Role of norepinephrine in the pathophysiology and treatment of mood disorders.

For four decades, norepinephrine (NE) has been postulated to play an important, possibly primary, role in the pathophysiology and subsequent treatment of mood disorders. The long-held hypothesis was that depression and pathological elation are direct functions of low and high activity of norepinephrine-containing neurons, respectively. Decades of research in this field have been devoted to further clarifying this relationship. However, there continues to be inconsistencies in the data, with different studies finding significant differences in NE metabolites and changes in receptor populations. Furthermore, antidepressants that do not act directly on the NE system appear to be quite effective in the treatment of depression. Although differential 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 system with the pathological changes found in depression. Norepinephrine clearly has an important role in this disease, but absolute changes in its activity are less likely to be the primary cause of the disorder. Evidence for dysregulation of the locus ceruleus-NE system in depression is quite apparent, however, contributing to disrupted attention, concentration, memory, arousal, and sleep. Homeostatic changes likely occur after chronic treatment with antidepressants, allowing a new regulatory state to occur in which NE modulation is once again effective. The availability of new tools such as selective ligands for the NE transporter that can be utilized with positron emission tomography imaging will undoubtedly advance the field.