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Psychosomatic Medicine 64:699-706 (2002)
© 2002 American Psychosomatic Society

ORIGINAL ARTICLES

Depression and Coronary Artery Atherosclerosis and Reactivity in Female Cynomolgus Monkeys

Carol A. Shively, PhD, J. Koudy Williams, DVM, Kathy Laber-Laird, DVM and Raymond F. Anton, PhD

From Wake Forest University School of Medicine (C.A.S., J.K.W.), Winston–Salem, NC; and Medical University of South Carolina (K.L.-L., R.F.A.), Charleston, SC.

Address reprint requests to: Carol A. Shively, Department of Pathology (Comparative Medicine), Wake Forest University School of Medicine, Medical Center Boulevard, Winston–Salem, NC 27157-1040. Email cshively{at}wfubmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Depression and coronary heart disease (CHD) are comorbid conditions, and it is thought that depression may increase the risk of CHD. However, the evidence for the latter relationship is sparse and difficult to collect. Cynomolgus monkeys (Macaca fascicularis) have been used effectively as animal models of CHD risk and depression. Here we report the results of a comparison of physiological characteristics, coronary artery reactivity, and atherosclerosis in 16 depressed and 26 nondepressed female cynomolgus monkeys.

METHODS: Forty-two females were housed in single cages for 3 months and in their final social groups for 26 months, during which time they consumed an atherogenic diet.

RESULTS: During the 26-month social grouping period, 16 of the females displayed behavioral depression, defined as a slumped or collapsed body posture accompanied by a relative lack of responsiveness to environmental stimuli. These depressed monkeys had higher heart rates throughout the study, even during the single-caging period, suggesting a priori differences in the autonomic function of females that displayed behavioral depression relative to those that did not. Hypothalamic-pituitary-adrenal function was impaired in all females during the single-caging period and during new group formation. By 26 months in the final social groups, females that never displayed depression were more sensitive to glucocorticoid negative feedback in a dexamethasone suppression test than females that displayed behavioral depression. Depressed females had poorer quality ovarian function than their nondepressed counterparts. There was no difference between depressed and nondepressed females in coronary artery atherosclerosis extent or cineangiographically determined coronary vasomotor responses to infused vasoactive substances (vascular reactivity).

CONCLUSION: Depression did not appear to be associated with CHD risk in these female monkeys.

Key Words: CHD, • depression, • females, • monkey, • cortisol, • heart rate.

Abbreviations: CAA = coronary artery atherosclerosis;; CHD = coronary heart disease;; DST = dexamethasone suppression tests;; HPA = hypothalamic-pituitary-adrenal;; HR = heart rate;; MI = myocardial infarction.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Social status is inversely associated with depression in human beings. Likewise, social status and coronary heart disease (CHD) risk are inversely related (1, 2). Depression and coronary heart disease are comorbid conditions. Depression after myocardial infarction (MI) is common and associated with greatly increased mortality from a subsequent coronary event (3, 4). Depression may cause CHD. If so, there would be a compelling rationale for aggressively treating depression that occurs earlier in life in order to reduce the later risk of CHD. However, data supporting the hypothesis that depression causes CHD has been difficult to gather. To date, a handful of prospective studies have found that depression predicts later CHD (5–10). These studies were comprised mostly of men and together identified a relatively small number of cases in which depression occurred before CHD/MI. Little information is available on women, although depression is twice as likely in women as in men (11, 12). Furthermore, there are also several large prospective studies in which depression did not predict CHD or cardiovascular disease (CVD) (13–15). In most studies, depression was measured once, at baseline, precluding analysis of whether the course of the disease over the follow-up period explained variability in the results. Adding to the contradictions in the data are observations of little or no relation between depression and the degree of coronary stenosis in patients undergoing coronary catheterization (16–19), or calcification determined by computed tomography (20). Thus, whether depression causes CHD needs further clarification.

