Anxiety and depression as prodromes of Parkinson's disease: prospective findings from the Moli-sani study.

Anxiety or depression are considered prodromes of Parkinson's disease (PD), though their temporal pattern is not fully defined. This study investigates the temporal relationship between drug-treated anxiety or depression and the clinical onset of PD motor symptoms.We used data from the Moli-sani study, which included 23,395 participants (52% women; mean age 55 ± 12 years, 15 year median follow-up). Participants free of PD at baseline were classified as either non-exposed (N = 20,033) or as having anxiety or depression (N = 1,760), based on both self-reporting and documented use of appropriate medications. Individuals with only one criterion (N = 1,602) were analysed separately. Incident PD cases were identified through regional health records and validated by neurologists and medical records. We used Cox models with inverse probability weighting based on propensity scores.A total of 306 PD cases were recorded (337,372 person-years). Individuals with both self-reported anxiety or depression and medication use had double PD hazard versus non-exposed (HR = 2.02, 95%CI: 1.45-2.80). This association was confirmed with validated PD cases (N = 144; HR = 1.96; 95%CI: 1.21-3.17), and was more evident in those treated for both conditions (N = 395; HR = 3.18, 95%CI: 1.90-5.31). No association emerged for those meeting only one criterion. Excluding subjects with a progressively shorter interval between the onset of anxiety or depression and study exit clearly attenuated the association, which nearly disappeared when the interval was > 10 years. The temporal pattern observed suggests that anxiety and depression requiring pharmacological treatment may represent time-dependent prodromal manifestations of clinical PD, emerging up to 10 years before motor symptoms.