© Springer International Publishing Switzerland 2015
Kristina Orth-Gomér, Neil Schneiderman, Viola Vaccarino and Hans-Christian Deter (eds.)Psychosocial Stress and Cardiovascular Disease in Women10.1007/978-3-319-09241-6_55. Depression and Cardiovascular Disease in Women: Behavioral and Biological Mechanisms Involved in this Association
(1)
Health Clinical Psychology, University of Miami, Miami, FL, USA
(2)
Behavioral Medicine Unit, University of Miami, Miami, FL, USA
Abstract
Cardiovascular disease (CVD) and depression are conditions that frequently co-occur, particularly among women. It has been estimated that about one in every five patients with CVD meets criteria for major depressive disorder, and an even greater number endorse subclinical levels of depressive symptoms. Most importantly, prospective studies have demonstrated that depression is a strong predictor of CVD onset, cardiac adverse events, and mortality from CVD. This association appears to be more pronounced among women. As evidence accumulates, great interest has been given to putative mechanisms that may account for this association and both behavioral and biological pathways have been proposed. The leading behavioral hypotheses suggest depression is likely to increase the risk of CVD through its influence on medication adherence and/or poor health behaviors. Biological pathways posited to link these two conditions include the inflammatory response, hypothalamic-pituitary-adrenal axis activity, genetic influences, and the adipokine, leptin. Although further research is needed to better integrate the behavioral and biological pathways linking these two conditions, intervention efforts are already on their way. Various randomized clinical control trials targeting depressive symptoms among men and women with CVD have been conducted, increasing our knowledge on how to safely address depression in the context of CVD.
Keywords
DepressionCardiovascular diseaseGenderInflammationSomatic symptomFatigueExhaustionInterventionsIntroduction
Cardiovascular disease (CVD) is the leading cause of death worldwide (World Health Organization [WHO] 2013). Although traditionally considered a male disease, in 2011 approximately eight million women died from CVD, an estimate comparable to that of men and greater than the number of deaths attributable to the next seven causes of death in women combined (WHO 2013). Over the past decade, death rates from CVD have significantly declined (Go et al. 2014), yet disease burden remains high and the absolute number of women dying from CVD has continued to rise. Marked gender differences in the incidence and presentation of CVD are now widely recognized. For instance, it has now been established that CVD presents on average 10 years later in women than in men, however, prognosis is poorer among women with manifest CVD despite their having a lower biological risk profile (Andrikopoulos et al. 2006; Vaccarino et al. 2001b; Worrall-Carter et al. 2011). Given this apparent “paradox”, the psychosocial risk profile of women has begun receiving increasing attention over the past few years. Psychosocial factors associated with adverse CVD outcomes, in particular major depression and subclinical depressive symptoms, may provide important insights on the cardiovascular health of women. In this chapter, we summarize the evidence linking depression and CVD in women, discuss potential behavioral and biological mechanisms underlying this association, and present the results of interventions targeting depressive symptoms among women with CVD.
Depression and CVD: Considering Sex Differences
Major depressive disorder (MDD) is a primary cause of morbidity and mortality around the world (Murray and Lopez 1996), and is expected to become the second leading cause of worldwide disability by 2030 (Mathers and Loncar 2006). According to the Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association [APA] 2013), MDD is characterized by two or more major depressive episodes. Symptoms of MDD include two core features, depressed mood and/or markedly diminished interest or pleasure. Other cognitive and somatic symptoms include changes in appetite, disrupted sleep, psychomotor agitation, fatigue or loss of energy, feelings of worthlessness, indecisiveness, and recurrent thoughts of death (APA 2013).
