A Dopaminergic Hypothesis of Major Depression

Abstract

The dopaminergic system appears to play a role in the etiopathogenesis of major depression that is analogous to the roles hypothesized for norepinephrine and serotonin. Three distinct groups of dopaminergic neurons project via the nigrostriatal, mesolimbic, and mesocortical pathways, and they are involved in motor functioning, major depression, cognition, and a variety of behaviors related to reward and motivation. The five dopamine-receptor subtypes provide an additional level of organization of the dopaminergic system; medications that are direct agonists or antagonists for specific receptors will have more selective effects within the dopaminergic system. A variety of studies in animals, as well as clinical observations, are consistent with a dopamine-deficiency hypothesis of major depression. Depletion of dopamine levels by drugs such as reserpine and tetrabenazine, or through the long-term use of stimulants, has been reported to produce major depressive episodes in vulnerable individuals. The association of depression with Parkinson's disease provides important additional support for the dopaminergic hypothesis of depression. Electroconvulsive therapy, which enhances dopaminergic transmission, improves both depression and the motor symptoms of Parkinson's disease. The development of more selective medications will help to clarify the precise role of the dopaminergic system and specific receptor subtypes in the etiopathogenesis of major depression.