The dopamine agonist upholds a large effect in this 12-month trial
STUDY: Browning M et al, Lancet Psychiatry 2025, 12(8):579-589
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: National Institute of Health and Care Research (UK)
Background
Pramipexole, a dopamine agonist approved for Parkinson’s disease and restless legs, targets anhedonia through dopaminergic D3 pathways. In small trials of unipolar and bipolar disorder, it had a large effect, but this is the first well-powered trial to test it in treatment-resistant depression, and it did so for the acute and maintenance phase.
The Study
151 adults with treatment-resistant unipolar depression — moderate to severe, with a median episode duration of 8.5 years and an average of 3–4 failed antidepressants — were randomized to pramipexole (titrated to 2.5 mg nightly) or placebo added to their current antidepressant for 48 weeks. The primary endpoint was change in depression severity at 12 weeks on the Depression scale (QIDS-SR16).
The graph tells the story. Over the year, the confidence limits showed no overlap between placebo and pramipexole lines. At 12 weeks, it produced a large effect size (0.87), in line with the effect size of IV ketamine. Response rates were 44% vs. 16%, and remission rates were 28% vs. 8% — a number needed to treat of 4. Benefits extended to anhedonia, anxiety, and functioning, and held at 48 weeks.
Side effects
Pramipexole’s raises hedonic drive, and that is its main risk. Like other D3 agonists, it is associated with rare cases of hedonic dysregulation, sometimes called pathological gambling, but it can take other forms like shopping, hypersexuality, or in more benign cases, organizing the garage all weekend (it is not, however, associated with other manic symptoms and the medication did not cause mania in bipolar trials). This study was the first to quantify that risk, which estimated at 3%. That is lower than the 20-30% risk seen in Parkinson’s disease, either because Parkinson’s injures frontal control circuits or depression starts out with a low hedonic drive.
Other side effects included somnolence (16%) and nausea (26%). One patient developed hallucinations, which is a known risk but the authors thought it was due to steroid use. Overall, 20% stopped pramipexole due to side effects, versus 5% on placebo.
Limitations: Functional unblinding (70-77% correctly guessed their treatment).
Practice Implications
This study changes practice, making pramipexole a first-line consideration for treatment resistant depression. Why?
- Safer and more effective than antipsychotics and lithium.
- Its greater efficacy, supported by observational data where pramipexole worked after aripiprazole, ECT, and an average of 6 antidepressants failed. While pramipexole beat placebo over a year, antipsychotics failed in 3/4 of their “long term” trials, which only lasted 6 months.
- The major risk is shared by the D3 antipsychotics (aripiprazole, brexpiprazole, and cariprazine), but it lacks other risks of TD, metabolic syndrome, prolactinemia, NMS, temperature and EPS.
- Although 1 in 5 stopped pramipexole due to nausea, this side effect is usually avoidable by titrating slowly (0.25 mg qhs for 1 wk, raise by 0.25 mg every week to target of 1-1.5 mg, then reassess and titrate as needed) and treating with ondansetron, ginger, or a proton pump inhibitor (lansoprazole, pantoprazole, esomeprazole, and rabeprazole worked in some trials).
- Pramipexole lacks weight gain, cognitive, and sexual side effects.
More on how to use it in the Carlat Report and Difficult to Treat Depression.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- What have you seen with pramipexole in depression?
