Multiple Adverse Outcomes Associated with Risperidone in People with Dementia: An Individual Participant Data Meta-Analysis

INTRODUCTION AND OBJECTIVES: Risperidone has modest efficacy for behaviours and psychological symptoms of dementia and is associated with many adverse events. Current guidelines limit its use to no longer than 12-16 weeks. This study aims to evaluate adverse outcomes over time, identify key predictors, and examine high-risk subgroups to inform safer prescribing. METHOD: A one-stage individual participant data meta-analysis of six randomised controlled trials (risperidone: n = 1009; placebo: n = 712) was conducted. Mixed-effect generalised linear models and proportional hazards mixed-effects models estimated treatment effects, predictors, and subgroup differences for adverse outcomes over varying time periods. RESULTS: Risperidone was associated with increased risks of cerebrovascular (hazard ratio [HR] 4.11; 95% confidence interval [CI] 1.77-9.51; p = 0.001) and major cardiovascular events (HR 2.00; 95% CI 1.23-3.26; p = 0.006), with median (interquartile range) onset at 4.3 (5.9) and 4.8 (6.8) weeks of treatment, respectively. Somnolence occurred consistently during treatment, whereas upper respiratory tract infections (odds ratio [OR] 2.31; 95% CI 1.24-4.32; p = 0.009) and extrapyramidal symptoms emerged (OR 2.93; 95% CI 1.68-5.08; p < 0.001) after week 4. Older age, male sex, and baseline cardiac pharmacotherapy use predicted serious adverse outcomes. CONCLUSION: Most adverse effects occur after 4 weeks of treatment. Attention to baseline risk factors is essential to minimise harm. Risk-benefit calculators may guide individualised prescribing.