Pramipexole for Anhedonic Depression

Automat, Edward Hopper (1927)

A dopamine agonist cuts anhedonia in half and improves physical activity

STUDY: Ventorp F et al, Nature Medicine 2026
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: Swedish Research Council and other non-industry groups.

Background

Anhedonia — the loss of ability to feel pleasure or drive — impairs recovery and affects up to 70% of patients with depression. SSRIs don’t improve it reliably. Anhedonia involves dopamine, and the dopamine pathway runs through the ventral striatum. Pramipexole, a dopamine agonist with efficacy in treatment-resistant depression, has uncontrolled and basic science data suggesting it helps. This is the first controlled trial to test it specifically for anhedonia.

The Study

• 82 adults with major depression, dysthymia, or bipolar depression with significant anhedonia.
• Randomized to flexible-dose pramipexole (added to ongoing antidepressant/mood stabilizer) or placebo for 9 weeks, followed by a 6-month open-label extension.
• Primary outcome: change in Snaith–Hamilton Pleasure Scale (SHAPS) scores from baseline to week 9.

Results

Pramipexole reduced SHAPS scores by 6.5 points versus 2.4 points with placebo (moderate effect size of 0.62, p = 0.006). The gain emerged quickly: significant advantage for pramipexole appeared by week 3 and held through week 9.

At week 9, 39% of pramipexole-treated patients showed ≥ 50% reduction in anhedonia versus 31% on placebo. Overall depression severity (on the Montgomery–Åsberg Depression Rating Scale) favored pramipexole when analyzed across all timepoints, though the 9-week endpoint alone missed significance.

Pramipexole also beat placebo on apathy and objective measures of physical activity. Light physical activity increased at weeks 4, 5, and 7, with effect sizes ranging from 0.57 to 0.87.

Brain imaging (7-Tesla fMRI during a monetary incentive delay task) showed pramipexole preserved reward-related ventral striatal activation, while placebo recipients showed a decline in this activation, suggesting biological target engagement.

During the 6-month open-label extension, improvements in anhedonia and depression sustained. Among those who completed six months, 59% showed ≥50% reduction in anhedonia and 38% achieved remission.

Mean end-point dose was 3.5 mg daily, which is much higher than most studies go (average 1.5 mg) or even the higher dose used in the TRD trial (2.5 mg). Going above 3 mg brings a risk of hallucinations, though that was not seen in this trial.

Side Effects

Sleep disturbances (72% vs 33% on placebo), nausea (60% vs 14%), dizziness, fatigue, and anxiety were more frequent with pramipexole. Two patients developed mild manic symptoms, both of which resolved after dose reduction or discontinuation. Brief increases in buying-related impulsive control symptoms appeared early but resolved by week 6. No gambling emerged. Overall dropout during the RCT was low.

In the open-label extension, the most common adverse events were sleep disturbance, fatigue, anxiety, and nausea.

Limitations

Blinding integrity was asymmetric: placebo recipients correctly guessed their allocation 67% of the time, while pramipexole recipients were near chance at 44% (similar problems in most antidepressant trials).

The mechanism analyses (fMRI, biomarkers) were conducted in subsamples with modest power, so findings are suggestive rather than definitive.

Personal Note

One of the authors, Vladimir Maletic, passed away as the paper went to print. Vladimir had a talent for making medical science practical, and you can view his 2023 slides on anhedonia here. His 2017 book on how the body causes depression, from genetics to inflammation, is a classic.

Practice Implications

1. Learn how to use pramipexole in Difficult to Treat Depression.
2. Although this trial tested it as augmentation, it has RCT evidence as monotherapy in depression (in bipolar, I would use a mood stabilizer with it).
3. When starting it, I’ll often explain, “It looks like you’ve tried a lot of meds, but most of them affect serotonin and norepinephrine. Have you heard of dopamine, which is involved in motivation, drive, that feeling that tasks are rewarding and life is meaningful?”
4. Usually they resonate with that, and I’ll add “You’ve never tried a medication that targets dopamine directly. This one does, but it never gained FDA approval because its antidepressant effects were discovered just as it was going generic.”
5. That leads into a discussion of the main risk: “If it pushes your drive too high, you may spend too much money or engage in pleasurable activities too much, although there are no reports of excess substance use on it.”

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

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