Overview: toward a dysregulation hypothesis of depression

The authors suggest that the activity of neurotransmitter systems in the affective disorders and related psychiatric syndromes may be better understood as a reflection of a relative failure in their regulation, rather than as simple increases or decreases in their activity. A model organized around the concept of "dysregulation" posits that persistent impairment in one or more neurotransmitter homeostatic regulatory mechanisms confers a trait vulnerability to unstable or erratic neurotransmitter output. Evidence from clinical and animal model studies for dysregulation of the noradrenergic system in depression is examined with respect to criteria generated by such a general model, and a specific configuration of noradrenergic dysregulation in some forms of depression is proposed.