Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia

Abstract

The mortality of chronic heart failure (CHF) doubles either when CHF patients are depressed or when their plasma norepinephrine (NE) level exceeds those of controls by Ϸ40%. We hypothesized that patients with major depression had centrally driven, sustained, stress-related, and treatment-reversible increases in plasma NE capable of increasing mortality in CHF patients with depression. We studied 23 controls and 22 medication-free patients with melancholic depression. In severely depressed patients before and after electroconvulsive therapy (ECT), we measured cerebrospinal fluid (CSF) NE, plasma NE, plasma epinephrine (EPI), and plasma cortisol hourly for 30 h. In mildly-to-moderately depressed melancholic patients, we assessed basal and stress-mediated arterial NE appearance. Severely depressed patients had significant increases in mean around-the-clock levels of CSF NE (P < 0.02), plasma NE (P < 0.02), plasma EPI (P < 0.02), and plasma cortisol (P < 0.02). CSF NE, plasma NE, and cortisol all rose together throughout the night and peaked in the morning. Each fell to control values after ECT. Mildly-to-moderately melancholic patients also had increased basal (P < 0.05) and stress-related (P < 0.03) arterial NE-appearance rates. Severely melancholic depressed, medication-free patients had around-the-clock increases in plasma NE levels capable of increasing mortality in CHF. Twenty-four-hour indices of central noradrenergic, adrenomedullary, and adrenocortical secretion were also elevated. Concurrent diurnal rhythms of these secretions could potentiate their cardiotoxicity. Even mildly-to-moderately depressed melancholic patients had clinically relevant increases in the arterial NE-appearance rate. These findings will not apply to all clinical subtypes of major depression.cerebrospinal fluid ͉ epinephrine ͉ major depression ͉ cardiovascular disease ͉ chronic heart failure T he coexistence of major depression with chronic heart failure (CHF) doubles the mortality of CHF (1-3). CHF patients with asymptomatic left ventricular dysfunction coupled with high plasma norepinephrine (NE) levels also have a doubling in mortality (4). In one study, plasma NE levels equal to 40% or greater than those in their controls also doubled CHF mortality (5). Even a modest (25%) increase in plasma NE levels over 4 months more than doubled mortality in CHF patients (6). Prior studies have shown that elevated NE levels in patients with CHF can be further increased in an additive fashion by the superimposition of complications known to be associated with increased NE levels (7). Thus, substantially increased NE release in depression would result in significant increases in the burden of NE hypersecretion in patients with CHF who become depressed.Evidence of increased NE secretion in major depression could help explain increased mortality in patients with CHF who are depressed. However, results from prior studies of NE secretion in depression have been contradictory (reviewed in ref. 8). This ambiguity is likely to reflect almost exclusive ...

Effects of Antidepressants, but not Psychopathology, on Cardiac Sympathetic Control: A Longitudinal Study

“…mental health-care practice, reflects the general population of depressed and anxiety patients. Several reports using different SNS indices also found increased sympathetic activity in depressed or anxious subjects (Esler et al, 1982;Gold et al, 2005;Guinjoan et al, 1995;Light et al, 1998;Koschke et al, 2009). These previous reports focused on general sympathetic activity, whereas we measured sympathetic control more narrowly by its effects on cardiac contractility.…”

“…Various studies reported increased sympathetic activity in depressed and anxious subjects compared with healthy controls, measured by different indices like spillover of norepinephrine (NE) and epinephrine (EPI), skin conductance responses, QT interval variability (QTvi), or the pre-ejection period (PEP) (Light et al, 1998;Esler et al, 1982;Guinjoan et al, 1995;Gold et al, 2005;Koschke et al, 2009;Barton et al, 2007). However, other studies reported no association between psychopathology and SNS activity or reported decreased SNS activity in subjects with depressive or anxiety disorders (Wilkinson et al, 1998;Esler et al, 2004;Roth et al, 2008;Ahrens et al, 2008), so findings remain inconclusive.…”

“…Guinjoan et al (1995) described a higher sympathetic skin response in 18 melancholically depressed patients compared with 18 healthy controls. Gold et al (2005), reported higher plasma NE levels in 10 subjects with severe melancholic depression than in 12 healthy controls. Light et al (1998) also found higher plasma NE levels in high-symptom group compared with a low-symptom group.…”

Depression and Osteoporosis in Men: Association or Casual Link?

“…36 Sympatho-adrenal dysregulation is another common finding in depressed subjects, as evidenced by increased catecholamine turnover and increased catecholamine urinary excretion in severe depression. 37,38 The coexisting dysregulation of HPA and sympatho-adrenal axes in depression may result from a defect at or above the level of the hypothalamus, leading to hypersecretion of corticotropin-releasing hormone (CRH). Interestingly enough, ACTH response to exogenous ovine CRH is attenuated in depression, suggesting that the pituitary corticotroph cell is restrained by the negative feedback of glucocorticoids.…”

Abnormal function of monoamine oxidase-A in comorbid major depressive disorder and cardiovascular disease: Pathophysiological and therapeutic implications (Review)

“…It has been proposed that enhanced cortisol agonistic effects during depressive episodes may contribute to an elevation in MAO-A levels (53). Severely depressed patients had significant increases in blood pressure, CSF and plasma NE, as well as elevated plasma cortisol (115). Notably, elevated platelet MAO activity associated with increased cortisol levels has been described in depression; platelet MAO activity has also been associated with severity of depressive symptoms (116).…”