Depression and Cardiovascular Risk: Epidemiology, Mechanisms, and Implications

Chapter 17

Depression and Cardiovascular Risk: Epidemiology, Mechanisms, and Implications Jessica Hatch and Benjamin I. Goldstein Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto Faculty of Medicine, Toronto, ON, Canada

EPIDEMIOLOGY Relative Prevalence of Cardiovascular Disease Among People With Major Depressive Disorder Depression affects 6.8% of adults in United States, with an increasing prevalence of depression over time, 13.8 million in 2005 to 15.4 million adults in 2010 [1,2]. Moreover, 1 in 5 adults over 50 have vascular depression in their lifetime, which corresponds to 3.4% of US adults (2.6 million people) [3]. Respectively, the economic burden of direct and indirect costs increased from $173.2 billion in 2005 to $210.5 billion USD in 2010, which is a 21.5% increase in cost over a 5-year period [1]. Cardiovascular disease (CVD) accounts for about ⅓ of overall deaths in the United States and, from 2011 to 2012, the annual cost of CVD was estimated as $316.6 billion USD [4,5]. This can also be reflected through the increased rates of CVD-related inpatient treatments, which have increased by 28% from 2010 to 2011 [4,5]. Together, MDD and CVD are among the most costly and burdensome medical conditions in North America, costing over $400 billion USD combined [1,4,5]. Moreover, depression incurs greater medical costs for all medical care (i.e., not mental health specific, e.g., primary care), compared to patients without depression symptoms or diagnoses [6–10]. For example, depressed patient primary care costs were $1366 greater per year compared to nondepressed patients [9]. Similar findings have been noted for inpatient and outpatient care costs. In population studies controlling for medication use and cardiovascular risk factors (CVRFs), such as tobacco use and hypertension, adults with MDD are still at an elevated risk for new-onset CVD and CVD mortality [11–17]. Moreover, depression contributes about 4 million disability-adjusted life years among those with ischemic heart disease [18]. Depression is ranked third for reducing quality-adjusted life years, controlling for age, sex, and severity of illness [7,19]. Depression has also been shown to additively contribute to functional impairment among patients with chronic illnesses, including heart disease and diabetes, controlling for the severity of the chronic illness [7,20,21]. In summary, there is increased prevalence of CVD among adults with MDD; moreover, the co-occurrence of these conditions leads to excess healthcare costs and increased disability.

Age and Sex in Relation to the Depression-Cardiovascular Link Both depression and CVD have differential prevalence and disease burden depending on age and sex. Depression among youth has also been associated with CVD risk behaviors such as the use of tobacco at an earlier age, a known risk factor for future CVD [22]. In longitudinal studies, adolescents with depression had a significantly greater risk of obesity in young adulthood, compared to nondepressed adolescents [23,24]. Importantly, CVD development begins in childhood, and risk assessment in childhood and adolescence is predictive of future CVD [25–27]. Recently, an American Heart Association statement positioned youth with major depressive disorder (MDD) to be a Tier-II moderate-risk condition for accelerated atherosclerosis [25]. The statement also notes that if an adolescent with MDD also has two or more traditional CVRFs (e.g., obesity and tobacco use), they are placed in Tier-I high-risk condition for accelerated atherosclerosis, alongside conditions such as chronic kidney disease, type-I diabetes mellitus, and homozygous familial hypercholesterolemia [25,27]. The premature development of atherosclerosis and CVD among those with MDD is apparent among Neurobiology of Depression. https://doi.org/10.1016/B978-0-12-813333-0.00017-2 Copyright © 2019 Elsevier Inc. All rights reserved.

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adult studies with new-onset CVD occurring approximately 6 years earlier among those with MDD compared to adults without mood disorders [28]. The prevalence of MDD has increased significantly from 2005 to 2015, particularly among youth relative to older age groups [29]. Overall, there is a trend of increasing risk and burden of heart disease over the lifespan. While it is generally thought that heart disease is more prevalent among males, the sex discrepancies in CVD prevalence is dependent on age group [30]. In a study of young adults aged 17–39, the relative risk for CVD mortality among men was 2.37 (95% CI: 0.85–6.58), and among women the relative risk for CVD mortality was 3.20 (95% CI: 1.24–7.76) [31]. Among middle-aged adults, males have a higher level of ischemic heart disease burden compared to females, as male heart disease burden peaks about 5 years prior; after the age of 80, there are no longer sex differences for ischemic heart disease [18,30]. The comorbidity of depression and CVD is more prevalent among females in community samples and in CVD clinical settings [14,18,32– 39]. There are also differences in the risk contributed by traditional CVRFs between the sexes. For instance, diabetes and low levels of high-density lipoprotein are greater risk factors for the development of coronary artery disease (CAD) among females compared to males, whereas tobacco use is a greater risk for CAD development among males compared to females [40,41]. In a meta-analysis of nine studies (N ¼ 171,701), obese participants were 32% more likely to have depression; interestingly, this association was particularly strong among obese versus nonobese women [42]. However, studies have also reported there were no significant differences in the effect of depression on CVD between men and women [43]. Further research is needed on the mechanisms underlying the impact of aging and sex on CVD risk among people with depression [30].

