could be related to receptor sensitivity. Almost invariably, researchers have reported enhanced platelet responsiveness of 5-HT2A receptors in patients with depression (44–47), suggesting an etiological role for the 5-HT2A receptor in thrombotic complications in cardiovascular compromised depressed patients.

In a recent issue of this Journal, von Känel et al. (48) thoroughly reviewed literature on the effects of psychological factors on coagulation, anticoagulation, and fibrinolysis measures and discussed the implications for cardiovascular disease. Research on state of activation of platelets in patients with depression has also been done by measuring 1) plasma levels of platelet-specific substances that are released from platelet granules, 2) plasma levels of molecules that are exposed on and shed from the platelet surface, and 3) agonist-induced platelet aggregation. None of the above-mentioned markers is perfect but gives information about the state of platelet activation (49). It has to be taken in account that markers may be sensitive to phlebotomy technique, diurnal variation and laboratory techniques. Moreover, aspirin and other cardiovascular medication, such as statins, beta-blockers, and nitrates, have been shown to influence platelet function (49).

This paper 1) reviews research regarding platelet activation and aggregation in depressed patients with or without cardiovascular disease, 2) reviews data on platelet 5-HT2A receptor signaling, and 3) proposes a pathophysiologic mechanism regarding the platelet 5-HT2A receptor, which might contribute to explain the hypothesized relationship between increased cardiac morbidity and mortality and depressive disorder. Lastly, suggestions for future research are given. The literature search was done by checking MEDLINE Advanced and PsycInfo from 1990 to 2003 and through checking the bibliographies of these sources. The following key words were used for searching: platelet activation, platelet aggregation, depression, depressive disorder, ischemic heart disease, calcium, and serotonin. Before reviewing the literature on research about platelet activation in depressed patients with or without concomitant cardiovascular disease, the physiology of platelet activation will be summarized.

Physiology of Platelet Activation
Exposure of platelets to damaged endothelium, shear stress, hypercholesterolemia, and circulating substances, like serotonin, can all initiate platelet activation. On activation, first a shape change of platelets is observed. This is followed by exposure of platelet membrane receptors and proteins and a release reaction consisting of extrusion of active substances from intraplatelet organelles by a mechanism of exocytose. Released substances from platelets induce local platelet adhesion, aggregation, vasoconstriction, and clot formation, eventually leading to local vascular occlusion. The external plasma membrane and the open canalicular system are studded with glycoproteins that act as receptors for different ligands. Serotonin can bind platelet 5-HT transporters and 5-HT2A receptors. Stimulation of platelet 5-HT2A receptors leads to a series of postreceptor signals that ultimately induce calcium mobilization from internal storage sites (50, 51). Calcium mobilization is required for platelet activation in the approximate order of shape change, aggregation, dense granule secretion, and {alpha}-granule secretion. Calcium is also required for the hydrolyses of platelet membrane phosphatidylinositol and phosphatidylcholine, yielding arachidonic acid (AA), which is converted into thromboxanes, prostaglandins, and prostacyclines. This conversion of AA is blocked by aspirin (52). Thromboxane A2 is a potent vasoconstrictor and inducer of the release reaction. Other plasma proteins such as fibrinogen, collagen, fibronectin, and laminin contribute to adhesion, aggregation, and extrusion of mitogenic substances on binding to their respective receptors (GP IIb/IIIa, {alpha}2ß1, {alpha}5ß1, {alpha}6ß1). Two additional receptors are involved in platelet adhesion: GP Ib/IX/V, the receptor for von Willebrand factor, and GP IV as receptor for collagen and thrombospondin (53). Recently, CD40L has been identified as another important pro-thrombotic and pro-inflammatory receptor of the platelet (54). It is well documented that serotonin potentiates platelet responses to agonists such as adenosine diphosphate (ADP), collagen, or thrombin (55, 56). Also stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface (57). {alpha}-Granulae contain platelet factor 4 (PF4), ß-thromboglobulin (ßTG), platelet-derived growth factor, factor V, and von Willebrand factor. PF4 inactivates heparin and facilitates ADP-induced platelet aggregation. ßTG is an antiheparin molecule inhibiting endothelial prostacyclin (vasodilator) secretion. Fusion of the {alpha}-granule membrane with the platelet membrane leads to expression of P-selectin on the platelet surface, acting as receptor for neutrophils and monocytes on thrombin-activated platelets (53). Another organelle in the platelet is the dense body that contains ATP (adenosine triphosphate), ADP, catecholamines, calcium ions, and serotonin. Enzymatic degradation of serotonin occurs either by monoamine oxidase A in the liver or in pulmonary endothelium. Serotonin is taken up by platelets. As long as platelets do not aggregate, peripheral blood contains little or no free serotonin (58).

As already mentioned, platelet function can be studied in several ways. Clinical studies on platelet activation in depressed patients with or without cardiovascular disease are reviewed which measured: 1) platelet-specific release products, such as ßTG and PF4, 2) molecules that are expressed on and shed from the platelet surface, such as P-selectin, glycoprotein IIb/IIIa, phosphatidylserine, and activated factor V, and 3) agonist-induced platelet aggregation.

