The Interface of Coronary Artery Disease and Depression: Pathophysiology and Diagnosis

Abstract

Coronary Artery Disease (CAD) and depression are two of the most common human health problems. The association between CAD and depression is suggested to be bidirectional: depression is highly prevalent among patients with CAD and depression behaves as a risk factor for the development of CAD. Both diseases are complex disorders that are influenced by genetic and environmental factors. It has been suggested that depression is associated with both physiological and psychosocial changes that are deleterious to the cardiovascular system; although, the mechanisms underlying this connection remain unclear. There is a large body of literature demonstrating that proinflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of depressive disorders and antidepressant response. Although, it has been suggested that sex differences in the prevalence of major depression among cardiac patients exist: the prevalence of major depression is approximately two-times greater in women with CAD compared to men, similar to the general population. Depression is under-recognized in CAD patients because healthcare providers rarely use standardized screening instruments. For this reason, its important a systematic screening for depression in all CAD patients.

The aim of the present review was to systematically report current evidence on the biological mechanism at the base of depression-CAD relationship and the diagnostic method available in CAD patients.

Keywords: Coronary Artery Disease; Depression; Plasma Biomarkers; Life style

Introduction

Depression and Coronary Artery Disease (CAD) are both extremely prevalent diseases that compromised quality of life and life expectancy. It is well known that depression is highly prevalent among patients with CAD [1] and depression behaves as a risk factor for the development of CAD [2,3]. For this reason, the relationship between depression and CAD has been proposed to be bidirectional. Many prospective and retrospective studies have investigated the association of existing depression and CAD founding a significant positive correlation with a moderate effect size of 1.5–2.7 [4-6]. In addition, several studies have investigated the role of depression status as a prognostic factor in patients with existing CAD, suggesting that depressed patients have a 1.6–2.7-fold increased risk for further cardiovascular events within 24 months [7,8]. In patients with cardiovascular disease, the prevalence of major depression ranges around 15–20% [9], and the prevalence of elevated depression symptoms have been reported to be as high as 50% [10]. In particular, in patients with acute myocardial infarction, major depression was identified in 19.8% [1]. The presence of a depressive episode in CAD patients is associated with an elevated risk of secondary acute ischemic events, poorer compliance with risk factor interventions, and increased mortality independently of traditional cardiac risk factors [11,8].

Pathway linking depression and CAD

Established coronary risk factors such as hypercholesterolemia, hypertension, diabetes, obesity, and smoking are bound to accumulate in depressed patients [12]. A number of reasonable bio behavioral mechanisms are suggested to underlie the relationship between depression and CAD: treatment adherence and lifestyle factors such as smoking, heavy alcohol use, and physical inactivity. Depression is associated with an unhealthy lifestyle, such as decreased adherence to dietary and exercise regiments, increased alcohol intake and rates of smoking [13,14]. For these reasons, it has been suggested that depression is associated with both physiological and psychosocial changes that are deleterious to the cardiovascular system; although, the mechanisms underlying this connection remain unclear [15]. Depression is also associated with physiopathological changes that negatively influence the cardiovascular system, among which nervous system activations, cardiac rhythm disturbances, multi distrectual inflammation, and hypercoagulability (Figure).

The evidence of less Heart Rate Variability (HRV) in CAD patients with depression than non-depressed cardiac patients [16] may explain the possible role of autonomic imbalance in depression and CAD. Absence of HRV realizes a sympathetic-vagal disparity and is a risk factor for ventricular arrhythmias and sudden cardiac death in patients with cardiovascular disease [17]. This is aggravated among depressed patients with myocardial infarction, suggesting that low heart rate variability may facilitate the adverse outcome of depression on survival after a myocardial infarction.

