Antipsychotics associated with a wide range of adverse outcomes in dementia

Behavioural and psychological symptoms (e.g., apathy, depression, aggression, anxiety, irritability, delirium, psychosis) are common features of dementia and can negatively impact the quality of life of patients and caregivers. Antipsychotics are commonly prescribed to manage these symptoms, despite concerns about their safety. However, they should usually only be prescribed when nondrug measures are ineffective, patients are at risk of harming themselves or others, or are experiencing agitation, hallucinations or delusions that cause severe distress. If antipsychotics are used, they should be prescribed at the lowest effective dose and for the shortest possible duration.1Canadian product monographs for atypical antipsychotics warn of increased mortality in elderly patients with dementia. This is based on an analyses of 13 placebo-controlled trials with various atypical antipsychotics showing a 1.6-fold increase in death rate. Most of the deaths were either cardiovascular (e.g., heart failure, sudden death) or infectious in nature (e.g., pneumonia).2To further investigate the range of adverse outcomes associated with antipsychotics in adults with dementia, researchers used linked primary and secondary care data in England to assess the adverse outcomes potentially associated with typical and atypical antipsychotic use.1 The study included adults (≥ 50 years) with a diagnosis of dementia from 1998–2018 (n=173,910; 63.0% women). Each new antipsychotic user (n=35,339, 62.5% women) was matched with up to 15 nonusers using incidence density sampling.1The main outcomes were the occurrence of stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia and acute kidney injury. Results were stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. Appendicitis and cholecystitis (combined) was used as a negative control to detect potential unmeasured confounding.1Results showed the following:Compared with nonuse, any typical/atypical antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current typical/atypical antipsychotic use (within 90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio [HR] 2.19, 95% confidence interval (CI) 2.10–2.28), acute kidney injury (HR 1.72, CI 1.61–1.84), venous thromboembolism (HR 1.62, CI 1.46–1.80), stroke (HR 1.61, CI 1.52–1.71), fracture (HR 1.43, CI 1.35–1.52), myocardial infarction (HR 1.28, CI 1.15–1.42) and heart failure (HR 1.27, CI 1.18–1.37). No increased risks were seen for ventricular arrhythmia or the negative control outcome (appendicitis and cholecystitis). In the 90 days after typical/atypical antipsychotic initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% versus 1.49% in the matched cohort of nonusers (difference 2.99%, CI 2.77%–3.22%).The number needed to harm (NNH) ranged from nine for pneumonia to 167 for myocardial infarction during the first 180 days after initiation of antipsychotics. This means that over the 180-day period after drug initiation, use of antipsychotics might be associated with one additional case of pneumonia for every nine patients treated, and one additional case of myocardial infarction for every 167 patients treated.Increased risks were observed among current and recent users and were highest in the first week after initiation of antipsychotic treatment.In the 90 days after a prescription, risks of stroke, heart failure, fracture, pneumonia, and acute kidney injury were higher for typical antipsychotics versus atypical antipsychotics.Haloperidol was associated with higher risks for fracture, pneumonia and acute kidney injury than risperidone.Risks of almost all adverse outcomes were higher for haloperidol than for quetiapine. No significant differences were found between risperidone and quetiapine for risks of myocardial infarction, heart failure or fracture, but risks for stroke, venous thromboembolism, pneumonia and acute kidney injury were lower for quetiapine versus risperidone.1The authors concluded that use of typical and atypical antipsychotics (compared with nonuse) in adults with dementia is associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia andacute kidney injury, but not ventricular arrhythmia. This range of adverse outcomes is broader than what has previously been highlighted in regulatory alerts, with the highest risk occurring soon (during the first week) after initiation of treatment.1 The modest (at best) benefit of antipsychotics on behavioural and psychological symptoms of dementia needs to be weighed against the risk of the wide range serious adverse outcomes identified in this study. If antipsychotics are prescribed for patients with dementia, they should be used for the shortest duration possible and treatment plans should be reviewed regularly with patients and their caregivers to reassess the need for continued treatment.1References:Mok PLH, Carr MJ, Guthrie B, et al. Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study. BMJ 2024;385:e076268. (accessed May 7, 2024).Otsuka Canada Pharmaceutical Inc. Rexulti (brexpiprazole tablets) product monograph. Saint-Laurent, QC; January 23, 2024. (accessed May 7, 2024).

Antipsychotics associated with a wide range of adverse outcomes in dementia

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