Editors' ChoiceDepression

Boosting dopamine to lift depression?

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Science Translational Medicine  16 Nov 2016:
Vol. 8, Issue 365, pp. 365ec183
DOI: 10.1126/scitranslmed.aal0071

Depression is a prevalent, often chronic psychiatric disorder in which patients frequently report diminished feelings of reward and motivation. On behavioral tests, depressed patients benefit less during learning of new associations after receiving a reward. This dysfunction in reward processing has in turn been linked to a blunted dopamine response in the striatum, resulting in altered communication between the striatum and cortical regions. But could boosting dopamine activity in depressed patients restore both cortico-striatal function and reward learning?

In a new study, Admon et al. tested this idea using an acute dose of the dopamine D2/D3 receptor antagonist amisulpride (or a placebo) in 46 depressed patients and 43 healthy controls. Amisulpride has been shown to indirectly increase dopamine in rodents and may be a promising tool for understanding the role of dopamine in depression. On functional magnetic resonance imaging (fMRI) scans, depressed patients who received the drug showed increased activity in the striatum and increased striato-cortical connectivity compared with those who received placebo. Interestingly, the response of depressed patients to amisulpride was greater on several measures than the response to drug of healthy participants, which suggested a greater initial dopaminergic abnormality in the depressed patients. Admon et al. thus provide direct evidence for the involvement of dopamine in the impaired reward circuitry in depression. Unfortunately, improved function of the reward neural circuitry did not translate to normalization of reward learning, as depressed patients still showed impaired reward learning after treatment with amisulpride. The inability to restore reward learning after boosting dopamine with amisulpride suggests that there is much more to understanding defective reward circuitry than simply low dopamine. Whereas the authors suggest that chronic dosing with amisulpride may be required to improve the symptoms of depression, the dissociation between brain activation and behavioral changes is itself instructive, providing a new avenue for future investigations. It is through mechanism-focused intervention studies, such as this one, that we can discover what the best paths may be toward more effective antidepressant treatments and which metrics best indicate success.

R. Admon et al., Dopaminergic enhancement of striatal response to reward in major depression. Am. J. Psychiatry 10.1176/appi.ajp.2016.16010111(2016). [Abstract]

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