Abnormal platelet function has been identified as possible links between depression and CAD. The role of platelets in atherosclerosis, thrombosis and acute coronary syndromes is well known. In addition, it was demonstrated that plasma levels of platelet factor IV and beta-thromboglobulin, markers of platelet activation, are higher in depressed patients with ischemic heart disease than in nondepressed patients with ischemic heart disease and control patients [18]. Interestingly, in depressed patients with myocardial infarction, treatment with a selective serotonin reuptake inhibitor, the sertraline, cause less activation of platelets and endothelial cells [19].

Biological mechanisms that might link these two conditions together include the Hypothalamic–Pituitary–Adrenal (HPA) axis and Sympathetic Adrenal Medullary (SAM) activation. This contribution may be mediated by the loss of glucocorticoid receptor-mediated negative feedback on inflammatory signaling. It is also worth noting that the disruptions of the HPA axis may be reciprocally regulated by altered expression of pro-inflammatory cytokines constituting a complex bidirectional biological crosstalk [20]. Dysregulation of the HPA axis may also lead to sympathoadrenal hyperactivity via central pathways. Sympathoadrenal activation leads to catecholamine production and subsequent tachycardia, vasoconstriction, and platelet activation [21].

The contribution of inflammation to the overall development of cardiac disease is well documented. Inflammation plays a key role in the initiation and promotion of atherosclerosis and may lead to Acute Coronary Syndrome by induction of plaque instability. For this reason, numerous inflammatory markers have been extensively investigated as potential candidates for the enhancement of cardiovascular risk assessment [22].

Some studies investigating also immune system functioning in subjects with depression and found high levels of inflammatory markers, particularly C-reactive protein and cytokines (interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-a (TNF-a)), in individuals with depression [23,24]. Since vagal tone inhibits the secretion of inflammatory cytokines, treatments that stimulate the vagus nerve such as exercise, biofeedback, and meditation may have favorable anti-inflammatory consequences [25]. Peripheral concentrations of inflammatory biomarkers, vascular endothelial dysfunction, and heightened platelet reactivity may be important processes that contribute to depression in CAD patients [26]. It is thought that repeated or prolonged activity of inflammatory processes and related pathophysiology can contribute to the persistence of depressive episodes and lead to neurodegeneration [27]. The proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) have direct inhibitory effects on adult hippocampal neurogenesis [28,29]. Cytokines include a number of pleiotropic proteins that have been extensively implicated in the process of inflammation. One of the major subset of mediator contributing in the interaction between inflammatory cells and endothelial and smooth muscle cells and the subsequent perpetuation of the inflammatory reaction are cytokines, especially the interleukins, and macrophage-associated cytokines like tumor necrosis factor (TNF)-a and interferon (IFN)-?. Their serum levels correlate positively with occurrence and severity of CAD, underlining their central role in the pathogenesis of atherosclerosis [30].

A large number of clinical studies have reported that Brain Derived Neurotropic Factor (BDNF) plasma and serum levels are significantly decreased in depressed patients, and that this decrease is normalized by antidepressant treatments [31-33]. These findings suggest that blood BDNF may be a useful biomarker for depression and that it could have a potential role in the pathophysiology and treatment of mood disorders. In fact, BDNF plays a critical role in regulating both vascular development and response to injury, and promotes survival, differentiation, and maintenance of neurons in peripheral and nervous system [34]. BDNF is also expressed in atherosclerotic coronary arteries [35] suggesting its possible role in the pathogenesis of CAD. The precise role of BDNF in the pathogenesis of CAD is not clear but appears to be associated with an increased inflammatory response by activated T cells and macrophages in atherosclerotic coronary arteries [36]. A previous work by Bozzini S et al. (2009) was aimed to study the possible correlation between the Val66Met polymorphisms in BDNF gene and depression in CAD patients [37]. They showed the possible involvement of the AA genotype and in the predisposition to CAD associated with depression. This polymorphism has been found to be associated with neuropsychiatric disorders including Alzheimer’s disease, Parkinson’s disease, depression, and bipolar disorder [38- 41]. Humans carrying the Met allele have smaller hippocampal volumes and perform poorly on hippocampal dependent memory tasks [42,43]. It has previously been shown that Met variant alters the intracellular trafficking and activity-dependent secretion of BDNF in neurosecretory cells and neurons [42,44].