In attempting to establish a novel risk factor, one criterion is whether there are plausible mechanisms that might relate the two phenomena. There are several potential mechanisms through which depression may increase CHD risk. Depressed people smoke more than the remainder of the population (21). Depression may increase platelet aggregation by increasing sympathetic catecholamines (22, 23). Depression is associated with increased heart rate (HR) and decreased HR variability, which are hypothesized to indicate autonomic dysregulation. Autonomic dysregulation is hypothesized to increase risk of ventricular fibrillation and CHD death (24–26). (A fourth potential mechanism may involve the hypercortisolemia characteristic of depression. While cortisol is known to have a broad array of metabolic effects, some of which affect CHD risk, the impact of hypercortisolemia on CHD development is not well understood.) Thus, there seem to be plausible mechanisms through which depression might exacerbate CHD.

Given that it is biologically plausible to hypothesize that depression may increase the risk of CHD, experimental approaches to evaluate the relationship between the two diseases would be helpful. Cynomolgus monkeys (Macaca fascicularis) have been a useful model in which to study the effects of many classical and novel risk factors on atherogenesis and coronary artery reactivity, including social status and social stress. These monkeys live in groups and organize themselves by social status hierarchies. Like humans, female cynomolgus monkeys are protected against coronary artery atherosclerosis (CAA) relative to their male counterparts (27). However, females that are ovariectomized, or intact females that are low in the social status hierarchy (subordinate) are not protected, and their CAA extent is as great as that of males (28). It is believed that impaired reactivity of coronary arteries may contribute to the pathogenesis of CHD. The coronary arteries of ovariectomized females and intact socially subordinate females constrict in response to acetylcholine, whereas those of intact, socially dominant females dilate (29). Since subordinate females have impaired ovarian function, it has been hypothesized that impaired dilator responses and exacerbated CAA in subordinate females may be due to a relative lack of estradiol (28, 29).

Social stress is thought to precipitate depression in human beings (30–32). Young macques (Macaca spp.) have been used for decades to study despair and depressive reactions to the social stress of maternal separation (33). In those studies, depression was defined as a slumped or collapsed body posture accompanied by a lack of responsiveness to environmental stimuli. Depressive reactions to social stress are observed in adult monkeys also, but until recently, depression in adult macaques has been understudied. We have developed a monkey model of depression in adult females using the definition in Suomi et al. (33) in response to the social stress of subordination (34). Socially subordinate female cynomolgus monkeys, living in small social groups, are aggressed more and spend more time in fearful scanning of the social environment and less time as recipients of the active affiliative behavior of being groomed. Furthermore, they are hypercortisolemic, have higher heart rates in response to a novel environment (35), and have decreased D2 receptor binding potential in basal ganglia and perhaps elsewhere in the central nervous system (CNS) (35, 36). These behavioral and physiological characteristics suggest that socially subordinate females are stressed.

In order to further understand the nature of the relationship between social status, social stress, and disease susceptibility, an experiment was carried out in which the social status of female monkeys in small social groups was established and then the constituency of these small groups was altered such that half of the subordinates became dominant and half of the dominant females became subordinate (see Methods section for details). The females lived in their final social groupings for over 2 years. Females that changed social status, regardless of current rank, had worsened CAA (37). Also in this experiment, social status affected coronary artery reactivity but differently than the way it affected atherogenesis (29). The coronary arteries of current dominants dilated (+9 ± 2%) whereas those of current subordinates constricted (-6 ± 2%) in response to acetylcholine, and this effect was irrespective of social status history. Social status affected ovarian function. Current subordinates, irrespective of social status history, had lower mean peak luteal-phase progesterone concentrations and fewer ovulatory menstrual cycles than current dominants (34). Thus, ovarian dysfunction and CAA extent were not associated in this experiment (37). Social status also affected hypothalamic-pituitary-adrenal function. At the end of the experiment, current subordinates, irrespective of prior social status, had higher baseline cortisol concentrations, secreted more cortisol after dexamethasone suppression, and were less sensitive than dominants to dexamethasone suppression (34). Socially subordinate females, particularly those with a history of social subordination (83%), were preferentially susceptible to depressive behavior (34).