Platelet Activation in Depression
It has been suggested that psychological stress activates platelets (59, 60). A significant relationship was found between stress-induced platelet activation and hostility as measured by ßTG levels in patients with CHD. Interestingly, a positive relationship was also found between type A behavior and ßTG levels (61). The same group replicated this finding with another marker of platelet activation, fibrinogen receptor activation, and binding. In both studies, no difference in platelet activation between CHD patients and controls could be found (62). The study of Laghrissi-Thode et al. (63) was the first to report significantly elevated mean ßTG and PF4 plasma levels in 21 depressed patients suffering concurrently from IHD as compared with patients with IHD alone (N = 8) and controls (N = 17). The increased levels remained elevated despite the use of aspirin in 18 of the 21 patients with depression and IHD. Also, Pollock et al. (64) found significantly elevated mean ßTG and PF4 plasma levels in 17 depressed patients with IHD, but results have to be interpreted cautiously because the control group was not adequate to draw conclusions on the effect of depression alone (it consisted of 16 healthy controls). To investigate enhanced platelet reactivity in depressive post-MI patients, Kuijpers et al. (65) compared 12 post-MI patients with depression to 12 post-MI patients without depression. A significant increase of PF4 was detected in the depressed group and a trend toward significance for ßTG levels. Although sample size was small, baseline characteristics of both groups were homogeneous. Confounding factors such as aspirin use, use of other cardiovascular medication, and smoking were evenly distributed. The first study to assess platelet activation in somatically healthy depressed patients was done by Musselman et al. (66). Annexine V, PAC1, anti-LIBS1, ßTG, and PF4 plasma levels were assessed in 12 medication-free patients with major depression and 8 normal controls at rest and following orthostatic challenge. Depressed patients exhibited significantly higher procoagulant activity at baseline as compared with controls as assessed by annexin V binding (detects phosphatidylserine) and following orthostatic challenge as assessed by PAC1 (detects fibrinogen binding site of activated GPIIb/IIIa receptor) and anti-LIBS1 (detects GP IIIa epitope). No significant increase was detected in other markers of platelet activation, possibly due to the small size of both groups. In a second study by the same group (67), again significant increases in some but not all platelet activation markers were found in depressed patients versus normal controls. However, results are difficult to interpret because both the depressed and the control groups were heterogeneous for risk factors for IHD (eg, hypertension, smoking, elevated cholesterol) and family history for psychiatric disorders. Enhanced collagen-induced platelet secretion but not anti-LIBS binding was reported in a study comparing 21 depressed patients with 21 nondepressed patients (68). Baseline characteristics were not significantly different for confounding factors such as smoking or medication. In a group of elderly depressed subjects with low cardiovascular disease burden, increased levels of ßTG and PF4 were assessed as compared with elderly controls (69). The first study (70) assessing P-selectin expression by Western blotting technique showed significant elevation of P-selectin on platelet membranes in a group of 19 depressed patients as compared with 17 controls. The finding was replicated in a study comparing 15 depressed patients (13 unipolar, 2 bipolar) with 15 healthy controls. Other markers of platelet activation such as GPIb receptor expression and CD63 were also significantly increased, except from integrin receptor {alpha}IIbßIIIa (71). Finally, increased secretion of ßTG and PF4 and increased anti-LIBS binding were assessed in a recent study by Musselman et al. (72). The study, however, has several limitations, including relatively small sample sizes, diverse cohorts, and differences in current medications.

Summarizing, although some studies had small groups and some had heterogeneous populations, making interpretation of the data more difficult, there is an indication of enhanced platelet activation in depressed patients as detected by plasma levels of platelet secretion products and procoagulant platelet protein expression.

Several studies addressed the effects of antidepressive medication on parameters of platelet activation. Platelet activation in the depressed group was significantly reduced after 6 weeks of open label treatment with paroxetine as demonstrated by diminished plasma levels of PF4 and diminished expression of activated factor V and P-selectin (67). Six weeks open label sertraline resulted in significant decrease of collagen-induced platelet secretion in 21 treated depressed patients (68). This decrease was not correlated to changes in Beck Depression Inventory scores. In the previously mentioned study of Pollock et al. (64), after 6 weeks double-blind treatment with either paroxetine or nortriptyline, mean PF4 and ßTG plasma levels decreased significantly in the patients treated with paroxetine but not with nortriptyline, while there was no difference in responder rate. No effect was found on P-selectin expression in depressed patients after 8 weeks open label treatment with bupropion (70). In a large cohort, Serebruany et al. (73) retrospectively compared differences in platelet activation in 126 patients with a selective serotonin reuptake inhibitor (SSRI) (N = 34) or without an SSRI (N = 92) before undergoing elective coronary artery stenting. Patients taking SSRI medication (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram) had significant lower expression of GPIIb/IIIa receptor and P-selectin; however, no significant difference could be found in other markers of platelet activation. The study has several limitations, more notably the absence of clinical diagnoses of depression, the heterogeneous population, the different cardiological medications, and the different antidepressant medications.

In summary (Table 1), the limited number of studies relating on effect of medication show that some antidepressants seem to have an effect on platelet activation in depressed patients with or without concomitant IHD by an as yet unknown mechanism. The effect does not seem to be related to the antidepressive effect per se as no relation of platelet activation to Hamilton Depression scores or recovery was found. SSRIs all reduce platelet 5-HT uptake but have varying effects on 5-HT2A downregulation. Fluoxetine and paroxetine have been reported to have either no effect or increase 5-HT2A receptor number, and citalopram has been shown to downregulate the 5-HT2A receptor (74). The 5-HT2A receptor antagonist ketanserin has been shown to protect against platelet aggregation in animal models (75). Data on platelet activation in patients on antidepressive medication with 5-HT2A receptor antagonistic properties are not as yet available. Such studies are necessary to assess the possible role of 5-HT2A receptors in enhanced platelet reactivity in depressed patients.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Assessment of platelet activation in depressed patients with or without concomittant cardiovascular disease
 
