Adverse outcomes between VMAT2 and anticholinergics in tardive dyskinesia: A target trial emulation

AIM: Vesicular monoamine transporter 2 (VMAT2) inhibitors have been approved for the treatment of tardive dyskinesia (TD), whereas anticholinergic agents are still widely used for this condition. This study aimed to compare the risk of major clinical adverse outcomes among patients with TD treated with VMAT2 inhibitors versus anticholinergic agents. METHODS: This retrospective cohort study used the TriNetX collaborative network, which aggregates de-identified electronic health records (EHRs) across the United States. Adults aged≧18 years with TD who initiated anticholinergic agents or VMAT2 inhibitors for the first time between 2019 and 2025 were included. We applied a target trial emulation framework under the intention-to-treat principle. 1:1 propensity score matching was applied. Cox hazard regression was used to assess the primary outcomes: incident fall, injury, fracture, and mortality, and secondary outcomes: incident delirium, dementia, and arrythmia. RESULTS: After propensity score matching, 2749 patients (mean age: 59 years; 34% male) were included in each treatment group with well-balanced demographics. Compared with anticholinergic therapy, VMAT2 inhibitors were associated with significantly lower risks of fall (HR = 0.83, 95% CI = 0.73-0.93), injury (HR = 0.77, 95% CI = 0.71-0.85), fracture (HR = 0.82, 95 % CI = 0.72-0.94), and mortality (HR = 0.71, 95% CI = 0.58-0.87). Secondary outcomes also favored VMAT2 inhibitors, with reduced risks of delirium (HR = 0.39, 95% CI = 0.29-0.52), dementia (HR = 0.55, 95 % CI = 0.45-0.69), and arrhythmia (HR = 0.72, 95% CI = 0.60-0.85). CONCLUSION: This real-world study suggests that VMAT2 inhibitors may offer a safer therapeutic option than anticholinergic agents for TD management, supporting their potential clinical advantage and the need for further long-term validation.