In order to further characterize the behavioral depression exhibited by these monkeys and to determine whether developing behavioral depression worsened health over and above that caused by the stress of subordination, the subjects of this study were divided into those that ever (N = 16) and those that never (N = 26) exhibited behavioral depression. In the following report, we describe the progression over a 26-month period of physiological changes associated with depressive behavior in female cynomolgus monkeys consuming an atherogenic diet and the relationship between depression and coronary artery atherosclerosis and reactivity.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
The methods used in this study have been described in detail elsewhere (29, 34, 37) and are described briefly below.

Subjects
Forty-eight adult (6–12 years of age as estimated by dentition) female cynomolgus monkeys (Macaca fascicularis) were obtained from Charles River Research Primates (Port Washington, NY). During the experiment, 6 animals died of causes unrelated to the experiment, resulting in a final sample size of 42. All procedures involving monkeys were conducted in accordance with state and federal laws, standards of the department of Health and Human Services, and guidelines established by the institutional Animal Care and Use Committee. The monkeys were fed a moderately atherogenic diet ad libitum for 32 months; the diet contained 0.25 mg cholesterol/Cal and 40% of calories from fat (37).

Experimental Design
The experimental design is depicted in Figure 1. The monkeys were housed in quarantine for 3 months in single cages (preexperimental phase) and then assigned randomly to four-member social groups for an 8-week period during which their social status stabilized and was determined (experimental phase I). The animals were designated first, second, third, or fourth ranking. First- and second-ranking females were considered dominant, and third- and fourth-ranking females were considered subordinate. The animals were then assigned to new social groupings of four animals each, based on their social status, for the remaining 26-month experimental period. Animals that were previously dominant were housed together and animals that were previously subordinate were housed together. Linear social status hierarchies reformed; half of the subordinate animals became dominant and half of the dominant animals became subordinate (experimental phase II). This manipulation produced four groups, females that were initially 1) dominant and remained dominant after social regrouping (Dom, Dom: N = 11); 2) dominant and became subordinate after regrouping (Dom, Sub: N = 11); 3) subordinate and became dominant after social regrouping (Sub, Dom: N = 8); and 4) subordinate and remained subordinate after regrouping (Sub, Sub: N = 12). This resulted in a 2 x 2 classification of social status: initial social statusdom, sub x manipulated social statusdom, sub. It is important to note that the monkeys were in their final social groups for over 90% of the experimental period. Because young female cynomolgus monkeys acquire their social status early in life and their social status tends to be stable (38), in the experiment reported here, initial social status may be considered a longstanding behavioral characteristic of the individual, whereas current social status represents an experimentally manipulated state of social environmental stress.



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  		Fig. 1. Experimental design.

 
Social Status
Social status was determined monthly throughout the experiment by recording the outcomes of aggressive interactions between cagemates. The animal in each social group that defeated all other group members was designated the first-ranking monkey. The animal that defeated all but the first-ranking monkey was designated the second-ranking monkey, etc. As observed in previous experiments, the resulting social status hierarchies for each social group were stable over time (38). Thus, the only significant changes in social status were observed when social group constituency was changed at the end of experimental phase I.

Behavioral Depression
Time spent depressed was defined as a slumped or collapsed body posture accompanied by a relative lack of responsiveness to environmental stimuli to which other monkeys are attending (33). Time spent depressed while monkeys were in body contact, close, or alone was recorded in addition to other social behaviors twice a week throughout experimental phase II using a 30-minute group ad libitum observation method, punctuated with scan samples every minute (34). Sixteen females engaged in the depressive behavior during experimental phase II. Fourteen of these were current subordinates, and of the 14, 10 had a history of social subordination in experimental phase I. Thus, 83% of current subordinates with a history of social subordination were preferentially susceptible to behavioral depression (34).

