Pathophysiology
Hypothalamic-Pituitary-Adrenocortical and Sympathomedullary Hyperactivity

Advances in biological psychiatry have included the discovery of numerous neurochemical, neuroendocrine, and neuroanatomic alterations in unipolar depression. Often proposed as important adjuncts in the diagnosis of depressed subjects, some of these biological markers may reflect important pathophysiologic alterations that contribute to the increased vulnerability of depressed patients to CVD. These markers include hypothalamic-pituitary-adrenocortical (HPA) and sympathoadrenal hyperactivity, diminished heart rate variability (HRV), alterations in platelet receptors and/or reactivity, increased secretion of proinflammatory cytokines, and ventricular instability and myocardial ischemia in reaction to mental stress (Fig. 91–1).

Two primary components that are central to the “fight or flight” stress response observed by Cannon in 1911 and the “general adaptation syndrome” described by Selye in 1956 are the HPA axis and the sympathoadrenal system. In response to stress, hypothalamic neurons containing corticotropin-releasing factor (CRF) increase the synthesis and release of corticotropin (ACTH), β -endorphin, and other pro-opiomelanocortin (POMC) products from the anterior pituitary gland. Many studies have documented evidence of HPA axis hyperactivity in medication-free patients with major depression (i.e., elevated CRF concentrations in cerebrospinal fluid), blunting of the ACTH response to CRF administration, nonsuppression of cortisol secretion after dexamethasone administration, hypercortisolemia, and pituitary and adrenal gland enlargement, as well as direct evidence of increased numbers of hypothalamic CRF neurons in postmortem brain tissue from depressed patients compared with controls. Administered corticosteroids have long been known to induce hypercholesterolemia, hypertriglyceridemia, and hypertension. Other atherosclerosis-inducing actions of steroids include injury to vascular endothelial cells and intima and the inhibition of normal healing. Indeed, elevated morning plasma cortisol concentrations have been significantly correlated with moderate-to-severe coronary atherosclerosis in young and middle-aged men.

Many patients with major depression also exhibit dysregulation of the sympathoadrenal system. The adrenal medulla and sympathetic nervous system (SNS) together constitute the sympathoadrenal system. Although central nervous system (CNS) regulation of the sympathoadrenal system has been only partially characterized, hypothalamic CRF-containing neurons provide stimulatory input to several autonomic centers that are involved in regulating sympathetic activity. Nerve impulses from regulatory centers in the CNS control catecholamine release from the sympathoadrenal system. Physiologic and pathologic conditions causing sympathoadrenal activation include physical activity, coronary artery ischemia, heart failure, and mental stress. Epinephrine in plasma is derived from the adrenal medulla, whereas plasma norepinephrine (NE) concentrations reflect the secretion of NE largely from sympathetic nerve terminals, with the remaining NE provided by the adrenal medulla and extraadrenal chromaffin cells. Peripheral plasma NE concentrations are determined not only by the rate of release from sympathetic nervous system nerve terminals but also by reuptake into presynaptic terminals, local metabolic degradation, and redistribution into multiple physiologic compartments. Hypersecretion of NE in unipolar depression has been documented by elevated plasma NE and NE metabolite concentrations and elevated urinary concentrations of NE and its metabolites, though discordant reports exist. Not only do depressed patients exhibit higher basal plasma concentrations of NE, those with melancholia exhibit even greater elevations in plasma NE concentrations when subjected to orthostatic challenge than do normal control subjects and depressed patients without melancholia. Furthermore, depressed patients who are dexamethasone (DST) nonsuppressors exhibit significantly higher basal and cold-stimulated plasma concentrations of NE than do depressed patients who are DST suppressors. After treatment with tricyclic antidepressants (TCAs), urinary excretion of NE and its metabolites diminish together with plasma NE concentrations, although Veith and colleagues reported that chronic treatment with desipramine increased plasma concentrations of NE. Thus, sympathoadrenal hyperactivity seems to represent a state rather than a trait marker of depression, possibly reflecting increased CRF release within the CNS.

Sympathoadrenal hyperactivity contributes to the development of CVD through effects of catecholamines on the heart, blood vessels, and platelets. Sympathoadrenal activation modifies the function of circulating platelets through direct effects on platelets, catecholamine-induced changes in hemodynamic factors (increased shear stress), circulating lipids, and inhibition of vascular eicosanoid synthesis. Arachidonic acid metabolites such as prostaglandins and leukotrienes contribute to diverse circulatory and hemostatic functions, including inhibition of platelet aggregation, and vascular contractility and permeability. Elevations of plasma NE levels are found most frequently in young hypertensive patients and in subjects with high-cardiac-output borderline hypertension who later proceed to established high-resistance hypertension. Even normotensive depressed patients have been found to exhibit greater heart rates at rest, after orthostasis, and after exercise in comparison with normal controls. These depressed patients also exhibited increased plasma concentrations of NE and serotonin (5-HT) at rest. Thus, the sympathoadrenal hyperactivity observed in many patients with major depression may contribute to the development of CVD through the effects of catecholamines on cardiac function and platelets.