Pramipexole for TRD: Promising 48-Week Results
Published: June 29, 2025, in The Lancet Psychiatry
Study: Pramipexole augmentation for the acute phase of treatment‑resistant, unipolar depression: a placebo‑controlled, double‑blind, randomised trial in the UK (The Lancet Psychiatry, Volume 12, Issue 8, 579 – 589)
📌 Study Summary
A multi-center, randomized, double-blind UK trial evaluated pramipexole augmentation in adults with treatment‑resistant depression (TRD) who had not responded adequately to standard antidepressants.
- Participants: 150 adults (mean age ~45; ~56% women) with unipolar TRD
- Design: Pramipexole titrated to 2.5 mg/day or placebo, added to existing antidepressants, for 48 weeks
Key Findings at Week 12:
- Mean QIDS‑SR₁₆ reduction: -6.4 points (pramipexole) vs –2.4 points (placebo)
- QIDS-SR16 Response Rate: 44% (pramipexole) vs 16% (placebo); p = 0.0011
- QIDS-SR16 Remission Rate: 28% (pramipexole) vs 8% (placebo); p = 0.0026
- QIDS-C (Clinical reported) score change: −6.1 points (pramipexole) vs −3.0 (placebo); p < 0.0001
- GAD-7 score change: −4.1 points (pramipexole) vs −1.5 (placebo); p = 0.0007
- Anhedonia: SHAPS score change: −3.8 points (pramipexole) vs −1.5 (placebo); p = 0.0003
Key Findings at Week 48:
- QIDS-SR16 score change: −6.1 points (pramipexole) vs −4.0 (placebo); p = 0.021
- WSAS (Work and Social Adjustment Scale) score change: −6.8 points (pramipexole) vs −3.3 (placebo); p = 0.03
⚠️ Adverse Events:
Adverse Events ≥10% in Either Group
Substantially higher in Pramipexole group:
- Nausea: 67% vs 41% (+26%)
- Dizziness: 56% vs 36% (+20%)
- Somnolence: 24% vs 8% (+16%)
- Vomiting: 29% vs 12% (+17%)
- Headache: 63% vs 49% (+14%)
- Malaise: 19% vs 9% (+10%)
- Diarrhea: 17% vs 9% (+8%)
- Middle insomnia: 13% vs 1% (+12%)
- Abdominal pain: 11% vs 1% (+10%)
- Sleep disorder: 28% vs 19% (+9%)
Higher in Placebo group:
Migraine: 5% vs 17% (−12%)
Adverse Events of Special Interest
- Impulse control disorder: 3% vs 0% (+3%)
- Substance-induced psychotic symptoms: 1% vs 0% (+1%)
Suicidal Ideations:
Lower in the pramipexole group than in the placebo group by the 3rd week of treatment.
Hypomania Risk:
- Altman Self-Rating Mania scale scores: raised in the pramipexole group by the 2nd week of treatment.
- Hypomania: 1 (Pramipexole) & 1 (Placebo)
Medication Discontinuation Due to Side Effects:
- 20% (pramipexole) vs 5% (placebo)
✅ Conclusion:
Pramipexole augmentation appears to be a clinically effective, long-term option for TRD, offering a viable dopaminergic pathway alternative when traditional augmenters fall short. Still, higher withdrawal rates necessitate clinician vigilance in side effect management.
💬 Clinical Commentary:
- Long-term augmentation data: This is the largest TRD augmentation trial to run for nearly a year, offering insights on sustained efficacy.
- Dopaminergic target: Unlike SSRIs/SNRIs, pramipexole targets dopamine—supporting a different neurochemical pathway in TRD.
- Magnitude of effect: A ~4‑point QIDS difference is clinically meaningful, parallel to effect sizes seen with lithium or atypical antipsychotics.
- Tolerability concerns: A 20% dropout rate underscores the need for careful dose titration and managing side effects.
🎓 Practice Implications:
- Consider pramipexole for patients unresponsive to first‑line augmentation—especially when dopaminergic enhancement is well tolerated.
- Initiate at low doses and titrate slowly during the first 12 weeks to reduce nausea and sleep-related side effects.
- Monitor for impulse control disorders and side effected mentioned above.
FOR ACADEMY MEMBERS:
This chapter will be summarized in the following sections:
- Mechanism of Action: behind Pramipexole’s efficacy for MDD augmentation.
- Who is a Good Candidate: for Pramipexole trial?
- Recommended Dose for Pramipexole: how to initiate & titrate in adults and elderly patients?
- Onset of Response: how long will it take to achieve a response after reaching the therapeutic dose?
- Side Effects: with pramipexole treatment.
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