Dexamethasone Suppression Test
A morning blood sample was taken for baseline cortisol concentration determinations, an evening dose of dexamethasone was administered, and a second blood sample was obtained the next morning for cortisol concentration determination. Blood samples were taken within 5 minutes of capture and sedation with ketamine hydrochloride (10 mg/kg). The difference between the first and second morning cortisol concentrations (percent suppression) was calculated as an indicator of sensitivity to negative feedback (39). The dexamethasone suppression tests (DSTs) were done at the end of the 90-day single-caging period and 5, 20, and 26 months after the monkeys began living in their second (and final) social groups. In order to determine the optimal dexamethasone dose, we administered 60 µg/kg body weight (IM) to half the monkeys and 130 µg/kg body weight (IM) to half the monkeys at the DST done at the end of the 90-day single-caging period. Postdexamethasone cortisol concentrations and percent change from baseline were analyzed with a two-way (social status dominant, subordinate x dose low, high) ANOVA. There were no significant (p<= .05) main or interaction effects of dose. Thus, these data were collapsed in subsequent analyses. For all subsequent time points, the dexamethasone dose used was 130 µg/kg body weight IM.

Overnight Heart Rates
Physiological responsivity was assessed by recording telemetered heart rate. After capture and sedation with ketamine hydrochloride (10 mg/kg), each monkey was outfitted with a nylon mesh protective jacket over a portable electrocardiogram telemetry unit. After overnight recovery from sedation, heart rate recording began the afternoon of the next day (approximately 1500 hours) and continued until the following morning (approximately 0700 hours). These heart rate recordings were done at the end of the single-caging period (N = 25 randomly chosen) and 2, 13, and 24 months (in all 42 monkeys) after the monkeys began living in their final social groups (35). Because the single-cage phase was short, there was time to sample heart rate in only a random sample of N = 25. The nadir of the heart rate diurnal rhythm occurs between 2400 and 0400 hours. Heart rate was averaged over this time period for analysis.

Reproductive System Function
The monkeys were trained to present themselves for vaginal swabbing to detect menses and for femoral venipuncture to collect blood for progesterone assay three times a week throughout experimental phase II. Luteal-phase progesterone concentration was used as an indicator of the quality of a menstrual cycle. High progesterone concentrations (>4 ng/ml) indicate that ovulation has occurred; low progesterone concentrations (<2 ng/ml) indicate an anovulatory cycle; and concentrations between 2 and 4 ng/ml suggest luteal-phase impairment (40, 41). The highest progesterone value found during the luteal phase was used to represent that menstrual cycle, and mean peak progesterone concentrations were calculated for analysis. Average cycle length and the number of cycles each female had during experimental phase II were also calculated for analysis.

Coronary Artery Reactivity
Coronary artery reactivity was measured just before necropsy. Monkeys were anesthetized with ketamine hydrochloride (10–15 mg/kg body weight, IM) and butorphanol (0.025 mg/kg, IM). Periodic doses of both agents were given to maintain light anesthesia. A catheter was inserted into the right femoral artery and advanced to the midthoracic aorta for measurement of BP and heart rate. A custom-designed 3-F (tapered to 1.8-F) catheter was inserted into the left femoral artery and advanced to the left main coronary artery with fluoroscopic guidance. Blood pressure was monitored from the tip of the coronary catheter to exclude damping and significant obstruction of coronary blood flow. Using an infusion pump, serial 2.5-minute intracoronary infusions were made in the following sequence: 1) 5% dextrose in water (control), 2) acetylcholine 10-6 mol/liter (estimated assuming left coronary blood flow of 10 ml/minute9, 3) nitroglycerine (40 µg/minute), 4) control, and 5) serotonin (10-6 mol/liter). After each infusion, cineangiographic images were obtained in the 30° right anterior oblique projection at 60 frames/second. Images were taken during a hand injection of 2 ml of nonionic contrast solution into the left main coronary artery. Approximately 10 minutes elapsed between drug infusions and 30 minutes between nitroglycerin and the second control. Because of the lasting effects of serotonin on arteries, the order of infusions was not randomized. Quantitative angiography was done in the Wake Forest University School of Medicine Cardiology Image Analysis Laboratory. Measurements were made without knowledge of experimental group assignment. This method has been validated previously for evaluation of coronary artery reactivity in monkeys (29).

