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Norepinephrine and selective norepinephrine reuptake inhibitors in depression and mood disorders: their pivotal roles.

More than 40 years of research through experimental models and in the clinical setting have clearly indicated the importance of the norepinephrine (NE) system in the pathophysiology of depression and mood disorders. Data amassed from basic research and clinical trials of pharmacologic agents have demystified the workings of this system and, most recently, have shown how this system works in concert with other neuronal systems — in particular, the serotonin (5-HT) system — in patients with these complex disorders. Three specific monoamine neurotransmitters, NE, 5-HT and dopamine, have been linked to depression and mood disorders. Researchers have theorized that one or another of these neurotransmitters is the key to the pathophysiology of these psychologic disorders. Yet, since the 1980s, the field of psychiatry has focused almost exclusively on the 5-HT system to expand knowledge about the pathophysiology of depression and anxiety. This focus paved the way to the “serotonin age” in psychopharmacologic treatment. Recent clinical evidence promises to level the playing field for the competing theories as to which neuronal system is responsible for the development of depression and mood disorders. This evidence indicates that psychopharmacologic agents with potent effects on NE neurotransmission are highly effective antidepressants. In fact, preclinical research has clearly shown that the 5-HT, NE and dopamine systems interact extensively, and it would be difficult to investigate how a given pharmacologic agent affects one system without considering its influences on the others. For example, NE receptor antagonists directly affect the 5-HT system, and selective serotonin reuptake inhibitors (SSRIs) ultimately influence the NE system. In other words, it appears that previous attempts to find a single hypothesis to explain the complex causes of mood and anxiety disorders and their treatment have been relatively simplistic. For a more complete understanding of how to manage these disorders, we need thorough knowledge of the NE system, how pharmacologic agents act within it and how they influence other neurotransmitter systems, such as the 5-HT system. New treatment paradigms are emerging as our knowledge of the interdependence of monoamine neurotransmitters expands and as new research about the role of other biochemical messengers is undertaken. Our growing knowledge of the interconnections among these systems is also helping us to appreciate the importance of tandem behavioural and psychopharmacologic approaches to the treatment of depression, because both can affect the physiology of these systems.