Noradrenergic Function in Depressive Disorders

Since the elaboration of the catecholamine hypothesis of affective disorders more than twenty years ago, researchers have attempted to test it mainly by measuring norepinephrine (NE) and 3-methoxy-4hydroxyphenyl-glycol (MHPG), a major NE metabolite in urine, plasma, and cerebrospinal fluid (CSF). MHPG is the only quantitatively significant brain NE metabolite entering the circulation and therefore had originally been thought to reflect brain “activity” (Schildkraut, Orsulak, Schatzberg, Gudeman, Cole, Rohde, & LaBrie, 1978). It was subsequently demonstrated that the CNS contributes 20%–30% of NE metabolites to the circulation. Of this, only 50% of central MHPG appears as MHPG in the urine; the remainder is metabolized to other metabolites, of which 3-methoxy-4-hydroxyvanillyl-mandelic-acid (VMA) predominates. Peripherally released NE contributes the other 50% of circulating MHPG (Filser, Spira, Fischer, Gattaz, & Muller, 1988; Kopin, 1985; Kopin, 1984). Pathways of NE metabolism are shown in Figure 1.