Pharmacogenomic studies have evaluated the moderating effect of specific genetic variation on response to antidepressant therapies and Single-Nucleotide Polymorphisms (SNPs) in several genes was found to be associated with response or adverse effects with antidepressant [45]. These included, among others, 5-hydroxytryptamine and the serotonin transporter (SLC6A4) long/short variants. Evidences suggest that BDNF can enhance serotoninergic transmission that modulates different brain functions and it is known to regulate sleep, appetite, pain, and inflammation [46]. The complex serotonin (5-HT) neuronal system is under a bottleneck control by a single protein, 5-HT transporter (5-HTT). By controlling reuptake of 5-HT from the extracellular space, 5-HTT regulates the duration and strength of the interactions between 5-HT and its receptors. A polymorphism within the 5-HTT 5’ upstream region (5-HTTLPR) has been reported, the majority of which is composed of either 14 (S) or 16 (L) repetitive elements. In humans, although infrequent, 18 and 20 repetitive elements (XL) are also present [47-50]. An in vitro transcriptional assay indicated that the activity of the human 5-HTT promoter is regulated by these polymorphic repetitive elements, resulting in differences in the efficacy of 5-HTT reuptake among the allelic variants [51]. It previously observed a significant increase of L/L genotype and a decrease of S/L genotype respect to controls and a greater frequency of L allele, responsible for enhancing the efficiency of transcription, in CAD patients. These results may be responsible of the increased capacity of platelet serotonin uptake previously observed in patients with CAD [37].

Diagnosis of depression in CAD patients

Depression is under-recognized in CAD patients because healthcare providers rarely use standardized screening instruments [52-54]. The American Heart Association (AHA) recommends systematic screening for depression in all CAD patients using the Patients Health Questionnaire-2 (PHQ-2) [55], which was approved by the American Psychiatric Association. It has been shown that 20% of patients with recent myocardial infarction meet the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for major depression and score higher on depressive manifestations [56]. For the identification of depressed subjects, there are several questionnaires. The Patient Health Questionnaire (PHQ-2) provides two queries that are suggested to identify depressed patients [57]. If the answer is “yes” to one or both questions, it is recommended PHQ-9, a screening tool of depression concise, containing nine questions, to which most of the patients are able to respond fully without assistance [The MacArthur Initiative on Depression and Primary Care. Patient health questionnaire tool kit for clinicians. Available from: ]. It provides a conditional diagnosis of depression as well as the layering of gravity, which is useful for the choice of treatment and monitoring.

The Hospital Anxiety and Depression Scale (HADS) [58] was shown to be a reliable depression screening instrument in general practice and in medical patients, but yielded conflicting results in CAD patients [59,60]. In CAD patients, the Beck Depression Inventory-II (BDI-II) [61] is widely used, but there are a few studies evaluating the psychometric properties of the BDI-II in stable CAD patients [62,63]. In 2011, Bunevicius A et al. evaluated the internal consistency and psychometric properties of the HADS and the BDI-II for screening of major depressive episodes in CAD patients undergoing rehabilitation. They found that internal consistencies of the HADS and BDI-II are high. The BDI-II and HADS-A demonstrate the higher sensitivity compared to the HADS-D and HADS-total for screening of major depressive episodes in CAD patients. Positive predictive values for the BDI-II and for the HADS were low indicating that a large proportion of patients with positive screening results did not meet criteria for major depressive episodes [64].

