Dopaminergic Modulation of Social Reward Anticipation in Depression: Neural Effects of Amisulpride Versus Placebo

Reward processing deficits are a well-established mechanism underlying anhedonia, a core symptom of Major Depressive Disorder (MDD). Given the role of dopamine in mesocorticolimbic reward pathways, this study examined whether a single low dose of amisulpride (100 mg), which is thought to enhance dopaminergic transmission through presynaptic D2/3 autoreceptor blockade, modulates brain activation during the anticipation of social rewards. A total of 58 participants with MDD and 57 healthy controls (HCs) participated in a double-blind, placebo-controlled, randomized trial. They received either amisulpride or placebo before completing a Social Incentive Delay task during functional magnetic resonance imaging (fMRI). Neural activation was examined in the ventral and dorsal striatum, pallidum, ventral tegmental area (VTA), anterior insula, and ventromedial prefrontal cortex. Anhedonia was assessed using self-report measures. Behaviorally, participants responded faster to reward than no-reward cues, with no significant differences between groups (MDD vs. HCs) or treatment conditions (amisulpride vs. placebo). On a neural level, amisulpride enhanced VTA activation during the anticipation of social rewards compared to no-reward cues. Relative to HCs, participants with MDD showed reduced right putamen activity when anticipating highly rewarding cues, which was not significantly affected by amisulpride. Within the MDD-amisulpride group, exploratory analyses revealed positive associations between anhedonia severity and activity in the putamen, VTA, and anterior insula, and higher striatal activity correlated with faster responses to highly rewarding cues. These findings suggest that while amisulpride enhances VTA activity during the anticipation of social rewards, core striatal deficits in MDD remain, underscoring both the potential and limitations of dopaminergic modulation in addressing social anhedonia.