The limbic system is a complex set of structures that includes the hypothalamus, the hippocampus, the amygdala, and several nearby areas. It seems to be primarily responsible for emotional life and the formation of memories. As described earlier, the hypothalamus is mainly responsible for homeostasis and thereby regulates heart rate, blood pressure, breathing, and gastrointestinal motility and also regulates behavior and arousal in response to hunger, thirst, and emotional circumstances (eg, pain, pleasure, sex, fear, or hostility).
Repeated stress especially affects the hippocampus, which participates in verbal memory and is particularly important for the memory of context, that is, the time and place of events that have a strong emotional bias . Moreover, glucocorticoids are involved in remembering the context in which an emotionally laden event took place. The hippocampus also regulates the stress response and acts to inhibit the response of the HPA axis to stress.
The hypothalamus, especially the arcuate nucleus, is relatively accessible to circulating factors and receives inputs from other areas of the brain, including the tractus solitarius and the area postrema . The hypothalamus receives signals that relate to total energy stores in fat and to immediate changes in energy availability, including insulin, leptin, and nutrients within the gut. Afferent signals from the gut to the brain are carried in vagal and splanchnic nerve pathways. The gut also releases several hormones that have incretin- (GLP-1, GIP), hunger- (Ghrelin), and satiety-stimulating (PYY, GLP-1, OXM) actions . In addition, major afferent input originates from the adipose tissue. The adipocyte is now recognized as a bona fide endocrine cell. Adipocyte hormones such as adiponectin, resistin, and visfatin influence appetite, glucose homeostasis and insulin sensitivity, and vascular function, among other functions .
The hypothalamus integrates these peripheral and central signals and exerts homeostatic control over food intake, levels of physical activity, basal energy expenditure, and endocrine systems.
There is no doubt that food intake in humans is influenced by emotional factors, social cues, and learned behavior. Functional neuroimaging techniques have provided the first insight in the response of the brain to nutritional stimuli. Differences regarding both the need to eat and the pleasure of eating between obese and lean individuals have been noted .
In obese individuals the decrease in hypothalamic activity following a meal is significantly reduced compared with lean individuals. Importantly, the neural substrates of the sensory perception of food overlap extensively with the brain representation of reward. Dopamine is the neurotransmitter that plays a central role in mediating the anticipation of reward. Abnormalities in dopaminergic transmission can be evidenced in obese individuals . A decreased D2 receptor function in this same reward area of the brain has been shown, varying inversely with body mass index.
Various other data suggest that the link between chronic psychologic distress and adverse behavior such as overeating may be centrally mediated [83,84]. Normally, glucocorticoids help end acute stress responses by exerting negative feedback on the HPA axis. In contrast, it has been shown in a rat model that glucocorticoids occupy central glucocorticoid receptors during chronic stress, with resultant activation of the chronic stress response network, including continued glucocorticoid production . This combination of chronic stress and high glucocorticoid levels seems to stimulate a preferential desire to ingest sweet and fatty foods, presumably by affecting dopaminergic transmission in areas of the brain associated with motivation and reward . Similar to observations in obese individuals, diminished do-pamine D2-binding potential within midbrain systems under conditions of chronic stress has been shown by positron-emission tomography scanning in the Cynomolgus monkey . It has been demonstrated that in humans this area is involved specifically in food motivation .
Recent evidence also links brain areas associated with reward with those that sense physical pain. It is common notion that chronic pain can cause depression, and depression can increase pain. Most patients who have depression also present with mainly physical symptoms . Studies using functional MRI have shown that social rejection lights up brain areas that are also key regions in the response to physical pain. The area of the anterior cingulate cortex that is activated by visceral pain also is activated in cases of social rejection . The importance of these brain areas is underscored by the observation that the right ventral prefrontal cortex that mitigates emotional distress caused by pain is activated when placebo administration relieves pain .
