A new study in The BMJ finds, however, that the harms are greater and more extensive than previously realized and that the risks are highest soon after initiating the drugs.
Despite safety concerns, antipsychotics have continued to be widely prescribed for behavioral and psychological symptoms of dementia such as apathy, depression, aggression, anxiety, irritability, delirium, and psychosis. Warnings about increased risks for stroke and death have not done much to stem the tide, according to a British study led by the University of Manchester.
The study team used a population-matched cohort study to investigate the risks of multiple adverse outcomes associated with the use of antipsychotics in people with dementia. Data were from the Clinical Practice Research Datalink in England.
The study population included 173,910 adults aged 50 years and older—63% of them women—with a diagnosis of dementia between January 1, 1998, and May 31, 2018. Each new antipsychotic user (n = 35,339; 62.5% women) was matched with up to 15 nonusers using incidence density sampling.
The researchers focused on outcomes including stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use.
The results indicated that, compared with nonuse, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of:
• Pneumonia (hazard ratio [HR] 2.19; 95% CI, 2.10-2.28)
• Acute kidney injury (HR 1.72, 1.61-1.84)
• Venous thromboembolism (HR 1.62, 1.46-1.80)
• Stroke (HR 1.61, 1.52-1.71)
• Fracture (HR 1.43, 1.35-1.52)
• Myocardial infarction (HR 1.28, 1.15-1.42)
• Heart failure (HR 1.27, 1.18-1.37).
“In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%),” the researchers pointed out.
The study team concludes, “The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.”
With dementia, features such as apathy, depression, aggression, anxiety, irritability, delirium, and psychosis can negatively impact the quality of life of patients and their caregivers, and also are associated with instituionalzation, according to background information in the article.
Antipsychotics are commonly prescribed for the management of behavioral and psychological symptoms of dementia, despite ongoing concerns about their safety.
“During the COVID-19 pandemic, the proportion of people with dementia prescribed antipsychotics increased, possibly owing to worsened behavioral and psychological symptoms of dementia linked to lockdown measures or reduced availability of non-pharmaceutical treatment options,” according to the report. Most guidelines suggest that antipsychotics should only be prescribed for the treatment of behavioral and psychological symptoms of dementia if nondrug interventions have been ineffective, if patients are at risk of harming themselves or others or are experiencing agitation, hallucinations, or delusions causing them severe distress. The clinical guidance also usually calls for antipsychotics being prescribed at the lowest effective dose and for the shortest possible time.
In the United States, atypical antipsychotics (AAPs) are often used off-label to manage dementia-associated neuropsychiatric symptoms. In 2005, the FDA issued a boxed warning for the use of AAPs in elderly patients. That followed a 2003 warning about the increased risks of cerebrovascular adverse events (eg, stroke, transient ischaemic attack) associated with the use of atypical antipsychotics in older adults with dementia.
The warning was extended to typical antipsychotics in 2008 after two observational studies reported that the risk of death associated with their use among older people might be even greater than for atypical antipsychotics.
In a related commentary, Raya Elfadel Kheirbek, MD, of the University of Maryland School of Medicine and Cristina LaFon of the Geriatrics Research, Education and Clinical Center, at the Veterans Affairs Medical Center, both in Baltimore, said findings of this study provided healthcare professionals with more nuanced data to help with personalized treatment decisions.
The researchers explained that international guidelines advise restricting use to adults with severe behavioral and psychological symptoms of dementia, but the rate of prescribing has risen in recent years, possibly because of the relative scarcity of effective nondrug alternatives and the substantial resources needed to implement them.
“Increased priority on more patient-centric care, tailored care plans, regular reassessment of management options, and a move away from the overprescription of antipsychotics is overdue,” the researchers wrote.
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