The role of dopamine in the pathophysiology of depression.

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine(DA)signalingcouldresultfromeitherdiminishedDAreleasefrompresynaptic neuronsorimpairedsignaltransduction,eitherduetochangesinreceptornumberor functionand/oralteredintracellularsignalprocessing.Therearedatasupportingeachofthesemechanisms,althoughinterpretationofpreviousresearchisconfoundedbyissuesaroundstudypopulation, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possiblyreflectedbyacompensatoryup-regulationofD2receptors.ThesealterationsinDAsignalingmay underlie the findings of increased “liking” or “high” feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depressionisjustifiedtoimproveoutcomesforpatientswithtreatment-resistantandnonremittingdepression.