Association between anxiety disorder, anxiolytic drugs, and risk of incident Parkinson's disease

Abstract

In this prospective cohort study, we analysed data from 502,364 participants (ages 40-69) in the UK Biobank, with follow-up until 2024. Logistic and Cox regression analysis identified generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD) as independent risk factors for Parkinson's disease (PD), with post-traumatic stress disorder (PTSD) patients under 71 also at increased risk. Panic disorder (PAD) showed no association with PD. Further analysis of anxiolytic drug use revealed that selective serotonin reuptake inhibitors (SSRIs), benzodiazepines (BDZs), medium-to-high frequency use of tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs) were linked to PD incidence, while low-frequency use of TCAs and SNRIs was not. Mediation analysis indicated that GAD influenced PD risk through the thalamus, brainstem, and left putamen, while OCD and PTSD affected PD risk via brain regions including the angular gyrus, thalamus, and postcentral gyrus. These findings provide novel insights into PD mechanisms and potential therapeutic targets.

Fig. 1. Forest plot of four anxiety disorders and PD.

GAD generalised anxiety disorder, PAD phobic anxiety disorders, OCD obsessive-compulsive disorder, PTSD post-traumatic stress disorder. Model 0 includes four types of anxiety disorders (GAD, PAD, OCD, and PTSD). Model 1 = Model 0 + age + sex + ethnicity + education; Model 2 = Model 1 + smoking status + alcohol intake + BMI + TDI + coffee intake; Model 3 = Model 2 + PRS + hypertension + migraine + depression + sleep disorder.

Fig. 2. Forest plot of four anxiolytic drugs and PD.

a selective serotonin reuptake inhibitors; b benzodiazepines; c tricyclic antidepressants; d serotonin norepinephrine reuptake inhibitors. Model 0 = four types of anxiolytic drugs (SSRIs, BDZs, TCAs, and SNRIs). Model 1 = Model 0 + age + sex + ethnicity + education; Model 2 = Model 1 + smoking status + alcohol intake + BMI + TDI + coffee intake; Model 3 = Model 2 + PRS + hypertension + migraine + depression + sleep disorder.

Fig. 3. Mediation effects of regional brain volume on the association between anxiety disorders and anxiolytic drugs with the incidence of Parkinson’s disease.

a β1*β2 the indirect effect, β the total effect, β’ the direct effect. MEP mediation effect proportion, GAD generalised anxiety disorder, OCD obsessive-compulsive disorder, PTSD post-traumatic stress disorder, SSRIs selective serotonin reuptake inhibitors, BDZs benzodiazepines, SNRIs serotonin norepinephrine reuptake inhibitors. b Visualisation of regional brain volumes with mediation effects. L left, R right. The structural localisation of positive brain volume clusters was conducted using the Automated Anatomical Labelling of Activations in SPM with a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain (AAL), available online (https://neurovault.org/images/14257/), and the results were visualised using the Brain ViewNet system (BrainView, USA).