Platelet Aggregation in Depression
Another way to measure platelet activity is to measure spontaneous or agonist-induced aggregation. Nugent et al. (76) preincubated plasma of a volunteer with plasma of either depressed patients or age-matched controls. Platelet aggregation in plasma was measured after stimulation with (among others) serotonin, ADP, and collagen. A significant reduction of platelet aggregation response in plasma of depressed patients was detected as compared with controls. Serotonin-amplified platelet aggregation was assessed in a group of 76 depressed patients. No difference could be detected as compared with the normal controls, who were however significantly older (5 years) and had a significantly greater percentage of women (77). There was no correlation between symptom severity or anxiety scores and platelet aggregation values. There was no difference between patients with and without a comorbid diagnosis of borderline personality disorder. Musselman et al. (66) assessed platelet aggregation in platelet rich plasma after stimulation with collagen and ADP. An increased collagen-induced platelet aggregation was detected in depressed patients following orthostatic challenge. The same group (67) could not replicate this finding in a study in which depressed patients and controls underwent a larger amount of exercise (60 seconds stepping on and off a platform) as compared with the mild orthostatic challenge in the previous study. As already mentioned, it must be noted that both the control group and the depressed group were heterogeneous for confounding factors such as IHD risk factors and family history, which hampers interpretation of the data. In a study by Maes et al. (78), depressed patients did not exhibit increased platelet aggregation as measured in platelet rich plasma after stimulation with ADP and collagen. Lederbogen et al. (79) studied platelet aggregation in 22 depressed patients both before and after 5 weeks of open label amitriptyline or paroxetine as well as in 24 healthy control subjects. The aim of the study was to evaluate whether remission of psychopathology, not which type of antidepressant, would influence platelet aggregability. Platelet aggregation was assessed in washed and rediluted platelets after stimulation with collagen and thrombin. Higher thrombin-induced platelet aggregability was found in the depressed group, which persisted after improvement of depressive symptomatology after 5 weeks of treatment with amitriptyline or paroxetine. No data are available on any difference in amitriptyline versus the paroxetine group. In the aforementioned study of Serebruany et al. (73), decreased ADP and collagen-induced platelet aggregation were reported in patients on SSRIs. In a recent paper, whole blood aggregation in response to stimulation with serotonin and ADP was assessed in 15 depressed patients versus 15 matched controls (80). A significant increased platelet aggregation to serotonin but not ADP was found in the depressed group as compared with controls. A nonsignificant difference between depressed and control subjects in ADP-induced platelet aggregation was also reported measured by Walsh et al. (71).

In summary (Table 1), because of the great variability in procedures, it is not possible to pool results of platelet aggregation studies. In patients with a depressive disorder, measurement of increased platelet aggregation was detected after stimulation in vitro with serotonin and not ADP, a non 5-HT agonist, which suggests that in depressive subjects hypercoagulability might in part be associated with 5-HT receptors.

Platelet Signal Transduction and Responsivity to Receptor Stimulation
The aforementioned investigations evaluated aspects of platelet procoagulant status by measuring plasma levels of platelet release reaction products, by quantifying platelet surface protein expression, and by assessing platelet aggregatory response to stimulation with agonists. The mechanism behind the increased platelet procoagulant status has been investigated but not yet resolved. Platelet response to serotonin is mediated by the 5-HT2A receptor. Increase in the effectiveness of serotonin to activate 5-HT2A receptors could be explained by increased number of receptors on the platelet membrane, increased affinity of the receptor, or an increase in signal transduction somewhere beyond receptor stimulation. Serotonin operates by binding to the serotonin receptor, which belongs to the GPCRs. When the 5-HT receptor is activated, the coupled G protein is subsequently activated, which in turn stimulates the membrane effector protein protein phospholipase C. Phosphorylation (by protein phospholipase C) of phosphatidylinositol 4,5-biphosphate results in formation of the second messengers diacylglycerol and inositol 1,4,5-triphosphate. Inositol 1,4,5-triphosphate directly induces calcium release and diacylglycerol indirectly by stimulation of protein kinase C (Figure 1). Calcium mobilization is the common final pathway leading to platelet activation. Recent research suggests that depression is associated with dysregulation of the 5-HT-receptor signal-transduction mechanism (81, 82). Moreover, mood-stabilizing drugs appear to interact with neural signal transduction systems (82, 83). Post 5-HT2A receptor response can be studied by quantification of serotonin-induced calcium mobilization. Although some studies found no significant difference (50, 84), evidence for significantly augmented platelet calcium mobilization in response to serotonin in patients with major depression as compared with controls is abundant (44–46, 51, 85–90) . Increased platelet 5-HT2A receptor sensitivity was found in depressed patients without antidepressant medication (51, 85–90) as assessed by calcium response to serotonin stimulation. This increase as compared with healthy controls was also detected in some studies on depressive patients receiving antidepressive medication, mostly tricyclics (44, 45, 89). Only one study reported a significantly lower response to serotonin stimulation in the group of depressive patients on SSRIs as compared with patients not taking SSRI medication (46). The medication and dosages were, however, not specified. In only one study (46), a positive correlation was found between calcium response and symptom level.



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 1. Signal transduction of the 5-HT2A receptor. PIP2 = phosphatidylinositol 4,5-biphosphate; IP3 = inositol 1,4,5-triphosphate; DG = diacylglycerol.

 
Summarizing, patients with a depressive disorder show signs of a hyperactive platelet 5-HT2A receptor signal transduction system as measured by increased platelet calcium mobilization after stimulation of the platelet with serotonin. In the above-mentioned studies, patients treated with an antidepressant still appeared to have an increased 5-HT2A receptor response to stimulation with serotonin, although attenuated (46, 82, 84).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 DISCUSSION
REFERENCES
 
Several studies have been done assessing the state of platelet activation in depressed patients with or without concomitant cardiovascular disease. Depression was associated with increased platelet reactivity as assessed by increased plasma levels of PF4 and ßTG, and increased expression of procoagulant platelet surface receptors. Enhanced platelet activation was also found in patients with depression and IHD as compared with nondepressed patients with IHD. Preliminary data showed that sertraline and paroxetine influenced platelet activation by lowering PF4 and ßTG plasma levels and by decreasing pro-coagulant receptor expression on the platelet membrane surface. Mechanisms by which these SSRIs lower platelet hyperactivity are not clear.

