Pramipexole is a selective agonist at the dopamine D3 receptor, which is thought to regulate hedonic drive. It is FDA approved in Parkinson’s disease and restless legs syndrome, and has five randomized controlled trials in depression. In unipolar depression it worked as monotherapy or augmentation, and in bipolar depression it worked as augmentation of a mood stabilizer (Gauthier C et al, Clin Neuropharmacol 2017;40(6):264–267).

Pramipexole’s most common side effects are nausea, hypotension, and fatigue, which are reduced by titrating it slowly and giving the dose at night. Start with 0.125–0.25 mg qhs and raise by 0.25 mg every 5–7 days toward a target dose of 0.75–2 mg qhs. Pramipexole has a low risk of weight gain and sexual dysfunction.

Serious side effects are pathological gambling, hallucinations, and daytime somnolence. Pathological gambling is part of a spectrum of hedonic behaviors called hedonistic homeostatic dysregulation (HDD) that can include excessive masturbation, overspending on eBay, and gambling into severe debt. Aripiprazole, another D3 agonist, can also cause these problems. HDD usually occurs without manic symptoms, and it is more common when dopaminergics are used in Parkinson’s disease than when they are used in mood disorders (Cartoon J & Ramalingam J, Australas Psychiatry 2019;27(5):456–461).

Long-term pramipexole use has been associated with congestive heart failure, but that association did not hold up in controlled investigations. Early reports of melanoma on pramipexole have since been linked to Parkinson’s disease itself rather than the medication, and warnings of melanoma were removed from the prescribing information in 2018.