Impact of Depression on Subsequent CVD In the late 1930s, one of the first documentations of elevated mortality among those with depression (six times greater than the general population) noted that heart diseases accounted for 40% of deaths among those who were depressed [41,44]. Initially, research focused on personality types and the effect of specific traits (e.g., hostility); however, current research focuses on physical measures of cardiovascular and/or vascular structure and function. There has also been an improvement in the assessment of depression through the use of structured validated assessment tools [41]. While this has improved the assessment of depression in these studies, there is not a consensus on which measurement tools to use. This may potentially contribute to different findings between studies and has impacted their comparability [41]. Regardless, recent prospective studies have reported depression to be an independent predictor of CAD among an initially healthy sample [41,45]. In a meta-analysis including 11 studies, the relative risk of depression as a predictor of new-onset CAD among those with primary depression was found to be 1.64 (CI ¼ 1.29–2.08) [45]. This is in agreement with a recent meta-analysis that found the global relative risk of developing ischemic heart disease among those with depression to be 1.56 (CI ¼ 1.30–1.87) [46]. A limitation of some of these studies is the possibility that there was already subclinical development of atherosclerosis or subclinical CVD at the time of baseline assessment [11]. This limitation has been addressed in a few studies. For example, one study excluded participants who developed CVD within 2 years of their intake visit, based on the idea that subclinical CVD would have been present at intake in order for clinical CVD to be observed during the following 2 years [11,41]. MDD has been associated with an increased risk of: stroke, coronary artery disease, type II diabetes mellitus, hypertension, myocardial infarction, HRV, among other CVD and risk conditions, compared to adults without MDD or any other major psychiatric condition [14,36,41,42,47–51]. In a case-control study, patients with diabetes mellitus were more likely to be depressed (OR ¼ 2, 95% CI: 1.8, 2.2), compared to the nondiabetic control group [52]. One of the major CVD risk factors associated with depression is the metabolic syndrome [53,54]. Metabolic syndrome, as defined by the international diabetes federation, is central obesity and two or more of: dyslipidemia, elevated blood pressure, or elevated fasting glucose [55]. Metabolic syndrome is associated with increased risk of diabetes mellitus and CVD [55]. The prevalence of metabolic syndrome among adults with depression is 35.1%, which is 13% greater than the general population [53]. Similarly, obesity—a major risk factor for CVD—is prevalent among those with MDD (65.3%; OR: 4.84, 2.1–10.7) compared to adults without depression (24%), controlling for the effects of age, sex, occupational status, and education [56]. Likewise, there is an increased risk of CVD mortality among adults with MDD compared to HC adults. In a meta-analysis of 11 cohort studies (n ranged from 730 to 7894, mean follow-up: 3–37 years), the relative risk for adults with depression to develop coronary heart disease was 1.6 (0.29–2.08), including studies which controlled for age, gender, race, education, and traditional CVRFs [45,57]. Similarly, the prevalence of minor depression among adults with type II diabetes mellitus ranged from 4.3% for current depression to 13.9% for past depression [58]. Several community studies have found that depression predicted CAD independent of CVRFs (including combination of: diabetes, family history of MI/CAD, smoking, lipids, hypertension, exercise, cholesterol, blood pressure, BMI, alcohol use, CHF, and cognitive functioning) [11–13,15–17]. Not only is depression predictive of new-onset CVD, it is associated with poor outcome and a

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fourfold increase in CVD mortality [14]. Interestingly, there have been associations with depression symptoms and symptom burden with CVD risk, vascular function, and structure. In an adult twin study of 289 males, unaffected twins had better cerebral blood flow compared to depressed twins, indicating an association between depression and cerebral microvascular function and structure [59]. Similarly, among a study of 135 women, self-reported depression symptom burden was significantly associated with peripheral microvascular pulse-wave amplitude, as measured by peripheral arterial tonometry [60]. Interestingly, a dose-response relationship has also been reported for depression and the development of heart disease, where greater levels of depression symptom severity had greater relative risk for CVD endpoints [11,15,16,51,61–65]. Similarly, ischemic heart disease risk has been shown to have a dose-response relationship with major depression [18]. For instance, in a study of adults (19–79 years old) with chest pain, unit increases in Beck depression Inventory scores were associated with a 5%–6% increase in CAD or abnormal coronary angiography [51].

Impact of Depression and Its Treatment on Outcome of CVD There is a plethora of research on primary CVD (i.e., antecedent to depression) and onset of depression symptoms, as well as the role of depression in recovery post-CVD/vascular surgery/treatment. For instance, adults suffering from depression postmyocardial infarction are more likely to have another myocardial infarction, as well as have poorer prognosis, compared to those without depression/depressive symptoms [66,67]. Similarly, adults with depression poststroke have worse outcomes compared to those without depression [68]. Depression severity has also been shown to be predictive of CVD events and mortality [69]. In a study of 352 post-MI participants, depression severity (BDI score) predicted CVDrelated mortality and cardiac events over a 1-year follow-up period, controlling for CVRFs [69]. Similarly, cardiac mortality was significantly more likely to occur post-MI among men with higher scores of psychological distress, including depression, during a 5-year follow-up period [70]. A study of 430 patients with unstable angina similarly found that depression independently predicted cardiac events (OR ¼ 6.73 [CI ¼ 2.43–18.64]) [36]. Moreover, this work on post-MI and angina has also been extended to CAD, whereby depression conferred a significantly greater risk of CVD morbidity [71]. Similarly, among patients with CAD, depression was significantly associated with symptoms of chest pain at a 5-year follow-up, controlling for baseline ejection fraction, CVD treatments, and number of occluded vessels [72]. Also, vascular dysfunction (i.e., deficits in perfusion) in adults predicts and is associated with depressive symptoms and behavior [73]. The investigation of post-MI depression had varying degrees of screening or diagnostic criteria for depression, which resulted in a wide range of the prevalence of depression among post-MI patients (10%–87%) [41]. Since the use of more structured depression diagnoses and study timelines, the prevalence of depression post-MI/CVD has now been reported to be approximately 20%, with wider ranges seen for depression symptoms rather than diagnosis [41]. Likewise, it has been shown that post-MI patients who previously did not have depression are at greater risk for developing depression for 1-year post-MI [74]. Post-MI depression has been shown to be predicted by: previous MI, family history of psychiatric illness, poor functioning post-MI, and poor support systems [41]. It is also important to note that post-CVD depression has been shown to persist posthospitalization.

MECHANISMS The following is a nonexhaustive selective summary of putative mechanisms linking depression with CVD. Although the focus here is on biological mechanisms, it is well-recognized that early adversity, stress, and suboptimal lifestyle including nutrition, smoking, exercise, and sleep all contribute to the consistency and magnitude of the association between CVD and MDD [75–84]. It is important to note that prior evidence suggests that no single mechanism accounts for a large proportion of the CVD-MDD link, suggesting that, as might be expected, this link is best understood as multifactorial [85].

Inflammation Elevated inflammation is associated with both CVD and MDD [51,78]. MDD and CVD are thought to be states of chronic inflammation [86–88], although inflammation is also relevant in acute coronary syndromes [89]. The bidirectionality between CVD and MDD has been proposed to be via inflammatory processes, whereby either condition leads to elevated inflammation, which can then lead to the other condition [51,90,91]. Inflammation independently contributes to endothelial dysfunction, controlling for age, BMI, smoking status, cholesterol, blood pressure, and insulin sensitivity [92]. Under normal conditions, inflammation plays a role in acute injury response. In a chronic inflammatory state, flow-mediated dilation is impaired and there is an increase in vasoconstriction and reductions in endothelium-derived vasodilators, such as nitric oxide [93]. Chronic inflammation is associated with vascular endothelial dysfunction, atherosclerosis, and CVRFs

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[92,94–96]. Endothelial dysfunction is thought to be an early stage in the development of atherosclerosis [96]. For example, the Framingham offspring study found that elevated pro-inflammatory interleukin (IL)-6 was associated with endothelial dysfunction [97]. Likewise, inflammation-associated deficits in flow-mediated dilation have been noted in postmyocardial infarction [98]. Notably, reduction of inflammatory cytokines leads to improved endothelial functioning [99]. Meta-analytic data confirm that inflammatory markers are increased during depression [100]. Longitudinal studies in MDD have also found significant correlations between changes in PIMs and changes in depressive symptoms [88]. Elevated inflammation may lead to depression symptoms through a number of potential mechanisms, including (but not limited to) interactions with other processes such as glucocorticoid dynamics, monoamine metabolism, and oxidative stress, mechanical effects such as blood-brain barrier disruption, activation of astrocytes and microglia, and neurotoxicity [88,101–112]. Pathways linking peripheral and brain inflammation include neural, humoral, gut microbiota, and immune cells [88,113,114]. In addition to the known anti-inflammatory effects of antidepressant medications, studies have reported that cognitive behavior therapy is associated with reduced inflammation and that high baseline inflammation reduces response to therapy [115]. Electroconvulsive therapy is associated with an acute pro-inflammatory response followed by reductions in inflammatory marker levels with continued treatment [116].

