Major depression is a significant independent risk factor for the development of ischemic heart disease and is a potentially lethal comorbid condition in post-myocardial infarction patients. The pathophysiology that links major depression to the occurrence of heart disease is not known. Preliminary observations indicate that platelet reactivity is increased in depression, which implies that depressed patients may be prone to thrombus formation, hence at increased risk for catastrophic cardiac events. There are considerable data indicating that the serotonergic system is altered in depression, both in the central nervous system (CNS) and in the platelets. In the periphery, the most notable and consistently replicated observation of serotonergic alteration is an increased B max for the serotonin-2A (5-HT2A) receptor on the platelets of depressed individuals. The platelet 5-HT2A receptor plays a central role in platelet reactivity and thrombus formation, and may be involved in regulating the expression of platelet specific genes in megakaryocytes, the cells from which platelets are derived. While not tested directly, the overarching hypothesis for this proposal is that major depression adversely increases platelet reactivity, which leads to increased risk of developing heart disease. The principal hypotheses that will be tested are that: 1) Platelets from depressed patients are produced in a """"""""upregulated"""""""" state, with increased amounts of a number of transcripts that encode platelet specific genes, the result being the platelets are more reactive and prone to thrombus formation. 2) The platelet serotonergic system, in particular the 5-HT2A receptor, is altered in depression which in turn contributes to the increased platelet reactivity observed in depression, and the relevant alteration may occur in the megakaryocytes. 3) Alterations in the concentration of one or more humoral factors (interleukins, cytokines, stress hormones) orchestrate the alterations in platelet reactivity and serotonergic functioning observed in depression. Patients suffering from major depression will be recruited and their condition treated. Their platelets will be sampled before and after treatment and the amounts of transcripts that encode platelet reactivity molecules will be measured. The circulating concentration of three hormones, cortisol, interleukin-1 and interleukin-6 will be measured before and after treatment, and correlated to platelet reactivity.