Regarding platelet aggregation, studies are inconclusive. Methodological differences in measuring and inducing platelet aggregation may be at the basis of the described varying results. Studies that did use collagen or ADP as agonists found no difference in platelet aggregation between depressed patients and controls. One study assessed the aggregatory response of platelets to stimulation with serotonin in whole blood. In this study, a significant increase of platelet aggregation in depressed patients as compared with controls was found.

Up to now, evidence for the hypothesis that depression is associated with changes in central serotonergic function is still growing. A limited number of in vivo studies and several postmortem findings point toward central upregulation of the 5-HT2A receptor, decrease of the 5-HT transporter receptor, and decreased rate of 5-HT uptake in patients with depressive disorder (18, 19, 25). The data are conflicting as to whether the same changes are present in serotonin receptors in the periphery. There is considerable evidence that in depression, platelet 5-HT transporter binding sites are decreased (16, 37, 38) and some studies reported increased platelet 5-HT2A receptor binding (38–40), although studies using other ligands yielded different results (25).

Enhanced platelet activation at the site of coronary artery stenosis is a risk factor for an acute thromboembolic event such as a recurrent infarction (75) and on the long-term elevated platelet reactivity has been associated with a higher rate of cardiovascular events in a follow-up period of 5 years (91). At the site of vascular injury, one can postulate that upregulation or increased sensitivity of 5-HT2A/1B receptors and downregulated 5-HT transporter receptors could result in more serotonin reaching 5-HT2A/1B receptors on platelets and vascular endothelium and smooth muscle cells. Thus, increased platelet reactivity, together with the local effects of accumulation of serotonin at the atherosclerotic site (which results in decreased antithrombotic and antiadhesive endothelial function) may lead to increased thromboembolic events. Indeed, serotonin not only causes vasoconstriction and aggregation of platelets but also acts as a growth factor for smooth muscle cells and proliferation of endothelial cells and seems to induce endothelial injury itself (32–36, 42).

In the last decade, aspirin has proven to reduce thrombotic complications, but aspirin alone is not sufficient to inhibit platelet-induced thrombosis in the case of artery stenting (92). Indeed, in the above-mentioned studies, enhanced platelet reactivity remained in depressed patients with IHD as compared with nondepressed patients with IHD, despite the use of aspirin. This may imply that other mechanisms behind increased platelet reactivity in depressed MI patients are involved other than the pathway blocked by aspirin. 5-HT2A receptors are not influenced by routine antithrombotic medication. Based on the finding that in several studies a hyperactive platelet 5-HT2A receptor signal transduction was detected in depressed patients, a possible mechanism contributing to increased cardiac morbidity and mortality in depression may be increased platelet reactivity based on increased responsiveness of the platelet 5-HT2A receptor to serotonin in depressed patients. Next, a genetic factor cannot be excluded regarding upregulation or supersensitivity of platelet transporter receptors and platelet 5-HT2A receptors. This factor could act at the level of the megakaryocyte (in humans 35,000 platelets/µl/d are produced), as platelets are anuclear themselves. A recent study found an association between the genotype of the 5-HT transporter-linked promoter region (the recessive l allele is associated with the production of a greater number of serotonin transporters) and increased ßTG and PF4 levels of depressed elderly subjects (69), suggesting a genetic factor that may influence cardiovascular mortality in depressed patients. Regarding the 5-HT2A receptor, an association has been found between allele C of the 102T/C polymorphism in 5-HT2A receptor gene and major depressive disorder, but the significance is as yet unknown (93). More studies are needed to confirm changes in platelet activation and changes in the coagulation and fibrinolytic systems in depressed patients. Regarding data on platelet activation, studies have either small sample sizes or miss an adequate control group to draw conclusions. Assessment of platelet activation in a homogeneous group of depressed patients with coronary artery disease, both before and after treatment in a double blind, placebo-controlled design with an antidepressant with 5-HT2A receptor antagonistic properties, might shed more light on the above-mentioned hypothesis (94).

Received for publication November 19, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 REFERENCES
 