Overall lifetime and 12-month prevalence of MDD among US adults is 16.5 % (Kessler et al. 2005a) and 6.7 % (Kessler et al. 2005b), respectively; and similar estimates have been reported around the world (Seedat et al. 2009). However, marked gender differences in the prevalence of MDD is perhaps the most replicated finding in the mental health literature. In an international study of 72,933 adults from 15 countries conducted as part of the WHO World Mental Health Survey Initiative (Seedat et al. 2009), women had a significantly higher lifetime risk of MDD than their male counterparts. Results indicated that overall, women are approximately twice as likely to be diagnosed with MDD as men (OR = 1.9, 95 % Confidence Intervals [CI] = 1.8–2.0).
MDD is particularly prevalent among patients with CVD. Evidence suggests that approximately one in every five patients with CVD meet criteria for MDD (Thombs et al. 2006). In hospital settings, studies show that MDD is present in 15–20 % of patients after myocardial infarction (MI). Prevalence rates are even higher for women (Pilote et al. 2007), and younger women appear to be especially vulnerable to depression after MI (Mallik et al. 2006). Estimates are comparable among patients hospitalized for unstable angina, angioplasty, bypass or valve surgery (Frasure-Smith and Lesperance 2006), and slightly higher among those with congestive heart failure (CHF) (Rutledge et al. 2006a). In community samples, prevalence of depression is also considerably higher among those with CVD when compared to healthy controls (Egede 2007; Moussavi et al. 2007). Data from 30,801 adults from the National Health Interview Survey in the USA showed that prevalence of depression was significantly higher among individuals living with CVD (9.3, 8.0 and 7.9 % among individuals with coronary heart disease [CHD], hypertension and CHF, respectively), when compared to disease-free individuals (4.8 %) (Egede 2007). In this study, gender was a significant predictor of an MDD diagnosis, with increased odds of depression among women with (OR = 1.48, 95 % CI = 1.22–1.77) and without medical illness (2.65, 2.19–3.21). Reports based on the WHO World Health Survey show comparable findings (Moussavi et al. 2007).
Beyond the frequent comorbidity of MDD and CVD, research shows that the presence of depressive symptoms, even in the absence of a clinical diagnosis, is associated with greater incidence of CVD and worse outcomes among CVD patients. Prospective studies have often measured depressive symptoms with the use of self-reported questionnaires such as the Beck Depression Inventory-II (BDI-II) (Beck et al. 1961), the Center for Epidemiological Studies Depression Scale (CES-D) (Orme et al. 1986), and the Hospital Anxiety and Depression Scale (Zigmond and Snaith 1983). The use of self-reported scales is particularly cost-effective, especially within the context of comprehensive epidemiological studies, and allows for a continuous rather than dichotomous assessment of depressive symptom severity.
Findings from these prospective studies have revealed a robust linear association between the presence of depressive symptoms and CVD endpoints. A meta-analytic review of ten rigorous longitudinal studies with follow-up periods of 5–40 years showed that depressive symptoms contribute a significant independent risk of CHD onset (RR = 1.64) (Wulsin and Singal 2003). Depressed affect was also predictive of fatal and nonfatal CHD events with adjusted relative risk estimates of 1.5 and 1.6, respectively (Anda et al. 1993). In the case of stroke, a recent meta-analysis of 28 prospective cohort studies with follow-up periods ranging from 2 to 29 years, revealed that hazards ratios for total stroke, fatal stroke, and ischemic stroke were 1.45, 1.55, and 1.25, respectively (Pan et al. 2011b).
The detrimental effect of depression on patients with established CVD or after an acute event is perhaps most striking. Literature suggests that depressive symptoms are associated with recurrence and mortality in post-MI patients (Frasure-Smith et al. 1995; Lesperance et al. 2002; Mayou et al. 2000), with re-hospitalization rates and death in CHF failure patients (Friedmann et al. 2006; Jiang et al. 2001; Sherwood et al. 2007; Vaccarino et al. 2001a), and poorer prognosis for stroke patients (Pan et al. 2011a). In addition, depression is the strongest predictor of patient symptom severity and health-related quality of life (Rumsfeld et al. 2003; Sullivan et al. 2004), particularly among women. Specifically, depressed women with CHD were more likely to experience angina, as well as to report lower role-physical functioning, vitality and role-emotional functioning than their male counterparts.
