Role of Norepinephrine in Depression

This article reviews the role of norepinephrine (NE) and serotonin (5-HT) in depression and thetherapeutic effects of antidepressant drugs from the perspective of human neurotransmitter depletionstudies. The data reviewed suggest that both noradrenergic and serotonergic systems are involved inantidepressant action, but the specific impairment that underlies depression is unclear and is likely tovary among patients. Results from neurotransmitter depletion studies in depressed patients who haveresponded to treatment suggest that, while interactions between NE and 5-HT are likely, neither ofthese 2 neurotransmitter systems is the final common pathway for the therapeutic effect of antidepressantdrugs. NE-selective antidepressant drugs appear to be primarily dependent on the availability ofNE for their effects. Likewise, 5-HT-selective antidepressants appear to be primarily dependent onthe availability of 5-HT for their effects. Antidepressants that cause effects on both noradrenergic andserotonergic systems—such as mirtazapine—may be dependent on the availability of both neurotransmittersfor their effects. Neither 5-HT nor NE depletion induced clinical depression in healthy subjectsor worsened depression in unmedicated symptomatic patients with major depression. This findingsuggests that the cause of depression is more complex than just an alteration in the levels of 5-HTand/or NE. For some patients, depression may be more directly caused by dysfunction in brain areasor neuronal systems modulated by monoamine systems. We propose that antidepressant drugs mayenhance neurotransmission in normal noradrenergic or serotonergic neurons and, through a time-dependentbut as yet undiscovered process, restore function to brain areas modulated by monoamineneurons. Future research should focus on understanding the adaptive changes that follow enhancementof synaptic levels of monoamines in neuronal circuits of the frontal cortex, amygdala, and hippocampus.Research investigating the neurobiology of depression may be more informed if the focusis shifted to investigating areas of the brain modulated by monoamine systems rather than the monoaminesystems themselves.