Necropsy and Measurement of Atherosclerosis
At the time of necropsy, the animals were anesthetized deeply with pentobarbital (60 mg/kg), the cardiovascular system was flushed with normal saline, and the heart was removed and perfused with 10% neutral buffered formalin under a pressure of 100 mm Hg. After pressure fixation, five serial blocks were taken from each of the left circumflex, left anterior descending, and right coronary arteries. One section from each block was stained, projected, and the area occupied by the intima and intimal lesion was measured by a technician blinded to the experimental group assignments of the animals. The mean of the 15 sections from the three arteries was calculated for analysis. The left iliac artery was opened longitudinally, and three crowsfoot sections were taken and immersion fixed in 4% paraformaldehyde. The mean of the three sections was calculated for analysis.

Analysis
Before analysis, atherosclerosis data were transformed to reduce skewness and equalize group variance. These data are presented as untransformed values in original units derived from the mean (±SEM) of the transformed distribution. ANOVA, Pearson r and {chi}2 were used for analysis. F tests are from one-way ANOVAs with two groups (depressed, not depressed) unless otherwise stated. All probability values are the results of two-sided tests, and p values <=.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Overnight Heart Rates
Nighttime baseline heart rates were compared between the 16 depressed females and the 26 nondepressed females at three time points during experimental phase II (2 x 3 ANOVA) (Figure 2). All heart rates increased over the 26 months in the second social groups (main effect of time: F = 22.6, p = .001). We found that, throughout the second social grouping period, females that exhibited behavioral depression had higher overnight baseline heart rates than those that never exhibited behavioral depression (main effect of group F = 5.0, p = .03). Heart rates were recorded in a randomly chosen subset of the monkeys while in single cages, before their first social grouping. Interestingly, females that later exhibited behavioral depression in social groups had higher overnight heart rates in single cages than those that never exhibited behavioral depression (F = 5.0, p = .04).



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  		Fig. 2. Nighttime baseline heart rate (2400–0400) recorded during the single-caging phase (N = 25) and 2, 13, and 24 months after the second (and final) social groups were formed.

 
Dexamethasone Suppression Test
The percent decrease in cortisol concentrations following dexamethasone were compared between the 16 females that ever displayed behavioral depression and the 26 that never displayed behavioral depression (Figure 3). Initially, hypothalamic-pituitary-adrenal (HPA) function appeared to be relatively impaired in all animals while they were subjected to the stress of single caging and new social group formation. That is, the ability to suppress cortisol production in both groups was uniformly poor in single cages and after 5 months of housing in their second social groups. By 20 months after the formation of the second (and final) social groups, HPA function of females never displaying behavioral depression appeared to improve. Before 26 months in their second social group, there were no differences between females that did display and those that did not display behavioral depression. By the end of 26 months in their second social group (in which the behavioral depression was observed), nondepressed females were more sensitive to glucocorticoid negative feedback than depressed females (F = 8.53, p = .006) (34). The difference emerged as females that never displayed behavioral depression in their second social groups became more sensitive to glucocorticoid negative feedback whereas the depressed females did not.



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  		Fig. 3. Dexamethasone suppression test: percent decrease in cortisol concentration recorded during the single-caging phase and 5, 20, and 27 months after the second (and final) social groups were formed.

 
Reproductive System Function
Mean peak luteal-phase progesterone concentrations were significantly lower in females that exhibited behavioral depression than those that did not (F = 4.12, p = .049) (Table 1). The total number of menstrual cycles (F = 0.05, p = .83) and the number of menstrual cycles that were ovulatory (F = 0.22, p = .64), impaired (F = 2.42, p = .13), or anovulatory (F = 0.01, p = .94) were not significantly different between females that did and did not exhibit behavioral depression. These results were unchanged when the data were expressed as percent of cycles that were either ovulatory, impaired, or anovulatory.


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  		Table 1. Reproductive and Cardiovascular System Endpoints
 
Cardiovascular System
Atherosclerosis extent in the coronary arteries (F = 0.47, p = .50) and the left common iliac artery (F = 0.03, p = .86) were not different between females that did and did not exhibit behavioral depression (Table 1). Coronary artery reactivity to acetylcholine (F = 0.39, p = .54), nitroglycerin (F = 0.05, p = .82), and serotonin (F = 0.17, p = .68) also were not different between females that did and did not exhibit behavioral depression. Pearson r correlations between behavioral depression and CAA extent (r = -0.01) and between behavioral depression and coronary artery reactivity to acetylcholine (r = -0.04) were also not significant.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
Previously, we have observed in female cynomolgus monkeys that social subordination is stressful and associated with impaired reproductive function, impaired HPA function, exaggerated HR responses to stress (35), and exacerbated CAA (28). When subordinates become dominant, their HPA function, ovarian function, and coronary artery dilator responses improve dramatically (28, 34). In spite of these improvements, CAA is notably exacerbated by changing social status, whether the individual becomes dominant or becomes subordinate (37). This effect was also apparent in the left common iliac artery, and the correlation between atherosclerosis extent in the coronary arteries and the left common iliac was high (r = 0.83, p< 0.001), suggesting that the effects of changing social status on atherosclerosis may occur throughout the arterial tree (unpublished data). This experimental evidence is reminiscent of observations made in human populations of an association between social status incongruity and CHD and CHD risk factors such as hypercholesterolemia and hypertension (42–45). Indeed, the potential for generating stress by incongruity between an individual’s behavior and his/her psychosocial environment was pointed out at least 20 years ago (46). Unlike CAA, the prevalence of depression was not exacerbated by changing social status. Instead, depression was most prevalent in subordinate females, especially those with a history of social subordination.

Throughout the study, monkeys that exhibited depressive behavior had higher heart rates than those that did not. Increased heart rates are also characteristic of depressed human beings, with or without CHD, providing further evidence supporting the validity of using this monkey model to study depression (24–26). In this study, heart rate observed during single caging predicted behavioral differences observed later in social groups, implying a trait rather than a state variable. This observation suggests that monkeys that became depressed were initially different in autonomic function from monkeys that did not become depressed. Single caging is stressful to monkeys, as exemplified by our prior observation that HR increases when monkeys are moved from social groups to single cages and decreases when the same monkeys are restored to their social groups (48). In the current experiment, heart rates of all monkeys in single cages were high and dropped after being moved to social groups. However, monkeys that had the highest HR response to the stress of single caging later exhibited depressive behavior while in social groups and maintained higher rates than nondepressed monkeys. For most of the depressed monkeys, social living was also stressful due to subordinate social status. Perhaps the monkeys who displayed behavioral depression were predisposed to hyperrespond to social stress.

The pattern of HPA function over the course of the experiment was different than that observed for heart rates. In single cages, all monkeys appeared to be relatively insensitive to glucocorticoid negative feedback as reflected by the DST, and this observation reveals the profound nature of the stress of single caging. Initially, when groups of monkeys are formed, aggression is high and affiliation is low. New group formation can be a stressful event. Perhaps that is why it took months for nondepressed females to recover glucocorticoid sensitivity. After several months in social groups, females that never exhibited depressive behavior appeared to become more sensitive to glucocorticoid negative feedback. Thus, the HPA axis was aberrant in depressed females because it did not recover after social stability was achieved. Insensitivity to glucocorticoid negative feedback is also characteristic of a significant proportion of depressed human beings, further evidence supporting the validity of this model to study depression. Note that the two major stress-responsive systems, the autonomic nervous system and the HPA axis, had divergent patterns in this study.