Oxidative Stress The central nervous system and the heart demand greater cellular energy metabolism compared to other organs and systems in the body [117]. Under normal conditions, mitochondria produce the majority of reactive oxygen species (ROS) via electron transport chain production of the high energy molecule, adenosine triphosphate (ATP) [118]. During a state of oxidative stress, ROS can inhibit electron transport chain complex function and reduce ATP production [118]. This mitochondrial dysfunction can, therefore, lead to heart and brain functional changes, as they both have higher cellular energy metabolism requirements [117–120]. Numerous studies have examined a variety of oxidative stress measures in relation to depression. A recent meta-analysis, including 115 articles, concluded that there are reduced antioxidant markers and increased oxidative damage products in patients with depression as compared to controls [121]. Another recent meta-analysis reached similar conclusions, highlighting consistently increased levels of the oxidative stress markers 8-OHdG and F2-isoprostanes in depression [122]. Antidepressant treatments are also associated with oxidative stress. In a preclinical study, lamotrigine, aripiprazole, and escitalopram mitigated the effect of depression on brain measures of oxidative stress [123]. Treatments including repetitive transcranial stimulation [124] are associated with reduced oxidative stress markers. Minocycline has been associated with attenuated increases in oxidative stress during the course of depression [125]. Finally, high levels of oxidative stress are associated with reduced response to treatment with SSRIs among adults with depression [126], and relatedly, higher baseline oxidative stress predicts impaired antidepressant effects of omega-3 fatty acids in coronary artery disease patients [127]. Oxidative stress and inflammatory pathways are highly integrated; increases in oxidative stress lead to increased inflammation and vice versa [128,129]. Therefore, the mechanisms by which oxidative stress can play a role in the comorbidity between MDD and CVD can contribute to the inflammatory pathways discussed above. Moreover, metabolic alterations and direct effects on vascular endothelium have been noted for oxidative stress [128–130]. For example, metabolic syndrome, highly prevalent among those with MDD and CVD, is associated with decreased antioxidant capacity and increased levels ROS [130]. Oxidative stress is linked with all metabolic syndrome components and importantly is associated with the onset of CVD [130]. As noted above, foam cell production can also be initiated through oxidized lipids and/or proteins [130]. Increases in oxidative lipid compounds via activated endothelium increase local macrophages and inflammation and increased ROS production is thought to play a major role in reduced endothelium-derived nitric oxide [130]. In addition to biological plausibility, there is evidence that oxidative stress is associated with CVD in clinical samples. For example, higher oxidative stress levels are independently associated with increased number of affected coronary vessels [131], and higher oxidative stress burden is associated with increased mortality in coronary artery disease patients [132,133].

Hypothalamic-Pituitary-Adrenal Axis In prolonged states of stress, the role of cortisol and the HPA axis can contribute to the development of CVD and symptoms of depression [25,51,57,75]. For instance, elevated cortisol can lead to depression symptoms and the development of CAD [41,51,75,134]. However, the mechanism by which the sympathetic nervous system contributes to both CVD and depression is more complex than elevated cortisol and is likely a combination of proposed mechanisms. The stress response involves the release of corticotropin-releasing factor from hypothalamic neurons, which leads to stimulation of autonomic centers including the anterior pituitary. Upon stimulation, the anterior pituitary increases production and release of

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corticotropin and beta-endorphin [75,135]. The combined actions of the sympathetic nervous system and the adrenal medulla are thought to be overactive among depressed adults compared to those without depression [75,136]. In addition to the release of corticotropin, catecholamines (e.g., norepinephrine) are released which lead to physiological responses such as: increased heart rate, blood pressure, and release of stored glucose [135,136]. This response, as a part of the fight/flight response, is beneficial in acute stress conditions, as it accommodates increased metabolic demands of a highly aroused state [135,136]. In chronic stress conditions, the activation of the adrenal medulla and sympathetic nervous system can contribute to coronary ischemia, heart failure, and depression [75].

Serotonin and Platelets Serotonin plays a role in the HPA-axis pathways, platelet aggregation, and coronary vasoconstriction [75]. In addition to elevated norepinephrine, there are elevated levels of serotonin among those with depression. Both of these neurotransmitters can contribute to the development of atherosclerosis and cardiac function [75]. Alternatively, elevated levels of CVRFs, such as blood pressure and serum lipids, can increase the activation of platelets via increases in serotonin [75,137]. Platelets are involved in injury response and are involved in the development of atherosclerosis [46,75,137]. In the event of vascular injury, platelets stimulate vasoconstriction and attach to the vessel endothelium, where they are activated by thrombin to recruit more platelets for aggregation [46,75,137]. Additionally, activated platelets can stimulate macrophages to increase intake of lipids and contribute further to the adhesion and formation of foam cells [75]. Therefore, increased activation of platelets plays a role in the development and progression of atherosclerosis and CVD. In depressed adults, there is an overactivation of platelets, which can contribute to the increased prevalence and risk of atherosclerosis and CVD compared to nondepressed adults [75].

Autonomic Nervous System Dysfunction The autonomic nervous system, comprising the sympathetic and parasympathetic nervous system, is implicated in both depression and CVD. Autonomic nervous system regulates cardiovascular homeostasis and can change heart rate, contractility, vascular tone, and electrochemical conduction [49]. Heart rate variability, which is the variation between two successive intervals in a sinus rhythm, is a beat-to-beat measure of homeostatic vascular response and autonomic activity [49,75]. Greater heart rate variability indicates responsiveness to physiological changes and is indicative of good vascular and autonomic system regulation [49,138]. Adults with depression have been shown to have low heart rate variability irrespective of whether or not they have CVD [75,139]. Taken together, overactivation of the HPA axis can lead to increased release of stress hormones and neurotransmitters including norepinephrine. Norepinephrine and serotonin are elevated in both CVD and depression and can lead to aggregation of platelets, increased heart rate, lipid and glucose release from energy stores (as discussed above), increased macrophage recruitment, and uptake of lipids. The HPA axis plays a role in autonomic nervous system activity [49,75]. In the case of depression, increased sympathetic nervous system and decreased parasympathetic activity can lead to diminished vascular homeostasis, as observed by reduced heart rate variability [49,50,138,139].