Although the evidence on the relationship between depression and CVD is compelling, drawing clinical implications for women is challenging due to the widespread underrepresentation of women in past studies. The mean percentage of women enrolled in CVD trials is 30 % (Melloni et al. 2010). In fact, a recent literature review on the association between depression and CVD among women showed that only 2 of more than 20 studies reviewed included a sample with 30 % or more women (Doering and Eastwood 2011). Despite its limitations, these studies inform our understanding of the role of depression/depressive symptoms in the context of CVD. It is worth noting, in addition, that various recent studies, such as the Women’s Health Initiative (WHI) (Wassertheil-Smoller et al. 2004), the Study of Women’s Health Across the Nation (SWAN) (Janssen et al. 2011), the Women’ Ischemia Syndrome Evaluation (WISE) study (Rutledge et al. 2006b), and the Stockholm Female Coronary Risk Study (FemCOR) (Orth-Gomer and Leineweber 2005), have specifically recruited women in order to better elucidate the nature and presentation of CVD among women. These studies have largely replicated previous findings on the association between depression and CVD morbidity and mortality in primarily samples of men and evidenced the presence of stronger associations between depression/depressive symptoms and CVD among middle age women (Janssen et al. 2011; Wassertheil-Smoller et al. 2004; Whang et al. 2009).
Subtypes of Depression and CVD
As the relationship between depression/depressive symptoms and CVD becomes better established, research efforts have begun focusing on providing a better characterization of the distinctive nature of depression in the context of CVD. The literature on the topic to date suggests differential predictive effects of depression depending on the dimension of depressive symptoms endorsed (somatic vs. cognitive depressive symptoms) (de Jonge et al. 2006; Hoen et al. 2010; Linke et al. 2009; Schiffer et al. 2009; Seedat et al. 2009; Stewart et al. 2007), as well as the number of depressive episodes experienced (single episode vs. recurrent depression) (Windle and Windle 2013). Greater understanding of the specific depressive symptoms and specific presentation of depression associated with an increased risk of CVD is likely to have important implications for treatment and aid in the identification of relevant behavioral and biological pathways linking these two conditions.
Somatic Vs. Cognitive Depressive Symptoms
Several recent studies have reported a differential effect of depressive symptom dimensions and CVD-related outcomes. Findings suggest somatic depressive symptoms may have stronger associations with cardiovascular events than cognitive depressive symptoms (de Jonge et al. 2006; Hoen et al. 2010; Linke et al. 2009; Schiffer et al. 2009; Seedat et al. 2009; Stewart et al. 2007). For example, somatic symptoms were shown to predict cardiac events after MI (de Jonge et al. 2006), among women undergoing angiography for suspected MI (Linke et al. 2009), in patients with stable CHD (Hoen et al. 2010), CHF (Schiffer et al. 2009), and even among those free of clinically significant CHD (Stewart et al. 2007), while no associations were reported for cognitive symptoms.
Interpretation of the evidence is challenging due to the various inconsistencies among studies in regards to the classification of symptoms as “somatic” or “cognitive”. While some investigators have based classification on “face validity” of depression scale items, others have relied on principal component or factor analysis. Inconsistent findings may therefore be a result of differences in analytic procedures or decision rules (Carney and Freedland 2012). For example, “indecisiveness” would be classified as a cognitive symptom if based on item face validity, yet in the study by de Jonge et al. (2006), it held the second highest loading on the somatic factor and was, therefore, classified as somatic. Other possible reasons for the differential prediction of somatic vs. cognitive items include: (1) differences in the frequency and severity of depressive symptom subtypes as somatic symptoms may be more prevalent among CHD patients (Martens et al. 2006); (2) reporting/gender biases, patients with CHD, particularly men, may perceive the endorsement of somatic items as less riskier and stigmatizing (Ketterer et al. 2004); and (3) the possibility that somatic items may be expressions of a different underlying condition.