These stress-induced changes (ie, allostatic load) are not without consequences. MRI has shown that stress-related disorders such as recurrent depressive illness or posttraumatic stress disorder are associated with atrophy of the hippocampus [92,93]. Impairment of the hippocampus decreases the reliability and accuracy of contextual memories. This decrement may exacerbate stress by preventing access to the information needed to decide that a situation is not an emotional or physical threat. Also, the suppression of routine sensory input from the body that normally occurs might, under these circumstances, be felt as discomfort or pain. There is evidence that an-tidepressants can reverse these changes .
From the previous discussion, it has become clear that some parts of the pathophysiologic basis for the association between depression, cardiovascular diseases, and the metabolic syndrome are gradually becoming clearer, but these associations are complex and should be modeled over the lifetime. Because exposure to various disease risks (ie, physical, psychosocial stress, and behavioral stressors) in humans changes over time, and risks cluster together in variable fashion, it is evident that a simple cause-and-effect approach does not fit the individual patient. One must define the chain of risk (as discussed later) with its mediating and modifying factors that have played and still play a role. For this reason an integrated approach with close attention to the history and actual needs and expectations of the individual patient in both the biologic and psychosocial domains is necessary.
It is not necessary to identify with certainty or to address every component cause or risk to prevent or avoid further deterioration of a disease. To understand this notion, one needs to address the issue of causation once more. When one defines a cause of a disease as an event, condition, or characteristic that preceded the disease and without which the disease either would not have occurred at all or would not have occurred until some later time, it follows that no specific event, condition, or characteristic is sufficient by itself to produce disease . A sufficient cause can be defined as a set of minimal conditions and events that over time inevitably produce disease. A minimal cause implies that all of the conditions or events are necessary for disease occurrence. For a disease to occur, a multitude of component causes are needed that act over time in a chain of risk that in turn involves mediating and modifying factors. The importance of this notion is that most identified causes are neither necessary nor sufficient to produce disease. Vice-versa, a cause need not be either necessary or sufficient for its removal to result in disease prevention in some individuals. Because each individual has a unique chain of risks over time, it should come as no surprise that until now it has been difficult to prove that treatment for depression benefits the cardiovascular outcome after myocardial infarction .
This lack of proof, however, does not preclude the possibility that some subjects do benefit in this respect. Although the therapeutic advice in this context should be based on the overall outcome of such intervention studies,
PHYSIOLOGICAL -• Stop smoking ADDICTIONS
BREAK MOOD-REGULATING HABITS
Change from BREAK HABITS —• sedentary to active lifestyle
PHYSIOLOGICAL -• Stop smoking ADDICTIONS
BREAK MOOD-REGULATING HABITS
Change from BREAK HABITS —• sedentary to active lifestyle
Fig. 2. Hierarchy of interventions relative to their complexity. (From Rozanski A. Integrating psychologic approaches into the behavioral management of cardiac patents. Psychosom Med 2005;67(Suppl 1):S68; with permission.)
it is important to pay proper attention to all three biopsychosocial domains, and thus the individual situation of a patient, and to act as one deems necessary for the general health of the patient. This approach is, at the same time, the most difficult, because inducing patients to make behavioral changes is much more difficult than prescribing some medication (Fig. 2) . Such an approach, however, will best address the patients' physical, emotional, and social well being and, importantly, create a trusting patient-doctor relationship. It is evident that current medical services, which by definition act upon simple cause-and-effect disease models, do not suffice to provide this kind of patient-tailored therapy.
 Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415-28.
 Alberti KG, Zimmet P, Shaw J, for the IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet 2005;366:1059-62.
 Kahn R, Buse J, Ferrannini E, et al. The American Diabetes Association. European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28:2289-304.
 Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
 Engum A, Mykletun A, Midthjell K, et al. Depression and diabetes: a large population-based study of sociodemographic, lifestyle, and clinical factors associated with depression in type 1 and type 2 diabetes. Diabetes Care 2005;28:1904-9.
 Kinder LS, Carnethon MR, Palaniappan LP, et al. Depression and the metabolic syndrome in young adults: findings from the Third National Health and Nutrition Examination Survey. Psychosom Med 2004;66:316-22.