Gender studies

Women have traditionally received less focus in heart disease research relative to men, despite well-known gender differences indicating comparative less aggressive treatments, less accurate diagnostic tests, and higher post-myocardial infarction mortality among women [65,66]. Depression rates among women exceeded for men by factor of more than 2 to 1 [67] and they may be associated with clinical symptoms that affect cardiac diagnosis and treatment [65]. Biological factors suchas hormones and psychosocial factors such as role overload have been postulated to explain this gender difference [68]. Although it has been suggested that sex differences in the prevalence of major depression among cardiac patients exist [69]. A meta-analysis performed by Shanmugasegaram S et al., in 2012 demonstrated that the prevalence of major depression is approximately two-times greater in women with CAD compared to men, similar to the general population [70].

Conclusion

Clinical and preclinical studies have identified a number of factors that may serve as putative biomarkers for diagnosing and treating depression in CAD. However, the utility of any given growth factor, cytokine, endocrine factor, or metabolic marker to serve as a clinically useful biomarker is limited by a lack of sensitivity and specificity. A number of behavioral mechanisms were suggested to underlie the relationship between depression and CAD: treatment adherence and lifestyle factors such as smoking, heavy alcohol use, and physical inactivity. Depression foresees reduced adherence to prescribed regimens and it is also related with increased alcohol intake and physical inactivity, with increased rates of smoking and may lower the success of smoking cessation programs in CAD patients.

Similar to the general population, the prevalence of major depression is approximately two-times greater in women with CAD compared to men. Given the poorer prognosis associated with comorbid major depression in CAD it is important to devote more attention to identify and address potential factors that could account for gender differences in depression. CAD-related mortality in women is high and the prevalence of depression among women in the general population is big. Guidelines require screening of depression in patients with ischemic heart disease, from which women could benefit, stressing the need to systematically assess the presence or absence of a gender gap in depression.

As the link between depression and CAD has become increasingly predictable and established between specialists, pharmacologic and no pharmacologic interventions on depression in patients with heart disease have come into practice. Therapeutic advances have shown a persuasive link between successful management of depression in patients with CAD and a reduction of cardiovascular events. However, the investigations addressing this hypothesis have demonstrated a variety of conclusions. Some mechanisms were proposed to explain antidepressant toxicity, such as ventricular arrhythmias from prolonged QTc, vasoconstriction form serotonin and bleeding to platelet inhibition from Selective Serotonin Reuptake inhibitors (SSRi). Other studies indicate mood and cardiac prognosis improvement in persistent depression among post-acute coronary syndrome patients by antidepressant and/or psychotherapy. However, the literature does not indicate clear superiority of any particular psychotherapy and the treatment response and medical prognosis of different patients’ subgroups appear heterogeneous [71].

Depressive symptoms and CAD are both associated with increased inflammation and exercise intervention have been shown to reduce inflammation in these patients with a significant reduction in morbidity and mortality [72,73]. Some studies reported that physical activity plays a particularly important role in reduction the risk of cardiovascular events among CAD patients with depressive symptoms [74]. However, CAD patients with depressive symptoms are less prone to increase physical activity over 12 month compared with those without depressive symptoms [75]. Of note, increased physical activity may ameliorate depressive symptoms; by itself, an intensive 16-week aerobic exercise regimen has shown to be as effective as pharmacologic therapy in treating older adults for major depressive disorder [76].

Depressive symptoms should be seen by the cardiologist emerging risk factor for cardiovascular disease, and as such, its early detection through simple questionnaires should more lead to a longterm lifestyle change, as well as a therapeutic treatment.