Some researchers argue that there is considerable overlap between somatic depressive symptoms and the symptoms of heart disease. Somatic depressive symptoms typically include tiredness and fatigue, changes in sleeping pattern, and changes in appetite (Dozois et al. 1998); however, of these, only fatigue is typically considered a symptom of heart disease. Greater overlap exists perhaps between somatic depressive symptoms and cytokine-related syndromes, such as “sickness behavior” and “vital exhaustion”, constructs that are also associated with CVD risk. Sickness behavior has been conceptualized as a behavioral syndrome induced by exogenous pro-inflammatory cytokines and its primary features include anhedonia, fatigue, changes in eating habits, altered sleeping pattern, reduced overall activity level, and cognitive difficulties (Dantzer 2001). Similarly, vital exhaustion involves a state of excessive fatigue, loss of energy, increased irritability, and demoralization (Appels et al. 1993). Because of the considerable overlap among the constructs of somatic depression, sickness behavioral, and vital exhaustion, these terms may largely reflect the same underlying construct.
Although this question has created considerable debate in the research community (Kopp et al. 1998; Kudielka et al. 2004; Wojciechowski et al. 2000), differentiation of each construct has proven challenging. Psychometric measures of sickness syndrome are not yet available, and correlations between depression inventories and the Maastricht Questionnaire (Appels et al. 1987), a measure of vital exhaustion, range from 0.6 (Kopp et al. 1998) to 0.8 (Wojciechowski et al. 2000). In fact, a study of post-MI patients examining the association between several depression measures and the Maastricht Questionnaire using factor analysis suggested all measures were indicators of the same underlying construct (Wojciechowski et al. 2000). Interestingly, a recent report of the Stockholm Female Coronary Angiography Study examined the prospective relationship between vital exhaustion subcomponents, depressed mood vs. fatigue, and coronary atherosclerosis (Zimmermann-Viehoff et al. 2013). Results showed an association between vital exhaustion and accelerated coronary atherosclerosis progression that was largely driven by depressed mood as opposed to fatigue.
Clearly, more research is needed to better describe the symptom nature and presentation of depression among CVD patients. Tracking symptom consistency/changes over time and their association with biological processes including pro-inflammatory cytokines will better inform our understanding of the symptomatology of depression in CVD.
Single Episode Vs. Recurrent Depression
A study by Windle and Windle (2013) recently examined the concurrent and prospective associations between a history of single and recurrent major depression and the presence and incidence of CVD in a community sample of 557 middle-aged women (Windle and Windle 2013). Results indicated that history of recurrent major depressive episodes, but not single episode MDD, was associated with the presence of CVD (assessed by self-report of heart attack or MI, stroke and/or angina) at baseline and predicted the onset of CVD after a 5-year interval. These findings were in line with other cross-sectional reports indicating that recurrence or persistence of depression is more strongly associated with established CVD (Holzel et al. 2011), subclinical markers of CVD including carotid atherosclerotic plaque (Jones et al. 2003); and endothelial dysfunction (Wagner et al. 2006).
Replicating these provocative findings is of key importance given that the chronic nature of recurrent depression, and the subclinical depressive symptoms that have been shown to continue even in periods of remission (Kennedy and Paykel 2004; Solomon et al. 2000), may provide a plausible explanation for MDD’s long-term impact on behavioral and biological pathways leading to CVD.
Mechanisms Linking Depression and CVD
In spite of the large amount of research the relationship between depression and CVD has produced, little is known about the mechanisms linking these two conditions. The following section will present the leading hypothesis on potential behavioral and biological mechanisms involved in the association between depression and CVD.
