Highlight
This population-based study analyzes electronic health records to emulate target trials comparing dopamine-enhancing therapies to commonly prescribed comparators in adults with non-neovascular age-related macular degeneration (AMD). Use of levodopa, with or without carbidopa, was associated with a significantly reduced 3-year risk of progression to neovascular AMD (nAMD), while dopamine receptor D2 (DRD2) agonists did not show a statistically significant protective effect. These findings suggest a potential role of dopaminergic signaling modulation in slowing AMD progression, warranting further prospective evaluation.
Study Background
Age-related macular degeneration (AMD) is a leading cause of central vision impairment and blindness worldwide, particularly among older adults. The neovascular (wet) form of AMD, characterized by choroidal neovascularization, frequently results in rapid and severe vision loss. Despite advances in anti-vascular endothelial growth factor (VEGF) therapies that improve outcomes in established nAMD, preventing or delaying the transition from non-neovascular (dry) AMD remains a clinical challenge. Emerging research highlights the dopaminergic system’s impact on retinal physiology and possible implications for neurodegeneration and vascular regulation within the retina. This raises the hypothesis that dopamine-enhancing agents might modulate AMD progression pathways.
Study Design
This retrospective cohort study emulated four separate target trials using data from the TriNetX U.S. Collaborative Network, which aggregates electronic health records from 69 healthcare organizations. Inclusion criteria included adults aged 18 years or older diagnosed with non-neovascular AMD between May 2005 and May 2025. Patients with prior neovascular AMD or prior exposure to other dopamine-enhancing agents such as selegiline, rasagiline, or tolcapone were excluded to reduce confounding.
The interventions studied were initiation of (1) levodopa with or without carbidopa or (2) DRD2 agonists—specifically pramipexole, ropinirole, bromocriptine, rotigotine, and cabergoline. Each treatment cohort was independently matched 1:1 via propensity score matching against comparator cohorts initiating pantoprazole or gabapentin, chosen as active comparators without known dopaminergic effects. Matching incorporated demographics, social determinants, comorbidities, and baseline AMD stage to balance covariates.
The primary endpoint was the 3-year risk of conversion from non-neovascular AMD to neovascular AMD. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using time-to-event analyses, with statistical significance set at P < 0.05.
Key Findings
A total of 1312 levodopa users were matched to 1312 pantoprazole users; similarly, 1675 levodopa users were matched with 1675 gabapentin users. For DRD2 agonists, 1603 patients were matched to 1603 pantoprazole controls, and 2779 were matched to 2779 gabapentin controls.
Levodopa ± carbidopa use was associated with a statistically significant reduction in 3-year risk of nAMD conversion compared to pantoprazole (HR 0.67; 95% CI, 0.45–0.98) and gabapentin (HR 0.69; 95% CI, 0.50–0.95). These HRs indicate a 31–33% relative risk reduction in progression to neovascular disease.
Conversely, DRD2 agonist use did not significantly change the risk of conversion compared to either pantoprazole (HR 0.81; 95% CI, 0.58–1.13) or gabapentin (HR 0.92; 95% CI, 0.72–1.19), suggesting no robust protective effect.
No major safety signals or adverse event data were discussed in the abstract, likely reflecting limitations of electronic health record analyses focusing primarily on disease conversion outcomes.
Expert Commentary
The observed association between levodopa use and reduced AMD progression may reflect dopaminergic modulation of retinal metabolism or vascular mechanisms critical to choroidal neovascularization. Levodopa serves as a dopamine precursor, potentially restoring dopaminergic tone more broadly, while DRD2 agonists act selectively at dopamine receptor subtype 2, which may not replicate levodopa’s full spectrum of effects.
Limitations include the retrospective nature and inherent biases of electronic health record data, residual confounding despite propensity matching, absence of detailed ophthalmologic imaging or functional vision data, and lack of randomized treatment assignment. Additionally, the pharmacodynamics and dosing strategies of dopaminergic agents in AMD warrant closer investigation.
Nonetheless, these findings provide rationale for prospective clinical trials to evaluate levodopa or related dopamine-enhancing therapies as potential preventive agents for AMD progression. Current AMD management guidelines do not address dopaminergic modulation, making this an innovative and potentially impactful area of research.
Conclusion
This large, population-based analysis using target trial emulation indicates that levodopa ± carbidopa therapy is associated with a meaningful reduction in 3-year risk of conversion from non-neovascular to neovascular AMD. Dopamine receptor D2 agonists did not confer similar benefits. These results support the hypothesis that dopaminergic signaling plays a role in AMD pathophysiology and progression. Prospective interventional studies are justified to clarify causality, optimal therapeutic regimens, and safety profiles, potentially expanding the armamentarium for AMD prevention.
Funding and ClinicalTrials.gov Registration
The original study was published in the American Journal of Ophthalmology in June 2026 (PMID: 42336230). Details on funding sources and clinical trial registration were not specified in the abstract.
References
- Fazal O, Loya A, Muayad J, et al. Dopamine-Enhancing Therapies and Risk of Neovascular AMD Conversion: A Target Trial Emulation. Am J Ophthalmol. 2026 Jun 23; PMID: 42336230.
- Bhutto IA, McLeod DS, Hasegawa T, et al. Dopaminergic pathways in human retina and relevance to age-related macular degeneration. Retina. 2017;37(12):2343–2349.
- Chew EY. Age-related macular degeneration: zenith and nadir. Am J Ophthalmol. 2013;156(2):198–204.
- Yoshida S, Wakada M, Shimizu M, et al. Neuroprotective effects of dopamine against oxidative stress in cultured retinal cells. Neurosci Lett. 2014;570:58–62.
