Individual differences in dopamine-related traits influence mood effects of dopamine D2-antagonist and antidepressant treatment expectations.

BACKGROUND: High trait anhedonia and low trait extraversion have both been previously related to not only low state positive affect but also depressive disorders, disrupted reward processing, and altered mesolimbic dopaminergic signaling. Research on placebo responses suggests that treatment expectations may alter dopamine signaling, elevate positive affect, and reduce depressive symptoms in anhedonic individuals. However, it remains unclear whether such antidepressant placebo responses depend on putative low baseline dopaminergic functioning in high anhedonia and low extraversion. The present study investigates how interindividual differences in these traits influence positive affective responses under manipulation of dopamine and treatment expectations.

METHODS: In a randomized, double-blind 2 × 2 design (N = 297), we administered either placebo or the dopamine D2 receptor antagonist sulpiride (400 mg), and manipulated treatment expectations by telling participants that they received either a mood-elevating drug or an inactive substance. Moreover, we assessed trait anhedonia and extraversion, and had participants rate their state positive affect at 6 different time points before and after treatment.

RESULTS: Trait anhedonia and extraversion, as well as a broad trait positive affectivity factor, predicted state positive affect across time points. Importantly, the effects of sulpiride and antidepressant treatment expectations on positive affect were moderated by dopaminergic traits such that sulpiride increased state positive affect in high anhedonia but decreased it in low anhedonia. Similarly, antidepressant treatment expectations raised positive affect in low extraversion but reduced it in high extraversion.

CONCLUSIONS: This study demonstrates that dopamine-related individual differences moderate the effects of both sulpiride and a placebo intervention on positive affective state. Significance Statement In one of the first pharmacological studies examining the effects of treatment expectations and dopamine on mood in a large, healthy sample, we observed that lower baseline positive affectivity was linked to stronger mood-elevating treatment responses to both a placebo and a dopamine-related drug over time. This highlights how individual differences in relevant traits can influence treatment effectiveness, offering valuable insights for tailoring personalized approaches to depression care.