Behavioral Factors
Several lines of evidence suggest depression increases risk of CVD morbidity and mortality through its influence on behavioral factors. Research on behavioral mechanisms has mostly focused on medication adherence and poor health behaviors including cigarette smoking, physical inactivity, and consumption of a high-fat diet.
Medication adherence. Non-adherence to medication regimens is an increasingly recognized cause of adverse CVD outcomes. For example, in the Heart and Soul study, a study of 1,015 outpatients with CHD, non-adherence to medication was associated with a twofold increase rate of subsequent cardiovascular events (Gehi et al. 2007). Depressive symptoms are likely to impact patients’ ability to take medications as prescribed. In fact, various studies have shown depression is an independent predictor of medication adherence (Carney et al. 1995; Gehi et al. 2007). Gender has also been identified as an important predictor of adherence, with women reporting lower rates of medication adherence than men (Gehi et al. 2007).
Health behaviors. One of the health behaviors that has most commonly been linked to depression and is highly predictive of cardiovascular events is cigarette smoking. Results of a 21-year longitudinal study (Fergusson et al. 2003) indicated a possible causal link between depression and smoking. Investigators showed that those meeting criteria for MDD at baseline had subsequently elevated rates of daily smoking and nicotine dependence (Fergusson et al. 2003). Behaviors that promote weight gain, such as physical inactivity and consumption of a high-fat diet, have also been linked to both depression and CVD (Herva et al. 2006a, b; Raikkonen et al. 2007). The role of health behaviors as mediators of the depression-CVD association has been formally examined in various prospective cohort studies (Hamer et al. 2008; Nabi et al. 2008; Whooley et al. 2008). Results indicate that although the relationship between depression and adverse cardiovascular events generally remains unaltered after adjustment for comorbid conditions and disease severity indicators, it is largely attenuated after accounting for both cigarette smoking and physical inactivity (Blumenthal et al. 2004; Brummett et al. 2003; Hamer et al. 2008; Whooley et al. 2008).
Although promoting medication adherence and health behaviors among patients with depression/depressive symptoms shows promise, few reports have examined sex differences related to behavioral factors in the context of depression and CVD. Future research efforts should aim at further elucidating sex differences in the contribution of each of these behavioral pathways on the CVD-depression relationship.
Biological Factors
Various hypotheses about biological mechanisms relating depression to CVD have been proposed in recent years. The leading biological hypotheses to date suggest important roles for: (1) inflammation, (2) the hypothalamic-pituitary-adrenal (HPA) axis, and (3) genetic factors. In addition, a novel mechanistic hypothesis has recently proposed the adipokine, leptin, may have act as a mediator in the relationship between depression and CVD.
Inflammation. CVD is now considered a chronic inflammatory disease (Ross 1999). Inflammatory markers, including pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and acute phase proteins, such as C-reactive protein (CRP), have been widely studied in the context of CVD and shown to predict future cardiovascular events (Cesari et al. 2003; Pearson et al. 2003; Ridker et al. 2000). Similarly, an activation of the immune system is characteristic of MDD (Kim et al. 2007; Sperner-Unterweger 2005). Significantly higher levels of inflammatory cytokines have been found in depressed subjects when compared to healthy controls (Goldbacher and Matthews 2007; Howren et al. 2009; Mossner et al. 2007) and a linear association between inflammation and severity of depressive symptomatology has been reported (Benedetti et al. 2002; Suarez 2004). Prospective designs have also demonstrated that baseline depressive symptoms were predictive of 6-year changes in IL-6 even after controlling for important demographic, biomedical, and behavioral factors (Stewart et al. 2009). As evidence accumulates, the notion that depression may also be conceptualized as an inflammatory condition is receiving increased acceptance.
