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 approximately 40%. 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.