CHD is the leading cause of morbidity and mortality of women in the US, exceeding that of all cancers combined. The extent of coronary artery atherosclerosis (CAA) at menopause is an important determinant of postmenopausal CHD risk. A major challenge is to identify premenopausal attributes which influence CAA extent at the menopause. This application is focused on determining the relative contribution of depression to premenopausal CAA, and whether it is a source of """"""""reversible"""""""" risk. Although the appearance of CHD is predated by depression, suggesting that depression may be an independent risk factor for CHD, CAA develops for decades before the appearance of CHD symptoms, and the temporal relationship between depression and CAA is unclear. One common underlying mechanism implicated in both the pathology of depression and CHD is the serotonergic system. Importantly, there is initial evidence that selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, have beneficial effects on processes that promotes atherogenesis (platelet activation, inflammation, low heart rate variability). Using premenopausal cynomolgus monkeys (Macaca fascicularis), an established model for the study of both coronary artery atherogenesis and depressive behavior, we propose to determine for the first time the temporal relationship between depression and subclinical CAA progression. Furthermore, we will examine the cardiovascular and behavioral effects of manipulating neural serotonergic function with SSRI's. Monkeys will be fed an atherogenic diet and depressive behavior recorded during an 18-month pretreatment period. Atherosclerosis extent will be determined by iliac biopsy. The monkeys then will be treated with an SSRI or placebo, balanced on pretreatment depressive behavior, and atherosclerosis progression will be assessed after 18 months.
The specific aims are to determine: the magnitude of the relationship between depressive behavior and atherosclerosis; whether atherosclerosis progression is slowed by treatment targeting the neural serotonin system, or by reductions in depressive behavior, or both; pathophysiologic characteristics (e.g. platelet activation, inflammatory processes, heart rate variability, ovarian dysfunction, plasma lipids) associated with both early atherogenesis and depressive behavior; and the effects of treatment on these characteristics. The results will be relevant to public health as they will determine the relative importance of premenopausal depression to later risk for CHD and whether that risk is reversible, shape the timing and aggressiveness of antidepressant therapy, and provide evidence supporting the need for a prospective clinical trial powered to detect changes in cardiovascular outcomes with SSRI treatment. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL087103-01A1
Application #
7317031
Study Section
Special Emphasis Panel (ZRG1-MESH-L (02))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$683,779
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Maldjian, Joseph A; Shively, Carol A; Nader, Michael A et al. (2016) Multi-Atlas Library for Eliminating Normalization Failures in Non-Human Primates. Neuroinformatics 14:183-90
Shively, Carol A; Register, Thomas C; Appt, Susan E et al. (2015) Effects of long-term sertraline treatment and depression on coronary artery atherosclerosis in premenopausal female primates. Psychosom Med 77:267-78
Willard, Stephanie L; Uberseder, Beth; Clark, Ashlee et al. (2015) Long term sertraline effects on neural structures in depressed and nondepressed adult female nonhuman primates. Neuropharmacology 99:369-78
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Groban, Leanne; Kitzman, Dalane W; Register, Thomas C et al. (2014) Effect of depression and sertraline treatment on cardiac function in female nonhuman primates. Psychosom Med 76:137-46
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Willard, Stephanie L; Hemby, Scott E; Register, Thomas C et al. (2014) Altered expression of glial and synaptic markers in the anterior hippocampus of behaviorally depressed female monkeys. Neurosci Lett 563:1-5
Silverstein, Marnie G; Kaplan, Jay R; Appt, Susan E et al. (2014) Effect of soy isoflavones on thyroid hormones in intact and ovariectomized cynomolgus monkeys (Macaca fascicularis). Menopause 21:1136-42
Shively, Carol A; Register, Thomas C; Higley, J Dee et al. (2014) Sertraline effects on cerebrospinal fluid monoamines and species-typical socioemotional behavior of female cynomolgus monkeys. Psychopharmacology (Berl) 231:1409-16

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