The fact that CVD and depression are both accompanied by chronic activation of the inflammatory responses, however, does not unavoidably suggest a mediating role of inflammatory cytokines. In a prospective design that examined the CVD-depression relationship, inflammatory markers only partially explained the association between depression symptoms and the onset of cardiac events (Whooley et al. 2008). Due to these and other comparable results (Hamer et al. 2008; Nabi et al. 2008), investigators have hypothesized that inflammation may interact with other behavioral and biological pathways to increase the risk for both CVD and depression. In the case of behavioral factors, physical activity may be particularly relevant, given the lack of physical exercise has been associated with increased inflammation (Kasapis and Thompson 2005). It is likely that lack of physical activity during a depressive episode may result in increased levels of inflammation, thus also heightening the risk of CVD. Interactions of the immune responses with the other biological mechanisms presented in this section have also been proposed.
HPA axis activity. The HPA axis plays a key role in the acute stress response. In the presence of an acute stressor, HPA axis activation leads to short-term release of cortisol in order to facilitate physiological stress responses. Under chronic stress, however, the HPA axis becomes dysregulated leading to overproduction of corticotrophin-releasing hormone (CRH) and hypercortisolemia (Watson et al. 2006). Depression and CVD have both been consistently associated with HPA axis dysregulation (Brown et al. 2004; Herbert 2013; Hamer and Malan 2010). Specifically, hypercortisolemia has been linked to the presence and development of carotid atherosclerotic plaque and coronary artery calcification (Dekker et al. 2008; Hamer et al. 2012).
Interestingly, pro-inflammatory cytokines are believed to be the drivers of the HPA axis dysregulation. Research from animal models shows that inflammatory cytokines directly stimulate the production of CRH, thus leading to increases in cortisol secretion (Sim et al. 2012). Similarly, clinical studies show remission from depression results in reductions in inflammatory cytokines that are accompanied by a normalization of HPA axis function (Himmerich et al. 2006). More complex models integrating the role of both inflammation and the HPA axis in the context of the CVD-depression association have yet to be tested and should be the focus of future research.
Genetic factors. Both depression and CVD are considered heritable conditions. Heritability of death from CHD is estimated at 57 %, and 30 % for men and women, respectively (Zdravkovic et al. 2002), while heritability of depression is estimated at 37 % (P. F. Sullivan et al. 2000). Given the high co-occurrence of depression and CVD, it is likely that a common core biological pathway, that is genetically determined, may manifest with both CVD and depression phenotypes (Mulle and Vaccarino 2013). Twin studies have provided support for this hypothesis showing that the CVD-depression association among twin pairs is best explained by both common genetic factors (most prevalent among monozygotic twins) and unique environmental experiences (most prevalent among discordant dizygotic twins) (Scherrer et al. 2003; Su et al. 2010; Vaccarino et al. 2009). Research in this area has also linked depression and inflammation through common genetic pathways (Su et al. 2009a, b). Specifically, a study reported that approximately 2/3 of the co-variation between IL-6 and depressive symptoms was explained by common genetic influences (Su et al. 2009b).
Sex differences are important when exploring the role of genetic factors in the CVD-depression relationship, since genetic influences in the heritability of depression appear to be larger among women (42 %) when compared to men (29 %) (Kendler et al. 2006, 2009). A study based on data from the Swedish twin registry showed that common genetic factors significantly contributed to the CVD-depression association in women of all age groups (Kendler et al. 2009). Among men, however, genetic influences contributed to this relationship only among those of young age; environmental influences appeared to play a larger role as age increased. Another area in which genetic sex differences are important involves leukotrienes, the most potent inflammatory mediators. A recent investigation showed that a six-single nucleotide polymorphism haplotype in the leukotriene A4 hydrolase gene had a protective effect on depression in women, but not men (Zhao et al. 2009). The same haplotype exerted a protective effect on coronary artery disease among women.