References

1. Thombs BD, Bass EB, Ford DE, Stewart KJ, Tsilidis KK, Patel U, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med. 2006; 21: 30-38.
2. Bush DE, Ziegelstein RC, Tayback M, Richter D, Stevens S, Zahalsky H, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol. 2001; 88: 337-341.
3. Carney RM, Freedland KE, Sheline YI, Weiss ES. Depression and coronary heart disease: a review for cardiologists. Clin Cardiol. 1997; 20: 196-200.
4. Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehouwer C, Beekman A. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int J Geriatr Psychiatry. 2007; 22: 613-626.
5. Rugulies R. Depression as a predictor for coronary heart disease. a review and meta-analysis. Am J Prev Med. 2002; 23: 51-61.
6. Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J. 2006; 27: 2763-2774.
7. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med. 2004; 66: 802-813.
8. van Melle JP, de Jonge P, Spijkerman TA, Tijssen JG, Ormel J, van Veldhuisen DJ, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med. 2004; 66: 814-822.
9. Lett HS, Blumenthal JA, Babyak MA, Strauman TJ, Robins C, Sherwood A. Social support and coronary heart disease: epidemiologic evidence and implications for treatment. Psychosom Med. 2005; 67: 869-878.
10. Lespérance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation. 2002; 105: 1049-1053.
11. 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: 1913-1921.
12. Joynt KE, Whellan DJ, O'Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiatry. 2003; 54: 248-261.
13. Glassman AH, Helzer JE, Covey LS, Cottler LB, Stetner F, Tipp JE, et al. Smoking, smoking cessation, and major depression. JAMA. 1990; 264: 1546-1549.
14. Camacho TC, Roberts RE, Lazarus NB, Kaplan GA, Cohen RD. Physical activity and depression: evidence from the Alameda County Study. Am J Epidemiol. 1991; 134: 220-231.
15. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999; 99: 2192-2217.
16. Carney RM, Saunders RD, Freedland KE, Stein P, Rich MW, Jaffe AS. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol. 1995; 76: 562-564.
17. Gehi A, Mangano D, Pipkin S, Browner WS, Whooley MA. Depression and heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Arch Gen Psychiatry. 2005; 62: 661-666.
18. Laghrissi-Thode F, Wagner WR, Pollock BG, Johnson PC, Finkel MS. Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry. 1997; 42: 290-295.
19. Serebruany VL, Glassman AH, Malinin AI, Nemeroff CB, Musselman DL, van Zyl LT, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation. 2003; 108: 939-944.
20. Sasayama D, Hori H, Iijima Y, Teraishi T, Hattori K, Ota M, et al. Modulation of cortisol responses to the DEX/CRH test by polymorphisms of the interleukin-1beta gene in healthy adults. Behav Brain Funct. 2011; 7: 23.
21. Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010; 90: 513-557.
22. Bozzini S, Falcone C. Inflammation in Ischemic Heart Disease. J Dis Markers. 2015; 2: 1026.
23. Whooley MA, Caska CM, Hendrickson BE, Rourke MA, Ho J, Ali S. Depression and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biol Psychiatry. 2007; 62: 314-320.
24. Empana JP, Sykes DH, Luc G, Juhan-Vague I, Arveiler D, Ferrieres J, et al. Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction [PRIME) Circulation. 2005; 111: 2299–2305.
25. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007; 117: 289-296.
26. Celano CM, Huffman JC. Depression and cardiac disease: a review. Cardiol Rev. 2011; 19: 130-142.
27. Maes M, Ruckoanich P, Chang YS, Mahanonda N, Berk M. Multiple aberrations in shared inflammatory and oxidative &nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Progr. Neuro-Psychopharmacol. Biol. Psychiatry. 2011: 35: 769–783.
28. Iosif RE, Ekdahl CT, Ahlenius H, Pronk CJ, Bonde S, Kokaia Z, et al. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci. 2006; 26: 9703-9712.
29. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003; 302: 1760-1765.
30. Schuett H, Schieffer B. Targeting cytokine signaling as an innovative therapeutic approach for the prevention of atherosclerotic plaque development. Curr Atheroscler Rep. 2012; 14: 187-189.
