Neurobiology of Serotonin Norepinephrine Reuptake Inhibitors

Major depressive disorder (MDD) is a complex condition resulting from numerous genetic and physiologic factors. This article reviews the neurochemical mechanisms underlying MDD, summarizes recent genetic findings, and examines the efficacy of various treatments. The norepinephrine (NE) and serotonin (5-HT) pathways affect several areas of the nervous system that are disrupted in MDD, and agents that increase levels of either NE (NE reuptake inhibitors [NRIs]) or 5-HT (selective serotonin reuptake inhibitors [SSRIs]) are known to be effective in alleviating MDD symptoms. The dual-action hypothesis suggests that drugs affecting both neurotransmitters simultaneously (serotonin norepinephrine reuptake inhibitors [SNRIs]) may have a greater therapeutic effect in some patients than either NRIs or SSRIs alone. Literature shows that this hypothesis is valid, but the magnitude of the effect is smaller than might be predicted, possibly because of genetic heterogeneity among patients or differences in selectivity among the various SNRIs, and because modulation of 5-HT and NE activity does not entirely explain the pathophysiology of MDD. Until it is possible to select patients who are more likely to respond to specific classes of drugs based on certain genes or biomarkers, data suggest that dual-acting antidepressants are slightly more effective than those that are selective for a single neurotransmitter in the treatment of patients with MDD.