Pramipexole Promising for Treatment-Resistant Depression, But Side Effects Remain a Concern: Study Suggests
UK: A recent UK-based clinical trial published in The Lancet Psychiatry has highlighted the potential of pramipexole, a dopamine agonist typically used for Parkinson’s disease, as an effective augmentation therapy for patients with treatment-resistant unipolar depression. The study demonstrated a notable reduction in depressive symptoms over 12 weeks, though some tolerability issues remain.
Depression remains a major global health burden, and nearly 30% of individuals do not respond adequately to first-line antidepressants. For such patients, augmentation strategies are often explored. Pramipexole, with its dopaminergic mechanism, has been considered a potential candidate, but robust clinical data on its efficacy and tolerability in this setting have been limited until now.
This multicentre, double-blind, placebo-controlled trial was conducted across nine NHS Trusts in England and included 151 adults with treatment-resistant major depressive disorder. Participants continued their existing antidepressant regimen and were randomly assigned to receive either pramipexole (titrated to 2.5 mg daily) or a matching placebo for 48 weeks. The primary outcome focused on changes in depressive symptoms, measured by the Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR16) scale at 12 weeks.
Based on the study, the researchers reported the following findings:
- The pramipexole group showed a significantly greater reduction in depressive symptoms compared to the placebo group.
- The adjusted mean decrease in QIDS-SR16 scores was 6.4 points for pramipexole versus 2.4 points for placebo.
- The mean difference in symptom reduction between groups was −3.91.
- The standardized effect size (d=0.87) indicated a strong therapeutic response.
- The number needed-to-treat (NNT) was 4, suggesting high clinical effectiveness.
- Treatment discontinuation due to adverse events occurred in 20% of patients in the pramipexole group, compared to 5% in the placebo group.
- Reported side effects included nausea, headaches, and sleep disturbances, aligning with the known safety profile of pramipexole.
The trial stands out for its scale and duration, making it the largest and longest evaluation of pramipexole in treatment-resistant depression to date. Previous studies were typically limited by short durations and lower doses, whereas this trial reached an average dose of 2.3 mg at 12 weeks.
The researchers conclude that pramipexole may serve as a valuable option for patients who do not respond to traditional antidepressants, though its tolerability must be carefully monitored. Future research should focus on comparing pramipexole with other established augmentation therapies, improving tolerability, and assessing long-term outcomes and cost-effectiveness.
These findings also emphasize the broader value of drug repurposing in psychiatry, offering cost-efficient paths to novel treatment strategies by leveraging existing safety data. Pramipexole’s promising results signal that other dopaminergic agents might also hold potential in managing treatment-resistant depression.
Reference:
Browning M, Cowen PJ, Galal U, Baldwin A, Cleare AJ, Evans J, Huys QJM, Kessler D, Kurkar M, Nixon N, Rastogi A, Watson S, Yu LM, Mort S, Simon J, Laszewska A, Lewis AC, Roberts SM, Fiske V, Frending LM, Money C, Godlewska BR, Ryland HT, Halahakoon DC, Wright LA, Salas B, Peddada A, Wahba M, Taylor KS, Kerr-Gaffney J, Swiffen D, Zangani C, Smith KA, Harmer CJ, Geddes JR; PAX-D study group. Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK. Lancet Psychiatry. 2025 Jun 27:S2215-0366(25)00194-4. doi: 10.1016/S2215-0366(25)00194-4. Epub ahead of print. PMID: 40602411.