  1. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-months survival. JAMA 1993; 270: 1819–25.[Abstract/Free Full Text]
  2. Ladwig KH, Kieser M, Konig J, Breithardt G, Borggrefe M. Affective disorders and survival after acute myocardial infarction (results from the post-infarction late potential study). Eur Heart J 1991; 12: 959–64.
  3. Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, van Tilburg W. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry 2001; 58: 221–7.[Abstract/Free Full Text]
  4. Jiang W, Alexander J, Christopher E, Kuchibhatla M, Gaulden L, Cuffe M, Blazing M, Davenport C, Califf R, Krishnan R, O’Connor CM. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med 2001; 161: 1849–56.[Abstract/Free Full Text]
  5. Abramson J, Berger A, Krumholz HM, Vaccarino V. Depression and risk of heart failure among older persons with isolated systolic hypertension. Arch Intern Med 2001; 161: 1725–30.[Abstract/Free Full Text]
  6. Denollet J. Personality and mortality after myocardial infarction. Psychosom Med 1995; 57: 582–91.[Abstract/Free Full Text]
  7. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996; 93: 1976–80.[Abstract/Free Full Text]
  8. Bush DE, Ziegelstein RC, Tayback M, Richter D, Stevens S, Zahalsky H, Fauerbach JA. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001; 88: 337–41.[CrossRef][Medline]
  9. Ariyo AA, Haan M, Tangen CM, Rutledge JC, Cushman M, Dobs A, Furberg CD. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation 2000; 102: 1773–9.[Abstract/Free Full Text]
  10. Welin C, Lappas G, Wilhelmsen L. Independent importance of psychosocial factors for prognosis after myocardial infarction. J Intern Med 2000; 247: 629–39.[CrossRef][Medline]
  11. Irvine J, Basinski A, Baker B, Jandciu S, Paquette M, Cairns J, Connolly S, Roberts R, Gent M, Dorian P. Depression and risk of sudden cardiac death after acute myocardial infarction: testing for the confounding effects of fatigue. Psychosom Med 1999; 61: 729–37.[Abstract/Free Full Text]
  12. Mayou RA, Gill D, Thompson DR, Day A, Hicks N, Volmink J, Neil A. Depression and anxiety as predictors of outcome after myocardial infarction. Psychosom Med 2000; 62: 212–9.[Abstract/Free Full Text]
  13. Lane D, Carroll D, Ring C, Beevers DG, Lip GY. Effects of depression and anxiety on mortality and quality-of-life 4 months after myocardial infarction. J Psychosom Res 2000; 49: 229–38.[CrossRef][Medline]
  14. Denollet J, Vaes J, Brutsaert DL. Inadequate response to treatment in coronary heart disease: adverse effects of type D personality and younger age on 5-year prognosis and quality of life. Circulation 2000; 102: 630–5.[Abstract/Free Full Text]
  15. Maes M, Meltzer HY. The serotonin hypothesis of major depression. New York: Raven Press; 1995.
  16. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994; 40: 288–95.[Abstract/Free Full Text]
  17. Staley JK, Malison RT, Innis RB. Imaging of the serotonergic system: interactions of neuroanatomical and functional abnormalities of depression. Biol Psychiatry 1998; 44: 534–49.[CrossRef][Medline]
  18. Yates M, Leake A, Candy JM, Fairbairn AF, McKeith IG, Ferrier IN. 5HT2 receptor changes in major depression. Biol Psychiatry 1990; 27: 489–96.[CrossRef][Medline]
  19. Hrdina PD, Demeter E, Vu TB, Sotonyi P, Palkovits M. 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: increase in 5-HT2 sites in cortex and amygdala. Brain Res 1993; 614: 37–44.[CrossRef][Medline]
  20. Stanley M, Mann JJ. Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1983; 1: 214–6.[CrossRef][Medline]
  21. Mann JJ, Stanley M, McBride PA, McEwen BS. Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims. Arch Gen Psychiatry 1986; 43: 954–9.[Abstract/Free Full Text]
  22. Cheetham SC, Crompton MR, Katona CL, Horton RW. Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 1988; 443: 272–80.[CrossRef][Medline]
  23. Stockmeier CA, Dilley GE, Shapiro LA, Overholser JC, Thompson PA, Meltzer HY. Serotonin receptors in suicide victims with major depression. Neuropsychopharmacology 1997; 16: 162–73.[CrossRef][Medline]
  24. Lowther S, De Paermentier F, Crompton MR, Katona CL, Horton RW. Brain 5-HT2 receptors in suicide victims: violence of death, depression and effects of antidepressant treatment. Brain Res 1994; 642: 281–9.[CrossRef][Medline]
  25. Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS. Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 1998; 44: 1090–8.[CrossRef][Medline]
  26. Meyer JH, Kapur S, Houle S, DaSilva J, Owczarek B, Brown GM, Wilson AA, Kennedy SH. Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study. Am J Psychiatry 1999; 156: 1029–34.[Abstract/Free Full Text]
  27. Yatham LN, Liddle PF, Shiah IS, Scarrow G, Lam RW, Adam MJ, Zis AP, Ruth TJ. Brain serotonin2 receptors in major depression: a positron emission tomography study. Arch Gen Psychiatry 2000; 57: 850–8.[Abstract/Free Full Text]
  28. Attar-Levy D, Martinot JL, Blin J, Dao-Castellana MH, Crouzel C, Mazoyer B, Poirier MF, Bourdel MC, Aymard N, Syrota A, Feline A. The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol Psychiatry 1999; 45: 180–6.[CrossRef][Medline]
  29. Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J. Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 1997; 171: 444–8.[Abstract/Free Full Text]
  30. Mayberg HS, Robinson RG, Wong DF, Parikh R, Bolduc P, Starkstein SE, Price T, Dannals RF, Links JM, Wilson AA, Ravert HT, Wagner HN. PET imaging of cortical S2 serotonin receptors after stroke: lateralized changes and relationship to depression. Am J Psychiatry 1988; 145: 937–43.[Abstract/Free Full Text]
  31. D’Haenen H, Bossuyt A, Mertens J, Bossuyt-Piron C, Gijsemans M, Kaufman L. SPECT imaging of serotonin2 receptors in depression. Psychiatry Res 1992; 45: 227–37.[Medline]
  32. Ishida T, Hirata K, Sakoda T, Kawashima S, Akita H, Yokoyama M. Identification of mRNA for 5-HT1 and 5-HT2 receptor subtypes in human coronary arteries. Cardiovasc Res 1999; 41: 267–74.[Abstract/Free Full Text]
  33. Pakala R, Willerson JT, Benedict CR. Mitogenic effect of serotonin on vascular endothelial cells. Circulation 1994; 90: 1919–26.[Abstract/Free Full Text]
