Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders

There is abundant evidence for abnormalities of the norepinephrine (NE) and serotonin (5HT) neurotransmitter systems in depression and anxiety disorde rs. The majority of evidence supports underactivation of serotonergic funct ion and complex dysregulation of noradrenergic function, most consistent wi th overactivation of this system. Treatment for these disorders requires pe rturbation of these systems. Reproducible increases in serotonergic functio n and decreases in noradrenergic function accompany treatment with antidepr essants, and these alterations may be necessary for antidepressant efficacy . Dysregulation of these systems clearly mediates many symptoms of depressi on and anxiety. The underlying causes of these disorders, however, are less likely to be found within the NE and 5HT systems, per se. Rather their dys function is likely due to their role in modulating, and being modulated by, other neurobiologic systems that together mediate the symptoms of affectiv e illness. Clarification of noradrenergic and serotonergic modulation of va rious brain regions may yield a greater understanding of specific symptomat ology, as well as the underlying circuitry involved in euthymic and abnorma l mood and anxiety states. Disrupted cortical regulation may mediate impair ed concentration and memory, together with uncontrollable worry. Hypothalam ic abnormalities likely contribute to altered appetite, libido, and autonom ic symptoms. Thalamic and brainstem dysregulation contributes to altered sl eep and arousal states. Finally, abnormal modulation of cortical-hippocampa l-amygdala pathways may contribute to chronically hypersensitive stress and fear responses, possibly mediating features of anxiety, anhedonia, aggress ion, and affective dyscontrol. The continued appreciation of the neural cir cuitry mediating affective states and their modulation by neurotransmitter systems should further the understanding of the pathophysiology of affectiv e and anxiety disorders. (C) 2000 Wiley-Liss, Inc.