The noradrenergic symptom cluster: clinical expression and neuropharmacology

Signs and symptoms of depression can be linked to one or more monoaminergic systems, specifically the norepinephrine (NE), the dopamine (DA), and the serotonin (5-HT) systems. In particular, the modulation of energy, vigilance, and arousal can be directly linked to the NE system. There is, however, a great deal of overlap in the modulation of the symptoms of depression between these monoaminergic systems. There are considerable reciprocal interactions between the NE, DA, and the 5-HT systems. When using a selective serotonin reuptake inhibitor (SSRI), for example, 5-HT transmission is enhanced, but at the same time there is a dampening of the activity of NE and DA neurons through inhibitory 5-HT(2A) and 5-HT(2C) receptors, respectively. This could explain the residual symptoms of fatigue, lack of energy, and anhedonia, often seen after patients present an overall positive response to a SSRI. Using a dual 5-HT and NE reuptake inhibitor (SNRI), such as milnacipran, would result in an additional increase in NE activity. Futhermore, inhibiting NE reuptake increases DA availability in the frontal cortex since DA is mainly cleared by the NE transporters in several brain regions. A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI.