Antipsychotics for dementia linked to more harms than previously acknowledged

Risks highest soon after starting drugs, underscoring need for increased caution in early stages of treatment, say experts

Antipsychotic use in people with dementia is associated with higher risks of a wide range of serious health outcomes compared with non-use, according to a new study from a collaboration across the Universities of Manchester, Nottingham, Edinburgh and Dundee.

Higher rates of stroke, blood clots, heart attack, heart failure, fracture, pneumonia, and acute kidney injury were observed in the study are Research (NIHR)and published in The BMJ today (17/04/24) The findings show a considerably wider range of harms associated with antipsychotic use in people with dementia than previously acknowledged in regulatory alerts, with risks highest soon after starting the drugs, underscoring the need for increased caution in the early stages of treatment.

Despite safety concerns, antipsychotics continue to be widely prescribed for behavioural and psychological symptoms of dementia such as apathy, depression, aggression, anxiety, irritability, delirium, and psychosis.

Previous regulatory warnings when prescribing antipsychotics for these symptoms were based on evidence of increased risks for stroke and death, but evidence of other adverse outcomes was less conclusive amongst people with dementia.

To address this uncertainty, The University of Manchester researchers set out to investigate the risks of several adverse outcomes potentially associated with antipsychotic use in people with dementia.

The outcomes of interest were stroke, major blood clots (venous thromboembolism), heart attack (myocardial infarction), heart failure, irregular heart rhythm (ventricular arrhythmia), fractures, pneumonia, and acute kidney injury.

Using linked primary care, hospital, and mortality data in England, they identified 173,910 people (63% women) diagnosed with dementia at an average age of 82 between January 1998 and May 2018 who had not been prescribed an antipsychotic in the year before their diagnosis.

Each of the 35,339 patients prescribed an antipsychotic on or after the date of their dementia diagnosis was then matched with up to 15 randomly selected patients who had not used antipsychotics.

In recent years, it has become clear that more people with dementia are being prescribed antipsychotic drugs, despite existing regulatory safety warnings. It is important that any potential benefits of antipsychotic treatment are weighed carefully against the risk of serious harm, and treatment plans need to be regularly reviewed in all’health and care settings
The most commonly prescribed antipsychotics were risperidone, quetiapine, haloperidol, and olanzapine, which together accounted for almost 80% of all prescriptions.

Potentially influential factors including personal patient characteristics, lifestyle, pre-existing medical conditions, and prescribed drugs were also taken into account.

Compared with non-use, antipsychotics were associated with increased risks for all’outcomes, except ventricular arrhythmia. For example, in the first three months of treatment, rates of pneumonia among antipsychotic users were 4.48% vs 1.49% for non-users. At one year, this rose to 10.41% for antipsychotic users vs 5.63% for non-users.

Risks were also high among antipsychotic users for acute kidney injury (1.7-fold increased risk), as well as stroke and venous thromboembolism (1.6-fold increased risk) compared with non-users.

For almost all’outcomes, risks were highest during the first week of antipsychotic treatment, particularly for pneumonia.

The researchers estimate that over the first six months of treatment, antipsychotic use might be associated with one additional case of pneumonia for every 9 patients treated, and one additional heart attack for every 167 patients treated. At two years, there might be one additional case of pneumonia for every 15 patients treated, and one additional heart attack for every 254 patients treated.

This was a large analysis based on reliable health data. However, because it was an observational study, no firm conclusions can be drawn about cause and effect. And although a range of factors have been adjusted for, the possibility that other unmeasured variables may have affected the results can’t be ruled out.

Senior author Prof Darren M Ashcroft, University of Manchester, Director of NIHR Greater Manchester Patient Safety Research Collaboration (PSRC), NIHR Senior Investigator said: "In recent years, it has become clear that more people with dementia are being prescribed antipsychotic drugs, despite existing regulatory safety warnings. It is important that any potential benefits of antipsychotic treatment are weighed carefully against the risk of serious harm, and treatment plans need to be regularly reviewed in all’health and care settings."

Co-investigator Prof Tony Avery, OBE, University of Nottingham, and NIHR Senior Investigator said: "For many years there have been safety concerns about the use of antipsychotics for managing the behavioural and psychological symptoms of dementia, with increased risk of stroke and death being reported. Our study shows that the use of antipsychotics in this group of patients is also associated with other harms including pneumonia, venous thromboembolism, myocardial infarction, heart failure, fracture, and acute kidney injury. This means that it is even more important to take account of risk of harm when considering prescribing these medicines, and to use alternative approaches wherever possible."

Lead author Dr Pearl Mok, Research Fellow, University of Manchester said: "With the number of people living with dementia forecast to increase greatly in the coming years, further research into safer drug and more efficacious non-drug treatments for behavioural and psychological symptoms of dementia are needed."

Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study is published in the