Leptin. The peptide hormone, leptin, is encoded by the obese (ob) gene (Lu 2007) and produced primarily by differentiated adipocytes. It communicates the state of body energy repletion to the central nervous system (CNS) in order to suppress food intake and permit energy expenditure (Lu 2007; Munzberg et al. 2005). Therefore, its levels drop during starvation when fat deposits are depleted and rise during re-feeding (Taylor and Macqueen 2010). Although it was initially identified as an anti-obesity hormone that acted as a negative feedback signal to control energy homeostasis, evidence suggests that most obese individuals have elevated circulating levels of leptin as a consequence of their increased fat mass and do not respond to these levels by reducing food intake. This under-responsiveness has led researchers to believe that obesity is associated with a state of leptin resistance, similar to the state of insulin resistance found in type 2 diabetes (Munzberg et al. 2005). Leptin resistance can be a consequence of abnormalities at several levels, including impaired transport of leptin across the blood–brain barrier, reduced function of the leptin receptor, and defects in leptin signal transduction (Munzberg and Myers 2005).
Due to the phenomenon of “leptin resistance”, the association between leptin levels and depressive symptoms is largely moderated by adiposity. Low levels of leptin have been associated with elevated depressive symptoms among lean rodents (Lu et al. 2000) and humans (Westling et al. 2004). Indeed, preliminary pharmacological studies indicate leptin has antidepressant-like effects (Lu et al. 2006). In the context of obesity, however, and due to the under-responsiveness to leptin, or leptin resistance, a positive association between depression and elevated (not reduced) levels of leptin has been reported (Antonijevic et al. 1998; Labad et al. 2012; Lu 2007; Pasco et al. 2008).
Research on the role of leptin as a mediator in the relationship between depression and CVD is still scarce. A recent study reported an association between circulating leptin levels and depressive symptoms in a sample of obese patients at high risk for CVD (Chirinos et al. 2013). Specifically, there was an important independent relationship between elevated circulating levels of leptin and somatic depressive symptoms. Interestingly, this association was independent of inflammatory markers, CRP and IL-6, insulin resistance, age and gender. No significant association was found between leptin and total depressive symptoms or cognitive depressive symptoms. Other previous studies reporting a potential role of leptin in the depression-CVD association have been conducted in clinical populations at high risk for CVD, such as patients with type 2 diabetes (Antonijevic et al. 1998; Lu 2007; Pasco et al. 2008). Some of these studies suggest a potential moderating effect of gender in the association between depression and elevated leptin levels, and have reported positive associations between circulating leptin and depressive symptoms among women only (Hafner et al. 2012; Labad et al. 2012; Antonijevic et al. 1998; Cizza et al. 2012; Pasco et al. 2008).
The mechanisms relating somatic or total depressive symptoms and circulating leptin levels are still unclear. However, leptin appears to interact with various key pathophysiological mechanisms in the CVD-depression relationship. Leptin, for example, has been shown to up-regulate the innate immune response by increasing the production of pro-inflammatory cytokines such as IL-6 and TNF-a (Wozniak et al. 2009). Other posited mechanisms include an interaction between leptin signaling, the mesolimbic dopamine pathway (Fulton et al. 2006), and the HPA axis (Lu 2007; Plotsky et al. 1998), as well as a possible neurotropic action of leptin (Ahima et al. 1999).
Although these provocative findings suggest common biological mechanisms in the co-occurrence of CVD and depression, further research is needed to better elucidate the behavioral and mechanistic pathways involved in this association. Most importantly, given that various mechanisms appear to interact with each other to increase the risk of depression in the context of CVD, more comprehensive models incorporating multiple pathways and bi-directional relationship are needed to better understand this relationship. In addition, few mechanistic hypotheses have been proposed on sex-specific pathways. Finally, future research on the moderating role of sex within potential behavioral and biological pathways relating depression and CVD should be conducted in order to better inform clinical interventions.
Interventions Targeting Depressive Symptoms in CVD Populations
To date, various randomized control trials designed to target depressive symptoms in CVD populations have been conducted. The largest of these trials included pharmacological interventions, such as the Sertraline Antidepressant Heart Attack Trial (SADHEART), the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE), and the Myocardial Infarction and Depression-Intervention Trial (MIND-IT); as well as behavioral interventions, such as the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study.