TREATMENT The following is a nonexhaustive selective summary of treatments that target CVRFs and that have dual potential benefits for CVD and MDD. Although the focus here is on pharmacological treatments, it is well-recognized that intervening on behavioral lifestyle factors such as mindfulness, exercise, nutrition, and other targets also offers potential benefits [140–142].

Omega 3 Supplementation Omega-3 supplementation has been suggested to be beneficial for both the cardiovascular system and the brain (e.g., improved memory). There are scientific findings to support these claims, for example, lower levels of omega-3 are associated with risk for CAD and depression [143]. Likewise, higher intake of omega-3 was associated with greater gray matter volume in the corticolimbic circuitry; this circuitry is involved in emotion regulation [144]. Omega-3 has been studied as docosahexaenoic acid (DHA), as well as ethyl ester of eicosapentaenoic acid (E-EPA), with mixed findings [145]. In a casecontrol study of depressed patients with recent acute coronary syndromes, the depressed group had lower serum levels of omega-3 and DHA compared to the control group [143]. Conversely, a placebo-controlled study of middle-aged adults

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found that there was no significant difference in depression symptom reduction between the omega-3 group and placebogroup [146]. E-EPA has been shown to improve depression ratings, as an adjunctive treatment to antidepressant use, for major depression in adults [145]. This is in agreement with a meta-analysis of 28 studies, which concluded that EPA is more beneficial as a supplement to the treatment of depression [147]. This, however, was not supported in a placebo-controlled study of patients with CHD and depression, who received sertraline with both EPA and DHA [148]. Among youth (6–12 years of age), omega-3 has been shown to be an effective monotherapy for depression symptoms, compared to placebo [149]. This may indicate that earlier supplementation of omega-3 may provide more benefit for the reduction of depression symptoms. Further research on whether there is benefit of omega-3 as an adjunctive or monotherapy treatment for depression among those with and without CVD is needed, with focus on the dosing of EPA and DHA over a longer treatment course. It would also be interesting to see if omega-3 supplementation early in life has an effect on CVD and/or depression later in life.

Anti-Inflammatories Elevated inflammation has been repeatedly found in both CVD and major depression [51]. For instance, the acute-phase reactant C-reactive protein is clinically used as a marker of acute CVD [86]. Likewise, acetylsalicylic acid reduces mortality post-MI and is preventative of future MI, strokes, and blood-clots [87]. Several studies have assessed the efficacy and safety of using anti-inflammatory medication to treat depression. In a meta-analysis of anti-inflammatory medications among depressed adults, those taking celecoxib were more likely to have treatment response and achieve remission [150]. A study among adults with current depression found that celecoxib coadministration with reboxetine (a norepinephrine reuptake inhibitor; antidepressant) and celecoxib with placebo lead to significant reductions in depression symptoms compared to reboxetine alone [151]. Similar results have been found for the use of celecoxib as an adjunctive treatment to fluoxetine for major depression, whereby the celecoxib coadministered with fluoxetine significantly improved symptoms of depression compared to fluoxetine alone [152]. There has also been interest in the use of the natural health product curcumin for the treatment of depression, which has been shown to have effects on monoamines, inflammation, and oxidative stress pathways, as well as the stress response via the HPA axis [153]. A placebo-controlled study of adults with major depression found that curcumin treatment reduced self-reported depression scores, compared to placebo [153]. Further research on appropriate dosing and treatment duration is needed. The antidepressant effects of celecoxib and curcumin support the role of inflammatory processes in the biology of depression [152,153].

Metabolism: Metformin, Orlistat, and Sibutramine As discussed, there is a high prevalence of CVRFs and CVD risk conditions, such as diabetes and obesity, among those with depression. Medications affecting lipid profile, blood glucose levels, and abdominal obesity have been investigated for their possible antidepressant effects. Metformin, a medication used for the treatment of type II diabetes mellitus, has beneficial effects for patients who also have abdominal obesity [154]. In a study of adults with depression and comorbid type II diabetes mellitus, those who received metformin had greater improvements in depression, cognition, as well as changes in glucose metabolism, compared to the placebo group [154]. The use of drugs that affect metabolic profiles in groups at risk for CVD, such as those with depression, may actually confer greater CVD risk [155]. For example, sibutramine, an appetite suppressant, has been discontinued in several countries for increased risk of MI, stroke, and other CVD events [155]. One study, however, found that among obese adults, sibutramine in combination with a low-calorie diet leads to greater reductions in depression ratings, compared to orlistat and diet [156]. There is a limited number of this drug class that are approved for use among youth, and there has been mixed findings on CVRF and depression improvements. For example, among youth, orlistat improved BMI, but two participants became depressed [157]. Another study did not report any changes in mood after treatment [158].

Statins Statins, also known as hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been used for several years to reduce plasma cholesterol levels [159,160]. Statin reduction in cholesterol levels is associated with CVD risk and mortality reduction. Studies have also found that clinical use of statins has also been associated with reduction in symptoms of depression [159,160]. There are mixed findings regarding the efficacy of statins for antidepressant effects, and the mechanism underlying this antidepressant effect has not been fully elucidated [159–162]. In a meta-analysis of seven studies (n ¼ 9187), those who were receiving statin therapy were less likely to develop depression [161]. For instance, in a

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follow-up study of 140 patients using statins and 231 nonstatin using patients, the risk of developing depression was lower among the patients using statins [160]. Interestingly, the reduction in risk for depression was independent of the drug altering effects on cholesterol levels [160]. Potential pathways in which statins could lead to a reduced risk in depression have been studied. One study found that among patients treated with statins, some statins resulted in an inhibition of Th1 Cytokines (e.g., interferon-gamma) and a promotion of Th2 cytokines (e.g., interleukin 10) [162]. The enzyme capable of tryptophan degradation is inducible by interferon-gamma, which has been found in patients with CHD [162]. Since tryptophan, a precursor to serotonin, is being degraded, this may increase risk for depression [162].

CONCLUSION This selective overview reflects a fraction of the literature on the increasingly recognized link between MDD and CVD. Over the past 20 years, research findings have yielded increasing recognition by clinicians, the public, media, and health systems that the link between MDD and CVD requires purposeful consideration when planning treatment and organizing health services. Whereas much attention has been given to the impact of MDD on CVD outcomes, the field is still in the early stages of examining vascular-related treatments for the purpose of improving depression symptoms. Similarly, while for each of the mechanisms reviewed here, there is abundant literature within CVD and MDD, comparatively few studies have specifically examined these mechanisms for the purposes of understanding the CVD-MDD link within the same study. Taking into consideration how important early life and development is in terms of both CVD and MDD, future studies addressing these topics from a lifespan perspective will be particularly important for guiding our understanding of etiopathology and treatment [163,164].