A critical current goal in behavioral medicine is to determine who becomes depressed. In this experiment, individuals that had unusually high heart rate responses to the stress of single caging and those that were subordinate, particularly accompanied by a history of subordination, exhibited depression. Concerning behaviors (other than the depressed posture) that might predict depression, no differences were observed in aggressive or affiliative behavior between dominants that were previously subordinate and those that were previously dominant. Likewise, there were no differences in these behaviors between subordinates that were previously dominant vs. previously subordinate (unpublished data). However, depression occurred in almost all subordinates that were previously subordinate but in only a third of subordinates that were previously dominant. Thus, current behavior did not provide insight into which monkeys became depressed. A subsequent experiment, currently underway, is designed to characterize individual differences more closely in order to determine which individuals become depressed.

The monkeys exhibiting behavioral depression were physiologically different than those that did not exhibit this behavior in ways that suggest an increased risk for atherosclerosis. However, there was no difference in atherosclerosis extent in depressed vs. nondepressed monkeys. In attempting to reconcile this observation with what is known about the relationship between depression and CHD in human beings, several points are relevant. The atherogenesis in these monkeys was in response to 32 months of exposure to a diet containing fat and cholesterol, resulting in quite a bit of fatty streak, fatty plaque, and fibrous plaque and some necrosis and calcification. This exposure time is equivalent to approximately one ninth of their life span and resulted in atherosclerosis that was in the early to middle stages of development (47). Risk factors may affect CHD risk during early atherogenesis, later during the progressive complication of plaques, or even later at the point of initiation of atherothrombotic events. Risk factors may not necessarily influence disease progression at every point in time. Depression in human beings is most clearly associated with CHD morbidity/mortality in patients that have already had an MI and, presumably, advanced CAA. The atherosclerosis extent in these monkeys was moderate, and there were no clinical signs of disease. Thus, it may be that depression does not affect the earlier stages of atherogenesis. Second, it may be that depression affects the probability of MI and subsequent MI and does not affect preclinical development of CHD. These two interpretations are consistent with the hypothesis that depression is associated with abnormal electrical activity in the heart and autonomic dysregulation. Third, severe depression has been more clearly associated with CHD than mild depression in human beings (49). The monkeys exhibiting behavioral depression in this experiment were functional in their social groups for two and half years, albeit at a suboptimal level, suggesting that the depression observed in these monkeys was not severe. Thus, these data may support the hypothesis that severe, but not mild, depression affects CHD risk. The little coronary artery atherosclerosis observed in monkeys exhibiting behavioral depression would be consistent with all of these explanations.

It is notable that increased depression and CHD are associated with low social status in human beings and female cynomolgus monkeys. It may be that low social status causes social stress, which in turn increases risk of depression and early moderate atherogenesis. Depression may increase the likelihood of a clinical event in persons with advanced atherosclerosis. This postulation represents our current working hypothesis and does not preclude an element of heritability in any of the components of the model.

Finally, it was striking that nearly all subordinates with a history of social subordination displayed behavioral depression and developed little coronary artery atherosclerosis. An alternative interpretation of these data are that the social withdrawal and conservation of energy and resources characteristic of depression may be an adaptive strategy to reduce stress and its pathophysiological sequelae in individuals at high risk for a poor outcome from clinically detectable CHD. The withdrawal-conservation theory of depression, articulated by Engel (50, 51), elaborated in the separation-induced infant monkey model of depression (52, 53) and resurrected in recent evolutionary perspectives on psychiatric phenomena (54), may deserve fresh attention in light of this observation.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This research was supported by grants from the National Institutes of Health (HL-39789, HL-14164, and HL-45666).

Received for publication April 13, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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C. A. Shively, D. P. Friedman, H. D. Gage, M. C. Bounds, C. Brown-Proctor, J. B. Blair, J. A. Henderson, M. A. Smith, and N. Buchheimer
Behavioral Depression and Positron Emission Tomography-Determined Serotonin 1A Receptor Binding Potential in Cynomolgus Monkeys.
Arch Gen Psychiatry, April 1, 2006; 63(4): 396 - 403.
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