  34. Willerson JT, Yao SK, McNatt J, Benedict CR, Anderson HV, Golino P, Murphree SS, Buja LM. Frequency and severity of cyclic flow alternations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury. Proc Natl Acad Sci USA 1991; 88: 10624–8.[Abstract/Free Full Text]
  35. Miyata K, Shimokawa H, Higo T, Yamawaki T, Katsumata N, Kandabashi T, Tanaka E, Takamura Y, Yogo K, Egashira K, Takeshita A. Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model. J Cardiovasc Pharmacol 2000; 35: 294–301.[CrossRef][Medline]
  36. Nilsson T, Longmore J, Shaw D, Pantev E, Bard JA, Branchek T, Edvinsson L. Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol 1999; 372: 49–56.[CrossRef][Medline]
  37. Rosel P, Menchon JM, Vallejo J, Arranz B, Navarro MA, Liron F, Alvarez P. Platelet [3H]imipramine and [3H]paroxetine binding in depressed patients. J Affect Disord 1997; 44: 79–85.[CrossRef][Medline]
  38. Rosel P, Arranz B, Vallejo J, Alvarez P, Menchon JM, Palencia T, Navarro MA. Altered [3H]imipramine and 5-HT2 but not [3H]paroxetine binding sites in platelets from depressed patients. J Affect Disord 1999; 52: 225–33.[CrossRef][Medline]
  39. Pandey GN, Pandey SC, Janicak PG, Marks RC, Davis JM. Platelet serotonin-2 receptor binding sites in depression and suicide. Biol Psychiatry 1990; 28: 215–22.[CrossRef][Medline]
  40. Pandey GN, Pandey SC, Dwivedi Y, Sharma RP, Janicak PG, Davis JM. Platelet serotonin-2A receptors: a potential biological marker for suicidal behavior. Am J Psychiatry 1995; 152: 850–5.[Abstract/Free Full Text]
  41. Willerson JT. Serotonin and thrombotic complications. J Cardiovasc Pharmacol 1991; 17 (suppl): 13–20.[Medline]
  42. Vikenes K, Farstad M, Nordrehaug JE. Serotonin is associated with coronary artery disease and cardiac events. Circulation 1999; 100: 483–9.[Abstract/Free Full Text]
  43. Schini-Kerth VB, Fisslthaler B, Van Obberghen-Schilling E, Busse R. Serotonin stimulates the expression of thrombin receptors in cultured vascular smooth muscle cells: role of protein kinase C and protein tyrosine kinases. Circulation 1996; 93: 2170–7.[Abstract/Free Full Text]
  44. Eckert A, Gann H, Riemann D, Aldenhoff J, Muller WE. Elevated intracellular calcium levels after 5-HT2 receptor stimulation in platelets of depressed patients. Biol Psychiatry 1993; 34: 565–8.[CrossRef][Medline]
  45. Konopka LM, Cooper R, Crayton JW. Serotonin-induced increases in platelet cytosolic calcium concentration in depressed, schizophrenic, and substance abuse patients. Biol Psychiatry 1996; 39: 708–13.[CrossRef][Medline]
  46. Delisi SM, Konopka LM, O’Connor FL, Crayton JW. Platelet cytosolic calcium responses to serotonin in depressed patients and controls: relationship to symptomatology and medication. Biol Psychiatry 1998; 43: 327–34.[CrossRef][Medline]
  47. Mendelson SD. The current status of the platelet 5-HT(2A) receptor in depression. J Affect Disord 2000; 57: 13–24.[CrossRef][Medline]
  48. von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63: 531–44.[Abstract/Free Full Text]
  49. Gurney D, Lip GY, Blann AD. A reliable plasma marker of platelet activation: does it exist? Am J Hematol 2002; 70: 139–44.[CrossRef][Medline]
  50. Suzuki K, Kusumi I, Sasaki Y, Koyama T. Serotonin-induced platelet intracellular calcium mobilization in various psychiatric disorders: is it specific to bipolar disorder? J Affect Disord 2001; 64: 291–6.[CrossRef][Medline]
  51. Kusumi I, Koyama T, Yamashita I. Serotonin-induced platelet intracellular calcium mobilization in depressed patients. Psychopharmacology (Berl) 1994; 113: 322–7.[CrossRef][Medline]
  52. Bithell TC. The physiology of primary hemostasis. In: M.Wintrobe, editor. Wintrobe’s Clinical Hematology, Vol. 1. London: Lea & Febiger; 1993. p. 540–55.
  53. Gawaz M, Neumann FJ, Schomig A. Evaluation of platelet membrane glycoproteins in coronary artery disease: consequences for diagnosis and therapy. Circulation 1999; 99: E1–E11.
  54. Andre P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 2002; 106: 896–9.[Free Full Text]
  55. Vanags DM, Rodgers SE, Duncan EM, Lloyd JV, Bochner F. Potentiation of ADP-induced aggregation in human platelet-rich plasma by 5-hydroxytryptamine and adrenaline. Br J Pharmacol 1992; 106: 917–23.[Medline]
  56. Vanags DM, Lloyd JV, Rodgers SE, Bochner F. ADP, adrenaline and serotonin stimulate inositol 1,4,5-trisphosphate production in human platelets. Eur J Pharmacol 1998; 358: 93–100.[CrossRef][Medline]
  57. Dale GL, Friese P, Batar P, Hamilton SF, Reed GL, Jackson KW, Clemetson KJ, Alberio L. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature 2002; 415: 175–9.[CrossRef][Medline]
  58. Vanhoutte PM. Platelet-derived serotonin, the endothelium and cardiovascular disease. J Cardiovasc Pharmacol 1991; 17 (suppl 5): 6–12.
  59. Markovitz JH, Matthews KA. Platelets and coronary heart disease: potential psychophysiologic mechanisms. Psychosom Med 1991; 53: 643–68.[Abstract/Free Full Text]
  60. Malkoff SB, Muldoon MF, Zeigler ZR, Manuck SB. Blood platelet responsivity to acute mental stress. Psychosom Med 1993; 55: 477–82.[Abstract/Free Full Text]
  61. Markovitz JH, Matthews KA, Kiss J, Smitherman TC. Effects of hostility on platelet reactivity to psychological stress in coronary heart disease patients and in healthy controls. Psychosom Med 1996; 58: 143–9.[Abstract/Free Full Text]
  62. Markovitz JH. Hostility is associated with increased platelet activation in coronary heart disease. Psychosom Med 1998; 60: 586–91.[Abstract/Free Full Text]
  63. Laghrissi-Thode F, Wagner WR, Pollock BG, Johnson PC, Finkel MS. Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 1997; 42: 290–5.[CrossRef][Medline]
  64. Pollock BG, Laghrissi-Thode F, Wagner WR. Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol 2000; 20: 137–40.[CrossRef][Medline]
  65. Kuijpers PMJC, Hamulyak K, Strik JMH, Wellens HJJ, Honig A. Beta-thromboglobulin and platelet factor 4 levels in post myocardial infarction patients with major depression. Psychiatry Res 2002; 109: 207–10.[CrossRef][Medline]
  66. Musselman DL, Tomer A, Manatunga AK, Knight BT, Porter MR, Kasey S, Marzec U, Harker LA, Nemeroff CB. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996; 153: 1313–7.[Abstract/Free Full Text]
