Role of norepinephrine in the pathophysiology and treatment of mood disorders

For four decades, norepinephrine (NE) has been postulated to play an import ant, possibly primary, role in the pathophysiology and subsequent treatment of mood disorders. The long-held hypothesis was that depression and pathol ogical elation are direct functions of low and high activity of norepinephr ine-containing neurons, respectively. Decades of research in this field hav e been devoted to further clarifying this relationship. However, there cont inues to be inconsistencies in the data, with different studies finding sig nificant differences in NE metabolites and changes in receptor populations. Furthermore, anti-depressants that do not act directly on the NE system ap pear to be quite effective in the treatment of depression. Although differe ntial NE activity and treatment response may be partially due to different subtypes of depression, this clearly does not explain all the data. This review attempts to consolidate the relevant physiology of the NE syste m with the pathological changes found in depression. Norepinephrine clearly has an important role in this disease, but absolute changes in its activit y are less likely to be the primary cause of the disorder. Evidence for dys regulation of the locus ceruleus-NE system in depression is quite apparent however, contributing to disrupted attention, concentration, memory, arousa l, and sleep. Homeostatic changes likely occur after chronic treatment with antidepressants, allowing a new regulatory state to occur in which NE modu lation is once again effective. The availability of new tools such as selec tive ligands for the NE transporter that can be utilized with positron emis sion tomography imaging will undoubtedly advance the field. (C) 1999 Societ y of Biological Psychiatry.