Identification of Drugs Associated with Lower Risk of Parkinson's Disease Using a Systematic Screening Approach in a Nationwide Nested Case-Control Study.

Introduction: Drugs for other indications may be repurposable as disease-modifying drugs for Parkinson's disease (PD). A systematic hypothesis-free approach can enable identification of candidates for repurposing. We applied a hypothesis-free systematic approach to identify drugs associated with lower risk of PD to discover candidates with potential for repurposing as disease-modifying drugs for PD and to illustrate challenges in observational studies that simultaneously investigate multiple repurposing candidates. Methods: The Finnish Parkinson's disease study (FINPARK), a nationwide nested case-control study, was randomized to screening (10,183 cases, 67,849 controls) and replication (10,184 cases, 67,754 controls) samples, including cases diagnosed in 1998-2015. After screening all univariable associations of register-derived exposure to individual-drug, group- and subgroup level since 1995 (exposure ≥3 years before outcome, threshold P = 0.1), different exposure periods were used in confounder-adjusted replication analyses. Results: In screening stage, the group-level (antipsoriatics and antigout preparations) and subgroup-level (cicatrizants, topical antipsoriatics, antigout preparations and mydriatics and cycloplegics) associations were mainly due to individual drugs. Seven other drugs (eg methotrexate, drugs for chronic obstructive pulmonary disease, COPD and/or asthma) were associated with lower risk. Associations of antigout preparations and antipsoriatics were replicated. COPD/asthma drugs, methotrexate and diabetes drugs were studied in separate, indication-restricted designs. Discussion: The results reflect the known risk factors and the implied role of the immune system in PD pathogenesis and spurious associations. They underline the importance of controlling for confounding by indication, which is challenging to apply to systematic screening.