The efficacy of antidepressant use has been tested in two major randomized clinical control trials. SADHEART (Glassman et al. 2002), one of the largest pharmacological trials conducted, was the first trial to demonstrate the safety and efficacy of sertraline in reducing depression among patients with acute MI or unstable angina. Results of this study showed largely beneficial effects of sertraline in treating MDD. In fact, participants randomized to receive sertraline showed depressive symptom improvement, had fewer rates of cardiac events, as well as decreased levels of platelet and endothelial activation markers (Glassman et al. 2002, 2006). Another trial to test the effectiveness of antidepressants in CVD patients was the MIND-IT study (van Melle et al. 2007). MIND-IT was a large multi-center randomized clinical control trial of 2,177 MI patients who were randomized to receive mirtazapine, a nontricyclic antidepressant that promotes noradrenergic and serotonergic neurotransmission, or placebo (van Melle et al. 2007). Investigators, however, found no differences between the intervention and control group in depressive symptoms or cardiac event rates (van Melle et al. 2007).
Behavioral interventions have used cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) to address depressive symptoms among patients with CVD. The CREATE trial, for example, studied the added benefit of interpersonal psychotherapy (ITP) in addition to pharmacological treatment among Canadian CVD patients (Lesperance et al. 2007). In this 2 × 2 factorial design, investigators randomized participants twice to receive: (1) IPT vs. Clinical Management (20 min weekly session to evaluate course of depression, cardiac symptoms and medication side-effects); and (2) the selective serotonin receptor inhibitor (SSRI), Citoplan vs. Placebo. Although citoplan proved to be more effective in reducing depressive symptoms than placebo, no added benefit of ITP over clinical management was reported (Lesperance et al. 2007).
The largest randomized clinical trial examining the effects of CBT on depressive symptoms, social isolation, recurrent MI, and mortality in post-MI patients was ENRICHD trial (Enhancing recovery in coronary heart disease patients (ENRICHD): Study design and methods. The ENRICHD investigators (2000)). A total of 2,481 post-MI patients were recruited in this multi-center study and randomized to a CBT or usual care condition. Pharmacological therapy was offered if patients did not show symptom reduction after 5 weeks in therapy. Symptom reduction was significantly greater among participants randomized to CBT when compared to the controls at the 6-month follow-up; however, no differences in symptoms were reported at the 30-month assessment (Berkman et al. 2003). In addition, no significant effects on event-free survival were observed among intervention participants when compared to controls. Interestingly, post-hoc analysis revealed that the intervention resulted in a significant reduction in all-cause and cardiovascular mortality among White men only, highlighting the importance of tailoring interventions to the specific needs of women and under representing minorities (Schneiderman et al. 2004).
Lessons from ENRICHD informed the design and implementation of the SWITCHD study (Orth-Gomer et al. 2009). Although not directly targeting depressive symptoms, this trial was specifically designed to address psychosocial distress among women with CHD. A total of 237 women hospitalized for acute MI, coronary bypass grafting, or percutaneous coronary intervention were randomized to a group-based intervention or treatment as usual (Orth-Gomer et al. 2009). The group-based intervention consisted of 20 sessions over the course of a year and provided information on CVD risk factors, relaxation techniques, methods of self-monitoring and cognitive restructuring, self-care and compliance with clinical advice. Most importantly, it addressed psychosocial stressors that might differentially impact women such as competing family and work obligations. Results from this trial showed an overwhelming advantage of the intervention over usual care (Orth-Gomer et al. 2009). In fact, randomization to the intervention yielded a threefold protective effect on cardiovascular mortality when compared to treatment as usual. To date, results of this trial are the most compelling evidence that addressing psychosocial distress (and therefore, indirectly depressive symptoms) may convey a survival advantage among women with CVD.
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