Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression - the PRIME-PRAXOL randomized controlled trial

Here, we examined the efficacy and target engagement of dopamine agonist pramipexole in treating a cross-diagnostic sample of mood disorders characterized by severe anhedonia. Patients with major depressive disorder, dysthymia or bipolar depression, all with significant anhedonia symptoms per the Snaith-Hamilton Pleasure Scale (SHAPS), were randomized to either a flexible-dose add-on of pramipexole or placebo for nine weeks. Primary outcome was change in total SHAPS score. Accelerometers were used during the study to assess treatment-associated changes in physical activity. 7-Tesla functional magnetic resonance imaging (fMRI) with the Monetary Incentive Delay task was used to investigate reward related neural response in the ventral striatum before and after treatment. Mixed models were used to investigate between-group differences in symptom improvement. In the intention-to-treat sample (pramipexole: n=41; placebo: n=41) the mean decrease in SHAPS score from baseline to week 9 in the pramipexole group was 6.5 points compared to 2.4 in the placebo group yielding a between-group difference in mean change of 4.1 (p=0.005, Hedge's g=0.63). Pramipexole was superior to placebo on several of the secondary outcomes related to anhedonia and apathy. These findings were supported by accelerometry data, which showed that pramipexole significantly increased light physical activity throughout the study, compared to placebo (p<0.01, pramipexole: n=32; placebo: n=29). Adjusted mean signal intensity for reward-related activation in bilateral ventral striatum showed a significant group difference (p=0.030; Hedge's g=0.32, pramipexole: n=25; placebo: n=23). In patients receiving pramipexole (but not placebo) there was a trend suggesting that greater reductions in anhedonic symptoms were associated with increased treatment-related activation in the ventral striatum in response to reward cues. (rho=–0.38, p=0.060). Drop-out rate was 6% and the intervention was generally well tolerated with no serious adverse events. These findings demonstrate that pramipexole is an efficacious and safe add-on option for treating anhedonia in mood disorders. This treatment not only alleviates subjective symptoms of anhedonia but also objectively boosts light physical activity and increases activation in the brain's reward system. These findings suggest that pramipexole effectively targets the neurocircuits involved in motivation and reward. ClinicalTrials.gov identifier: NCT05355337.