Effect of Antipsychotics on Mortality Risk in Patients With Dementia With and Without Comorbidities

Ane Nørgaard MD, PhD; Christina Jensen-Dahm MD, PhD; Theresa Wimberley MSc, PhD; Jesper Hastrup Svendsen MD, DMSc; Kazi Ishtiak-Ahmed PhD; Thomas Munk Laursen MSc, PhD; Gunhild Waldemar MD, DMSc; Christiane Gasse RPharm, PhD


J Am Geriatr Soc. 2022;70(4):1169-1179. 

In This Article

Abstract and Introduction


Background: We investigated the mortality risk associated with the initiation of antipsychotic treatment among patients with dementia and whether comorbidities related to the cardiovascular system and diabetes interact with antipsychotic treatment to increase the mortality risk beyond the risk of death independently associated with antipsychotics and comorbidity alone.

Methods: We designed a matched cohort study using nationwide registry data. All Danish residents aged 65–95 years diagnosed with dementia between 2009 and 2014 were included. Dementia was assessed as a first-time registered dementia diagnosis in the Danish National Patient Register or the Danish Psychiatric Central Research Register and/or a first-time prescription for antidementia medication. Patients exposed to antipsychotics were matched with up to three unexposed patients. Cox proportional hazards models were used to compare rates of death within 180 days after the initiation of antipsychotic treatment. The models were adjusted for potential confounders. Analyses were stratified for diabetes, heart disease, and cerebrovascular disease, and we calculated the relative excess risk due to interaction (RERI).

Results: The study cohort included 8244 exposed patients and 24,730 unexposed patients. A total of 5938 patients died during the first 180 days of follow-up. Patients exposed to antipsychotics had a significantly higher adjusted risk of death (hazard ratio: 1.35, 95% confidence interval: 1.27–1.43) than unexposed patients. Crude mortality rates were higher among patients with heart disease and diabetes when antipsychotic treatment was initiated compared with patients without comorbidities. Relative risk estimates did not differ between patients with and without heart disease, cerebrovascular disease, and diabetes, and RERI suggested no positive additive interaction. Risk analysis suggested higher mortality in patients without cerebrovascular disease who initiated antipsychotics.

Conclusion: This nationwide study adds to the evidence that antipsychotic treatment is associated with increased mortality and suggests that attention should be paid to all initiators of antipsychotics irrespective of cardiovascular disease and diabetes.


Antipsychotic drugs are commonly used to treat behavioral and psychological symptoms in patients with dementia. However, the treatment may cause side effects and can lead to serious adverse events and death.[1,2] Clinical trials (typical trial duration of 10 weeks[3]) found an increased mortality during antipsychotic treatment which led to warnings against antipsychotic treatment for patients with dementia.[4] Population-based studies found an increased short-term (6–12 months) mortality among patients treated with antipsychotic drugs.[5–7]

The side effects of antipsychotic treatment are manifold and include QT prolongation, orthostatic hypotension, sedation, Parkinsonism, and metabolic disturbances. The possible mechanisms leading to increased mortality may be linked to these side effects. QT prolongation may lead to ventricular tachyarrhythmias and sudden cardiac death,[8,9] orthostatic hypotension may lead to falls and ischemic stroke,[10] and sedation may lead to aspiration pneumonia.[11,12] Thus, antipsychotic treatment may negatively influence the cardiovascular and metabolic systems, and patients with preexisting cardiovascular comorbidity could be at higher risk of adverse events and death during antipsychotic treatment.

A Danish study of older adults found that people with preexisting cardiovascular disease had a greater risk of major cardiovascular events during antipsychotic treatment compared with people without cardiovascular disease.[13] A small Finnish study investigated the mortality risk during antipsychotic treatment among community-dwelling older people in different comorbidity groups. People with respiratory disease at baseline had the highest risk of death associated with antipsychotic treatment.[14] However, none of the studies focused on older adults with dementia.

To date, no large-scale studies have explicitly investigated whether the effect of antipsychotic treatment on the risk of death among patients with dementia varies across groups of patients with or without preexisting comorbidities. In fact, many observational studies have adjusted for comorbidity in the statistical analyses[1,5–7] and, thus, did not evaluate the potential interaction between comorbidity and antipsychotic treatment. Therefore, the aims of this study were to investigate (i) the 180-day mortality risk associated with antipsychotic drug treatment in patients with dementia and (ii) whether specific preexisting comorbid conditions (heart disease, cerebrovascular disease, and diabetes) interact with antipsychotic treatment leading to an increased mortality beyond the risk of death independently associated with antipsychotic treatment and comorbidity alone.