  67. Musselman DL, Marzec UM, Manatunga A, Penna S, Reemsnyder A, Knight BT, Baron A, Hanson SR, Nemeroff CB. Platelet reactivity in depressed patients treated with paroxetine: preliminary findings. Arch Gen Psychiatry 2000; 57: 875–82.[Abstract/Free Full Text]
  68. Markovitz JH, Shuster JL, Chitwood WS, May RS, Tolbert LC. Platelet activation in depression and effects of sertraline treatment: an open-label study. Am J Psychiatry 2000; 157: 1006–8.[Abstract/Free Full Text]
  69. Whyte EM, Pollock BG, Wagner WR, Mulsant BH, Ferrell RE, Mazumdar S, Reynolds CF 3rd. Influence of serotonin-transporter-linked promoter region polymorphism on platelet activation in geriatric depression. Am J Psychiatry 2001; 158: 2074–6.[Abstract/Free Full Text]
  70. Piletz JE, Zhu H, Madakasira S, Pazzaglia P, Lindsay DeVane C, Goldman N, Halaris A. Elevated P-selectin on platelets in depression: response to bupropion. J Psychiatr Res 2000; 34: 397–404.[CrossRef][Medline]
  71. Walsh MT, Dinan TG, Condren RM, Ryan M, Kenny D. Depression is associated with an increase in the expression of the platelet adhesion receptor glycoprotein Ib. Life Sci 2002; 70: 3155–65.[CrossRef][Medline]
  72. Musselman DL, Marzec U, Davidoff M, Manatunga AK, Gao F, Reemsnyder A, Duggirala S, Larsen H, Taylor RW, Hanson S, Nemeroff CB. Platelet activation and secretion in patients with major depression, thoracic aortic atherosclerosis, or renal dialysis treatment. Depress Anxiety 2002; 15: 91–101.[CrossRef][Medline]
  73. Serebruany VL, O’Connor CM, Gurbel PA. Effect of selective serotonin reuptake inhibitors on platelets in patients with coronary artery disease. Am J Cardiol 2001; 87: 1398–400.[CrossRef][Medline]
  74. Gray JA, Roth BL. Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists. Brain Res Bull 2001; 56: 441–51.[CrossRef][Medline]
  75. Willerson JT, Eidt JF, McNatt J, Yao SK, Golino P, Anderson HV, Buja LM. Role of thromboxane and serotonin as mediators in the development of spontaneous alterations in coronary blood flow and neointimal proliferation in canine models with chronic coronary artery stenoses and endothelial injury. J Am Coll Cardiol 1991; 17: B101–10.
  76. Nugent DF, Dinan TG, Leonard BE. Further characterization of the inhibition of platelet aggregation by a plasma factor(s) in unmedicated unipolar depressed patients. J Affect Disord 1995; 33: 227–31.[CrossRef][Medline]
  77. McBride PA, Brown RP, DeMeo M, Keilp J, Mieczkowski T, Mann JJ. The relationship of platelet 5-HT2 receptor indices to major depressive disorder, personality traits, and suicidal behavior. Biol Psychiatry 1994; 35: 295–308.[CrossRef][Medline]
  78. Maes M, Van der Planken M, Van Gastel A, Desnyder R. Blood coagulation and platelet aggregation in major depression. J Affect Disord 1996; 40: 35–40.[CrossRef][Medline]
  79. Lederbogen F, Gilles M, Maras A, Hamann B, Colla M, Heuser I, Deuschle M. Increased platelet aggregability in major depression? Psychiatry Res 2001; 102: 255–61.[CrossRef][Medline]
  80. Shimbo D, Child J, Davidson K, Geer E, Osende JI, Reddy S, Dronge A, Fuster V, Badimon JJ. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am J Cardiol 2002; 89: 331–3.[CrossRef][Medline]
  81. Karege F, Bovier P, Rudolph W, Gaillard JM. Platelet phosphoinositide signaling system: an overstimulated pathway in depression. Biol Psychiatry 1996; 39: 697–702.[CrossRef][Medline]
  82. Rehavi M, Jerushalemi Z, Aviv A, Laor N, Podliszewski E, Karp L, Shavit S, Weizman R. Interaction between antidepressants and phosphoinositide signal transduction system in human platelets. Biol Psychiatry 1993; 33: 40–4.[CrossRef][Medline]
  83. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial [see comments]. Arch Gen Psychiatry 1999; 56: 407–12.[Abstract/Free Full Text]
  84. Bothwell RA, Eccleston D, Marshall E. Platelet intracellular calcium in patients with recurrent affective disorders. Psychopharmacology (Berl) 1994; 114: 375–81.[CrossRef][Medline]
  85. Kusumi I, Koyama T, Yamashita I. Serotonin-stimulated Ca2+ response is increased in the blood platelets of depressed patients. Biol Psychiatry 1991; 30: 310–2.[CrossRef][Medline]
  86. Mikuni M, Kagaya A, Takahashi K, Meltzer HY. Serotonin but not norepinephrine-induced calcium mobilization of platelets is enhanced in affective disorders. Psychopharmacology 1992; 106: 311–4.[CrossRef][Medline]
  87. Delisi JS, Konopka LM, Russell K, O’Connor FL, Cooper R, Crayton JW. Platelet cytosolic calcium hyperresponsivity to serotonin in patients with hypertension and depressive symptoms. Biol Psychiatry 1999; 45: 1035–41.[CrossRef][Medline]
  88. Dwivedi Y, Janicak PG, Pandey GN. Elevated [3H]inositol 1,4,5-trisphosphate binding sites and expressed inositol 1,4,5-trisphosphate receptor protein level in platelets of depressed patients. Psychopharmacology (Berl) 1998; 138: 47–54.[CrossRef][Medline]
  89. Tomiyoshi R, Kamei K, Muraoka S, Muneoka K, Takigawa M. Serotonin-induced platelet intracellular Ca2+ responses in untreated depressed patients and imipramine responders in remission. Biol Psychiatry 1999; 45: 1042–8.[CrossRef][Medline]
  90. Plein H, Berk M, Eppel S, Butkow N. Augmented platelet calcium uptake in response to serotonin stimulation in patients with major depression measured using Mn2+ influx and 45Ca2+ uptake. Life Sci 2000; 66: 425–31.[CrossRef][Medline]
  91. Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549–54.[Abstract]
  92. Amoroso G, van Veldhuisen DJ, Tio RA, Mariani M. Pathophysiology of vascular endothelium and circulating platelets: implications for coronary revascularisation and treatment. Int J Cardiol 2001; 79: 265–75.[CrossRef][Medline]
  93. Du L, Bakish D, Lapierre YD, Ravindran AV, Hrdina PD. Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder. Am J Med Genet 2000; 96: 56–60.[CrossRef][Medline]
  94. van den Brink RHS, van Melle J, Honig A, Schene AH, Crijns HJGM, Lambert FPG, Ormel J. Treatment of depression after myocardial infarction and the effects on cardiac prognosis and quality of life: Rationale and outline of the Myocardial INfarction and Depression-Intervention Trial (MIND-IT). Am Heart J 2002; 144: 219–25.[Medline]



