The adverse effects of depression on cardiovascular disease also may be mediated by platelet mechanisms. Markovitz and Matthews first proposed that enhanced platelet responses to psychologic stress may trigger adverse coronary artery ischemic events. This association between platelet activation and vascular disease is supported indirectly by studies linking cerebrovascular disease and depression. The Established Populations for Epidemiologic Studies of the Elderly prospectively studied 10,294 persons age 65 and older for 6 years and determined that rates of stroke (adjusted for age, physical disability, and other medical disorders) were 2.3 to 2.7 times higher in persons designated with “high” versus “low” levels of depressive symptoms. In another prospective study, 103 consecutive stroke patients were assessed for major depression or dysthymia approximately 2 weeks after a stroke. Patients with major depression or dysthymia were 3.4 times more likely to have died during the 10-year follow-up period than were nondepressed patients (p= .007), even after controlling for confounding variables (age, medical comorbidity, type of stroke, and lesion location; p= .03).
Platelets play a central role in hemostasis, thrombosis, the development of atherosclerosis, and acute coronary syndromes through their interactions with both subendothelial components of damaged vessel walls and plasma coagulation factors, primarily thrombin. Human platelets contain adrenergic, serotonergic, and dopaminergic receptors. Through activation of platelet alpha2 adrenoceptors, increases in circulating catecholamines (>4 nmol/L) potentiate the effects of other agonists and, at higher concentrations, initiate platelet thrombotic responses, including secretion, aggregation, and activation of the arachidonate pathway. After injury to vessel endothelium, platelets and circulating leukocytes attach to the newly exposed subendothelial layer.
Platelet adhesion to exposed collagen (and other components of the subendothelial matrix) and to thrombin stimulates platelet activation. Activation converts platelet membrane GPIIb/IIIa complexes into functional receptors for fibrinogen. Activation also is accompanied by extrusion or secretion of platelet storage granule contents into the extracellular environment. Platelets activated at the site of an injury to the vessel wall accelerate the local formation of thrombin and release a variety of products from their storage granules, including chemotactic and mitogenic factors, inducing leukocyte migration from the bloodstream and vascular cell proliferation. These secreted platelet products [e.g., platelet factor 4, β-thromboglobulin (β-TG), and 5-HT] stimulate and recruit other platelets and cause irreversible platelet–platelet aggregation, ultimately leading to the formation of a fused platelet thrombus. Platelets also contribute to vascular damage by stimulating lipoprotein uptake by macrophages and mediating vasoconstriction through the production and/or release of substances such as thromboxane A2, platelet-activating factor, and 5-HT. Clinical trials have confirmed the importance of platelets in vascular damage; antiaggregating medications are useful in secondary prevention, delay the progression of atherosclerotic lesions, and improve post-MI outcomes.
The authors sought to determine whether heightened susceptibility to platelet activation might be a mechanism by which depression in physically healthy young volunteers acts as a significant risk factor for cardiovascular and cerebrovascular disease and/or increased mortality after MI. Utilizing fluorescence-activated flow cytometric analysis, we discovered that in comparison to normal controls, relatively, young, medically healthy, depressed patients without any other risk factors for CAD exhibited enhanced baseline platelet activation as well as increased platelet responsiveness. Moreover, in another study, in comparison to normal controls, depressed patients with one or more traditional risk factors for CAD exhibited, under basal conditions, increased circulating platelets that had proceeded to irreversible degranulation.
Indeed patients suffering from comorbid CVD and major depression also exhibit increased platelet activation as measured by markedly elevated plasma concentrations of the platelet secretion products PF4 and β-TG compared with nondepressed, age-matched patients with CVD.114 Interestingly, increased platelet activation has also been documented in CVD patients with the negative emotion, hostility, in comparison to healthy controls. Although the mechanism or mechanisms responsible remain unknown, heightened susceptibility to platelet activation and secretion may contribute, at least in part, to the increased vulnerability of depressed patients to CVD and/or mortality after an MI.
Serotonin secreted by platelets induces both platelet aggregation and coronary vasoconstriction, both of which are mediated by 5-HT2 receptors. Vasoconstriction occurs especially when normal endothelial cell counterregulatory mechanisms of vascular relaxation are defective, as often occurs in patients with CAD. Indeed, essential hypertension, elevated plasma cholesterol levels, older age, and smoking, which are well-known predisposing factors for the development of CVD, all contribute to 5-HT-mediated platelet activation. Moreover, alterations in platelet 5-HT-mediated activation also have been described in affective disorders, most notably major depression. Considerable evidence has accrued in the last two decades that supports the hypothesis that alterations in CNS and platelet serotonergic function occur in depressed patients.
Serotonin-mediated platelet activation can contribute to the development of atherosclerosis, thrombosis, and vasoconstriction. Even though 5-HT is a weak platelet agonist, it markedly amplifies platelet reactions to a variety of other agonists such as adenosine diphosphate (ADP), thromboxane A2, catecholamines, and thrombin. Through an action on 5-HT2 receptors, serotonin enhances platelet aggregation and the release of intragranular products and arachidonic acid metabolites in response to otherwise ineffective agonist concentrations. This 5-HT-induced platelet amplification occurs at the low concentrations attained when 5-HT is released from seeping platelets subjected to shear stresses and from platelet activation by contact with an arterial wall lesion. Interestingly, several investigators have reported increases in platelet 5-HT2 binding density in depressed patients. Moreover, the changes appear to be state-dependent in that 5-HT2-binding-site density returned to control values only in patients who showed clinical improvement. Depressed patients have been found to exhibit significant reductions in the number of platelet and brain 5-HT transporter sites as detected by [3H] imipramine binding as well as by the more selective ligand [3H] paroxetine. The increased 5-HT2-receptor-binding density and decreased 5-HT-transporter sites suggest that depressed patients may be particularly susceptible to 5-HT-mediated platelet activation and coronary artery vasoconstriction. Decreased numbers of platelet 5-HT transporters would potentially hinder the uptake and storage of periplatelet serotonin, exposing the increased numbers of 5-HT2 receptors to 5-HT.
Platelets from depressed patients also exhibit significantly increased elevations of intracellular free calcium concentration, [Ca2+]i, after 5-HT-induced stimulation in comparison to controls. Even functionally trivial increases in intraplatelet calcium “prime” the platelet secretion and aggregation response to stimulation by even a “weak” agonist such as 5-HT or in response to increased blood flow. Thus, platelets with elevated [Ca2+]i, as are observed in depressed patients, probably would exhibit increased activation in comparison with normal comparison subjects under basal conditions or in response to shear-induced aggregation (e.g., after an orthostatic challenge). More recently, antidepressants that inhibit the reuptake of serotonin into neurons (and platelets) have been shown to normalize the abnormally heightened platelet activation and secretion observed in patients with depression, without and with CVD.
Depression and Comorbid Medical Illness
Depression and Cardiovascular Disease: Clinical Samples
Anxiety Disorders and Cardiovascular Disease
Diminished Heart Rate Variability
Hypothalamic - Pituitary - Adrenocortical and Sympathomedullary Hyperactivity
Increased Secretion of Proinflammatory Cytokines
Pathophysiology of Anxiety
Treatment of Major Depression and Anxiety Disorders in Patients with Cardiovascular Disease
Effects of Mood and Anxiety Disorders: Future Directions for Research
Revision date: June 20, 2011
Last revised: by Dave R. Roger, M.D.