 Haslam DW, James WP. Obesity. Lancet 2005;366:1197-209.
 Everson-Rose SA, Meyer PM, Powell LH, et al. Depressive symptoms, insulin resistance, and risk of diabetes in women at midlife. Diabetes Care 2004;27:2856-62.
 Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med 2002;23(1):51-61.
 Rozanski A, Blumenthal JA, Davidson KW, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005;45:637-51.
 Yusuf S, Hawken S, Ounpuu S, et al. INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52.
 Alexopoulos GS, Meyers BS, Young RC, et al. 'Vascular depression' hypothesis. Arch Gen Psychiatry 1997;54:915-22.
 Ben-Shlomo Y, Kuh D. A life course approach to chronic disease epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives. Int J Epidemiol 2002;31: 285-93.
 Frankel S, Elwood P, Sweetnam P, et al. Birthweight, body-mass index in middle age, and incident coronary heart disease. Lancet 1996;348:1478-80.
 Lithell HO, McKeigue PM, Berglund L, et al. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years. BMJ 1996;312:406-10.
 Eriksson JG, ForsenT, Tuomilehto J, et al. Early growth and coronary heart disease in later life: longitudinal study. BMJ 2001;322:949-53.
 Wiles NJ, Peters TJ, Leon DA, et al. Birth weight and psychological distress at age 45-51 years: results from the Aberdeen Children of the 1950s cohort study. Br J Psychiatry 2005; 187:21-8.
 Kuh D, Hardy R, Langenberg C, et al. Mortality in adults aged 26-54 years related to socioeconomic conditions in childhood and adulthood: post war birth cohort study. BMJ 2002; 325:1076-80.
 Kaplan GA. Going back to understand the future: socioeconomic position and survival after myocardial infarction. Ann Intern Med 2006;144:137-9.
 Brunner EJ, Marmot MG, Nanchahal K, et al. Social inequality in coronary risk: central obesity and the metabolic syndrome. Evidence from the Whitehall II study. Diabetologia 1997;40(11):1341-9.
 Fryers T, Melzer D, Jenkins R, et al. The distribution of the common mental disorders: social inequalities in Europe. Clin Pract Epidemol Ment Health 2005;1:14.
 Selye H. Syndrome produced by diverse nocuous agents. Nature 1936;138:32.
 McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med 1998;338(3): 171-9.
 Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002;3:655-66.
 Tracey KJ. The inflammatory reflex. Nature 2002;420(6917):853-9.
 Hanley AJ, Wagenknecht LE, D'Agostino RB Jr, et al. Identification of subjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome. Diabetes 2003;52(11):2740-7.
 Okamura F, Tashiro A, Utumi A, et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism 2000; 49:1255-60.
 Ramasubbu R. Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases. Med Hypotheses 2002;59:537-51.
 Lawlor DA, Smith GD, Ebrahim S. British Women's Heart and Health Study. Association of insulin resistance with depression: cross sectional findings from the British Women's Heart and Health Study. BMJ 2003;327:1383-4.
 Timonen M, Laakso M, Jokelainen J, et al. Insulin resistance and depression: cross sectional study. BMJ 2005;330:17-8.
 Weber-Hamann B, Hentschel F, Kniest A, et al. Hypercortisolemic depression is associated with increased intra-abdominal fat. Psychosom Med 2002;64:274-7.
 Brunner EJ, Hemingway H, Walker BR, et al. Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study. Circulation 2002;106: 2659-65.
 Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect "Cushing's disease of the omentum''? Lancet 1997;349:1210-3.
 Kreier F, Yilmaz A, Kalsbeek A, et al. Hypothesis: shifting the equilibrium from activity to food leads to autonomic unbalance and the metabolic syndrome. Diabetes 2003;52:2652-6.
 Festa A, D'Agostino R Jr, Hales CN, et al. Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects. Diabetes Care 2000;23:624-8.
 Panzer C, Lauer MS, Brieke A, et al. Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes 2002;51:803-7.
 Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 2005;67(Suppl 1):S29-33.
 Carnethon MR, Golden SH, Folsom AR, et al. Prospective investigation of autonomic nervous system function and the development of type 2 diabetes: the Atherosclerosis Risk In Communities study, 1987-1998. Circulation 2003;107:2190-5.
 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115-26.
 Rajagopalan S, Brook R, Rubenfire M, et al. Abnormal brachial artery flow-mediated vasodilation in young adults with major depression. Am J Cardiol 2001;88:196-8.
 Vitale Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334(15):952-7.
 Serne EH, Gans RO, ter Maaten JC, et al. Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions. Cardiovasc Res 2001; 49(1):161-8.
 Vita JA, Keaney JF Jr, Larson MG, et al. Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation 2004;110:3604-9.
 Vitale C, Mercuro G, Cornoldi A, et al. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med 2005;258(3):250-6.
 Yudkin JS, Eringa E, Stehouwer CD. "Vasocrine" signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 2005;365(9473):1817-20.
 Schneider DJ. Abnormalities of coagulation, platelet function, and fibrinolysis associated with syndromes of insulin resistance. Coron Artery Dis 2005;16(8):473-6.
 Bruce EC, Musselman DL. Depression, alterations in platelet function, and ischemic heart disease. Psychosom Med 2005;67(Suppl 1):S34-6.
 Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005;62(7):792-8.
 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-95.
 Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350:1387-97.
 Anisman H, Merali Z. Cytokines, stress, and depressive illness. Brain Behav Immun 2002;16: 513-24.
 Miller GE, Rohleder N, Stetler C, et al. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med 2005;67(5):679-87.
 Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 2000;49(5):677-83.
 Leor J, Poole WK, Kloner RA. Sudden cardiac death triggered by an earthquake. N Engl J Med 1996;334:413-9.
 Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539-48.
 Schnall PL, Pieper C, Schwartz JE, et al. The relationship between job strain, work place diastolic blood pressure, and left ventricular mass index. JAMA 1990;263:1929-35.
 Theorell T, Perski A, Akerstedt T, et al. Changes in job strain in relation to changes in physiological state. A longitudinal study. Scand J Work Environ Health 1988;14(3):189-96.
 Suarez EC, Kuhn CM, Schanberg SM, et al. Neuroendocrine, cardiovascular, and emotional responses of hostile men: the role of interpersonal challenge. Psychosom Med 1998;60:78-88.
 Raikkonen K, Lassila R, Keltikangas-Jarvinen L, et al. Association of chronic stress with plasminogen activator inhibitor-1 in healthy middle-aged men. Arterioscler Thromb Vasc Biol 1996;16:363-7.
 Markowe HLJ, Marmot MG, Shipley MJ, et al. Fibrinogen: a possible link between social class and coronary heart disease. BMJ 1985;291:1312-4.
 Eaker ED, Sullivan LM, Kelly-Hayes M, et al. Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring study. Psychosom Med 2005;67:692-6.
 Sapolsky RM, Alberts SC, Altman J. Hypercortisolism associated with social subordinance or social isolation among wild baboons. Arch Gen Psychiatry 1997;54:1137-43.
 Watson SL, Shively CA, Kaplan JR, et al. Effects of chronic social separation on cardiovascular disease risk factors in female Cynomolgus monkeys. Atherosclerosis 1998;137:259-66.
 Christakis NA, Allison PD. Mortality after the hospitalization of a spouse. N Engl J Med 2006;354:719-30.
 Kral BG, Becker LC, Blumenthal RS, et al. Exaggerated reactivity to mental stress is associated with exercise-induced myocardial ischemia in an asymptomatic high-risk population. Circulation 1997;96:4246-53.
 Krantz DS, Helmers KF, Bairey CN, et al. Cardiovascular reactivity and mental stress-induced myocardial ischemia in patients with coronary artery disease. Psychosom Med 1991;53:1-12.
 Matthews KA, Woodall KL, Allen MT. Cardiovascular reactivity to stress predicts future blood pressure status. Hypertension 1993;22:479-85.