This article has been cited by other articles:


Home page
 Eur Heart JHome page
M. U. Zafar, M. Paz-Yepes, D. Shimbo, G. Vilahur, M. M. Burg, W. Chaplin, V. Fuster, K. W. Davidson, and J. J. Badimon
Anxiety is a better predictor of platelet reactivity in coronary artery disease patients than depression
Eur. Heart J., January 22, 2010; (2010): ehp602v1 - ehp602.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. W. Adams, J. Ramirez, Y. Shi, W. Thomsen, J. Frazer, M. Morgan, J. E. Edwards, W. Chen, B. R. Teegarden, Y. Xiong, et al.
APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology
J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 96 - 103.
[Abstract] [Full Text] [PDF]

Home page
 Mayo Clin Proc.Home page
R. C. Ziegelstein, K. Parakh, A. Sakhuja, and U. Bhat
Depression and Coronary Artery Disease: Is There a Platelet Link?
Mayo Clin. Proc., November 1, 2007; 82(11): 1366 - 1368.
[Full Text] [PDF]

Home page
 Psychosom. Med.Home page
M. S. Roy, A. Roy, and M. Affouf
Depression is a Risk Factor for Poor Glycemic Control and Retinopathy in African-Americans With Type 1 Diabetes
Psychosom Med, July 1, 2007; 69(6): 537 - 542.
[Abstract] [Full Text] [PDF]

Home page
 AMERICAN JOURNAL OF LIFESTYLE MEDICINEHome page
R. F. Zoeller JR
Physical Activity: Depression, Anxiety, Physical Activity, and Cardiovascular Disease: What's the Connection?
American Journal of Lifestyle Medicine, May 1, 2007; 1(3): 175 - 180.
[Abstract] [PDF]

Home page
 Psychosom. Med.Home page
T. Rutledge, S. E. Reis, M. Olson, J. Owens, S. F. Kelsey, C. J. Pepine, S. Mankad, W. J. Rogers, G. Sopko, C. E. Cornell, et al.
Depression is associated with cardiac symptoms, mortality risk, and hospitalization among women with suspected coronary disease: the NHLBI-sponsored WISE study.
Psychosom Med, March 1, 2006; 68(2): 217 - 223.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
D. S. Sheps and A. Rozanski
From Feeling Blue to Clinical Depression: Exploring the Pathogenicity of Depressive Symptoms and Their Management in Cardiac Practice
Psychosom Med, May 1, 2005; 67(Supplement_1): S2 - S5.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. Rozanski, J. A. Blumenthal, K. W. Davidson, P. G. Saab, and L. Kubzansky
The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: The emerging field of behavioral cardiology
J. Am. Coll. Cardiol., March 1, 2005; 45(5): 637 - 651.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schins, A.
Right arrow Articles by Hamulyák, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schins, A.
Right arrow Articles by Hamulyák, K.
Related Collections
Right arrow Genetics
Right arrow Depression
Right arrow Psychophysiology
Right arrow Coronary Artery Disease
Right arrow Other Cardiovascular Medicine

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS