"Efficacy, safety and certainty of evidence for selective D1/D5 dopamine receptor partial agonists in Parkinson's disease: a systematic review, meta-analysis and GRADE assessment".

BACKGROUND: Selective D1/D5 dopamine receptor partial agonists are proposed to provide motor benefit without the impulse control disorders and somnolence associated with D2/D3 dopamine agonists. With tavapadon under regulatory review, no quantitative synthesis of this drug class exists. METHODS: Embase, MEDLINE, PubMed, Scopus and ClinicalTrials.gov were searched from inception to 31 May 2026 for randomised, double-blind, placebo-controlled trials of selective D1/D5 partial agonists in Parkinson's disease (PROSPERO CRD420261347585). Random-effects models (REML) were used. Risk of bias was assessed with RoB 2 and certainty of evidence with GRADE. RESULTS: Seven trials (1,540 participants) were included; five entered quantitative synthesis. In early-stage monotherapy, tavapadon improved the combined MDS-UPDRS Parts II and III score by 10.55 points versus placebo (95% CI - 13.11 to - 7.99; two trials). In levodopa-treated patients with motor fluctuations, good ON-time increased by 1.09 h per day (0.57 to 1.61; two trials). Adverse events (RR 1.36, 1.09 to 1.71), nausea (6.38, 3.23 to 12.59), dizziness (3.03, 2.15 to 4.27) and discontinuation due to adverse events (2.72, 1.07 to 6.96) were more frequent with tavapadon. Serious adverse events were not increased (Peto OR 1.13, 0.69 to 1.85). Impulse control disorder (RR 2.02, 0.51 to 8.00; nine events, one trial) and somnolence (1.20, 0.37 to 3.92) were rated at very low certainty. No outcome reached high certainty. CONCLUSION: Selective D1/D5 partial agonism improves motor function in early-stage and levodopa-treated Parkinson's disease, at moderate certainty. Its proposed neuropsychiatric advantage over D2/D3 agonists remains untested: no trial used an active comparator or exceeded 27 weeks.