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Abstract & Commentary
Synopsis: This study provides direct evidence for enhanced in vivo platelet reactivity and platelet product release (e.g., PF-4 and B-TG) in depressed patients with ischemic heart disease.
Source: Laghrissi-Thode F, et al. Biol Psychiatry 1997; 42:290-295.
Clinical depression has recently been recognized as an independent risk factor for cardiac mortality in patients 6, 12, and 18 months after myocardial infarction (MI).1-2 This remains true even after controlling for other post-MI risk factors, such as left ventricular dysfunction, complex arrhythmias, and history of prior MI.3
The underlying mechanism(s) of this increased mortality in depressed patients post-MI have not fully elucidated. This study investigated the hypothesis that patients suffering from ischemic heart disease (IHD) and depression concurrently may have abnormal platelet activation resulting in an increased risk of thrombosis. Platelets activated at the interface with a vessel wall injury accelerate the local formation of thrombin and release a variety of endogenous products from their storage granules, including platelet factor 4 (PF-4), B-thromboglobulin (B-TG), and serotonin. PF-4, a protein synthesized by megakaryocytes, was originally recognized by its ability to neutralize the anticoagulant activity of heparin.
Interestingly, platelets have been proposed as a model for central nervous system presynaptic nerve terminals, including serotonin terminals. Serotonin is a weak agonist of platelet aggregation compared to thrombin, but markedly amplifies platelet reactions to other agonists (adenosine 5’-diphosphate, thromboxane A2, catecholamines, or thrombin).
In the current study, Laghrissi-Thode and colleagues evaluated three groups: healthy controls (n = 17), nondepressed patients with IHD (n = 8), and depressed patients with IHD (n = 21). Criteria for ischemic heart disease were defined by any of the following in the three months prior to the study: 1) MI; 2) coronary artery bypass graft; 3) angioplasty; or 4) angiographic evidence of luminal narrowing of a major coronary artery or one of its primary branches. Severity of IHD was assessed by the results of coronary angiography; cardiac function was assessed by the left ventricular ejection fraction. The Structured Clinical Interview for DSM-III-R was used to diagnose depression and exclude other diagnoses, and the Hamilton Depression Rating Scale was used to rate the severity of depression. PF-4 and B-TG were markedly elevated in the patients with both depression and IHD compared to the other groups. No association was found between measures of platelet activation and angiographic results, left ventricular ejection fraction, age, sex, or race.
Comment by Donald M. Hilty, MD
Further research is needed to investigate if alterations of the serotonin (5-HT) system in depressed patients with IHD contribute to PF-4 and B-TG elevations and if this phenomenon is reversed by successful treatment of depression. Unpublished data from the same author indicate that a selective serotonin reuptake inhibitor, paroxetine (Paxil), lowered similarly elevated levels of PF-4 and B-TG from four to eight times to approximately two times the level of controls and patients with IHD; interestingly, a tricyclic antidepressant, nortriptyline (Pamelor), did not lower the levels at all.
Depressed patients without IHD also appear to have abnormal platelet reactivity.4 Depressed patients (n = 12), compared to healthy controls (n = 8), exhibited increased platelet activation at baseline and following orthostatic challenge, using monoclonal antibodies sensitive to detecting phase-specific stages of platelet activation.
Unquestionably, the evidence to date necessitates the screening for depression in patients with cardiovascular disease and implementing treatment if there is evidence of depression. To date, no single antidepressant or class of antidepressants has documented superiority in terms of efficacy in patients with cardiac disease. (Dr. Hilty is Assistant Professor of Clinical Psychiatry, University of California, Davis, Sacramento, CA.)
1. Frasure-Smith N, et al. JAMA 1993;270:1819-1825.
2. Frasure-Smith N, et al. Circulation 1995;91:999-1005.
3. Ladwig KH, et al. Eur Heart J 1991;12:959-964.
4. Musselman DL, et al. Am J Psychiatry 1996;153: 1313-1317.
a. increased platelet reactivity.
b. decreased platelet reactivity.