 Everson SA, Kaplan GA, Goldberg DE, et al. Anticipatory blood pressure response to exercise predicts future high blood pressure in middle-aged men. Hypertension 1996;27: 1059-64.
 Everson SA, Lynch JW, Chesney MA, et al. Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study. BMJ 1997;314:553-8.
 KamarckTW, Everson SA, Kaplan GA, etal. Exaggerated blood pressure responses during mental stress are associated with enhanced carotid atherosclerosis in middle-aged Finnish men: findings from the Kuopio Ischemic Heart Disease Study. Circulation 1997;96:3842-8.
 Matthews KA, Owens JF, Kuller LH, et al. Stress induced pulse pressure change predicts women's carotid atherosclerosis. Stroke 1998;29:1525-30.
 Spieker LE, Hurlimann D, Ruschitzka F, et al. Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors. Circulation 2002;105(24):2817-20.
 Broadley AJ, Korszun A, Abdelaal E, et al. Inhibition of cortisol production with metyra-pone prevents mental stress-induced endothelial dysfunction and baroreflex impairment. J Am Coll Cardiol 2005;46(2):344-50.
 Cardillo C, Kilcoyne CM, Cannon RO III, et al. Impairment of the nitric oxide-mediated vasodilator response to mental stress in hypertensive but not in hypercholesterolemic patients. J Am Coll Cardiol 1998;32(5):1207-13.
 McCabe PM, Gonzales JA, Zaias J, et al. Social environment influences the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Circulation 2002;105: 354-9.
 Cohen S, Tyrrell DAJ, Smith AP. Psychological stress and susceptibility to the common cold. N Engl J Med 1991;325:606-12.
 Cohen S, Doyle WJ, Skoner DP, et al. Social ties and susceptibility to the common cold. JAMA 1997;277(24):1940-4.
 Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science 2005;307(5717):1909-14.
 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89(6):2548-56.
 Tataranni PA, DelParigi A. Functional neuroimaging: a new generation of human brain studies in obesity research. Obes Rev 2003;4(4):229-38.
 Wang GJ, VolkowND, Logan J, etal. Brain dopamine and obesity. Lancet 2001;357:354-7.
 McElroy SL, Kotwal R, Malhotra S, et al. Are mood disorders and obesity related? A review for the mental health professional. J Clin Psychiatry 2004;65:634-51.
 Dallman MF, La Fluer S, Pecoraro NC, et al. Minireview: glucocorticoids—food intake, abdominal obesity, and wealthy nations in 2004. Endocrinology 2004;145:2633-8.
 Bhatnagar S, Dallman M. Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress. Neuroscience 1998;84:1025-39.
 Lindley SE, Bengoechea TG, Schatzberg AF, et al. Glucocorticoid effects on mesotelence-phalic dopamine neurotransmission. Neuropsychopharmacology 1999;21:399-407.
 Morgan D, Grant KA, Gage HD, et al. Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci 2002;5:169-74.
 Volkow ND, Wang GJ, Fowler JS, et al. "Nonhedonic" food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. Synapse 2002;44: 175-80.
 Kirmayer LJ, Robbins JM, Dworkind M, et al. Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry 1993;150(5):734-41.
 Eisenberger NI, Lieberman MD, Williams KD. Does rejection hurt? An FMRI study of social exclusion. Science 2003;302(5643):290-2.
 Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303(5661):1162-7.
 Sapolsky RM. Why stress is bad for your brain. Science 1996;273:749-50.
 McEwen BS, Magarinos AM. Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci 1997;821:271-84.
 Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. Lancet 2006;367(9505):153-67.
 Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health 2005;95(Suppl 1):S144-50.
 Rees K, Bennett P, West R, et al. Psychological interventions for coronary heart disease. Cochrane Database Syst Rev 2004;4:CD002902.
 Rozanski A. Integrating psychologic approaches into the behavioral management of cardiac patients. Psychosom Med 2005;67(Suppl 1):S67-73.
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