Older adults are particularly vulnerable to drug-drug interactions and drug-disease interactions associated with antipsychotics because of their frequent use of multiple medications (ie, polypharmacy) and the occurrence of multiple comorbidities (ie, polymorbidity), respectively. Also, older adults are more sensitive to the adverse effects of antipsychotics because of age-related physiologic changes, including increased permeability of the blood-brain barrier and reduced central cholinergic activity.
The widespread off-label use of antipsychotics for the management of BPSD coupled with its associated health risks, especially an increased risk of mortality among patients with dementia, caught the attention of regulators. In 2005, the FDA cited a higher risk of death in older adults with dementia when they issued a public health advisory and asked manufacturers of those drugs to add a boxed warning to their product labeling.
6 The evidence leading to the boxed warning was derived primarily from a meta-analysis
11 that assessed the increased mortality rate in patients with dementia who used antipsychotics. The study evaluated 15 placebo-controlled trials and found that the mortality rate in patients with dementia taking antipsychotics was approximately 1.6 times higher than that in the placebo groups.
6,11 Although the trials did not include all atypical antipsychotics, the FDA concluded that the mortality risk was related to the common pharmacologic effects of all atypical antipsychotics. The mortality risk was considered a class effect because the increase in mortality was seen with all 3 chemical classes of atypical antipsychotics; sensitivity analyses did not show evidence of differential risks for individual drugs.
11
In 2008, the FDA issued a boxed warning
7 for typical antipsychotics after 2 observational epidemiologic studies suggested that the mortality rate in patients taking typical antipsychotics for BPSD was comparable to that in patients taking atypical antipsychotics.
12,13 The greatest increase in risk of death occurred within 30 days of initiating typical antipsychotic use and was attributable to cardiovascular-related events.
12,13 The extent to which the findings of increased mortality in observational studies may be attributed to an antipsychotic as opposed to other factors, however, is not clear.
The use of antipsychotics in older adults carries other health risks aside from increased risk of death. Antipsychotics differ in their drug-drug interaction, drug-disease interaction, and adverse effect profiles.
2 Regarding the latter item, each antipsychotic adverse effect profile is unique, based on different binding affinities to various neurotransmitter receptors (eg, dopamine, histamine).
2 A summary of the potentially serious adverse effects of antipsychotics in older adults is shown in the
Figure. In general, typical antipsychotics are more likely to cause extrapyramidal symptoms, and atypical antipsychotics are more likely to cause metabolic syndrome.
1,2,23 Still, notable differences exist even within classes. For instance, among atypical antipsychotics, metabolic syndrome is most commonly associated with the use of clozapine, olanzapine, and quetiapine and less commonly associated with aripiprazole and risperidone.
2,23 Similarly, anticholinergic toxicity is most commonly associated with the use of typical antipsychotics, with the exception of haloperidol and the atypical antipsychotic clozapine because of their much higher affinity for the muscarinic acetylcholine receptors compared with other antipsychotics.
2
From 2009 through 2011, 89,094 emergency department (ED) visits were attributed to adverse drug events (ADEs) due to psychiatric medications each year. Antipsychotics were implicated in 24.2% of cases, antidepressants in 28.5%, and sedatives and hypnotics in 34.5%.
24 Per 10,000 outpatient visits during which a psychiatric medication was prescribed, antipsychotics were the cause of the second highest ADE rate (11.7 of 10,000 outpatient visits; 95% CI, 10.1-13.2) among all psychiatric medications. Although the types of ADE visits varied across the psychiatric medication classes, typical antipsychotics (26.1 of 10,000 outpatient visits), and specifically haloperidol (43.3 of 10,000 outpatient visits), had especially high rates,
24 which was likely attributed to management-emergent extrapyramidal symptoms.
25