31. Huang TL, Lee CT, Liu YL. Serum brain-derived neurotrophic factor levels in patients with major depression: effects of antidepressants. J Psychiatr Res. 2008; 42: 521-525.
32. Okamoto T, Yoshimura R, Ikenouchi-Sugita A, Hori H, Umene-Nakano W, Inoue Y, et al. Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1185-1190.
33. Yoshimura R, Mitoma M, Sugita A, Hori H, Okamoto T, Umene W, et al. Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 1034-1037.
34. Donovan MJ, Miranda RC, Kraemer R, McCaffrey TA, Tessarollo L, Mahadeo D, et al. Neurotrophin and neurotrophin receptors in vascular smooth muscle cells. Regulation of expression in response to injury. Am J Pathol. 1995; 147: 309-324.
35. Ejiri J, Inoue N, Kobayashi S, Shiraki R, Otsui K, Honjo T, et al. Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease. Circulation. 2005; 112: 2114-2120.
36. Gopalakrishnan P, Ragland MM, Tak T. Gender differences in coronary artery disease: review of diagnostic challenges and current treatment. Postgrad Med. 2009; 121: 60-68.
37. Bozzini S, Gambelli P, Boiocchi C, Schirinzi S, Falcone R, Buzzi P, et al. Coronary artery disease and depression: possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms. Int J Mol Med. 2009; 24: 813-818.
38. Ventriglia M, Bocchio Chiavetto L, Benussi L, Binetti G, Zanetti O, Riva MA, et al. Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol Psychiatry. 2002; 7: 136-137.
39. Momose Y, Murata M, Kobayashi K, Tachikawa M, Nakabayashi Y, Kanazawa I, et al. Association studies of multiple candidate genes for Parkinson's disease using single nucleotide polymorphisms. Ann Neurol. 2002; 51: 133-136.
40. Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A, et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology. 2003; 28: 397-401.
41. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet. 2002; 71: 651-655.
42. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003; 112: 257-269.
43. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003; 23: 6690-6694.
44. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004; 24: 4401-4411.
45. Lin E, Chen PS. Pharmacogenomics with antidepressants in the STAR*D study. Pharmacogenomics. 2008; 9: 935-946.
46. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008; 33: 73-83.
47. Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD. Serotonin 5-hydroxytryptamine (2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J Pharmacol Exp Ther. 2008; 327: 316-323.
48. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996; 66: 2621-2624.
49. Delbrück SJ, Wendel B, Grunewald I, Sander T, Morris-Rosendahl D, Crocq MA, et al. A novel allelic variant of the human serotonin transporter gene regulatory polymorphism. Cytogenet Cell Genet. 1997; 79: 214-220.
50. Murakami F, Shimomura T, Kotani K, Ikawa S, Nanba E, Adachi K. Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese. J Hum Genet. 1999; 44: 15-17.
51. Narita N, Narita M, Takashima S, Nakayama M, Nagai T, Okado N. Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population. Pediatrics. 2001; 107: 690-692.
52. Feinstein RE, Blumenfield M, Orlowski B, Frishman WH, Ovanessian S. A national survey of cardiovascular physicians' beliefs and clinical care practices when diagnosing and treating depression in patients with cardiovascular disease. Cardiol Rev. 2006; 14: 164-169.
53. Gelenberg AJ. Using assessment tools to screen for, diagnose, and treat major depressive disorder in clinical practice. J Clin Psychiatry. 2010; 71.
54. Williams JW, Pignone M, Ramirez G, Perez Stellato C. Identifying depression in primary care: a literature synthesis of case-finding instruments. Gen Hosp Psychiatry. 2002; 24: 225-237.
55. Lichtman JH, Bigger Jr JT, Blumenthal JA, Frasure-Smith N, Kaufmann PG, Lespérance F. Council on Clinical Cardiology, American Heart Association Council on Epidemiology and Prevention, American Heart Association Interdisciplinary Council on Quality of Care and Outcomes Research,American Psychiatric Association. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association. Circulation. 2008; 118: 1768–1775.
56. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR) 4th edition. Washington, DC: American Psychiatric Association. 2000.
57. Whooley MA, Simon GE. Managing depression in medical outpatients. N Engl J Med. 2000; 343: 1942-1950.
58. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983; 67: 361-370.
59. Haworth JE, Moniz-Cook E, Clark AL, Wang M, Cleland JG. An evaluation of two self-report screening measures for mood in an out-patient chronic heart failure population. International Journal of Geriatric Psychiatry 2007; 22: 1147–1153.
60. Martin CR, Thompson DR, Barth J. Factor structure of the Hospital Anxiety and Depression Scale in coronary heart disease patients in three countries. J Eval Clin Pract. 2008; 14: 281-287.
61. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory [BDI-II). 2nd edition. San Antonio, TX: The Psychological Association. 1996.
62. Frasure-Smith N, Lespérance F, Prince RH, Verrier P, Garber RA, Juneau M, et al. Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet. 1997; 350: 473-479.
63. Low GD, Hubley AM. Screening for depression after cardiac events using the Beck Depression Inventory-II and the Geriatric Depression Scale. Social Indicators Research: An International and Interdisciplinary Journal for Quality-of-Life Measurement. 2007; 82: 527–543.
64. Bunevicius A, Staniute M, Brozaitiene J, Bunevicius R. Diagnostic accuracy of self-rating scales for screening of depression in coronary artery disease patients. J Psychosom Res. 2012; 72: 22-25.
65. Shaw LJ, Miller DD, Romeis JC, Kargl D, Younis LT, Chaitman BR. Gender differences in the noninvasive evaluation and management of patients with suspected coronary artery disease. Ann Intern Med. 1994; 120: 559-566.
66. Krumolz HM, Douglas PS, Lauer MS, Pasternak RC. Selection of patients for coronary angiography and coronary revascularization early after myocardial infarction: is there evidence for a gender bias? Ann Intern Med 1992; 116: 785–790.
67. Strong DR, Kahler CW, Colby SM, Griesler PC, Kandel D. Linking measures of adolescent nicotine dependence to a common latent continuum. Drug Alcohol Depend. 2009; 99: 296-308.
68. Kornstein SG. Gender differences in depression: implications for treatment. J Clin Psychiatry. 1997; 58: 12-18.
69. Frasure-Smith N, Lespérance F. Depression and anxiety as predictors of 2-year cardiac events in patients with stable coronary artery disease. Arch Gen Psychiatry. 2008; 65: 62-71.
70. Shanmugasegaram S, Russell KL, Kovacs AH, Stewart DE, Grace SL. Gender and sex differences in prevalence of major depression in coronary artery disease patients: a meta-analysis. Maturitas. 2012; 73: 305-311.
71. Ramamurthy G, Trejo E, Faraone SV. Depression treatment in patients with coronary artery disease: a systematic review. Prim Care Companion CNS Disord. 2013; 15.
72. Zarin DA, Young JL, West JC. Challenges to evidence-based medicine: a comparison of patients and treatments in randomized controlled trials with patients and treatments in a practice research network. Soc Psychiatry Psychiatr Epidemiol. 2005; 40: 27-35.
73. Taylor RS, Unal B, Critchley JA, Capewell S. Mortality reductions in patients receiving exercise-based cardiac rehabilitation: how much can be attributed to cardiovascular risk factor improvements? Eur J Cardiovasc Prev Rehabil. 2006; 13: 369-374.
74. Charlson ME, Peterson JC, Boutin-Foster C, Briggs WM, Ogedegbe GG, McCulloch CE, et al. Changing health behaviors to improve health outcomes after angioplasty: a randomized trial of net present value versus future value risk communication. Health Educ Res. 2008; 23: 826-839.
75. Peterson JC. The adaptive neuroplasticity hypothesis of behavioral maintenance. Neural Plast. 2012; 516364.
76. Blumenthal JA, Babyak MA, Moore KA, Craighead WE, Herman S, Khatri P, et al. Effects of exercise training on older patients with major depression. Arch Intern Med. 1999; 159: 2349-2356.