REFERENCES [1] Greenberg PE, Fournier A-A, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry 2015;76:155–62. [2] Patten SB, Williams JV, Lavorato DH, Bulloch AG, Wiens K, Wang J. Why is major depression prevalence not changing? J Affect Disord 2016;190:93–7. [3] Gonza´lez HM, Tarraf W, Whitfield K, Gallo JJ. Vascular depression prevalence and epidemiology in the United States. J Psychiatr Res 2012;46:456–61. [4] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despr
es J-P, Fullerton HJ. Heart disease and stroke statistics—2016 update. Circulation 2016;133:e38–e360. [5] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despr
es J-P, Fullerton HJ, Howard VJ. Heart disease and stroke statistics-2015 update a report from the American Heart Association. Circulation 2015;131:E29–E322. [6] Callahan CM, Hui SL, Nienaber NA, Musick BS, Tierney WM. Longitudinal study of depression and health services use among elderly primary care patients. J Am Geriatr Soc 1994;42:833–8. [7] Katon WJ. Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Biol Psychiatry 2003;54:216–26. [8] Katon WJ, Lin E, Russo J, Un€utzer J. Increased medical costs of a population-based sample of depressed elderly patients. Arch Gen Psychiatry 2003;60:897–903. [9] Simon GE, VonKorff M, Barlow W. Health care costs of primary care patients with recognized depression. Arch Gen Psychiatry 1995;52:850–6. [10] Un€ utzer J, Patrick DL, Simon G, Grembowski D, Walker E, Rutter C, Katon W. Depressive symptoms and the cost of health services in HMO patients aged 65 years and older: a 4-year prospective study. JAMA 1997;277:1618–23. [11] Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, Marks J. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of US adults. Epidemiology 1993;285–94. [12] Ariyo AA, Haan M, Tangen CM, Rutledge JC, Cushman M, Dobs A, Furberg CD. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation 2000;102:1773–9. [13] Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang N-Y, Klag MJ. Depression is a risk factor for coronary artery disease in men: the precursors study. Arch Intern Med 1998;158:1422–6. [14] Frasure-Smith N, Lesp
erance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993;270:1819–25. [15] Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, van Tilburg W. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry 2001;58:221–7. [16] Sesso HD, Kawachi I, Vokonas PS, Sparrow D. Depression and the risk of coronary heart disease in the Normative Aging Study. Am J Cardiol 1998;82:851–6. [17] Whooley MA, Browner WS. Association between depressive symptoms and mortality in older women. Arch Intern Med 1998;158:2129–35. [18] Charlson FJ, Moran AE, Freedman G, Norman RE, Stapelberg NJ, Baxter AJ, Vos T, Whiteford HA. The contribution of major depression to the global burden of ischemic heart disease: a comparative risk assessment. BMC Med 2013;11:250.

192

Neurobiology of Depression

[19] Un€ utzer J, Patrick DL, Diehr P, Simon G, Grembowski D, Katon W. Quality adjusted life years in older adults with depressive symptoms and chronic medical disorders. Int Psychogeriatr 2000;12:15–33. [20] Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med 2000;160:3278–85. [21] Sullivan M, LaCroix A, Baum C, Resnick A, Pabiniak C, Grothaus L. Coronary disease severity and functional impairment: how strong is the relation? J Am Geriatr Soc 1996;44:1461–5. [22] Patton G, Carlin J, Coffey C, Wolfe R, Hibbert M, Bowes G. Depression, anxiety, and smoking initiation: a prospective study over 3 years. Am J Public Health 1998;88:1518–22. [23] Goodman E, Whitaker RC. A prospective study of the role of depression in the development and persistence of adolescent obesity. Pediatrics 2002;110:497–504. [24] Richardson LP, Davis R, Poulton R, McCauley E, Moffitt TE, Caspi A, Connell F. A longitudinal evaluation of adolescent depression and adult obesity. Arch Pediatr Adolesc Med 2003;157:739–45. [25] Goldstein BI, Carnethon MR, Matthews KA, McIntyre RS, Miller GE, Raghuveer G, Stoney CM, Wasiak H, McCrindle BW. Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease. Circulation 2015;132:965–86. [26] Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, Jacobson M, Mahoney L, Mietus-Snyder M, Rocchini A. Noninvasive assessment of subclinical atherosclerosis in children and adolescents. Hypertension 2009;54:919–50. [27] Kavey R-EW, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J. Cardiovascular risk reduction in highrisk pediatric patients. Circulation 2006;114:2710–38. [28] Goldstein BI, Schaffer A, Wang S, Blanco C. Excessive and premature new-onset cardiovascular disease among adults with bipolar disorder in the US NESARC cohort. J Clin Psychiatry 2015;76:163–9. [29] Weinberger A, Gbedemah M, Martinez A, Nash D, Galea S, Goodwin R. Trends in depression prevalence in the USA from 2005 to 2015: widening disparities in vulnerable groups. Psychol Med 2017;1–10. [30] Patten SB, Williams JV, Lavorato DH, Wang JL, Bulloch AG, Sajobi T. The association between major depression prevalence and sex becomes weaker with age. Soc Psychiatry Psychiatr Epidemiol 2016;51:203–10. [31] Shah AJ, Veledar E, Hong Y, Bremner JD, Vaccarino V. Depression and history of attempted suicide as risk factors for heart disease mortality in young individuals. Arch Gen Psychiatry 2011;68:1135–42. [32] Tobet S, Handa R, Goldstein J. Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease. Pfl€ ugers Arch 2013;465:585–94. [33] Carney RM, Freedland KE, Rich MW, Smith LJ, Jaffe AS. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease. Am J Med 1993;95:23–8. [34] Carney RM, Rich MW, Tevelde A, Saini J, Clark K, Jaffe AS. Major depressive disorder in coronary artery disease. Am J Cardiol 1987;60:1273–5. [35] Lesp
erance F, Frasure-Smith N. Depression in patients with cardiac disease: a practical review. J Psychosom Res 2000;48:379–91. [36] Lesp
erance F, Frasure-Smith N, Juneau M, Th
eroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med 2000;160:1354–60. [37] Schleifer SJ, Macari-Hinson MM. The nature and course of depression following myocardial infarction. Arch Intern Med 1989;149:1785–9. [38] Stern MJ, Pascale L, Ackerman A. Life adjustment postmyocardial infarction: determining predictive variables. Arch Intern Med 1977;137:1680–5. [39] Forrester AW, Lipsey JR, Teitelbaum ML, Depaulo JR, Andrzejewski PL, Robinson RG. Depression following myocardial infarction. Int J Psychiatry Med 1992;22:33–46. [40] Knopp RH. Risk factors for coronary artery disease in women. Am J Cardiol 2002;89:28–34. [41] Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003;54:227–40. [42] Pereira-Miranda E, Costa PR, Queiroz VA, Pereira-Santos M, Santana ML. Overweight and obesity associated with higher depression prevalence in adults: a systematic review and meta-analysis. J Am Coll Nutr 2017;36:223–33. [43] Frasure-Smith N, Lesperance F, Juneau M, Talajic M, Bourassa MG. Gender, depression, and one-year prognosis after myocardial infarction. Psychosom Med 1999;61:26–37. [44] Malzberg B. Mortality among patients with involution melancholia. Am J Psychiatry 1937;93:1231–8. [45] Rugulies R. Depression as a predictor for coronary heart disease: a review and meta-analysis. Am J Prev Med 2002;23:51–61. The full text of this article is available via AJPM online at www.ajpm-online.net. [46] Packham M, Nishizawa E, Mustard J. Response of platelets to tissue injury. Biochem Pharmacol 1968;17:171–84. [47] Vancampfort D, Mitchell AJ, Hert M, Sienaert P, Probst M, Buys R, Stubbs B. Type 2 diabetes in patients with major depressive disorder: a metaanalysis of prevalence estimates and predictors. Depress Anxiety 2015;32:763–73. [48] Rutledge T, Hogan BE. A quantitative review of prospective evidence linking psychological factors with hypertension development. Psychosom Med 2002;64:758–66. [49] Stapelberg NJ, Hamilton-Craig I, Neumann DL, Shum DH, McConnell H. Mind and heart: heart rate variability in major depressive disorder and coronary heart disease-a review and recommendations. Aust N Z J Psychiatry 2012;46:946–57. [50] Stein PK, Carney RM, Freedland KE, Skala JA, Jaffe AS, Kleiger RE, Rottman JN. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res 2000;48:493–500. [51] Sotelo JL, Nemeroff CB. Depression as a systemic disease. Pers Med Psychiatry 2017;1:11–25. [52] Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes. Diabetes Care 2001;24:1069–78.

