Swedish Trial Investigates Pramipexole’s Efficacy in Treating Anhedonia in Depressive Disorders

A randomized controlled trial conducted in Lund, Sweden, is evaluating the effectiveness of pramipexole, a dopamine agonist, in reducing anhedonia—a core symptom of major depressive disorder (MDD), dysthymia, and bipolar disorder, according to a study protocol published in Nature Portfolio. The trial, registered under ClinicalTrials.gov identifiers NCT05355337 and NCT05825235, aims to assess pramipexole’s impact on anhedonia through a combination of self-reported measures, neuroimaging, and biomarker analysis.

Study Design and Intervention

The trial enrolled 80 participants aged 18–75 with a diagnosis of MDD, dysthymia, or bipolar disorder with a depressive episode, who had not achieved remission from at least one adequate antidepressant trial. Participants were randomly assigned to receive either pramipexole or a placebo for nine weeks, followed by a six-month open-label extension phase. The primary outcome was the change in the Scale for Assessment of Anhedonia (SHAPS) total score, a self-reported measure of anhedonia’s consummatory phase, from baseline to week 9.

Pramipexole was administered in a flexible dose regimen, with weekly dose adjustments based on tolerability and clinical response. The study utilized a double-blind design, with participants, researchers, and evaluators unaware of treatment assignments. An unblinded statistician generated the randomization sequence, and an independent research nurse managed the medication packaging to maintain blinding.

Neuroimaging and Biomarker Assessments

Substudies included 7-Tesla functional magnetic resonance imaging (fMRI) using the Monetary Incentive Delay (MID) task to evaluate ventral striatal activity during reward anticipation. Participants also underwent cognitive testing, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Wisconsin Card Sorting Test (WCST), as well as blood and cerebrospinal fluid (CSF) sampling to measure dopamine metabolites like homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC).

Physical activity was monitored via accelerometers, with data analyzed for sedentary behavior (SED), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). The study also collected secondary outcomes, including inflammatory markers like C-reactive protein (CRP) and measures of reward responsiveness using the Probability Reward Task (PRT).

Eligibility and Safety Measures

Participants were required to have clinically significant anhedonia, defined by SHAPS scores of 3 or 4 on at least three items. Exclusion criteria included pregnancy, recent psychotherapy initiation, active substance use disorder, and neurological conditions like Parkinson’s disease. Safety assessments were conducted at all study visits, with adverse events documented and evaluated for severity and potential link to pramipexole.

The trial’s statistical analysis plan, published in the Nature Portfolio Reporting Summary, used mixed-effects models for repeated measures (MMRM) to evaluate longitudinal outcomes. A prespecified interim analysis in June 2024 adjusted the sample size based on updated standard deviations, though no treatment effects were observed before week 3.

Implications and Next Steps

The study’s findings could advance understanding of anhedonia’s neurobiological underpinnings and the role of dopaminergic modulation in treating depressive symptoms. If pramipexole demonstrates efficacy, it may offer a novel therapeutic approach for patients with treatment-resistant anhedonia. Results from the open-label extension phase, which began in 2024, are anticipated to provide longer-term safety and efficacy data.

Researchers note that the study’s focus on reward circuit dysfunction aligns with growing evidence linking anhedonia to altered dopamine signaling. However, the trial’s reliance on self-reported measures and small subsample sizes for neuroimaging and biomarker analyses highlight the need for larger, multi-center studies to confirm these preliminary findings.