Depression: The Case for a Monoamine Deficiency

The monoamine hypothesis of depression predicts that the underlying pathophysiologic basis ofdepression is a depletion in the levels of serotonin, norepinephrine, and/or dopamine in the centralnervous system. This hypothesized pathophysiology appears to be supported by the mechanism of actionof antidepressants: agents that elevate the levels of these neurotransmitters in the brain have allbeen shown to be effective in the alleviation of depressive symptoms. However, intensive investigationhas failed to find convincing evidence of a primary dysfunction of a specific monoamine systemin patients with major depressive disorders. Understanding of the etiology of depression has beenhampered by the absence of direct measurements of monoamines in humans. However, the monoaminedepletion paradigm, which reproduces the clinical syndrome, allows a more direct method forinvestigating the role of monoamines. Results from such studies show that antidepressant responsesare transiently reversed, with the response being dependent on the class of antidepressant. In contrast,monoamine depletion does not worsen symptoms in depressed patients not taking medication, nordoes it cause depression in healthy volunteers with no depressive illness. In conclusion, it is clear thatantidepressant agents in current use do indeed require intact monoamine systems for their therapeuticeffect. However, some debate remains as to the precise role that a deficiency in monoamine system(s)may play in depression itself.