Pramipexole for Anhedonic Depression

Summary

The heterogeneity of depression suggests that several different neurocircuits and pathophysiological mechanisms are involved. Anhedonia - the inability to experience pleasure from, or the lack of motivation to carry out, usually enjoyable activities - is a promising endophenotype within the depression spectrum, with a distinct pathophysiology involving dopaminergic mesolimbic projections. Anhedonia is common in depression and associated with treatment resistance. Pramipexole, an agonist to the dopamine -receptor 3, is an established treatment of Parkinson's disease. Based on its mechanism of action, pramipexole might be efficacious in a subtype of depression characterized by anhedonia and lack of motivation - symptoms linked to dopaminergic hypofunction. This is supported by animal data, clinical experience, and recent pilot study data, but randomized controlled trials (RCTs) are lacking. In this double-blind placebo-controlled RCT the anti-anhedonic and antidepressant effects of add-on pramipexole will be tested, using an "enriched population study design" including only depressed patients with significant anhedonia. To better understand the neurobiology of anhedonia in depression and to identify treatment predictors, simultaneous assessments of anhedonia-related neurocircuitry using (f)MRI will be done, and anhedonia-related biomarkers in blood and cerebrospinal fluid analyzed. The aim of the study is to confirm the efficacy of pramipexole in this depression subtype, which would be an important step towards personalized medicine in psychiatry.

Timeline

Start

2023-02-08

Primary completion

2025-06-04

Completion

2025-06-04

Publications

• Ventorp F, Asp M, Olsson S, Lindahl J, Moller S, Svensson M, Angeby F, Pravdinske A, Tjernberg J, Schrey S, Stahl D, Magnusson V, Eliasson E, Agelii-Weber A, Stalhammar E, van Westen D, Deierborg T, Mansson KNT, Pizzagalli DA, Hammar A, Tornberg AB, Bjorkstrand J, Lindqvist D. Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial. Nat Med. 2026 Jun 12. doi: 10.1038/s41591-026-04465-9. Online ahead of print.
• Lindahl J, Asp M, Stahl D, Tjernberg J, Eklund M, Bjorkstrand J, van Westen D, Jensen J, Mansson K, Tornberg A, Svensson M, Deierborg T, Ventorp F, Lindqvist D. Add-on pramipexole for anhedonic depression: study protocol for a randomised controlled trial and open-label follow-up in Lund, Sweden. BMJ Open. 2023 Nov 30;13(11):e076900. doi: 10.1136/bmjopen-2023-076900.

Drugs

Indications