Depression and Cardiovascular Risk: Epidemiology, Mechanisms, and Implications Chapter 17

193

[53] Moreira FP, Jansen K, de Azevedo Cardoso T, Mondin TC, da Silva Magalha˜es PV, Kapczinski F, de Mattos Souza LD, da Silva RA, Oses JP, Wiener CD. Metabolic syndrome in subjects with bipolar disorder and major depressive disorder in a current depressive episode: population-based study: metabolic syndrome in current depressive episode. J Psychiatr Res 2017;92:119–23. [54] Kozumplik O, Uzun S. Metabolic syndrome in patients with depressive disorder-features of comorbidity. Psychiatr Danub 2011;23:84–8. [55] Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the international diabetes federation. Diabet Med 2006;23:469–80. [56] Koksal UI, Erturk Z, Koksal AR, Ozsenel EB, Kaptanogullari OH. What is the importance of body composition in obesity-related depression? Eurasian J Med 2017;49:102. [57] Wulsin LR. Is depression a major risk factor for coronary disease? A systematic review of the epidemiologic evidence. Harv Rev Psychiatry 2004;12:79–93. [58] Golden SH, Shah N, Naqibuddin M, Payne JL, Hill-Briggs F, Wand GS, Wang N-Y, Langan S, Lyketsos C. The prevalence and specificity of depression diagnosis in a clinic-based population of adults with type 2 diabetes mellitus. Psychosomatics 2017;58:28–37. [59] Vaccarino V, Votaw J, Faber T, Veledar E, Murrah NV, Jones LR, Zhao J, Su S, Goldberg J, Raggi JP. Major depression and coronary flow reserve detected by positron emission tomography. Arch Intern Med 2009;169:1668–76. [60] Tomfohr LM, Murphy ML, Miller GE, Puterman E. Multiwave associations between depressive symptoms and endothelial function in adolescent and young adult females. Psychosom Med 2011;73:456. [61] Wassertheil-Smoller S, Applegate WB, Berge K, Chang CJ, Davis BR, Grimm R, Kostis J, Pressel S, Schron E. Change in depression as a precursor of cardiovascular events. Arch Intern Med 1996;156:553–61. [62] de Leon CFM, Krumholz HM, Seeman TS, Vaccarino V, Williams CS, Kasl SV, Berkman LF. Depression and risk of coronary heart disease in elderly men and women: New Haven EPESE, 1982-1991. Arch Intern Med 1998;158:2341–8. [63] Ferketich AK, Schwartzbaum JA, Frid DJ, Moeschberger ML. Depression as an antecedent to heart disease among women and men in the NHANES I study. Arch Intern Med 2000;160:1261–8. [64] Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996;93:1976–80. [65] Pratt LA, Ford DE, Crum RM, Armenian HK, Gallo JJ, Eaton WW. Depression, psychotropic medication, and risk of myocardial infarction. Circulation 1996;94:3123–9. [66] Huffman JC, Smith FA, Quinn DK, Fricchione GL. Post-MI psychiatric syndromes: six unanswered questions. Harv Rev Psychiatry 2006;14:305–18. [67] Januzzi JL, Stern TA, Pasternak RC, DeSanctis RW. The influence of anxiety and depression on outcomes of patients with coronary artery disease. Arch Intern Med 2000;160:1913–21. [68] Werheid K. A two-phase pathogenetic model of depression after stroke. Gerontology 2016;62:33–9. [69] Ahern DK, Gorkin L, Anderson JL, Tierney C, Hallstrom A, Ewart C, Capone RJ, Schron E, Kornfeld D, Herd JA. Biobehavioral variables and mortality or cardiac arrest in the Cardiac Arrhythmia Pilot Study (CAPS). Am J Cardiol 1990;66:59–62. [70] Frasure-Smith N. In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men. Am J Cardiol 1991;67:121–7. [71] Frasure-Smith N, Lesp
erance F, Gravel G, Masson A, Juneau M, Talajic M, Bourassa MG. Social support, depression, and mortality during the first year after myocardial infarction. Circulation 2000;101:1919–24. [72] Sullivan MD, LaCroix AZ, Spertus JA, Hecht J. Five-year prospective study of the effects of anxiety and depression in patients with coronary artery disease. Am J Cardiol 2000;86:1135–8. [73] Popa-Wagner A, Buga AM, Tica AA, Albu CV. Perfusion deficits, inflammation and aging precipitate depressive behaviour. Biogerontology 2014;15:439–48. [74] Lesperance F, Frasure-Smith N, Talajic M. Major depression before and after myocardial infarction: its nature and consequences. Psychosom Med 1996;58:99–110. [75] Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55:580–92. [76] Follick MJ, Ahern DK, Gorkin L, Niaura RS, Herd JA, Ewart C, Schron EB, Kornfeld DS, Capone RJ, Investigators C. Relation of psychosocial and stress reactivity variables to ventricular arrhythmias in the Cardiac Arrhythmia Pilot Study (CAPS). Am J Cardiol 1990;66:63–7. [77] Jiang W, Babyak M, Krantz DS, Waugh RA, Coleman RE, Hanson MM, Frid DJ, McNulty S, Morris JJ, O’connor CM. Mental stress-induced myocardial ischemia and cardiac events. JAMA 1996;275:1651–6. [78] Halaris A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr Top Behav Neurosci 2017;31:45–70. [79] Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry 2010;67:113. [80] Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry 2012;169:141–51. [81] Miller GE, Cole SW. Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biol Psychiatry 2012;72:34–40. [82] Clarke G, Harvey AG. The complex role of sleep in adolescent depression. Child Adolesc Psychiatr Clin N Am 2012;21:385–400.

