Repurposing Dopamine Agonist Pramipexole for Disabling Anhedonia

Pramipexole, a dopamine agonist used to treat symptoms of Parkinson disease, was associated with improvements in anhedonia and apathy as well as increased physical activity in patients with mood disorder, in a placebo-controlled trial that measured efficacy for anhedonia and explored the relation of clinical improvement to increased reward-signaling from ventral striatal activation.¹

Daniel Lindqvist, MD, PhD, Unit for Biological and Precision Psychiatry, Department of Clinical Sciences Lund, Lund University, Lund, Sweden, et al note that mood disorders are a leading causes of disability worldwide, and that the symptom of anhedonia is particularly disabling, associated with poor treatment response, functional impairment, and increased risk of suicide.

"However, effective treatments specifically targeting anhedonia remain limited," they observe.

The investigators explain that the potential of dopamine agonists for treating depression subtypes marked by severe anhedonia is linked to the possibility that symptoms of low motivation and reduced reward-seeking arise with dysregulation of reward processing in the mesolimbic dopamine pathway. High concentration of D₃ dopamine receptors in the nucleus accumbens of the ventral striatum, then, represents a promising therapeutic target for these agents.

Lindqvist et al identified pramipexole as a likely candidate to repurpose for anhedonic depression as it has high affinity for D₃ receptors, it has been reported to improve anhedonia as well as motor symptoms in Parkinson disease, and to exert antidepressant effect and, at higher doses, improve anhedonia in patients with treatment-resistant depression.

Assessing Behavioral and Neurophysiologic Changes

The randomized, double-blind, placebo-controlled trial of pramipexole was conducted with patients with clinically significant anhedonia and either major depressive disorder, dysthymia, or bipolar disorder. "We specifically selected patients with prominent anhedonia and used anhedonia, rather than overall depression severity as our primary treatment target," Lindqvist told Psychiatric Times.

The investigators randomly assigned 85 participants (from 284 screened) to receive 9 weeks of either pramipexole (n=43) or placebo (n=42) added to their ongoing treatment regimen. Participants had demonstrated significant anhedonia on baseline, scoring 3 or 4 points on 3 or more items on the Snaith-Hamilton Please Scale (SHAPS). A 6-month open-label extension with pramipexole was available, with 54 of 65 eligible participants choosing to enroll and 37 completing the 6-month period.

In addition to the primary outcome of change in total SHAPS score, taken at 4, 7, and 9 weeks, the investigators applied a range of measures including accelerometers worn by the participants to provide an indication of treatment-associated change in physical activity. In addition, functional magnetic resonance imaging (fMRI) was obtained in 48 participants (pramipexole n=25, placebo n=23) to assess engagement of pramipexole with ventral striatum function during reward processing.

"Most antidepressant trials rely heavily on patients reporting how they feel," Lindqvist commented. "These measures are obviously important, but they are subjective and can be affected by recall, expectations and other forms of reporting bias. We therefore wanted to determine whether improvement in anhedonia was also reflected in an objective change in patient's everyday behavior.

"This is particularly relevant for anhedonia," he explained, "which is not only about experiencing less pleasure but also about reduced motivation and engagement in activities.Using accelerometers allowed us to continuously measure physical activity in patients' everyday lives.

Pramipexole Augmentation Improved Anhedonia

The primary outcome of SHAPS scores were decreased more in the pramipexole group than in those receiving placebo at the intermediate time points, and remained lower at the 9-week endpoint (mean 34.98±8.04 vs 37.26±7.43). This indication that pramipexole produced greater overall improvement in anhedonia compared with placebo across weeks 3-9 was reinforced by continued SHAPS score reduction in the extended open-label phase, for both those who had initially received pramipexole and those crossing over from placebo.

Interestingly, there was no significant difference between the treatment and placebo groups at 9 weeks on secondary outcome measures with the Montgomery-Ȧsberg Depression Rating Scale (MADRS-S) and the Hamilton Depression Rating Scale 6-item subscale (HDRS-6); but there was statistically significant advantage of pramipexole on both scales in analysis across all 3 time points.

"When we analyzed the full trajectory across the randomized phase, there was a significant overall treatment effect favoring pramipexole on both the MADRS-S and HDRS-6," Lindqvist remarked. "Although the between-group differences at the final week did not reach statistical significance, the effect sizes at week 9 were still in the small-to-moderate range.

Lindqvist suggested that the study design, weighing the cohort with patients with prominent anhedonia, could have contributed to finding less robust effect of pramipexole on general depressive symptoms than on anhedonia. "This may have enriched the sample for patients particularly likely to improve in reward- and motivation-related symptoms, rather than all dimensions of depression," he indicated.

The measure of increased light physical activity from the accelerometer readings, quantified as average minutes per day, also favored pramipexole at intermediate time points, but without statistical difference from placebo at 9 weeks.

"I think this finding needs to be interpreted cautiously," Lindqvist remarked."When we analyzed physical activity across the entire nine-week randomized period, there was a significant overall treatment effect favoring pramipexole.

Lindqvist suggested the lack of statistical difference at 9 weeks could reflectmethodology rather than transience of drug effect. "Compliance with wearing the accelerometers decreased toward the end of the study, leaving fewer valid observations at the final assessment, and therefore reducing statistical power," he noted.

"Importantly, the overall longitudinal treatment effect remained significant.There were also supportive findings in the subsequent open-label phase," Lindqvist reported. "Their physical activity increased markedly toward the levels seen in patients originally assigned to pramipexole."

The fMRI assessments revealed that pramipexole modulated reward-related ventral striatal activation during the Monetary Incentive Delay (MID) task testing of motivation and incentive processing. The investigators reported that the placebo group exhibited a decrease in ventral striatal activation, while this response was generally preserved in the pramipexole group—which, they suggested, might reflect protection against task habituation.

"Taken together, the present fMRI findings provide evidence of neural target engagement by pramipexole and indicate that modulation of ventral striatal function during reward processing may contribute to its therapeutic effects on anhedonia," the investigators concluded.

Lindqvist remarked that the exploration of possible mechanisms, in addition to measuring efficacy for symptoms, was an important goal of this trial.

"One of the major goals of precision psychiatry is to move beyond simply asking whether a treatment works, and toward understanding how it works and in whom it is most likely to work," Lindqvist said. "We therefore wanted to determine whether the clinical effects of pramipexole were accompanied by measurable changes in the brain system that we hypothesized the drug was targeting."

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

Reference

1. Ventorp F, Asp M, Olsson S, et al. Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial. Nat Med. 2026;32(7):2570-2578.