Towards safer risperidone prescribing in Alzheimers Disease

Background In the treatment of psychosis, agitation and aggression in Alzheimers disease (AD), guidelines emphasise the need to use the lowest possible dose of antipsychotic drugs, but provide no information on optimal dosing. Aims This analysis investigated the pharmacokinetic profiles of risperidone and active metabolite, 9-hydroxy (OH)-risperidone, and how this related to emergent extrapyramidal side effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness-AD study. Method A statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and active moiety (combined concentrations) (108 CATIE-AD participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model based predictions were used to simulate the dose adjustments needed to avoid EPS. Results The model showed an age-related reduction in risperidone clearance (p<0.0001), and estimated that 22% of patients had slower active moiety clearance (concentration-to-dose ratio 20.2 (SD 7.2) versus 7.6 (SD 4.9) ng/mL per mg/day, Mann Whitney U, p<0.0001). Higher average and trough 9-OH-risperidone concentrations (p<0.0001), and lower Mini-Mental State Examination (MMSE) scores (p<0.0001), were associated with EPS. Model based predictions suggest the optimum dose ranged from 0.25mg/day in those aged 85 years with MMSEs of 5, to 1mg/day in those aged 75 years with MMSEs of 15, with alternate day dosing required for those with slower drug clearance. Conclusions Our findings argue for age and MMSE related dose adjustments and suggest that a single plasma sample could be used to identify those with slower drug clearance.