194

Neurobiology of Depression

[83] Cappuccio FP, Cooper D, D’Elia L, Strazzullo P, Miller MA. Sleep duration predicts cardiovascular outcomes: a systematic review and metaanalysis of prospective studies. Eur Heart J 2011;32:1484–92. [84] Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH. Smoking and mental illness: a population-based prevalence study. JAMA 2000;284:2606–10. [85] Carney RM, Freedland KE. Depression and coronary heart disease. Nat Rev Cardiol 2017;14:145–55. [86] Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:363–9. [87] Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–9. [88] Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732–41. [89] Poole L, Dickens C, Steptoe A. The puzzle of depression and acute coronary syndrome: reviewing the role of acute inflammation. J Psychosom Res 2011;71:61–8. [90] Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002;90:1279–83. [91] Shimbo D, Chaplin W, Crossman D, Haas D, Davidson KW. Role of depression and inflammation in incident coronary heart disease events. Am J Cardiol 2005;96:1016–21. [92] Esteve E, Castro A, Lo´pez-Bermejo A, Vendrell J, Ricart W, Ferna´ndez-Real J-M. Serum interleukin-6 correlates with endothelial dysfunction in healthy men independently of insulin sensitivity. Diabetes Care 2007;30:939–45. [93] Verma S, Wang C-H, Li S-H, Dumont AS, Fedak PW, Badiwala MV, Dhillon B, Weisel RD, Li R-K, Mickle DA. A self-fulfilling prophecy. Circulation 2002;106:913–9. [94] Ferna´ndez-Real JM. Insulin resistance and atherosclerosis. The impact of oxidative stress on endothelial function. Rev Esp Cardiol 2008;8:42–9. [95] Bautista L. Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence. J Hum Hypertens 2003;17:223–30. [96] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. [97] Vita JA, Keaney JF, Larson MG, Keyes MJ, Massaro JM, Lipinska I, Lehman BT, Fan S, Osypiuk E, Wilson PW. Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation 2004;110:3604–9. [98] Kovacs I, Toth J, Tarjan J, Koller A. Correlation of flow mediated dilation with inflammatory markers in patients with impaired cardiac function. Beneficial effects of inhibition of ACE. Eur J Heart Fail 2006;8:451–9. [99] Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804–9. [100] Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67:446–57. [101] Barkhudaryan N, Dunn AJ. Molecular mechanisms of actions of interleukin-6 on the brain, with special reference to serotonin and the hypothalamopituitary-adrenocortical axis. Neurochem Res 1999;24:1169–80. [102] Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009;66:407–14. [103] M€ uller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog NeuroPsychopharmacol Biol Psychiatry 1998;22:1–33. [104] Aktas O, Ullrich O, Infante-Duarte C, Nitsch R, Zipp F. Neuronal damage in brain inflammation. Arch Neurol 2007;64:185–9. [105] Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001;2:734–44. [106] Wersching H, Duning T, Lohmann H, Mohammadi S, Stehling C, Fobker M, Conty M, Minnerup J, Ringelstein EB, Berger K, Deppe M, Knecht S. Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 2010;74:1022–9. [107] Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes. Neuroimmunomodulation 2002;10:319–27. [108] Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 1995;2:241–8. [109] Rao JS, Harry GJ, Rapoport SI, Kim HW. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 2010;15:384–92. [110] Knijff EM, Breunis MN, van Geest MC, Kupka RW, Ruwhof C, de Wit HJ, Nolen WA, Drexhage HA. A relative resistance of T cells to dexamethasone in bipolar disorder. Bipolar Disord 2006;8:740–50. [111] Miller AH, Pariante CM, Pearce BD. Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression. Adv Exp Med Biol 1999;461:107–16. [112] Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C, Miller AH. The proinflammatory cytokine, interleukin-1{alpha}, reduces glucocorticoid receptor translocation and function. Endocrinology 1999;140:4359–66. [113] D’Mello C, Swain MG. Immune-to-brain communication pathways in inflammation-associated sickness and depression. Curr Top Behav Neurosci 2017;31:73–94. [114] Maes M. The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 2008;29:287–91.

Depression and Cardiovascular Risk: Epidemiology, Mechanisms, and Implications Chapter 17

