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

Abstract

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.