SYMPATHETIC NERVOUS-SYSTEM ACTIVITY IN MAJOR DEPRESSION - BASAL AND DESIPRAMINE-INDUCED ALTERATIONS IN PLASMA NOREPINEPHRINE KINETICS

Background: To determine whether elevations of plasma norepinephrine ( NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function. Methods: SNS activity was assessed in depres sed patients and controls by an isotope-dilution, plasma NE kinetic te chnique using mathematical modeling and compartmental analysis. This a pproach provided estimates of the rate of NE appearance into an extrav ascular compartment, which is the site of endogenous NE release from S NS nerves, the corresponding rate of NE appearance into plasma, and th e rate of NE clearance from plasma. Results: Norepinephrine appearance into the extravascular and vascular compartments was significantly el evated in 17 depressed patients compared with that in 36 controls. The rate of NE clearance from plasma was similar in both groups. This is compatible with increased SNS activity in major depression. Desipramin e, given for 2 days, significantly reduced the concentration of NE in plasma of patients and controls by markedly suppressing the rates of e xtravascular and vascular NE appearance, compatible with a short-term reduction in SNS activity. Desipramine prolonged the rate of NE cleara nce from plasma, consistent with a blockade of NE re-uptake into SNS n erve terminals. The initial suppression of SNS activity by desipramine was reversed by long-term (28 days) treatment of patients, with extra vascular and vascular NE appearance rates returning to approximately b asal levels. An associated rise in plasma NE concentrations compared w ith the baseline was attributable to a progressive reduction in plasma NE clearance. Conclusion: Sympathetic nervous system activity is elev ated in major depression and is suppressed by short-term desipramine a dministration. The demonstration of SNS reactivation occurring with pr olonged desipramine treatment is compatible with the theory that long- term treatment desensitizes CNS alpha(2)-adrenergic receptors and emph asizes the value of examining the temporal course of responses to phar macological challenges of neuroendocrine systems. Previously reported elevations of plasma NE during prolonged administration of tricyclic a ntidepressants are probably the result of a reduction in plasma NE cle arance, not an increase in SNS activity.