195

[115] Lopresti AL. Cognitive behaviour therapy and inflammation: a systematic review of its relationship and the potential implications for the treatment of depression. Aust N Z J Psychiatry 2017;51:565–82. [116] Yrondi A, Sporer M, Peran P, Schmitt L, Arbus C, Sauvaget A. Electroconvulsive therapy, depression, the immune system and inflammation: a systematic review. Brain Stimul 2018;11:29–51. [117] Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003;9:1062–8. [118] Tiwari BS, Belenghi B, Levine A. Oxidative stress increased respiration and generation of reactive oxygen species, resulting in ATP depletion, opening of mitochondrial permeability transition, and programmed cell death. Plant Physiol 2002;128:1271–81. [119] Shen GX. Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidase this review is one of a selection of papers published in a special issue on oxidative stress in health and disease. Can J Physiol Pharmacol 2010;88:241–8. [120] Tobe EH. Mitochondrial dysfunction, oxidative stress, and major depressive disorder. Neuropsychiatr Dis Treat 2013;9:567. [121] Liu T, Zhong S, Liao X, Chen J, He T, Lai S, Jia Y. A meta-analysis of oxidative stress markers in depression. PLoS ONE 2015;10. [122] Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW. Is depression associated with increased oxidative stress? A systematic review and metaanalysis. Psychoneuroendocrinology 2015;51:164–75. [123] Eren I, Naziroglu M, Demirdas A. Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain. Neurochem Res 2007;32:1188–95. [124] Durmaz O, Ispir E, Baykan H, Alisik M, Erel O. The impact of repetitive transcranial magnetic stimulation on oxidative stress in subjects with medication-resistant depression. J ECT 2018;34:127–31. [125] Murrough JW, Huryk KM, Mao X, Iacoviello B, Collins K, Nierenberg AA, Kang G, Shungu DC, Iosifescu DV. A pilot study of minocycline for the treatment of bipolar depression: effects on cortical glutathione and oxidative stress in vivo. J Affect Disord 2018;230:56–64. [126] Lindqvist D, Dhabhar FS, James SJ, Hough CM, Jain FA, Bersani FS, Reus VI, Verhoeven JE, Epel ES, Mahan L, Rosser R, Wolkowitz OM, Mellon SH. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 2017;76:197–205. [127] Mazereeuw G, Herrmann N, Andreazza AC, Scola G, Ma DWL, Oh PI, Lanctot KL. Oxidative stress predicts depressive symptom changes with omega-3 fatty acid treatment in coronary artery disease patients. Brain Behav Immun 2017;60:136–41. ´ , Esquivel-Chirino C, Durante-Montiel I, Sa´nchez[128] Ferna´ndez-Sa´nchez A, Madrigal-Santilla´n E, Bautista M, Esquivel-Soto J, Morales-Gonza´lez A Rivera G, Valadez-Vega C, Morales-Gonza´lez JA. Inflammation, oxidative stress, and obesity. Int J Mol Sci 2011;12:3117–32. [129] Berk M, Kapczinski F, Andreazza A, Dean O, Giorlando F, Maes M, Y€ucel M, Gama C, Dodd S, Dean B. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35:804–17. [130] Grattagliano I, Palmieri VO, Portincasa P, Moschetta A, Palasciano G. Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem 2008;19:491–504. [131] Vassalle C, Petrozzi L, Botto N, Andreassi MG, Zucchelli GC. Oxidative stress and its association with coronary artery disease and different atherogenic risk factors. J Intern Med 2004;256:308–15. [132] Patel RS, Ghasemzadeh N, Eapen DJ, Sher S, Arshad S, Ko YA, Veledar E, Samady H, Zafari AM, Sperling L, Vaccarino V, Jones DP, Quyyumi AA. Novel biomarker of oxidative stress is associated with risk of death in patients with coronary artery disease. Circulation 2016;133:361–9. [133] Vassalle C, Bianchi S, Bianchi F, Landi P, Battaglia D, Carpeggiani C. Oxidative stress as a predictor of cardiovascular events in coronary artery disease patients. Clin Chem Lab Med 2012;50:1463–8. [134] Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999;99:2192–217. [135] McEwen BS. Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci 1998;840:33–44. [136] Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis. Trends Neurosci 1997;20:78–84. [137] Levine SP, Towell BL, Suarez AM, Knieriem LK, Harris MM, George JN. Platelet activation and secretion associated with emotional stress. Circulation 1985;71:1129–34. [138] Pizzi C, Manzoli L, Mancini S, Costa GM. Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function. Eur Heart J 2008;29:1110–7. [139] Vaccarino V, Lampert R, Bremner JD, Lee F, Su S, Maisano C, Murrah NV, Jones L, Jawed F, Afzal N. Depressive symptoms and heart rate variability: evidence for a shared genetic substrate in a study of twins. Psychosom Med 2008;70:628–36. [140] Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO. Exercise treatment for depression: efficacy and dose response. Am J Prev Med 2005;28:1–8. [141] Brown SW, Welsh MC, Labb
e EE, Vitulli WF, Kulkarni P. Aerobic exercise in the psychological treatment of adolescents. Percept Mot Skills 1992;74:555–60. [142] Loucks EB, Schuman-Olivier Z, Britton WB, Fresco DM, Desbordes G, Brewer JA, Fulwiler C. Mindfulness and cardiovascular disease risk: state of the evidence, plausible mechanisms, and theoretical framework. Curr Cardiol Rep 2015;17:112. [143] Frasure-Smith N, Lesp
erance F, Julien P. Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol Psychiatry 2004;55:891–6. [144] Conklin SM, Gianaros PJ, Brown SM, Yao JK, Hariri AR, Manuck SB, Muldoon MF. Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults. Neurosci Lett 2007;421:209–12.

196

Neurobiology of Depression

[145] Nemets B, Stahl Z, Belmaker R. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477–9. [146] Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HFS, Puryear LJ. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003;160:996–8. [147] Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr 2009;28:525–42. [148] Carney RM, Freedland KE, Rubin EH, Rich MW, Steinmeyer BC, Harris WS. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. JAMA 2009;302:1651–7. [149] Nemets H, Nemets B, Apter A, Bracha Z, Belmaker R. Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry 2006;163:1098–100. [150] K€ ohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, Krogh J. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiat 2014;71:1381–91. [151] Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, Mohebbi-Rasa S, Raznahan M, Kamalipour A. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 2009;26:607–11. [152] M€ uller N, Schwarz M, Dehning S, Douhe A, Cerovecki A, Goldstein-M€uller B, Spellmann I, Hetzel G, Maino K, Kleindienst N. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006;11:680–4. [153] Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord 2014;167:368–75. [154] Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, Wang B. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol 2014;41:650–6. [155] Scheen AJ. Cardiovascular risk-benefit profile of sibutramine. Am J Cardiovasc Drugs 2010;10:321–34. [156] Kiortsis D, Tsouli S, Filippatos T, Konitsiotis S, Elisaf M. Effects of sibutramine and orlistat on mood in obese and overweight subjects: a randomised study. Nutr Metab Cardiovasc Dis 2008;18:207–10. [157] Chanoine J-P, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. JAMA 2005;293:2873–83. [158] Norgren S, Danielsson P, Jurold R, L€otborn M, Marcus C. Orlistat treatment in obese prepubertal children: a pilot study. Acta Paediatr 2003;92:666–70. [159] Tsai S-J. Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression. Med Hypotheses 2007;68:1296–9. [160] Young-Xu Y, Chan KA, Liao JK, Ravid S, Blatt CM. Long-term statin use and psychological well-being. J Am Coll Cardiol 2003;42:690–7. [161] Parsaik AK, Singh B, Hassan MM, Singh K, Mascarenhas SS, Williams MD, Lapid MI, Richardson JW, West CP, Rummans TA. Statins use and risk of depression: a systematic review and meta-analysis. J Affect Disord 2014;160:62–7. [162] Wirleitner B, Sperner-Unterweger B, Fuchs D. Statins to reduce risk of depression. J Am Coll Cardiol 2004;43:1132. [163] Goldstein BI, Carnethon MR, Matthews KA, McIntyre RS, Miller GE, Raghuveer G, Stoney CM, Wasiak H, McCrindle BW. Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease. A scientific statement from the American Heart Association. Circulation 2015;132:965–86. [164] Goldstein BI. Reducing the cost and burden of depression: incorporate heart and get an early start. J Clin Psychiatry 2015;76:e216–7.