Levodopa-accelerated frailty: a hypothesis for a cumulative iatrogenic burden in Parkinson's disease.

Levodopa remains the cornerstone of symptomatic treatment in Parkinson's disease, providing substantial motor benefit and improved quality of life. While epidemiological studies have suggested improved survival in the modern levodopa era compared with the pre-levodopa era, these observations derive primarily from observational cohorts rather than randomized trials. Yet many patients experience severe functional decline after 5-10 years, a paradox that challenges the reputation of our most potent therapy. Similar divergences between early symptomatic benefit and adverse long-term outcomes have been observed in other areas of medicine. For example, positive inotropic agents such as milrinone improved short-term exercise tolerance in heart failure but were later associated with increased mortality in long-term trials. Antiarrhythmic agents encainide and flecainide effectively suppressed ventricular arrhythmias yet increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST). In diabetes, intensive glucose lowering strategies improved metabolic control but increased cardiovascular mortality in the ACCORD trial, and earlier studies of tolbutamide in the University Group Diabetes Program (UGDP) also suggested excess cardiovascular deaths despite improved glycemic control. These examples illustrate how therapies with clear short-term physiological benefits may reveal unanticipated risks when evaluated over longer time horizons. Similarly, the long-term use of levodopa may introduce a cumulative burden of complications that may independently accelerate decline. We propose the conceptual framework of